Patent Publication Number: US-2021164011-A1

Title: Binding fusion proteins, binding fusion protein-drug conjugates, xten-drug conjugates and methods of making and using same

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation application of U.S. application Ser. No. 15/955,046, filed Apr. 17, 2018 which is a continuation application of U.S. application Ser. No. 14/977,035, filed Dec. 21, 2015, which is a continuation application of U.S. application Ser. No. 13/631,361, filed Sep. 28, 2012 which is a continuvation application of International patent Application PCT/US2011/030992, filed Apr. 1, 2011 which claims the benefit of U.S. Provisional Application Ser. No. 61/341,720 filed Apr. 2, 2010, and 61/341,996 filed Apr. 8, 2010, each of which is incorporated herein by reference in its entirety. 
    
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH 
     This invention was made with government support under SBIR grant 2R44GM079873-02 awarded by the National Institutes of Health. The government has certain rights in the invention. 
    
    
     SEQUENCE LISTING 
     The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Dec. 27, 2012, is named 3280873 Ltd and is 2,247,117 bytes in size. 
     BACKGROUND OF THE INVENTION 
     Antibodies or immunoglobulins are molecules that recognize and bind to specific cognate antigens or ligands. Because of their exclusive specificities, antibodies, particularly monoclonal antibodies, have been widely used in the diagnosis and treatment of a variety of human diseases. 
     Full-length antibodies comprise two heavy chains linked together by disulfide bonds and two light chains, each light chain being linked to one of the heavy chains by a disulfide bond. Each chain has a variable domain (V H  or V L ) at the N-terminus and one or more constant domains at the C-terminus; the constant domain of the light chain is aligned with and disulfide bonded to the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Each of the variable domains of the heavy and light chain includes framework regions (FRs) and hypervariable regions and an intrachain disulfide bond. (See e.g. Chothia et al.,  J. Mol. Biol.  186:651-663 (1985); Novotny and Haber,  Proc. Natl. Acad. Sci. USA  82:45924596 (1985); Padlar et al.,  Mol. Immunol.,  23(9): 951-960 (1986); and S. Miller,  J. Mol. Biol.,  216:965-973 (1990). Antibodies can be derived from native antibodies or synthesized that may include combinations of heavy and light chain variable domains so as to form an antigen binding site. The types of antibody fragments include, for example, Fab, Fab′, F(ab′) 2 , Fv, scFv, Fd, and Fd′ fragments. However, expression of antibody fragments in bacterial hosts, including domain antibody fragments (dAb), Fv fragments, single-chain Fv fragments (scFv), Fab fragments, Fab′2 fragments, and many non-antibody proteins (such as FnIII domains) can result in the formation of inclusion bodies in the cytoplasm, adding to the complexity and cost of production (Kou, G., et al., 2007, Protein Expr Purif. 52, 131; Cao, P., et al. 2006, Appl Microbiol Biotechnol., 73, 151; Chen, L. H et al., 2006, Protein Expr Purif.; 46, 495). In addition, the stability and/or production yields of scFv or Fab fragments of natural antibodies produced in host cells have been found to be insufficient. Honneger et al.,  J. Mol. Biol.,  309:687-699 (2001), and the stability of scFv fragments is not always correlated with expression yield in the bacterial periplasm (Worn et al.,  J. Mol. Biol.,  305:989-1010 (2001). The many factors that affect the periplasmic expression yield and/or stability of scFv are not yet fully understood and may be unpredictable. In addition, the procedures for extracting periplasmic proteins are not as robust as extraction from the cytoplasm, which contributes to low yields. Thus, because there remains a need for improving the process of producing antibodies and antibody fragments, particularly in soluble form, finding alternative proteins that can bind antigens and that can be produced with improved yields in cell culture, especially with a bacterial cell culture, is desirable. 
     SUMMARY OF THE INVENTION 
     The present invention relates generally to novel, selectable binding fusion proteins useful as agents for the treatment of any disease or condition that is improved, ameliorated, or inhibited by the administration of proteins that bind certain proteins, carbohydrates or glycoprotein targets associated with the disease, disorder or condition. In particular, the present invention provides compositions of binding fusion proteins comprising extended recombinant polypeptides with a non-repetitive sequence and unstructured conformation (XTEN) linked to one or more polypeptide targeting moieties exhibiting binding affinity to certain targets. The binding fusion proteins of the embodiments disclosed herein exhibit one or more or any combination of the properties and/or the embodiments as detailed herein. 
     In some embodiments, the invention provides isolated binding fusion proteins comprising an extended recombinant polypeptide (XTEN) linked to a targeting moiety with binding affinity to a target selected from Table 1 or Table 2, wherein the fusion protein exhibits a terminal half-life that is longer than about 48 h, or about 72 h, or about 96 h, or about 120 h, or about 10 days, or about 21 days, or about 30 days when administered to a subject. In one embodiment of the foregoing, the XTEN is characterized in that the sequence comprises at least about 36, or at least about 72, or at least about 98, or at least about 144, or at least about 288, or at least about 576, or at least about 864, or at least about 1000, or at least about 1400, or at least about 2000, to about 3000 amino acid residues, the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues constitutes more than about 80%, or about 85%, or about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 100%, of the total amino acid sequence of the XTEN, the XTEN sequence is substantially non-repetitive in that (i) the XTEN sequence contains no three contiguous amino acids that are identical unless the amino acids are serine, (ii) at least about 80% of the XTEN sequence consists of non-overlapping sequence motifs, each of the sequence motifs comprising about 9 to about 14 amino acid residues, wherein any two contiguous amino acid residues does not occur more than twice in each of the sequence motifs; or (iii) the XTEN sequence has an average subsequence score of less than 3, the XTEN sequence lacks a predicted T-cell epitope when analyzed by TEPITOPE algorithm, wherein the TEPITOPE algorithm prediction for epitopes within the XTEN sequence is based on a score of −6, −7, or −8, or −9, or −10, the XTEN sequence has greater than 90% random coil formation, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% random coil formation as determined by GOR algorithm; and the XTEN sequence has less than 2% alpha helices and 2% beta-sheets as determined by Chou-Fasman algorithm. In another embodiment of the foregoing, the XTEN is further characterized in that the sum of asparagine and glutamine residues is less than 10% of the total amino acid sequence of the XTEN, the sum of methionine and tryptophan residues is less than 2% of the total amino acid sequence of the XTEN 
     In another embodiment, the XTEN of the binding fusion protein is further characterized in that no one type of amino acid constitutes more than about 16%, or 24%, or about 30% of the XTEN sequence. In another embodiment, the XTEN of the binding fusion protein is further characterized in that at least about 80%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% of the XTEN sequence consists of non-overlapping sequence motifs wherein each of the sequence motifs has about 12 amino acid residues and wherein the sequence of any two contiguous amino acid residues does not occur more than twice in each of the sequence motifs, and the sequence motifs consist of four to six types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P). In one embodiment, greater than 90% of the XTEN sequence consists of non-overlapping sequence motifs, wherein the sequence motifs are from one or more sequences of Table 3. In another embodiment, the XTEN sequence exhibits at least about 80%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% or 100% sequence identity to a sequence selected from any one of Table 4, Table 11, Table 12, Table 13, Table 14, or Table 15, when optimally aligned. In another embodiment, the invention provides an isolated binding fusion protein comprising a sequence that has at least about 80%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% or 100% sequence identity to a sequence selected from any one of Table 25, Table 40 or Table 41. 
     The subject binding fusion proteins exhibit enhanced pharmacokinetic properties. In one embodiment the enhanced pharmacokinetic property is a terminal half-life that is greater than about 24 h, or greater than about 48 h, or greater than about 72 h, or greater than about 96 h, or greater than about 120 h, or greater than about 144 h, or greater than about 7 days, or greater than about 10 days, or greater than about 14 days, or greater than about 21 days when administered to a subject, wherein the pharmacokinetic properties are ascertained by measuring blood concentrations of the fusion protein over time after administration of a dose to a subject. In one embodiment, the enhanced pharmacokinetic property encompasses an increase in terminal half-life of at least about two fold, or at least about three-fold, or at least about four-fold, or at least about five-fold, or at least about six-fold, or at least about eight-fold, or at least about ten-fold, or at least about 20-fold compared to the targeting moiety not linked to the XTEN and administered to a subject at a comparable dose. 
     In one embodiment, the targeting moiety of the isolated binding fusion protein is selected from the group consisting of antibody, antibody fragment, scFv, diabody, domain antibody, cytokine receptor, and immunoglobulin superfamily receptor. In one embodiment, the targeting moiety is a scFv. In another embodiment, the targeting moiety is a scFv with binding affinity to Her2. In some embodiments, the binding fusion protein is multivalent, comprising two, or three, or four, or five, or six, or seven, or eight targeting moieties. In one embodiment of the foregoing, the multivalent targeting moiety is a scFv. In one embodiment the multivalent targeting moieties can exhibit specific binding affinity to the same target, wherein the targets are selected from Table 1 or Table 2. In one embodiment, the multivalent targeting moieties can exhibit specific binding affinity to two or more targets, wherein the targets are selected from Table 1 or Table 2. In any of the embodiments described in this paragraph, the binding affinity constant (K d ) for the one or more targeting moieties of the subject binding fusion protein and a target ligand is less than about 10 −4  M, alternatively less than about 10 −5 M, alternatively less than about 10 −6  M, alternatively less than about 10 −7  M, alternatively less than about 10 −8  M, alternatively less than about 10 −9 M, or less than about 10 −10  M, or less than about 10 −11 M, or less than about 10 −12 M. 
     In one embodiment, the binding fusion protein can comprise a second XTEN having at least about 48 amino acid residues linked to the N-terminus of the binding fusion protein, wherein the expression of the binding fusion protein in a host cell comprising an expression vector coding the binding fusion protein is enhanced compared to the expression in a host cell comprising an expression vector encoding a corresponding binding fusion protein lacking the second XTEN. In one embodiment of the foregoing, the second XTEN exhibits at least 90% sequence identity, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% or 100% sequence identity to an XTEN sequence selected from AE48, AM 48, AE624, AE912 or AM923. In another embodiment of the foregoing, the incorporation into a host cell of a polynucleotide encoding a binding fusion protein comprising N-terminal XTEN can result in an expression level that is enhanced at least 50%, or at least about 75%, or at least about 100%, or at least about 150%, or at least about 200% or more compared to the expression levels in a comparable host cell with a polynucleotide encoding a binding fusion protein without the N-terminal XTEN. 
     The invention provides binding fusion proteins in various configurations. In one embodiment, the invention provides an isolated binding fusion protein of formula I: 
       (XTEN) x -TM-(XTEN) y   I
 
     wherein independently for each occurrence, XTEN is an extended recombinant polypeptide comprising greater than about 36 to about 3000 amino acids with a substantially non-repetitive sequence wherein the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues constitutes more than about 80% of the total amino acid sequence of the XTEN, x is either 0 or 1, y is either 0 or 1, wherein x+y≥1, and TM is a targeting moiety with specific binding affinity to a target selected from Table 1 or Table 2. 
     In another embodiment, the invention provides an isolated binding fusion protein of formula II: 
       (XTEN) x -TM1-L-TM2-(XTEN) y   II
 
     wherein independently for each occurrence, XTEN is an extended recombinant polypeptide comprising greater than about 36 to about 3000 amino acids with a substantially non-repetitive sequence wherein the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues constitutes more than about 80% of the total amino acid sequence of the XTEN, x is either 0 or 1, y is either 0 or 1, wherein x+y≥1, TM1 is a targeting moiety with specific binding affinity to a target selected from Table 1, TM2 is a targeting moiety with binding affinity to a target selected from Table 1 or Table 2 that may be identical or may be different to TM1, and L is a linker sequence having between 1 to about 300 amino acid residues. In one embodiment, the linker can be a sequence in which at least 80% of the residues are comprised of amino acids glycine, serine, and/or glutamate, such as, but not limited to a sequence with about 80-100% sequence identify to the sequence GSGEGSEGEGGGEGSEGEGSGEGGEGEGSG (SEQ ID NO: 1), or a portion or a multimer thereof. 
     In another embodiment, the invention provides an isolated binding fusion protein of formula III 
       TM1-XTEN-TM2  III
 
     wherein independently for each occurrence XTEN is an extended recombinant polypeptide comprising greater than about 400 to about 3000 amino acids with a substantially non-repetitive sequence wherein the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues constitutes more than about 80% of the total amino acid sequence of the XTEN, x is either 0 or 1, y is either 0 or 1, wherein x+y≥1, TM1 is a targeting moiety with specific binding affinity to a target ligand selected from Table 1 or Table 2; and TM2 is a targeting moiety with binding affinity to a target selected from Table 1 or Table 2 that may be identical or may be different to the target bound by TM1, 
     In another embodiment, the invention provides a multivalent binding fusion protein with three binding moieties of formula IV: 
       (XTEN) x -TM1-L1-TM2-L2-TM3-(XTEN) y   IV
 
     wherein independently for each occurrence: XTEN is an extended recombinant polypeptide as described above, x is either 0 or 1; y is either 0 or 1, wherein x+y≥1; TM1 is a targeting moiety with binding affinity to a target ligand selected from Table 1 or Table 2; TM2 is a targeting moiety with binding affinity to the target ligand selected from Table 1 or Table 2 that may be identical or may be different to TM1; TM3 is a targeting moiety with binding affinity to the target ligand selected from Table 1 or Table 2 that may be identical or may be different to either TM1 or TM2; L1 is a linker sequence having between 1 to about 300 amino acid residues as described for formula II, and wherein the linker sequence is covalently bound to the C terminus of TM1 and the N terminus of TM2; and L2 is a linker sequence that may be identical to or different from L1, having between 1 to about 300 amino acid residues as described as for formula II, and wherein the linker sequence is covalently bound to the C terminus of TM2 and the N terminus of TM3. 
     In some embodiments, the invention provides an isolated fusion protein with a single targeting moiety, wherein the targeting moiety exhibits binding specific affinity to a target selected from Table 1 or Table 2. In one embodiment of the foregoing, the target is selected from IL17, IL17R, RSV, HER2, IL12, IL23, RANKL, NGF, CD80, CD86, CD3, CD40, EGFR, TNFalpha, cMET, IL6R, and elastase. In other embodiments, the invention provides an isolated fusion protein with multiple targeting moieties (e.g., two, or three, or four, or five, or six, or seven or more targeting moieties) wherein the targeting moiety exhibits binding affinity to one or more targets selected from Table 1 or Table 2. In one embodiment of the foregoing, the one or more targets are selected from IL17, IL17R, RSV, HER2, IL12, IL23, RANKL, NGF, CD80, CD86, CD3, CD40, EGFR, TNFalpha, cMET, IL6R, and elastase. In a preferred embodiment of the foregoing, the two or more targeting moieties are scFv. In any of the embodiments hereinabove described in this paragraph, the binding affinity constant (K d ) for the one or more targeting moieties of the subject binding fusion protein and a target ligand is less than about 10 −5  M, alternatively less than about 10 −6  M, alternatively less than about 10 −7  M, alternatively less than about 10 −8  M, alternatively less than about 10 −9 M, or less than about 10 −10  M, or less than about 10 −11 M, or less than about 10 −12 M. 
     In some embodiments, binding fusion proteins exhibit an increased apparent molecular weight as determined by size exclusion chromatography, compared to the actual molecular weight, wherein the apparent molecular weight is at least about 100 kD, 150 kD, 200 kD, 300 kD, 400 kD, 500 kD, 600 kD, or 700 kD, while the actual molecular weight of the fusion protein is less than about 25 kD. Accordingly, the binding fusion proteins can have an apparent molecular weight that is about 4-fold greater, or about 5-fold greater, or about 6-fold greater, or about 7-fold greater, or about 8-fold greater than the actual molecular weight of the binding fusion protein. In one embodiment, the isolated binding fusion protein of the foregoing embodiments exhibits an apparent molecular weight factor under physiologic conditions that is greater than about 4, or about 5, or about 6, or about 7, or about 8. 
     In another embodiment, the invention provides isolated binding fusion protein of any one of the preceding embodiments, further comprising one or more molecules of a drug selected from Table 9. In one embodiment, the drug is covalently attached by a cross-linker to the XTEN, preferably through one or more cysteine or lysine amino acid residues incorporated into the XTEN. In another embodiment, the drug is covalently attached by a cross-linker to the targeting moiety, preferably through one or more cysteine or lysine amino acid residues incorporated into the targeting moiety. The binding fusion protein drug conjugates can be in different configurations. In one embodiment, the invention provides a binding fusion protein-drug conjugate composition of formula V: 
       [(D-CL) z1 -XTEN] x -TM-[XTEN-(CL-D) z2 ] y   V
 
     wherein independently for each occurrence: x is either 0 or 1; y is either 0 or 1; XTEN is a cysteine- or lysine-engineered extended recombinant polypeptide as described above; TM is a targeting moiety with binding affinity to a target ligand selected from Table 1 or Table 2 (which may comprise more than one binding domain joined by linkers); CL is a cross-linker as defined herein; D is a drug moiety selected from Table 9 or a pharmaceutically acceptable salt, acid or derivative thereof; and z1 and z2 each are independently an integer from 1 to 100. Exemplary binding fusion protein-drug conjugate compositions of Formula V can comprise XTEN that have from 1 to about 100 cysteine or lysine engineered amino acids, or from 1 to about 50 cysteine or lysine engineered amino acids, or from 1 to about 40 cysteine or lysine engineered amino acids, or from 1 to about 20 cysteine or lysine engineered amino acids, or from 1 to about 10 cysteine or lysine engineered amino acids, or from 1 to about 5 cysteine or lysine engineered amino acids that are available for conjugation to drug molecules. 
     In another embodiment, the invention provides a binding fusion protein-drug conjugate composition of formula VI: 
       [(D-CL) z1 -XTEN] x -TM1-L-TM2-[XTEN-(CL-D) z2 ] y   VI
 
     wherein independently for each occurrence: x is either 0 or 1, and y is either 0 or 1; XTEN is a either a cysteine- or lysine-engineered extended recombinant polypeptide as described; TM1 is a targeting moiety with binding affinity to a target ligand selected from Table 1 or Table 2 (which may comprise more than one binding domain joined by linkers); TM2 is a targeting moiety with binding affinity to a target ligand selected from Table 1 or Table 2 (which may comprise more than one binding domain joined by linkers) that may be identical or may be different to TM1; and L is a linker sequence having between 1 to about 300 amino acid residues wherein the linker sequence is covalently bound to the C terminus of TM1 and the N terminus of TM2; D is a drug moiety selected from Table 9 or a pharmaceutically acceptable salt, acid or derivative thereof; CL is a cross-linker as defined herein; and z1 and z2 each are independently an integer from 0 to 100. Exemplary binding fusion protein-drug conjugate compositions of Formula VI can comprise XTEN that have from 1 to about 100 cysteine or lysine engineered amino acids, or from 1 to about 50 cysteine or lysine engineered amino acids, or from 1 to about 40 cysteine or lysine engineered amino acids, or from 1 to about 20 cysteine or lysine engineered amino acids, or from 1 to about 10 cysteine or lysine engineered amino acids, or from 1 to about 5 cysteine or lysine engineered amino acids that are available for conjugation to drug molecules. 
     The invention provides compositions of the isolated binding fusion proteins of any of the foregoing embodiments. In one embodiment, the invention provides a pharmaceutical composition comprising a binding fusion protein of any of the foregoing embodiments and at least one pharmaceutically acceptable carrier. In another embodiment, the invention provides kits, comprising packaging material and at least a first container comprising the pharmaceutical composition of the foregoing embodiment and a label identifying the pharmaceutical composition and storage and handling conditions, and a sheet of instructions for the reconstitution and/or administration of the pharmaceutical compositions to a subject. 
     The invention further provides methods of use of the pharmaceutical compositions comprising the fusion protein of any of the foregoing embodiments in the treatment of a disease, disorder or condition in a subject in need thereof. In one embodiment of the method, the disease, disorder or condition is selected from the group consisting of breast carcinoma, lung carcinoma, gastric carcinoma, esophageal carcinoma, colorectal carcinoma, liver carcinoma, ovarian carcinoma, thecoma, arrhenoblastoma, cervical carcinoma, endometrial carcinoma, endometriosis, fibrosarcoma, choriocarcinoma, head and neck cancer, nasopharyngeal carcinoma, laryngeal carcinoma, hepatoblastoma, Kaposi&#39;s sarcoma, melanoma, skin carcinoma, hemangioma, cavernous hemangioma, hemangioblastoma, pancreas carcinoma, retinoblastoma, astrocytoma, glioblastoma, Schwannoma, oligodendroglioma, medulloblastoma, neuroblastoma, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, urinary tract carcinoma, thyroid carcinoma, Wilm&#39;s tumor, renal cell carcinoma, and prostate carcinoma. 
     In one embodiment, the invention provides a method of treating a disease or condition mediated by or associated with a target of Table 1 or Table 2, comprising administering the pharmaceutical composition described above using a therapeutically effective amount to a subject in need thereof. In one embodiment, the target of Table 1 is a tumor associated antigen, such as but not limited to the antigens of Table 2. In one embodiment, the invention provides a method of treatment wherein the binding fusion protein exhibits binding to the tumor associated antigen HER2. In a one embodiment of the method, the administration of the pharmaceutical composition using a therapeutically effective amount to a subject has a growth inhibitory effect on a tumor cell. The method of treatment can comprise administering the pharmaceutical composition by an appropriate route, including subcutaneously, intramuscularly, intravitreally, or intravenously. In one embodiment, multiple consecutive doses of the pharmaceutical composition are administered at a therapeutically effective dose regimen, and can result in an improvement in at least one measured parameter relevant for the metabolic disease, disorder or condition. In one embodiment, the therapeutically effective dose regimen can be achieved using a two administrations of pharmaceutical composition per month dosing regimen for the length of the dosing period. In one embodiment, the therapeutically effective dose regimen is achieved using a one administration of pharmaceutical composition per month dosing regimen for the length of the dosing period. In another embodiment, the binding fusion protein has a growth inhibitory effect on SK-BR-3 cells in a cell culture assay. 
     The invention provides isolated nucleic acids comprising a polynucleotide sequence selected from (a) a polynucleotide encoding the binding fusion protein of any of the foregoing embodiments, or (b) the complement of the polynucleotide of (a). In one embodiment of the foregoing, the isolated nucleic acid comprises a polynucleotide sequence that has at least 80% sequence identity, or about 85%, or at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% to about 100% sequence identity to (a) a polynucleotide sequence that encodes a polypeptide selected from any one of Table 25, Table 40 or Table 41; or (b) the complement of the polynucleotide of (a). The invention provides expression vectors comprising the nucleic acid of any of the embodiments hereinabove described in this paragraph. In one embodiment, the expression vector of the foregoing further comprises a recombinant regulatory sequence operably linked to the polynucleotide sequence. In another embodiment, the polynucleotide sequence of the expression vectors of the foregoing is fused in frame to a polynucleotide encoding a secretion signal sequence, which can be a prokaryotic signal sequence. In one embodiment, the secretion signal sequence is selected from OmpA, DsbA, and PhoA signal sequences. 
     The invention provides a host cell, which can comprise an expression vector disclosed in the foregoing paragraph. In one embodiment, the host cell is a prokaryotic cell, such as, but not limited to  E. coli . In another embodiment, the host cell is a eukaryotic cell, such as, but not limited to CHO. 
     The invention also provides host cells comprising an expression vector, wherein the expression vector encodes a binding fusion protein comprising an N-terminal XTEN optimized for expression. In one embodiment of the foregoing, the vector comprises a sequence that encodes a polypeptide sequence that exhibits at least about 80%, more preferably at least about 90%, more preferably at least about 91%, more preferably at least about 92%, more preferably at least about 93%, more preferably at least about 94%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, more preferably at least 99%, or exhibits 100% sequence identity to the amino acid sequence of AE48. AM48, AE624, AE912, or AM923. In one embodiment, the expression level of the encoded binding fusion protein in the host cell is enhanced compared to the expression level in a corresponding host cell comprising an expression vector encoding a binding fusion protein lacking the N-terminal XTEN optimized for expression. In one embodiment, the expression level is enhanced at least about 50%, or about 75%, or about 100%, or about 150%, or about 200%, or about 400% compared to a corresponding binding fusion protein not comprising the N-terminal XTEN sequence. 
     INCORPORATION BY REFERENCE 
     All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The features and advantages of the invention may be further explained by reference to the following detailed description and accompanying drawings that sets forth illustrative embodiments. 
         FIG. 1A - FIG. 1B  show schematic representations of an exemplary scFv binding fusion protein with a single targeting moiety depicted in an N- to C-terminus orientation.  FIG. 1A  shows the configuration of a scFv binding fusion protein ( 100 ) with the single chain Fv targeting moiety in a “relaxed” conformation, comprising an N-terminal XTEN sequence ( 101 ), a VL binding domain sequence ( 102 ), a linker sequence ( 103 ), a VH binding domain sequence ( 104 ), and an XTEN carrier sequence ( 105 ) at the C-terminus.  FIG. 1B  shows the flexible linker permitting the two binding domains to come into association to form the antigen binding site of the scFv targeting moiety. 
         FIG. 2A - FIG. 2B  show schematic representations of exemplary components of a scFv binding fusion protein with two targeting moieties depicted in an N- to C-terminus orientation.  FIG. 2A  shows the configuration of a scFv binding fusion protein ( 107 ) with two single chain Fv targeting moieties in a “relaxed” conformation, each comprising an N-terminal XTEN sequence ( 101 ), a VL binding domain sequence ( 102 ), a linker sequence ( 103 ), a VH binding domain sequence ( 104 ), a second linker sequence joining the first and the second targeting moieties ( 106 ) and an XTEN carrier sequence ( 105 ) at the C-terminus.  FIG. 2B  shows the flexible linkers permitting the two binding domains to come into association to form the antigen binding site of the two respective scFv targeting moieties. 
         FIG. 3A - FIG. 3B  show schematic representations of an exemplary monomeric diabody binding fusion protein that can form two antigen binding sites.  FIG. 3A  shows the configuration of a diabody binding fusion protein ( 108 ) with the two targeting moieties in a “relaxed” conformation, each comprising an N-terminal XTEN sequence ( 101 ), a first VL binding domain sequence ( 102 ), a short linker sequence joining the adjacent VL and VH ( 103 ), a first VH binding domain sequence ( 104 ), a second linker sequence joining the first and the second targeting moieties ( 106 ), a second VH binding domain ( 109 ) intended to pair with the first VL binding domain ( 104 ), a second VL ( 110 ) intended to pair with the first VH ( 104 ) and an XTEN carrier sequence ( 105 ) at the C-terminus.  FIG. 3B  shows the flexible middle linker permitting two binding domains (VL and VH) from the opposite ends of the molecule (rather than the two adjacent binding domains that are constrained because of the short linker) to come into association to form the two antigen binding sites, resulting in two diabody targeting moieties within the monomeric binding fusion protein. 
         FIG. 4A - FIG. 4B  show schematic representations of an exemplary VEGF cytokine binding fusion protein.  FIG. 4A  shows the configuration of the binding fusion protein ( 114 ) with the dimer binding regions in a “relaxed” conformation, each comprising an N-terminal XTEN sequence ( 101 ), a first D2 domain sequence ( 111 ), a short linker sequence joining the adjacent domain units ( 103 ), a first D3 domain sequence ( 112 ), a second flexible linker sequence joining the first and the second binding domains ( 106 ), a second VH binding domain ( 109 ) intended to pair with the first VL binding domain ( 104 ), a second D2 domain ( 111 ), a short linker sequence joining the adjacent domain units ( 103 ), a second D3 domain sequence ( 112 ), and an XTEN carrier sequence ( 105 ) at the C-terminus. In the schematic, the dimeric VEGF target ( 113 ) has begun to associate with one of the binding domains.  FIG. 4B  shows the flexible middle linker permitting two binding domains of the molecule to surround the dimeric VEGF ( 113 ) to form the binding complex that sequesters the VEGF molecule. 
         FIG. 5  shows schematic representations of an exemplary receptor binding fusion protein comprising Ig-like binding domains. The binding fusion protein ( 115 ) has an N-terminal XTEN sequence ( 101 ) and in this case, two Ig-like binding regions ( 116 ), a flexible linker sequence joining the adjacent Ig-like binding regions ( 106 ) that would permit the two binding regions to sequester the target ligand, and an XTEN carrier sequence ( 105 ) at the C-terminus. 
         FIG. 6A - FIG. 6D  show schematic representations of exemplary genes that encode binding fusion proteins, all depicted in a 5′ to 3′ orientation, with all component sequences linked in frame.  FIG. 6A  shows the configuration of a gene encoding scFv binding fusion proteins ( 100 ) in two configurations (5′ to 3′) with a single targeting moiety, with the first having nucleotides encoding a VL binding domain sequence ( 202 ), a linker sequence ( 203 ), a VH binding domain sequence ( 204 ), and an XTEN carrier sequence ( 205 ) at the 3′-end. Below that is the opposite configuration, with nucleotides encoding an N-terminal XTEN ( 201 ), linked to nucleotides encoding a VL binding domain sequence ( 202 ), a linker sequence ( 203 ), and a VH binding domain sequence,  FIG. 6B  shows the configuration of a gene encoding a diabody binding fusion protein that can form two antigen binding sites ( 208 ), with the top construct shown comprising, at the 5′ end, genes for a first VL binding domain sequence ( 202 ), a short linker sequence joining the adjacent VL and VH genes ( 303 ), a first VH binding domain sequence ( 204 ), a second linker sequence (that can be an XTEN) joining the first and the second targeting moieties ( 206 ), a second VH binding domain ( 209 ), a second VL binding domain ( 210 ) and an XTEN carrier sequence ( 205 ) at the 3′ end. The lower gene encodes, at the 5′ end, an N-terminal XTEN ( 201 ), a first VL binding domain sequence ( 202 ), a short linker sequence joining the adjacent VL and VH genes ( 203 ), a first VH binding domain sequence ( 204 ), a second linker sequence (than can be an XTEN) joining the first and the second targeting moieties ( 206 ), a second VH binding domain ( 209 ), a second VL binding domain ( 210 ) and an XTEN carrier sequence ( 205 ) at the 3′ end.  FIG. 6C  shows the configuration of a gene encoding a cytokine binding protein. The gene encodes, at the 5′ end, an N-terminal XTEN ( 201 ), a first D2 binding domain sequence ( 211 ), a short linker sequence joining the adjacent domain genes ( 203 ), a first D3 binding domain sequence ( 212 ), a second linker sequence ( 206 ) (than can be an XTEN) joining the first and the second targeting moieties, a second D2 binding domain ( 211 ), a second D3 binding domain ( 212 ) and an XTEN carrier sequence ( 205 ) at the 3′ end.  FIG. 6D  shows three configurations, 5′ to 3′, of genes encoding a domain antibody binding fusion protein ( 217 ). The genes encode, where shown, an N-terminal XTEN ( 201 ), the VHH binding domain sequence ( 218 ), and an XTEN carrier sequence ( 205 ) at the 3′ end. 
         FIG. 7  is a schematic flowchart of representative steps in the assembly, production and the evaluation of a XTEN. 
         FIG. 8  is a schematic flowchart of representative steps in the assembly of a targeting moiety-XTEN polynucleotide construct encoding, in this case, an anti-Her2 binding fusion protein. Individual oligonucleotides  501  are annealed into sequence motifs  502  such as a 12 amino acid motif (“12-mer”), which is ligated to additional sequence motifs from a library to create a pool that encompasses the desired length of the XTEN  504 , as well as ligated to a smaller concentration of an oligo containing BbsI, and KpnI restriction sites  503 . The resulting pool of ligation products is gel-purified and the band with the desired length of XTEN is cut, resulting in an isolated XTEN gene with a stopper sequence  505 . The XTEN gene is cloned into a stuffer vector. In this case, the vector encodes an optional CBD sequence  506  and a GFP gene  508 . Digestion is than performed with BbsI/HindIII to remove  507  and  508  and place the stop codon. The resulting product is then cloned into a BsaI/HindIII digested vector containing a gene encoding the svFv anti-Her2, resulting in the gene  500  encoding an binding fusion protein. 
         FIG. 9  is a schematic flowchart of representative steps in the assembly of a gene encoding a binding fusion protein comprising a targeting moiety and XTEN, its expression and recovery as a fusion protein, and its evaluation as a candidate binding fusion protein product. 
         FIG. 10A - FIG. 10D  is a schematic representation of the design of anti-Her2 binding fusion protein expression vectors with different processing strategies.  FIG. 10A  shows an expression vector encoding XTEN fused to the 3′ end of the sequence encoding anti-Her2 binding moiety. Note that no additional leader sequences are required in this vector.  FIG. 10B  depicts an expression vector encoding XTEN fused to the 5′ end of the sequence encoding anti-Her2 binding moiety with a CBD leader sequence and a TEV protease site.  FIG. 10C  depicts an expression vector as in  FIG. 10B  where the CBD and TEV processing site have been replaced with an optimized N-terminal leader sequence (NTS).  FIG. 10D  depicts an expression vector encoding an NTS sequence, an XTEN, a sequence encoding anti-Her2 binding moiety, and then a second sequence encoding an XTEN. 
         FIG. 11  shows results of expression assays for the indicated constructs comprising GFP and XTEN sequences, conducted as described in Example 14. The expression cultures were assayed using a fluorescence plate reader (excitation 395 nm, emission 510 nm) to determine the amount of GFP reporter present and the results are graphed as box and whisker plots. 
         FIG. 12  shows three randomized libraries used for the third and fourth codons in the N-terminal sequences of clones from LCW546, LCW547 and LCW552. The libraries were designed with the third and fourth residues modified such that all combinations of allowable XTEN codons were present at these positions, as shown. In order to include all the allowable XTEN codons for each library, nine pairs of oligonucleotides encoding 12 amino acid motifs with codon diversities of third and fourth residues were designed, annealed and ligated into the NdeI/BsaI restriction enzyme digested stuffer vector pCW0551 (Stuffer-XTEN_AM875-GFP), and transformed into  E. coli  BL21Gold(DE3) competent cells to obtain colonies of the three libraries LCW0569 (SEQ ID NOS 863-864), LCW0570 (SEQ ID NOS 865-866), and LCW0571 (SEQ ID NOS 867-868). 
         FIG. 13  shows a histogram of a retest of the top 75 clones after the optimization step, as described in Example 15, for GFP fluorescence signal relative to the benchmark CBD AM875 construct. The results indicated that several clones were now superior to the benchmark clones seen in  FIG. 11 . 
         FIG. 14  is a schematic of a combinatorial approach undertaken for the union of codon optimization preferences for two regions of the N-terminus 48 amino acids. The approach created novel 48mers at the N-terminus of the XTEN protein for evaluation of the optimization of expression for leader sequences to enhance expression of XTEN proteins where the XTEN is N-terminal to the targeting moieties. 
         FIG. 15  shows an SDS-PAGE gel confirming expression of preferred clones obtained from the XTEN N-terminal codon optimization experiments, in comparison to benchmark XTEN clones comprising CBD leader sequences at the N-terminus of the construct sequences. 
         FIG. 16A - FIG. 16C  show an SDS-PAGE gel of samples from a stability study of the fusion protein of XTEN_AE864 fused to the N-terminus of GFP.  FIG. 16A  shows the results after in vitro incubation of GFP-XTEN in cynomolgus monkey plasma and and  FIG. 16C  shows the results after incubation in rat kidney lysate for up to 7 days at 37° C. with samples analyzed by SDS PAGE followed by detection using Western analysis and detection with antibodies against GFP, as described in Example 56. In addition,  FIG. 16B  shows the results of GFP-XTEN administered to cynomolgus monkeys in which samples were withdrawn at 0, 1 and 7 days and analyzed by SDS PAGE followed by detection using Western analysis and detection with antibodies against GFP. 
         FIG. 17A - FIG. 17C  show the characterization of multivalent scFv binding fusion proteins.  FIG. 17A  is a schematic representation of two variations of multivalent scFv binding fusion proteins, with a monospecific construct on the left comprising two targeting moieties directed to HER2 and a bispecific construct on the right comprising a targeting moiety to HER2 and a second targeting moiety to EGFR.  FIG. 17B  shows an SDS-PAGE of materials following purification, as described in Example 29. Lane 1 shows the molecular weight standards, lane 2 shows the purified aHER2-XTEN-aHER2, and lane 3 shows the purified bispecific aHER2-XTEN-aEGFR.  FIG. 17C  shows the results of SEC analysis of aHER2-XTEN-aEGFR compared to molecular weight standards, and demonstrates that no dimers or other higher-order oligomers are formed and that the protein has an approximate apparent molecular weight of approximately 500 kDa, as described in Example 37. 
         FIG. 18  shows results of a binding activity assay of aHER2-XTEN-aEGFR bispecific binding fusion protein to its respective targets using an ELISA format, as described in Example 37. 
         FIG. 19A - FIG. 19B  show a schematic of two scFv binding fusion protein constructs with a GFP tag and flow cytometry results of cell binding assays.  FIG. 19A  is a schematic of aCD3-XTEN-GFP and aHER2-XTEN-GFP constructs.  FIG. 19B  shows the output of flow-cytometry in which the two constructs were individually reacted with Jurkat CD3+ and SK-BR3 HER2+ cells, as described in Example 36, demonstrating the binding specificity of the respective constructs towards their ligands and the lack of binding to the heterologous targets. 
         FIG. 20A - FIG. 20B  show results from characterization assays of a bispecific scFv binding fusion protein, as described in Example 36.  FIG. 20A  shows an SDS-PAGE gel of the purified aHER2-aCD3-XTEN.  FIG. 20B  shows the output of a size exclusion chromatography (SEC) analysis of the aHER2-aCD3-XTEN compared to molecular weight standards, and demonstrates that no dimers or other higher-order oligomers are formed and that the protein has an approximate apparent molecular weight of approximately 500 kDa, approximately five-fold higher than the mass indicated in the SDS-PAGE assay of  FIG. 20A . 
         FIG. 21A - FIG. 21C  show results from characterization assays of a bispecific scFv binding fusion protein, as described in Example 36.  FIG. 21A  shows results of a binding assay performed by ELISA comparing a scFv of anti-Her2 on the N-terminus of a binding fusion protein to a bispecific scFv of anti-CD3 on the N-terminus and anti-Her2 on the C-terminus of an XTEN, against wells coated with HER2, showing that the bispecific retains binding affinity to the HER2 target.  FIGS. 21B  and C show results of a flow cytometry cell binding assays using the mono- and bispecific constructs, respectively, against HER2-expressing SK-BR-3 cells. The results show greater signal for the N-terminal anti-Hers scFv-XTEN ( FIG. 21B ) than the bispecific construct, consistent with that of the ELISA study, but that the bispecific construct nevertheless retains good binding activity. 
         FIG. 22  shows results from a flow cytometry assay to characterize the binding of aCD3-XTEN-GFP to CD3-positive Jurkat cells. The assay was performed using anti-GFP antibody detection of aCD3-XTEN-GFP reacted in the presence of a 10-fold molar excess of aHER2-aCD3-XTEN, as described in Example 36. The results show that excess bispecific aHER2-aCD3-XTEN competitively displaces the monospecific aCD3-XTEN-GFP protein and eliminates the observed MFI shift. 
         FIG. 23  shows results from a tumor cell killing assay in which varying concentrations of the bispecific aHER2-XTEN-aCD3 were incubated with either M21 or SK-BR-3 target cells for 24 h, as described in Example 36, followed by staining with propidium iodide to measure killing, shown in the bar graph as the proportion of dead tumor cells for the two cell lines. 
         FIG. 24A - FIG. 24B  show schematic representations of single and multivalent Vhh binding fusion protein constructs and their characterization.  FIG. 24A  shows schematic portrayals of monomeric, dimeric, tetrameric, and hexameric anti-EGFR Vhh constructs linked by XTEN, with a C-terminal GFP.  FIG. 24B  show SDS-PAGE of lysate and the purified Vhh constructs, as described in Example 38, demonstrating the purity and the “ladder” increase in molecular weight with increasing units of the anti-EGFR Vhh targeting moiety. 
         FIG. 25  show the output of a size exclusion chromatography (SEC) analysis of the monomeric and multivalent anti-EGFR Vhh binding fusion protein constructs of  FIG. 24A  compared to molecular weight standards, as described in Example 38. The results demonstrate proportional increases approximate apparent molecular weight of the constructs with increasing numbers of Vhh targeting moieties, compared to the molecular weights determined by SDS-PAGE in  FIG. 24B  and listed in Table 26. 
         FIG. 26A - FIG. 26B  show results of binding characterization ELISA assays of monomeric and multivalent targeting moiety anti-EGFR Vhh binding fusion protein constructs, as described in Example 38 (the constructs depicted schematically in  FIG. 24A ).  FIG. 26A  shows results of the ELISA signal generated using equi-molar concentrations of the various monomeric or multivalent anti-EGFR Vhh binding fusion proteins against the EGFR target.  FIG. 26B  shows the results of binding curves for the same constructs at various dilutions, with the multivalent forms resulting in more signal than the construct with a single Vhh targeting moiety. 
         FIG. 27  shows the results of a binding characterization ELISA assay of two anti-CD40 scFv binding fusion protein constructs, AC384 (closed squares) and AC385 (open squares), against human CD40, as described in Example 34. 
         FIG. 28A - FIG. 28B  show the results of characterization assays for an anti-IL6R binding fusion protein.  FIG. 28A  shows the uniformity of the purified protein assessed by SEC, which showed a monodispersed peak with minimal contamination.  FIG. 28B  shows results of an ELISA binding assay of the anti-IL6R binding fusion protein against human IL6R, as described in Example 33. 
         FIG. 29  shows the results of a binding characterization ELISA assay of anti-Her2 binding protein with two anti-Her2 targeting moieties against human HER2, as described in Example 35. 
         FIG. 30  shows the near UV circular dichroism spectrum of Ex4-XTEN_AE864, performed as described in Example 52. 
         FIG. 31  shows the pharmacokinetic profile (plasma concentrations) in cynomolgus monkeys after single doses of different compositions of GFP linked to unstructured polypeptides of varying length, administered either subcutaneously or intravenously, as described in Example 53. The compositions were GFP-L288, GFP-L576, GFP-XTEN_AF576, GFP-Y576 and XTEN_AD836-GFP. Blood samples were analyzed at various times after injection and the concentration of GFP in plasma was measured by ELISA using a polyclonal antibody against GFP for capture and a biotinylated preparation of the same polyclonal antibody for detection. Results are presented as the plasma concentration versus time (h) after dosing and show, in particular, a considerable increase in half-life for the XTEN_AD836-GFP, the composition with the longest sequence length of XTEN. The construct with the shortest sequence length, the GFP-L288 had the shortest half-life. 
         FIG. 32  shows results of a size exclusion chromatography analysis of glucagon-XTEN construct samples measured against protein standards of known molecular weight, with the graph output as absorbance versus retention volume, as described in Example 60. The glucagon-XTEN constructs are 1) glucagon-Y288; 2) glucagonY-144; 3) glucagon-Y72; and 4) glucagon-Y36. The results indicate an increase in apparent molecular weight with increasing length of the XTEN component. 
         FIG. 33  shows overlays of SEC chromatograms of three aHer2-XTEN(Cys)-AF680 conjugated fusion proteins with three different XTEN; AE864, AE576, and AE288 (top to bottom), performed as described in Example 41. The chromatograms show that the Alexa Fluor 680 was successfully conjugated to the aHer2-XTEN(Cys) protein as the retention time of the absorbance of the Alexa Fluor 680 (A690) overlaps with that of the aHer2-XTEN(Cys) protein (A280) for all three samples, and that the constructs eluted in a proportional fashion relative to length of the XTEN component. Note that dye retention time is significantly shifted from the expected elution time of free dye at ˜52 minutes. Additionally, the relative lack of material that elutes ahead of the various aHer2-XTEN(Cys) peaks indicates a lack of aggregation and a monodispersed product. 
         FIG. 34A - FIG. 34C  show output of flow cytometry assays for the three fusion proteins described in  FIG. 33  compared to unlabeled Herceptin and control IgG-AF680 conjugate, measuring forward and side scatter vs. FL4 for Alexa680, as described in Example 41.  FIG. 34A  is the output of the aHer2-XTEN_AE864-AF680 assay.  FIG. 34B  is the output of the aHer2-XTEN_AE576-AF680 assay, and  FIG. 34C  is the output of the aHer2-XTEN_AE288-AF680 assay. 
         FIG. 35  shows the graphed results of in vivo imaging data from female nu/nu mice bearing SKOV3 tumor cells given a single injection of high or low dose aHer2-XTEN-AE-288-Cys-AF680, aHer2-XTEN-AE-576-Cys-AF680, aHer2-XTEN-AE-864-Cys-AF680 or Herceptin-AF680 control, as described in Example 41. 
         FIG. 36  shows the graphed results of ex vivo imaging data from the same treatment groups as per  FIG. 36 , demonstrating that all aHer2-XTEN binding fusion protein constructs had penetration into the assayed tissues, with the longer AE864 XTEN construct demonstrating the highest levels compared to the other two, as described in Example 41. 
         FIG. 37  is a schematic of the logic flow chart of the algorithm SegScore. In the figure the following legend applies: i, j—counters used in the control loops that run through the entire sequence; HitCount—this variable is a counter that keeps track of how many times a subsequence encounters an identical subsequence in a block; SubSeqX—this variable holds the subsequence that is being checked for redundancy; SubSeqY—this variable holds the subsequence that the SubSeqX is checked against; BlockLen—this variable holds the user determined length of the block; SegLen—this variable holds the length of a segment. The program is hardcoded to generate scores for subsequences of lengths 3, 4, 5, 6, 7, 8, 9, and 10; Block—this variable holds a string of length BlockLen. The string is composed of letters from an input XTEN sequence and is determined by the position of the i counter; SubSeqList—this is a list that holds all of the generated subsequence scores. 
         FIG. 38  depicts the application of the algorithm SegScore to a hypothetical XTEN of 11 amino acids in order to determine the repetitiveness. An XTEN sequence (SEQ ID NO: 869) consisting of N amino acids is divided into N-S+1 subsequences of length S (S=3 in this case). A pair-wise comparison of all subsequences is performed and the average number of identical subsequences is calculated to result, in this case, in a subsequence score of 1.89. 
         FIG. 39A - FIG. 39E  illustrate the use of donor XTEN sequences to produce truncated XTEN sequences.  FIG. 39A  provides the sequence of AG864 (SEQ ID NO: 870), with the underlined sequence used to generate an AG576 (SEQ ID NO: 871) sequence.  FIG. 39B  provides the sequence of AG864 (SEQ ID NO: 872), with the underlined sequence used to generate an AG288 (SEQ ID NO: 873) sequence.  FIG. 39C  provides the sequence of AG864 (SEQ ID NO: 874), with the underlined sequence used to generate an AG144 (SEQ ID NO: 875) sequence.  FIG. 39D  provides the sequence of AE864 (SEQ ID NO: 876), with the underlined sequence used to generate an AE576 (SEQ ID NO: 877) sequence.  FIG. 39E  provides the sequence of AE864 (SEQ ID NO: 878), with the underlined sequence used to generate an AE288 (SEQ ID NO: 879) sequence. 
         FIG. 40A - FIG. 40D  show various schematic examples of XTEN-based protein-drug conjugates, with the chemically conjugated drug-crosslinker ligand designated “D”.  FIG. 40A  shows three XTEN-drug conjugates, with 1, 2 and 4 drug molecules conjugated to the XTEN.  FIG. 40B  shows four configurations of BFP-D with the binding domain (“BD”) linked to the N- or C-terminus of XTEN of the fusion protein and either 1, 3 or 4 drug molecules conjugated to the XTEN carrier by cross-linkers.  FIG. 40C  shows four configurations of BFP-D with the scFv binding domain on the N- or C-terminus of the XTEN and either 1, 3 or 4 drug molecules conjugated to the XTEN carrier by cross-linkers.  FIG. 40D  shows four configurations of multivalent BFP-D with two binding domains (“BD”) on the N- or C-terminus or configurations with an N-terminal XTEN and either 1, 2, 3 or 4 drug molecules conjugated to the XTEN carrier or N-terminal XTEN by cross-linkers. 
         FIG. 41A - FIG. 41D  show various schematic examples of the conjugation process to make conjugates with multiple drug ligands using orthogonal coupling chemistries.  FIG. 41A  shows a two-step process of coupling of one drug-crosslinker ligand (D1) to an internal cysteine of a cysteine-engineered XTEN and a second, different drug-crosslinker ligand (D2) to the N-terminus of XTEN.  FIG. 41B  shows a two-step process of coupling of one ligand to an internal cysteine cysteine-engineered XTEN and two ligands to amino groups in a recombinant binding domain (BD).  FIG. 41C  shows a two-step process of coupling of two drug ligands (D1) to two internal cysteine of a cysteine-engineered XTEN and a second drug ligand (D2) to the N-terminus of XTEN.  FIG. 41D  shows a two-step process of coupling two drug ligands (D1) to XTEN internal cysteines and 1 drug-crosslinker ligand (D2) to the N-terminus and two additional D2 drug-crosslinker ligands to internal lysine residues of the engineered XTEN. 
         FIG. 42A - FIG. 42B  show results of analytical assays of XTEN conjugated with cross-linked FITC, as described in Example 63.  FIG. 42A  shows the co-migration in a gel imaged by UV light box to show the large apparent MW of FITC-containing conjugated species, also detected by SEC at OD214 (protein signal) and OD495 (FITC signal) in a SEC column, indicating successful labeling of the XTEN with minimal free dye contamination. The materials by lane (left to right, after the MW standards are: labeled FITC-CL-CBD-XTEN; labeled FITC-CL-XTEN; purified FITC-CL-XTEN; purified FITC-CL-XTEN; and purified FITC-CL-XTEN. The gel was imaged by UV light box to show FITC apparent MW of FITC containing species.  FIG. 42B  shows the results of SEC analysis of FITC-conjugated XTEN, showing the overlap of the output of materials detected at OD214 and OD495, and also the apparent large molecular weight. 
         FIG. 43  shows results of SEC analyses of the peak elution fractions of conjugates of GFP cross-linked to XTEN and free GFP, as described in Example 64. Cross-linking was confirmed by co-migration of the OD214 protein signal and OD395 GFP signal in the SEC column. 
         FIG. 44  shows the results of pharmacokinetic assays of GFP-X-XTEN and FITC-X-XTEN tested in cynomolgus monkeys, as described in Example 65. 
         FIG. 45  shows a schematic of the orthogonal chemistry process to create a BFP-D comprising a scFv anti-HER2 with paclitaxel conjugated to the XTEN, resulting in aHER2-XTEN-CL-paclitaxel. The paclitaxel is first reacted with an activated linker, then conjugated to a cysteine-engineered XTEN, as described in Example 66. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Before the embodiments of the invention are described, it is to be understood that such embodiments are provided by way of example only, and that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. 
     Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. 
     Definitions 
     As used herein, the following terms have the meanings ascribed to them unless specified otherwise. 
     As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a cell” includes a plurality of cells, including mixtures thereof. 
     The terms “polypeptide”, “peptide”, and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. 
     As used herein the term “amino acid” refers to either natural and/or unnatural or synthetic amino acids, including but not limited to glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics. Standard single or three letter codes are used to designate amino acids. 
     The term “natural L-amino acid” means the L optical isomer forms of glycine (G), proline (P), alanine (A), valine (V), leucine (L), isoleucine (I), methionine (M), cysteine (C), phenylalanine (F), tyrosine (Y), tryptophan (W), histidine (H), lysine (K), arginine (R), glutamine (Q), asparagine (N), glutamic acid (E), aspartic acid (D), serine (S), and threonine (T). 
     The term “non-naturally occurring,” as applied to sequences and as used herein, means polypeptide or polynucleotide sequences that do not have a counterpart to, are not complementary to, or do not have a high degree of homology with a wild-type or naturally-occurring sequence found in a mammal. For example, a non-naturally occurring polypeptide or fragment may share no more than 99%, 98%, 95%, 90%, 80%, 70%, 60%, 50% or even less amino acid sequence identity as compared to a natural sequence when suitably aligned. 
     The terms “hydrophilic” and “hydrophobic” refer to the degree of affinity that a substance has with water. A hydrophilic substance has a strong affinity for water, tending to dissolve in, mix with, or be wetted by water, while a hydrophobic substance substantially lacks affinity for water, tending to repel and not absorb water and tending not to dissolve in or mix with or be wetted by water. Amino acids can be characterized based on their hydrophobicity. A number of scales have been developed. An example is a scale developed by Levitt, M, et al., J Mol Biol (1976) 104:59, which is listed in Hopp, T P, et al., Proc Natl Acad Sci USA (1981) 78:3824. Examples of “hydrophilic amino acids” are arginine, lysine, threonine, alanine, asparagine, and glutamine. Of particular interest are the hydrophilic amino acids aspartate, glutamate, and serine, and glycine. Examples of “hydrophobic amino acids” are tryptophan, tyrosine, phenylalanine, methionine, leucine, isoleucine, and valine. 
     A “fragment” is a truncated form of a native biologically active protein that retains at least a portion of the therapeutic and/or biological activity. A “variant” is a protein with sequence homology to the native biologically active protein that retains at least a portion of the therapeutic and/or biological activity of the biologically active protein. For example, a variant protein may share at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity with the reference biologically active protein. As used herein, the term “biologically active protein moiety” includes proteins modified deliberately, as for example, by site directed mutagenesis, insertions, or accidentally through mutations. 
     A “host cell” includes an individual cell or cell culture which can be or has been a recipient for the subject vectors. Host cells include progeny of a single host cell. The progeny may not necessarily be completely identical (in morphology or in genomic of total DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a vector of this invention. 
     “Isolated,” when used to describe the various polypeptides disclosed herein, means polypeptide that has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. As is apparent to those of skill in the art, a non-naturally occurring polynucleotide, peptide, polypeptide, protein, antibody, or fragments thereof, does not require “isolation” to distinguish it from its naturally occurring counterpart. In addition, a “concentrated”, “separated” or “diluted” polynucleotide, peptide, polypeptide, protein, antibody, or fragments thereof, is distinguishable from its naturally occurring counterpart in that the concentration or number of molecules per volume is generally greater than that of its naturally occurring counterpart. In general, a polypeptide made by recombinant means and expressed in a host cell is considered to be “isolated.” 
     An “isolated” polynucleotide or polypeptide-encoding nucleic acid or other polypeptide-encoding nucleic acid is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source of the polypeptide-encoding nucleic acid. An isolated polypeptide-encoding nucleic acid molecule is other than in the form or setting in which it is found in nature. Isolated polypeptide-encoding nucleic acid molecules therefore are distinguished from the specific polypeptide-encoding nucleic acid molecule as it exists in natural cells. However, an isolated polypeptide-encoding nucleic acid molecule includes polypeptide-encoding nucleic acid molecules contained in cells that ordinarily express the polypeptide where, for example, the nucleic acid molecule is in a chromosomal or extra-chromosomal location different from that of natural cells. 
     A “chimeric” protein contains at least one fusion polypeptide comprising regions in a different position in the sequence than that which occurs in nature. The regions may normally exist in separate proteins and are brought together in the fusion polypeptide; or they may normally exist in the same protein but are placed in a new arrangement in the fusion polypeptide. A chimeric protein may be created, for example, by chemical synthesis, or by creating and translating a polynucleotide in which the peptide regions are encoded in the desired relationship. 
     “Conjugated” and “conjugation” refers to the covalent joining together of two or more chemical elements or components by chemical reaction, rather than recombinantly; e.g., a drug and an XTEN. 
     A “cross-linker” or “CL” means a chemical moiety comprising a covalent bond, drug-linker, or a chain of atoms that covalently conjugate a drug moiety to a protein. Cross-linker components can comprise one or two reactive groups to facilitate the conjugation of a drug and a protein, and the reactive groups can have been blocked by protecting groups to permit the selective conjugation with a given drug or protein reactant. 
     A “reactive group” is a chemical structure or functional group that is part of or that can be coupled to a reactant for conjugation. Examples for reactive groups are amino groups, carboxyl groups, sulfhydryl groups, hydroxyl groups, aldehyde groups, azide groups. Some reactive groups can be activated to facilitate coupling with a second reactive group, such as a cross-linker component. Examples for activation are the reaction of a carboxyl group with carbodiimide, the conversion of a carboxyl group into an activated ester, the conversion of a carboxyl group into an azide function, or the conversion of a hydroxyl to a thiol. 
     The term “cytotoxic agent” as used herein refers to a substance that causes destruction of cells. The term is intended to include radioactive isotopes, drugs, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including synthetic analogs and derivatives thereof. 
     The term “cytostatic agent” refers to a substance that has the effect of limiting the function of cells, such as limiting cellular growth or proliferation of cells. 
     A “drug” is a non-protein chemical compound useful in the treatment of a disease, disorder or condition in a subject; e.g., cancer, inflammatory diseases or conditions such as rheumatoid arthritis, metabolic disorders such as diabetes, infectious diseases, diseases of the organs such as asthma, or generalized conditions such as pain and hypertension, etc. Administration of a drug to a subject or to a cell can, for example, result in a pharmacologic effect, a therapeutic effect, an inhibitory effect, or result in cell death. 
     In the context of polypeptides, “fusion”, “fused” and “linked,” are used interchangeably herein. These terms refer to the joining together of two more protein components, by whatever means including chemical conjugation or recombinant means. For example, a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence. Generally, “operably linked” means that the DNA sequences being linked are contiguous, and in reading phase or in-frame. An “in-frame fusion” refers to the joining of two or more open reading frames (ORFs) to form a continuous longer ORF, in a manner that maintains the correct reading frame of the original ORFs. Thus, the resulting recombinant fusion protein is a single protein containing two ore more segments that correspond to polypeptides encoded by the original ORFs (which segments are not normally so joined in nature). 
     In the context of polypeptides, a “linear sequence” or a “sequence” is an order of amino acids in a polypeptide in an amino to carboxyl terminus direction in which residues that neighbor each other in the sequence are contiguous in the primary structure of the polypeptide. A “partial sequence” is a linear sequence of part of a polypeptide that is known to comprise additional residues in one or both directions. 
     “Heterologous” means derived from a genotypically distinct entity from the rest of the entity to which it is being compared. For example, a glycine rich sequence removed from its native coding sequence and operatively linked to a coding sequence other than the native sequence is a heterologous glycine rich sequence. The term “heterologous” as applied to a polynucleotide, a polypeptide, means that the polynucleotide or polypeptide is derived from a genotypically distinct entity from that of the rest of the entity to which it is being compared. 
     The terms “polynucleotides”, “nucleic acids”, “nucleotides” and “oligonucleotides” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. 
     The term “complement of a polynucleotide” denotes a polynucleotide molecule having a complementary base sequence and reverse orientation as compared to a reference sequence, such that it could hybridize with a reference sequence with complete fidelity. 
     “Recombinant” as applied to a polynucleotide means that the polynucleotide is the product of various combinations of in vitro cloning, restriction and/or ligation steps, and other procedures that result in a construct that can potentially be expressed in a host cell. 
     The terms “gene” or “gene fragment” are used interchangeably herein. They refer to a polynucleotide containing at least one open reading frame that is capable of encoding a particular protein after being transcribed and translated. A gene or gene fragment may be genomic or cDNA, as long as the polynucleotide contains at least one open reading frame, which may cover the entire coding region or a segment thereof. A “fusion gene” is a gene composed of at least two heterologous polynucleotides that are linked together. 
     “Homology” or “homologous” refers to sequence similarity or interchangeability between two or more polynucleotide sequences or two or more polypeptide sequences. When using a program such as BestFit to determine sequence identity, similarity or homology between two different amino acid sequences, the default settings may be used, or an appropriate scoring matrix, such as blosum45 or blosum80, may be selected to optimize identity, similarity or homology scores. Preferably, polynucleotides that are homologous are those which hybridize under stringent conditions as defined herein and have at least 70%, preferably at least 80%, more preferably at least 90%, more preferably 95%, more preferably 97%, more preferably 98%, and even more preferably 99% sequence identity to those sequences. 
     The terms “stringent conditions” or “stringent hybridization conditions” includes reference to conditions under which a polynucleotide will hybridize to its target sequence, to a detectably greater degree than other sequences (e.g., at least 2-fold over background). Generally, stringency of hybridization is expressed, in part, with reference to the temperature and salt concentration under which the wash step is carried out. Typically, stringent conditions will be those in which the salt concentration is less than about 1.5 M Na ion, typically about 0.01 to 1.0 M Na ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30° C. for short polynucleotides (e.g., 10 to 50 nucleotides) and at least about 60° C. for long polynucleotides (e.g., greater than 50 nucleotides)—for example, “stringent conditions” can include hybridization in 50% formamide, 1 M NaCl, 1% SDS at 37° C., and three washes for 15 min each in 0.1×SSC/1% SDS at 60° C. to 65° C. Alternatively, temperatures of about 65° C., 60° C., 55° C., or 42° C. may be used. SSC concentration may be varied from about 0.1 to 2×SSC, with SDS being present at about 0.1%. Such wash temperatures are typically selected to be about 5° C. to 20° C. lower than the thermal melting point © for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength and pH) at which 50% of the target sequence hybridizes to a perfectly matched probe. An equation for calculating Tm and conditions for nucleic acid hybridization are well known and can be found in Sambrook, J. et al. (1989) Molecular Cloning: A Laboratory Manual, 2 nd  ed., vol. 1-3, Cold Spring Harbor Press, Plainview N.Y.; specifically see volume 2 and chapter 9. Typically, blocking reagents are used to block non-specific hybridization. Such blocking reagents include, for instance, sheared and denatured salmon sperm DNA at about 100-200 μg/ml. Organic solvent, such as formamide at a concentration of about 35-50% v/v, may also be used under particular circumstances, such as for RNA:DNA hybridizations. Useful variations on these wash conditions will be readily apparent to those of ordinary skill in the art. 
     The terms “percent identity” and “% identity,” as applied to polynucleotide sequences, refer to the percentage of residue matches between at least two polynucleotide sequences aligned using a standardized algorithm. Such an algorithm may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences. Percent identity may be measured over the length of an entire defined polynucleotide sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polynucleotide sequence, for instance, a fragment of at least 45, at least 60, at least 90, at least 120, at least 150, at least 210 or at least 450 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures or Sequence Listing, may be used to describe a length over which percentage identity may be measured. 
     “Percent (%) amino acid sequence identity,” with respect to the polypeptide sequences identified herein, is defined as the percentage of amino acid residues in a query sequence that are identical with the amino acid residues of a second, reference polypeptide sequence or a portion thereof, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Percent identity may be measured over the length of an entire defined polypeptide sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70 or at least 150 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures or Sequence Listing, may be used to describe a length over which percentage identity may be measured. 
     The term “non-repetitiveness” as used herein in the context of a polypeptide refers to a lack or limited degree of internal homology in a peptide or polypeptide sequence. The term “substantially non-repetitive” can mean, for example, that there are few or no instances of four contiguous amino acids in the sequence that are identical amino acid types or that the polypeptide has a subsequence score (defined infra) of 10 or less or that there isn&#39;t a pattern in the order, from N- to C-terminus, of the sequence motifs that constitute the polypeptide sequence. The term “repetitiveness” as used herein in the context of a polypeptide refers to the degree of internal homology in a peptide or polypeptide sequence. In contrast, a “repetitive” sequence may contain multiple identical copies of short amino acid sequences. For instance, a polypeptide sequence of interest may be divided into n-mer sequences and the number of identical sequences can be counted. Highly repetitive sequences contain a large fraction of identical sequences while non-repetitive sequences contain few identical sequences. In the context of a polypeptide, a sequence can contain multiple copies of shorter sequences of defined or variable length, or motifs, in which the motifs themselves have non-repetitive sequences, rendering the full-length polypeptide substantially non-repetitive. The length of polypeptide within which the non-repetitiveness is measured can vary from 3 amino acids to about 200 amino acids, about from 6 to about 50 amino acids, or from about 9 to about 14 amino acids. “Repetitiveness” used in the context of polynucleotide sequences refers to the degree of internal homology in the sequence such as, for example, the frequency of identical nucleotide sequences of a given length. Repetitiveness can, for example, be measured by analyzing the frequency of identical sequences. 
     A “vector” is a nucleic acid molecule, preferably self-replicating in an appropriate host, which transfers an inserted nucleic acid molecule into and/or between host cells. The term includes vectors that function primarily for insertion of DNA or RNA into a cell, replication of vectors that function primarily for the replication of DNA or RNA, and expression vectors that function for transcription and/or translation of the DNA or RNA. Also included are vectors that provide more than one of the above functions. An “expression vector” is a polynucleotide which, when introduced into an appropriate host cell, can be transcribed and translated into a polypeptide(s). An “expression system” usually connotes a suitable host cell comprised of an expression vector that can function to yield a desired expression product. 
     “Serum degradation resistance,” as applied to a polypeptide, refers to the ability of the polypeptides to withstand degradation in blood or components thereof, which typically involves proteases in the serum or plasma. The serum degradation resistance can be measured by combining the protein with human (or mouse, rat, monkey, as appropriate) serum or plasma, typically for a range of days (e.g. 0.25, 0.5, 1, 2, 4, 8, 16 days), typically at about 37° C. The samples for these time points can be run on a Western blot assay and the protein is detected with an antibody. The antibody can be to a tag in the protein. If the protein shows a single band on the western, where the protein&#39;s size is identical to that of the injected protein, then no degradation has occurred. In this exemplary method, the time point where 50% of the protein is degraded, as judged by Western blots or equivalent techniques, is the serum degradation half-life or “serum half-life” of the protein. 
     The term “t 1/2 ” as used herein means the terminal half-life calculated as ln(2)/K e1 . K e1  is the terminal elimination rate constant calculated by linear regression of the terminal linear portion of the log concentration vs. time curve. Half-life typically refers to the time required for half the quantity of an administered substance deposited in a living organism to be metabolized or eliminated by normal biological processes. The terms “t 1/2 ”, “terminal half-life”, “elimination half-life” and “circulating half-life” are used interchangeably herein. 
     “Apparent molecular weight factor” or “apparent molecular weight” are related terms referring to a measure of the relative increase or decrease in apparent molecular weight exhibited by a particular amino acid sequence. The apparent molecular weight factor is determined using size exclusion chromatography (SEC) and similar methods by comparing to globular protein standards and is measured in “apparent kD” units. The apparent molecular weight factor is the ratio between the apparent molecular weight factor and the actual molecular weight; the latter predicted by adding, based on amino acid composition, the calculated molecular weight of each type of amino acid in the composition. 
     The “hydrodynamic radius” or “Stokes radius” is the effective radius (Rh in nm) of a molecule in a solution measured by assuming that it is a body moving through the solution and resisted by the solution&#39;s viscosity. In the embodiments of the invention, the hydrodynamic radius measurements of the XTEN fusion proteins correlate with the ‘apparent molecular weight factor’, which is a more intuitive measure. The “hydrodynamic radius” of a protein affects its rate of diffusion in aqueous solution as well as its ability to migrate in gels of macromolecules. The hydrodynamic radius of a protein is determined by its molecular weight as well as by its structure, including shape and compactness. Methods for determining the hydrodynamic radius are well known in the art, such as by the use of size exclusion chromatography (SEC), as described in U.S. Pat. Nos. 6,406,632 and 7,294,513. Most proteins have globular structure, which is the most compact three-dimensional structure a protein can have with the smallest hydrodynamic radius. Some proteins adopt a random and open, unstructured, or ‘linear’ conformation and as a result have a much larger hydrodynamic radius compared to typical globular proteins of similar molecular weight. 
     “Physiological conditions” refer to a set of conditions in a living host as well as in vitro conditions, including temperature, salt concentration, pH, that mimic those conditions of a living subject. A host of physiologically relevant conditions for use in in vitro assays have been established. Generally, a physiological buffer contains a physiological concentration of salt and is adjusted to a neutral pH ranging from about 6.5 to about 7.8, and preferably from about 7.0 to about 7.5. A variety of physiological buffers is listed in Sambrook et al. (1989). Physiologically relevant temperature ranges from about 25° C. to about 38° C., and preferably from about 35° C. to about 37° C. 
     A “reactive group” is a chemical structure that can be coupled to a second reactive group. Examples for reactive groups are amino groups, carboxyl groups, sulfhydryl groups, hydroxyl groups, aldehyde groups, azide groups. Some reactive groups can be activated to facilitate coupling with a second reactive group. Non-limiting examples for activation are the reaction of a carboxyl group with carbodiimide, the conversion of a carboxyl group into an activated ester, or the conversion of a carboxyl group into an azide function. 
     “Controlled release agent”, “slow release agent”, “depot formulation” or “sustained release agent” are used interchangeably to refer to an agent capable of extending the duration of release of a polypeptide of the invention relative to the duration of release when the polypeptide is administered in the absence of agent. Different embodiments of the present invention may have different release rates, resulting in different therapeutic amounts. 
     The terms “antigen”, “target antigen” or “immunogen” are used interchangeably herein to refer to the structure or binding determinant that an antibody fragment or an antibody fragment-based therapeutic binds to or has specificity against. 
     The terms “specific binding” or “specifically bind” are used interchangeably herein to refer to the high degree of binding affinity of a targeting moiety or binding fusion protein to its corresponding target. Typically, specific binding as measured by one or more of the assays disclosed herein would have a dissociation constant or K d  of less than about 10 −6 M. 
     The term “payload” as used herein refers to a protein or peptide sequence that has biological or therapeutic activity; the counterpart to the pharmacophore of small molecules. Examples of payloads include, but are not limited to, cytokines, enzymes, hormones and blood and growth factors. Payloads can further comprise genetically fused or chemically conjugated moieties such as chemotherapeutic agents, antiviral compounds, toxins, or contrast agents. These conjugated moieties can be joined to the rest of the polypeptide via a linker which may be cleavable or non-cleavable. 
     The term “antagonist”, as used herein, includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native polypeptide disclosed herein. Methods for identifying antagonists of a polypeptide may comprise contacting a native polypeptide with a candidate antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the native polypeptide. In the context of the present invention, antagonists may include proteins, nucleic acids, carbohydrates, antibodies or any other molecules that decrease the effect of a biologically active protein. 
     The term “agonist” is used in the broadest sense and includes any molecule that mimics a biological activity of a native polypeptide disclosed herein. Suitable agonist molecules specifically include agonist antibodies or antibody fragments, fragments or amino acid sequence variants of native polypeptides, peptides, small organic molecules, etc. Methods for identifying agonists of a native polypeptide may comprise contacting a native polypeptide with a candidate agonist molecule and measuring a detectable change in one or more biological activities normally associated with the native polypeptide. 
     “Activity” for the purposes herein refers to an action or effect of a component of a fusion protein consistent with that of the corresponding native biologically active protein, wherein “biological activity” refers to an in vitro or in vivo biological function or effect, including but not limited to receptor binding, antagonist activity, agonist activity, or a cellular or physiologic response. 
     As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” is used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. 
     A “therapeutic effect”, as used herein, refers to a physiologic effect, including but not limited to the cure, mitigation, amelioration, or prevention of disease in humans or other animals, or to otherwise enhance physical or mental wellbeing of humans or animals, caused by a fusion polypeptide of the invention other than the ability to induce the production of an antibody against an antigenic epitope possessed by the biologically active protein. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. 
     The terms “therapeutically effective amount” and “therapeutically effective dose”, as used herein, refers to an amount of a biologically active protein, either alone or as a part of a fusion protein composition, that is capable of having any detectable, beneficial effect on any symptom, aspect, measured parameter or characteristics of a disease state or condition when administered in one or repeated doses to a subject. Such effect need not be absolute to be beneficial. 
     The term “therapeutically effective dose regimen”, as used herein, refers to a schedule for consecutively administered doses of a biologically active protein, either alone or as a part of a fusion protein composition, wherein the doses are given in therapeutically effective amounts to result in sustained beneficial effect on any symptom, aspect, measured parameter or characteristics of a disease state or condition. 
     I). General Techniques 
     The practice of the present invention employs, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA, which are within the skill of the art. See Sambrook, J. et al., “Molecular Cloning: A Laboratory Manual,” 3 rd  edition, Cold Spring Harbor Laboratory Press, 2001; “Current protocols in molecular biology”, F. M. Ausubel, et al. eds., 1987; the series “Methods in Enzymology,” Academic Press, San Diego, Calif.; “PCR 2: a practical approach”, M. J. MacPherson, B. D. Hames and G. R. Taylor eds., Oxford University Press, 1995; “Antibodies, a laboratory manual” Harlow, E. and Lane, D. eds., Cold Spring Harbor Laboratory, 1988; “Goodman &amp; Gilman&#39;s The Pharmacological Basis of Therapeutics,” 11 th  Edition, McGraw-Hill, 2005; and Freshney, R.I., “Culture of Animal Cells: A Manual of Basic Technique,” 4 th  edition, John Wiley &amp; Sons, Somerset, N J, 2000, the contents of which are incorporated in their entirety herein by reference. 
     II). Binding Fusion Protein Compositions 
     (a) The present invention relates, in part, to binding fusion protein (“BFP”) compositions comprising fusion proteins of polypeptide targeting moieties linked to one or more extended recombinant polypeptides (“XTEN”). In particular, the invention provides isolated binding fusion protein compositions useful in the treatment of diseases, disorders or conditions in which the targeting moiety can be directed to an antigen, ligand, or receptor implicated in, associated with, or that modulates a disease, disorder or condition, while the XTEN carrier portion can be designed to confer a desired half-life or enhanced pharmaceutical property on the binding fusion protein, as described more fully below. The binding fusion proteins of the present invention may act as agonists or antagonists. In one embodiment, the composition can further comprise a second targeting moiety or multiple targeting moieties that can have binding affinity for the same or a different target, resulting in bispecific or multivalent binding fusion proteins. The invention provides several different forms and configurations of targeting moieties and XTEN. The binding fusion proteins of the embodiments disclosed herein exhibit one or more or any combination of the properties and/or the embodiments as detailed herein. 
     Targets 
     In general, the targeting moieties of the subject binding fusion protein compositions exhibit a binding specificity to a given target or another desired biological characteristic when used in vivo or when utilized in an in vitro assay. The subject binding fusion proteins comprising two or more targeting moieties can be designed to bind the same target, different epitopes on the same target, or different targets by the selective incorporation of targeting moieties with binding affinity to the respective binding sites. 
     The targets to which the targeting moieties of the subject binding fusion protein compositions can be directed include cytokines, cytokine-related proteins, cytokine receptors, chemokines, chemokines receptors, cell surface receptors or antigens, hormones or similar circulating proteins or peptides, oligonucleotides, or enzymatic substrates. The targets are generally associated with a disease, disorder or condition. As used herein, “a target associated with a disease, disorder or condition” means that the target is either expressed or overexpressed by disease cells or tissues, the target causes or is a mediator or is a by-product of the disease, disorder or condition, or the target is generally found in higher concentrations in a subject with the disease, disorder or condition, or the target is found in higher than baseline concentrations within or proximal to the areas of the disease, disorder or condition in the subject. A non-limiting example of the foregoing is the target HER2, which is implicated in approximately 30 percent of breast cancers due to an amplification of the HER2/neu gene or over-expression of its protein product. Over-expression of the HER2 receptor in breast cancer is associated with increased disease recurrence and worse prognosis, and a humanized anti-Her2/neu antibody is used in treatment of breast cancers expressing the HER2 receptor (see for example U.S. Pat. No. 4,753,894). 
     In one embodiment, the one or more targeting moieties can have binding affinity to targets selected from, but not limited to the targets of Table 1. 
     
       
         
           
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Targets for targeting moieties 
               
               
                 Target 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 ABCF1; ACVR1; ACVR1B; ACVR2; ACVR2B; ACVRL1; ADORA2A; Aggrecan; AGR2; AICDA; 
               
               
                 AIF1; AIG1; AKAP1; AKAP2; AMH; AMHR2; ANGPT1; ANGPT2; ANGPTL3; ANGPTL4; 
               
               
                 ANPEP; APC; APOC1; APRIL; AR; AZGP1 (zinc-a-glycoprotein); A4 integrin; B7; B7.1; B7.2; BAD; 
               
               
                 BAFF; BAG1; BAI1; BCL2; BCL6; BDNF; BLNK; BLR1 (MDR15); BlyS; BMP1; BMP2; BMP3B 
               
               
                 (GDF10); BMP4; BMP6; BMP8; BMPR1A; BMPR1B; BMPR2; BPAG1 (plectin); BRCA1; C19orf10 
               
               
                 (IL27w); C3; C4A; C5; C5R1; CANT1; CASP1; CASP4; CAV1; CCBP2 (D6/JAB61); CCL1 (1-309); 
               
               
                 CCL11 (eotaxin); CCL13 (MCP-4); CCL15 (MIP-1d); CCL16 (HCC-4); CCL17 (TARC); CCL18 
               
               
                 (PARC); CCL19 (MIP-3b); CCL2 (MCP-1); MCAF; CCL20 (MIP-3a); CCL21 (MIP-2); SLC; exodus- 
               
               
                 2; CCL22 (MDC/STC-1); CCL23 (MPIF-1); CCL24 (MPIF-2/eotaxin-2); CCL25 (TECK); CCL26 
               
               
                 (eotaxin-3); CCL27 (CTACK/ILC); CCL28; CCL3 (MIP-1a); CCL4 (MIP-1b); CCL5 (RANTES); 
               
               
                 CCL7 (MCP-3); CCL8 (mcp-2); CCNA1; CCNA2; CCND1; CCNE1; CCNE2; CCR1 
               
               
                 (CKR1/HM145); CCR2 (mcp-1RB/RA); CCR3 (CKR3/CMKBR3); CCR4; CCR5 
               
               
                 (CMKBR5/ChemR13); CCR6 (CMKBR6/CKR-L3/STRL22/DRY6); CCR7 (CKR7/EBI1); CCR8 
               
               
                 (CMKBR8/TER1/CKR-L1); CCR9 (GPR-9-6); CCRL1 (VSHK1); CCRL2 (L-CCR); CD164; CD19; 
               
               
                 CD1C; CD20; CD200; CD-22; CD24; CD28; CD3; CD37; CD38; CD3E; CD3G; CD3Z; CD4; CD11a 
               
               
                 (LFA-1 integrin alphaL); CD40; CD40L; CD44; CD45RB; CD52; CD69; CD72; CD74; CD79A; 
               
               
                 CD79B; CD8; CD80; CD81; CD83; CD86; CD340; CDH1 (E-cadherin); CDH10; CDH12; CDH13; 
               
               
                 CDH18; CDH19; CDH20; CDH5; CDH7; CDH8; CDH9; CDK2; CDK3; CDK4; CDK5; CDK6; 
               
               
                 CDK7; CDK9; CDKN1A (p21Wap1/Cip1); CDKN1B (p27Kip1); CDKN1C; CDKN2A (p16INK4a); 
               
               
                 CDKN2B; CDKN2C; CDKN3; CEBPB; CER1; CHGA; CHGB; Chitinase; CHST10; CKLFSF2; 
               
               
                 CKLFSF3; CKLFSF4; CKLFSF5; CKLFSF6; CKLFSF7; CKLFSF8; CLDN3; CLDN7 (claudin-7); 
               
               
                 CLN3; CLU (clusterin); cMET; CMKLR1; CMKOR1 (RDC1); CNR1; COL18A1; COL1A1; 
               
               
                 COL4A3; COL6A1; CR2; CRP; CSF1 (M-CSF); CSF2 (GM-CSF); CSF3 (GCSF); CTLA4; CTNNB1 
               
               
                 (b-catenin); CTSB (cathepsin B); CX3CL1 (SCYD1); CX3CR1 (V28); CXCL1 (GRO1); CXCL10(IP- 
               
               
                 10); CXCL11 (I-TAC/IP-9); CXCL12 (SDF1); CXCL13; CXCL14; CXCL16; CXCL2 (GRO2); 
               
               
                 CXCL3 (GRO3); CXCL5 (ENA-78/LIX); CXCL6 (GCP-2); CXCL9 (MIG); CXCR3 (GPR9/CKR- 
               
               
                 L2); CXCR4; CXCR6 (TYMSTR/STRL33/Bonzo); CYB5; CYC1; CYSLTR1; DAB2IP; DES; 
               
               
                 DKFZp451J0118; DNCL1; DPP4; E2F1; ECGF1; EDG1; EFNA1; EFNA3; EFNB2; EGF; EGFR; 
               
               
                 ELAC2; elastase; ENG; ENO1; ENO2; ENO3; EPHB4; EPO; ERBB-2 (Her2); EREG; ERK8; ESR1; 
               
               
                 ESR2; F3 (TF); FADD; FasL; FASN; FCER1A; FCER2; FCGR3A; FGF; FGF1 (aFGF); FGF10; 
               
               
                 FGF11; FGF12; FGF12B; FGF13; FGF14; FGF16; FGF17; FGF18; FGF19; FGF2 (bFGF); FGF20; 
               
               
                 FGF21; FGF22; FGF23; FGF3 (int-2); FGF4 (HST); FGF5; FGF6 (HST-2); FGF7 (KGF); FGF8; 
               
               
                 FGF9; FGFR3; FIGF (VEGFD); FIL1 (EPSILON); FIL1 (ZETA); FLJ12584; FLJ25530; FLRT1 
               
               
                 (fibronectin); FLT1; FOS; FOSL1 (FRA-1); FY (DARC); GABRP (GABAa); GAGEB1; GAGEC1; 
               
               
                 GALNAC4S-6ST; GATA3; GDF5; GFI1; GGT1; GM-CSF; GNAS1; GNRH1; GPR2 (CCR10); 
               
               
                 GPR31; GPR44; GPR81 (FKSG80); GRCC10 (C10); GRP; GSN (Gelsolin); GSTP1; HAVCR2; 
               
               
                 HDAC4; HDAC5; HDAC7A; HDAC9; HER2; HGF; HIF1A; HIP1; histamine and histamine receptors; 
               
               
                 HLA-A; HLA-DRA; HM74; HMOX1; HUMCYT2A; ICEBERG; ICOSL; ID2; IFN-a; IFNA1; IFNA2; 
               
               
                 IFNA4; IFNA5; IFNA6; IFNA7; IFNB1; IFNgamma; IFNW1; IGBP1; IGF1; IGF1R; IGF2; IGFBP2; 
               
               
                 IGFBP3; IGFBP6; IL-1; IL10; IL10RA; IL10RB; IL11; IL11RA; IL-12; IL12A; IL12B; IL12RB1; 
               
               
                 IL12RB2; IL13; IL13RA1; IL13RA2; IL14; IL15; IL15RA; IL16; IL17; IL17B; IL17C; IL17R; IL18; 
               
               
                 IL18BP; IL18R1; IL18RAP; IL19; IL1A; IL1B; IL1F10; IL1F5; IL1F6; IL1F7; IL1F8; IL1F9; 
               
               
                 IL1HY1; IL1R1; IL1R2; IL1RAP; IL1RAPL1; IL1RAPL2; IL1RL1; IL1RL2; IL1RN; IL2; IL20; 
               
               
                 IL20RA; IL21R; IL22; IL22R; IL22RA2; IL23; IL24; IL25; IL26; IL27; IL28A; IL28B; IL29; IL2RA; 
               
               
                 IL2RB; IL2RG; IL3; IL30; IL3RA; IL4; IL4R; IL5; IL5RA; IL6; IL6R; IL6ST (glycoprotein 130); IL7; 
               
               
                 IL7R; IL8; IL8RA; IL8RB; IL8RB; IL9; IL9R; ILK; INHA; INHBA; INSL3; INSL4; IRAK1; IRAK2; 
               
               
                 ITGA1; ITGA2; ITGA3; ITGA6 (a6 integrin); ITGAV; ITGB3; ITGB4 (b 4 integrin); JAG1; JAK1; 
               
               
                 JAK3; JUN; K6HF; KAI1; KDR; KITLG; KLF5 (GC Box BP); KLF6; KLK10; KLK12; KLK13; 
               
               
                 KLK14; KLK15; KLK3; KLK4; KLK5; KLK6; KLK9; KRT1; KRT19 (Keratin 19); KRT2A; 
               
               
                 KRTHB6 (hair-specific type II keratin); LAMA5; LEP (leptin); LFA3; LIGHT; Lingo-p75; Lingo- 
               
               
                 Troy; LPS; LTA (TNF-b); LTB; LTB4R (GPR16); LTB4R2; LTBR; MACMARCKS; MAG or Omgp; 
               
               
                 MAP2K7 (c-Jun); MDK; MIB1; midkine; MIF; MIP-2; MKI67 (Ki-67); MMP2; MMP9; MS4A1; 
               
               
                 MSMB; MT3 (metallothionectin-III); MTSS1; MUC1 (mucin); MYC; MYD88; NCK2; neurocan; 
               
               
                 NFKB1; NFKB2; NGFB (NGF); NGFR; NgR-Lingo; NgR-Nogo66 (Nogo); NgR-p75; NgR-Troy; 
               
               
                 NME1 (NM23A); NOX5; NPPB; NROB1; NROB2; NR1D1; NR1D2; NR1H2; NR1H3; NR1H4; 
               
               
                 NRII2; NRII3; NR2C1; NR2C2; NR2E1; NR2E3; NR2F1; NR2F2; NR2F6; NR3C1; NR3C2; NR4A1; 
               
               
                 NR4A2; NR4A3; NR5A1; NR5A2; NR6A1; NRP1; NRP2; NT5E; NTN4; ODZ1; OPRD1; P2RX7; 
               
               
                 PAP; PART1; PATE; PAWR; PCA3; PCNA; PDGFA; PDGFB; PECAM1; PF4 (CXCL4); PGF; PGR; 
               
               
                 phosphacan; PIAS2; PIK3CG; PLAU (uPA); PLG; PLXDC1; PPBP (CXCL7); PPID; PR1; PRKCQ; 
               
               
                 PRKD1; PRL; PROC; PROK2; PSAP; PSCA; PTAFR; PTEN; PTGS2 (COX-2); PTN; RAC2 
               
               
                 (p21Rac2); RANKL; RARB; RGS1; RGS13; RGS3; RNF110 (ZNF144); ROBO2; RSV; SI00A2; 
               
               
                 SCGB1D2 (lipophilin B); SCGB2A1 (mammaglobin 2); SCGB2A2 (mammaglobin 1); SCYE1 
               
               
                 (endothelial Monocyte-activating cytokine); SDF2; SERPINA1; SERPINA3; SERPINB5 (maspin); 
               
               
                 SERPINE1 (PAI-1); SERPINF1; SHBG; SLA2; SLC2A2; SLC33A1; SLC43A1; SLIT2; SPP1; 
               
               
                 SPRR1B (Spr1); ST6GAL1; STAB1; STAT6; STEAP; STEAP2; TB4R2; TBX21; TCP10; TDGF1; 
               
               
                 TEK; TGFA; TGFB1; TGFB111; TGFB2; TGFB3; TGFBI; TGFBR1; TGFBR2; TGFBR3; TH1L; 
               
               
                 THBS1 (thrombospondin-1); THBS2; THBS4; THPO; TIE (Tie-1); TIMP3; tissue factor; TLR10; 
               
               
                 TLR2; TLR3; TLR4; TLR5; TLR6; TLR7; TLR8; TLR9; TNF; TNF-a; TNFAIP2 (B94); TNFAIP3; 
               
               
                 TNFRSF11A; TNFRSF1A; TNFRSF1B; TNFRSF21; TNFRSF5; TNFRSF6 (Fas); TNFRSF7; 
               
               
                 TNFRSF8; TNFRSF9; TNFSF10 (TRAIL); TNFSF11 (TRANCE); TNFSF12 (APO3L); TNFSF13 
               
               
                 (April); TNFSF13B; TNFSF14 (HVEM-L); TNFSF15 (VEGI); TNFSF18; TNFSF4 (OX40 ligand); 
               
               
                 TNFSF5 (CD40 ligand); TNFSF6 (FasL); TNFSF7 (CD27 ligand); TNFSF8 (CD30 ligand); TNFSF9 
               
               
                 (4-1BB ligand); TOLLIP; Toll-like receptors (TLR1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 to TLR-13); 
               
               
                 TOP2A (topoisomerase Iia); TP53; TPM1; TPM2; TRADD; TRAF1; TRAF2; TRAF3; TRAF4; 
               
               
                 TRAF5; TRAF6; TREM1; TREM2; TRPC6; TSLP; TWEAK; VAP1; VEGF; VEGFB; VEGFC; 
               
               
                 versican; VHL C5; VLA-1; VLA-4; XCL1 (lymphotactin); XCL2 (SCM-1b); XCR1 (GPR5/CCXCR1); 
               
               
                 YY1; ZFPM2. 
               
               
                   
               
            
           
         
       
     
     In one embodiment, the one or more targeting moieties can have binding affinity to one or more tumor-associated antigens (TAA) known to be expressed on tumor or cancer cells or are otherwise associated with tumors or cancers. Tumor-associated antigens are known in the art, and are generally regarded as effective cellular targets for cancer diagnosis and therapy. In particular, researchers have sought to identify TAA that are specifically expressed on the surface of one or more particular types of cancer cell as compared to on one or more normal non-cancerous cells, and has given rise to the ability to specifically target cancer cells for destruction via antibody-based therapies. Non-limiting examples of TAA are listed in Table 2. In one embodiment, a binding fusion protein comprises a targeting moiety with binding affinity to a TAA target selected from Table 2. In another embodiment, the binding fusion protein comprises two or more targeting moieties that have binding affinity to one or more TAA targets selected from the targets of Table 2. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Tumor-associated antigen targets 
               
            
           
           
               
               
            
               
                 TAA targets (synonyms) 
                 Accession Number and References 
               
               
                   
               
               
                 Her2 (ErbB2) 
                 GenBank accession no. M11730; U.S. Pat. No. 5,869,445; 
               
               
                   
                 WO2004048938; WO2004027049; WO2004009622; 
               
               
                   
                 WO2003081210; WO2003089904; WO2003016475; 
               
               
                   
                 US2003118592; WO2003008537; WO2003055439; 
               
               
                   
                 WO2003025228; WO200222636; WO200212341; 
               
               
                   
                 WO200213847; WO200214503; WO200153463; 
               
               
                   
                 WO200141787; WO200044899; WO200020579; 
               
               
                   
                 WO9630514; EP1439393; WO2004043361; 
               
               
                   
                 WO2004022709; WO200100244 
               
               
                 BMPR1B (bone morphogenetic protein 
                 GenBank accession no. NM_001203; WO2004063362; 
               
               
                 receptor-type IB) 
                 WO2003042661; US 2003134790; WO2002102235; 
               
               
                   
                 WO2003055443; WO200299122; WO2003029421; 
               
               
                   
                 WO2003024392; WO200298358&#39; WO200254940; 
               
               
                   
                 WO200259377; WO200230268 
               
               
                 E16 (LAT1, SLC7A5) 
                 GenBank accession no. NM_003486); WO2004048938; 
               
               
                   
                 WO2004032842; WO2003042661; WO2003016475; 
               
               
                   
                 WO200278524; WO200299074; WO200286443; 
               
               
                   
                 WO2003003906; WO200264798; WO200014228; 
               
               
                   
                 US2003224454; WO2003025138 
               
               
                 STEAP1 (six transmembrane epithelial 
                 GenBank accession no. NM_012449; WO2004065577; 
               
               
                 antigen of prostate) 
                 WO2004027049; EP1394274; WO2004016225; 
               
               
                   
                 WO2003042661; US2003157089; US2003185830; 
               
               
                   
                 US2003064397; WO200289747618; WO2003022995 
               
               
                 STEAP2 (six transmembrane epithelial 
                 GenBank accession no. AF455138; WO2003087306; 
               
               
                 antigen of prostate 2) 
                 US2003064397; WO200272596; WO200172962; 
               
               
                   
                 WO2003104270; WO2003104270; US2004005598; 
               
               
                   
                 WO2003042661; US2003060612; WO200226822; 
               
               
                   
                 WO200216429 
               
               
                 CA125/0772P (MUC16) 
                 GenBank accession no. AF361486; WO2004045553; 
               
               
                   
                 WO200292836; WO200283866; US2003124140 
               
               
                 megakaryocyte potentiating factor 
                 GenBank accession no. NM _005823; WO2003101283; 
               
               
                 (MPF, mesothelin) 
                 WO2002102235; WO2002101075; WO200271928; 
               
               
                   
                 WO9410312 
               
               
                 Na/Pi cotransporter type IIb (NaPi3b) 
                 GenBank accession no. NM_006424; WO2004022778; 
               
               
                   
                 EP1394274; WO2002102235; EP875569; WO200157188; 
               
               
                   
                 WO2004032842; WO200175177 
               
               
                 Semaphorin 5b (SEMA5B, SEMAG) 
                 GenBank accession no. AB040878; WO2004000997; 
               
               
                   
                 WO2003003984; WO200206339; WO200188133; 
               
               
                   
                 WO2003054152; WO2003101400 
               
               
                 Prostate cancer stem cell antigen 
                 GenBank accession no. AY358628; US2003129192; 
               
               
                 (PSCA hlg) 
                 US2004044180; US2004044179; US2003096961; 
               
               
                   
                 US2003232056; WO2003105758; US2003206918; 
               
               
                   
                 EP1347046; WO2003025148 
               
               
                 ETBR (Endothelin type B receptor) 
                 GenBank accession no. AY275463; WO2004045516; 
               
               
                   
                 WO2004048938; WO2004040000; WO2003087768; 
               
               
                   
                 WO2003016475; WO2003016475; WO200261087; 
               
               
                   
                 WO2003016494; WO2003025138; WO200198351; 
               
               
                   
                 EP522868; WO200177172; US2003109676; U.S. Pat. No. 
               
               
                   
                 6,518,404; U.S. Pat. No. 5,773,223; WO2004001004 
               
               
                 TRPV4 (Transient receptor potential 
                 U.S. patent application No. 20090208514 
               
               
                 cation channel, subfamily V) 
               
               
                 CDC45L 
                 GenBank Accession NO. AJ223728; U.S. patent 
               
               
                   
                 application No. 20090208514 
               
               
                 CRIPTO (CR, CR1, CRGF) 
                 GenBank accession no. NP_003203 or NM_003212; 
               
               
                   
                 US2003224411; WO2003083041; WO2003034984; 
               
               
                   
                 WO200288170; WO2003024392; WO200216413; 
               
               
                   
                 WO200222808; U.S. Pat. No. 5,854,399; 
               
               
                   
                 U.S. Pat. No. 5,792,616 
               
               
                 CD21 (CR2 (Complement receptor 2) 
                 GenBank accession no. M26004; WO2004045520; 
               
               
                 or C3DR (C3d/Epstein Barr virus 
                 US2004005538; WO2003062401; WO2004045520; 
               
               
                 receptor) 
                 WO9102536; WO2004020595 
               
               
                 CD79b (CD79B, CD79β, IGb 
                 GenBank accession no. NM_000626 or 11038674; 
               
               
                 (immunoglobulin-associated beta), 
                 WO2004016225; WO2003087768; US2004101874; 
               
               
                 B29) 
                 WO2003062401; WO200278524; US2002150573; U.S. Pat. 
               
               
                   
                 No. 5,644,033; WO2003048202; WO 99/558658, U.S. Pat. 
               
               
                   
                 No. 6,534,482; WO200055351 
               
               
                 FcRH2 (IFGP4, IRTA4, SPAP1A 
                 GenBank accession no. NM_030764, AY358130; 
               
               
                 (SH2 domain containing phosphatase 
                 WO2004016225; WO2003077836; WO200138490; 
               
               
                 anchor protein 1a), SPAP1B, SPAP1C) 
                 WO2003097803; WO2003089624 
               
               
                 NCA (CEACAM6) 
                 GenBank accession no. M18728; WO2004063709; 
               
               
                   
                 EP1439393; WO2004044178; WO2004031238; 
               
               
                   
                 WO2003042661; WO200278524; WO200286443; 
               
               
                   
                 WO200260317 
               
               
                 MDP (DPEP1) 
                 GenBank accession no. BC017023; WO2003016475; 
               
               
                   
                 WO200264798 
               
               
                 IL20Rα (IL20Ra, ZCYTOR7) 
                 GenBank accession no. AF184971; EP1394274; 
               
               
                   
                 US2004005320; WO2003029262; WO2003002717; 
               
               
                   
                 WO200222153; US2002042366; WO200146261; 
               
               
                   
                 WO200146232; WO9837193 
               
               
                 BECAN (Brevican core protein) 
                 GenBank accession no. AF229053; US2003186372; 
               
               
                   
                 US2003186373; US2003119131; US2003119122; 
               
               
                   
                 US2003119126; US2003119121; US2003119129; 
               
               
                   
                 US2003119130; US2003119128; US2003119125; 
               
               
                   
                 WO2003016475; WO200202634 
               
               
                 EphB2R (DRT, ERK, Hek5, EPHT3, 
                 GenBank accession no. NM_004442; WO2003042661; 
               
               
                 Tyro5) 
                 WO200053216; WO2004065576 (Claim 1); 
               
               
                   
                 WO2004020583; WO2003004529; WO200053216 
               
               
                 B7h (ASLG659) 
                 GenBank accession no. AX092328; US20040101899; 
               
               
                   
                 WO2003104399; WO2004000221; US2003165504; 
               
               
                   
                 US2003124140; US2003065143; WO2002102235; 
               
               
                   
                 US2003091580; WO200210187; WO200194641; 
               
               
                   
                 WO200202624; US2002034749; WO200206317; 
               
               
                   
                 WO200271928; WO200202587; WO200140269; 
               
               
                   
                 WO200036107; WO2004053079; WO2003004989; 
               
               
                   
                 WO200271928 
               
               
                 PSCA (Prostate stem cell antigen 
                 GenBank accession no. AJ297436; WO2004022709; 
               
               
                 precursor 
                 EP1394274; US2004018553; WO2003008537 (Claim 1); 
               
               
                   
                 WO200281646; WO2003003906; WO200140309; 
               
               
                   
                 US2001055751; WO200032752; WO9851805; 
               
               
                   
                 WO9851824; WO9840403 
               
               
                 BAFF-R (B cell-activating factor 
                 GenBank accession No. AF116456; WO2004058309; 
               
               
                 receptor, BLyS receptor 3, BR3) 
                 WO2004011611; WO2003045422; WO2003014294; 
               
               
                   
                 WO2003035846; WO200294852; WO200238766; 
               
               
                   
                 WO200224909 
               
               
                 CD22 (B-cell receptor CD22-β-form, 
                 GenBank accession No. AK026467; WO2003072036 
               
               
                 BL-CAM, Lyb-8, Lyb8, SIGLEC-2, 
               
               
                 FLJ22814) 
               
               
                 CD79a (immunoglobulin-associated 
                 GenBank accession No. NP_001774.10; WO2003088808, 
               
               
                 alpha) 
                 US20030228319; WO2003062401; US2002150573; 
               
               
                   
                 WO9958658; WO9207574; U.S. Pat. No. 5,644,033 
               
               
                 CXCR5 (Burkitt&#39;s lymphoma 
                 GenBank accession No. NP_001707.1; WO2004040000; 
               
               
                 receptor 1) 
                 WO2004015426; US2003105292; U.S. Pat. No. 6,555,339; 
               
               
                   
                 WO200261087; WO200157188; WO200172830; 
               
               
                   
                 WO200022129; WO9928468; U.S. Pat. No. 5,440,021; 
               
               
                   
                 WO9428931; WO9217497 
               
               
                 HLA-DOB 
                 GenBank accession No. NP_002111.1; WO9958658; U.S. 
               
               
                   
                 Pat. No. 6,153,408; U.S. Pat. No. 5,976,551; 
               
               
                   
                 U.S. Pat. No. 6,011,146 
               
               
                 P2X5 
                 GenBank accession No. NP_002552.2; WO2004047749; 
               
               
                   
                 WO2003072035; WO200222660; WO2003093444; 
               
               
                   
                 WO2003087768; WO2003029277 
               
               
                 CD72 (B-cell differentiation antigen 
                 GenBank accession No. NP_001773.1; WO2004042346; 
               
               
                 CD72, Lyb-2) 
                 WO2003026493; WO200075655 
               
               
                 CD180 (LY64) 
                 GenBank accession No. NP_005573.1; US2002193567; 
               
               
                   
                 WO9707198; WO2003083047; WO9744452 
               
               
                 FcRH1 (Fc receptor-like protein 1) 
                 GenBank accession No. NP_443170.1) WO2003077836; 
               
               
                   
                 WO200138490; WO2003089624; EP1347046; 
               
               
                   
                 WO2003089624 
               
               
                 IRTA2 (Immunoglobulin superfamily 
                 GenBank accession No. Human: AF343662, AF343663, 
               
               
                 receptor translocation associated 2) 
                 AF343664, AF343665, AF369794, AF397453; 
               
               
                   
                 WO2003024392; WO2003077836; WO200138490 
               
               
                 TENB2 (TMEFF2, tomoregulin, 
                 GenBank accession No. AF179274; AY358907, CAF85723, 
               
               
                 TPEF, HPP1) 
                 CQ782436; WO2004074320; WO2003042661; 
               
               
                   
                 WO2003009814; EP1295944; WO200230268; 
               
               
                   
                 WO200190304; US2004249130; US2004022727; 
               
               
                   
                 WO2004063355; US2004197325; US2003232350; 
               
               
                   
                 US2004005563; US2003124579 
               
               
                 CS1 (CRACC, 19A, APEX-1, 
                 GenBank Accession No. NM 021181; US 20100168397 
               
               
                 FOAP12) 
               
               
                 DLL4 
                 GenBank Accession No. NM 019074; US 20100303812 
               
               
                 Lewis Y 
                 ADB235860; U.S. Pat. No. 7,879,983 
               
               
                 CD40 (Bp50, CDW40, MGC9013, 
                 AL035662.65; U.S. Pat. No. 6,946,129 
               
               
                 TNFRSF5, p50) 
               
               
                 OBA1 (5T4) 
                 GenBank Accession No. NP_001159864.1; US 
               
               
                   
                 20100021483 
               
               
                 p97 
                 Woodbury et al., 1980, Proc. Natl. Acad. Sci. USA 77: 
               
               
                   
                 2183-2186; Brown et al., 1981, J. Immunol. 127: 539-546 
               
               
                 carcinoembryonic antigen (CEA) 
                 GenBank Accession No. NP_004354.2; U.S. Pat. No. 6,676,924 
               
               
                 TAG-72 
                 U.S. Pat. No. 7,256,004 
               
               
                 DNA 
               
               
                 Neuropilin-1 (NRP1) 
                 GenBank Accession No. NP_001019799.1; US 
               
               
                   
                 20080213268 
               
               
                 A33 
                 GenBank Accession No. NP_005805.1; U.S. Pat. No. 7,579,187 
               
               
                 Mucin-1 (MUC1) 
                 GenBank Accession No. NP_001018016.1; 
               
               
                   
                 NP_001018017.1; U.S. Pat. No. 7,183,388 
               
               
                 ED-B fibronectin 
                 U.S. Pat. No. 7,785,591 
               
               
                 Thomsen-Friedenreich antigen (TF) 
                 U.S. Pat. No. 7,374,755; US 20100297159 
               
               
                   
               
            
           
         
       
     
     (b) Extended Recombinant Polypeptides 
     In one aspect, the invention provides XTEN polypeptide compositions that are useful as a fusion protein partner to which one or more targeting moieties can be linked, resulting in a binding fusion protein. XTEN are generally extended length polypeptides with non-naturally occurring, substantially non-repetitive sequences that are composed mainly of small hydrophilic amino acids, with the sequence having a low degree or no secondary or tertiary structure under physiologic conditions. XTEN have utility as fusion protein partners in that they serve in various roles, conferring certain desirable pharmacokinetic, physicochemical and pharmaceutical properties, amongst other properties described below, when linked to a targeting moiety to a create a fusion protein. 
     In some embodiments, XTEN are long polypeptides having greater than 100 to about 3000 residues, and preferably 400 to about 3000 residues when used as a carrier or cumulatively when more than one XTEN unit is used in a single fusion protein with a targeting moiety; e.g., a linker and a carrier or an N-terminal XTEN and a carrier. In other embodiments, shorter XTEN sequences can be used as linkers to join components of the binding fusion proteins or to enhance expression as an N-terminal XTEN, as described more fully below. 
     The selection criteria for the XTEN used to create the inventive compositions generally relate to attributes of physical/chemical properties and conformational structure of the XTEN that can be, in turn, used to confer enhanced pharmaceutical and pharmacokinetic properties to the compositions. The XTEN of the present invention may exhibit one or more of the following advantageous properties: conformational flexibility, enhanced aqueous solubility, high degree of protease resistance, low immunogenicity, low binding to mammalian receptors, and increased hydrodynamic (or Stokes) radii; properties that can make them particularly useful as fusion protein partners and scaffolds for drug conjugates. Non-limiting examples of the properties of the inventive compositions that may be enhanced by XTEN include increases in the overall solubility and/or metabolic stability, reduced susceptibility to proteolysis, reduced immunogenicity, reduced rate of absorption when administered subcutaneously or intramuscularly, and enhanced pharmacokinetic properties such as longer terminal half-life and increased area under the curve (AUC), slower absorption after subcutaneous or intramuscular injection (compared to agents not linked to XTEN administered by a parenteral route) such that the C max  is lower, which may, in turn, result in reductions in adverse effects that, collectively, can result in an increased period of time that a fusion protein composition administered to a subject retains therapeutic activity. 
     A variety of methods and assays are known in the art for determining the physical/chemical properties of proteins such as the compositions comprising the inventive XTEN; properties such as secondary or tertiary structure, solubility, protein aggregation, melting properties, contamination and water content. Such methods include analytical centrifugation, EPR, HPLC-ion exchange, HPLC-size exclusion, HPLC-reverse phase, light scattering, capillary electrophoresis, circular dichroism, differential scanning calorimetry, fluorescence, HPLC-ion exchange, HPLC-size exclusion, IR, NMR, Raman spectroscopy, refractometry, and UV/Visible spectroscopy. Additional methods are disclosed in Arnau et al, Prot Expr and Purif (2006) 48, 1-13. Application of these methods to the invention would be within the grasp of a person skilled in the art. 
     In one embodiment, XTEN are designed to behave like denatured peptide sequences under physiological conditions, despite the extended length of the polymer. Denatured describes the state of a peptide in solution that is characterized by a large conformational freedom of the peptide backbone. Most peptides and proteins adopt a denatured conformation in the presence of high concentrations of denaturants or at elevated temperature. Peptides in denatured conformation have, for example, characteristic circular dichroism (CD) spectra and are characterized by a lack of long-range interactions as determined by NMR. “Denatured conformation” and “unstructured conformation” are used synonymously herein. In one embodiment, the invention provides XTEN sequences that, under physiologic conditions, can resemble denatured sequences largely devoid in secondary structure. In one embodiment, the XTEN sequences can be substantially devoid of secondary structure under physiologic conditions. “Largely devoid,” as used in this context, means that less than 50% of the XTEN amino acid residues of the XTEN sequence contribute to secondary structure as measured or determined by the means described herein. “Substantially devoid,” as used in this context, means that at least about 60%, or about 70%, or about 80%, or about 90%, or about 95%, or at least about 99% of the XTEN amino acid residues of the XTEN sequence do not contribute to secondary structure, as measured or determined by the means described herein. 
     A variety of methods have been established in the art to discern the presence or absence of secondary and tertiary structures in a given polypeptide. In particular, secondary structure can be measured spectrophotometrically, e.g., by circular dichroism spectroscopy in the “far-UV” spectral region (190-250 nm). Secondary structure elements, such as alpha-helix and beta-sheet, each give rise to a characteristic shape and magnitude of CD spectra. Secondary structure can also be predicted for a polypeptide sequence via certain computer programs or algorithms, such as the well-known Chou-Fasman algorithm (Chou, P. Y., et al. (1974)  Biochemistry,  13: 222-45) and the Garnier-Osguthorpe-Robson (“GOR”) algorithm (Gamier J, Gibrat J F, Robson B. (1996), GOR method for predicting protein secondary structure from amino acid sequence. Methods Enzymol 266:540-553), as described in US Patent Application Publication No. 20030228309A1. For a given sequence, the algorithms can predict whether there exists some or no secondary structure at all, expressed as the total and/or percentage of residues of the sequence that form, for example, alpha-helices or beta-sheets or the percentage of residues of the sequence predicted to result in random coil formation (which lacks secondary structure). 
     In one embodiment, the XTEN sequences used in the subject fusion protein compositions have an alpha-helix percentage ranging from 0% to less than about 5% as determined by the Chou-Fasman algorithm. In another embodiment, the XTEN sequences of the fusion protein compositions have a beta-sheet percentage ranging from 0% to less than about 5% as determined by the Chou-Fasman algorithm. In some embodiments, the XTEN sequences of the fusion protein compositions have an alpha-helix percentage ranging from 0% to less than about 5% and a beta-sheet percentage ranging from 0% to less than about 5% as determined by the Chou-Fasman algorithm. In one embodiment, the XTEN sequences of the fusion protein compositions have an alpha-helix percentage less than about 2% and a beta-sheet percentage less than about 2%. The XTEN sequences of the fusion protein compositions have a high degree of random coil percentage, as determined by the GOR algorithm. In some embodiments, an XTEN sequence have at least about 80%, more preferably at least about 90%, more preferably at least about 91%, more preferably at least about 92%, more preferably at least about 93%, more preferably at least about 94%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, and most preferably at least about 99% random coil, as determined by the GOR algorithm. In one embodiment, the XTEN sequences of the fusion protein compositions have an alpha-helix percentage ranging from 0% to less than about 5% and a beta-sheet percentage ranging from 0% to less than about 5% as determined by the Chou-Fasman algorithm and at least about 90% random coil, as determined by the GOR algorithm. In another embodiment, the XTEN sequences of the fusion protein compositions have an alpha-helix percentage less than about 2% and a beta-sheet percentage less than about 2% at least about 90% random coil, as determined by the GOR algorithm. 
     1. Non-Repetitive Sequences 
     It is specifically contemplated that the XTEN sequences of the binding fusion protein embodiments are substantially non-repetitive. In general, repetitive amino acid sequences have a tendency to aggregate or form higher order structures, as exemplified by natural repetitive sequences such as collagens and leucine zippers. These repetitive amino acids may also tend to form contacts resulting in crystalline or pseudocrystaline structures. In contrast, the low tendency of non-repetitive sequences to aggregate enables the design of long-sequence XTENs with a relatively low frequency of charged amino acids that would otherwise be likely to aggregate if the sequences were repetitive. In one embodiment, the XTEN sequences have greater than about 36 to about 1000 amino acid residues, or greater than about 100 to about 3000 amino acid residues in which no three contiguous amino acids in the sequence are identical amino acid types unless the amino acid is serine, in which case no more than three contiguous amino acids are serine residues. In the foregoing embodiment, the XTEN sequence is “substantially non-repetitive.” In another embodiment, as described more fully below, the XTEN sequences of the compositions comprise non-overlapping sequence motifs of 9 to 14 amino acid residues wherein the motifs consist of 4 to 6 types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the sequence of any two contiguous amino acid residues in any one motif is not repeated more than twice in the sequence motif. In the foregoing embodiment, the XTEN sequence is “substantially non-repetitive.” 
     The degree of repetitiveness of a polypeptide or a gene can be measured by computer programs or algorithms or by other means known in the art. According to the current invention, algorithms to be used in calculating the degree of repetitiveness of a particular polypeptide, such as an XTEN, are disclosed herein, and examples of sequences analyzed by algorithms are provided (see Examples, below). In one embodiment, the repetitiveness of a polypeptide of a predetermined length can be calculated (hereinafter “subsequence score”) according to the formula given by Equation I: 
                     Subsequence                 score     =         ∑     i   =   1     m          Count   i       m           I             wherein:  m =(amino acid length of polypeptide)−(amino acid length of subsequence)+1; and
         Count, =cumulative number of occurrences of each unique subsequence within sequence,       

     An algorithm termed “SegScore” was developed to apply the foregoing equation to quantitate repetitiveness of polypeptides, such as an XTEN, providing the subsequence score wherein sequences of a predetermined amino acid length are analyzed for repetitiveness by determining the number of times (a “count”) a unique subsequence of length “s” appears in the set length, divided by the absolute number of subsequences within the predetermined length of the sequence.  FIG. 37  depicts a logic flowchart of the SegScore algorithm, while  FIG. 38  portrays a schematic of how a subsequence score is derived for a fictitious XTEN with 11 amino acids and a subsequence length of 3 amino acid residues. For example, a predetermined polypeptide length of 200 amino acid residues has 192 overlapping 9-amino acid subsequences and 198 3-mer subsequences, but the subsequence score of any given polypeptide will depend on the absolute number of unique subsequences and how frequently each unique subsequence (meaning a different amino acid sequence) appears in the predetermined length of the sequence. In the context of the present invention wherein the algorithm is used to determine the degree of repetitiveness in a polypeptide, the variable “amino acid length of polypeptide” is set to 200 amino acids and the variable “amino acid length of subsequence” is set to 3 amino acids. Thus, the subsequence score will equal the sum of occurrences of each unique 3-mer frame across a 200 consecutive amino acid sequence of the polypeptide divided by the absolute number of unique 3-mer subsequences within the 200 amino acid sequence. Examples of such subsequence scores derived from the first 200 amino acids of repetitive and non-repetitive polypeptides are presented in Example 58. 
     In one embodiment, the present invention provides binding fusion proteins comprising one XTEN in which the XTEN has a subsequence score of less than 10, or less than 9, or less than 8, or less than 7, or less than 6, or less than 5, or less. In another embodiment, the invention provides binding fusion proteins comprising two more XTEN in which at least one XTEN has a subsequence score of less than 10, or less than 9, or less than 8, or less than 7, or less than 6, or less than 5, or less. In yet another embodiment, the invention provides binding fusion proteins comprising at least two XTEN in which each individual XTEN of 36 or more amino acids has a subsequence score of less than 10, or less than 9, or less than 8, or less than 7, or less than 6, or less than 5, or less. In the embodiments of this paragraph, the XTEN is characterized as “substantially non-repetitive.”. 
     It is believed that the non-repetitive characteristic of XTEN of the present invention contributes to many of the enhanced physicochemical and biological properties of the binding fusion proteins; either solely or in conjunction with the choice of the particular types of amino acids that predominate in the XTEN of the compositions disclosed herein. These properties include a higher degree of expression of the fusion protein in the host cell, greater genetic stability of the gene encoding XTEN, and a greater degree of solubility and less tendency to aggregate of the resulting binding fusion proteins compared to fusion proteins comprising polypeptides having repetitive sequences. These properties permit more efficient manufacturing, lower cost of goods, and facilitate the formulation of XTEN-comprising pharmaceutical preparations containing extremely high drug concentrations, in some cases exceeding 100 mg/ml. Furthermore, the XTEN polypeptide sequences of the embodiments are designed to have a low degree of internal repetitiveness in order to reduce or substantially eliminate immunogenicity when administered to a mammal. Polypeptide sequences composed of short, repeated motifs largely limited to only three amino acids, such as glycine, serine and glutamate, may result in relatively high antibody titers when administered to a mammal despite the absence of predicted T-cell epitopes in these sequences. This may be caused by the repetitive nature of polypeptides, as it has been shown that immunogens with repeated epitopes, including protein aggregates, cross-linked immunogens, and repetitive carbohydrates are highly immunogenic and can, for example, result in the cross-linking of B-cell receptors causing B-cell activation. (Johansson, J., et al. (2007) Vaccine, 25:1676-82; Yankai, Z., et al. (2006) Biochem Biophys Res Commun, 345:1365-71; Hsu, C. T., et al. (2000) Cancer Res, 60:3701-5); Bachmann M F, et al. Eur J Immunol. (1995) 25(12):3445-3451). 
     2. Exemplary Sequence Motifs 
     The present invention encompasses XTEN used as fusion partners that comprise multiple units of shorter sequences, or motifs, in which the amino acid sequences of the motifs are non-repetitive. The non-repetitive property is met despite the use of a “building block” approach using a library of sequence motifs that are multimerized to create the XTEN sequences. Thus, while an XTEN sequence may consist of multiple units of as few as four different types of sequence motifs, because the motifs themselves generally consist of non-repetitive amino acid sequences, the overall XTEN sequence is designed to render the sequence substantially non-repetitive. 
     In one embodiment, XTEN have a non-repetitive sequence of greater than about 36 to about 3000 amino acid residues wherein at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 97%, or about 100% of the XTEN sequence consists of non-overlapping sequence motifs, wherein each of the motifs has about 9 to 36 amino acid residues. In other embodiments, at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 97%, or about 100% of the XTEN sequence consists of non-overlapping sequence motifs wherein each of the motifs has 9 to 14 amino acid residues. In still other embodiments, at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 97%, or about 100% of the XTEN sequence component consists of non-overlapping sequence motifs wherein each of the motifs has 12 amino acid residues. In these embodiments, it is preferred that the sequence motifs be composed mainly or exclusively of small hydrophilic amino acids, such that the overall sequence has an unstructured, flexible characteristic. Examples of amino acids that are included in XTEN are, e.g., arginine, lysine, threonine, alanine, asparagine, glutamine, aspartate, glutamate, serine, and glycine. As a result of testing variables such as codon optimization, assembly polynucleotides encoding sequence motifs, expression of protein, charge distribution and solubility of expressed protein, and secondary and tertiary structure, it was discovered that XTEN compositions with enhanced characteristics mainly include glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues wherein the sequences are designed to be substantially non-repetitive. In one embodiment, XTEN sequences have predominately four to six types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) or proline (P) that are arranged in a substantially non-repetitive sequence that is greater than about 36 to about 3000 amino acid residues in length. In some embodiments, XTEN have sequences of greater than about 36 to about 3000 amino acid residues wherein at least about 80% of the sequence consists of non-overlapping sequence motifs wherein each of the motifs has 9 to 36 amino acid residues wherein each of the motifs consists of 4 to 6 types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the content of any one amino acid type in the full-length XTEN does not exceed 30%. In other embodiments, at least about 90% of the XTEN sequence consists of non-overlapping sequence motifs wherein each of the motifs has 9 to 36 amino acid residues wherein the motifs consist of 4 to 6 types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the content of any one amino acid type in the full-length XTEN does not exceed 30%. In other embodiments, at least about 90% of the XTEN sequence consists of non-overlapping sequence motifs wherein each of the motifs has 12 amino acid residues consisting of 4 to 6 types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the content of any one amino acid type in the full-length XTEN does not exceed 30%. In yet other embodiments, at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, to about 100% of the XTEN sequence consists of non-overlapping sequence motifs wherein each of the motifs has 12 amino acid residues consisting of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the content of any one amino acid type in the full-length XTEN does not exceed 30%. 
     In still other embodiments, XTENs comprise non-repetitive sequences of greater than about 36 to about 3000 amino acid residues wherein at least about 80%, or at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of the sequence consists of non-overlapping sequence motifs of 9 to 14 amino acid residues wherein the motifs consist of 4 to 6 types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the sequence of any two contiguous amino acid residues in any one motif is not repeated more than twice in the sequence motif. In other embodiments, at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of an XTEN sequence consists of non-overlapping sequence motifs of 12 amino acid residues wherein the motifs consist of four to six types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the sequence of any two contiguous amino acid residues in any one sequence motif is not repeated more than twice in the sequence motif. In other embodiments, at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of an XTEN sequence consists of non-overlapping sequence motifs of 12 amino acid residues wherein the motifs consist of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the sequence of any two contiguous amino acid residues in any one sequence motif is not repeated more than twice in the sequence motif. In yet other embodiments, XTENs consist of 12 amino acid sequence motifs wherein the amino acids are selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the sequence of any two contiguous amino acid residues in any one sequence motif is not repeated more than twice in the sequence motif, and wherein the content of any one amino acid type in the full-length XTEN does not exceed 30%. In the foregoing embodiments hereinabove described in this paragraph, the XTEN sequences are “substantially non-repetitive.” 
     In some embodiments, the invention provides compositions comprising one, or two, or three, or four or more non-repetitive XTEN sequence(s) of about 36 to about 1000 amino acid residues, or cumulatively about 100 to about 3000 amino acid residues wherein at least about 80%, or at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% to about 100% of the sequence consists of multiple units of two or more non-overlapping sequence motifs selected from the amino acid sequences of Table 3, wherein the overall sequence remains substantially non-repetitive. In some embodiments, the XTEN comprises non-overlapping sequence motifs in which about 80%, or at least about 85%, or at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% or about 100% of the sequence consists of multiple units of two or more non-overlapping sequences selected from a single motif family selected from Table 3, resulting in a family sequence. As used herein, “family” means that the XTEN has motifs selected only from a single motif category from Table 3; i.e., AD, AE, AF, AG, AM, AQ, BC, or BD XTEN, and that any other amino acids in the XTEN not from a family motif are selected to achieve a needed property, such as to permit incorporation of a restriction site by the encoding nucleotides, incorporation of a cleavage sequence, or to achieve a better linkage to an binding protein component. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 XTEN Sequence Motifs of 12 Amino Acids and Motif 
               
               
                 Families 
               
            
           
           
               
               
               
            
               
                 Motif Family* 
                 MOTIF SEQUENCE 
                 SEQ ID NO: 
               
               
                   
               
            
           
           
               
               
               
            
               
                 AD 
                 GESPGGSSGSES 
                 2 
               
               
                   
               
               
                 AD 
                 GSEGSSGPGESS 
                 3 
               
               
                   
               
               
                 AD 
                 GSSESGSSEGGP 
                 4 
               
               
                   
               
               
                 AD 
                 GSGGEPSESGSS 
                 5 
               
               
                   
               
               
                 AE, AM 
                 GSPAGSPTSTEE 
                 6 
               
               
                   
               
               
                 AE, AM, AQ 
                 GSEPATSGSETP 
                 7 
               
               
                   
               
               
                 AE, AM, AQ 
                 GTSESATPESGP 
                 8 
               
               
                   
               
               
                 AE, AM, AQ 
                 GTSTEPSEGSAP 
                 9 
               
               
                   
               
               
                 AF, AM 
                 GSTSESPSGTAP 
                 10 
               
               
                   
               
               
                 AF, AM 
                 GTSTPESGSASP 
                 11 
               
               
                   
               
               
                 AF, AM 
                 GTSPSGESSTAP 
                 12 
               
               
                   
               
               
                 AF, AM 
                 GSTSSTAESPGP 
                 13 
               
               
                   
               
               
                 AG, AM 
                 GTPGSGTASSSP 
                 14 
               
               
                   
               
               
                 AG, AM 
                 GSSTPSGATGSP 
                 15 
               
               
                   
               
               
                 AG, AM 
                 GSSPSASTGTGP 
                 16 
               
               
                   
               
               
                 AG, AM 
                 GASPGTSSTGSP 
                 17 
               
               
                   
               
               
                 AQ 
                 GEPAGSPTSTSE 
                 18 
               
               
                   
               
               
                 AQ 
                 GTGEPSSTPASE 
                 19 
               
               
                   
               
               
                 AQ 
                 GSGPSTESAPTE 
                 20 
               
               
                   
               
               
                 AQ 
                 GSETPSGPSETA 
                 21 
               
               
                   
               
               
                 AQ 
                 GPSETSTSEPGA 
                 22 
               
               
                   
               
               
                 AQ 
                 GSPSEPTEGTSA 
                 23 
               
               
                   
               
               
                 BC 
                 GSGASEPTSTEP 
                 24 
               
               
                   
               
               
                 BC 
                 GSEPATSGTEPS 
                 25 
               
               
                   
               
               
                 BC 
                 GTSEPSTSEPGA 
                 26 
               
               
                   
               
               
                 BC 
                 GTSTEPSEPGSA 
                 27 
               
               
                   
               
               
                 BD 
                 GSTAGSETSTEA 
                 28 
               
               
                   
               
               
                 BD 
                 GSETATSGSETA 
                 29 
               
               
                   
               
               
                 BD 
                 GTSESATSESGA 
                 30 
               
               
                   
               
               
                 BD 
                 GTSTEASEGSAS 
                 31 
               
               
                   
               
               
                 *Denotes individual motif sequences that, when used together in various permutations, results in a “family sequence”  
               
            
           
         
       
     
     In some embodiments of XTEN families, an XTEN sequence comprises multiple units of non-overlapping sequence motifs of the AD motif family, or an XTEN sequence comprises multiple units of non-overlapping sequence motifs of the AE motif family, or an XTEN sequence comprises multiple units of non-overlapping sequence motifs of the AF motif family, or an XTEN sequence comprises multiple units of non-overlapping sequence motifs of the AG motif family, or an XTEN sequence comprises multiple units of non-overlapping sequence motifs of the AM motif family, or an XTEN sequence comprises multiple units of non-overlapping sequence motifs of the AQ motif family, or an XTEN sequence comprises multiple units of non-overlapping sequence motifs of the BC family, or an XTEN sequence comprises multiple units of non-overlapping sequence motifs of the BD family, with the resulting XTEN exhibiting the range of homology described above. In other embodiments, the XTEN comprises multiple units of motif sequences from two or more of the motif families of Table 3, selected to achieve desired physicochemical characteristics, including such properties as net charge, lack of secondary structure, or lack of repetitiveness that may be conferred by the amino acid composition of the motifs, described more fully below. In the embodiments hereinabove described in this paragraph, the motifs incorporated into the XTEN can be selected and assembled using the methods described herein to achieve an XTEN of about 36 to about 3000 amino acid residues. Non-limiting examples of XTEN family sequences are presented in Table 4. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 XTEN Polypeptides 
               
            
           
           
               
               
               
            
               
                 XTEN 
                   
                 SEQ ID 
               
               
                 Name 
                 Amino Acid Sequence 
                 NO: 
               
               
                   
               
            
           
           
               
               
               
            
               
                 AE42_1 
                 TEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGS 
                 32 
               
               
                   
               
               
                 AE42_2 
                 PAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSG 
                 33 
               
               
                   
               
               
                 AE42_3 
                 SEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSP 
                 34 
               
               
                   
               
               
                 AG42_1 
                 GAPSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGPSGP 
                 35 
               
               
                   
               
               
                 AG42_2 
                 GPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGASP 
                 36 
               
               
                   
               
               
                 AG42_3 
                 SPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGA 
                 37 
               
               
                   
               
               
                 AG42_4 
                 SASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATG 
                 38 
               
               
                   
               
               
                 AE48 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGS 
                 39 
               
               
                   
               
               
                 AM48 
                 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGS 
                 40 
               
               
                   
               
               
                 AE144 
                 GSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEG 
                 41 
               
               
                   
                 SAPGSEPATSGSETPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSESA 
                   
               
               
                   
                 TPESGPGSEPATSGSETPGTSTEPSEGSAP 
                   
               
               
                   
               
               
                 AF144 
                 GTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGSTSESPSG 
                 42 
               
               
                   
                 TAPGSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASPGSTSSTAESPGPGTSPSG 
                   
               
               
                   
                 ESSTAPGTSPSGESSTAPGTSPSGESSTAP 
                   
               
               
                   
               
               
                 AG144_ 
                 PGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSSPSAST 
                 43 
               
               
                 1 
                 GTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGASP 
                   
               
               
                   
                 GTSSTGSPGASPGTSSTGSPGTPGSGTASSS 
                   
               
               
                   
               
               
                 AG144_ 
                 SGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSP 
                 44 
               
               
                 2 
                 GSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGA 
                   
               
               
                   
                 TGSPGSSPSASTGTGPGSSPSASTGTGPGASP 
                   
               
               
                   
               
               
                 AG144_ 
                 GTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSAST 
                 45 
               
               
                 3 
                 GTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSP 
                   
               
               
                   
                 SASTGTGPGASPGTSSTGSPGASPGTSSTGSP 
                   
               
               
                   
               
               
                 AG144_ 
                 GTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSS 
                 46 
               
               
                 4 
                 TGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSSPS 
                   
               
               
                   
                 ASTGTGPGTPGSGTASSSPGSSTPSGATGSP 
                   
               
               
                   
               
               
                 AE288 
                 GTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPE 
                 47 
               
               
                   
                 SGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESA 
                   
               
               
                   
                 TPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEG 
                   
               
               
                   
                 SAP 
                   
               
               
                   
               
               
                 AG288_ 
                 ASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGTP 
                 48 
               
               
                 1 
                 GSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSS 
                   
               
               
                   
                 PGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTS 
                   
               
               
                   
                 STGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGAS 
                   
               
               
                   
                 PGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSP 
                   
               
               
                   
                 GSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGS 
                   
               
               
                   
               
               
                 AG288_ 
                 PGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGT 
                 49 
               
               
                 2 
                 ASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSP 
                   
               
               
                   
                 SASTGTGPGSSPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSP 
                   
               
               
                   
                 GSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGA 
                   
               
               
                   
                 TGSPGSSPSASTGTGPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGSSTP 
                   
               
               
                   
                 SGATGS 
                   
               
               
                   
               
               
                 AG288_ 
                 GSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSSPSAST 
                 50 
               
               
                 3 
                 GTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGASP 
                   
               
               
                   
                 GTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSP 
                   
               
               
                   
                 GTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSGA 
                   
               
               
                   
                 TGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGTPG 
                   
               
               
                   
                 SGTASSSP 
                   
               
               
                   
               
               
                 AF504 
                 GASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGA 
                 51 
               
               
                   
                 TGSPGSXPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPG 
                   
               
               
                   
                 SGTASSSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSP 
                   
               
               
                   
                 GASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSXPSASTGTGPGSSPSAST 
                   
               
               
                   
                 GTGPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASP 
                   
               
               
                   
                 GTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSP 
                   
               
               
                   
                 GSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSS 
                   
               
               
                   
                 TGSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTP 
                   
               
               
                   
                 SGATGSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSP 
                   
               
               
                   
               
               
                 AF540 
                 GSTSSTAESPGPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGSTSSTAES 
                 52 
               
               
                   
                 PGPGTSTPESGSASPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSES 
                   
               
               
                   
                 PSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGST 
                   
               
               
                   
                 SESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSTSESPSGTAP 
                   
               
               
                   
                 GTSTPESGSASPGSTSSTAESPGPGSTSSTAESPGPGTSTPESGSASPGTSTPESGS 
                   
               
               
                   
                 ASPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGSTSES 
                   
               
               
                   
                 PSGTAPGSTSESPSGTAPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSASPGST 
                   
               
               
                   
                 SESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAP 
                   
               
               
                   
                 GTSTPESGSASPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGSTSSTAES 
                   
               
               
                   
                 PGPGTSTPESGSASPGSTSESPSGTAP 
                   
               
               
                   
               
               
                 AD576 
                 GSSESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSSESGSSEGGPGSSESGSSE 
                 53 
               
               
                   
                 GGPGSSESGSSEGGPGSSESGSSEGGPGESPGGSSGSESGSEGSSGPGESSGSSES 
                   
               
               
                   
                 GSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSGGEPSESGSSGESPGGSSGSESG 
                   
               
               
                   
                 ESPGGSSGSESGSGGEPSESGSSGSSESGSSEGGPGSGGEPSESGSSGSGGEPSES 
                   
               
               
                   
                 GSSGSEGSSGPGESSGESPGGSSGSESGSGGEPSESGSSGSGGEPSESGSSGSGGE 
                   
               
               
                   
                 PSESGSSGSSESGSSEGGPGESPGGSSGSESGESPGGSSGSESGESPGGSSGSESGE 
                   
               
               
                   
                 SPGGSSGSESGESPGGSSGSESGSSESGSSEGGPGSGGEPSESGSSGSEGSSGPGE 
                   
               
               
                   
                 SSGSSESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSGGEPSESGSSGESPGG 
                   
               
               
                   
                 SSGSESGESPGGSSGSESGSSESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGS 
                   
               
               
                   
                 GGEPSESGSSGSGGEPSESGSSGESPGGSSGSESGSEGSSGPGESSGSSESGSSEG 
                   
               
               
                   
                 GPGSEGSSGPGESS 
                   
               
               
                   
               
               
                 AE576 
                 GSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEG 
                 54 
               
               
                   
                 SAPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGS 
                   
               
               
                   
                 PTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGP 
                   
               
               
                   
                 GSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPE 
                   
               
               
                   
                 SGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 TEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETP 
                   
               
               
                   
                 GTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEP 
                   
               
               
                   
                 SEGSAP 
                   
               
               
                   
               
               
                 AF576 
                 GSTSSTAESPGPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGSTSSTAES 
                 55 
               
               
                   
                 PGPGTSTPESGSASPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSES 
                   
               
               
                   
                 PSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGST 
                   
               
               
                   
                 SESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSTSESPSGTAP 
                   
               
               
                   
                 GTSTPESGSASPGSTSSTAESPGPGSTSSTAESPGPGTSTPESGSASPGTSTPESGS 
                   
               
               
                   
                 ASPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGSTSES 
                   
               
               
                   
                 PSGTAPGSTSESPSGTAPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSASPGST 
                   
               
               
                   
                 SESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAP 
                   
               
               
                   
                 GTSTPESGSASPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGSTSSTAES 
                   
               
               
                   
                 PGPGTSTPESGSASPGSTSESPSGTAPGSTSSTAESPGPGTSTPESGSASPGTSTPE 
                   
               
               
                   
                 SGSASP 
                   
               
               
                   
               
               
                 AG576 
                 PGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSG 
                 56 
               
               
                   
                 ATGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGTP 
                   
               
               
                   
                 GSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSPSASTGTG 
                   
               
               
                   
                 PGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSTPSG 
                   
               
               
                   
                 ATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSS 
                   
               
               
                   
                 TPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGS 
                   
               
               
                   
                 PGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTS 
                   
               
               
                   
                 STGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTP 
                   
               
               
                   
                 GSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTG 
                   
               
               
                   
                 PGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSAST 
                   
               
               
                   
                 GTGPGASPGTSSTGS 
                   
               
               
                   
               
               
                 AE624 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSP 
                 57 
               
               
                   
                 TSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTST 
                   
               
               
                   
                 EPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEG 
                   
               
               
                   
                 TSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATS 
                   
               
               
                   
                 GSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPA 
                   
               
               
                   
                 GSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESAT 
                   
               
               
                   
                 PESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPA 
                   
               
               
                   
                 GSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAP 
                   
               
               
                   
               
               
                 AD836 
                 GSSESGSSEGGPGSSESGSSEGGPGESPGGSSGSESGSGGEPSESGSSGESPGGSS 
                 58 
               
               
                   
                 GSESGESPGGSSGSESGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGESP 
                   
               
               
                   
                 GGSSGSESGESPGGSSGSESGESPGGSSGSESGSSESGSSEGGPGSSESGSSEGGP 
                   
               
               
                   
                 GSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSGGEPSE 
                   
               
               
                   
                 SGSSGESPGGSSGSESGESPGGSSGSESGSGGEPSESGSSGSEGSSGPGESSGSSES 
                   
               
               
                   
                 GSSEGGPGSGGEPSESGSSGSEGSSGPGESSGSSESGSSEGGPGSGGEPSESGSSG 
                   
               
               
                   
                 ESPGGSSGSESGSGGEPSESGSSGSGGEPSESGSSGSSESGSSEGGPGSGGEPSES 
                   
               
               
                   
                 GSSGSGGEPSESGSSGSEGSSGPGESSGESPGGSSGSESGSEGSSGPGESSGSEGS 
                   
               
               
                   
                 SGPGESSGSGGEPSESGSSGSSESGSSEGGPGSSESGSSEGGPGESPGGSSGSESG 
                   
               
               
                   
                 SGGEPSESGSSGSEGSSGPGESSGESPGGSSGSESGSEGSSGPGSSESGSSEGGPG 
                   
               
               
                   
                 SGGEPSESGSSGSEGSSGPGESSGSEGSSGPGESSGSEGSSGPGESSGSGGEPSES 
                   
               
               
                   
                 GSSGSGGEPSESGSSGESPGGSSGSESGESPGGSSGSESGSGGEPSESGSSGSEGS 
                   
               
               
                   
                 SGPGESSGESPGGSSGSESGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPG 
                   
               
               
                   
                 SGGEPSESGSSGSSESGSSEGGPGESPGGSSGSESGSGGEPSESGSSGSSESGSSEG 
                   
               
               
                   
                 GPGESPGGSSGSESGSGGEPSESGSSGESPGGSSGSESGSGGEPSESGSS 
                   
               
               
                   
               
               
                 AE864 
                 GSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEG 
                 59 
               
               
                   
                 SAPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGS 
                   
               
               
                   
                 PTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGP 
                   
               
               
                   
                 GSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPE 
                   
               
               
                   
                 SGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 TEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETP 
                   
               
               
                   
                 GTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETP 
                   
               
               
                   
                 GTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGS 
                   
               
               
                   
                 PTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAP 
                   
               
               
                   
               
               
                 AF864 
                 GSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGS 
                 60 
               
               
                   
                 ASPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSES 
                   
               
               
                   
                 PSGTAPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTS 
                   
               
               
                   
                 PSGESSTAPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAP 
                   
               
               
                   
                 GSTSESPSGTAPGTSTPESGSASPGSTSSTAESPGPGTSTPESGSASPGSTSESPSG 
                   
               
               
                   
                 TAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASPGSTSST 
                   
               
               
                   
                 AESPGPGSTSSTAESPGPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGST 
                   
               
               
                   
                 SESPSGTAPGSTSESPSGTAPGTSTPESGPXXXGASASGAPSTXXXXSESPSGTAP 
                   
               
               
                   
                 GSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSG 
                   
               
               
                   
                 TAPGTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSG 
                   
               
               
                   
                 ESSTAPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGST 
                   
               
               
                   
                 SESPSGTAPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGTSTPESGSASP 
                   
               
               
                   
                 GSTSSTAESPGPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSSTAES 
                   
               
               
                   
                 PGPGTSPSGESSTAPGTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGTSPSG 
                   
               
               
                   
                 ESSTAPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSSPSASTGTGPGSS 
                   
               
               
                   
                 TPSGATGSPGSSTPSGATGSP 
                   
               
               
                   
               
               
                 AG864 
                 GASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGA 
                 61 
               
               
                   
                 TGSPGSSPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPG 
                   
               
               
                   
                 SGTASSSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSP 
                   
               
               
                   
                 GASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSAST 
                   
               
               
                   
                 GTGPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASP 
                   
               
               
                   
                 GTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSP 
                   
               
               
                   
                 GSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSS 
                   
               
               
                   
                 TGSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTP 
                   
               
               
                   
                 SGATGSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPG 
                   
               
               
                   
                 ASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSST 
                   
               
               
                   
                 GSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPS 
                   
               
               
                   
                 GATGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGS 
                   
               
               
                   
                 SPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSAS 
                   
               
               
                   
                 TGTGPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSS 
                   
               
               
                   
                 TPSGATGSPGASPGTSSTGSP 
                   
               
               
                   
               
               
                 AM875 
                 GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGS 
                 62 
               
               
                   
                 ASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPAT 
                   
               
               
                   
                 SGSETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAP 
                   
               
               
                   
                 GTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGS 
                   
               
               
                   
                 GTASSSPGSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGS 
                   
               
               
                   
                 PAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGASASGAPSTGGTSESATPESG 
                   
               
               
                   
                 PGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSGES 
                   
               
               
                   
                 STAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSEPATSGSETPGTSES 
                   
               
               
                   
                 ATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGS 
                   
               
               
                   
                 EPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESPGPGTSTPESGSAS 
                   
               
               
                   
                 PGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSSTPSGA 
                   
               
               
                   
                 TGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGSPA 
                   
               
               
                   
                 GSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSTEPSEGSAP 
                   
               
               
                   
               
               
                 AE912 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSP 
                 63 
               
               
                   
                 TSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTST 
                   
               
               
                   
                 EPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEG 
                   
               
               
                   
                 TSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATS 
                   
               
               
                   
                 GSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPA 
                   
               
               
                   
                 GSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESAT 
                   
               
               
                   
                 PESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPA 
                   
               
               
                   
                 GSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
                 TSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESAT 
                   
               
               
                   
                 PESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSE 
                   
               
               
                   
                 SATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEG 
                   
               
               
                   
                 TSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 AP 
                   
               
               
                   
               
               
                 AM923 
                 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGTSTEPS 
                 64 
               
               
                   
                 EGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTS 
                   
               
               
                   
                 ESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESAT 
                   
               
               
                   
                 PESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTST 
                   
               
               
                   
                 EPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPG 
                   
               
               
                   
                 SSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTST 
                   
               
               
                   
                 EEGSPAGSPTSTEEGTSTEPSEGSAPGASASGAPSTGGTSESATPESGPGSPAGSP 
                   
               
               
                   
                 TSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESSTAPGTPG 
                   
               
               
                   
                 SGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSEPATSGSETPGTSESATPESGPG 
                   
               
               
                   
                 SEPATSGSETPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSEPATSGSE 
                   
               
               
                   
                 TPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESPGPGTSTPESGSASPGSTSESP 
                   
               
               
                   
                 SGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSSTPSGATGSPGSSP 
                   
               
               
                   
                 SASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEE 
                   
               
               
                   
                 GSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPGTSTEPSEG 
                   
               
               
                   
                 SAPGTSTEPSEGSAP 
                   
               
               
                   
               
               
                 AM131 
                 GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGS 
                 65 
               
               
                 8 
                 ASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPAT 
                   
               
               
                   
                 SGSETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAP 
                   
               
               
                   
                 GTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGS 
                   
               
               
                   
                 GTASSSPGSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGS 
                   
               
               
                   
                 PAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGPEPTGPAPSGGSEPATSGSETP 
                   
               
               
                   
                 GTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTS 
                   
               
               
                   
                 TEEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSES 
                   
               
               
                   
                 PSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGTSESATPESGP 
                   
               
               
                   
                 GTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSPSGESS 
                   
               
               
                   
                 TAPGTSPSGESSTAPGTSPSGESSTAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEP 
                   
               
               
                   
                 SEGSAPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGS 
                   
               
               
                   
                 STPSGATGSPGASPGTSSTGSPGASASGAPSTGGTSPSGESSTAPGSTSSTAESPG 
                   
               
               
                   
                 PGTSPSGESSTAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSSPSAST 
                   
               
               
                   
                 GTGPGSSTPSGATGSPGASPGTSSTGSPGTSTPESGSASPGTSPSGESSTAPGTSPS 
                   
               
               
                   
                 GESSTAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGSTSESPSGTAPGS 
                   
               
               
                   
                 TSESPSGTAPGTSTPESGSASPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSA 
                   
               
               
                   
                 PGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGSSTPSGATGSPGASPGTSS 
                   
               
               
                   
                 TGSPGSSTPSGATGSPGSTSESPSGTAPGTSPSGESSTAPGSTSSTAESPGPGSSTP 
                   
               
               
                   
                 SGATGSPGASPGTSSTGSPGTPGSGTASSSPGSPAGSPTSTEEGSPAGSPTSTEEG 
                   
               
               
                   
                 TSTEPSEGSAP 
                   
               
               
                   
               
               
                 BC 864 
                 GTSTEPSEPGSAGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGSEPATSGT 
                 66 
               
               
                   
                 EPSGSEPATSGTEPSGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPAT 
                   
               
               
                   
                 SGTEPSGTSTEPSEPGSAGSEPATSGTEPSGSEPATSGTEPSGTSTEPSEPGSAGTS 
                   
               
               
                   
                 TEPSEPGSAGSEPATSGTEPSGSEPATSGTEPSGTSEPSTSEPGAGSGASEPTSTEP 
                   
               
               
                   
                 GTSEPSTSEPGAGSEPATSGTEPSGSEPATSGTEPSGTSTEPSEPGSAGTSTEPSEP 
                   
               
               
                   
                 GSAGSGASEPTSTEPGSEPATSGTEPSGSEPATSGTEPSGSEPATSGTEPSGSEPA 
                   
               
               
                   
                 TSGTEPSGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGS 
                   
               
               
                   
                 EPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSGASEPTSTEPGSEPATSGTEP 
                   
               
               
                   
                 SGSGASEPTSTEPGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPATSG 
                   
               
               
                   
                 TEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPATSGTEPSGTSTEPSEPGSAGSEPA 
                   
               
               
                   
                 TSGTEPSGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPSEPGSAGT 
                   
               
               
                   
                 STEPSEPGSAGTSTEPSEPGSAGTSEPSTSEPGAGSGASEPTSTEPGTSTEPSEPGS 
                   
               
               
                   
                 AGTSTEPSEPGSAGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGSEPATS 
                   
               
               
                   
                 GTEPSGSEPATSGTEPSGSEPATSGTEPSGSEPATSGTEPSGTSEPSTSEPGAGSEP 
                   
               
               
                   
                 ATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPG 
                   
               
               
                   
                 TSTEPSEPGSA 
                   
               
               
                   
               
               
                 BD864 
                 GSETATSGSETAGTSESATSESGAGSTAGSETSTEAGTSESATSESGAGSETATS 
                 67 
               
               
                   
                 GSETAGSETATSGSETAGTSTEASEGSASGTSTEASEGSASGTSESATSESGAGS 
                   
               
               
                   
                 ETATSGSETAGTSTEASEGSASGSTAGSETSTEAGTSESATSESGAGTSESATSES 
                   
               
               
                   
                 GAGSETATSGSETAGTSESATSESGAGTSTEASEGSASGSETATSGSETAGSETA 
                   
               
               
                   
                 TSGSETAGTSTEASEGSASGSTAGSETSTEAGTSESATSESGAGTSTEASEGSAS 
                   
               
               
                   
                 GSETATSGSETAGSTAGSETSTEAGSTAGSETSTEAGSETATSGSETAGTSESAT 
                   
               
               
                   
                 SESGAGTSESATSESGAGSETATSGSETAGTSESATSESGAGTSESATSESGAGS 
                   
               
               
                   
                 ETATSGSETAGSETATSGSETAGTSTEASEGSASGSTAGSETSTEAGSETATSGS 
                   
               
               
                   
                 ETAGTSESATSESGAGSTAGSETSTEAGSTAGSETSTEAGSTAGSETSTEAGTST 
                   
               
               
                   
                 EASEGSASGSTAGSETSTEAGSTAGSETSTEAGTSTEASEGSASGSTAGSETSTE 
                   
               
               
                   
                 AGSETATSGSETAGTSTEASEGSASGTSESATSESGAGSETATSGSETAGTSESA 
                   
               
               
                   
                 TSESGAGTSESATSESGAGSETATSGSETAGTSESATSESGAGSETATSGSETAG 
                   
               
               
                   
                 TSTEASEGSASGTSTEASEGSASGSTAGSETSTEAGSTAGSETSTEAGSETATSGS 
                   
               
               
                   
                 ETAGTSESATSESGAGTSESATSESGAGSETATSGSETAGSETATSGSETAGSET 
                   
               
               
                   
                 ATSGSETAGTSTEASEGSASGTSESATSESGAGSETATSGSETAGSETATSGSET 
                   
               
               
                   
                 AGTSESATSESGAGTSESATSESGAGSETATSGSETA 
                   
               
               
                   
               
               
                 AE948 
                 GTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEG 
                 68 
               
               
                   
                 SAPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSESA 
                   
               
               
                   
                 TPESGPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 TEPSEGSAPGSEPATSGSETPGTSTEPSEGSAPGSEPATSGSETPGSEPATSGSETP 
                   
               
               
                   
                 GTSTEPSEGSAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSEPATSGS 
                   
               
               
                   
                 ETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGTSESA 
                   
               
               
                   
                 TPESGPGSEPATSGSETPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 ESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAP 
                   
               
               
                   
                 GTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSPAGSPTS 
                   
               
               
                   
                 TEEGSPAGSPTSTEEGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGSPAGS 
                   
               
               
                   
                 PTSTEEGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSEPATSGSETPGSEPATSGSETP 
                   
               
               
                   
                 GSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTS 
                   
               
               
                   
                 TEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTS 
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAP 
                   
               
               
                   
                 GTSTEPSEGSAPGTSESATPESGPGTSESATPESGP 
                   
               
               
                   
               
               
                 AE1044 
                 GSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTS 
                 69 
               
               
                   
                 TEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPAT 
                   
               
               
                   
                 SGSETPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGSE 
                   
               
               
                   
                 PATSGSETPGTSTEPSEGSAPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEE 
                   
               
               
                   
                 GTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSESATPE 
                   
               
               
                   
                 SGPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGTSTEPSEGSAPGTSESA 
                   
               
               
                   
                 TPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETP 
                   
               
               
                   
                 GTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSESA 
                   
               
               
                   
                 TPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGSEPATSGSETPGSEPATSGSETPGTSESATPESGPGTSESATPESGP 
                   
               
               
                   
                 GTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGSPAGSPTS 
                   
               
               
                   
                 TEEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSEPAT 
                   
               
               
                   
                 SGSETPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSESATPE 
                   
               
               
                   
                 SGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGTSESATPESGPGTST 
                   
               
               
                   
               
               
                 AE1140 
                 GSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSEPATSGSETPGTSESATPE 
                 70 
               
               
                   
                 SGPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSE 
                   
               
               
                   
                 PATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEE 
                   
               
               
                   
                 GTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEG 
                   
               
               
                   
                 SAPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSESA 
                   
               
               
                   
                 TPESGPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGSPAGSPTSTEEGSP 
                   
               
               
                   
                 AGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGSEPATSGSETP 
                   
               
               
                   
                 GTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEG 
                   
               
               
                   
                 SAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSEPAT 
                   
               
               
                   
                 SGSETPGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGSE 
                   
               
               
                   
                 PATSGSETPGSEPATSGSETPGSEPATSGSETPGTSESATPESGPGTSESATPESGP 
                   
               
               
                   
                 GTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGSPAGSPTSTEEGSPA 
                   
               
               
                   
               
               
                 AE1236 
                 GSPAGSPTSTEEGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGS 
                 71 
               
               
                   
                 ETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEP 
                   
               
               
                   
                 SEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 TEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAP 
                   
               
               
                   
                 GSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTS 
                   
               
               
                   
                 TEEGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGTSESATPESGPGSPAGS 
                   
               
               
                   
                 PTSTEEGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEG 
                   
               
               
                   
                 SAPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSEPAT 
                   
               
               
                   
                 SGSETPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSP 
                   
               
               
                   
                 AGSPTSTEEGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETP 
                   
               
               
                   
                 GTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEG 
                   
               
               
                   
                 SAPGSEPATSGSETPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGS 
                   
               
               
                   
                 PTSTEEGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGSEPATSGSETPGTSTEPSEGSAPGSPAGSPTSTEE 
                   
               
               
                   
                 GSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTS 
                   
               
               
                   
                 TEEGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGSEP 
                   
               
               
                   
               
               
                 AE1332 
                 GSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSEPATSGS 
                 72 
               
               
                   
                 ETPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESA 
                   
               
               
                   
                 TPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSE 
                   
               
               
                   
                 PATSGSETPGSEPATSGSETPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSESATPESGPGSPAGSPTS 
                   
               
               
                   
                 TEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEP 
                   
               
               
                   
                 SEGSAPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAP 
                   
               
               
                   
                 GTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGS 
                   
               
               
                   
                 ETPGSEPATSGSETPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSESA 
                   
               
               
                   
                 TPESGPGSEPATSGSETPGSEPATSGSETPGTSESATPESGPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETP 
                   
               
               
                   
                 GSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPE 
                   
               
               
                   
                 SGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGTSESATPESGPGTSTEP 
                   
               
               
                   
                 SEGSAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGSP 
                   
               
               
                   
                 AGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGSPAGSPTSTEE 
                   
               
               
                   
                 GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGSEPATSGS 
                   
               
               
                   
                 ETPGSEPATSGSETPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTST 
                   
               
               
                   
               
               
                 AE1428 
                 GSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGTSESATPE 
                 73 
               
               
                   
                 SGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEP 
                   
               
               
                   
                 SEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTS 
                   
               
               
                   
                 ESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETP 
                   
               
               
                   
                 GTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGSPAGS 
                   
               
               
                   
                 PTSTEEGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGSP 
                   
               
               
                   
                 AGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGSEPATSGSETP 
                   
               
               
                   
                 GTSTEPSEGSAPGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSEPATSGS 
                   
               
               
                   
                 ETPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGTSESA 
                   
               
               
                   
                 TPESGPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGP 
                   
               
               
                   
                 GTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGS 
                   
               
               
                   
                 ETPGTSTEPSEGSAPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGS 
                   
               
               
                   
                 PTSTEEGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPE 
                   
               
               
                   
                 SGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSPA 
                   
               
               
                   
               
               
                 AE1524 
                 GTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTS 
                 74 
               
               
                   
                 TEEGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSESA 
                   
               
               
                   
                 TPESGPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 TEPSEGSAPGSEPATSGSETPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAP 
                   
               
               
                   
                 GSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSEPATSGS 
                   
               
               
                   
                 ETPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGSEPAT 
                   
               
               
                   
                 SGSETPGTSTEPSEGSAPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGSE 
                   
               
               
                   
                 PATSGSETPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSEPATSGS 
                   
               
               
                   
                 ETPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEP 
                   
               
               
                   
                 SEGSAPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSTEPSEGSAPGSEPATSGSETPGSEPATSGSETPGSEPATSGSETPGTSESATPE 
                   
               
               
                   
                 SGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTS 
                   
               
               
                   
                 ESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGP 
                   
               
               
                   
                 GSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGTSTEPSEG 
                   
               
               
                   
                 SAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGSPA 
                   
               
               
                   
               
               
                 AE1620 
                 GSEPATSGSETPGTSTEPSEGSAPGSEPATSGSETPGTSTEPSEGSAPGTSESATPE 
                 75 
               
               
                   
                 SGPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESA 
                   
               
               
                   
                 TPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 ESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETP 
                   
               
               
                   
                 GTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGS 
                   
               
               
                   
                 ETPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGTSESA 
                   
               
               
                   
                 TPESGPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEE 
                   
               
               
                   
                 GSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGTSTEPSEG 
                   
               
               
                   
                 SAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGSPAGS 
                   
               
               
                   
                 PTSTEEGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 TEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSESATPE 
                   
               
               
                   
                 SGPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSTEP 
                   
               
               
                   
                 SEGSAPGSEPATSGSETPGSEPATSGSETPGTSESATPESGPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSESATPESGP 
                   
               
               
                   
                 GTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGSPAGSPTS 
                   
               
               
                   
                 TEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTST 
                   
               
               
                   
               
               
                 AE1716 
                 GTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGS 
                 76 
               
               
                   
                 ETPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGTSESA 
                   
               
               
                   
                 TPESGPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSEPATSGSETPGTS 
                   
               
               
                   
                 ESATPESGPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEE 
                   
               
               
                   
                 GSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSESATPE 
                   
               
               
                   
                 SGPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSESA 
                   
               
               
                   
                 TPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSP 
                   
               
               
                   
                 AGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGP 
                   
               
               
                   
                 GSEPATSGSETPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESA 
                   
               
               
                   
                 TPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGSP 
                   
               
               
                   
                 AGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSEPATSGSETPGTSESATPESGP 
                   
               
               
                   
                 GSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTS 
                   
               
               
                   
                 TEEGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGSEPAT 
                   
               
               
                   
                 SGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAP 
                   
               
               
                   
                 GSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTS 
                   
               
               
                   
                 TEEGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSE 
                   
               
               
                   
               
               
                 AE1812 
                 GTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSEPATSGS 
                 77 
               
               
                   
                 ETPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEP 
                   
               
               
                   
                 SEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSP 
                   
               
               
                   
                 AGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAP 
                   
               
               
                   
                 GTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTS 
                   
               
               
                   
                 TEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPAT 
                   
               
               
                   
                 SGSETPGTSTEPSEGSAPGSEPATSGSETPGSEPATSGSETPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAP 
                   
               
               
                   
                 GSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSEPAT 
                   
               
               
                   
                 SGSETPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGP 
                   
               
               
                   
                 GSEPATSGSETPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSESATPE 
                   
               
               
                   
                 SGPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESA 
                   
               
               
                   
                 TPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 ESATPESGPGSEPATSGSETPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAP 
                   
               
               
                   
                 GSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGS 
                   
               
               
                   
                 ETPGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGSEP 
                   
               
               
                   
               
               
                 AE1908 
                 GSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEG 
                 78 
               
               
                   
                 SAPGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGSEPAT 
                   
               
               
                   
                 SGSETPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSFEE 
                   
               
               
                   
                 GSPAGSPTSTEEGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEG 
                   
               
               
                   
                 SAPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSEPATSGSETPGSEPAT 
                   
               
               
                   
                 SGSETPGSEPATSGSETPGTSESATPESGPGTSESATPESGPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEG 
                   
               
               
                   
                 SAPGSEPATSGSETPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGSEPAT 
                   
               
               
                   
                 SGSETPGSPAGSPTSTEEGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGSE 
                   
               
               
                   
                 PATSGSETPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAP 
                   
               
               
                   
                 GSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSEPATSGS 
                   
               
               
                   
                 ETPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGSPAGS 
                   
               
               
                   
                 PTSTEEGSPAGSPTSTEEGSPAGSPTSFEEGTSESATPESGPGSEPATSGSETPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGP 
                   
               
               
                   
                 GSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTS 
                   
               
               
                   
                 TEEGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEP 
                   
               
               
                   
               
               
                 AE2004 
                 GTSTEPSEGSAPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGS 
                 79 
               
               
                 A 
                 ETPGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGTSESATPESGPGSP 
                   
               
               
                   
                 AGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETP 
                   
               
               
                   
                 GTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTS 
                   
               
               
                   
                 TEEGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGSEPAT 
                   
               
               
                   
                 SGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSE 
                   
               
               
                   
                 PATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGP 
                   
               
               
                   
                 GTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSESATPESGPGTSESATPE 
                   
               
               
                   
                 SGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGSPAGS 
                   
               
               
                   
                 PTSTEEGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGP 
                   
               
               
                   
                 GSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGSPAGSPTS 
                   
               
               
                   
                 TEEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGS 
                   
               
               
                   
                 PTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGSPAGSPTSTEEGSPAGSPTSTEEGTS 
                   
               
               
                   
                 ESATPESGPGSEPATSGSETPGSEPATSGSETPGTSESATPESGPGSEPATSGSETP 
                   
               
               
                   
                 GTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGSPAGSPTS 
                   
               
               
                   
                 TEEGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSE 
                   
               
               
                   
               
               
                 AG948 
                 GSSTPSGATGSPGTPGSGTASSSPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTA 
                 80 
               
               
                   
                 SSSPGTPGSGTASSSPGTPGSGTASSSPGSSPSASTGTGPGTPGSGTASSSPGSSPS 
                   
               
               
                   
                 ASTGTGPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSTPSGATGSPG 
                   
               
               
                   
                 ASPGTSSTGSPGASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSST 
                   
               
               
                   
                 GSPGSSPSASTGTGPGASPGTSSTGSPGSSPSASTGTGPGASPGTSSTGSPGTPGS 
                   
               
               
                   
                 GTASSSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPG 
                   
               
               
                   
                 ASPGTSSTGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGAT 
                   
               
               
                   
                 GSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGTPGS 
                   
               
               
                   
                 GTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPG 
                   
               
               
                   
                 SSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSPSASTGTGPGSSTPSGAT 
                   
               
               
                   
                 GSPGASPGTSSTGSPGSSTPSGATGSPGTPGSGTASSSPGSSPSASTGTGPGSSTPS 
                   
               
               
                   
                 GATGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGS 
                   
               
               
                   
                 SPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASS 
                   
               
               
                   
                 SPGSSTPSGATGSPGSSPSASTGTGPGSSTPSGATGSPGSSPSASTGTGPGSSPSAS 
                   
               
               
                   
                 TGTGPGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGTP 
                   
               
               
                   
                 GSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGASPGTSSTGSPGSSTPSGATGS 
                   
               
               
                   
                 PGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSP 
                   
               
               
                   
               
               
                 AG1044 
                 GTPGSGTASSSPGTPGSGTASSSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSS 
                 81 
               
               
                   
                 TGSPGTPGSGTASSSPGSSPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPGASP 
                   
               
               
                   
                 GTSSTGSPGSSPSASTGTGPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGP 
                   
               
               
                   
                 GTPGSGTASSSPGTPGSGTASSSPGASPGTSSTGSPGSSTPSGATGSPGSSPSAST 
                   
               
               
                   
                 GTGPGTPGSGTASSSPGASPGTSSTGSPGTPGSGTASSSPGSSPSASTGTGPGSSP 
                   
               
               
                   
                 SASTGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSP 
                   
               
               
                   
                 GTPGSGTASSSPGSSPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPGSSTPSGA 
                   
               
               
                   
                 TGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGASP 
                   
               
               
                   
                 GTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSTSTGSP 
                   
               
               
                   
                 GSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTA 
                   
               
               
                   
                 SSSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGTPGSGTASSSPGSSTP 
                   
               
               
                   
                 SGATGSPGSSTPSGATGSPGASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPG 
                   
               
               
                   
                 ASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSPSASTGTGPGTPGSGTAS 
                   
               
               
                   
                 SSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGSTSPSASTGTGPGASPG 
                   
               
               
                   
                 TSSTGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGS 
                   
               
               
                   
                 STPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASS 
                   
               
               
                   
                 SPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSAS 
                   
               
               
                   
                 TGTGPGTPGSGTASSSPGSSPSASTGTGPGASPGTSSTGSPGSSTPSGATGSPGTP 
                   
               
               
                   
                 GSGTASSSPGSST 
                   
               
               
                   
               
               
                 AG1140 
                 GASPGTSSTGSPGSSPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPGASPGTSS 
                 82 
               
               
                   
                 TGSPGSSTPSGATGSPGTPGSGTASSSPGASPGTSSTGSPGTPGSGTASSSPGTPG 
                   
               
               
                   
                 SGTASSSPGSSTPSGATGSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSP 
                   
               
               
                   
                 GSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGTPGSGTA 
                   
               
               
                   
                 SSSPGASPGTSSTGSPGSSTPSGATGSPGTPGSGTASSSPGSSPSASTGTGPGSSTP 
                   
               
               
                   
                 SGATGSPGSSPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPGSSPSASTGTGPG 
                   
               
               
                   
                 TPGSGTASSSPGASPGTSSTGSPGSSTPSGATGSPGASPGTSSTGSPGSSPSASTGT 
                   
               
               
                   
                 GPGTPGSGTASSSPGTPGSGTASSSPGASPGTSSTGSPGTPGSGTASSSPGTPGSG 
                   
               
               
                   
                 TASSSPGSSPSASTGTGPGASPGTSSTGSPGSSTPSGATGSPGASPGTSSTGSPGSS 
                   
               
               
                   
                 PSASTGTGPGTPGSGTASSSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGS 
                   
               
               
                   
                 PGASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGT 
                   
               
               
                   
                 ASSSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGTPGSGTASSSPGSSP 
                   
               
               
                   
                 SASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSP 
                   
               
               
                   
                 GTPGSGTASSSPGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGTPGSGTA 
                   
               
               
                   
                 SSSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGSSPSASTGTGPGSSTP 
                   
               
               
                   
                 SGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSGATGSPG 
                   
               
               
                   
                 ASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGSSPSASTGT 
                   
               
               
                   
                 GPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGT 
                   
               
               
                   
                 SSTGSPGSST 
                   
               
               
                   
               
               
                 AG1236 
                 GSSPSASTGTGPGTPGSGTASSSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTA 
                 83 
               
               
                   
                 SSSPGASPGTSSTGSPGSSTPSGATGSPGTPGSGTASSSPGASPGTSSTGSPGTPGS 
                   
               
               
                   
                 GTASSSPGTPGSGTASSSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSGATGSPG 
                   
               
               
                   
                 ASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGTPGSGTASSSPGSSTPSGAT 
                   
               
               
                   
                 GSPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGTPGSGTASSSPGASPG 
                   
               
               
                   
                 TSSTGSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPG 
                   
               
               
                   
                 ASPGTSSTGSPGSSPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPGASPGTSST 
                   
               
               
                   
                 GSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGTPGS 
                   
               
               
                   
                 GTASSSPGSSTPSGATGSPGASPGTSSTGSPGSSTPSGATGSPGTPGSGTASSSPG 
                   
               
               
                   
                 SSPSASTGTGPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGAT 
                   
               
               
                   
                 GSPGASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGSSPSA 
                   
               
               
                   
                 STGTGPGTPGSGTASSSPGTPGSGTASSSPGASPGTSSTGSPGTPGSGTASSSPGA 
                   
               
               
                   
                 SPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGSSTPSGATGSPGASPGTSSTGS 
                   
               
               
                   
                 PGSSPSASTGTGPGTPGSGTASSSPGTPGSGTASSSPGSSPSASTGTGPGTPGSGT 
                   
               
               
                   
                 ASSSPGASPGTSSTGSPGSSTPSGATGSPGTPGSGTASSSPGASPGTSSTGSPGTP 
                   
               
               
                   
                 GSGTASSSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSPSASTGTG 
                   
               
               
                   
                 PGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSAST 
                   
               
               
                   
                 GTGPGASPGTSSTGSPGTPGSGTASSSPGSSPSASTGTGPGSSPSASTGTGPGASP 
                   
               
               
                   
                 GTSSTGSPGASP 
                   
               
               
                   
               
               
                 AG1332 
                 GSSTPSGATGSPGSSPSASTGTGPGTPGSGTASSSPGSSPSASTGTGPGASPGTSS 
                 84 
               
               
                   
                 TGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGSSTPSGATGSPGSSPS 
                   
               
               
                   
                 ASTGTGPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPG 
                   
               
               
                   
                 SSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGAT 
                   
               
               
                   
                 GSPGSSTPSGATGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGTPGS 
                   
               
               
                   
                 GTASSSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPG 
                   
               
               
                   
                 SSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSSTPSGATGSPGSSPSASTGTGPGSSTPSGATGSPGTPGSGTASSSPGSSPSAS 
                   
               
               
                   
                 TGTGPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGSSPSASTGTGPGAS 
                   
               
               
                   
                 PGTSSTGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSP 
                   
               
               
                   
                 GSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSTPSGA 
                   
               
               
                   
                 TGSPGTPGSGTASSSPGTPGSGTASSSPGSSPSASTGTGPGSSTPSGATGSPGSSTP 
                   
               
               
                   
                 SGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPG 
                   
               
               
                   
                 SSTPSGATGSPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSST 
                   
               
               
                   
                 GSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGSSPSASTGTGPGTPGS 
                   
               
               
                   
                 GTASSSPGASPGTSSTGSPGSSTPSGATGSPGTPGSGTASSSPGTPGSGTASSSPG 
                   
               
               
                   
                 SSTPSGATGSPGSSTPSGATGSPGTPGSGTASSSPGSSPSASTGTGPGSSPSASTGT 
                   
               
               
                   
                 GPGASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGASPGT 
                   
               
               
                   
                 SSTGSPGTPG 
                   
               
               
                   
               
               
                 AG1428 
                 GTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSSTPSGATGSPGTPGSGTA 
                 85 
               
               
                   
                 SSSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGSSPS 
                   
               
               
                   
                 ASTGTGPGSSTPSGATGSPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPG 
                   
               
               
                   
                 ASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGASPGTSST 
                   
               
               
                   
                 GSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGSSPSASTGTGPGSSPSA 
                   
               
               
                   
                 STGTGPGASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGA 
                   
               
               
                   
                 SPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGSSPSASTGTGPGASPGTSSTGS 
                   
               
               
                   
                 PGSSTPSGATGSPGASPGTSSTGSPGSSPSASTGTGPGSSTPSGATGSPGSSPSAST 
                   
               
               
                   
                 GTGPGSSPSASTGTGPGASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGASP 
                   
               
               
                   
                 GTSSTGSPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSP 
                   
               
               
                   
                 GSSTPSGATGSPGTPGSGTASSSPGTPGSGTASSSPGSSPSASTGTGPGSSTPSGA 
                   
               
               
                   
                 TGSPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGPGASP 
                   
               
               
                   
                 GTSSTGSPGSSTPSGATGSPGTPGSGTASSSPGASPGTSSTGSPGTPGSGTASSSP 
                   
               
               
                   
                 GASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGSSPSAST 
                   
               
               
                   
                 GTGPGTPGSGTASSSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGASP 
                   
               
               
                   
                 GTSSTGSPGSSTPSGATGSPGTPGSGTASSSPGSSPSASTGTGPGSSTPSGATGSP 
                   
               
               
                   
                 GSSTPSGATGSPGSSPSASTGTGPGSSTPSGATGSPGTPGSGTASSSPGSSPSAST 
                   
               
               
                   
                 GTGPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGTPG 
                   
               
               
                   
                 SGTASSSPGASP 
                   
               
               
                   
               
               
                 AG1524 
                 GSSTPSGATGSPGTPGSGTASSSPGTPGSGTASSSPGASPGTSSTGSPGSSTPSGA 
                 86 
               
               
                   
                 TGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSTPSGATGSPGTPG 
                   
               
               
                   
                 SGTASSSPGTPGSGTASSSPGSSPSASTGTGPGSSTPSGATGSPGSSPSASTGTGP 
                   
               
               
                   
                 GTPGSGTASSSPGASPGTSSTGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTA 
                   
               
               
                   
                 SSSPGSSTPSGATGSPGTPGSGTASSSPGSSPSASTGTGPGASPGTSSTGSPGASPG 
                   
               
               
                   
                 TSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGS 
                   
               
               
                   
                 SPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGSSPSASTGT 
                   
               
               
                   
                 GPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSPSASTGTGPGASPGT 
                   
               
               
                   
                 SSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGTP 
                   
               
               
                   
                 GSGTASSSPGTPGSGTASSSPGASPGTSSTGSPGSSTPSGATGSPGTPGSGTASSS 
                   
               
               
                   
                 PGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSG 
                   
               
               
                   
                 ATGSPGTPGSGTASSSPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSPGSS 
                   
               
               
                   
                 PSASTGTGPGTPGSGTASSSPGSSPSASTGTGPGASPGTSSTGSPGSSPSASTGTG 
                   
               
               
                   
                 PGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGT 
                   
               
               
                   
                 ASSSPGSSTPSGATGSPGTPGSGTASSSPGASPGTSSTGSPGSSTPSGATGSPGSST 
                   
               
               
                   
                 PSGATGSPGSSTPSGATGSPGTPGSGTASSSPGSSPSASTGTGPGSSPSASTGTGP 
                   
               
               
                   
                 GSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTA 
                   
               
               
                   
                 SSSPGASPGTSSTGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGSSTP 
                   
               
               
                   
                 SGATGSPGTPG 
                   
               
               
                   
               
               
                 AG1620 
                 GSSTPSGATGSPGSSTPSGATGSPGTPGSGTASSSPGSSPSASTGTGPGTPGSGTA 
                 87 
               
               
                   
                 SSSPGASPGTSSTGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGASPG 
                   
               
               
                   
                 TSSTGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGSSTPSGATGSPGS 
                   
               
               
                   
                 SPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTG 
                   
               
               
                   
                 SPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSG 
                   
               
               
                   
                 ATGSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSGATGSPGSSPSASTGTGPGSS 
                   
               
               
                   
                 PSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSPSASTGTG 
                   
               
               
                   
                 PGSSPSASTGTGPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGSSPSAST 
                   
               
               
                   
                 GTGPGSSTPSGATGSPGASPGTSSTGSPGSSTPSGATGSPGTPGSGTASSSPGSSP 
                   
               
               
                   
                 SASTGTGPGASPGTSSTGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSP 
                   
               
               
                   
                 GTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGTPGSGTA 
                   
               
               
                   
                 SSSPGSSPSASTGTGPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGSSTP 
                   
               
               
                   
                 SGATGSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPG 
                   
               
               
                   
                 SSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGSSPSASTGTGPGSSTPSGAT 
                   
               
               
                   
                 GSPGSSPSASTGTGPGSSTPSGATGSPGSSPSASTGTGPGTPGSGTASSSPGTPGS 
                   
               
               
                   
                 GTASSSPGSSTPSGATGSPGSSTPSGATGSPGTPGSGTASSSPGSSPSASTGTGPG 
                   
               
               
                   
                 SSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSGATGSPGASPGTSST 
                   
               
               
                   
                 GSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGTPGSGTASSSPGSSTPS 
                   
               
               
                   
                 GATGSPGSST 
                   
               
               
                   
               
               
                 AG1716 
                 GASPGTSSTGSPGSSPSASTGTGPGSSTPSGATGSPGSSPSASTGTGPGTPGSGTA 
                 88 
               
               
                   
                 SSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSTPSGATGSPGTPGS 
                   
               
               
                   
                 GTASSSPGSSPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPGSSPSASTGTGPG 
                   
               
               
                   
                 SSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGASPGTSSTGSPGSSTPSGATGSPGTPGSGTASSSPGSSPSASTGTGPGSSPSAS 
                   
               
               
                   
                 TGTGPGSSPSASTGTGPGTPGSGTASSSPGTPGSGTASSSPGSSTPSGATGSPGTP 
                   
               
               
                   
                 GSGTASSSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSS 
                   
               
               
                   
                 PGSSPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSG 
                   
               
               
                   
                 ATGSPGASPGTSSTGSPGTPGSGTASSSPGSSPSASTGTGPGTPGSGTASSSPGAS 
                   
               
               
                   
                 PGTSSTGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSP 
                   
               
               
                   
                 GTPGSGTASSSPGSSPSASTGTGPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTA 
                   
               
               
                   
                 SSSPGASPGTSSTGSPGSSTPSGATGSPGASPGTSSTGSPGSSPSASTGTGPGASPG 
                   
               
               
                   
                 TSSTGSPGSSPSASTGTGPGASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGT 
                   
               
               
                   
                 PGSGTASSSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGASPGTSSTG 
                   
               
               
                   
                 SPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSTPSGATGSPGTPGSG 
                   
               
               
                   
                 TASSSPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSS 
                   
               
               
                   
                 PSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSPSASTGTGPGSSTPSGATGS 
                   
               
               
                   
                 PGASPGTSSTGSPGASPGTSSTGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTS 
                   
               
               
                   
                 STGSPGTPG 
                   
               
               
                   
               
               
                 AG1812 
                 GSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTA 
                 89 
               
               
                   
                 SSSPGSSPSASTGTGPGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGASPG 
                   
               
               
                   
                 TSSTGSPGSSPSASTGTGPGTPGSGTASSSPGTPGSGTASSSPGASPGTSSTGSPGS 
                   
               
               
                   
                 STPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTG 
                   
               
               
                   
                 SPGSSTPSGATGSPGTPGSGTASSSPGSSPSASTGTGPGSSTPSGATGSPGTPGSG 
                   
               
               
                   
                 TASSSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGSSTPSGATGSPGSS 
                   
               
               
                   
                 TPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGS 
                   
               
               
                   
                 PGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGTPGSGTASSSPGSSPSAST 
                   
               
               
                   
                 GTGPGTPGSGTASSSPGASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGSST 
                   
               
               
                   
                 PSGATGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSP 
                   
               
               
                   
                 GASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGSSTPSGATGSPGSSTPSGA 
                   
               
               
                   
                 TGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGTPG 
                   
               
               
                   
                 SGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSP 
                   
               
               
                   
                 GASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSSTPSGA 
                   
               
               
                   
                 TGSPGTPGSGTASSSPGSSPSASTGTGPGASPGTSSTGSPGSSTPSGATGSPGTPG 
                   
               
               
                   
                 SGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGP 
                   
               
               
                   
                 GSSPSASTGTGPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSGA 
                   
               
               
                   
                 TGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGSSTP 
                   
               
               
                   
                 SGATGSPGASP 
                   
               
               
                   
               
               
                 AG1908 
                 GSSPSASTGTGPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSPSAST 
                 90 
               
               
                   
                 GTGPGSSPSASTGTGPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGTPG 
                   
               
               
                   
                 SGTASSSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGSSPSASTGTGP 
                   
               
               
                   
                 GSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSSPSASTGTGPGASPGTSS 
                   
               
               
                   
                 TGSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGASPGTSSTGSPGTPG 
                   
               
               
                   
                 SGTASSSPGTPGSGTASSSPGSSPSASTGTGPGSSTPSGATGSPGASPGTSSTGSP 
                   
               
               
                   
                 GSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSGATGSPGASPGTSS 
                   
               
               
                   
                 TGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGTPG 
                   
               
               
                   
                 SGTASSSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGASPGTSSTGSP 
                   
               
               
                   
                 GSSTPSGATGSPGTPGSGTASSSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSGA 
                   
               
               
                   
                 TGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGSSTP 
                   
               
               
                   
                 SGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPG 
                   
               
               
                   
                 SSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTAS 
                   
               
               
                   
                 SSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSA 
                   
               
               
                   
                 STGTGPGSSTPSGATGSPGTPGSGTASSSPGSSPSASTGTGPGASPGTSSTGSPGS 
                   
               
               
                   
                 STPSGATGSPGSSPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPGSSPSASTGT 
                   
               
               
                   
                 GPGTPGSGTASSSPGSSPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPGSSPSAS 
                   
               
               
                   
                 TGTGPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGSS 
                   
               
               
                   
                 PSASTGTGPGSSP 
                   
               
               
                   
               
               
                 AG2004 
                 GSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGA 
                 91 
               
               
                 A 
                 TGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSSPSASTGTGPGTPG 
                   
               
               
                   
                 SGTASSSPGASPGTSSTGSPGSSTPSGATGSPGTPGSGTASSSPGTPGSGTASSSP 
                   
               
               
                   
                 GSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSS 
                   
               
               
                   
                 TGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGSSPS 
                   
               
               
                   
                 ASTGTGPGSSTPSGATGSPGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPG 
                   
               
               
                   
                 SSPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSPSASTGTGPGSSPSASTGT 
                   
               
               
                   
                 GPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGTPGSG 
                   
               
               
                   
                 TASSSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGASPGTSSTGSPGSS 
                   
               
               
                   
                 TPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGS 
                   
               
               
                   
                 PGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGSSPSAST 
                   
               
               
                   
                 GTGPGTPGSGTASSSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGASP 
                   
               
               
                   
                 GTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSP 
                   
               
               
                   
                 GTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGSSPSAST 
                   
               
               
                   
                 GTGPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGSST 
                   
               
               
                   
                 PSGATGSPGASPGTSSTGSPGTPGSGTASSSPGTPGSGTASSSPGSSPSASTGTGP 
                   
               
               
                   
                 GASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSS 
                   
               
               
                   
                 TGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSPSASTGTGPGSSPS 
                   
               
               
                   
                 ASTGTGPGASP 
                   
               
               
                   
               
               
                 AE72B 
                 SPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESATPES 
                 92 
               
               
                   
                 GPGSEPATSGSETPG 
                   
               
               
                   
               
               
                 AE72C 
                 TSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTST 
                 93 
               
               
                   
                 EEGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE108 
                 TEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEP 
                 94 
               
               
                 A 
                 SEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTS 
                   
               
               
                   
               
               
                 AE108 
                 GSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPE 
                 95 
               
               
                 B 
                 SGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAP 
                   
               
               
                   
               
               
                 AE144 
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSET 
                 96 
               
               
                 A 
                 PGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATP 
                   
               
               
                   
                 ESGPGSPAGSPTSTEEGSPAGSPTSTEEGS 
                   
               
               
                   
               
               
                 AE144 
                 SEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGS 
                 97 
               
               
                 B 
                 APGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSP 
                   
               
               
                   
                 TSTEEGSPAGSPTSTEEGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE180 
                 TSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPA 
                 98 
               
               
                 A 
                 GSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPG 
                   
               
               
                   
                 SEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSEPATS 
                   
               
               
                   
               
               
                 AE216 
                 PESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSE 
                 99 
               
               
                 A 
                 SATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPG 
                   
               
               
                   
                 TSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTST 
                   
               
               
                   
                 EEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESAT 
                   
               
               
                   
               
               
                 AE252 
                 ESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSES 
                 100 
               
               
                 A 
                 ATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGT 
                   
               
               
                   
                 STEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSET 
                   
               
               
                   
                 PGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSG 
                   
               
               
                   
                 SETPGTSESATPESGPGTSTEPSE 
                   
               
               
                   
               
               
                 AE288 
                 TPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSE 
                 101 
               
               
                 A 
                 PATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGP 
                   
               
               
                   
                 GSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEG 
                   
               
               
                   
                 SAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPAT 
                   
               
               
                   
                 SGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTS 
                   
               
               
                   
                 ESA 
                   
               
               
                   
               
               
                 AE324 
                 PESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTST 
                 102 
               
               
                 A 
                 EPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSE 
                   
               
               
                   
                 TPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESAT 
                   
               
               
                   
                 PESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPA 
                   
               
               
                   
                 GSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATS 
                   
               
               
                   
               
               
                 AE360 
                 PESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPA 
                 103 
               
               
                 A 
                 GSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSP 
                   
               
               
                   
                 TSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEP 
                   
               
               
                   
                 ATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 SEPATSGSETPGTSESAT 
                   
               
               
                   
               
               
                 AE396 
                 PESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPA 
                 104 
               
               
                 A 
                 GSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
                 TSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESAT 
                   
               
               
                   
                 PESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSE 
                   
               
               
                   
                 SATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEG 
                   
               
               
                   
                 TSTEPSEGSAPGTSTEPS 
                   
               
               
                   
               
               
                 AE432 
                 EGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSE 
                 105 
               
               
                 A 
                 SATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPG 
                   
               
               
                   
                 SPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESAT 
                   
               
               
                   
                 PESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSE 
                   
               
               
                   
                 SATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPG 
                   
               
               
                   
                 TSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTST 
                   
               
               
                   
                 EEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATS 
                   
               
               
                   
               
               
                 AE468 
                 EGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSE 
                 106 
               
               
                 A 
                 SATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESAT 
                   
               
               
                   
                 PESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSE 
                   
               
               
                   
                 SATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEG 
                   
               
               
                   
                 TSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSE 
                   
               
               
                   
                 TPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATS 
                   
               
               
                   
                 GSETPGTSESAT 
                   
               
               
                   
               
               
                 AE504 
                 EGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPA 
                 107 
               
               
                 A 
                 GSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPG 
                   
               
               
                   
                 SEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTST 
                   
               
               
                   
                 EEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESAT 
                   
               
               
                   
                 PESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTST 
                   
               
               
                   
                 EPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPG 
                   
               
               
                   
                 SPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPES 
                   
               
               
                   
                 GPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPS 
                   
               
               
                   
               
               
                 AE540 
                 TPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTS 
                 108 
               
               
                 A 
                 TEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAP 
                   
               
               
                   
                 GTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGS 
                   
               
               
                   
                 ETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESA 
                   
               
               
                   
                 TPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETP 
                   
               
               
                   
                 GTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGS 
                   
               
               
                   
                 ETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESA 
                   
               
               
                   
                 TPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSP 
                   
               
               
                   
                 AGSPTSTEEGTSTEPSEGSAPGTSTEP 
                   
               
               
                   
               
               
                 AE576 
                 TPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTS 
                 109 
               
               
                 A 
                 ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAP 
                   
               
               
                   
                 GTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGP 
                   
               
               
                   
                 GSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPE 
                   
               
               
                   
                 SGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEP 
                   
               
               
                   
                 SEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSE 
                   
               
               
                   
                 PATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETP 
                   
               
               
                   
                 GTSESA 
                   
               
               
                   
               
               
                 AE612 
                 GSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPA 
                 110 
               
               
                 A 
                 GSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESAT 
                   
               
               
                   
                 PESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPA 
                   
               
               
                   
                 GSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
                 TSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESAT 
                   
               
               
                   
                 PESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSE 
                   
               
               
                   
                 SATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEG 
                   
               
               
                   
                 TSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESAT 
                   
               
               
                   
               
               
                 AE648 
                 PESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTST 
                 111 
               
               
                 A 
                 EPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPG 
                   
               
               
                   
                 SEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSE 
                   
               
               
                   
                 SATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEG 
                   
               
               
                   
                 SPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSE 
                   
               
               
                   
                 TPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSP 
                   
               
               
                   
                 TSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPA 
                   
               
               
                   
                 GSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPG 
                   
               
               
                   
                 SEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSEPATSGSETPGTSESAT 
                   
               
               
                   
               
               
                 AE684 
                 EGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTST 
                 112 
               
               
                 A 
                 EPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 TSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSE 
                   
               
               
                   
                 TPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPS 
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSE 
                   
               
               
                   
                 SATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESAT 
                   
               
               
                   
                 PESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSE 
                   
               
               
                   
                 SATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEG 
                   
               
               
                   
                 TSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSE 
                   
               
               
                   
                 TPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATS 
                   
               
               
                   
               
               
                 AE720 
                 TSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGT 
                 113 
               
               
                 A 
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESG 
                   
               
               
                   
                 PGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSE 
                   
               
               
                   
                 GSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPA 
                   
               
               
                   
                 TSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGT 
                   
               
               
                   
                 STEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSA 
                   
               
               
                   
                 PGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATP 
                   
               
               
                   
                 ESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAG 
                   
               
               
                   
                 SPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGT 
                   
               
               
                   
                 SESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTE 
                   
               
               
                   
                 EGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPT 
                   
               
               
                   
                 STEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPA 
                   
               
               
                   
                 TSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTE 
                   
               
               
                   
               
               
                 AE756 
                 TSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGT 
                 114 
               
               
                 A 
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESG 
                   
               
               
                   
                 PGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSE 
                   
               
               
                   
                 GSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPA 
                   
               
               
                   
                 TSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGT 
                   
               
               
                   
                 STEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSA 
                   
               
               
                   
                 PGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATP 
                   
               
               
                   
                 ESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAG 
                   
               
               
                   
                 SPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGT 
                   
               
               
                   
                 SESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTE 
                   
               
               
                   
                 EGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPT 
                   
               
               
                   
                 STEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPA 
                   
               
               
                   
                 TSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGS 
                   
               
               
                   
                 EPATSGSETPGTSES 
                   
               
               
                   
               
               
                 AE792 
                 EGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSE 
                 115 
               
               
                 A 
                 SATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSE 
                   
               
               
                   
                 TPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSP 
                   
               
               
                   
                 TSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTST 
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 SPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSP 
                   
               
               
                   
                 TSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSE 
                   
               
               
                   
                 SATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPG 
                   
               
               
                   
                 TSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESAT 
                   
               
               
                   
                 PESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTST 
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPS 
                   
               
               
                   
               
               
                 AE828 
                 PESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSE 
                 116 
               
               
                 A 
                 SATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPS 
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSE 
                   
               
               
                   
                 SATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTST 
                   
               
               
                   
                 EEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATS 
                   
               
               
                   
                 GSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPA 
                   
               
               
                   
                 GSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPG 
                   
               
               
                   
                 SEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 APGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSP 
                   
               
               
                   
                 TSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSE 
                   
               
               
                   
                 SATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPG 
                   
               
               
                   
                 TSTEPSEGSAPGSEPATSGSETPGTSESAT 
                   
               
               
                   
               
               
                 AG72A 
                 GPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGASPGT 
                 117 
               
               
                   
                 SSTGSPGTPGSGTASS 
                   
               
               
                   
               
               
                 AG72B 
                 GSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSS 
                 118 
               
               
                   
                 TGSPGTPGSGTASSSP 
                   
               
               
                   
               
               
                 AG72C 
                 SPSASTGTGPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATG 
                 119 
               
               
                   
                 SPGSSTPSGATGSPGA 
                   
               
               
                   
               
               
                 AG108 
                 SASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGP 
                 120 
               
               
                 A 
                 GASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGASP 
                   
               
               
                   
               
               
                 AG108 
                 PGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSG 
                 121 
               
               
                 B 
                 ATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGTPGSGTASSS 
                   
               
               
                   
               
               
                 AG144 
                 PGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSSPSAST 
                 122 
               
               
                 A 
                 GTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGASP 
                   
               
               
                   
                 GTSSTGSPGASPGTSSTGSPGTPGSGTASSS 
                   
               
               
                   
               
               
                 AG144 
                 PSGATGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGP 
                 123 
               
               
                 B 
                 GSSPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSAST 
                   
               
               
                   
                 GTGPGSSPSASTGTGPGASPGTSSTGSPGASP 
                   
               
               
                   
               
               
                 AG180 
                 TSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGS 
                 124 
               
               
                 A 
                 SPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASS 
                   
               
               
                   
                 SPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGASPGT 
                   
               
               
                   
                 SSTGSPGTPGS 
                   
               
               
                   
               
               
                 AG216 
                 TGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGAS 
                 125 
               
               
                 A 
                 PGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGASPGTSSTGSP 
                   
               
               
                   
                 GASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTA 
                   
               
               
                   
                 SSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSG 
                   
               
               
                   
               
               
                 AG252 
                 TSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGS 
                 126 
               
               
                 A 
                 SPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASS 
                   
               
               
                   
                 SPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGASPGT 
                   
               
               
                   
                 SSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSS 
                   
               
               
                   
                 TPSGATGSPGSSTPSGATGSPGASPG 
                   
               
               
                   
               
               
                 AG288 
                 TSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGS 
                 127 
               
               
                 A 
                 SPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASS 
                   
               
               
                   
                 SPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGASPGT 
                   
               
               
                   
                 SSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSS 
                   
               
               
                   
                 TPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGS 
                   
               
               
                   
                 PGTPGS 
                   
               
               
                   
               
               
                 AG324 
                 TSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPG 
                 128 
               
               
                 A 
                 ASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGAT 
                   
               
               
                   
                 GSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSA 
                   
               
               
                   
                 STGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGS 
                   
               
               
                   
                 SPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGSSTP 
                   
               
               
                   
               
               
                 AG360 
                 TSSTGSPGASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPG 
                 129 
               
               
                 A 
                 ASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTAS 
                   
               
               
                   
                 SSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSA 
                   
               
               
                   
                 STGTGPGSSPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGS 
                   
               
               
                   
                 SPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATG 
                   
               
               
                   
                 SPGSSPSASTGTGPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGSSTPSG 
                   
               
               
                   
                 ATGSPGSSTPSGATGSPGASPG 
                   
               
               
                   
               
               
                 AG396 
                 GATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGT 
                 130 
               
               
                 A 
                 PGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTG 
                   
               
               
                   
                 SPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSG 
                   
               
               
                   
                 TASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGA 
                   
               
               
                   
                 SPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTG 
                   
               
               
                   
                 PGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTS 
                   
               
               
                   
                 STGSPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGAS 
                   
               
               
                   
                 PGT 
                   
               
               
                   
               
               
                 AG432 
                 GATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGS 
                 131 
               
               
                 A 
                 STPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTG 
                   
               
               
                   
                 SPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGASPGT 
                   
               
               
                   
                 SSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTP 
                   
               
               
                   
                 GSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTG 
                   
               
               
                   
                 PGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSAST 
                   
               
               
                   
                 GTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGPGASP 
                   
               
               
                   
                 GTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGSSTPS 
                   
               
               
                   
               
               
                 AG468 
                 TSSTGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPG 
                 132 
               
               
                 A 
                 ASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTAS 
                   
               
               
                   
                 SSPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPG 
                   
               
               
                   
                 TSSTGSPGASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPG 
                   
               
               
                   
                 ASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTAS 
                   
               
               
                   
                 SSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSA 
                   
               
               
                   
                 STGTGPGSSPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGS 
                   
               
               
                   
                 SPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATG 
                   
               
               
                   
                 SPGSSPSASTGTGPGASPG 
                   
               
               
                   
               
               
                 AG504 
                 TSSTGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPG 
                 133 
               
               
                 A 
                 ASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTAS 
                   
               
               
                   
                 SSPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPG 
                   
               
               
                   
                 TSSTGSPGASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPG 
                   
               
               
                   
                 ASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTAS 
                   
               
               
                   
                 SSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSA 
                   
               
               
                   
                 STGTGPGSSPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGS 
                   
               
               
                   
                 SPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATG 
                   
               
               
                   
                 SPGSSPSASTGTGPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGSSTP 
                   
               
               
                   
               
               
                 AG540 
                 TSSTGSPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPG 
                 134 
               
               
                 A 
                 ASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSST 
                   
               
               
                   
                 GSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGSSPSA 
                   
               
               
                   
                 STGTGPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGA 
                   
               
               
                   
                 SPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGS 
                   
               
               
                   
                 PGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSG 
                   
               
               
                   
                 ATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSS 
                   
               
               
                   
                 TPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGS 
                   
               
               
                   
                 PGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSSPSASTGTGPGTPGSGT 
                   
               
               
                   
                 ASSSPGSSTPSGATGSPGSSTPSGATGSPGASPG 
                   
               
               
                   
               
               
                 AG576 
                 TSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGS 
                 135 
               
               
                 A 
                 SPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTG 
                   
               
               
                   
                 SPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSG 
                   
               
               
                   
                 ATGSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGAS 
                   
               
               
                   
                 PGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSP 
                   
               
               
                   
                 GASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGA 
                   
               
               
                   
                 TGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPS 
                   
               
               
                   
                 ASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPG 
                   
               
               
                   
                 SSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSSTPS 
                   
               
               
                   
                 GATGSPGASPG 
                   
               
               
                   
               
               
                 AG612 
                 STGSPGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSST 
                 136 
               
               
                 A 
                 PSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSP 
                   
               
               
                   
                 GASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGASPGTSS 
                   
               
               
                   
                 TGSPGASPGTSSTGSPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGASP 
                   
               
               
                   
                 GTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSP 
                   
               
               
                   
                 GASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGA 
                   
               
               
                   
                 TGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGASP 
                   
               
               
                   
                 GTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSP 
                   
               
               
                   
                 GSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGA 
                   
               
               
                   
                 TGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGTPG 
                   
               
               
                   
                 SGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTS 
                   
               
               
                   
               
               
                 AG648 
                 GTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSGATGSPG 
                 137 
               
               
                 A 
                 SSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTAS 
                   
               
               
                   
                 SSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSPSASTGTGPGTPGS 
                   
               
               
                   
                 GTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPG 
                   
               
               
                   
                 SSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGAT 
                   
               
               
                   
                 GSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGTPGS 
                   
               
               
                   
                 GTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPG 
                   
               
               
                   
                 TPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTAS 
                   
               
               
                   
                 SSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPG 
                   
               
               
                   
                 TSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPG 
                   
               
               
                   
                 ASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSST 
                   
               
               
                   
                 GSPGSSPSASTGTGPGTPGSGTASSSPGSSTP 
                   
               
               
                   
               
               
                 AG684 
                 TSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGS 
                 138 
               
               
                 A 
                 STPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTG 
                   
               
               
                   
                 SPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSPSAS 
                   
               
               
                   
                 TGTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSS 
                   
               
               
                   
                 TPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGS 
                   
               
               
                   
                 PGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTS 
                   
               
               
                   
                 STGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGAS 
                   
               
               
                   
                 PGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSP 
                   
               
               
                   
                 GTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSAST 
                   
               
               
                   
                 GTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSP 
                   
               
               
                   
                 SASTGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGP 
                   
               
               
                   
                 GASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGA 
                   
               
               
                   
                 TGSPGASPG 
                   
               
               
                   
               
               
                 AG720 
                 TSSTGSPGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGS 
                 139 
               
               
                 A 
                 STPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATG 
                   
               
               
                   
                 SPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGASPGT 
                   
               
               
                   
                 SSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGA 
                   
               
               
                   
                 SPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGS 
                   
               
               
                   
                 PGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSTPSG 
                   
               
               
                   
                 ATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGAS 
                   
               
               
                   
                 PGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSP 
                   
               
               
                   
                 GSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGA 
                   
               
               
                   
                 TGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGTPG 
                   
               
               
                   
                 SGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSP 
                   
               
               
                   
                 GASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSSPSAST 
                   
               
               
                   
                 GTGPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGASPG 
                   
               
               
                   
               
               
                 AG756 
                 TSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGS 
                 140 
               
               
                 A 
                 SPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASS 
                   
               
               
                   
                 SPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGASPGT 
                   
               
               
                   
                 SSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSS 
                   
               
               
                   
                 TPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGS 
                   
               
               
                   
                 PGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSPSAST 
                   
               
               
                   
                 GTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSST 
                   
               
               
                   
                 PSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSP 
                   
               
               
                   
                 GSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSS 
                   
               
               
                   
                 TGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGASP 
                   
               
               
                   
                 GTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSP 
                   
               
               
                   
                 GTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSAST 
                   
               
               
                   
                 GTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSP 
                   
               
               
                   
                 SASTGTGPGASPGTSSTGSPGASPG 
                   
               
               
                   
               
               
                 AG792 
                 TSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGS 
                 141 
               
               
                 A 
                 SPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASS 
                   
               
               
                   
                 SPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGASPGT 
                   
               
               
                   
                 SSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSS 
                   
               
               
                   
                 TPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGS 
                   
               
               
                   
                 PGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSPSAST 
                   
               
               
                   
                 GTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSST 
                   
               
               
                   
                 PSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSP 
                   
               
               
                   
                 GSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSS 
                   
               
               
                   
                 TGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGASP 
                   
               
               
                   
                 GTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSP 
                   
               
               
                   
                 GTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSAST 
                   
               
               
                   
                 GTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSP 
                   
               
               
                   
                 SASTGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGP 
                   
               
               
                   
                 GASPG 
                   
               
               
                   
               
               
                 AG828 
                 TSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGS 
                 142 
               
               
                 A 
                 SPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASS 
                   
               
               
                   
                 SPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGASPGT 
                   
               
               
                   
                 SSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSS 
                   
               
               
                   
                 TPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGS 
                   
               
               
                   
                 PGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSPSAST 
                   
               
               
                   
                 GTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSST 
                   
               
               
                   
                 PSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSP 
                   
               
               
                   
                 GSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSS 
                   
               
               
                   
                 TGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGASP 
                   
               
               
                   
                 GTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSP 
                   
               
               
                   
                 GTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSAST 
                   
               
               
                   
                 GTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSP 
                   
               
               
                   
                 SASTGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGP 
                   
               
               
                   
                 GASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGSSTP 
               
               
                   
               
            
           
         
       
     
     In other embodiments, the binding fusion protein composition comprises one or more non-repetitive XTEN sequences of about 36 to about 3000 amino acid residues, wherein at least about 80%, or at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% to about 100% of the sequence consists of non-overlapping 36 amino acid sequence motifs selected from one or more of the polypeptide sequences of Tables 11-14, either as a family sequence, or where motifs are selected from two or more families of motifs. 
     In those embodiments wherein the XTEN component of the fusion protein has less than 100% of its amino acids consisting of four to six amino acid selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), or less than 100% of the sequence consisting of the sequences from any one of Tables 4 or 11-14, the other amino acid residues are selected from any other of the 14 natural L-amino acids, but are preferentially selected from hydrophilic amino acids such that the XTEN sequence contains at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% hydrophilic amino acids. The XTEN amino acids that are not glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) are interspersed throughout the XTEN sequence, are located within or between the sequence motifs, or are concentrated in one or more short stretches of the XTEN sequence. In such cases where the XTEN component of the binding fusion protein comprises amino acids other than glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), it is preferred that the amino acids not be hydrophobic residues and should not substantially confer secondary structure of the XTEN component. Hydrophobic residues that are less favored in construction of XTEN include tryptophan, phenylalanine, tyrosine, leucine, isoleucine, valine, and methionine. Additionally, one can design the XTEN sequences to contain less than 5% or less than 4% or less than 3% or less than 2% or less than 1% or none of the following amino acids: cysteine (to avoid disulfide formation and oxidation), methionine (to avoid oxidation), asparagine and glutamine (to avoid desamidation). Thus, in some embodiments, the XTEN component of the fusion protein comprising other amino acids in addition to glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) would have a sequence with less than 5% of the residues contributing to alpha-helices and beta-sheets as measured by the Chou-Fasman algorithm and have at least 90%, or at least about 95% or more random coil formation as measured by the GOR algorithm. 
     3. Length of Sequence 
     In another aspect, the invention provides binding fusion protein compositions comprising an binding protein and one or more XTEN polypeptides wherein the length of the XTEN sequences are chosen based on the property or function to be achieved. Depending on the intended property or function, the binding fusion protein compositions comprise short or intermediate length XTEN and/or longer XTEN sequences that can serve as carriers. The subject binding fusion proteins encompass XTEN or fragments of XTEN with lengths of about 6, or about 12, or about 36, or about 40, or about 100, or about 144, or about 288, or about 401, or about 500, or about 600, or about 700, or about 800, or about 900, or about 1000, or about 1500, or about 2000, or about 2500, or up to about 3000 amino acid residues in length. In other cases, the XTEN sequences can be about 6 to about 50, or about 100 to 150, about 150 to 250, about 250 to 400, about 400 to about 500, about 500 to 900, about 900 to 1500, about 1500 to 2000, or about 2000 to about 3000 amino acid residues in length. In the embodiments of the binding fusion proteins, the one or more XTEN or fragments of XTEN sequences individually exhibit at least about 80% sequence identity, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity compared to a motif or an XTEN selected from any one of Tables 4 or 11-14, or a fragment thereof with comparable length. In some embodiments, the bind fusion proteins comprise a first and at least a second XTEN sequence, wherein the cumulative length of the residues in the XTEN sequences is greater than about 100 to about 3000 amino acid residues and the XTEN can be identical or they can be different in sequence or in length. As used herein, “cumulative length” is intended to encompass the total length, in amino acid residues, when more than one XTEN is incorporated into the binding fusion proteins of the embodiments. In one embodiment of the foregoing, the first and at least the second sequences each exhibit at least about 80% sequence identity, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity compared to one or more XTEN sequences from Table 4, or fragments thereof. 
     As described more fully below, methods are disclosed in which the binding fusion protein is designed by selecting the length of the XTEN to confer a target half-life or other physicochemical property on a fusion protein administered to a subject. When XTEN are used as a carrier, the invention takes advantage of the discovery that increasing the length of the non-repetitive, unstructured polypeptides enhances the unstructured nature of the XTENs and correspondingly enhances the biological and pharmacokinetic properties of fusion proteins comprising the XTEN carrier. As described more fully in the Examples, proportional increases in the length of the XTEN, even if created by a repeated order of single family sequence motifs (e.g., the four AE motifs of Table 3), result in a sequence with a higher percentage of random coil formation, as determined by GOR algorithm, or reduced content of alpha-helices or beta-sheets, as determined by Chou-Fasman algorithm, compared to shorter XTEN lengths. In addition, increasing the length of the unstructured polypeptide fusion partner, as described in the Examples, results in a fusion protein with a disproportionate increase in terminal half-life compared to fusion proteins with unstructured polypeptide partners with shorter sequence lengths. In general, XTEN cumulative lengths longer that about 400 residues incorporated into the binding fusion protein compositions result in longer half-life compared to shorter cumulative lengths; e.g., shorter than about 280 residues. 
     In some embodiments, where the XTEN serve primarily as a carrier, the invention encompasses binding fusion protein compositions comprising one or more XTEN wherein the cumulative XTEN sequence length of the fusion protein(s) is greater than about 100, or greater than about 200, or greater than about 400, or greater than about 500, or greater than about 600, or greater than about 800, or greater than about 900, or greater than about 1000 to about 3000 amino acid residues, wherein the fusion protein exhibits enhanced pharmacokinetic properties when administered to a subject compared to a binding protein not linked to XTEN and administered at a comparable dose. In one embodiment of the foregoing, the one or more XTEN sequences exhibit at least about 80%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98% or more identity to a sequence selected from Table 4, or fragments thereof, and the remainder of the carrier sequence(s) contain at least 90% hydrophilic amino acids and less than about 2% of the overall sequence consists of hydrophobic or aromatic amino acids or cysteine. The enhanced pharmacokinetic properties of the binding fusion proteins in comparison to binding proteins not linked to XTEN are described more fully, below. 
     4. XTEN Segments 
     In one aspect, the invention provides XTEN of short or intermediate lengths, wherein the choice of the XTEN confers different functions or properties to the binding fusion proteins. In particular binding fusion protein configuration designs, where the XTEN serve as a flexible linker, or are designed to interfere with clearance receptors, or where a short or intermediate length of XTEN is used to facilitate tissue penetration or to vary the strength of interactions of the binding fusion protein with its target, or where it is desirable to distribute the cumulative length of XTEN in at least two segments of short or intermediate length, the invention provides binding fusion proteins comprising one or more truncated XTEN sequences. 
     The XTEN of short or intermediate lengths can be an XTEN or a fragment of an XTEN of a length of from about 6 amino acids to about 600 amino acids, or about 12 to about 288 amino acids, or about 36 to about 144 amino acids, or about 42 to about 96 amino acids in length. Non-limiting examples of short or intermediate length XTEN contemplated for inclusion in the binding fusion proteins embodiments of the disclosure are presented in Table 4, but can also include fragments of the motifs of Table 3 or fragments of the sequences of Table 4 used singly or linked in combination using the methods disclosed herein to achieve an XTEN of a given length, including lengths encompassed by the ranges disclosed above. In non-limiting examples, as schematically depicted in  FIGS. 39A-C , the AG864 sequence of 864 amino acid residues can be truncated to yield an AG144 with 144 residues, an AG288 with 288 residues, an AG576 with 576 residues, or other intermediate lengths, while the AE864 sequence ( FIGS. 39D-E ) can be truncated to yield an AE288 or AE576 or other intermediate lengths. It is specifically contemplated that such an approach can be utilized with any of the XTEN embodiments described herein or with any of the sequences listed in Table 4 to result in XTEN of a desired length. 
     In another aspect, the invention provides XTEN of longer lengths wherein the sequence is substantially non-repetitive. The incorporation of longer length XTEN as carriers into binding fusion proteins confers enhanced properties on the fusion proteins compared to fusion partners of shorter length XTEN, including slower rates of systemic absorption, increased bioavailability, and increased half-life after subcutaneous or intramuscular administration to a subject, and longer terminal half-life or area under the curve. In one embodiment, the XTEN of longer lengths have greater than about 400, or greater than about 600, or greater than about 800, or greater than about 900, or greater than about 1000, or greater than about 1100, or greater than about 1200, or greater than about 1300, or greater than about 1400, or greater than about 1500, or greater than about 1600, or greater than about 1700, or greater than about 1800, or greater than about 1900, or greater than about 2000, up to about 3000 amino acid residues or more in length, wherein the assembled XTEN is substantially non-repetitive. 
     In some embodiments, the binding fusion proteins comprise at least two XTEN segments in which the XTEN segments can be identical or they can be different wherein the cumulative length of the XTEN components are greater than about 100 to about 3000 amino acid residues and comprises at least one sequence segment of at least about 36 to about 923, or at least about 42 to about 875, or at least about 96 to about 576, or at least about 100 to about 288, or at least about 132 to about 144 amino acid residues wherein the sequence segment(s) consists of at least four, or at least five, or at least six different types of amino acids and the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues in the sequence segment(s) constitutes at least about 80%, or at least about 85%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% of the total amino acid sequence of the sequence segment and at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98% of the remainder of the XTEN sequence(s) consist of hydrophilic amino acids and less than about 2% of the remainder of the XTEN sequence(s) consists of hydrophobic or aromatic amino acids, or cysteine. In another embodiment, the invention provides an isolated binding fusion protein wherein the cumulative length of the XTEN component is greater than about 100 to about 3000 amino acid residues and comprises at least one sequence segment of at least about 36 to about 923, or at least about 42 to about 875, or at least about 96 to about 576, or at least about 100 to about 288, or at least about 132 to about 144 amino acid residues wherein the sequence segment(s) the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues in the sequence segment(s) constitutes at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% of the total amino acid sequence of the sequence segment and wherein the subsequence score of a segment or the cumulative segments is less than 10, or less than 9, or less than 8, or less than 7, or less than 6, or less than 5, and at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98% of the remainder of the XTEN sequence(s) consist of hydrophilic amino acids and less than about 2% of the remainder of the XTEN sequence(s) consists of hydrophobic, aromatic or cysteine amino acids. 
     5. N-Terminal XTEN Expression-Enhancing Sequences 
     In one embodiment, the invention provides a short-length XTEN sequence designed to be incorporated as the N-terminal portion of the binding fusion protein, wherein the expression of the fusion protein is enhanced in a host cell transformed with a suitable expression vector comprising an optimized N-terminal leader sequence (that encodes the N-terminal XTEN) incorporated into the polynucleotide encoding the binding fusion protein. It has been discovered, as described in Examples 14-17, that a host cell transformed with such an expression vector comprising an optimized N-terminal leader sequence (NTS) in the binding fusion protein gene results in greatly-enhanced expression of the binding fusion protein compared to the expression of a corresponding binding fusion protein from a polynucleotide not comprising the NTS, and can obviate the need for incorporation of a non-XTEN leader sequence used to enhance expression. In one embodiment of the foregoing, the invention provides binding fusion proteins comprising an NTS wherein the expression of the binding fusion protein from the encoding gene in a host cell is enhanced about 50%, or about 75%, or about 100%, or about 150%, or about 200%, or about 400% compared to expression of a binding fusion protein not comprising the N-terminal XTEN sequence (where the encoding gene lacks the NTS). 
     In one embodiment of the foregoing, the N-terminal XTEN polypeptide comprises a sequence that exhibits at least about 80%, more preferably at least about 90%, more preferably at least about 91%, more preferably at least about 92%, more preferably at least about 93%, more preferably at least about 94%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, more preferably at least 99%, or exhibits 100% sequence identity to the amino acid sequence of AE48 or AM48, the respective sequences as follows:
         AE48: MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGS (SEQ ID NO: 143) AM48: MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGS (SEQ ID NO: 144)       

     In another embodiment, the short-length N-terminal XTEN can be linked to an XTEN of longer length to form the N-terminal region of the binding fusion protein, wherein the polynucleotide sequence encoding the short-length N-terminal XTEN confers the property of enhanced expression in the host cell, and wherein the long length of the expressed XTEN contributes to the enhanced properties of the XTEN carrier in the fusion protein, as described above. In the foregoing, the short-length XTEN can be linked to any of the XTEN disclosed herein (e.g., an XTEN of Table 4) and the resulting XTEN can, in turn, be linked to the N-terminal of any of the targeting moieties disclosed herein (e.g., a targeting moiety directed to a target of Table 1) as a component of the binding fusion protein. Alternatively, polynucleotides encoding the short-length XTEN (or its complement) can be linked to polynucleotides encoding any of the XTEN (or its complement) disclosed herein and the resulting gene encoding the N-terminal XTEN can, in turn, be linked to the 5′ end of polynucleotides encoding any of the targeting moieties (or to the 3′ end of its complement) disclosed herein. In preferred embodiments of the foregoing, the N-terminal XTEN polypeptide with long length can exhibit at least about 80%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least 99%, or exhibits 100% sequence identity to an amino acid sequence selected from the group consisting of the sequences AE624, AE912, and AM923. 
     In any of the foregoing N-terminal XTEN embodiments described above, the N-terminal XTEN can have from about one to about six additional amino acid residues, preferably selected from glycine, serine, threonine, glutamate, proline and alanine, to accommodate the endonuclease restriction sites that is employed to join the nucleotides encoding the N-terminal XTEN to the gene encoding the targeting moiety of the fusion protein. Non-limiting examples of amino acids compatible with the restrictions sites and the preferred amino acids are listed in Table 6, below. The methods for the generation of the N-terminal sequences and incorporation into the fusion proteins of the invention are described more fully in the Examples. 
     6. Net Charge 
     In other embodiments, the XTEN polypeptides have an unstructured characteristic imparted by incorporation of amino acid residues with a net charge and containing a low proportion or no hydrophobic amino acids in the XTEN sequence. The overall net charge and net charge density is controlled by modifying the content of charged amino acids in the XTEN sequences, either positive or negative, with the net charge typically represented as the percentage of amino acids in the polypeptide contributing to a charged state beyond those residues that are cancelled by a residue with an opposing charge. In some embodiments, the net charge density of the XTEN of the compositions may be above +0.1 or below −0.1 charges/residue. By “net charge density” of a protein or peptide herein is meant the net charge divided by the total number of amino acids in the protein or propeptide. In other embodiments, the net charge of an XTEN can be about 0%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% or more. In some embodiments, the XTEN sequence comprises charged residues separated by other residues such as serine or glycine, which leads to better expression or purification behavior. Based on the net charge, some XTENs have an isoelectric point (pI) of 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, or even 6.5. In one embodiment, the XTEN will have an isoelectric point between 1.5 and 4.5 and carry a net negative charge under physiologic conditions. 
     Since most tissues and surfaces in a human or animal have a net negative charge, in some embodiments, the XTEN sequences are designed to have a net negative charge to minimize non-specific interactions between the XTEN containing compositions and various surfaces such as blood vessels, healthy tissues, or various receptors. Not to be bound by a particular theory, the XTEN can adopt open conformations due to electrostatic repulsion between individual amino acids of the XTEN polypeptide that individually carry a net negative charge and that are distributed across the sequence of the XTEN polypeptide. Such a distribution of net negative charge in the extended sequence lengths of XTEN can lead to an unstructured conformation that, in turn, can result in an effective increase in hydrodynamic radius. In preferred embodiments, the negative charge of the subject XTEN is conferred by incorporation of glutamic acid residues. For example, where an XTEN with a negative charge is desired, the XTEN can be selected solely from an AE family sequence, which has approximately a 17% net charge due to incorporated glutamic acid, or can include varying proportions of glutamic acid-containing motifs of Table 3 to provide the desired degree of net charge. Non-limiting examples of AE XTEN include, but are not limited to the AE36, AE42, AE48, AE144, AE288, AE576, AE624, AE864, and AE912 polypeptide sequences of Tables 4 or 12, or fragments thereof. In one embodiment, an XTEN sequence of Tables 4 or 11-15 can be modified to include additional glutamic acid residues to achieve the desired net negative charge. Accordingly, in one embodiment the invention provides XTEN in which the XTEN sequences contain about 1%, 2%, 4%, 8%, 10%, 15%, 17%, 20%, 25%, or even about 30% glutamic acid. Generally, the glutamic residues are spaced uniformly across the XTEN sequence. In some cases, the XTEN can contain about 10-80, or about 15-60, or about 20-50 glutamic residues per 20 kDa of XTEN that can result in an XTEN with charged residues that would have very similar pKa, which can increase the charge homogeneity of the product and sharpen its isoelectric point, enhance the physicochemical properties of the resulting binding fusion protein for, and hence, simplifying purification procedures. In one embodiment, the invention contemplates incorporation of aspartic acid residues into XTEN in addition to glutamic acid in order to achieve a net negative charge. 
     In other cases, where no net charge is desired, the XTEN can be selected from, for example, AG XTEN components, such as the AG motifs of Table 3, or those AM motifs of Table 3 that have approximately no net charge. Non-limiting examples of AG XTEN include, but are not limited to AG42, AG144, AG288, AG576, and AG864 polypeptide sequences of Tables 4 or 14, or fragments thereof. In another embodiment, the XTEN can comprise varying proportions of AE and AG motifs in order to have a net charge that is deemed optimal for a given use or to maintain a given physicochemical property. 
     Not to be bound by a particular theory, the XTEN of the binding fusion protein compositions with the higher net charge are expected to have less non-specific interactions with various negatively-charged surfaces such as blood vessels, tissues, or various receptors, which would further contribute to reduced active clearance. Conversely, it is believed that the XTEN of the binding fusion protein compositions with a low or no net charge would have a higher degree of interaction with surfaces that can potentiate the activity of the associated binding protein, given the known contribution of phagocytic cells in the inflammatory process in the lung. 
     The XTEN of the compositions of the present invention generally have no or a low content of positively charged amino acids. In some embodiments, the XTEN may have less than about 10% amino acid residues with a positive charge, or less than about 7%, or less than about 5%, or less than about 2%, or less than about 1% amino acid residues with a positive charge. However, the invention contemplates constructs where a limited number of amino acids with a positive charge, such as lysine, are incorporated into XTEN to permit conjugation between the epsilon amine of the lysine and a reactive group on a peptide, a linker bridge, or a reactive group on a drug or small molecule to be conjugated to the XTEN backbone. In one embodiment of the foregoing, the XTEN has between about 1 to about 100 lysine residues, or about 1 to about 70 lysine residues, or about 1 to about 50 lysine residues, or about 1 to about 30 lysine residues, or about 1 to about 20 lysine residues, or about 1 to about 10 lysine residues, or about 1 to about 5 lysine residues, or alternatively only a single lysine residue. Using the foregoing lysine-containing XTEN, fusion proteins are constructed that comprises XTEN, a binding protein, plus a chemotherapeutic agent useful in the treatment of diseases or disorders, wherein the maximum number of molecules of the agent incorporated into the XTEN component is determined by the numbers of lysines or other amino acids with reactive side chains (e.g., cysteine) incorporated into the XTEN. 
     As hydrophobic amino acids impart structure to a polypeptide, the invention provides that the content of hydrophobic amino acids in the XTEN will typically be less than 5%, or less than 2%, or less than 1% hydrophobic amino acid content. In one embodiment, the amino acid content of methionine and tryptophan in the XTEN component of a binding fusion protein is typically less than 5%, or less than 2%, and most preferably less than 1%. In another embodiment, the XTEN will have a sequence that has less than 10% amino acid residues with a positive charge, or less than about 7%, or less that about 5%, or less than about 2% amino acid residues with a positive charge, the sum of methionine and tryptophan residues will be less than 2%, and the sum of asparagine and glutamine residues will be less than 10% of the total XTEN sequence. 
     7. Low Immunogenicity 
     In another aspect, the invention provides compositions in which the XTEN sequences have a low degree of immunogenicity or are substantially non-immunogenic. Several factors can contribute to the low immunogenicity of XTEN, e.g., the non-repetitive sequence, the unstructured conformation, the high degree of solubility, the low degree or lack of self-aggregation, the low degree or lack of proteolytic sites within the sequence, and the low degree or lack of epitopes in the XTEN sequence. 
     Conformational epitopes are formed by regions of the protein surface that are composed of multiple discontinuous amino acid sequences of the protein antigen. The precise folding of the protein brings these sequences into a well-defined, stable spatial configurations, or epitopes, that can be recognized as “foreign” by the host humoral immune system, resulting in the production of antibodies to the protein or triggering a cell-mediated immune response. In the latter case, the immune response to a protein in an individual is heavily influenced by T-cell epitope recognition that is a function of the peptide binding specificity of that individual&#39;s HLA-DR allotype. Engagement of a MHC Class II peptide complex by a cognate T-cell receptor on the surface of the T-cell, together with the cross-binding of certain other co-receptors such as the CD4 molecule, can induce an activated state within the T-cell. Activation leads to the release of cytokines further activating other lymphocytes such as B cells to produce antibodies or activating T killer cells as a full cellular immune response. 
     The ability of a peptide to bind a given MHC Class II molecule for presentation on the surface of an APC (antigen presenting cell) is dependent on a number of factors; most notably its primary sequence. In one embodiment, a lower degree of immunogenicity may be achieved by designing XTEN sequences that resist antigen processing in antigen presenting cells, and/or choosing sequences that do not bind MHC receptors well. The invention provides binding fusion proteins with substantially non-repetitive XTEN polypeptides designed to reduce binding with MHC II receptors, as well as avoiding formation of epitopes for T-cell receptor or antibody binding, resulting in a low degree of immunogenicity. Avoidance of immunogenicity is, in part, a direct result of the conformational flexibility of XTEN sequences; i.e., the lack of secondary structure due to the selection and order of amino acid residues. For example, of particular interest are sequences having a low tendency to adapt compactly folded conformations in aqueous solution or under physiologic conditions that could result in conformational epitopes. The administration of fusion proteins comprising XTEN, using conventional therapeutic practices and dosing, would generally not result in the formation of neutralizing antibodies to the XTEN sequence, and may also reduce the immunogenicity of the targeting moiety fusion partner in the binding fusion protein compositions. 
     In one embodiment, the XTEN sequences utilized in the subject fusion proteins can be substantially free of epitopes recognized by human T cells. The elimination of such epitopes for the purpose of generating less immunogenic proteins has been disclosed previously; see for example WO 98/52976, WO 02/079232, and WO 00/3317 which are incorporated by reference herein. Assays for human T cell epitopes have been described (Stickler, M., et al. (2003)  J Immunol Methods,  281: 95-108). Of particular interest are peptide sequences that can be oligomerized without generating T cell epitopes or non-human sequences. This can be achieved by testing direct repeats of these sequences for the presence of T-cell epitopes and for the occurrence of 6 to 15-mer and, in particular, 9-mer sequences that are not human, and then altering the design of the XTEN sequence to eliminate or disrupt the epitope sequence. In one embodiment, the XTEN sequences are substantially non-immunogenic by the restriction of the numbers of epitopes of the XTEN predicted to bind MHC receptors. With a reduction in the numbers of epitopes capable of binding to MHC receptors, there is a concomitant reduction in the potential for T cell activation as well as T cell helper function, reduced B cell activation or upregulation and reduced antibody production. The low degree of predicted T-cell epitopes can be determined by epitope prediction algorithms such as, e.g., TEPITOPE (Sturniolo, T., et al. (1999) Nat Biotechnol, 17: 555-61), as shown in Example 59. The TEPITOPE score of a given peptide frame within a protein is the log of the K d  (dissociation constant, affinity, off-rate) of the binding of that peptide frame to multiple of the most common human MHC alleles, as disclosed in Sturniolo, T. et al. (1999) Nature Biotechnology 17:555). The score ranges over at least 20 logs, from about 10 to about −10 (corresponding to binding constraints of 10e 10  K d  to 10e 10  K d ), and can be reduced by avoiding hydrophobic amino acids that can serve as anchor residues during peptide display on MHC, such as M, I, L, V, F. In some embodiments, an XTEN component incorporated into a binding fusion protein does not have a predicted T-cell epitope at a TEPITOPE threshold score of about −5, or −6, or −7, or −8, or −9, or at a TEPITOPE score of −10. As used herein, a score of “−9” would be a more stringent TEPITOPE threshold than a score of −5. 
     In another embodiment, the inventive XTEN sequences, including those incorporated into the subject binding fusion proteins, can be rendered substantially non-immunogenic by the restriction of known proteolytic sites from the sequence of the XTEN, reducing the processing of XTEN into small peptides that can bind to MHC II receptors. In another embodiment, the XTEN sequence can be rendered substantially non-immunogenic by the use a sequence that is substantially devoid of secondary structure, conferring resistance to many proteases due to the high entropy of the structure. Accordingly, the reduced TEPITOPE score and elimination of known proteolytic sites from the XTEN may render the XTEN compositions, including the XTEN of the binding fusion protein compositions, substantially unable to be bound by mammalian receptors, including those of the immune system. In one embodiment, an XTEN of a binding fusion protein can have &gt;100 nM K d  binding to a mammalian receptor, or greater than 500 nM K d , or greater than 1 μM K d  towards a mammalian cell surface or circulating polypeptide receptor. 
     Additionally, the non-repetitive sequence and corresponding lack of epitopes of XTEN can limit the ability of B cells to bind to or be activated by XTEN. A repetitive sequence is recognized and can form multivalent contacts with even a few B cells and, as a consequence of the cross-linking of multiple T-cell independent receptors, can stimulate B cell proliferation and antibody production. In contrast, while a XTEN can make contacts with many different B cells over its extended sequence, each individual B cell may only make one or a small number of contacts with an individual XTEN due to the lack of repetitiveness of the sequence. As a result, XTENs typically may have a much lower tendency to stimulate proliferation of B cells and thus an immune response. In one embodiment, the binding fusion protein may have reduced immunogenicity as compared to the corresponding targeting moiety that is not fused. In one embodiment, the administration of up to three parenteral doses of a binding fusion protein to a mammal may result in detectable anti-binding fusion protein IgG at a serum dilution of 1:100 but not at a dilution of 1:1000. In another embodiment, the administration of up to three parenteral doses of a binding fusion protein to a mammal may result in detectable anti-targeting moiety IgG at a serum dilution of 1:100 but not at a dilution of 1:1000. In another embodiment, the administration of up to three parenteral doses of a binding fusion protein to a mammal may result in detectable anti-XTEN IgG at a serum dilution of 1:100 but not at a dilution of 1:1000. In the foregoing embodiments, the mammal can be a mouse, a rat, a rabbit, or a cynomolgus monkey. 
     An additional feature of XTENs with non-repetitive sequences relative to sequences with a high degree of repetitiveness can be that non-repetitive XTENs form weaker contacts with antibodies. Antibodies are multivalent molecules. For instance, IgGs have two identical binding sites and IgMs contain 10 identical binding sites. Thus antibodies against repetitive sequences can form multivalent contacts with such repetitive sequences with high avidity, which can affect the potency and/or elimination of such repetitive sequences. In contrast, antibodies against non-repetitive XTENs may yield monovalent interactions, resulting in less likelihood of immune clearance such that the binding fusion protein compositions can remain in circulation for an increased period of time. 
     8. Increased Hydrodynamic Radius 
     In another aspect, the present invention provides XTEN in which the XTEN polypeptides can have a high hydrodynamic radius that confers a corresponding increased apparent molecular weight factor to fusion protein incorporating the XTEN. As detailed in Example 40, the linking of XTEN to targeting moiety sequences can result in binding fusion protein compositions that can have increased hydrodynamic radii, increased apparent molecular weight factor, and increased apparent molecular weight factor compared to a targeting moiety not linked to an XTEN. For example, in therapeutic applications in which prolonged half-life is desired, compositions in which a XTEN with a high hydrodynamic radius is incorporated into a fusion protein comprising one or more targeting moieties can effectively enlarge the hydrodynamic radius of the composition beyond the glomerular pore size of approximately 3-5 nm (corresponding to an apparent molecular weight of about 70 kDA) (Caliceti. 2003. Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev 55:1261-1277), resulting in reduced renal clearance of circulating proteins. The hydrodynamic radius of a protein is determined by its molecular weight as well as by its structure, including shape and compactness. Not to be bound by a particular theory, the XTEN can adopt open conformations due to electrostatic repulsion between individual charges of the peptide or the inherent flexibility imparted by the particular amino acids in the sequence that lack potential to confer secondary structure. The open, extended and unstructured conformation of the XTEN polypeptide can have a greater proportional hydrodynamic radius compared to polypeptides of a comparable sequence length and/or molecular weight that have secondary and/or tertiary structure, such as typical globular proteins. Methods for determining the hydrodynamic radius are well known in the art, such as by the use of size exclusion chromatography (SEC), as described in U.S. Pat. Nos. 6,406,632 and 7,294,513. As the results of Example 40 demonstrate, the addition of increasing lengths of XTEN to a payload polypeptide results in proportional increases in the parameters of hydrodynamic radius, apparent molecular weight factor, and apparent molecular weight factor, permitting the tailoring of binding fusion proteins to desired characteristic cut-off apparent molecular weight factors or hydrodynamic radii. Accordingly, in certain embodiments, the binding fusion protein can be configured with an XTEN such that the fusion protein can have a hydrodynamic radius of at least about 5 nm, or at least about 8 nm, or at least about 10 nm, or 12 nm, or at least about 15 nm. In the foregoing embodiments, the large hydrodynamic radius conferred by the XTEN in a binding fusion protein can lead to reduced renal clearance of the resulting fusion protein, leading to a corresponding increase in terminal half-life, an increase in mean residence time, and/or a decrease in renal clearance rate. 
     In another embodiment, an XTEN of a chosen length and sequence can be selectively incorporated into a binding fusion protein to create a fusion protein that will have, under physiologic conditions, an apparent molecular weight of at least about 150 kDa, or at least about 300 kDa, or at least about 400 kDa, or at least about 500 kDA, or at least about 600 kDa, or at least about 700 kDA, or at least about 800 kDa, or at least about 900 kDa, or at least about 1000 kDa, or at least about 1200 kDa, or at least about 1500 kDa, or at least about 1800 kDa, or at least about 2000 kDa, or at least about 2300 kDa or more. In another embodiment, an XTEN of a chosen length and sequence can be selectively linked to a targeting moiety to result in a binding fusion protein that has, under physiologic conditions, an apparent molecular weight factor of at least three, alternatively of at least four, alternatively of at least five, alternatively of at least six, alternatively of at least eight, alternatively of at least 10, alternatively of at least 15, or an apparent molecular weight factor of at least 20 or greater. In another embodiment, the binding fusion protein has, under physiologic conditions, an apparent molecular weight factor that is about 4 to about 20, or is about 6 to about 15, or is about 8 to about 12, or is about 9 to about 10 relative to the actual molecular weight of the fusion protein. 
     (c) Targeting Moieties 
     In another aspect of the invention, targeting moieties are disclosed that can be linked to one or more XTEN, resulting in monomeric binding fusion protein compositions. “Targeting moieties”, as used herein, refers to polypeptides that have specific binding affinity for a target ligand such as cytokines, chemokines, cytokine receptors, chemokines receptors, hormones, cell-surface receptors or antigens or glycoproteins, oligonucleotides, enzymatic substrates, antigenic determinants, or other binding sites that may be present in the circulation, or on the surface or in the cytoplasm of a target cell. Non-limiting, exemplary targets to which the targeting moieties of the subject compositions are directed are disclosed above; e.g., targets selected from Table 1 and Table 2. The invention provides multiple categories of targeting moieties that can be linked to one or more XTEN in various configurations, resulting in the inventive binding fusion protein compositions. As described more fully below, the targeting moieties can be derived from or based on sequences of antibodies, antibody fragments, receptors, immunoglobulin-like binding domains, or can be completely synthetic. The binding fusion proteins can comprise one or more functional antigen binding sites, the latter making the binding fusion protein “multivalent.” An “antigen binding site” of a binding fusion protein is one that is capable of binding a target antigen with at least a portion of the binding affinity of the parental antibody or receptor from which the antigen binding site is derived. The antigen binding site may itself be composed of more than one binding domain, linked together in the binding fusion proteins. “Binding domain” means a polypeptide sequence capable of attaching to an antigen or ligand but that may require additional binding domains to actually bind and/or sequester the antigen or ligand. A CDR from an antibody is an example of a binding domain. “Antibody” is used throughout the specification as a prototypical example of a targeting moiety but is not intended to be limiting. 
     Methods to measure binding affinity and/or other biologic activity of the binding fusion protein compositions of the invention can be those disclosed herein or methods generally known in the art. In addition, the physicochemical properties of the binding fusion protein may be measured to ascertain the degree of solubility, structure and retention of stability. Assays are conducted that allow determination of binding characteristics of the targeting moieties towards a ligand, including binding dissociation constant (K d , K on  and K off ), the half-life of dissociation of the ligand-receptor complex, as well as the activity of the binding fusion protein to inhibit the biologic activity of the sequestered ligand compared to free ligand (IC 50  values). The term “K d ”, as used herein, is intended to refer to the dissociation constant of a particular antibody-antigen interaction as is known in the art, and would apply as a parameter of the binding affinity of a targeting moiety to its cognate ligand for the subject compositions. The term “K on ”, as used herein, is intended to refer to the on rate constant for association of an antibody to the antigen to form the antibody/antigen complex as is known in the art. The term “K off ”, as used herein, is intended to refer to the off rate constant for dissociation of an antibody from the antibody/antigen complex as is known in the art. The term “IC 50 ” refers to the concentration needed to inhibit half of the maximum biological response of the ligand agonist, and is generally determined by competition binding assays. 
     Techniques such as flow cytometry or surface plasmon resonance can be used to detect binding events. The assays may comprise soluble antigens or receptor molecules, or may determine the binding to cell-expressed receptors. Such assays may include cell-based assays, including assays for proliferation, cell death, apoptosis and cell migration. The binding affinity of the subject compositions for the target ligands can be assayed using binding or competitive binding assays, such as Biacore assays with chip-bound receptors or binding proteins or ELISA assays, as described in U.S. Pat. No. 5,534,617, assays described in the Examples herein, radio-receptor assays, or other assays known in the art. The binding affinity constant can then be determined using standard methods, such as Scatchard analysis, as described by van Zoelen, et al., Trends Pharmacol Sciences (1998) 19)12):487, or other methods known in the art. In addition, libraries of sequence variants of targeting moieties can be compared to the corresponding native or parental antibodies using a competitive ELISA binding assay to determine whether they have the same binding specificity and affinity as the parental antibody, or some fraction thereof such that they are suitable for inclusion in the binding fusion proteins. The results of such assays can be used in an iterative process of sequence modification of the targeting moieties followed by binding and physicochemical characterization assays to guide the process by which specific constructs with the desired properties are selected. 
     In one embodiment, the invention provides isolated binding fusion proteins that competitively inhibit binding of an antibody to a target ligand, as determined by any method known in the art for determining competitive binding, such as the immunoassays described herein. The antibody can include the parental antibody from with the targeting moiety was derived or a positive control known to bind the target epitope or ligand. In preferred embodiments, the binding fusion protein competitively inhibits binding of the positive control to the ligand by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50% in a competitive binding assay against the positive control. 
     The invention provides isolated binding fusion proteins in which the binding affinity of the one or more targeting moieties for target ligands can be at least about 1%, or at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%, or at least about 99%, or at least about 99.9% or more of the affinity of a parental antibody not bound to XTEN for the target receptor or ligand. In one embodiment, the K d  between the one or more targeting moieties of the subject binding fusion protein and a target ligand is less than about 10 −4  M, alternatively less than about 10 −5 M, alternatively less than about 10 −6  M, alternatively less than about 10 −7  M, alternatively less than about 10 −8  M, alternatively less than about 10 −9 M, or less than about 10 −10  M, or less than about 10 −11 M, or less than about 10 −12 M. In the foregoing embodiment, the binding affinity of the binding fusion protein towards the target would be characterized as “specific.” The invention contemplates binding fusion proteins comprising two or more targeting moieties in which the binding affinities for the respective targeting moieties may independently be between the ranges of values of the foregoing. In any of the foregoing embodiments of the paragraph, the one or more targeting moieties of the subject binding fusion proteins specifically bind to a target of Table 1 or Table 2. 
     Binding fusion proteins of the present invention may also be described or specified in terms of the cross-reactivity of the targeting moiety. In one embodiment, the invention provides binding fusion proteins that do not bind any other analog, ortholog, or homolog of a target disclosed herein. In one embodiment, binding fusion proteins can bind polypeptides with at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 65%, at least 60%, at least 55%, and at least 50% sequence identity (as calculated using methods known in the art and described herein) to a polypeptide target described herein. 
     The binding fusion proteins of the present invention may act as agonists or antagonists. For example, the present invention includes binding fusion proteins comprising targeting moieties that disrupt receptor/ligand interactions either partially or fully. The invention features both receptor-specific BFP and ligand-specific BFP. The invention also features receptor-specific binding fusion proteins that do not prevent ligand binding but prevent receptor activation. Receptor activation, such as cell signaling, may be determined by techniques described herein or otherwise known in the art. For example, receptor activation can be determined by detecting the phosphorylation (e.g., tyrosine or serine/threonine) of the receptor or its substrate by immunoprecipitation followed by standard Western blot analysis techniques. In specific embodiments, binding fusion proteins are provided that can bind to and inhibit ligand or receptor activity by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50% of the activity compared to the activity in the absence of the binding fusion protein. 
     The invention provides receptor-specific binding fusion proteins that both prevent ligand binding and receptor activation as well as binding fusion proteins that recognize the receptor-ligand complex, yet, preferably, do not specifically recognize the unbound receptor or the unbound ligand. In one embodiment, the invention provides neutralizing binding fusion proteins that bind the ligand, thereby forming a neutralizing complex that prevents binding of the ligand to the receptor, or, in other cases, can bind the ligand but do not prevent the ligand from binding the receptor, yet nevertheless result in reduced receptor activation in comparison to non-complexed ligand. Further included in the invention are binding fusion proteins that activate the receptor. These BFP may act as receptor agonists, i.e., potentiate or activate either all or a subset of the biological activities of the ligand-mediated receptor activation. 
     In another embodiment, the invention provides isolated binding fusion proteins in which the fusion protein is designed to bind with high affinity to a target receptor, thereby resulting in antagonistic activity for the native ligand. In such cases, the BFPs can have affinity but no efficacy for their cognate receptors such that their binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at the receptors. Typically, such antagonistic activity will be of a competitive type, and a K i  can be determined. A non-limiting example of an antagonist BFP is a fusion protein comprising a targeting moiety configured to bind to an IL-1 receptor (IL-1R) such that the bound composition substantially interferes with the binding of IL-1 α and/or IL-1β to IL-1 receptor. In certain cases, the interference by an antagonist binding fusion protein (such as, but not limited to an anti-IL-1R binding fusion protein) with the binding of the native ligand to its cognate receptor can be at least about 1%, or about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 95%, or about 99% or more. In other embodiments, the invention provides isolated binding fusion proteins (such as, but not limited to anti-IL-1R binding fusion protein) wherein the binding of the isolated fusion protein to a cellular receptor elicits less than 20%, or less than 10%, or less than 5% activation of the signaling pathways of the cell with bound binding fusion protein antagonist in comparison to those evoked by the native ligand. 
     In one embodiment, the invention provides isolated binding fusion proteins comprising targeting moieties directed to one or more target cytokines, cytokine-related proteins, cytokine receptors, chemokines, chemokines receptors, cell surface receptors, hormones or similar circulating proteins or peptides, oligonucleotides, or enzymatic substrates. In one embodiment, the one or more targeting moieties can have specific binding affinity to targets selected from, but not limited to the targets of Table 1. In another embodiment, the one or more targeting moieties can have specific binding affinity to targets selected from, but not limited to the tumor associated antigen targets of Table 2. 
     The present invention provides a variety of binding fusion protein configurations in which the variations are based on inclusion of the type and relative position or number of binding domains, as well as the inclusion of linkers of pre-determined length and one or more XTEN sequences. By design, the resulting binding fusion protein compositions can be monomeric or multivalent, they can bind a single ligand or antigen, or be multimeric as to the number of binding units encompassed in the fusion protein. 
     In one embodiment, the invention provides binding fusion proteins comprising targeting moieties capable of binding to a single ligand. In another embodiment, the binding fusion proteins of the invention are multivalent and the targeting moieties specifically bind at least two different target antigens or ligands (“bifunctional” or “bispecific”), or different epitopes on the same ligand. The multivalent binding fusion proteins can be designed to be bifunctional in that they can incorporate heterologous binding domains from different “parental” antibodies and bind two different ligands or antigens in order to better effect a desired pharmacological response; e.g., dimerization of receptors on a target cell surface leading to cell signaling or, alternatively, cell death, or modulating a biological function of one or more targets. Multimeric binding fusion protein leading to cell death, whether by triggering apoptosis or necrosis, are expected to have utility in, particularly, the treatment of oncological disease. Non-limiting examples of pairs of targets contemplated as suitable for multivalent, bifunctional binding fusion proteins include: IGF1 and IGF2; IGF1/2 and Erb2B; VEGFR and EGFR; CD20 and CD3, CD138 and CD20, CD38 and CD20, CD38 &amp; CD138, CD40 and CD20, CD138 and CD40, CD38 and CD40. 
     In one embodiment, the binding fusion proteins of the invention specifically bind at least two cytokines, lymphokines, monokines, and/or polypeptide hormones. Non-limiting examples of pairs of targets to which bifunctional binding fusion proteins can bind are selected from, but not limited to IL-1α and IL-1β; IL-12 and IL-18, TNFα and IL-23, TNFα and IL-13; TNF and IL-18; TNF and IL-12; TNF and IL-1beta; TNF and MIF; TNF and IL-17; and TNF and IL-15; TNF and VEGF; VEGFR and EGFR; IL-13 and IL-9; IL-13 and IL-4; IL-13 and IL-5; IL-13 and IL-25; IL-13 and TARC; IL-13 and MDC; IL-13 and MIF; IL-13 and TGF-β; IL-13 and LHR agonist; IL-13 and CL25; IL-13 and SPRR2a; IL-13 and SPRR2b; IL-13 and ADAM8; and TNFα and PGE4, IL-13 and PED2, TNF and PEG2. 
     Examples of other pairs of targets suitable for multivalent bifunctional binding fusion proteins, include but are not limited to CD19 and CD20; CD-8 and IL-6; PDL-1 and CTLA-4; CTLA-4 and BTNO2; CSPGs and RGM A; IL-12 and IL-18; IL-12 and TWEAK; IL-13 and ADAM8; IL-13 and CL25; IL-13 and IL-1beta; IL-13 and IL-25; IL-13 and IL-4; IL-13 and IL-5; IL-13 and IL-9; IL-13 and LHR agonist; IL-13 and MDC; IL-13 and MIF; IL-13 and PED2; IL-13 and SPRR2a; IL-13 and SPRR2b; IL-13 and TARC; IL-13 and TGF-β; IL-1α and IL-1β; MAG and RGM A; NgR and RGM A; NogoA and RGM A; OMGp and RGM A; RGM A and RGM B; Te38 and TNFα; TNFα and IL-12; TNFα and IL-12p40; TNFα and IL-13; TNFα and IL-15; TNFα and IL-17; TNFα and IL-18; TNFα and IL-1beta; TNFα and IL-23; TNFα and MIF; TNFα and PEG2; TNFα and PGE4; TNFα and VEGF; TNFα and RANK ligand; TNFα and Blys; TNFα and GP130; TNFα and CD-22; and TNFα and CTLA-4. 
     In another embodiment the binding fusion proteins of the invention specifically bind to pairs of targets selected from, but not limited to CD and CD20; CD138 and CD40; CD19 and CD20; CD20 and CD3; CD38 &amp; CD138 CD38 and CD20; CD38 and CD40; CD40 and CD20; CD-8 and IL-6; CSPGs and RGM A; CTLA4 and BTNO2; IGF1 and IGF2; IGF1/2 and Erb2B; IL-12 and TWEAK; IL-13 and IL-1β; MAG and RGM A; NgR and RGM A; NogoA and RGM A; OMGp and RGM A; PDL-1 and CTLA4; RGM A and RGM B; Te38 and TNFα; TNFα and Blys; TNFα and CD-22; TNFα and CTLA-4; TNFα and GP130; TNFα and IL-12p40; and TNFα and RANK ligand. 
     The targeting moieties of the binding fusion proteins can be derived from one or more fragments of various monoclonal antibodies known in the art. Non-limiting examples of such monoclonal antibodies include, but are not limited to anti-TNF antibody (U.S. Pat. No. 6,258,562), anti-IL-12 and or anti-IL-12p40 antibody (U.S. Pat. No. 6,914,128); anti-IL-18 antibody (US 2005/0147610 A1), anti-RANKL (U.S. Pat. No. 7,411,050), anti-05, anti-CBL, anti-CD147, anti-gp120, anti-VLA4, anti-CD11a, anti-CD18, anti-VEGF, anti-CD40 L, anti-Id, anti-ICAM-1, anti-CXCL13, anti-CD2, anti-EGFR, anti-TGF-beta 2, anti-E-selectin, anti-Fact VII, anti-Her2/neu, anti-Fgp, anti-CD11/18, anti-CD14, anti-ICAM-3, anti-CD80, anti-CD4, anti-CD3, anti-CD23, anti-beta2-integrin, anti-alpha4beta7, anti-CD52, anti-HLA DR, anti-CD22, anti-CD20, anti-MIF, anti-CD64 (FcR), anti-TCR alpha beta, anti-CD2, anti-Hep B, anti-CA 125, anti-EpCAM, anti-gp120, anti-CMV, anti-gpllbllla, anti-IgE, anti-CD25, anti-CD33, anti-HLA, anti-VNRintegrin, anti-IL-1alpha, anti-IL-1beta, anti-IL-1 receptor, anti-IL-2 receptor, anti-IL-4, anti-IL4 receptor, anti-IL5, anti-IL-5 receptor, anti-IL-6, anti-IL-8, anti-IL-9, anti-IL-13, anti-IL-13 receptor, anti-IL-17, and anti-IL-23 (see Presta L G. 2005 Selection, design, and engineering of therapeutic antibodies J Allergy Clin Immunol. 116:731-6 and Clark, M., “Antibodies for Therapeutic Applications,” Department of Pathology, Cambridge University, UK, 15 Oct. 2000, published online at M. Clark&#39;s home page at the website for the Department of Pathology, Cambridge University). 
     In some embodiments, the targeting moieties are derived from one or more fragments of therapeutic monoclonal antibodies approved for use in humans or antibodies that have demonstrated efficacy in clinical trials or established preclinical models of diseases, disorders or conditions. Such therapeutic antibodies include, but are not limited to, rituximab, IDEC/Genentech/Roche (see for example U.S. Pat. No. 5,736,137), a chimeric anti-CD20 antibody used in the treatment of many lymphomas, leukemias, and some autoimmune disorders; ofatumumab, an anti-CD20 antibody approved for use for chronic lymphocytic leukemia, and under development for follicular non-Hodgkin&#39;s lymphoma, diffuse large B cell lymphoma, rheumatoid arthritis and relapsing remitting multiple sclerosis, being developed by GlaxoSmithKline; lucatumumab (HCD122), an anti-CD40 antibody developed by Novartis for Non-Hodgkin&#39;s or Hodgkin&#39;s Lymphoma (see, for example, U.S. Pat. No. 6,899,879), AME-133, an antibody developed by Applied Molecular Evolution which binds to cells expressing CD20 to treat non-Hodgkin&#39;s lymphoma, veltuzumab (hA20), an antibody developed by Immunomedics, Inc. which binds to cells expressing CD20 to treat immune thrombocytopenic purpura, HumaLYM developed by Intracel for the treatment of low-grade B-cell lymphoma, and ocrelizumab, developed by Genentech which is an anti-CD20 monoclonal antibody for treatment of rheumatoid arthritis (see for example U.S. Patent Application 20090155257), trastuzumab (see for example U.S. Pat. No. 5,677,171), a humanized anti-Her2/neu antibody approved to treat breast cancer developed by Genentech; pertuzumab, an anti-Her2 dimerization inhibitor antibody developed by Genentech in treatment of in prostate, breast, and ovarian cancers; (see for example U.S. Pat. No. 4,753,894); cetuximab, an anti-EGRF antibody used to treat epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type metastatic colorectal cancer and head and neck cancer, developed by Imclone and BMS (see U.S. Pat. No. 4,943,533; PCT WO 96/40210); panitumumab, a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor, EGFR, ErbB-1 and Herl, currently marketed by Amgen for treatment of metastatic colorectal cancer (see U.S. Pat. No. 6,235,883); zalutumumab, a fully human IgG1 monoclonal antibody developed by Genmab that is directed towards the epidermal growth factor receptor (EGFR) for the treatment of squamous cell carcinoma of the head and neck (see for example U.S. Pat. No. 7,247,301); nimotuzumab, a chimeric antibody to EGFR developed by Biocon, YM Biosciences, Cuba, and Oncosciences, Europe) in the treatment of squamous cell carcinomas of the head and neck, nasopharyngeal cancer and glioma (see for example U.S. Pat. Nos. 5,891,996; 6,506,883); alemtuzumab, a humanized monoclonal antibody to CD52 marketed by Bayer Schering Pharma for the treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma; muromonab-CD3, an anti-CD3 antibody developed by Ortho Biotech/Johnson &amp; Johnson used as an immunosuppressant biologic given to reduce acute rejection in patients with organ transplants; ibritumomab tiuxetan, an anti-CD20 monoclonal antibody developed by IDEC/Schering AG as treatment for some forms of B cell non-Hodgkin&#39;s lymphoma; gemtuzumab ozogamicin, an anti-CD33 (p67 protein) antibody linked to a cytotoxic chelator tiuxetan, to which a radioactive isotope is attached, developed by Celltech/Wyeth used to treat acute myelogenous leukemia; alefacept, an anti-LFA-3 Fc fusion developed by Biogen that is used to control inflammation in moderate to severe psoriasis with plaque formation; abciximab, made from the Fab fragments of an antibody to the IIb/IIIa receptor on the platelet membrane developed by Centocor/Lilly as a platelet aggregation inhibitor mainly used during and after coronary artery procedures; basiliximab, a chimeric mouse-human monoclonal antibody to the α chain (CD25) of the IL-2 receptor of T cells, developed by Novartis, used to prevent rejection in organ transplantation; palivizumab, developed by Medimmune; infliximab (REMICADE), an anti-TNFalpha antibody developed by Centocor/Johnson and Johnson, adalimumab (HUMIRA), an anti-TNFalpha antibody developed by Abbott, HUMICADE, an anti-TNFalpha antibody developed by Celltech, etanercept (ENBREL), an anti-TNFalpha Fc fusion developed by Immunex/Amgen, ABX-CBL, an anti-CD147 antibody developed by Abgenix, ABX-IL8, an anti-IL8 antibody developed by Abgenix, ABX-MA1, an anti-MUC18 antibody developed by Abgenix, Pemtumomab (R1549, 90Y-muHMFG1), an anti-MUC1 in development by Antisoma, Therex (R1550), an anti-MUC1 antibody developed by Antisoma, AngioMab (AS1405), developed by Antisoma, HuBC-1, developed by Antisoma, Thioplatin (AS1407) developed by Antisoma, ANTEGREN (natalizumab), an anti-alpha-4-beta-1 (VLA4) and alpha-4-beta-7 antibody developed by Biogen, VLA-1 mAb, an anti-VLA-1 integrin antibody developed by Biogen, LTBR mAb, an anti-lymphotoxin beta receptor (LTBR) antibody developed by Biogen, CAT-152, an anti-TGF-β2 antibody developed by Cambridge Antibody Technology, J695, an anti-IL-12 antibody developed by Cambridge Antibody Technology and Abbott, CAT-192, an anti-TGFβ1 antibody developed by Cambridge Antibody Technology and Genzyme, CAT-213, an anti-Eotaxin1 antibody developed by Cambridge Antibody Technology, LYMPHOSTAT-B, an anti-Blys antibody developed by Cambridge Antibody Technology and Human Genome Sciences Inc., TRAIL-R1mAb, an anti-TRAIL-R1 antibody developed by Cambridge Antibody Technology and Human Genome Sciences, Inc., bevacizumab (AVASTIN, rhuMAb-VEGF), an anti-VEGF antibody developed by Genentech, HERCEPTIN, an anti-HER receptor family antibody developed by Genentech, Anti-Tissue Factor (ATF), an anti-Tissue Factor antibody developed by Genentech, XOLAIR (Omalizumab), an anti-IgE antibody developed by Genentech, MLN-02 Antibody (formerly LDP-02), developed by Genentech and Millennium Pharmaceuticals, HUMAX CD4®, an anti-CD4 antibody developed by Genmab, tocilizuma, and anti-IL6R antibody developed by Chugai, HUMAX-IL15, an anti-IL15 antibody developed by Genmab and Amgen, HUMAX-Inflam, developed by Genmab and Medarex, HUMAX-Cancer, an anti-Heparanase I antibody developed by Genmab and Medarex and Oxford GlycoSciences, HUMAX-Lymphoma, developed by Genmab and Amgen, HUMAX-TAC, developed by Genmab, IDEC-131, and anti-CD40 L antibody developed by IDEC Pharmaceuticals, IDEC-151 (Clenoliximab), an anti-CD4 antibody developed by IDEC Pharmaceuticals, IDEC-114, an anti-CD80 antibody developed by IDEC Pharmaceuticals, IDEC-152, an anti-CD23 developed by IDEC Pharmaceuticals, anti-macrophage migration factor (MIF) antibodies developed by IDEC Pharmaceuticals, BEC2, an anti-idiotypic antibody developed by Imclone, IMC-1C11, an anti-KDR antibody developed by Imclone, DC101, an anti-flk-1 antibody developed by Imclone, anti-VE cadherin antibodies developed by Imclone, CEA-CIDE (labetuzumab), an anti-carcinoembryonic antigen (CEA) antibody developed by Immunomedics, Yervoy (ipilimumab), an anti-CTLA4 antibody developed by Bristol-Myers Sequibb in the treatment of melanoma, LYMPHOCIDE (Epratuzumab), an anti-CD22 antibody developed by Immunomedics, AFP-Cide, developed by Immunomedics, MyelomaCide, developed by Immunomedics, LkoCide, developed by Immunomedics, ProstaCide, developed by Immunomedics, MDX-010, an anti-CTLA4 antibody developed by Medarex, MDX-060, an anti-CD30 antibody developed by Medarex, MDX-070 developed by Medarex, MDX-018 developed by Medarex, OSIDEM (IDM-1), and anti-Her2 antibody developed by Medarex and Immuno-Designed Molecules, HUMAX®-CD4, an anti-CD4 antibody developed by Medarex and Genmab, HuMax-IL15, an anti-IL15 antibody developed by Medarex and Genmab, CNTO 148, an anti-TNFα antibody developed by Medarex and Centocor/J&amp;J, CNTO 1275, an anti-cytokine antibody developed by Centocor/J&amp;J, MOR101 and MOR102, anti-intercellular adhesion molecule-1 (ICAM-1) (CD54) antibodies developed by MorphoSys, MOR201, an anti-fibroblast growth factor receptor 3 (FGFR-3) antibody developed by MorphoSys, tremelimumab, an anti-CTLA-4 antibody developed by Pfizer, visilizumab, an anti-CD3 antibody developed by Protein Design Labs, HUZAF, an anti-gamma interferon antibody developed by Protein Design Labs, Anti-a 5β1 Integrin, developed by Protein Design Labs, anti-IL-12, developed by Protein Design Labs, ING-1, an anti-Ep-CAM antibody developed by Xoma, XOLAIR® (Omalizumab) a humanized anti-IgE antibody developed by Genentech and Novartis, and MLN01, an anti-Beta2 integrin antibody developed by Xoma; all of the above-cited antibody references in this paragraph are expressly incorporated herein by reference. The sequences for the above antibodies can be obtained from publicly available databases, patents, or literature references. 
     1. Exemplary Targeting Moieties 
     The following section provides a non-limiting list and description of exemplary targeting moieties and their use in binding fusion proteins. 
     Anti-Her2: 
     In one embodiment, the invention provides an isolated anti-Her2 binding fusion protein. “Anti-Her2” means a targeting moiety that specifically binds to the extracellular domain of the HER2/neu receptor (a.k.a. erbB-2 protein), including antibodies, antibody fragments, fragment dimers, traps, and other polypeptides with binding affinity to the domain IV of the HER2/erbB-2 protein. The HER2-encoding gene is found on band q21 of chromosome 17, generates a messenger RNA (MRNA) of 4.8 kb, and the protein encoded by the HER2 gene is 185,000 Daltons. In normal subject, ligands that bind to the HER2 receptor promote dimerization with other receptors, resulting in signal transduction and activation of the PI3K/Akt pathway and the MAPK pathway. 
     In approximately 25% of breast cancers, the HER2 gene is amplified by 2-fold to greater than 20-fold in each tumor cell nucleus relative to the number of copies of chromosome 17. Amplification of the HER2gene drives protein expression and the resulting increase in the number of receptors at the tumor-cell surface promotes receptor activation, leading to signaling, excessive cellular division, and the formation of tumors (Hicks, D G et al., HER2+ breast cancer: review of biologic relevance and optimal use of diagnostic tools. Am J Clin Pathol. (2008) 129(2):263-73). 
     The anti-Her2 used as a fusion partner with XTEN creates a binding fusion protein composition that has can have therapeutic utility when administered to a subject by binding to the extracellular domain of the extracellular segment of the HER2/neu receptor. Such binding can interfere with receptor dimerization and the resulting activation of EGFR intrinsic tyrosine kinase function (Yarden et al, Biochemistry, (1988), 27, 3114-3118; Schlessinger, Biochemistry, (1988), 27, 3119-3123), with the result that cells with bound receptors undergo arrest during the G1 phase of the cell cycle so there is reduced proliferation of tumor cells, as well as suppression of angiogenesis. 
     One object of the invention is to provide novel anti-Her2 binding fusion proteins comprising one or more binding moieties that specifically bind to erbB-2 protein and that do not substantially bind to normal human cells, which may be utilized for the treatment or prevention of erbB-2 expressing tumor cells, or for the immunological detection of erbB-2 expressing tumor cells. The CDR and FR residues of a humanized HER2 antibody have been reported in Carter et al.,  Proc. Natl. Acad. Sci. USA,  89:4285 (1992). In one embodiment, the anti-Her2 antibody compositions comprise a single anti-Her2 targeting moiety linked to at least a first XTEN. In another embodiment, the anti-Her2 compositions comprise a first and a second anti-Her2 targeting moiety, which may be the same or which may bind different epitopes of the erbB-2 protein. In one embodiment, the anti-Her2 component of a binding fusion protein comprises one or more complementarity determining regions (CDRs) of trastuzumab capable of binding to the domain IV of the extracellular segment of the HER2/neu receptor. 
     Another embodiment of the invention relates to a method of inhibiting growth of tumor cells by administering to a patient a therapeutically effective amount of anti-Her2 binding fusion protein composition capable of inhibiting the HER2 receptor function. A further embodiment of the invention relates to administering a therapeutically effective amount of anti-Her2 composition capable of inhibiting growth factor receptor function, and a therapeutically effective amount of a cytotoxic factor. Still another object of the invention is to provide methods for the treatment and/or prevention of erbB-2 receptor over-expressing tumors comprising the administration of an anti-tumor effective amount of at least one of the disclosed anti-Her2 fusion proteins capable of binding to cancer cells associated by the over-expression of erbB-2 protein. In another embodiment, the invention provides a method for the treatment and/or prevention of erbB-2 receptor over-expressing tumors comprising the administration of therapeutically-effective amounts of anti-Her2 fusion protein comprising a first and a second anti-Her2 binding moiety, which may be the same or which may bind different epitopes of the erbB-2 protein, capable of inhibiting the HER2 receptor function. Preferably, such combinations of binding moieties will exhibit better cytotoxic activity than would be expected for the sum of the cytotoxic activity of the individual antibodies at the same overall antibody concentration. Additionally, one or more of the administered antibodies may be conjugated to a cytotoxic moiety, e.g., an anti-tumor drug, toxin, or radionuclide. 
     Anti-RSV: 
     In another embodiment, the invention provides an isolated anti-RSV binding fusion protein. “Anti-RSV” means a targeting moiety that specifically binds to surface antigens of respiratory syncytial virus (RSV). An anti-RSV can be an antibody or fragment thereof that neutralizes RSV, preventing its ability to establish an infection in a mammal, or that contributes to the clearance of RSV from an infected host. The anti-RSV can be used as a fusion partner with XTEN to create a fusion protein composition that has prophylactic or therapeutic utility when administered to a subject, such as an infant at risk for RSV infection. In one embodiment, the anti-RSV component of a binding fusion protein comprises one or more complementarity determining regions (CDRs) of palivizumab. Antibodies to RSV have been described in U.S. Pat. No. 5,824,307. 
     Anti-cMet: 
     In another embodiment, the invention provides an isolated anti-cMet binding fusion protein. “Anti-cMet” means a targeting moiety that specifically binds to Met, or hepatocyte growth factor (HGF) receptor. MET is a proto-oncogene, with the encoded hepatocyte growth factor receptor (HGFR) or cMet having tyrosine-kinase activity essential for embryonic development and wound healing. Upon HGF binding and stimulation, MET induces several biological responses that collectively give rise to invasive growth. Abnormal MET activation in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, angiogenesis and formation of new blood vessels that supply the tumor with nutrients, and cancer spread to other organs (metastasis). MET is deregulated in many types of human malignancies, including cancers of kidney, liver, stomach, breast, and brain. Anti-cMET can be an targeting moiety that specifically binds to a HGF receptor, serving as an antagonist to HGF. The anti-cMET can be used as a fusion partner with XTEN to create a fusion protein composition that has prophylactic or therapeutic utility when administered to a subject for the treatment of MET-expressing tumors. In one embodiment, the anti-cMET component of a binding fusion protein comprises one or more complementarity determining regions (CDRs) of the antibody MetMab or PRO143966. Antibodies to cMet and their sequences have been described in U.S. Pat. Nos. 5,686,292. U.S. Pat. Nos. 6,468,529 7,476,724 and U.S. Patent Application Publication No. 20070092520. 
     Anti-IL6R: 
     In another embodiment, the invention provides an isolated anti-IL6R binding fusion protein. “Anti-IL6R” means a targeting moiety that specifically binds to an IL-6 receptor. Anti-IL6R can serve as an antagonist to IL-6. The anti-IL6R can be used as a fusion partner with XTEN to create a fusion protein composition that has prophylactic or therapeutic utility when administered to a subject for inflammatory conditions, such as arthritis or Crohn&#39;s disease. Tocilizuma has been shown to have clinical utility in moderate to severe rheumatoid arthritis, and has been approved by the FDA. In one embodiment, the anti-IL6R component of a binding fusion protein comprises one or more complementarity determining regions (CDRs) of tocilizuma. Antibodies to IL-6R have been described in U.S. Pat. Nos. 5,670,373, 5,795,965, 5,817,790, and 7,479,543. 
     Anti-IL17: 
     In another embodiment, the invention provides an isolated anti-IL17 binding fusion protein. “Anti-IL17” means a targeting moiety that specifically binds to the cytokine IL-17. IL-17 is a disulfide-linked homodimeric cytokine of about 32 kDa which is synthesized and secreted only by CD4+ activated memory T cells (reviewed in Fossiez et al., Int. Rev. Immunol., 16: 541-551 (1998)). Interleukin (IL-17) is a pro-inflammatory T cell cytokine that is expressed, for example, in the synovial fluid of patients with rheumatoid arthritis. IL-17 is a potent inducer of various cytokines such as TNF and IL-1, and IL-17 has been shown to have additive or even synergistic effects with TNF and IL-1. The anti-IL17 can be used as a fusion partner with XTEN to create a binding fusion protein composition that has prophylactic or therapeutic utility when administered to a subject for inflammatory conditions, such as arthritis or Crohn&#39;s disease, or in multiple sclerosis. LY2439821 is an antibody that has shown utility, when added to oral DMARDs, in improving signs and symptoms of rheumatoid arthritis. In one embodiment, the anti-IL6R component of a binding fusion protein comprises one or more complementarity determining regions (CDRs) of LY2439821. Anti-IL17 antibodies have been described in US Patent Application Nos. 20050147609 and 20080269467 and PCT application publication WO 2007/070750. 
     IL17R: 
     In another embodiment, the invention provides an isolated IL17R binding fusion protein. “IL17R” means a targeting moiety that specifically binds to the cytokine receptor for IL-17. Studies have shown that contacting T cells with a soluble form of the IL-17 receptor polypeptide inhibited T cell proliferation and IL-2 production induced by PHA, concanavalin A and anti-TCR monoclonal antibody (Yao et al.,  J. Immunol.,  155:5483-5486 [1995]). As interleukin (IL-17) is a pro-inflammatory T cell cytokine that is a potent inducer of various cytokines such as TNF and IL-1, the IL17R can be used as a fusion partner with XTEN to create a binding fusion protein composition to bind and neutralize IL-17. The IL17R can have therapeutic utility when administered to a subject for inflammatory conditions, such as rheumatoid arthritis or Crohn&#39;s disease. IL7R receptors and homologs have been cloned, as described in U.S. Pat. No. 5,869,286. 
     Anti-IL12: 
     In another embodiment, the invention provides an isolated anti-IL12 binding fusion protein. “Anti-IL12” means a targeting moiety that specifically binds to the cytokine IL-12 and, in some cases, IL-23. Biologically active IL-12 exists as a heterodimer comprised of 2 covalently linked subunits of 35 (p35) and 40 (p40) kD, the latter being known as IL-23. IL-12 is a cytokine that is an important part of the inflammatory response, and stimulates the production of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) from T and natural killer (NK) cells, and reduces IL-4 mediated suppression of IFN-γ. T cells that produce IL-12 have a coreceptor, CD30, which is associated with IL-12 activity. IL-12 has also been linked with autoimmunity and with psoriasis, with the interaction between T lymphocytes and stem cell keratinocytes that produce IL-12 being of significance. Ustekinumab is an anti-IL12/23 antibody that has demonstrated utility in the treatment of moderate to severe plaque psoriasis, and has been approved by the FDA. The anti-IL-12 can be used as a fusion partner with XTEN to create a fusion protein composition that has therapeutic utility when administered to a subject suffering from inflammatory conditions, such as, but not limited to, psoriasis, rheumatoid arthritis or Crohn&#39;s disease. In one embodiment, the anti-IL12 component of a binding fusion protein comprises one or more complementarity determining regions (CDRs) of the antibody ustekinumab. Antibodies to IL-12 and their use have been described in U.S. Pat. No. 7,279,157. 
     Anti-IL23: 
     In another embodiment, the invention provides an isolated anti-IL23 binding fusion protein. “Anti-IL23” means a targeting moiety that specifically binds to the cytokine IL-23. IL-23 is the name given to a factor that is composed of the p40 subunit of IL-12, and is a pro-inflammatory cytokine that is an important part of the inflammatory response against infection. IL-23 promotes upregulation of the matrix metalloprotease MMP9, increases angiogenesis and reduces CD8+ T-cell infiltration. IL-23 has been demonstrated to play a role in psoriasis, multiple sclerosis and inflammatory bowel. Ustekinumab is an anti-IL23 antibody that has demonstrated utility in psoriasis. The anti-IL-23 can be used as a fusion partner with XTEN to create a fusion protein composition that has therapeutic utility when administered to a subject suffering from inflammatory conditions, such as, but not limited to, psoriasis, rheumatoid arthritis or Crohn&#39;s disease. In one embodiment, the anti-IL23 component of a binding fusion protein comprises one or more complementarity determining regions (CDRs) of the antibody ustekinumab. Antibodies to IL-23 have been described in U.S. Pat. Nos. 7,491,391 and 7,247,711. 
     Anti-RANKL: 
     In another embodiment, the invention provides an isolated anti-RANKL binding fusion protein. “Anti-RANKL” means a targeting moiety that specifically binds to the protein RANKL (receptor activator of nuclear factor kappa B Ligand or RANK ligand). RANKL is a protein that acts as the primary signal to promote bone removal, driven by osteoclasts, which break bone down. In many bone loss conditions, RANKL overwhelms the body&#39;s natural defense against bone destruction. The anti-RANKL can be used as a fusion partner with XTEN to create a fusion protein composition that has therapeutic utility when administered to a subject by inhibiting the maturation of osteoclasts by binding to RANKL, protecting the bone from degradation and thus from osteoporosis. The binding fusion protein therefore mimics the endogenous effects of osteoprotegerin, another protein produced by osteoblasts which acts as an alternate receptor for RANKL, modulating the RANK/RANKL induced osteoclast activity. Antibodies to RANKL, such as denosumab, have demonstrated efficacy in Phase III trials demonstrated in post-menopausal osteoporosis. In one embodiment, the anti-RANKL component of a binding fusion protein comprises one or more complementarity determining regions (CDRs) of the antibody denosumab. Anti-RANKL antibodies have been described in U.S. Pat. No. 7,411,050. 
     CTLA4: 
     In another embodiment, the invention provides an isolated CTLA4 binding fusion protein. “CTLA4” means a targeting moiety that specifically binds to CD80 and CD86 on antigen-presenting cells, and can specifically bind B7. The CTLA4 can be used as a fusion partner with XTEN to create a fusion protein composition that has therapeutic utility when administered to a subject suffering from inflammatory conditions, such as, but not limited to, rheumatoid arthritis, psoriasis and in organ transplantation. Belatacept is a fusion protein composed of the Fc fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4 that has shown efficacy in providing extended graft survival. In one embodiment, the CTLA4 binding component of the binding fusion protein comprises one or more binding regions from belatacept. The cloning and use of CTLA4 compositions have been described in U.S. Pat. Nos. 5,434,131, 5,773,253, 5,851,795, 5,885,579, 7,094,874, and 7,439,230. 
     ANTI-CD3: 
     In another embodiment, the invention provides an isolated anti-CD3 binding fusion protein. “Anti-CD3” means a targeting moiety that specifically binds to CD3 T-cell receptor. T-Cell Co-Receptor is a protein complex composed of four distinct chains; a CD3γ chain, a CD3δ chain, and two CD3c chains. These chains associate with a molecule known as the T cell receptor (TCR) and the chain to generate an activation signal in T lymphocytes. Anti-CD3 monoclonal antibodies suppress immune responses by transient T-cell depletion and antigenic modulation of the CD3/T-cell receptor complex. For example, anti-CD3 treatment of adult nonobese diabetic (NOD) mice, a spontaneous model of T-cell-mediated autoimmune insulin-dependent diabetes mellitus, can inhibit the autoimmune process leading to diabetes. The use of anti-CD3 antibodies to treat diseases and disorders has been described, for example, in U.S. Pat. No. 4,515,893. In one embodiment, the CD3 binding component of the binding fusion protein comprises one or more complementarity determining regions (CDRs) of the antibody Muromonab-CD3. 
     ANTI-CD40: 
     In another embodiment, the invention provides an isolated anti-CD40 binding fusion protein. “Anti-CD40” means a targeting moiety that specifically binds to the cell-surface receptor CD-40. CD-40 is a cell-surface receptor that plays a role in immune responses, as well as cell growth and survival signaling when activated by CD40 ligand (CD40 L). CD40 is commonly over-expressed and activated in B-cell malignancies, such as multiple myeloma and lymphoma. The anti-CD40 can be used as a fusion partner with XTEN to create a fusion protein composition that can have therapeutic utility when administered to a subject suffering from various cancers, particularly B-cell malignancies. In one embodiment, the anti-CD40 component of a binding fusion protein comprises one or more complementarity determining regions (CDRs) of the antibody lucatumumab. Anti-CD40 antibodies have been described in U.S. Pat. No. 7,445,780, and U.S. Patent Appl. Nos. 20070110754 and 20080254026. 
     ANTI-TNFalpha: 
     In another embodiment, the invention provides an isolated anti-TNFalpha binding fusion protein. “Anti-TNFalpha” means a targeting moiety that specifically binds to the cytokine TNFalpha. TNFalpha, or cachexin, is a pro-inflammatory cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction. The primary role of TNF is in the regulation of immune cells. TNF is produced mainly by macrophages, but is also produced by lymphoid cells, mast cells, endothelial cells, cardiac myocytes, adipose tissue, fibroblasts, and neuronal tissue. Large amounts of TNF are released in response to lipopolysaccharide and Interleukin-1 (IL-1). TNF has been implicated in autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, Crohn&#39;s disease, psoriasis and refractory asthma, and plays a role in septic shock and other serious forms of acute inflammatory response and SIRS. The anti-IL-TNFalpha can be used as a fusion partner with XTEN to create a fusion protein composition that can have therapeutic utility in a wide variety of inflammatory disorders, including rheumatoid arthritis, ankylosing spondylitis, Crohn&#39;s disease, psoriasis and refractory asthma. Anti-TNFalpha antibodies, such as infliximab and etanercept have shown efficacy in psoriasis, Crohn&#39;s disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis and ulcerative colitis. In one embodiment, the anti-TNFalpha component of a binding fusion protein comprises one or more complementarity determining regions (CDRs) or binding regions of the infliximab or etanercept. Anti-TNF antibodies have been described in U.S. Pat. No. 6,790,444, and chimeric antibodies comprising a TNF receptor have been described in U.S. Pat. No. 5,605,690. 
     The invention provides binding fusion protein compositions in which the binding regions of the foregoing referenced exemplary targeting moieties are sequence variants. For example, it will be appreciated that various amino acid deletions, insertions and substitutions can be made in the targeting moiety to create variants without departing from the spirit of the invention with respect to the binding activity or the pharmacologic properties of the binding fusion protein. Examples of conservative substitutions for amino acids in polypeptide sequences are shown in Table 5. However, in embodiments of the binding fusion protein in which the sequence identity of the targeting moiety is less than 100% compared to a specific sequence referenced or disclosed herein, the invention contemplates substitution of any of the other 19 natural L-amino acids for a given amino acid residue of the given targeting moiety, which may be at any position within the sequence of the targeting moiety or binding region of the targeting moiety, including adjacent amino acid residues. If any one substitution results in an undesirable change in binding activity, then one of the alternative amino acids can be employed and the construct protein evaluated by the methods described herein (e.g., the assays of the Examples), or using any of the techniques and guidelines for conservative and non-conservative mutations set forth, for instance, in U.S. Pat. No. 5,364,934, the contents of which is incorporated by reference in its entirety, or using methods generally known in the art. In addition, variants can include, for instance, polypeptides wherein one or more amino acid residues are added or deleted at the N- or C-terminus of the referenced or disclosed amino acid sequence of a targeting moiety that retains some if not all of the binding activity of the referenced or disclosed targeting moiety; e.g., the ability to bind a target of Table 1 or Table 2. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Exemplary conservative amino acid substitutions 
               
            
           
           
               
               
               
            
               
                   
                 Original Residue 
                 Exemplary Substitutions 
               
               
                   
                   
               
               
                   
                 Ala (A) 
                 val; leu; ile 
               
               
                   
                 Arg (R) 
                 Lys; Gln; Asn 
               
               
                   
                 Asn (N) 
                 Gln; His; Llys; Arg 
               
               
                   
                 Asp (D) 
                 Glu 
               
               
                   
                 Cys (C) 
                 Ser 
               
               
                   
                 Gln (Q) 
                 Asn 
               
               
                   
                 Glu (E) 
                 Asp 
               
               
                   
                 Gly (G) 
                 Pro 
               
               
                   
                 His (H) 
                 Asn; Gln; Lys; Arg 
               
               
                   
                 Ile (I) 
                 Leu; Val; Met; Ala; Phe; Norleucine 
               
               
                   
                 Leu (L) 
                 Norleucine; Ile: Val; Met; Ala: Phe 
               
               
                   
                 Lys (K) 
                 Arg&#39; Gln; Asn 
               
               
                   
                 Met (M) 
                 Leu; Phe; Ile 
               
               
                   
                 Phe (F) 
                 Leu; Val; i = Lle; Ala 
               
               
                   
                 Pro (P) 
                 Gly 
               
               
                   
                 Ser (S) 
                 Thr 
               
               
                   
                 Thr (T) 
                 Ser 
               
               
                   
                 Trp (W) 
                 Tyr 
               
               
                   
                 Tyr(Y) 
                 Trp; Phe: Thr; Ser 
               
               
                   
                 Val (V) 
                 Ile; Leu; Met; Phe; Ala; Norleucine 
               
               
                   
                   
               
            
           
         
       
     
     2. Exemplary Forms of Targeting Moieties 
     The following section provides a non-limiting list and description of exemplary forms of targeting moieties. 
     “Antibody” or “antibodies”, as used here, refers to a targeting moiety consisting of one or more polypeptides substantially encoded by immunoglobulin genes or fragments of immunoglobulin genes, and is used in the broadest sense to cover intact monoclonal antibodies, multispecific antibodies (e.g. bispecific antibodies) formed from at least two intact antibodies or fragment thereof, and antibody fragments so long as they exhibit the desired biological activity; e.g., binding affinity to a target ligand or antigen. 
     Immunoglobulins can be assigned to different classes depending on the amino acid sequence of the constant domain of their heavy chains. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called a, 6, c, y, and μ, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. 
     The term “monoclonal” indicates the character of the targeting moiety antibody or antibody fragment as being obtained from a substantially homogeneous population of antibodies or fragments, and is not to be interpreted as requiring production of the antibody by a particular method. For example, while the monoclonal antibodies created in accordance with the methods of the present invention may be made by the hybridoma method first described by Kohler et al.,  Nature,  256:495 (1975), they may also be synthetics made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567) and expressed in either mammalian or non-mammalian hosts; e.g.,  E. coli . The substitution of immortalized cells with bacterial cells considerably simplifies procedures for preparing large amounts of the inventive binding fusion protein molecules. Furthermore, a recombinant production system allows the ability to produce tailor-made antibodies and fragments thereof, or even libraries to screen for specific attributes. For example, it is possible to produce chimeric molecules with new combinations of binding and effector functions, humanized antibodies and novel antigen-binding molecules, including bifunctional binding fusion proteins. Furthermore, the use of polymerase chain reaction (PCR) amplification (Saiki, R. K., et al., Science 239, 487-491 (1988)) to introduce variations into the sequence and isolate antibody producing sequences from cells has great potential for speeding up the timescale under which specificities can be isolated. Amplified V H  and V L  genes can be cloned directly into vectors for expression in bacteria or mammalian cells (Orlandi, R., et al., 1989, Proc. Natl. Acad. Sci., USA 86, 3833-3837; Ward, E. S., et al., 1989 supra; Larrick, J. W., et al., 1989, Biochem. Biophys. Res. Commun. 160, 1250-1255; Sastry, L. et al., 1989, Proc. Natl. Acad. Sci., USA, 86, 5728-5732). Soluble antibody fragments secreted from bacteria can then be screened in binding assays described herein, or others known in the art, to select those constructs with binding activities sufficient to meet the application. 
     The monoclonal antibodies herein specifically include “chimeric” antibodies in which a portion of the heavy and/or light chain is identical with or has a high degree of homology to corresponding parental sequences in antibodies derived from a particular first species, while the remainder of the chain(s) is identical with or has a high degree of homology to sequences in antibodies derived from a second species, wherein the resulting antibody exhibits the desired biological activity; e.g., binding affinity for the target antigen or ligand (U.S. Pat. No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-4855 (1984)). 
     The term “humanized” means forms of antibodies, including fragments, that are chimeric in that they include minimal sequence derived from non-human immunoglobulin but otherwise comprise sequence from human immunoglobulins. Methods for humanizing non-human antibodies have been described in the art. Preferably, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human (e.g., murine, rat, or non-human primate) and that are typically taken from a variable domain of a V L  or V H  chain having the desired specificity and affinity for the target ligand. Humanization can be essentially performed following the method of Winter and co-workers (Jones et al.,  Nature,  321:522-525 (1986); Riechmann et al.,  Nature,  332:323-327 (1988); Verhoeyen et al.,  Science,  239:1534-1536 (1988)), by substituting hypervariable region sequences for the corresponding sequences of a human antibody. Accordingly, such “humanized” antibodies are chimeric antibodies (see, e.g., U.S. Pat. No. 4,816,567) wherein all or a portion of the human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some hypervariable CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent (or other non-human species, e.g., non-human primates) antibodies. In one embodiment, humanized antibodies comprise residues that are not found in the recipient antibody or in the donor antibody to, for example, increase binding affinity or some other property. In general, humanized antibodies comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to or have sequences derived from those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence. The humanized antibody can optionally comprise at least a portion of an immunoglobulin constant region (Fc), preferably that of a human immunoglobulin. 
     The targeting moieties of the subject compositions can be derived from humanized antibodies. The choice of human variable domains, both light and heavy, to be used in the compositions is very important to reduce antigenicity of the antibody. For example, the sequence of the variable domain of a rodent antibody can be screened against a library of known human variable-domain sequences in order to select a sequence that is less likely to elicit an immune response in the recipient. In a corresponding fashion, the human sequence that is closest to that of the rodent can be used as the human framework (FR) for the humanized antibody (Sims et al.,  J. Immunol,  151:2296 (1993); Chothia et al.,  J. Mol. Biol.,  196:901 (1987)). The same framework may be used for several different humanized antibodies (Carter et al.,  Proc. Natl. Acad. Sci. USA,  89:4285 (1992); Presta et al.,  J. Immnol.,  151:2623 (1993)). 
     An additional property is that targeting moieties can be humanized yet retain high affinity for the antigen and other favorable biological properties. To achieve this goal, according to a preferred method, humanized targeting moieties are prepared by an iterative process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences followed by testing. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected and combined from the recipient and donor using standard recombinant DNA techniques so that the desired characteristic, such as increased affinity for the target antigen(s), can be achieved. In one embodiment, binding fusion protein constructs are created in which a sequence comprising linked heavy chain variable domains is linked to a heavy chain constant domain and sequence comprising linked light chain variable domains is linked to a light chain constant domain. Preferably the constant domains are human heavy chain constant domain and human light chain constant domain respectively. In a further embodiment of the foregoing, the fusion protein can be designed to include portions or all of a hinge region in order to permit dimerization of the binding fusion protein, and which can further comprise an XTEN linked to the C-terminus of the constant region. In an alternative embodiment, the binding fusion protein can be designed to incorporate a partial Fc without a hinge and with a CH2 domain that is truncated but retains FcRn binding in order to confer longer terminal half-life on the construct. In yet another embodiment, the binding fusion protein can be designed to incorporate a partial Fc without hinge but with a CH2 and CH3 domain, which can dimerize via the CH3 domain. In the embodiments hereinabove described in this paragraph, an XTEN can be linked to either the N- or C-terminus of the fusion protein, to enhance one or more properties of the resulting bind fusion protein. 
     “Antibody fragments” comprise a portion of an intact antibody or a synthetic or chimeric counterpart, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include molecules such as Fab fragments, Fab′ fragments, F(ab′) 2  fragments, Fd fragments, Fabc fragments, Fd fragments, Fabc fragments, domain antibodies (V HH ), single-chain antibody molecules (scFv), diabodies, individual antibody light chains, individual antibody heavy chains, chimeric fusions between antibody chains and other molecules, and the like. 
     A “Fab fragment” refers to a region of an antibody which binds to antigens. A Fab fragment is composed of one constant and one variable domain of each of the heavy and the light chain. These domains shape the paratope—the antigen binding site—at the amino terminal end of the monomer. The two variable domains bind the epitope on their specific antigens. A Fab fragment can be linked by a disulfide bond at the C-terminus. Fab fragments can be generated in vitro. For example, the enzyme papain can be used to cleave an immunoglobulin monomer into two Fab fragments and an Fc fragment. The enzyme pepsin cleaves below the hinge region, so a F(ab′)2 fragment and a Fc fragment is formed. As described more fully below, variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv), which retains the original specificity of the parent immunoglobulin. 
     The “light chains” of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains. 
     The term “variable” refers to the fact that portions of the variable domains differ extensively in sequence among antibodies and confer the binding specificity of each particular antibody for its particular antigen. The variability is concentrated in three segments called complementarity-determining regions (CDRs) or hypervariable regions, both in the light-chain and the heavy-chain variable domains; i.e., CDR1, CDR2 and CDR3. In particular, the CDR regions from antibodies can be incorporated into targeting moieties of the subject compositions, but can be individually selected from one or more antibodies to create the binding domain. The more highly conserved portions of variable domains are called the framework regions (FR), which may also be incorporated into targeting moieties. The variable domains of native heavy and light chains each comprise four FR regions, typically adopting a β-sheet configuration, connected by three CDRs that form loops. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al.,  NIH Publ. No.  91-3242, Vol. I, pages 647-669 (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit or participate in various effector functions, such as antibody-dependent cellular toxicity. 
     Single-Chain Variable Fragment Binding Fusion Proteins 
     In one aspect, the present invention provides single-chain variable fragment binding fusion protein compositions. The term “single-chain variable fragment” or “scFv” means an antibody fragment that comprises one V H  and one V L  domain of an antibody, wherein these domains are present in a single polypeptide chain, and are generally joined by a polypeptide linker between the domains that enables the scFv to form the desired structure for antigen binding Methods for making scFv&#39;s are known in the art (see, e.g., U.S. Pat. No. 6,806,079; Bird et al. (1988) Science 242:423-426; Huston et al. (1988) PNAS 85:5879-5883; Pluckthun in  The Pharmacology of Monoclonal Antibodies , vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315 (1994)). 
     A binding domain of the scFv binding fusion protein compositions of the invention can have the N- to C-terminus configuration VH-linker-VL or VL-linker-VH. The binding fusion proteins would include at least a first XTEN and optionally a second XTEN sequence linked to the N- or C-terminus of the fusion protein (as shown in  FIG. 1A - FIG. 1B ), resulting in at least the following structure permutations (N- to C-terminus); XTEN-VH-linker-VL; VH-linker-VL-XTEN; XTEN-VH-linker-VL-XTEN; XTEN-VL-linker-VH; VL-linker-VH-XTEN; XTEN-VL-linker-VH-XTEN. In one embodiment of the foregoing, the composition comprises an XTEN linked to the N-terminus of the fusion protein, wherein the expression of the fusion protein in a host cell transformed with a suitable expression vector comprising a polynucleotide encoding the fusion protein comprising the N-terminal sequence is enhanced compared to the expression of a corresponding fusion protein from a polynucleotide not comprising the N-terminal XTEN encoding sequence. In such cases, the N-terminal XTEN could either have just the short sequence that enhances expression, or could further include a long XTEN of at least greater than 400 to about 3000 amino acid residues between the N-terminal piece and a binding domain to confer enhanced pharmacokinetic or pharmaceutical properties to the fusion protein, as described above. In one embodiment of the foregoing, the N-terminal XTEN sequence comprises a sequence that exhibits at least about 80% sequence identity, or 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from AE48, AM48, AE624, AE913, and AM923. In another embodiment of the fusion proteins, the linkers, the N-terminal XTEN, as well as the long carrier XTEN can comprise a sequence that can be a fragment of or that exhibits at least about 80% sequence identity, or 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from any one of Tables 4 or 11-15. 
     The linkers utilized to join the components of the binding fusion proteins should be flexible in nature. In one embodiment the linker joining the VL and VH binding domains that form the antigen binding site of the scFv targeting moiety can have from about 15 to about 30 amino acid residues in length. In another embodiment, the linker can have from about 30 to about 200 amino acid residues, or about 40 to about 144 amino acid residues, or about 50 to about 96 amino acid residues. In any of the embodiments hereinabove described in this paragraph, the linker can be a sequence derived from a fragment of any of the XTEN sequences of Tables 4 or 11-15. In another embodiment, the linker can be a sequence in which at least 80% of the residues are comprised of amino acids glycine, serine, and/or glutamate, such as, but not limited to a sequence with about 80-100% sequence identify to the sequence GSGEGSEGEGGGEGSEGEGSGEGGEGEGSG (SEQ ID NO: 1), or a portion or a multimer thereof. 
     In one embodiment, the invention provides binding fusion proteins comprising two or more scFv targeting moieties (as shown in  FIG. 2A - FIG. 2B ). In one embodiment, the two or more scFv targeting moieties may be identical. In another embodiment, the two or more scFv targeting moieties may be different and may bind to different targets (e.g., two or more targets of Table 1) or to different epitopes on the same target. In the foregoing embodiments, the two or more scFv targeting moieties can be joined by a linker sequence. The invention contemplates that the linkers as well as the long carrier XTEN and the N-terminal XTEN can comprise a sequence that can be a fragment of or that exhibits at least about 80% sequence identity, or 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from any one of Tables 4 or 11-15. 
     The invention contemplates various configurations of the multivalent scFv-XTEN binding fusion proteins, with the two or more targeting moieties, linkers and one or more XTEN in various N- to C-terminus configuration; e.g., TM1-L-TM2-XTEN, XTEN-TM1-L-TM2, XTEN-TM1-L-TM2-XTEN, etc. 
     The general methodology for the assembly of the components, the expression and recovery, followed by characterization of the binding fusion protein is illustrated in  FIG. 9 . 
     Diabody Binding Fusion Proteins 
     In another aspect, the invention provides compositions of diabody binding fusion proteins. The term “diabody” or “diabodies”, as used herein, refers to fusion proteins comprising antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (V H ) connected to a light-chain variable domain (V L ) by a short linker in the same polypeptide chain. In one embodiment, the diabody binding fusion protein composition is a single polypeptide chain having two binding moieties, each with V L  and V H  interconnected by a flexible linker of about 30 to about 300 amino acid residues joining the C-terminus of one binding domain pair with the N-terminus of the second binding domain pair, and one or more XTEN on the N- and/or C-terminus (as shown in  FIG. 3A - FIG. 3B ). In this case, the composition is created by selective incorporation of a linker that is too short to allow pairing between the two adjacent domains, but the targeting moiety regions are connected by longer flexible linker to permit the association between the binding domains from the opposite ends of the fusion protein. For example, it is known that a scFv molecule with a linker 3-12 residues long cannot fold into a functional Fv domain but, generally, instead associates with a second scFv molecule to form a multivalent diabody with two binding sites, while a linker of 1-2 residues tends to favor triabody formation with three binding sites (John L. Atwell et al., Protein Engineering (1999) 12(7):597-604). Thus, in some embodiments, the invention provides diabody binding fusion proteins in which the adjacent binding domain pairs are linked by 1-2 or 3-12 amino acid residues and the binding domain pairs are, in turn, linked by a flexible XTEN linker. In one embodiment of the foregoing, the flexible linker can be an XTEN sequence of about 100 to about 300 amino acid residues. In another embodiment the flexible linker sequence can be comprised of amino acids such as glycine, serine, and/or glutamate making up about 80-100% of the sequence. In another embodiment, the linker can be a sequence in which at least 80% of the residues are comprised of amino acids glycine, serine, and/or glutamate, such as, but not limited to a sequence with about 80-100% sequence identify to the sequence GSGEGSEGEGGGEGSEGEGSGEGGEGEGSG (SEQ ID NO: 1), or a portion or a multimer thereof. 
     In one embodiment, the invention provides a diabody binding fusion protein that can be monospecific, binding one type of antigen. In another embodiment, the invention provides a bispecific diabody binding fusion protein in which the targeting moieties are directed to different antigens or different epitopes on the same antigen. In the foregoing embodiments, the specificity of the diabody binding fusion is determined by the incorporation of either identical or different respective VH and VL components. 
     An illustration of one example of a diabody binding fusion proteins is shown in  FIG. 2A - FIG. 2B , however the invention contemplates different configurations of the diabody binding fusion proteins; e.g., a different N- to C-terminus order of the VH and VL domains, or deleting one of the XTEN sequences from either the N- or C-terminus. 
     In one embodiment of the foregoing, the composition comprises an XTEN linked to the N-terminus of the diabody binding fusion protein, wherein the expression of the fusion protein in a host cell transformed with a suitable expression vector comprising a polynucleotide encoding the fusion protein comprising the N-terminal sequence is enhanced compared to the expression of a corresponding fusion protein from a polynucleotide not comprising the N-terminal XTEN encoding sequence. 
     In addition, the invention provides multimers that are trivalent (having three antigen-binding sites), tetravalent (having four antigen-binding sites), and so on. In another embodiment of the diabody fusion proteins, the linkers as well as the long carrier XTEN and the N-terminal XTEN can comprise a sequence that can be a fragment of or that exhibits at least about 80% sequence identity, or 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from any one of Tables 4 or 11-15. 
     The general methodology for the assembly of the components, the expression and recovery, followed by characterization of the binding fusion protein is illustrated in  FIG. 9 . 
     Domain Antibody Binding Fusion Proteins 
     In another aspect, the invention provides single chain fusion proteins comprising domain antibody targeting moieties linked to XTEN, wherein the fusion protein is able to bind to an antigen or ligand. As used herein, “domain antibody”, or “V HH ,” is an immunoglobulin having a variable region (V H ) with an antigen-binding site which will alone allows the recognition and complete binding of an antigen, linked to a constant region (C H ), but are devoid of the first domain of the constant region (C H 1) and are devoid of a V L  domain. The V HH  do not correspond to fragments obtained, for instance, by the degradation of a natural four-chain model immunoglobulin. V HH  are devoid of light chains, such that the variable domains of their heavy chains have properties differing from those of the four-chain immunoglobulin variable heavy chain (V H ), including no normal interaction sites with the V L  or with the C H 1 domain. V HH  can adopt a three-dimensional organization that distinguishes from the conventional three-dimensional organization of four-chain antibodies according to the description that is given by Chothier C. and Lesk A. M, (1987-J. Mol. Biol. 197, 901-917). V HH  can comprise type G immunoglobulins, especially of class 2 (IgG2) or class 3 (IgG3). The parental V HH  immunoglobulin sequences can be derived from certain animals, especially from members of the camelid family, or from sharks, which can then be generated in host cells by genetic engineering or by chemical synthesis. Appropriate host cells include bacteria (e.g.  E. coli ) and eukaryotic cells, such as yeasts or animal cells including mammalian cells, or plant cells. 
     In one embodiment, the binding fusion protein can comprise one V HH  targeting moiety. In another embodiment, the binding fusion protein can comprise two or more V HH  targeting moieties; e.g., two, or three, or four, or five, or six or more V HH  targeting moieties. In such case, the linker sequence between the V HH  fragments can be, for example, a sequence corresponding to a fragment of the hinge domain of an immunoglobulin (e.g. the long hinge domain) or can be a short XTEN sequence of about 30 to about 300 amino acid residues, or can be a sequence in which at least 80% of the residues are comprised of amino acids glycine, serine, and/or glutamate, such as, but not limited to a sequence with about 80-100% sequence identify to the sequence GSGEGSEGEGGGEGSEGEGSGEGGEGEGSG (SEQ ID NO: 1), or a portion or a multimer thereof. In one embodiment of the foregoing, the V HH  are hetero-specific with binding affinity to different epitopes of the same antigen. In another embodiment, the V HH  are hetero-specific with binding affinity to heterologous antigens. The invention contemplates that the V HH  binding fusion protein would comprise an additional XTEN sequence of at least greater than about 400 to about 3000 residues in which the XTEN would confer enhanced properties to the composition, as described above. Thus, the invention contemplates binding fusion protein configurations including, but not limited to V HH -XTEN; XTEN-V HH ; V HH —Linker-V HH -XTEN; XTEN-V HH -Linker-V HH ; and XTEN-V HH -Linker-V HH -XTEN, or multimers thereof. In the foregoing, for those configurations with two V HH , the V HH — can be identical or can be different, in the latter case binding two different ligands/antigens or different epitopes on the same ligand/antigen. In an embodiment of the foregoing domain binding fusion protein configurations, the composition comprises an XTEN linked to the N-terminus of the fusion protein, wherein the expression of the fusion protein in a host cell transformed with a suitable expression vector comprising a polynucleotide encoding the fusion protein comprising the N-terminal sequence is enhanced compared to the expression of a corresponding fusion protein from a polynucleotide not comprising the N-terminal XTEN encoding sequence. 
     In another embodiment of the domain fusion proteins, the linkers as well as the long carrier XTEN and the N-terminal XTEN can comprise a sequence that can be a fragment of or that exhibits at least about 80% sequence identity, or 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from any one of Tables 4 or 11-15. In another embodiment, the linker can be a sequence in which at least 80% of the residues are comprised of amino acids glycine, serine, and/or glutamate, such as, but not limited to a sequence with about 80-100% sequence identify to the sequence GSGEGSEGEGGGEGSEGEGSGEGGEGEGSG (SEQ ID NO: 1), or a portion or a multimer thereof. 
     The general methodology for the assembly of the components, the expression and recovery, followed by characterization of the binding fusion protein is illustrated in  FIG. 9 . 
     Cytokine Binding Fusion Proteins 
     In another aspect, the invention provides monomeric fusion proteins capable of binding a cytokine to form a nonfunctional complex, comprising receptor-like binding domains joined by an XTEN, wherein the resulting fusion protein has binding affinity for the target cytokine ligand. As used herein, “cytokines” means a category of soluble, small protein signaling molecules that are used extensively in cellular communication, including but not limited to interleukins, interferons, chemokines, growth factors, colony stimulating factors, tumor necrosis factors, peptide hormones, and other immunomodulating agents that mediate a variety of biological effects, including the regulation of the growth and differentiation of many cell types. The action of cytokines may be autocrine, paracrine, and endocrine. For example, human interleukin-17 is a cytokine which stimulates the expression of interleukin-6, intracellular adhesion molecule 1, interleukin-8, granulocyte macrophage colony-stimulating factor, and prostaglandin E2 expression, and plays a role in the preferential maturation of CD34+ hematopoietic precursors into neutrophils (Yao et al.,  J. Immunol.  155:5483 (1995); Fossiez et al.,  J. Exp. Med.  183:2593 (1996)). 
     Cytokines are generally bound by cell-surface receptors that, in turn, trigger cascades of intracellular signaling that alter cell functions. These may include upregulation and/or down-regulation of several genes and their transcription products, resulting in the production of other cytokines, an increase in the number of surface receptors for other molecules, or the suppression of their own effect by feedback inhibition. The term “receptor” denotes a cell-associated protein that binds to a bioactive molecule and mediates the effect of the ligand on the cell. “Receptor”, as used herein, includes, but is not limited to cytokine receptors and chemokines receptors. While many native cell receptors have binding domains that are immunoglobulin-like, the term “receptor” as used herein specifically excludes immunoglobulins that constitute antibodies or MHC receptors. 
     Receptors that bind cytokines are typically composed of one or more integral membrane proteins that have an extracellular component that binds the cytokine with high affinity and transduces this binding event to the cell through the transmembrane and cytoplasmic portions of the receptor subunits. The ligand-binding subunit of a receptor is referred to as the alpha chain, while other signal transducing subunits are named beta chains, or gamma chains. Thus, the ability to sequester cytokines, hormones or related ligands prior to binding to their natural cell receptors represents a mechanism to alter the pathogenesis of diseases, disorders or conditions. 
     Cytokine receptors have been grouped into several families on the basis of similarities in their extracellular ligand binding domains; immunoglobulin superfamily receptor, Class I cytokine receptor family, Class II cytokine receptor family, TNF receptor family, and chemokine receptor family. In some embodiments, the invention provides cytokine binding moieties that comprise binding domains, portions of binding domains, or sequences with sequence identity to members of the foregoing receptor families (except for antibody immunoglobulins specifically excluded above) linked to one or more XTEN sequences, wherein the cytokine binding moiety has at least a portion of the binding affinity compared to the native receptor and, when ligand is sequestered, is able to interfere with the binding of the target ligand to the native receptor. In another embodiment, the invention provides a receptor binding fusion protein that comprise binding domains, portions of binding domains, or sequences with sequence identity to immunoglobulin superfamily receptors linked to one or more XTEN sequences, wherein the binding domains have at least a portion of the binding affinity compared to the native receptor and, when ligand is sequestered, is able to interfere with the binding of the target ligand to the native receptor. 
     By “cytokine binding moiety” what is meant is at least that minimal portion of the extracellular ligand-binding domain of a cytokine receptor necessary to bind the cytokine. For example, while some cytokine receptors have components designated α and β, one skilled in the art would know which component of the receptor is the signal transducing component and which is the ligand-binding component. Thus to practice the present invention and create a high affinity binding protein for a cytokine, one of skill in the art would create an isolated nucleic acid comprising a nucleotide sequence encoding a first fusion polypeptide component comprising the amino acid sequence of the cytokine binding portion of the extracellular domain of the specificity determining component of the receptor; a nucleotide sequence encoding a second fusion polypeptide component comprising the amino acid sequence of a cytokine binding portion of the extracellular domain that may be the same or may be different from the first, and a nucleotide sequence encoding a third fusion polypeptide component comprising the amino acid sequence of an XTEN linking the binding components to create a gene encoding a high affinity cytokine binding fusion protein for the target cytokine. The general methodology for the assembly of the components, the expression and recovery, followed by characterization of the binding fusion protein is illustrated in  FIG. 9 . 
     As used herein, the term “binding domain” may itself include a multi-domain structure wherein two or more individual domains must be closely linked to form a single binding region. Examples of the foregoing are the native receptors to VEGF, flt-1 and flk-1, both of which have seven immunoglobulin-like domains in each of two arms that form the extracellular ligand-binding regions of the receptors (Matthews, et al., PNAS 88:9026 (1991)). However, it has been demonstrated that recombinant proteins comprising either two or three of the seven domains can, when paired with a corresponding second arm comprising either two or three domains, can bind VEGF with high affinity (see U.S. Pat. Nos. 5,952,199, 7,374,757). In some embodiments, VEGF cytokine binding fusion proteins comprise pairs of an Ig domain 2 (D2) and an Ig domain 3 (D3) derived from one or more VEGF receptors, as shown in  FIG. 4A - FIG. 4B . In one embodiment of the foregoing, the VEGF receptor is Flt-1. In another embodiment of the foregoing, the VEGF receptor is Flk-1. In yet another embodiment of the foregoing, the VEGF receptor is Flt-4. The domain units may comprise VEGF receptor domains connected directly to each other or, optionally, be connected via spacers or linkers, such as fragments of XTEN. 
     “Immunoglobulin-like domain” or “Ig-like domain” or “ligand-binding domain” refers to independent and distinct domains that are found in the extracellular ligand-binding region of cytokine receptors and it is specifically intended that the term encompass not only the complete wild-type domain, but also insertional, deletional and substitutional variants thereof that retain at least a portion of the binding affinity of the wild-type domain. It will be readily apparent to those of ordinary skill in the art that numerous variants of the domains or combinations of the domains of the cytokine binding proteins can be obtained which will retain substantially the same functional characteristics as the wild type domain. 
     The invention also contemplates cytokine binding fusion proteins comprising binding domains derived from multimeric receptors. Multimeric receptors include homodimers (e.g., PDGF receptor aa and ββ isoforms, erythropoietin receptor, MPL, and G-CSF receptor), heterodimers whose subunits each have ligand-binding and effector domains (e.g., PDGF receptor αβ isoform), and multimers having component subunits with disparate functions (e.g., IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, and GM-CSF receptors). 
     The invention contemplates a number of different constructs employing cytokine binding domains known to have affinity for target ligands of interest. Preferred embodiments of the invention include fusion protein compositions capable of binding a ligand comprising at least a first and a second polypeptide binding domain operatively fused to a linking component, wherein the linking component comprises a flexible XTEN sequence. In one embodiment of the foregoing, the composition further comprises at least a second XTEN as a carrier, wherein the carrier may enhance the pharmacokinetic or pharmaceutical properties of the fusion protein. In another embodiment of the foregoing, the composition comprises an XTEN linked to the N-terminus of the fusion protein, wherein the expression of the fusion protein in a host cell transformed with a suitable expression vector comprising a polynucleotide encoding the fusion protein comprising the N-terminal sequence is enhanced compared to the expression of a corresponding fusion protein from a polynucleotide not comprising the N-terminal XTEN encoding sequence. 
     In a particular feature of the cytokine binding fusion proteins, the unstructured characteristic of the XTEN linker permits the respective binding domains to adopt a flexible configuration to freely and correctly orient with the ligand for optimal binding. “Flexible configuration”, when used in reference to the cytokine binding protein compositions of the present disclosure, means that the receptor polypeptide sequences or domains of the fusion protein are not held in a particular configuration relative to each other but are free to move, under physiologic conditions, to the extent that the XTEN polypeptides tethered to the receptor polypeptides permit. Based upon these characteristics, it is believed that a binding domain of the fusion protein is more likely to encounter and attach to the target ligand, under physiologic conditions, compared to a construct wherein the domains are held in a fixed orientation, such as receptor traps in which the binding domains are fused to and held in place by the dimerization between Fc domains or heavy chains of IgG (see, e.g., U.S. Pat. No. 7,417,134). Not to be bound by a particular theory, upon encountering the target ligand under physiologic or assay conditions, the binding domains of the inventive fusion protein can mutually orientate substantially as in a native cytokine receptor, adopting a constrained configuration to sequester the ligand. “Sequester” or “sequestering” when used in reference to the activity of a cytokine binding fusion protein of the present invention means that the fusion protein binds to the target ligand to form a substantially nonfunctional complex, interfering with its ability to bind to a native receptor. As used herein, “substantially nonfunctional complex” means that the residual activity of the bound ligand and/or its ability to bind to its cognate receptor would be less than about 60%, or less than about 50%, or less than about 40%, or less than about 30%, or less than about 20%, or less than about 10%, or less than about 5%, or less than about 1% compared to un-bound ligand with a native receptor. The cytokine binding fusion proteins are thus antagonists. 
     In light of the foregoing, the binding fusion protein compositions can have an “open” conformation ( FIG. 4A ) such that, when a target molecule is in close proximity to the binding fusion protein, the interaction with the domains permits a change in conformation wherein both domain units come into association with the target ligand, creating a “closed” conformation ( FIG. 4B ), effectively sequestering the target molecule. 
     The fusion proteins of any of the foregoing cytokine binding protein embodiments can further comprise a second and optionally a third XTEN protein, as illustrated in  FIG. 4A - FIG. 4B , to impart the enhanced characteristics as a carrier or as a N-terminal XTEN, as described above. 
     In one embodiment, the cytokine binding proteins are multivalent fusion proteins comprising two binding region domains that are homologous, the XTEN linker, and can further comprise the additional XTEN sequences on the N- and/or C-terminus. 
     In another embodiment of the cytokine binding fusion proteins, the linkers as well as the long carrier XTEN and the N-terminal XTEN can comprise a sequence that can be a fragment of or that exhibits at least about 80% sequence identity, or 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from any one of Tables 4 or 11-15. 
     Receptor Binding Fusion Proteins 
     In another aspect, the invention provides binding fusion proteins comprised of at least a first binding region comprising a first and optionally a second binding domain derived from Ig-like domains from cell receptors linked to at least a first XTEN. A non-limiting example of the foregoing is a binding protein with Ig-like binding domains derived from the VEGF receptor, with XTEN linked to either the N- or C-terminus of the binding regions, as illustrated in  FIGS. 4 and 5 . In a particular embodiment of the foregoing, the binding fusion protein can comprise two Ig-like binding regions linked by a short XTEN linker of about 20 to about 200 amino acid residues (e.g., a fragment of an XTEN sequence of Table 4), and a longer XTEN carrier, wherein the VEGF binding regions can bind and substantially sequester dimeric VEGF. In another embodiment, the binding fusion protein can comprise two sets of two Ig-like binding regions, which can be identical or can be different domains, linked by a short XTEN linker of about 20 to about 200 amino acid residues, and one or more longer XTEN carriers, wherein the VEGF binding regions can bind and substantially sequester dimeric VEGF. The receptor binding fusion protein can also comprise a N-terminal XTEN, also illustrated in  FIG. 6A - FIG. 6D , wherein the expression of the fusion protein in a host cell transformed with a suitable expression vector comprising a polynucleotide encoding the fusion protein comprising the N-terminal sequence is enhanced compared to the expression of a corresponding fusion protein from a polynucleotide not comprising the N-terminal XTEN encoding sequence. In the foregoing embodiments hereinabove described in this paragraph, the linkers as well as the long carrier XTEN and the N-terminal XTEN can comprise a sequence that can be a fragment of or that exhibits at least about 80% sequence identity, or 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from any one of Tables 4 or 11-15. In another embodiment, the linker can be a sequence in which at least 80% of the residues are comprised of amino acids glycine, serine, and/or glutamate, such as, but not limited to a sequence with about 80-100% sequence identify to the sequence GSGEGSEGEGGGEGSEGEGSGEGGEGEGSG (SEQ ID NO: 1), or a portion or a multimer thereof. 
     In a particular feature of the above described embodiments, the cytokine binding fusion proteins can be produced as functionally-active monomers, a characteristic which is believed to require fewer manufacturing steps and result in a more homogenous product compared to constructs requiring a dimerization process (e.g., Fc conjugates) in order to recover a functional molecule. 
     Bispecific Antibodies 
     Bispecific antibodies are antibodies that have binding specificities for at least two different epitopes. A non-limiting example of a bispecific binding fusion protein would be one with two targeting moieties that may bind to two different epitopes of the ErbB2 protein. For example, one targeting moiety may bind an epitope in Domain 1 of ErbB2 such as the 7C2/7F3 epitope, the other may bind a different ErbB2 epitope, e.g. the 4D5 epitope. Other such bispecific binding fusion proteins may combine an ErbB2 binding site with binding site(s) for EGFR, ErbB3 and/or ErbB4. Alternatively, an anti-ErbB2 targeting moiety may be combined with a targeting moiety that binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2 or CD3), or Fc receptors for IgG (FcγR), such as FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16) so as to focus cellular defense mechanisms to the ErbB2-expressing cell. Bispecific binding fusion proteins can be prepared with targeting moieties that are multivalent scFv, multivalent domain antibodies, or diabodies. 
     (d) Configurations of Binding Fusion Proteins 
     The invention contemplates different configurations of binding fusion proteins, including but not limited to those comprising targeting moieties characterized as scFv, diabodies, domain antibodies, bifunctional antibodies or cytokine binding fusion proteins, linked to one or more XTEN, and optionally having one or more linkers. For binding fusion proteins with a single targeting moiety, the invention provides a monomeric binding fusion protein of formula I: 
       (XTEN) x -TM-(XTEN) y   I
 
     wherein independently for each occurrence: XTEN is an extended recombinant polypeptide as described above, x is either 0 or 1; y is either 0 or 1, wherein x+y≥1; and TM is a targeting moiety with binding affinity to a target, preferably a target selected from Table 1 or Table 2. In one embodiment, the TM comprises two or more binding domains that may be joined by a linker sequence of 1 to about 300 amino acid residues having a flexible, unstructured conformation. In one embodiment, the linker sequence is an XTEN having at least about 12 to about 300 amino acids exhibiting a flexible, unstructured characteristic, such as a fragment of an XTEN, such that the binding domains can thereby mutually orientate relative to each other and the ligand and adopt a constrained configuration to bind the target ligand. In another embodiment, the linker can be a sequence in which at least 80% of the residues are comprised of amino acids glycine, serine, and/or glutamate, such as, but not limited to a sequence with about 80-100% sequence identify to the sequence GSGEGSEGEGGGEGSEGEGSGEGGEGEGSG (SEQ ID NO: 1), or a portion or a multimer thereof. In another embodiment, wherein the TM comprises two or more binding domains, the binding domains may be identical or they may be different, and can comprise, for example, sequences derived from such V L  or V H  sequences, receptor binding domains, or Ig-like binding domains as necessary to bind with sufficient affinity to the target ligand. 
     In another embodiment, the invention provides a multivalent binding fusion protein with two binding moieties of formula II: 
       (XTEN) x -TM1-L-TM2-(XTEN) y   II
 
     wherein independently for each occurrence: XTEN is an extended recombinant polypeptide as described above, x is either 0 or 1; y is either 0 or 1, wherein x+y≥1; TM1 is a targeting moiety with binding affinity to a target, preferably a target selected from Table 1 or Table 2; TM2 is a targeting moiety with binding affinity to the target ligand that may be identical or may be different to TM1; and L is a linker sequence having between 1 to about 300 amino acid residues wherein the linker sequence is covalently bound to the C terminus of TM1 and the N terminus of TM2. In one embodiment, the respective TM may each comprise two or more binding domains that may be joined by an additional linker sequence of 1 to about 300 amino acid residues having a flexible, unstructured conformation. In one embodiment, the linker sequence is an XTEN or a fragment of an XTEN from any one of Tables 4 or 11-15 having at least about 12 to about 300 amino acids exhibiting a flexible, unstructured characteristic such that the binding domains can thereby mutually orientate relative to each other and the ligand and adopt a constrained configuration to bind to the target ligand. In another embodiment, the linker can be a sequence in which at least 80% of the residues are comprised of amino acids glycine, serine, and/or glutamate, such as, but not limited to a sequence with about 80-100% sequence identify to the sequence GSGEGSEGEGGGEGSEGEGSGEGGEGEGSG (SEQ ID NO: 1), or a portion or a multimer thereof. In another embodiment, wherein the TM comprises two or more binding domains, the binding domains may be identical or they may be different, and can comprise, for example, sequences derived from such VL or VH sequences, receptor binding domains, or Ig-like binding domains as necessary to bind with sufficient affinity to the target ligand. 
     In another embodiment, the invention provides a multivalent binding fusion protein with two binding moieties of formula III: 
       TM1-XTEN-TM2  III
 
     wherein independently for each occurrence: XTEN is an extended recombinant polypeptide as described above; TM1 is a targeting moiety with binding affinity to a target, preferably a target selected from Table 1 or Table 2; and TM2 is a targeting moiety with binding affinity to a target, preferably a target selected from Table 1 or Table 2 that may be identical or may be different to TM1. In one embodiment, the respective TM may each comprise two or more binding domains that may be joined by an additional linker sequence of 1 to about 300 amino acid residues having a flexible, unstructured conformation. In one embodiment, the linker sequence is an XTEN or a fragment of an XTEN from any one of Tables 4 or 11-15 having at least about 12 to about 300 amino acids exhibiting a flexible, unstructured characteristic such that the binding domains can thereby mutually orientate relative to each other and the ligand and adopt a constrained configuration to bind to the target ligand. In another embodiment, the linker can be a sequence in which at least 80% of the residues are comprised of amino acids glycine, serine, and/or glutamate, such as, but not limited to a sequence with about 80-100% sequence identify to the sequence GSGEGSEGEGGGEGSEGEGSGEGGEGEGSG (SEQ ID NO: 1), or a portion or a multimer thereof. In another embodiment, wherein the TM comprises two or more binding domains, the binding domains may be identical or they may be different, and can comprise, for example, sequences derived from such V L  or V H  sequences, receptor binding domains, or Ig-like binding domains as necessary to bind with sufficient affinity to the target ligand. 
     In another embodiment, the invention provides a multivalent binding fusion protein with three binding moieties of formula IV: 
       (XTEN) x -TM1-L1-TM2-L2-TM3-(XTEN) y   IV
 
     wherein independently for each occurrence: XTEN is an extended recombinant polypeptide as described above, x is either 0 or 1; y is either 0 or 1, wherein x+y≥1; TM1 is a targeting moiety with binding affinity to a target, preferably a target selected from Table 1 or Table 2; TM2 is a targeting moiety with binding affinity to a target, preferably a target selected from Table 1 or Table 2 that may be identical or may be different to TM1; TM3 is a targeting moiety with binding affinity to a target, preferably a target selected from Table 1 or Table 2 that may be identical or may be different to either TM1 or TM2; L1 is a linker sequence having between 1 to about 300 amino acid residues as described for formula II, and wherein the linker sequence is covalently bound to the C terminus of TM1 and the N terminus of TM2; and L2 is a linker sequence that may be identical to or different from L1, having between 1 to about 300 amino acid residues as described as for formula II, and wherein the linker sequence is covalently bound to the C terminus of TM2 and the N terminus of TM3. In one embodiment, the respective TM may each comprise two or more binding domains that may be joined by an additional linker sequence of 1 to about 300 amino acid residues having a flexible, unstructured conformation. In one embodiment, the linker sequence is an XTEN having at least about 12 to about 300 amino acids exhibiting a flexible, unstructured characteristic such that the binding domains can thereby mutually orientate relative to each other and the ligand and adopt a constrained configuration to bind to the target ligand. In another embodiment, wherein the TM comprises two or more binding domains, the binding domains may be identical or they may be different, and can comprise, for example, sequences derived from such VL or VH sequences, receptor binding domains, or Ig-like binding domains as necessary to bind with sufficient affinity to the target ligand. 
     The invention contemplates additional and alternative configurations of the foregoing embodiments, including additional targeting moieties, binding regions, linkers and XTEN configured in alternative permutations of order, N- to C-terminus, for the various components. The binding fusion proteins of the embodiments disclosed herein exhibit one or more or any combination of the properties and/or the embodiments as detailed herein. 
     (e) Configurations of Binding Fusion Proteins with Spacer and Cleavage Sequences 
     The invention contemplates configurations of binding fusion proteins, including but not limited to those comprising targeting moieties characterized as scFv, diabodies, domain antibodies, bifunctional antibodies or cytokine binding fusion proteins, in which the XTEN may be linked to targeting moieties by spacer sequences incorporated into or adjacent to the XTEN that are designed to incorporate or enhance a functionality or property to the composition, or as an aid in the assembly or manufacture of the binding fusion protein compositions. Such properties include, but are not limited to, inclusion of cleavage sequence(s) to permit release of components, inclusion of amino acids compatible with nucleotide restrictions sites to permit linkage of XTEN-encoding nucleotides to targeting moiety-encoding nucleotides or that facilitate construction of expression vectors, or to reduce steric hindrance in regions of the fusion proteins. 
     A spacer sequence can be introduced between an XTEN sequence and a targeting moiety component to decrease steric hindrance such that the targeting moiety component may assume its desired tertiary structure and/or interact appropriately with its target. For spacers and methods of identifying desirable spacers, see, for example, George, et al. (2003)  Protein Engineering  15:871-879, specifically incorporated by reference herein. In one embodiment, the spacer comprises one or more peptide sequences that are between 1-50 amino acid residues in length, or about 1-25 residues, or about 1-10 residues in length. Spacer sequences, exclusive of cleavage sites, can comprise any of the 20 natural L amino acids, and will preferably have XTEN-like properties in that 1) they will comprise hydrophilic amino acids that are sterically unhindered such as, but not limited to, glycine (G), alanine (A), serine (S), threonine (T), glutamate (E), proline (P) and aspartate (D); and 2) will be substantially non-repetitive. In some cases, the spacer can be polyglycines or polyalanines, or is predominately a mixture of combinations of glycine, serine and alanine residues. In one embodiment, a spacer sequence, exclusive of cleavage site amino acids, has about 1 to 10 amino acids that consist of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E), and proline (P) and are substantially devoid of secondary structure; e.g., less than about 10%, or less than about 5% as determined by the Chou-Fasman and/or GOR algorithms. In one embodiment, the spacer sequence is GPEGPS (SEQ ID NO: 145). In another embodiment, the spacer sequence is GPEGPS (SEQ ID NO: 145) linked to a cleavage sequence of Table 7. In addition, spacer sequences are designed to avoid the introduction of T-cell epitopes; determination of which are described above and in the Examples. 
     In one embodiment, the binding fusion protein comprises one or more spacer sequences linked at the junction(s) between the payload sequence and the one more XTEN incorporated into the fusion protein, wherein the spacer sequences comprise amino acids that are compatible with nucleotides encoding restriction sites. In another embodiment, the binding fusion protein comprises one or more spacer sequences linked at the junction(s) between the payload sequence and the one more XTEN incorporated into the fusion protein wherein the spacer sequences comprise amino acids that are compatible with nucleotides encoding restriction sites and the amino acids and the one more spacer sequence amino acids are chosen from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E), and proline (P). In another embodiment, the binding fusion protein comprises one or more spacer sequences linked at the junction(s) between the payload sequence and the one more XTEN incorporated into the fusion protein wherein the spacer sequences comprise amino acids that are compatible with nucleotides encoding restriction sites and the one more spacer sequences are chosen from the sequences of Table 6. The exact sequence of each spacer sequence is chosen to be compatible with cloning sites in expression vectors that are used for a particular binding fusion protein construct. For embodiments in which a single XTEN is attached to the N- or C-terminus, only a single spacer sequence at the junction of the two components would be required. As would be apparent to one of ordinary skill in the art, the spacer sequences comprising amino acids compatible with restriction sites could be omitted from the construct when an entire fusion protein gene is synthetically generated, rather than ligated using targeting moiety and XTEN encoding genes. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Spacer Sequences Compatible with Restriction Sites 
               
            
           
           
               
               
            
               
                 Spacer Sequence 
                 Restriction Enzyme 
               
               
                   
               
               
                 GSPG 
                 BsaI 
               
               
                 (SEQ ID NO: 146) 
                   
               
               
                   
               
               
                 ETET 
                 BsaI 
               
               
                 (SEQ ID NO: 147) 
                   
               
               
                   
               
               
                 PGSSS 
                 BbsI 
               
               
                 (SEQ ID NO: 148) 
                   
               
               
                   
               
               
                 GAP 
                 AscI 
               
               
                   
               
               
                 GPA 
                 FseI 
               
               
                   
               
               
                 GPSGP 
                 SfiI 
               
               
                 (SEQ ID NO: 149) 
                   
               
               
                   
               
               
                 AAA 
                 SacII 
               
               
                   
               
               
                 TG 
                 AgeI 
               
               
                   
               
               
                 GT 
                 KpnI 
               
               
                   
               
            
           
         
       
     
     In some embodiments, a spacer sequence in a binding fusion protein composition comprises one or more cleavage sequences, which are identical or different, wherein the cleavage sequence may be acted on by a protease to release the XTEN sequence(s) from the fusion protein. In one embodiment, the incorporation of the cleavage sequence into the binding fusion protein is designed to permit release of an targeting moiety that becomes active or more active upon its release from the XTEN component. The cleavage sequences are located sufficiently close to the targeting moiety sequences, generally within 18, or within 12, or within 6, or within 2 amino acids of the targeting moiety sequence, such that any remaining residues attached to the targeting moiety after cleavage do not appreciably interfere with the activity (e.g., such as binding to a target), yet provide sufficient access to the protease to be able to effect cleavage of the cleavage sequence. In some cases, the binding fusion protein comprising the cleavage sequences will also have one or more spacer sequence amino acids between the targeting moiety and the cleavage sequence or the XTEN and the cleavage sequence to facilitate access of the protease to the cleavage sequence; the spacer amino acids comprising any natural amino acid, including glycine, serine and alanine as preferred amino acids. In one embodiment, the cleavage site is a sequence that can be cleaved by a protease endogenous to the mammalian subject such that the fusion protein can be cleaved after administration to a subject. In one embodiment of the foregoing construct, the targeting moiety that is released from the fusion protein by cleavage of the cleavage sequence exhibits at least about a two-fold, or at least about a three-fold, or at least about a four-fold, or at least about a five-fold, or at least about a six-fold, or at least about a eight-fold, or at least about a ten-fold, or at least about a 20-fold increase in activity compared to the intact binding fusion protein. 
     Examples of cleavage sites contemplated by the invention include, but are not limited to, a polypeptide sequence cleavable by a mammalian endogenous protease selected from FXIa, FXIIa, kallikrein, FVIIIa, FVIIIa, FXa, FIla (thrombin), Elastase-2, granzyme B, MMP-12, MMP-13, MMP-17 or MMP-20, or by non-mammalian proteases such as TEV, enterokinase, PreScission™ protease (rhinovirus 3C protease), and sortase A. Sequences known to be cleaved by the foregoing proteases and others are known in the art. Exemplary cleavage sequences contemplated by the invention and the respective cut sites within the sequences are presented in Table 7, as well as sequence variants thereof. 
     In one embodiment, the invention provides binding fusion proteins comprising one or more cleavage sequences operably positioned to release the targeting moiety from the fusion protein upon cleavage, wherein the one or more cleavage sequences has at least about 86%, or at least about 92% or greater sequence identity to a sequence selected from Table 7. 
     In some embodiments, only the two or three amino acids flanking both sides of the cut site (four to six amino acids total) are incorporated into the cleavage sequence that, in turn, is incorporated into the fusion proteins of the embodiments. In other embodiments, the incorporated cleavage sequence of Table 7 can have one or more deletions or insertions or one or two or three amino acid substitutions for any one or two or three amino acids in the known sequence, wherein the deletions, insertions or substitutions result in reduced or enhanced susceptibility but not an absence of susceptibility to the protease, resulting in an ability to tailor the rate of release of the targeting moiety from the XTEN. Exemplary substitutions are shown in Table 7. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Protease Cleavage Sequences 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Exemplary 
                   
                   
                   
               
               
                 Protease Acting 
                 Cleavage 
                   
                   
                   
               
               
                 Upon Sequence 
                 Sequence 
                 SEQ ID NO: 
                 Minimal Cut Site* 
                 SEQ ID NO: 
               
               
                   
               
               
                 FXIa 
                 KLTR↓AET 
                 150 
                 KD/FL/T/R↓VA/VE/GT/GV 
                   
               
               
                   
               
               
                 FXIa 
                 DFTR↓VVG 
                 151 
                 KD/FL/T/R↓VA/VE/GT/GV 
                   
               
               
                   
               
               
                 FXIIa 
                 TMTR↓IVGG 
                 152 
                 NA 
                   
               
               
                   
               
               
                 Kallikrein 
                 SPFR↓STGG 
                 153 
                 —/—/FL/RY↓SR/RT/—/— 
                   
               
               
                   
               
               
                 FVIIa 
                 LQVR↓IVGG 
                 154 
                 NA 
                   
               
               
                   
               
               
                 FIXa 
                 PLGR↓IVGG 
                 155 
                 —/—/G/R↓—/—/—/— 
                   
               
               
                   
               
               
                 FXa 
                 TEGR↓TVGG 
                 156 
                 IA/E/GFP/R↓STI/VFS/—/G 
                   
               
               
                   
               
               
                 FIIa (thrombin) 
                 LTPR↓SLLV 
                 157 
                 —/—/PLA/R↓SAG/—/—/— 
                   
               
               
                   
               
               
                 Elastase-2 
                 LGPV↓SGVP 
                 158 
                 —/—/—/VIAT↓—/—/—/— 
                   
               
               
                   
               
               
                 Granzyme-B 
                 VAGD↓SLEE 
                 159 
                 V/—/—/D↓—/—/—/— 
                   
               
               
                   
               
               
                 MMP-12 
                 GPAG↓LGGA 
                 160 
                 G/PA/—/G↓L/—/G/— 
                 161 
               
               
                   
               
               
                 MMP-13 
                 GPAG↓LRGA 
                 162 
                 G/P/—/G↓L/—/GA/— 
                 163 
               
               
                   
               
               
                 MMP-17 
                 APLG↓LRLR 
                 164 
                 —/PS/—/—↓LQ/—/LT/— 
                   
               
               
                   
               
               
                 MMP-20 
                 PALP↓LVAQ 
                 165 
                 NA 
                   
               
               
                   
               
               
                 TEV 
                 ENLYFQ↓G 
                 166 
                 ENLYFQ↓G/S 
                 167 
               
               
                   
               
               
                 Enterokinase 
                 DDDK↓IVGG 
                 168 
                 DDDK↓IVGG 
                 169 
               
               
                   
               
               
                 Protease 3C 
                 LEVLFQ↓GP 
                 170 
                 LEVLFQ↓GP 
                 171 
               
               
                 (PreScission ™) 
                   
                   
                   
                   
               
               
                   
               
               
                 Sortase A 
                 LPKT↓GSES 
                 172 
                 L/P/KEAD/T↓G/—/EKS/S 
                 173 
               
               
                   
               
               
                 ↓indicates cleavage site NA: not applicable 
               
               
                 *the listing of multiple amino acids before, between, or after a slash indicate alternative amino acids that can be substituted at the position; “—” indicates that any amino acid may be substituted for the corresponding amino acid indicated in the middle column 
               
            
           
         
       
     
     (f) Methods of Use of Binding Fusion Proteins 
     In another aspect, the invention provides a method of for achieving a beneficial effect in a disease, disorder or condition mediated by a binding fusion protein. In one embodiment, the invention provides the use of a binding fusion protein derived from a parental antibody that binds to a target selected from the group consisting of the targets of Table 1 in treatment of a disease, disorder or condition to a subject in need thereof by the administration of a therapeutically effective amount of the binding fusion protein, wherein said administration leads to the eradication or amelioration of one or more of the physiological or clinical symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In another embodiment, the invention provides a method of treating a disease, disorder, or condition in a mammal comprising administering to the mammal a therapeutically effective amount of a binding fusion protein comprising one or more targeting moieties directed to one or more targets selected from Table 1, linked to one or more XTEN sequences molecules and, optionally, one or more linkers, to form the binding fusion protein, wherein the linkage does not substantially alter the essential functional properties of the binding fusion protein of binding affinity and sustained terminal half-life or reduced serum clearance rate as compared to that of the parental targeting moiety from which the binding fusion protein is derived, and wherein the administration of the binding fusion protein achieves a beneficial therapeutic effect. The effective amount can produce a beneficial effect in helping to treat (e.g., cure or reduce the severity) or prevent (e.g., reduce the likelihood of onset or severity) a disease, disorder or condition, such as, but not limited to a cancer, a cardiovascular disease or condition, an infectious disease, an inflammatory condition, a respiratory condition, organ transplant rejection, or a metabolic disease mediated by or associated with one or more targets, preferably selected from Table 1. 
     In one embodiment, the method comprises administering a therapeutically-effective amount of a pharmaceutical composition comprising a binding fusion protein composition comprising one or more targeting moieties linked to one or more XTEN sequence(s) and at least one pharmaceutically acceptable carrier to a subject in need thereof that results in an improvement in at least one parameter, physiologic condition, or clinical outcome mediated by the targeting moiety component(s). The method contemplates administration of the pharmaceutical composition by any route appropriate for the disease, disorder or condition being treated, including subcutaneously, intramuscularly, intravitreally, or intravenously. 
     The methods of the invention include administration of consecutive doses of a therapeutically effective amount of the pharmaceutical composition for a period of time sufficient to achieve and/or maintain the desired parameter or clinical effect, and such consecutive doses of a therapeutically effective amount establishes the therapeutically effective dose regimen for the pharmaceutical composition; i.e., the schedule for consecutively administered doses, wherein the doses are given in therapeutically effective amounts to result in a sustained beneficial effect on any clinical sign or symptom, aspect, measured parameter or characteristic of a metabolic disease state or condition, including, but not limited to, those described herein. 
     A therapeutically effective amount of the pharmaceutical composition may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the binding fusion protein are outweighed by the therapeutically beneficial effects. A prophylactically effective amount refers to an amount of pharmaceutical composition required for the period of time necessary to achieve the desired prophylactic result. 
     For the inventive methods, longer acting binding fusion protein compositions or pharmaceutical compositions are preferred, so as to improve patient convenience, to increase the interval between doses and to reduce the amount of drug required to achieve a sustained effect. In one embodiment, a method of treatment comprises administration of a therapeutically effective dose of a binding fusion protein to a subject in need thereof that results in a gain in time spent within a therapeutic window established for the fusion protein of the pharmaceutical composition compared to the corresponding targeting moiety component(s) not linked to the XTEN and administered at a comparable dose to a subject. In one embodiment, the gain in time spent within the therapeutic window is at least about three-fold, or at least about four-fold, or at least about five-fold, or at least about six-fold, or at least about eight-fold, or at least about 10-fold, or at least about 20-fold, or at least about 40-fold compared to the corresponding targeting moiety component not linked to the XTEN and administered at a comparable dose to a subject. The methods further provide that administration of multiple consecutive doses of a pharmaceutical composition administered using a therapeutically effective dose regimen to a subject in need thereof can result in a gain in time between consecutive C max  peaks and/or C min  troughs for blood levels of the binding fusion protein compared to the corresponding targeting moieties not linked to the XTEN. In the foregoing embodiment, the gain in time spent between consecutive C max  peaks and/or C min  troughs can be at least about three-fold, or at least about four-fold, or at least about five-fold, or at least about six-fold, or at least about eight-fold, or at least about 10-fold, or at least about 20-fold, or at least about 40-fold compared to the corresponding targeting moiety component(s) not linked to the XTEN and administered using a comparable dose regimen established for that targeting moiety. In the embodiments hereinabove described in this paragraph the administration of the fusion protein or pharmaceutical composition can result in an improvement in at least one parameter known to be useful for assessing the subject diseases, conditions or disorders) using a lower unit dose in moles of fusion protein compared to the corresponding targeting moiety component(s) not linked to the XTEN and administered at a comparable unit dose or dose regimen to a subject. 
     In one embodiment, the administration of a binding fusion protein or pharmaceutical composition can result in an improvement in one of the clinical, biochemical or physiologic parameters that is greater than that achieved by administration of the targeting moiety component not linked to XTEN, determined using the same assay or based on a measured clinical parameter. In another embodiment, administration of the binding fusion protein or pharmaceutical composition can result in improvement two or more clinical or metabolic-related parameters, each mediated by one of the different targeting moieties that collectively result in an enhanced effect compared the targeting moiety component not linked to the XTEN, determined using the same assays or based on measured clinical parameters. In another embodiment, administration of the binding fusion protein or pharmaceutical composition can result in activity in one or more of the clinical or biochemical or physiologic parameters that is of longer duration than the activity of one of the single targeting moiety components not linked to the XTEN, determined using that same assay or based on a measured clinical parameter. 
     In one embodiment, the binding fusion protein is used to treat VEGF-mediated disorders. In particular, the invention provides a method for treating a VEGF-mediated disease in a human patient with a binding fusion protein comprising one or more of the targeting moieties that binds to human VEGF, wherein the binding reduces the ability of the VEGF to bind its cognate receptor. Such binding fusion proteins can have prophylactic and therapeutic applications in a broad spectrum of VEGF-mediated disorders, including pathologies supported by blood vessel proliferation, i.e. angiogenesis, in a manner similar to the application of anti-VEGF antibodies in the treatment of such disease indications that is known in the art, which treatment indications include solid tumors ((Kim et al.  Nature  362:841-844 (1993); Warren et al.  I Clin. Invest.  95:1789-1797 (1995); Borgstrom et al.  Cancer Res.  56:4032-4039 (1996); and Melnyk et al.  Cancer Res.  56:921-924 (1996)) and intraocular neovascular syndromes such as proliferative retinopathies and age-related macular degeneration (AMD) (Adamis et al.  Arch. Ophthalmol.  114:66-71 (1996)). 
     Fusion proteins comprising the XTEN of the invention can approximate the in vivo pharmacokinetics (e.g. terminal half-life) of full-length antibody. Given these characteristics, it is believed that the binding fusion proteins of the invention comprising anti-VEGF targeting moieties display the same or substantially similar in vivo activities as full length anti-VEGF monoclonal antibody across a range of different parameters, including pharmacokinetic characteristics and therapeutic endpoints in an animal tumor model, supporting the utility of the binding fusion proteins in the same broad spectrum of neovascular disease indications that responds to full length anti-VEGF antibody treatment. 
     Any binding fusion protein disclosed herein that comprises a targeting moiety derived from an anti-VEGF antibody or fragment can be advantageously utilized in a method of treating a VEGF-mediated disease or disorder, such as neovascular disorders. In one embodiment, the invention provides a method of treating a neovascular disorder in a human patient comprising administering to the patient a therapeutically effective amount of a binding fusion protein or pharmaceutical composition wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to human VEGF. 
     In another embodiment, the invention provides a method of treating a solid tumor disorder in a human patient comprising administering to the patient an effective amount of a binding fusion protein or pharmaceutical composition wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to human VEGF. In yet another embodiment, the solid tumor disorder in the foregoing method is selected from the group consisting of breast carcinomas, lung carcinomas, gastric carcinomas, esophageal carcinomas, colorectal carcinomas, liver carcinomas, ovarian carcinomas, thecomas, arrhenoblastomas, cervical carcinomas, endometrial carcinoma, endometrial hyperplasia, endometriosis, fibrosarcomas, choriocarcinoma, head and neck cancer, nasopharyngeal carcinoma, laryngeal carcinomas, hepatoblastoma, Kaposi&#39;s sarcoma, melanoma, skin carcinomas, hemangioma, cavernous hemangioma, hemangioblastoma, pancreas carcinomas, retinoblastoma, astrocytoma, glioblastoma, Schwannoma, oligodendroglioma, medulloblastoma, neuroblastomas, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, urinary tract carcinomas, thyroid carcinomas, Wilm&#39;s tumor, renal cell carcinoma, prostate carcinoma, abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs&#39; syndrome. 
     In still another embodiment, the invention provides a method of treating an intraocular neovascular disorder in a human patient comprising administering to the patient a therapeutically effective amount of a binding fusion protein or pharmaceutical composition wherein at least one targeting moiety comprises an antigen binding site that binds to human VEGF. In a further embodiment, the intraocular neovascular disorder is selected from the group consisting of diabetic and other proliferative retinopathies including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, and age-related macular degeneration. 
     In another embodiment, the invention provides a method of inhibiting angiogenesis in a human patient comprising administering to the patient an effective amount of a binding fusion protein wherein at least one targeting moiety in the composition comprises an antigen binding site that binds to human VEGF. 
     In another embodiment, the binding fusion protein is used to treat disorders mediated by HER2-expressing cells. The invention provides a method for treating a human disease mediated by HER2-expressing cells with a binding fusion protein composition that is derived from a parental antibody that binds to HER2. Such compositions have prophylactic and therapeutic applications in a broad spectrum of HER2-expressing cell-mediated disorders, including pathologies supported by the proliferation of cells expressing HER2, such as cancers characterized by over-expression of HER2, in a manner similar to the application of full length anti-Her2 antibodies in the treatment of such disease indications that is known in the art, which treatment indications include HER2-overexpressing breast, ovarian and lung cancers. The choice of a targeting moiety for a binding fusion protein to be used in the method can be determined by in vitro binding assays or in vitro cell-killing assays as described in the Examples or are known in the art. For example, a candidate binding fusion protein against HER2 can be used in cytotoxicity tests using cell cultures of human breast cancer lines such as MCF-7, CAMA-1, SKBR-3, and BT-20, such as described in U.S. Pat. No. 4,753,894. In one embodiment, the invention provides a method of treating a HER2-expressing cell mediated disorder in a human patient comprising administering to the patient a therapeutically effective amount of a binding fusion protein or pharmaceutical composition wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to HER2. The disorder can be a HER2-expressing cell proliferative disorder, including a benign or malignant tumor characterized by the over-expression of the ErbB2 receptor, e.g. a cancer, such as, breast cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer. In addition, the invention contemplates the use of the foregoing composition in place of full-length anti-Her2 antibody in the treatment of HER2-overexpressing cancers as described in U.S. Pat. No. 5,725,856. 
     In another embodiment, the invention provides a method of treating disorders mediated by CD20-Expressing cells. The invention provides a method for treating a human disease mediated by CD20-expressing cells with a binding fusion protein composition that is derived from a parental antibody that binds to human CD20. Such compositions have prophylactic and therapeutic applications in a broad spectrum of CD20-expressing cell-mediated disorders, including pathologies supported by the proliferation of CD20-expressing cells, such as cancers of CD20-expressing cells, in a manner similar to the application of full length anti-CD20 antibodies in the treatment of such disease indications known in the art, which treatment indications include B-lymphocytic lymphomas, as described in U.S. Pat. No. 6,682,734. 
     In another embodiment, the invention provides a method of treating disorders mediated by CD18-expressing cells. The invention provides a method for treating a human disease mediated by CD18-expressing cells with a binding fusion protein composition that is derived from a parental antibody that binds to human CD18. Such compositions have prophylactic and therapeutic applications in a broad spectrum of CD18-expressing cell-mediated disorders, including pathologies supported by leukocyte adhesion, in a manner similar to the application of full length anti-CD18 antibodies in the treatment of such disease indications known in the art, which treatment indications include acute myocardial infarction and stroke. In one embodiment, the invention provides a method of treating a disorder in a human patient mediated by a CD18-expressing cell, comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the composition comprises an antigen binding site that binds to human CD18. In another embodiment, the CD18-expressing cell-mediated disorder is an inflammatory disorder, such as an ischemic reperfusion disorder, including acute myocardial infarction and stroke. In addition, the invention contemplates the use of the foregoing binding fusion protein in place of full-length anti-CD18 antibody in the treatment of stroke as described in PCT Publication WO 97/26912. 
     In another embodiment, the invention provides a method of treating a LFA-1-mediated disorder in a human, comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the composition comprises a targeting moiety that binds to human CD18. In addition, the invention contemplates the use of the foregoing binding fusion protein in place of full-length anti-CD18 antibody in the treatment of a LFA-1-mediated disorder, such as psoriasis and graft rejection, in a human patient as described in U.S. Pat. No. 5,622,700. 
     In another embodiment, the invention provides a method of treating disorders mediated by CD11a-expressing cells. In one embodiment, the invention provides a method for treating a human disease mediated by a CD11a-expressing cell with a binding fusion protein composition that is derived from a parental antibody that binds to human CD11a. Such compositions have prophylactic and therapeutic applications in a broad spectrum of CD11a-expressing cell-mediated disorders, including pathologies supported by leukocyte adhesion, in a manner similar to the application of full length anti-CD11a antibodies in the treatment of such disease indications known in the art, which treatment indications include psoriasis, asthma, graft rejection, and multiple sclerosis. In another embodiment, the invention provides a method of treating a LFA-1-mediated disorder in a human, comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the composition comprises an antigen binding site that binds to human CD11a. In addition, the invention contemplates the use of the foregoing binding fusion protein in place of full-length anti-CD11a antibody in the treatment of a LFA-1-mediated disorder, such as psoriasis and graft rejection, in a human patient as described in U.S. Pat. No. 5,622,700. In another aspect, the invention contemplates the use of the foregoing binding fusion proteins in place of full-length anti-CD11a antibody in the treatment of LFA-1-mediated disorders in a human patient as described in U.S. Pat. No. 6,037,454. 
     In another embodiment, the invention provides a method of treating IgE-mediated disorders. In one embodiment, the invention provides a method for treating an IgE-mediated disorder in a human patient with a binding fusion protein composition that is derived from a parental antibody that binds to human IgE. Such compositions have prophylactic and therapeutic applications in a broad spectrum of IgE-mediated disorders, including pathologies characterized by the overproduction and/or hypersensitivity to the immunoglobulin IgE, in a manner similar to the application of anti-IgE antibodies in the treatment of such disease indications known in the art, which treatment indications include allergic diseases, such as allergic asthma and allergic rhinitis. In one embodiment, the invention provides a method of treating an IgE-mediated disorder in a human patient comprising administering to the patient a therapeutically effective amount of a binding fusion protein described wherein at least one targeting moiety comprises an antigen binding site that binds to human IgE. In another embodiment, the IgE-mediated disorder is an allergic disease. In yet another embodiment, the IgE-mediated disorder is allergic asthma. In still another embodiment, the IgE-mediated disorder is allergic rhinitis. 
     In a further embodiment, the invention provides a method of treating an IgE-mediated disorder in a human patient comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the composition comprises an antigen binding site that competes with human Fc epsilonRl for binding to human IgE. In yet another embodiment, the invention provides a method of treating an IgE-mediated disorder in a human patient comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one antibody fragment in the binding fusion protein comprises an antigen binding site that binds to membrane-bound IgE on the surface of human B-lymphocytes but does not bind to soluble IgE bound to Fc epsilon RI receptor on the surface of human basophils. In addition, the invention contemplates the use of any of the foregoing binding fusion proteins in place of full length anti-human IgE antibody in the treatment of an IgE-mediated disorder, such as allergic diseases including allergic asthma and allergic rhinitis, in a human patient as described in PCT Application No. WO 99/01556. In another aspect, the invention contemplates the use of any of the foregoing binding fusion proteins in place of full length anti-human IgE antibody in the treatment of allergic asthma in a human patient as described in WO 97/04807. 
     In another embodiment, the invention provides a method of treating an allergic disease in a human patient comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that competes with human Fc epsilon RI for binding to human IgE. In yet another embodiment, the invention provides a method of treating an allergic disease in a human patient comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to membrane-bound IgE on the surface of human B-lymphocytes but does not bind to soluble IgE bound to Fc epsilon RI receptor on the surface of human basophils. 
     In another embodiment, the invention provides a method of treating allergic asthma in a human patient comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that competes with human Fc epsilon RI for binding to human IgE. In yet another embodiment, the invention provides a method of treating allergic asthma in a human patient comprising administering to the patient a therapeutically effective amount of any binding fusion protein described in this Section (II) wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to membrane-bound IgE on the surface of human B-lymphocytes but does not bind to soluble IgE bound to Fc epsilon RI receptor on the surface of human basophils. 
     TNF-α-Mediated Disorders 
     In one embodiment, the invention provides a method for treating a TNF-α-mediated disease with a binding fusion protein that is derived from a parental antibody that binds to human TNF-α. Such binding fusion proteins can have prophylactic and therapeutic applications in a broad spectrum of TNF-α-mediated disorders, including inflammatory disorders and immune disorders, in a manner similar to the application of full-length anti-human TNF-α antibodies in the treatment of such disease indications such as Crohn&#39;s disease, inflammatory bowel disease, and rheumatoid arthritis. 
     In one embodiment, the invention provides a method of treating an inflammatory disorder in a human patient comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to human TNF-α. In another embodiment, the inflammatory disorder is Crohn&#39;s disease. In yet another embodiment, the inflammatory disorder is inflammatory bowel disease. In still another embodiment, the inflammatory disorder is rheumatoid arthritis. The use of antibodies that bind to human TNF-α in the treatment of inflammatory conditions have been described, for example, in U.S. Pat. Nos. 5,672,347, 5,656,272, and 5,698,195. 
     Tissue Factor-Mediated Disorders 
     In one embodiment, the invention provides a method for treating a tissue factor-mediated disease with a binding fusion protein derived from a parental antibody that binds to human tissue factor. Such binding fusion proteins can have prophylactic and therapeutic applications in a broad spectrum of tissue factor-mediated disorders, including pathologies supported by blood coagulation and in the treatment of such disease indications as deep vein thrombosis, arterial thrombosis, atherosclerosis, vascular stenosis, myocardial ischemic diseases including acute myocardial infarction, reocclusion following angioplasty or atherectomy or thrombolytic treatment for acute myocardial infarction, angina, cerebral ischemic diseases including stroke, venous thrombophlebitis, and pulmonary embolism. In one embodiment, the invention provides a method of treating a tissue factor-mediated disease or disorder (such as the foregoing) in a human patient comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to human tissue factor. 
     In another embodiment, the invention provides a method of inhibiting blood coagulation in a human patient comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to human tissue factor, preventing the binding of coagulation factor VII. 
     Disorders Mediated by EGFR-Expressing Cells 
     In one embodiment, the invention provides a method for treating a human disease mediated by EGFR-expressing cells with a of the binding fusion protein that is derived from a parental antibody that binds to human EGFR (a.k.a., ErbB-1 or Her1). Such binding fusion proteins can have prophylactic and therapeutic applications in a broad spectrum of EGFR-expressing cell-mediated disorders, including pathologies supported by the proliferation of cells expressing EGFR, such as cancers characterized by over-expression of EGFR, including cancers of the breast, ovary, head and neck, brain, bladder, pancreas, and lung. 
     In one embodiment, the invention provides a method of treating a cell proliferation disorder in a human patient characterized by over-expression of EGFR comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to human EGFR. The disorder can be a benign or malignant tumor characterized by the over-expression of the EGFR, e.g. a cancer, such as, breast cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer. 
     Disorders Mediated by CD3-Expressing Cells 
     In one embodiment, the invention provides a method for treating a human disease or disorder mediated by CD3-expressing cells with a binding fusion protein that is derived from a parental antibody that binds to human CD3. Such binding fusion proteins can have prophylactic and therapeutic applications in a broad spectrum of CD3-expressing cell-mediated disorders, including conditions associated with the proliferation or activation of cells expressing CD3, such as immune disorders mediated by T-lymphocytes and graft rejection in transplant recipients. The use of anti-CD3 antibodies to treat diseases and disorders has been described, for example, in U.S. Pat. No. 4,515,893. In another aspect, the invention contemplates the use of the foregoing binding fusion protein in place of full length anti-human CD3 antibody in the treatment of acute allograft rejection in kidney transplant recipients as described for ORTHOCLONE OKT3 muromonab-CD3 in  Physician&#39;s Desk Reference,  52 nd  Edition (1998), pp. 1971-1974. 
     Disorders Mediated by TAC-Expressing Cells 
     In one embodiment, the invention provides a method for treating a human disease mediated by interleukin-2 receptor α-chain (TAC)-expressing cells with a binding fusion protein that is derived from a parental antibody that binds to human TAC. Such binding fusion proteins can have prophylactic and therapeutic applications in a broad spectrum of TAC-expressing cell-mediated disorders, including conditions created by the proliferation or activation of cells expressing TAC and immune disorders mediated by T-lymphocytes or B-lymphocytes, including graft rejection in transplant recipients. 
     In one embodiment, the invention provides a method of treating a disorder in a human patient mediated by a TAC-expressing cell, comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to human TAC. In another embodiment, the TAC-expressing cell-mediated disorder is characterized by the activation or proliferation of T-lymphocytes or B-lymphocytes, including immune disorders such as graft rejection in transplant recipients, graft-versus-host disease (GHVD), graft rejection in transplant recipients, such as acute graft rejection in renal transplant recipients, and autoimmune diseases such as Type I diabetes, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and myasthenia gravis. The use of antibodies to treat disorders mediated by interleukin-2 receptor α-chain with antibodies has been described in U.S. Pat. No. 5,693,761. 
     (g) Binding Fusion Protein-Drug Compositions and XTEN-Drug Compositions 
     The present invention relates in part to compositions of binding fusion proteins covalently linked to a drug, resulting in a binding fusion protein drug conjugate (“BFP-D”). In another aspect, the invention relates to compositions of XTEN covalently linked to a drug, resulting in an XTEN-drug conjugate (“XTEN-D”). In particular, the invention provides isolated BFP-D and XTEN-D compositions useful in the treatment of diseases, disorders or conditions. In one embodiment, the BFP-D comprises one or more targeting moieties of the binding fusion protein directed to an antigen, ligand, or receptor implicated in, associated with, or that modulates a disease, disorder or condition, while one or more XTEN of the binding fusion protein can be designed to serve as a carrier to which the drug is conjugated, conferring a desired half-life or enhanced pharmaceutical property on the binding fusion protein, as described more fully below, and the covalently-linked drug can be selectively delivered to a cell, tissue, or organ to effect a pharmacologic, cytotoxic, or cytostatic effect. Thus, the BFP-D generally comprises one or more of the following components: 1) XTEN; 2) targeting moiety; 3) cross-linker; and 4) drug. The XTEN-D generally comprise one or more of the following components: 1) XTEN; 2) cross-linker; and 3) drug. 
     Exemplary embodiments of targeting moieties, XTEN and fusion proteins of targeting moieties and XTEN have been described, above. The invention provides XTEN that further serve as a platform to which drugs can be conjugated, such that they serve as a “carrier”, conferring certain desirable pharmacokinetic, chemical and pharmaceutical properties to the compositions, amongst other properties described below. 
     In some embodiments, the XTEN component are engineered to incorporate a defined number of amino acid residues that contain reactive groups that can be used to conjugate to drugs and/or with cross-linking agents. In one embodiment, the reactive amino acid is cysteine (“cysteine-engineered XTEN”). In another embodiment, the reactive amino acid is lysine, which contains a positively charged hydrophilic ε-amino group (“lysine-engineered XTEN”). As used herein, a “cysteine-engineered XTEN” means an XTEN protein, as defined above, further comprising about 1 to about 100 cysteine amino acids, or from 1 to about 50 cysteine amino acids, or from 1 to about 40 cysteine amino acids, or from 1 to about 20 cysteine amino acids, or from 1 to about 10 cysteine amino acids, or from 1 to about 5 cysteine amino acids that are available for conjugation to drug molecules. As used herein, a “lysine-engineered XTEN” means an XTEN protein, as defined above, further comprising about 1 to about 100 lysine amino acids, or from 1 to about 50 lysine amino acids, or from 1 to about 40 lysine engineered amino acids, or from 1 to about 20 lysine engineered amino acids, or from 1 to about 10 lysine engineered amino acids, or from 1 to about 5 lysine engineered amino acids that are available for conjugation to drug molecules. 
     Generally, XTEN cysteine thiol groups are more reactive, i.e., more nucleophilic, towards electrophilic conjugation reagents than amine or hydroxyl groups. Cysteine residues have been introduced into proteins by genetic engineering techniques to form covalent attachments to ligands or to form new intramolecular disulfide bonds (Better et al (1994) J. Biol. Chem. 13:9644-9650; Bernhard et al (1994) Bioconjugate Chem. 5:126-132; Greenwood et al (1994) Therapeutic Immunology 1:247-255; Tu et al (1999) Proc. Natl. Acad. Sci USA 96:4862-4867; Kanno et al (2000) J. of Biotechnology, 76:207-214; Chmura et al (2001) Proc. Nat. Acad. Sci. USA 98(15):8480-8484; U.S. Pat. No. 6,248,564). 
     In one embodiment, the invention provides an isolated composition comprising a cysteine-engineered XTEN conjugated by a cross-linker to one or more drug molecules, wherein the drug is selected from Table 9. In another embodiment, the invention provides an isolated composition comprising a targeted cysteine-engineered XTEN conjugated by a cross-linker to one or more drug molecules, wherein the drug is selected from Table 9 and the targeted cysteine-engineered XTEN comprises one or more targeting moieties that exhibit binding affinity to one or more targets selected from Table 1 or Table 2. In another embodiment, the invention provides an isolated composition comprising a lysine-engineered XTEN conjugated by a cross-linker to one or more drug molecules, wherein the drug is selected from Table 9. In another embodiment, the invention provides an isolated composition comprising a targeted lysine-engineered XTEN conjugated by a cross-linker to one or more drug molecules, wherein the drug is selected from Table 9 and the targeted cysteine-engineered XTEN comprises one or more targeting moieties that exhibits binding affinity to one or more targets selected from Table 1 or Table 2. In one embodiment of the foregoing, only a single drug compound would be conjugated to the XTEN. In another embodiment, more than one drug compound may be conjugated to the XTEN by selective application of the conjugation methods and reactants, using the methods described herein or those known in the art. 
     In some cases, the compositions of the invention include cysteine-engineered XTEN where nucleotides encoding one or more amino acids of an XTEN are replaced with a cysteine amino acid to create the cysteine-engineered XTEN gene. In other cases, oligonucleotides encoding one or more motifs of about 9 to about 14 amino acids comprising codons encoding one or more cysteines are linked in frame with other oligos encoding XTEN motifs or full-length XTEN to create the cysteine-engineered XTEN gene. In one embodiment of the foregoing, where the one or more cysteines are inserted into an XTEN sequence during the creation of the XTEN gene, nucleotides encoding cysteine can be linked to codons encoding amino acids used in XTEN to create a cysteine-XTEN motif with the cysteine(s) at a defined position using the methods described herein (see Example 61 and  FIGS. 40-41 ), or by standard molecular biology techniques, and the motifs subsequently assembled into the gene encoding the full-length cysteine-engineered XTEN. In such cases, where, for example, nucleotides encoding a single cysteine are added to the DNA encoding a motif selected from Table 3, the resulting motif would have 13 amino acids, while incorporating two cysteines would result in a motif having 14 amino acids, etc. In other cases, a cysteine-motif can be created de novo and be of a pre-defined length and number of cysteine amino acids by linking nucleotides encoding cysteine to nucleotides encoding one or more amino acid residues used in XTEN (e.g., G, S, T, E, P, A) at a defined position, and the encoding motifs subsequently assembled by annealing with other XTEN-encoding motif sequences into the gene encoding the full-length XTEN, as described herein and illustrated in  FIGS. 7-8 . In cases where a lysine-engineered XTEN is utilized to make the compositions of the invention, the approaches described above would be performed with codons encoding lysine instead of cysteine. Thus, by the foregoing, a new XTEN motif can be created that could comprise about 9-14 amino acid residues and have one or more reactive amino acids; i.e., cysteine or lysine. Non-limiting examples of motifs suitable for use in an engineered XTEN that contain a single cysteine or lysine are: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 174) 
               
               
                   
                 GGSPAGSCTSP 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 175) 
               
               
                   
                 GASASCAPSTG 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 176) 
               
               
                   
                 GPEPTCPAPSG 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 177) 
               
               
                   
                 GGSPAGSKTSP 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 178) 
               
               
                   
                 GASASKAPSTG 
               
            
           
         
       
     
     In such cases where a gene encoding an XTEN with one or more cysteine and/or lysine motifs is to be constructed from existing XTEN modules, the gene can be designed and built by linking existing “building block” polynucleotides encoding both short- and long-length XTENs; e.g., AE48, AE144, AE288, AE576, AM48, AE864, AM875, AE912, AG864, or the nucleotides encoding the 36′mers of Examples 1-4, etc., which can be fused in frame with the nucleotides encoding the cysteine- and/or lysine—containing motifs to build an engineered XTEN in which the reactive cysteine and/or lysines are placed in one or more selected locations in the sequence in the desired quantity. Non-limiting examples of such engineered XTEN are provided in Table 8. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Cysteine- and lysine-engineered XTEN 
               
            
           
           
               
               
               
            
               
                   
                   
                 SEQ 
               
               
                 XTEN 
                   
                 ID 
               
               
                 Name* 
                 Amino Acid Sequence 
                 NO: 
               
               
                   
               
               
                 AE144- 
                 GSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPG 
                 179 
               
               
                 Island_Cys1 
                 SEPATSGSETPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGS 
                   
               
               
                 -AE576 
                 EPATSGSETPGTSTEPSEGSAPGGGSPAGSCTSPGGSPAGSPTSTEEGTSESATPESGPGT 
                   
               
               
                   
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGSEP 
                   
               
               
                   
                 ATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTE 
                   
               
               
                   
                 PSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPS 
                   
               
               
                   
                 EGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATP 
                   
               
               
                   
                 ESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPE 
                   
               
               
                   
                 SGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSET 
                   
               
               
                   
                 PGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGP 
                   
               
               
                   
                 GSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE912- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTSTEE 
                 180 
               
               
                 Island_Cys2 
                 GTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                 -AE144 
                 TSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGT 
                   
               
               
                   
                 STEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTST 
                   
               
               
                   
                 EPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPA 
                   
               
               
                   
                 TSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPS 
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATP 
                   
               
               
                   
                 ESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEG 
                   
               
               
                   
                 SAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSET 
                   
               
               
                   
                 PGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETP 
                   
               
               
                   
                 GTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPG 
                   
               
               
                   
                 TSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGT 
                   
               
               
                   
                 STEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGGA 
                   
               
               
                   
                 SASCAPSTGGGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 TEPSEGSAPGSEPATSGSETPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSE 
                   
               
               
                   
                 SATPESGPGSEPATSGSETPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE576- 
                 GSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPG 
                 181 
               
               
                 Island_Cys1 
                 TSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGT 
                   
               
               
                 -AE288 
                 SESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTST 
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSES 
                   
               
               
                   
                 ATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATP 
                   
               
               
                   
                 ESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTS 
                   
               
               
                   
                 TEEGTSESATPESGPGTSTEPSEGSAPGGGSPAGSCTSPGGTSESATPESGPGSEPATSGS 
                   
               
               
                   
                 ETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTE 
                   
               
               
                   
                 EGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETP 
                   
               
               
                   
                 GSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE48- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGGPEPTCPAPS 
                 182 
               
               
                 Island_Cys3 
                 GGGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSA 
                   
               
               
                 -AE864 
                 PGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGT 
                   
               
               
                   
                 STEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 ESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTST 
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTE 
                   
               
               
                   
                 PSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESA 
                   
               
               
                   
                 TPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSP 
                   
               
               
                   
                 TSTEEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATP 
                   
               
               
                   
                 ESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPE 
                   
               
               
                   
                 SGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSET 
                   
               
               
                   
                 PGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGP 
                   
               
               
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE288- 
                 GTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPG 
                 183 
               
               
                 Island_Cys1 
                 TSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSP 
                   
               
               
                 -AE288- 
                 AGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSE 
                   
               
               
                 Island_Cys1 
                 SATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTE 
                   
               
               
                 -AE288 
                 PSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGGGSPAGSCTSPGGTSES 
                   
               
               
                   
                 ATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEP 
                   
               
               
                   
                 SEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSP 
                   
               
               
                   
                 TSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATP 
                   
               
               
                   
                 ESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEG 
                   
               
               
                   
                 SAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGGGSPAGSCTSPGGTSESATPE 
                   
               
               
                   
                 SGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 APGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTE 
                   
               
               
                   
                 EGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGP 
                   
               
               
                   
                 GSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 SEPATSGSETPGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE48- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGGASASCAPST 
                 184 
               
               
                 Island_Cys2 
                 GGGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSA 
                   
               
               
                 -AE576- 
                 PGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEE 
                   
               
               
                 Island_Cys2 
                 GTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPG 
                   
               
               
                 -AE144 
                 TSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGT 
                   
               
               
                   
                 STEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 ESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTST 
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTE 
                   
               
               
                   
                 PSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESA 
                   
               
               
                   
                 TPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSP 
                   
               
               
                   
                 TSTEEGTSESATPESGPGTSTEPSEGSAPGGASASCAPSTGGGSEPATSGSETPGTSESA 
                   
               
               
                   
                 TPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSEPATS 
                   
               
               
                   
                 GSETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSE 
                   
               
               
                   
                 GSAPG 
                   
               
               
                   
               
               
                 AM48- 
                 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGGGSPAGSCTS 
                 185 
               
               
                 Island_Cys1 
                 PGGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSAS 
                   
               
               
                 -AM875 
                 PGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                   
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEP 
                   
               
               
                   
                 ATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAES 
                   
               
               
                   
                 PGPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESPG 
                   
               
               
                   
                 PGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESPGP 
                   
               
               
                   
                 GTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 SSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGS 
                   
               
               
                   
                 PAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AM48- 
                 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGGASASCAPST 
                 186 
               
               
                 Island_Cys2 
                 GGGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSAS 
                   
               
               
                 -AM1296 
                 PGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                   
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEP 
                   
               
               
                   
                 ATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGPEPTGPAPSGGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGTSESATPE 
                   
               
               
                   
                 SGPGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAP 
                   
               
               
                   
                 GTSPSGESSTAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                   
                 SPSGESSTAPGTSPSGESSTAPGTSPSGESSTAPGTSTEPSEGSAPGSPAGSPTSTEEGTST 
                   
               
               
                   
                 EPSEGSAPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGSSTP 
                   
               
               
                   
                 SGATGSPGASPGTSSTGSPGASASGAPSTGGTSPSGESSTAPGSTSSTAESPGPGTSPSGE 
                   
               
               
                   
                 SSTAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSSPSASTGTGPGSSTPSGA 
                   
               
               
                   
                 TGSPGASPGTSSTGSPGTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSTEPSEGSAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASP 
                   
               
               
                   
                 GSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPG 
                   
               
               
                   
                 SEPATSGSETPGSSTPSGATGSPGASPGTSSTGSPGSSTPSGATGSPGSTSESPSGTAPGT 
                   
               
               
                   
                 SPSGESSTAPGSTSSTAESPGPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSP 
                   
               
               
                   
                 AGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AM48- 
                 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGGPEPTCPAPS 
                 187 
               
               
                 Island_Cys3 
                 GGGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSAS 
                   
               
               
                 -AM875 
                 PGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                   
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEP 
                   
               
               
                   
                 ATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAES 
                   
               
               
                   
                 PGPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESPG 
                   
               
               
                   
                 PGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESPGP 
                   
               
               
                   
                 GTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 SSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGS 
                   
               
               
                   
                 PAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AM48- 
                 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGGPEPTCPAPS 
                 188 
               
               
                 Island_Cys3 
                 GGGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSAS 
                   
               
               
                 -AM875- 
                 PGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPG 
                   
               
               
                 Island_Cys3 
                 TSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                 -AM48 
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEP 
                   
               
               
                   
                 ATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAES 
                   
               
               
                   
                 PGPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESPG 
                   
               
               
                   
                 PGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESPGP 
                   
               
               
                   
                 GTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 SSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGS 
                   
               
               
                   
                 PAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGGPEPTCPAPSGGMAEPAGSPTSTEEGASPGTSSTGSPG 
                   
               
               
                   
                 SSTPSGATGSPGSSTPSGATGSPG 
                   
               
               
                   
               
               
                 AE144- 
                 GSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPG 
                 189 
               
               
                 Island_Lys1- 
                 SEPATSGSETPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGS 
                   
               
               
                 AE576 
                 EPATSGSETPGTSTEPSEGSAPGGGSPAGSKTSPGGSPAGSPTSTEEGTSESATPESGPGT 
                   
               
               
                   
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGSEP 
                   
               
               
                   
                 ATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTE 
                   
               
               
                   
                 PSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPS 
                   
               
               
                   
                 EGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATP 
                   
               
               
                   
                 ESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPE 
                   
               
               
                   
                 SGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSET 
                   
               
               
                   
                 PGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGP 
                   
               
               
                   
                 GSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE912- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTSTEE 
                 190 
               
               
                 Island_Lys2- 
                 GTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                 AE144 
                 TSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGT 
                   
               
               
                   
                 STEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTST 
                   
               
               
                   
                 EPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPA 
                   
               
               
                   
                 TSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPS 
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATP 
                   
               
               
                   
                 ESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEG 
                   
               
               
                   
                 SAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSET 
                   
               
               
                   
                 PGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETP 
                   
               
               
                   
                 GTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPG 
                   
               
               
                   
                 TSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGT 
                   
               
               
                   
                 STEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGGA 
                   
               
               
                   
                 SASKAPSTGGGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 TEPSEGSAPGSEPATSGSETPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSE 
                   
               
               
                   
                 SATPESGPGSEPATSGSETPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE576- 
                 GSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPG 
                 191 
               
               
                 Island_Lys1- 
                 TSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGT 
                   
               
               
                 AE288 
                 SESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTST 
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSES 
                   
               
               
                   
                 ATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATP 
                   
               
               
                   
                 ESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTS 
                   
               
               
                   
                 TEEGTSESATPESGPGTSTEPSEGSAPGGGSPAGSKTSPGGTSESATPESGPGSEPATSGS 
                   
               
               
                   
                 ETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTE 
                   
               
               
                   
                 EGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETP 
                   
               
               
                   
                 GSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE48- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGGASASKAPST 
                 192 
               
               
                 Island_Lys2- 
                 GGGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSA 
                   
               
               
                 AE864 
                 PGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGT 
                   
               
               
                   
                 STEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 ESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTST 
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTE 
                   
               
               
                   
                 PSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESA 
                   
               
               
                   
                 TPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSP 
                   
               
               
                   
                 TSTEEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATP 
                   
               
               
                   
                 ESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPE 
                   
               
               
                   
                 SGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSET 
                   
               
               
                   
                 PGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGP 
                   
               
               
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE288- 
                 GTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPG 
                 193 
               
               
                 Island_Lys1- 
                 TSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSP 
                   
               
               
                 AE288- 
                 AGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSE 
                   
               
               
                 Island_Lys1- 
                 SATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTE 
                   
               
               
                 AE288 
                 PSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGGGSPAGSKTSPGGTSES 
                   
               
               
                   
                 ATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEP 
                   
               
               
                   
                 SEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSP 
                   
               
               
                   
                 TSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATP 
                   
               
               
                   
                 ESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEG 
                   
               
               
                   
                 SAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGGGSPAGSKTSPGGTSESATPE 
                   
               
               
                   
                 SGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 APGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTE 
                   
               
               
                   
                 EGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGP 
                   
               
               
                   
                 GSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 SEPATSGSETPGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE48- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGGGSPAGSKTS 
                 194 
               
               
                 Island_Lys1- 
                 PGGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSA 
                   
               
               
                 AE576- 
                 PGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEE 
                   
               
               
                 Island_Lys1- 
                 GTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPG 
                   
               
               
                 AE144 
                 TSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGT 
                   
               
               
                   
                 STEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 ESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTST 
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTE 
                   
               
               
                   
                 PSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESA 
                   
               
               
                   
                 TPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSP 
                   
               
               
                   
                 TSTEEGTSESATPESGPGTSTEPSEGSAPGGGSPAGSKTSPGGSEPATSGSETPGTSESAT 
                   
               
               
                   
                 PESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSEPATSG 
                   
               
               
                   
                 SETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGS 
                   
               
               
                   
                 APG 
                   
               
               
                   
               
               
                 AM48- 
                 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGGGSPAGSKTS 
                 195 
               
               
                 Island_Lys1- 
                 PGGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSAS 
                   
               
               
                 AM875 
                 PGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                   
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEP 
                   
               
               
                   
                 ATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAES 
                   
               
               
                   
                 PGPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESPG 
                   
               
               
                   
                 PGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESPGP 
                   
               
               
                   
                 GTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 SSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGS 
                   
               
               
                   
                 PAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AM48- 
                 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGGASASKAPST 
                 196 
               
               
                 Island_Lys2- 
                 GGGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSAS 
                   
               
               
                 AM1296 
                 PGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                   
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEP 
                   
               
               
                   
                 ATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGPEPTGPAPSGGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGTSESATPE 
                   
               
               
                   
                 SGPGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAP 
                   
               
               
                   
                 GTSPSGESSTAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                   
                 SPSGESSTAPGTSPSGESSTAPGTSPSGESSTAPGTSTEPSEGSAPGSPAGSPTSTEEGTST 
                   
               
               
                   
                 EPSEGSAPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGSSTP 
                   
               
               
                   
                 SGATGSPGASPGTSSTGSPGASASGAPSTGGTSPSGESSTAPGSTSSTAESPGPGTSPSGE 
                   
               
               
                   
                 SSTAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSSPSASTGTGPGSSTPSGA 
                   
               
               
                   
                 TGSPGASPGTSSTGSPGTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSTEPSEGSAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASP 
                   
               
               
                   
                 GSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPG 
                   
               
               
                   
                 SEPATSGSETPGSSTPSGATGSPGASPGTSSTGSPGSSTPSGATGSPGSTSESPSGTAPGT 
                   
               
               
                   
                 SPSGESSTAPGSTSSTAESPGPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSP 
                   
               
               
                   
                 AGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AM48- 
                 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGGASASKAPST 
                 197 
               
               
                 Island_Lys2- 
                 GGGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSAS 
                   
               
               
                 AM875 
                 PGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                   
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEP 
                   
               
               
                   
                 ATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAES 
                   
               
               
                   
                 PGPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESPG 
                   
               
               
                   
                 PGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESPGP 
                   
               
               
                   
                 GTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 SSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGS 
                   
               
               
                   
                 PAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AM48- 
                 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGGASASKAPST 
                 198 
               
               
                 Island_Lys2- 
                 GGGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSAS 
                   
               
               
                 AM875- 
                 PGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPG 
                   
               
               
                 Island_Lys2- 
                 TSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                 AM48 
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEP 
                   
               
               
                   
                 ATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAES 
                   
               
               
                   
                 PGPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESPG 
                   
               
               
                   
                 PGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESPGP 
                   
               
               
                   
                 GTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 SSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGS 
                   
               
               
                   
                 PAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGGASASKAPSTGGMAEPAGSPTSTEEGASPGTSSTGSPG 
                   
               
               
                   
                 SSTPSGATGSPGSSTPSGATGSPG 
                   
               
               
                   
               
               
                 AE288- 
                 GTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPG 
                 199 
               
               
                 Island_Cys1 
                 TSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSP 
                   
               
               
                 -AE288- 
                 AGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSE 
                   
               
               
                 Island_Lys1- 
                 SATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTE 
                   
               
               
                 AE288 
                 PSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGGGSPAGSCTSPGGTSES 
                   
               
               
                   
                 ATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEP 
                   
               
               
                   
                 SEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSP 
                   
               
               
                   
                 TSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATP 
                   
               
               
                   
                 ESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEG 
                   
               
               
                   
                 SAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGGGSPAGSKTSPGGTSESATPE 
                   
               
               
                   
                 SGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 APGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTE 
                   
               
               
                   
                 EGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGP 
                   
               
               
                   
                 GSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 SEPATSGSETPGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE48- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGGGSPAGSCTS 
                 200 
               
               
                 Island_Cys1 
                 PGGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSA 
                   
               
               
                 -AE144- 
                 PGSEPATSGSETPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGP 
                   
               
               
                 Island_Cys1 
                 GSEPATSGSETPGTSTEPSEGSAPGGGSPAGSCTSPGSEPATSGSETPGTSESATPESGPG 
                   
               
               
                 - AE144- 
                 SEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSEPATSGSETPGS 
                   
               
               
                 Island_Cys1 
                 EPATSGSETPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGGG 
                   
               
               
                 -AE144- 
                 SPAGSCTSPGGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTS 
                   
               
               
                 Island_Cys1 
                 TEPSEGSAPGSEPATSGSETPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSE 
                   
               
               
                 -AE144 
                 SATPESGPGSEPATSGSETPGTSTEPSEGSAPGGGSPAGSCTSPGGSEPATSGSETPGTSE 
                   
               
               
                   
                 SATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSEPA 
                   
               
               
                   
                 TSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPS 
                   
               
               
                   
                 EGSAPG 
                   
               
               
                   
               
               
                 AE48- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGGGSPAGSKTS 
                 201 
               
               
                 Island_Lys1- 
                 PGGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSA 
                   
               
               
                 AE144- 
                 PGSEPATSGSETPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGP 
                   
               
               
                 Island_Lys1- 
                 GSEPATSGSETPGTSTEPSEGSAPGGGSPAGSKTSPGSEPATSGSETPGTSESATPESGPG 
                   
               
               
                 AE144- 
                 SEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSEPATSGSETPGS 
                   
               
               
                 Island_Lys1- 
                 EPATSGSETPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGGG 
                   
               
               
                 AE144- 
                 SPAGSKTSPGGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTS 
                   
               
               
                 Island_Lys1- 
                 TEPSEGSAPGSEPATSGSETPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSE 
                   
               
               
                 AE144 
                 SATPESGPGSEPATSGSETPGTSTEPSEGSAPGGGSPAGSKTSPGGSEPATSGSETPGTSE 
                   
               
               
                   
                 SATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSEPA 
                   
               
               
                   
                 TSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPS 
                   
               
               
                   
                 EGSAPG 
               
               
                   
               
            
           
         
       
     
     In another embodiment, where an existing full-length XTEN gene is to be modified with nucleotides encoding one or more reactive cysteine or lysine residues, an oligonucleotide can be created that encodes a cysteine or lysine and that exhibits partial homology to and can hybridize with one or more short sequences of the XTEN, resulting in a recombination event and substitution of a cysteine or the lysine codon for an existing codon of the XTEN gene (see, e.g., Example 61 for a description of the general methods). In one embodiment, the recombination results in a replacement with the amino acid sequence GGSPAGSCTSP. However, the oligonucleotides can be designed to place the cysteine (or lysine) in a different location in the motif or to include a second cysteine (or lysine) in the motif. The cysteine- or lysine-encoding oligonucleotides can be designed to hybridize with a given sequence segment at different points along the known XTEN sequence. Thus, the invention contemplates that multiple XTEN gene constructs can be created with cysteines or lysines inserted at different locations within the XTEN sequence by the selection of restriction sites within the XTEN sequence and the design of oligonucleotides appropriate for the given location and that encode a cysteine or lysine, including use of designed oligonucleotides that result in multiple insertions in the same XTEN sequence. By the design and selection of one or more such oligonucleotides in consideration of the known sequence of the XTEN, and the appropriate use of the methods of the invention, the potential number of substituted reactive cysteine or lysine residues inserted into the full-length XTEN can be estimated and then confirmed by sequencing the XTEN gene. 
     The design, selection, and preparation methods of the invention enable the creation of engineered XTEN that are reactive with electrophilic functionality. These methods further enable creation of XTEN-drug conjugate compositions with drug molecules at designated, designed, and selective sites, as illustrated schematically in  FIGS. 40-41 . Drugs may be site-specifically and efficiently coupled to cysteine-engineered XTEN and targeted cysteine-engineered XTEN of the invention with a thiol-reactive reagent. For example, reactive cysteine residues on a cysteine-engineered. XTEN allow specifically conjugating a drug moiety to each cysteine of the XTEN sequence by cross-linking with a thiol reactive group such as maleimide or haloacetyl.  FIG. 45  illustrates a specific example of the conjugation of pacitaxel to an anti-Her2 binding fusion protein by this approach. Generally, the nucleophilic reactivity of the thiol functionality of a cysteine residue to a maleimide group is about 1000 times higher compared to any other amino acid functionality in a protein, such as amine group of lysine residues or the N-terminal amino group. Thiol specific functionality in iodoacetyl and maleimide reagents may react with amine groups, but higher pH (&gt;9.0) and longer reaction times are required (Garman, 1997, Non-Radioactive Labelling: A Practical Approach, Academic Press, London). Typically, conjugation reactions with cysteine arc suitably performed at a pH below about 7, using reaction temperatures in the range of from about 5 up to about 40° C., and preferably in the range of from 10 up to 30° C. (see U.S. Pat. No. 6,048,720). 
     1. Drugs 
     The drugs to be incorporated into the BFP-D and XTEN-drug compositions of the invention have one or more pharmacologic activities. The drugs may include a cytotoxic or cytostatic agent (e.g., epaclitaxel, paclitaxel, docetaxel, doxetaxel, irinotecan, pemetrexed, chloranbucil, or gemcitabine), an anti-inflammatory agent, an opiod (e.g., morphine, oxycodone, hydromorphone), an analgesic, an anti-infective, or a fluorophore such as a fluorescent dye like fluorescein or rhodamine, a chelating agent for an imaging or radiotherapeutic metal, a peptidyl or non-peptidyl label or detection tag. In particular, drugs that have a high incidence of side effects or toxicity, or those for which localization at the site of disease or pathology is desired, are contemplated for incorporation into the BFP-D XTEN-drug conjugates of the invention. 
     Exemplary drugs for incorporation into the compositions of the invention are set forth in the official United States Pharmacopeia, official Homeopathic Pharmacopeia of the United States, or official National Formulary, in the Physician&#39;s Desk Reference (PDR) and in the Orange Book maintained by the U.S. Food and. Drug Administration (FDA). Preferred drugs are those having the needed reactive functional group or those that can be readily derivatized to provide the reactive functional group for conjugation and will retain at least a portion of the pharmacologic activity of the unconjugated drug when conjugated to XTEN. In one embodiment, the drug for conjugation to the subject XTEN or fusion proteins disclosed herein is an agent selected from Table 9, or a pharmaceutically acceptable salt, acid or derivative thereof. 
     
       
         
           
               
             
               
                 TABLE 9 
               
               
                   
               
               
                 Drugs for Conjugation to Engineered XTEN 
               
               
                 Drugs 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 Erlotinib; Bortezomib; Fulvestrant; Sutent (SU11248), Letrozole; Imatinib mesylate; PTK787/ZK 222584; 
               
               
                 Oxaliplatin; 5-FU (5-fluorouracil), leucovorin, rapamycin; lapatinib; lonafarnib; sorafenib; gefitinib; thiotepa; 
               
               
                 cyclosphosphamide; busulfan; improsulfan; piposulfan; benzodopa; carboquone; meturedopa; uredopa; 
               
               
                 altretamine; triethylenemelamine; triethylenephosphoramide; triethylenethiophosphoramide; trimethylomelamine; 
               
               
                 bullatacin; bullatacinone; camptothecin; topotecan; bryostatin; callystatin; CC-1065; adozelesin; calicheamycin; 
               
               
                 auristatin; carzelesin; bizelesin; cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; 
               
               
                 duocarmycin; eleutherobin; pancratistatin; sarcodictyin; spongistatin; chlorambucil; chlornaphazine; 
               
               
                 cholophosphamide; estramustine; ifosfamide; mechlorethamine; mechlorethamine oxide hydrochloride, 
               
               
                 melphalan; novembichin; phenesterine; prednimustine; trofosfamide; uracil mustard; carmustine; chlorozotocin; 
               
               
                 fotemustine; lomustine; nimustine; ranimnustine; calicheamicin; dynemicin; dynemicin A; clodronate; 
               
               
                 esperamicin; neocarzinostatin chromophore; aclacinomysins, actinomycin; anthramycin; azaserine; bleomycin; 
               
               
                 cactinomycin; carabicin; carminomycin; carzinophilin; chromomycinis; dactinomycin; daunorubicin; detorubicin; 
               
               
                 6-diazo-5-oxo-L-norleucine; doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2- 
               
               
                 pyrrolino-doxorubicin and deoxydoxorubicin); epirubicin; esorubicin; idarubicin; marcellomycin; mitomycin C; 
               
               
                 mycophenolic acid; nogalamycin; olivomycin; peplomycin; potfiromycin; puromycin; quelamycin; rodorubicin; 
               
               
                 streptonigrin; streptozocin; tubercidin; ubenimex; zinostatin; zorubicin; methotrexate; 5-fluorouracil (5-FU); 
               
               
                 fdenopterin; methotrexate; pteropterin; trimetrexate; fludarabine; 6-mercaptopurine; thiamiprine; thioguanine; 
               
               
                 ancitabine; azacitidine; 6-azauridine; carmofur; cytarabine; dideoxyuridine; doxifluridine; enocitabine; 
               
               
                 floxuridine; calusterone; dromostanolone propionate; epitiostanol; mepitiostane; testolactone; aminoglutethimide; 
               
               
                 mitotane; trilostane; frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; 
               
               
                 amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium 
               
               
                 acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansine; ansamitocins; 
               
               
                 mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 
               
               
                 podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; rhizoxin; ribavirin; zidovudine; acyclovir; 
               
               
                 gangcyclovir; vidarabine; idoxuridine; trifluridine; foscarnet; amantadine; rimantadine; saquinavir; indinavir; 
               
               
                 ritonavir; alpha-interferons and other interferons; AZT; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 
               
               
                 2;2′,2″-trichlorotriethylamine; T-2 toxin; verracurin A; roridin A; anguidine); urethan; vindesine; dacarbazine; 
               
               
                 mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; 
               
               
                 thiotepa; taxoids; epaclitaxel; paclitaxel; docetaxel; doxetaxel; irinotecan; pemetrexed chloranbucil; gemcitabine; 
               
               
                 6-thioguanine; mercaptopurine; methotrexate; cisplati; carboplatin; vinblastine; platinum; etoposide (VP-16); 
               
               
                 ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; 
               
               
                 xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; 
               
               
                 capecitabine; lidocaine; bupivacaine; memantine; donepezil; rivastigmine; galantamine; morphine; oxycodone; 
               
               
                 hydromorphone; oxymorphone; metopon; apomorphine; normorphine; etorphine; buprenorphine; meperidine; 
               
               
                 lopermide; anileridine; ethoheptazine; piminidine; betaprodine; diphenoxylate; fentanil; sufentanil; alfentanil; 
               
               
                 remifentanil; levorphanol; dextromethorphan; phenazocine; pentazocine; cyclazocine; methadone; isomethadone; 
               
               
                 propoxyphene; naloxone; naltrexone; treprostinil; N-methylnaloxone; 6-amino-14-hydroxy-17- 
               
               
                 allylnordesomorphine; naltrendol;, N-methylnaltrexone; nalbuphine; butorphanol; cyclazocine; pentazocine,; 
               
               
                 nalmephene; naltrindole; nor-binaltorphimine; oxilorphan; 6-amino-6-desoxo-naloxone; pentazocine; 
               
               
                 levallorphanmethylnaltrexone; buprenorphine; cyclorphan; levalorphan; cyclosporine; cyclosporine A; 
               
               
                 mycophenylate mofetil; sirolimus; tacrolimus; prednisone; azathioprine; methotrexate; cyclophosphamide; 
               
               
                 prednisone; aminocaproic acid; chloroquine; hydroxychloroquine; dexamethasone; chlorambucil; danazol; 
               
               
                 bromocriptine 
               
               
                   
               
            
           
         
       
     
     2. Conjugation: Cross-Linkers and Methods 
     The conjugation between the polypeptide (either an XTEN or a fusion partner, such as a targeting moiety) and the drug compound, optionally through a cross-linker, may be done according to methods known in the art, e.g. as described by Bodanszky in Peptide Synthesis, John Wiley, New York, 1976 and in WO 96/12505; Harris and Zalipsky, eds., Poly(ethylene glycol) Chemistry and Biological Applications, AZC, Washington; R. F. Taylor, (1991), “Protein immobilisation. Fundamental and applications”, Marcel Dekker, N.Y.; S. S. Wong, (1992), “Chemistry of Protein Conjugation and Crosslinking”, CRC Press, Boca Raton; G. T. Hermanson et al., (1993), “Immobilized Affinity Ligand Techniques”, Academic Press, N.Y.; as well as in U.S. Pat. Nos. 5,977,163, 6,262,107, 6,441,025, 7,026,440, 7,329,721, 7,528,202, 7,579,444, 7,659,361 and 7,851,437; U.S. Patent App. Publication Nos. 2002001628, 20020077290, 20040157782, and 20050238649; and PCT Publication Nos. WO 99/49901, WO 97/33552, WO 01/26693, and WO 01/70275, or by methods disclosed herein. The exemplary methods of the foregoing patents or references, or those described herein, may be applied generally to the various binding fusion proteins disclosed herein, resulting in the drug-binding fusion protein compositions, or to XTEN solely, resulting in the XTEN-D and/or BFP-D compositions of the invention. 
     Typically, attachment of a drug to a protein or other surface is accomplished using an activated drug derivative, that is to say, a drug having at least one activated terminus suitable for reaction with a nucleophilic center (e.g., lysine, cysteine and similar residues of proteins). Drug molecules having activated end groups suitable for reaction with the amino groups of proteins include those with functional groups such as aldehydes (Harris, J. M., Herati, R. S.,  Polym Prepr . ( Am. Chem. Soc ., Div.  Polym. Chem ), 32(1), 154-155 (1991), mixed anhydrides, N-hydroxysuccinimide esters, carbonylimadazolides, and chlorocyanurates (Herman, S., et al.,  Macromol. Chem. Phys.  195, 203-209 (1994)). Although many proteins have been shown to retain activity during modification, in some instances, drug attachment through protein amino groups can be undesirable, such as when derivatization of specific lysine residues inactivates the pharmacophore of the protein (Suzuki, T., et al.,  Biochimica et Biophysica Acta  788, 248-255 (1984)). Moreover, since many non-XTEN proteins possess several available/accessible amino groups, the resulting drug conjugates formed are typically mixtures of mono-, di-, tri-conjugated species and so on, which can be difficult and also time-consuming to characterize and separate. One method for avoiding these problems is to employ a site-selective reagent that targets functional groups other than amines. One particularly attractive target is the thiol group, which in proteins in present in the amino acid, cysteine. Cysteines are typically less abundant in proteins than lysines, thus reducing the likelihood of protein deactivation upon conjugation to these thiol-containing amino acids. Moreover, conjugation to cysteine sites can often be carried out in a well-defined manner, leading to the formation of single species polymer-conjugates. 
     The thiol-reactive reagent may be a multifunctional cross-linker reagent, a drug-linker, a capture reagent, i.e. affinity moiety, label reagent (e.g. a biotin-linker reagent), a detection label (e.g. a fluorophore reagent), a solid phase immobilization reagent (e.g. SEPHAROSE™, polystyrene, or glass), or a drug-cross-linker intermediate. One example of a thiol-reactive reagent is N-ethyl maleimide (NEM). In an exemplary embodiment, reaction of a thiol-XTEN with a biotin-linker reagent provides a biotinylated thiol-XTEN by which the presence and reactivity of the engineered cysteine residue may be detected and measured. Reaction of a thiol-XTEN with a multifunctional cross-linker reagent provides a thiol-XTEN with a functionalized cross-linker that may be further reacted with a drug moiety reagent or other label. In one embodiment, reaction of a thiol-XTEN or a targeted thiol-XTEN with a drug-linker intermediate provides a thiol-XTEN drug conjugate or a targeted thiol-XTEN drug conjugate, respectively. 
     A variety of linkage chemistries can be used for conjugation, including commercially available homo- or hetero-bifunctional cross-linker compounds, according to methods known and available in the art, such as those described, for example, in Hermanson, Greg T., Bioconjugate Techniques, Academic Press, Inc., 1995, and Wong, Shan S., Chemistry. Suitable cross-linking agents for use in preparing the compositions of the disclosure are commercially available from companies like Sigma-Aldrich, or Thermo Fisher Scientific Inc. (Pierce Protein Research Products). Of particular utility are cross-linker components that are available in activated form and can be directly used for conjugation. Examples of useful cross-linking agents are imidoesters, active halogens, maleimide, pyridyl disulfide, and NHS-esters. Homobifunctional cross-linking agents have two identical reactive groups and are often used in a one step chemical cross-linking procedure. Examples are BS3 (a non-cleavable water-soluble DSS analog), BSOCOES (base-reversible), DMA (Dimethyl adipimidate-2HCl), DMP (Dimethyl pimelimidate-2HCl), DMS (Dimethyl suberimidate-2HCl), DSG (5-carbon analog of DSS), DSP (Lomant&#39;s reagent), DSS (non-cleavable), DST (cleavable by oxidizing agents), DTBP (Dimethyl 3,3′-dithiobispropionimidate-2HCl), DTSSP, EGS, Sulfo-EGS, THPP, TSAT, PMPI (N[p-maleimidophenyl]isocyanate), DFDNB (1,5-Difluoro-2,4-dinitrobenzene) is especially useful for cross-linking between small spacial distances (Komblatt, J. A. and Lake, D. F. (1980). Cross-linking of cytochrome oxidase subunits with difluorodinitrobenzene. Can J. Biochem. 58, 219-224). 
     Sulfhydryl-reactive homobifunctional cross-linking agents are homobifunctional protein cross-linkers that react with sulfhydryls and are often based on maleimides and maleamic acid, which react with —SH groups, forming stable thioether linkages. The reaction can be conducted at a pH of from about 6 to about 10, and at, for example, a pH of about 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10, with optimal pH at about 6.5 to about 8. In embodiments based on maleimide cross-linkers, one can further increase the stability of conjugates the maleimide ring can be intentionally forced open by hydrolysis during the reaction using a pH of 7 to about 9 and reaction temperature of about 10° C. to 45° C., or about 18° C. to about 30° C., to provide conjugates where the maleimide component is converted to its more stable succinamic acid opened-ring form. 
     For drugs with conjugated maleimide cross-linkers, the method includes reacting the protein with an active agent that possesses a nucleophile under conditions effective to couple the drug-linker to the protein. An example of such a cross-linker and reaction include BM[PEO]3; an 8-atom polyether spacer that reduces potential for conjugate precipitation in sulfydryl-to-sulfhydryl cross-linking applications. BM[PEO]4 is similar but with an 11-atom spacer. BMB is a non-cleavable cross-linker with a four-carbon spacer. BMDB makes a linkage that can be cleaved with periodate. BMH is a widely used homobifunctional sulfhydryl-reactive cross-linker. BMOE has an especially short cross-linker. DPDPB and DTME are cleavable cross-linkers. HVBS does not have the hydrolysis potential of maleimides. TMEA is another option. Hetero-bifunctional cross-linking agents have two different reactive groups. Examples are NHS-esters and amines/hydrazines via EDC activation, AEDP, ASBA (photoreactive, iodinatable), EDC (water-soluble carbodiimide). Amine-Sulfhydryl reactive bifunctional cross-linkers are AMAS, APDP, BMPS, EMCA, EMCS, GMBS, KMUA, LC-SMCC, LC-SPDP, MBS, SBAP, SIA (extra short), SIAB, SMCC, SMPB, SMPH, SMPT, SPDP, Sulfo-EMCS, Sulfo-GMBS, Sulfo-KMUS, Sulfo-LC-SMPT, Sulfo-LC-SPDP, Sulfo-MBS, Sulfo-SIAB, Sulfo-SMCC, Sulfo-SMPB. Sulfhydryl-carbonyl reactive bifunctional cross linkers, such as KMUH (N-[k-Maleimidoundecanoic acid]hydrazide), BMPH (N-[B-Maleimidopropionic acid] hydrazide), EMCH ([N-e-Maleimidocaproic acid] hydrazide), MPBH (4-(4-N-Maleimidophenyl)butyric acid hydrazide hydrochloride), and PDPH (3-(2-Pyridyldithio)propionyl hydrazide). Amino-group reactive heterobifunctional cross-linking agents are ANB-NOS, MSA, NHS-ASA, SADP, SAED, SAND, SANPAH, SASD, SFAD, Sulfo-HSAB, Sulfo-NHS-LC-ASA, Sulfo-SADP, Sulfo-SANPAH, TFCS. Arginine-reactive cross-linking agents are, for example APG, which reacts specifically with arginines at pH 7-8. 
     For drugs with conjugated maleimide cross-linkers, the method includes reacting the protein with an active agent that possesses a nucleophile under conditions effective to couple the drug-linker to the Michael Addition Receptor protein via a Michael-type addition reaction to form a polymer-succinimide-linked protein-drug conjugate. A “Michael Addition Receptor”, as one skilled in the art will understand, is a moiety capable of reacting with a nucleophilic reagent so as to undergo a nucleophilic addition reaction characteristic of a Michael Addition reaction. After the nucleophilic addition occurs, the Michael Addition Receptor moiety is referred to as a “Michael Addition Adduct.” Typically, a Michael Addition is the nucleophilic addition of a carbanion or another nucleophile to an alpha, beta unsaturated carbonyl compound, such as a thioacid that is created by treating the cysteine residues of the engineered XTEN to obtain a thiol, then a thioacid. Alternatively, the epsilon amino groups of the lysine-engineered XTEN can be thioloated using thiolating reagents, for example, SPDP or iminothiolane, to create the Michael Addition Receptor. Such methods are known in the art (see, e.g., U.S. Pat. No. 5,708,146). 
     Functional groups on the drug to be conjugated can include carboxylic acid functional groups and chloroformate functional groups, which are useful reactive sites because they can react with epsilon amino groups of a lysine-engineered XTEN or a cross-linker to form an amide linkage. Also useful as a reactive site is a carbonate functional group, such as but not limited to p-nitrophenyl carbonate, which can react with an amino group to form a carbamate linkage. Where the drug is to be conjugated through a hydroxyl group to the XTEN, the hydroxyl end groups of the drug molecule must be modified and/or provided in activated form, i.e. with reactive functional groups (examples of which include primary amino groups, aminoxy, aldehyde, hydrazide (HZ), thiol, thiolate, succinate (SUC), succinimidyl succinate (SS), succinimidyl succinate “active ester”, succinimidyl succinamide (SSA), succinimidyl propionate (SPA), succinimidyl butanoate (SBA), succinimidyl carboxymethylate (SCM), benzotriazole carbonate (BTC), N-hydroxysuccinimide (NHS), aldehyde, nitrophenylcarbonate (NPC), and tresylate (TRES)). Other suitable reactive functional groups of drug molecules include acetal, aldehydes having a carbon length of 1 to 25 carbons (e.g., acetaldehyde, propionaldehyde, and butyraldehyde), aldehyde hydrate, alkenyl, acrylate, methacrylate, acrylamide, active sulfone, amine, hydrazide, thiol, alkanoic acids (e.g., carboxylic acid, carboxymethyl, propanoic acid, and butanoic acid), acid halide, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxal, dione, mesylate, tosylate, and tresylate. 
     The drug can also be conjugated using a heterocycle radical of a ring system. Heterocyclyl groups include a ring system in which one or more ring atoms is a heteroatom, e.g. nitrogen, oxygen, and sulfur. The heterocycle radical comprises 1 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. A heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system. Heterocycles are described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968); “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley &amp; Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. Examples of heterocycles that may be found in drugs suitable for conjugation include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4Ah-carbazolyl, carbazolyl, fl-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. 
     In some cases, the drug molecules are attached to the lysine- or cysteine engineered XTEN by cross-linkers having two reactive sites for binding to the drug and the XTEN. Preferred cross-inker groups are those that are relatively stable to hydrolysis in the circulation, are biodegradable and are nontoxic when cleaved from the conjugate. In addition, the use of cross-linkers can provide the potential for conjugates with an even greater flexibility between the drug and the XTEN, or provide sufficient space between the drug and the XTEN such that the XTEN does not interfere with the binding between the pharmacophore and its binding site. In one embodiment, a cross-linker has a reactive site that has an electrophilic group that is reactive to a nucleophilic group present on an XTEN. Preferred nucleophiles include thiol, thiolate, and amino. The heteroatom of the nucleophilic group of a lysine- or cysteine-engineered XTEN is reactive to an electrophilic group on a cross-linker and forms a covalent bond to the cross-linker unit. Useful electrophilic groups for cross-linkers include, but are not limited to, maleimide and haloacetamide groups, and provide a convenient site for attachment to the XTEN. 
     In another embodiment, a cross-linker has a reactive site that has a nucleophilic group that is reactive to an electrophilic group present on a drug. Useful electrophilic groups on a drug include, but are not limited to, hydroxyl, thiol, aldehyde and ketone carbonyl groups. The heteroatom of a nucleophilic group of a cross-linker can react with an electrophilic group on a drug and form a covalent bond. Useful nucleophilic groups on a cross-linker include, but are not limited to, hydrazide, oxime, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide. The electrophilic group on a drug provides a convenient site for attachment to a cross-inker. 
     For conjugation of drugs to the lysine epsilon amino group of lysine-engineered XTEN, use of reactive drug-N-hydroxylsuccinimide, or esters such as drug-succinimidyl propionate, or drug-succinimidyl butanoate or other drug-succinimide conjugates can be employed. Alternatively, lysine residues may be used to introduce free sulfhydryl groups through reaction with iminothiolane. Alternatively, targeting substance lysines may be linked to a heterobifunctional reagent having a free hydrazide or aldehyde group available for conjugation with an active agent. Reactive esters can couple at physiological pH, but less reactive derivatives typically require higher pH. Low temperatures may also be employed if a labile protein is being used. Under low temperature conditions, a longer reaction time may be used for the conjugation reaction. 
     Amino group conjugation with lysine residues is facilitated by the difference between the pKa values of the α-amino group of the N-terminal amino acid (approximately 7.6 to 8.0) and the ε-amino group of lysine (approximately 10). Conjugation of the terminal amino group often employs reactive drug-aldehydes (such as drug-propionaldehyde or drug-butylaldehyde), which are more selective for amines and thus are less likely to react with, for example, the imidazole group of histidine. In addition, lysinyl amino residues are reacted with succinic or other carboxylic acid anhydrides, or with N,N′-Disuccinimidyl carbonate (DSC), N,N′-carbonyl diimidazole (CDI), or p-nitrophenyl chloroformate to yield the activated succinimidyl carbonate, imidazole carbamate or p-nitrophenyl carbonate, respectively. Derivatization with these agents has the effect of reversing the charge of the lysinyl residues. Conjugation of a drug-aldehyde to the terminal amino group typically takes place in a suitable buffer performed at a pH which allows one to take advantage of the pKa differences between the ε-amino groups of the lysine residues and that of the α-amino group of the N-terminal residue of the protein; usually the pH for coupling lies in the range of from about pH 7 up to about 8. Useful methods for conjugation of the lysine epsilon amino group have been described in U.S. Pat. Nos. 4,904,584 and 6,048,720. 
     The person with ordinary skill in the art will be aware that the activation method and/or conjugation chemistry to be used depends on the reactive groups of the XTEN polypeptide as well as the functional groups of the drug moiety (e.g., being amino, hydroxyl, carboxyl, aldehyde, sulfhydryl, etc), the functional group of the drug-cross-linker reactant, or the functional group of the XTEN-cross-linker reactant. The drug conjugation may be directed towards conjugation to all available attachment groups on the engineered XTEN polypeptide such as the specific engineered attachment groups on the incorporated cysteine residues or lysine residues. In order to control the reactants such that the conjugation is directed to the appropriate reactive site, the invention contemplates the use of protective groups. A “protecting group” is a moiety that prevents or blocks reaction of a particular chemically reactive functional group in a molecule under certain reaction conditions. The protecting group will vary depending upon the type of chemically reactive group being protected as well as the reaction conditions to be employed, as well as the presence of additional reactive groups in the molecule. Non-limiting examples of functional groups which may be protected include carboxylic acid groups, hydroxyl groups, amino groups, hydroxyl groups, thiol groups, and carbonyl groups. Representative protecting groups for carboxylic acids and hydroxyls include esters (such as a p-methoxybenzyl ester), amides and hydrazides; for amino groups, carbamates (such as tert-butoxycarbonyl) and amides; for hydroxyl groups, ethers and esters; for thiol groups, thioethers and thioesters; for carbonyl groups, acetals and ketals; and the like. Such protecting groups are well-known to those skilled in the art and are described, for example, in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein. 
     The conjugation may be achieved in one step or in a stepwise manner (e.g., as described in WO 99/55377), such as through addition of a reaction intermediate cross-linker, using the cross-linkers disclosed herein or those known in the art to be useful for conjugation to cysteine or lysine residues of polypeptides to be linked to reactive functional groups on drug molecules. 
     In some cases, the method for conjugating a cross-linker to a cysteine-engineered XTEN may provide that the XTEN is pre-treated with a reducing agent, such as dithiothreitol (DTT) to reduce any cysteine disulfide residues to form highly nucleophilic cysteine thiol groups (—CH2 SH). The reducing agent is subsequently removed by any conventional method, such as by desalting. The partially reduced XTEN thus reacts with drug-linker compounds, or cross-linker reagents, with electrophilic functional groups such as maleimide or α-halo carbonyl, according to, for example, the conjugation method of Klussman, et al. (2004),  Bioconjugate Chemistry  15(4):765-773. Conjugation of a cross-linker or a drug to a cysteine residue typically takes place in a suitable buffer at pH 6-9 at temperatures varying from 4° C. to 25° C. for periods up to about 16 hours. Alternatively, the cysteine residues can be derivatized with an organic derivatizing agent. Suitable derivatizing agents and methods are well known in the art. For example, cysteinyl residues most commonly are reacted with α-haloacetates (and corresponding amines), such as chloroacetic acid or chloroacetamide, to give carboxymethyl or carboxyamidomethyl derivatives. Cysteinyl residues also are derivatized by reaction with bromotrifluoroacetone, α-bromo-β-(4-imidozoyl)propionic acid, chloroacetyl phosphate, N-alkylmaleimides, 3-nitro-2-pyridyl disulfide, methyl 2-pyridyl disulfide, p-chloromercuribenzoate, 2-chloromercuri-4-nitrophenol, or chloro-7-nitrobenzo-2-oxa-1,3-diazole. 
     In one embodiment, XTEN can be dissolved in 500 mM sodium borate and 500 mM sodium chloride at pH 8.0 and then is treated with an excess of 100 mM dithiothreitol (DTT). After incubation at 37° C. for about 30 minutes, the buffer is exchanged by elution over Sephadex G25 resin and eluted with PBS with 1 mM DTPA. The thiol/XTEN value is checked by determining the reduced XTEN concentration from the absorbance at 280 nm of the solution and the thiol concentration by reaction with DTNB (Aldrich, Milwaukee, Wis.) and determination of the absorbance at 412 nm. The reduced XTEN dissolved in PBS is chilled on ice. The drug cross-linker, e.g., MC-val-cit-PAB-MMAE in DMSO, dissolved in acetonitrile and water at known concentration, is added to the chilled reduced XTEN in PBS. After about one hour, an excess of maleimide is added to quench the reaction and cap any unreacted antibody thiol groups. The reaction mixture is concentrated by centrifugal ultrafiltration and the XTEN-MC-vc-PAB-MMAE, is purified and desalted by elution through G25 resin in PBS, filtered through 0.2 μm filters under sterile conditions, and held under suitable storage conditions. 
     Such an approach may used to conjugate other thiol-reactive agents to the cysteine of the XTEN, in which the reactive group is, for example, a maleimide, an iodoacetamide, a pyridyl disulfide, or other thiol-reactive conjugation partner linked to a drug partner (Haugland, 2003, Molecular Probes Handbook of Fluorescent Probes and Research Chemicals, Molecular Probes, Inc.; Brinkley, 1992, Bioconjugate Chem. 3:2; Garman, 1997, Non-Radioactive Labelling: A Practical Approach, Academic Press, London; Means (1990) Bioconjugate Chem. 1:2; Hermanson, G. in Bioconjugate Techniques (1996) Academic Press, San Diego, pp. 40-55, 643-671). Maleimides in particular are useful in cross-linking due to their susceptibility to additions across the double bond either by Michael additions or via Diels-Alder reactions. Bismaleimides are a class of maleimide compounds with two maleimide groups connected through a molecular unit and can be used as cross-linking reagents. 
     In some instances, the conjugation is performed under conditions aiming at reacting as many of the available XTEN attachment groups as possible with drug or drug-linker molecules. This is achieved by means of a suitable molar excess of the drug in relation to the polypeptide. Typical molar ratios of activated drug or drug-linker molecules to polypeptide are up to about 1000-1, such as up to about 200-1 or up to about 100-1. In some cases, the ratio may be somewhat lower, however, such as up to about 50-1, 10-1 or 5-1. Also equimolar ratios may be used. 
     In some case, the drug-containing conjugate compositions of the disclosure retain at least a portion of the pharmacologic activity compared to the corresponding unconjugated drug. In one embodiment, the drug conjugate retains at least about 1%, or at least about 5%, or at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95% of the pharmacologic activity of the unconjugated drug. 
     In other cases, the drug may be derivatized through a reactive functional group that is important for the biological activity of the drug thereby inhibiting or reducing the pharmacological activity of the drug to thereby convert the drug into a pharmacologically inactive or relatively inactive peptidyl derivative conjugate. In one embodiment, the prodrug cross-linker contains a peptide residue specifically tailored so as to render a drug conjugate of the present invention a selective substrate susceptible to enzymatic cleavage by one or more proteases, e.g., preferably lysosomal proteases, such as cathepsin B, C or D. The enzymatic cleavage reaction will remove the prodrug cross-linker from the drug moiety and affect the release of the drug in its pharmacologically active form. Representative hydrolytically degradable linkages in a cross-linker-drug conjugate include carboxylate ester, carbonate ester, phosphate ester, anhydride, acetal, ketal, acyloxyalkyl ether, imine, orthoester, and oligonucleotides. Esters such as carboxylate and carbonate esters are particularly preferred linkages. The particular linkage and linkage chemistry employed will depend upon the particular active agent, the presence of target and additional functional groups within the active agent, and the like; considerations that are within the knowledge of one skilled in the art. By such an approach, the inventive XTEN-drug and binding fusion protein-drug conjugate compositions administered to a subject may exhibit reduced toxicity or frequency of side effects compared to the corresponding free drug administered to a subject. Thus, the reduced toxicity of the XTEN-drug and binding fusion protein-drug conjugate compositions disclosed herein may permit the administration of higher amounts of drug, on a molar basis, compared to unconjugated drug. 
     The invention contemplates that the engineered XTEN, which incorporate either cysteine or lysine residues, may be conjugated with any drug moiety with a reactive functional group that can be covalently attached to the XTEN through a reactive cysteine thiol or epsilon amino group, respectively, either directly or by using a cross-linker, as described above. In another embodiment, the invention provides BFP-D compositions in which the drug can be conjugated to the targeting moiety of the binding protein component by conjugation to existing or incorporated cysteine or lysine residues, as well as N-terminal amino groups or C-terminal carboxyl groups that may be present. 
     (h) Release of Drug 
     The invention provides BFP-D and XTEN-drug compositions in which the drug can be released from the composition by either specific or non-specific mechanisms. In some cases, the drugs can be released by proteolytic degradation of those molecules taken up by cells. In one embodiment, the XTEN portion of the BFP-D or XTEN-drug is rapidly degraded by intracellular proteases, releasing the drug from the XTEN carrier. In other cases, the drug can be released by degradation of a cross-linker selected for inclusion into the BFP-D and XTEN-drug compositions based on its susceptibility to degradation. For example, it is known in the art that use of mild acid-cleavable linkers can promote drug release based on the observation that the pH inside tumors was often lower than normal physiological pH. In a non-limiting example, release of the conjugated drug component could be enhanced by incorporating a hydrazone as a cleavable unit and attaching a drug like doxorubicin to the protein component (either XTEN or the targeting moiety) via a thioether group, as described by Willner et al., U.S. Pat. No. 5,708,146; and Trail et al. Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates.  Science  261:212-215 (1993). In other cases, certain ester linkages can be incorporated into the linker between a protein and the drug that are labile; some by enzymes. (Gillimard and Saragovi,  Cancer Res.  61:694-699 (2001)). Other examples of enzymatically susceptible linkages include urethane or carbonate-containing linkages. In addition, hydrolytically unstable linkages include carboxylate ester, phosphate ester, anhydrides, acetals, ketals, acyloxyalkyl ether, imines, orthoesters, peptides and oligonucleotides. Based upon these characteristics, it is believed that the drug ligand will be released rapidly after cellular internalization of the BFP-D or XTEN-drug conjugates. 
     (i) Configurations of BFP-D and XTEN-Drug Compositions 
     The invention provides binding fusion protein-drug conjugates and XTEN-drug conjugates in various configurations. 
     In one embodiment, the invention provides a binding fusion protein-drug conjugate composition of formula V: 
       [(D-CL) z1 -XTEN] x -TM-[XTEN-(CL-D) z2 ] y   V
 
     wherein independently for each occurrence: xis either 0 or 1; y is either 0 or 1; XTEN is a cysteine- or lysine-engineered extended recombinant polypeptide as described above; TM is a targeting moiety with binding affinity to a target ligand selected from Table 1 or Table 2 (which may comprise more than one binding domain joined by linkers); CL is a cross-linker as defined herein; D is a drug moiety selected from Table 9 or a pharmaceutically acceptable salt, acid or derivative thereof; and z1 and z2 each independently is an integer from 1 to 100. The number of drug moieties that may be conjugated via a reactive cross-linker to an engineered XTEN molecule is limited by the number of reactive residues that are incorporated into the XTEN. Exemplary binding fusion protein-drug conjugate compositions of Formula V can comprise XTEN that have from 1 to about 100 cysteine or lysine engineered amino acids, or from 1 to about 50 cysteine or lysine engineered amino acids, or from 1 to about 40 cysteine or lysine engineered amino acids, or from 1 to about 20 cysteine or lysine engineered amino acids, or from 1 to about 10 cysteine or lysine engineered amino acids, or from 1 to about 5 cysteine or lysine engineered amino acids that are available for conjugation to drug molecules. In some cases, the binding fusion protein-drug conjugate retains at least about 1%, or at least about 5%, or at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95% of the pharmacologic activity of the unconjugated drug. 
     In another embodiment, the invention provides a binding fusion protein-drug conjugate composition of formula VI: 
       [(D-CL) z1 -XTEN] x -TM1-L-TM2-[XTEN-(CL-D) z2 ] y   VI
 
     wherein independently for each occurrence: x is either 0 or 1, and y is either 0 or 1; XTEN is a either a cysteine- or lysine-engineered extended recombinant polypeptide as described; TM1 is a targeting moiety with binding affinity to a target ligand selected from Table 1 or Table 2 (which may comprise more than one binding domain joined by linkers); TM2 is a targeting moiety with binding affinity to a target ligand selected from Table 1 or Table 2 (which may comprise more than one binding domain joined by linkers) that may be identical or may be different to TM1; and L is a linker sequence having between 1 to about 300 amino acid residues wherein the linker sequence is covalently bound to the C terminus of TM1 and the N terminus of TM2; D is a drug moiety selected from Table 9 or a pharmaceutically acceptable salt, acid or derivative thereof; CL is a cross-linker as defined herein; and z1 and z2 each independently is an integer from 0 to 100. Exemplary binding fusion protein-drug conjugate compositions of Formula VI can comprise XTEN that have from 1 to about 100 cysteine or lysine engineered amino acids, or from 1 to about 50 cysteine or lysine engineered amino acids, or from 1 to about 40 cysteine or lysine engineered amino acids, or from 1 to about 20 cysteine or lysine engineered amino acids, or from 1 to about 10 cysteine or lysine engineered amino acids, or from 1 to about 5 cysteine or lysine engineered amino acids that are available for conjugation to drug molecules. In addition, the invention contemplates additional compositions comprising multiple targeting moieties and XTEN in various permutations of configurations. In some cases, the binding fusion protein-drug conjugate retains at least about 1%, or at least about 5%, or at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95% of the pharmacologic activity of the unconjugated drug. 
     In another embodiment, the invention provides a pharmacologically active XTEN-drug conjugate composition of formula VII: 
       (CL-D) z -XTEN  VII
 
     wherein independently for each occurrence: XTEN is a either a cysteine- or lysine-engineered extended recombinant polypeptide as described above; D is a drug moiety selected from Table 9 or a pharmaceutically acceptable salt, acid or derivative thereof; CL is a cross-linker as defined herein; and z is an integer from 1 to 100. Exemplary XTEN-drug conjugate compositions of formula VII can comprise XTEN that have from 1 to about 100 cysteine or lysine engineered amino acids, or from 1 to about 50 cysteine or lysine engineered amino acids, or from 1 to about 40 cysteine or lysine engineered amino acids, or from 1 to about 20 cysteine or lysine engineered amino acids, or from 1 to about 10 cysteine or lysine engineered amino acids, or from 1 to about 5 cysteine or lysine engineered amino acids that are available for conjugation to drug molecules. In some cases, the XTEN-drug conjugate retains at least about 1%, or at least about 5%, or at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95% of the pharmacologic activity of the unconjugated drug. 
     In another embodiment, the invention provides a pharmacologically active XTEN-drug conjugate composition of formula VIII: 
       XTEN-(CL-D) z   VIII
 
     wherein independently for each occurrence: XTEN is a either a cysteine- or lysine-engineered extended recombinant polypeptide as described above; D is a drug moiety selected from Table 9 or a pharmaceutically acceptable salt, acid or derivative thereof; CL is a cross-linker as defined herein; and z is an integer from 1 to 100. Exemplary XTEN-drug conjugate compositions of formula VII can comprise XTEN that have from 1 to about 100 cysteine or lysine engineered amino acids, or from 1 to about 50 cysteine or lysine engineered amino acids, or from 1 to about 40 cysteine or lysine engineered amino acids, or from 1 to about 20 cysteine or lysine engineered amino acids, or from 1 to about 10 cysteine or lysine engineered amino acids, or from 1 to about 5 cysteine or lysine engineered amino acids that are available for conjugation to drug molecules. In some cases, the XTEN-drug conjugate retains at least about 1%, or at least about 5%, or at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95% of the pharmacologic activity of the unconjugated drug. 
     The invention contemplates that the BFP-D encompass compositions in which the targeting moiety component(s) of the subject compositions can be directed to any of the specific targets described herein, including a target selected from Table 1 or Table 2, the drug conjugated to the composition can be any of the drugs of Table 9 or a pharmaceutically acceptable salt, acid or derivative thereof, and the XTEN component(s) can be cysteine- or lysine-engineered XTEN derived from or exhibiting substantial sequence identity to any of the XTEN of Table 4 or a fragment or variant thereof, and has cross-linker components that link the drug molecule(s) to the protein component. In an embodiment of the foregoing, the BFP-D composition can have one or more engineered-XTENs in which the XTEN has about 80% sequence identity to a XTEN selected from Table 4, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% sequence identity to an XTEN selected from Table 4 and comprises one or more cysteine residues. In another embodiment of the foregoing, the BFP-D composition can have one or more engineered-XTENs in which the XTEN has about 80% sequence identity to a XTEN selected from Table 4, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% sequence identity to an XTEN selected from Table 4 and comprises one or more lysine residues. In any of the embodiments hereinabove described in this paragraph, the engineered XTEN can exhibit about 80% sequence identity to a XTEN selected from Table 8, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or exhibit 100% sequence identity to an XTEN selected from Table 8. 
     In an exemplary embodiment of a BFP-D, the binding fusion protein-drug composition comprises one or more anti-HER2 targeting moieties, an engineered XTEN, and one or more molecules of paclitaxel linked to the XTEN by a cross-linker. In another embodiment, the binding fusion protein-drug composition comprises one or more anti-HER2 targeting moieties, an engineered XTEN, and one or more molecules of docetaxel linked to the XTEN by a cross-linker. In another embodiment, the binding fusion protein-drug composition comprises one or more anti-HER2 targeting moieties, an engineered XTEN, and one or more molecules of irinotecan linked to the XTEN by a cross-linker. In any of the foregoing embodiments of the paragraph, the invention encompasses compositions that can be configured according to formula V or formula VI. 
     In an exemplary embodiment of an XTEN-D, the XTEN-drug composition comprises an engineered XTEN and one or more molecules of paclitaxel linked to the XTEN by a cross-linker. In another embodiment, the XTEN-drug composition comprises an engineered XTEN and one or more molecules of docetaxel linked to the XTEN by a cross-linker. In another embodiment, the XTEN-drug composition comprises an engineered XTEN and one or more molecules of irinotecan linked to the XTEN by a cross-linker. In any of the foregoing embodiments of the paragraph, the invention encompasses compositions that can be configured according to formula VI or formula VII. 
     Generally, binding fusion protein-drug conjugate compositions of the invention retain the antigen binding capability of their targeting moiety. In some cases, wherein the drugs are restricted to the XTEN carrier portion of the fusion protein, steric hindrance between the drug moiety, targeting moiety, and the target antigen or ligand is reduced. Thus, in preferred embodiments, engineered binding fusion protein-drug conjugates are capable of binding, preferably specifically, to target antigens and delivering the drug to the target location. Such antigens include, for example, tumor-associated antigens (TAA), cell surface receptor proteins and other cell surface molecules, transmembrane proteins, signaling proteins, cell survival regulatory factors, cell proliferation regulatory factors, molecules associated with tissue development or differentiation, lymphokines, cytokines, molecules involved in cell cycle regulation, molecules involved in vasculogenesis or angiogenesis. An antigen to which an engineered binding fusion protein-drug composition is capable of binding may be a member of a subset of one of the above-mentioned categories, wherein the other subset(s) of said category comprise other molecules/antigens that have a distinct characteristic (with respect to the antigen of interest). 
     The invention also contemplates that the XTEN-drug encompass compositions in which the drug conjugated to the XTEN can be any of the drugs of Table 9 or a pharmaceutically acceptable salt, acid or derivative thereof, and the XTEN component can be cysteine- or lysine-engineered XTEN derived from or exhibiting substantial sequence identity to any of the XTEN of Table 4 or a fragment or variant thereof, and has cross-linker components that link the drug molecule(s) to the XTEN component. In an embodiment of the foregoing, the XTEN-drug composition can have an engineered-XTENs in which the XTEN has about 80% sequence identity to a XTEN selected from Table 4, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% sequence identity to an XTEN selected from Table 4 and comprises one or more cysteine residues. In another embodiment of the foregoing, the XTEN-drug composition can have an engineered-XTEN in which the XTEN has about 80% sequence identity to a XTEN selected from Table 4, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or about 99% sequence identity to an XTEN selected from Table 4 and comprises one or more lysine residues. In some cases, the XTEN-drug encompass compositions in which the drug conjugated to the XTEN can be any of the drugs of Table 9 or a pharmaceutically acceptable salt, acid or derivative thereof, and the XTEN component can be cysteine- or lysine-engineered XTEN derived from or exhibiting substantial sequence identity to any of the engineered XTEN of Table 8 or a fragment or variant thereof, and has cross-linker components that link the drug molecule(s) to the cysteine or lysine residues of the XTEN component. In one embodiment of the foregoing, the engineered XTEN can exhibit about 80% sequence identity to a XTEN selected from Table 8, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or exhibits 100% sequence identity to an XTEN selected from Table 8. 
     (j) Methods of Use of BFP-Drug and XTEN-Drug Compositions 
     In another aspect, the invention provides a method of for achieving a beneficial effect in a disease, disorder or condition mediated by a BFP-D or XTEN-drug composition. In one embodiment, the invention provides the use of a BFP-D, in which the targeting moiety of the binding fusion protein is derived from a parental antibody that binds to a target selected from the group consisting of the targets of Table 1 or Table 2 and the drug is selected from Table 9, in treatment of a disease, disorder or condition to a subject in need thereof by administration of a therapeutically effective amount of the BFP-D, wherein said administration leads to the eradication or amelioration of one or more of the physiological or clinical symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In another embodiment, the invention provides a method of treating a disease, disorder, or condition in a mammal comprising administering to the mammal a therapeutically effective amount of a BFP-D comprising one or more targeting moieties directed to one or more targets selected from Table 1 or Table 2, linked to one or more XTEN sequences molecules and, optionally, one or more linkers, to form the binding fusion protein component, wherein the linkage does not substantially alter the essential functional properties of binding affinity and sustained terminal half-life or reduced serum clearance rate as compared to that of the parental targeting moiety from which the binding fusion protein component is derived and wherein the drug conjugated to the BFP-D is selected from Table 9, wherein the administration of the BFP-D to a subject in need thereof achieves a beneficial therapeutic effect. The effective amount can produce a beneficial effect in helping to treat (e.g., cure or reduce the severity) or prevent (e.g., reduce the likelihood of onset or severity) a disease, disorder or condition, such as, but not limited to a cancer, a cardiovascular disease or condition, an infectious disease, an inflammatory condition, a respiratory condition, organ transplant rejection, or a metabolic disease mediated by or associated with one or more targets selected from Table 1 or Table 2. 
     The incorporation of a drug into the inventive fusion proteins provides enhanced compositions that can result in the cure, mitigation, treatment, or prevention of diseases, disorders or conditions in man or other animals. The drug conjugates as represented by formula V or formula VI or formula VII or formula VIII of the present invention are effective for the usual purposes for which the corresponding drugs are effective. In one embodiment, the BFP-D compositions can have superior efficacy compared to the unconjugated drug because of the ability, inherent in the target moiety, to transport the drug to the desired cells where it is of particular benefit. Exemplary embodiments of the foregoing and representative data are provided in the Examples, below. In another embodiment, the BFP-D and XTEN-drug compositions can have superior efficacy compared to the unconjugated drug because of enhanced terminal half-life conferred by the XTEN carrier. In another embodiment, the invention provides BFP-D and XTEN-drug compositions that can have superior efficacy, an enhanced pharmacologic response, and/or reduced toxicity compared to the unconjugated drug because of the differential compartmentalization of the composition compared to the unconjugated drug; e.g., lack of penetration across the blood-brain barrier, nerve barriers, or cytoplasmic barriers of non-targeted cells. Exemplary embodiments of the foregoing and representative data are provided in the Examples, below. In a particular advantage of the inventive compositions, such enhanced properties permit lower-dose pharmaceutical formulations or treatment methods using a reduced dosage or dose regimen, both because of targeted delivery to tissues and cells and because of enhanced pharmacokinetic properties, resulting in a superior therapeutic index; i.e., improved efficacy with reduced toxicity. The invention provides for methods of using the conjugate compositions in therapeutic and diagnostic methods, for example for tumor targeting therapeutics having an altered rate of uptake or tissue diffusion as compared with the active drug alone. 
     In one embodiment, the method comprises administering a therapeutically-effective amount of a pharmaceutical composition comprising a BFP-D comprising one or more targeting moieties linked to one or more XTEN sequence(s) and at least one pharmaceutically acceptable carrier to a subject in need thereof that results in an improvement in at least one parameter, physiologic condition, or clinical outcome mediated by the targeting moiety component(s). In another embodiment, the method comprises administering a therapeutically-effective amount of a pharmaceutical composition comprising a drug, such as but not limited to a drug selected from Table 9, linked to an XTEN sequence and at least one pharmaceutically acceptable carrier to a subject in need thereof that results in an improvement in at least one parameter, physiologic condition, or clinical outcome mediated by the targeting moiety component(s). The methods contemplate administration of the pharmaceutical composition by any route appropriate for the disease, disorder or condition being treated, including subcutaneously, intramuscularly, intravitreally, or intravenously. 
     The methods of the invention may include administration of consecutive doses of a therapeutically effective amount of the pharmaceutical composition for a period of time sufficient to achieve and/or maintain the desired parameter or clinical effect, and such consecutive doses of a therapeutically effective amount establishes the therapeutically effective dose regimen for the pharmaceutical composition; i.e., the schedule for consecutively administered doses, wherein the doses are given in therapeutically effective amounts to result in a sustained beneficial effect on any clinical sign or symptom, aspect, measured parameter or characteristic of a metabolic disease state or condition, including, but not limited to, those described herein. 
     A therapeutically effective amount of the pharmaceutical composition may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the binding fusion protein are outweighed by the therapeutically beneficial effects. A prophylactically effective amount refers to an amount of pharmaceutical composition required for the period of time necessary to achieve the desired prophylactic result. 
     For the inventive methods, longer acting BFP-D or XTEN-drug compositions or pharmaceutical compositions comprising the BFP-D or XTEN-drug compositions are preferred, so as to improve patient convenience, to increase the interval between doses and to reduce the amount of drug required to achieve a sustained effect. In one embodiment, a method of treatment comprises administration of a therapeutically effective dose of a BFP-D or an XTEN-drug to a subject in need thereof that results in a gain in time spent within a therapeutic window established for the targeting moiety or drug components of the pharmaceutical composition compared to the corresponding drug component not linked to the fusion protein and administered at a comparable dose to a subject. In some cases, the gain in time spent within the therapeutic window is at least about three-fold, or at least about four-fold, or at least about five-fold, or at least about six-fold, or at least about eight-fold, or at least about 10-fold, or at least about 20-fold, or at least about 40-fold compared to the corresponding targeting moiety or drug components not linked to the fusion protein and administered at a comparable dose to a subject. The methods further provide that administration of multiple consecutive doses of a pharmaceutical composition administered using a therapeutically effective dose regimen to a subject in need thereof can result in a gain in time between consecutive C max  peaks and/or C min  troughs for blood levels of the composition compared to the corresponding targeting moiety or drug components not linked to the fusion protein. In the foregoing embodiment, the gain in time spent between consecutive C max  peaks and/or C min  troughs can be at least about three-fold, or at least about four-fold, or at least about five-fold, or at least about six-fold, or at least about eight-fold, or at least about 10-fold, or at least about 20-fold, or at least about 40-fold compared to the corresponding drug component(s) not linked to the fusion protein and administered using a comparable dose regimen established for that drug. In the embodiments hereinabove described in this paragraph the administration of the fusion protein or pharmaceutical composition can result in an improvement in at least one parameter known to be useful for assessing the subject diseases, conditions or disorders) using a lower unit dose in moles of fusion protein compared to the corresponding targeting moiety component(s) or the drug component(s) not linked to the fusion protein and administered at a comparable unit dose or dose regimen to a subject. 
     In one embodiment, the administration of a BFP-D or XTEN-drug pharmaceutical composition can result in an improvement in one of the clinical, biochemical or physiologic parameters that is greater than that achieved by administration of the targeting moiety or drug components not linked to XTEN, determined using the same assay or based on a measured clinical parameter. In another embodiment, administration of the BFP-D or XTEN-drug pharmaceutical composition can result in improvement two or more clinical or metabolic-related parameters, each mediated by one of the different targeting moieties that collectively result in an enhanced effect compared the targeting moiety component not linked to XTEN, determined using the same assays or based on measured clinical parameters. In another embodiment, administration of the binding fusion protein or pharmaceutical composition can result in activity in one or more of the clinical or biochemical or physiologic parameters that is of longer duration than the activity of one of the single targeting moiety or drug components not linked to XTEN, determined using that same assay or based on a measured clinical parameter. 
     The subject BFP-D or XTEN-drug conjugate compositions may be useful in the treatment of various diseases, disorders and conditions. In one embodiment, the disease is cancer, including carcinomas/tumors, melanomas, sarcomas, leukemias and lymphomas, and gliomas. Exemplary conditions or hyperproliferative disorders include benign or malignant tumors, neuronal, glial, astrocytal, hypothalamic, glandular, macrophagal, epithelial, stromal, blastocoelic, inflammatory, angiogenic and immunologic, including autoimmune, disorders. One or more compositions of the invention may be used in a combination with another treatment or drug to treat a patient. As used herein, a “patient” refers to any mammal, including a human, and may be afflicted with any disease, disorder or condition that may be effectively treated with a therapeutic antibody or a drug, including diseases, disorders or conditions associated with the targets of Tables 1 or 2 or diseases, disorders or conditions conventionally treated with the drugs of Table 9. Treatment with a conjugate may be a primary treatment for a disease or a disorder, or it may be adjuvant therapy for a disease or disorder. Furthermore, the treatment may be of an existing disease or may be prophylactic. Appropriate dosages and dose schedules for the inventive compositions may generally be determined using experimental models and/or clinical trials. The use of the minimum dosage that is sufficient to provide effective therapy may be preferred in some circumstances, such as when the drug is associated with harmful side effects. Patients may generally be monitored for therapeutic or prophylactic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those having ordinary skill in the art. Such methods will permit the establishment of the therapeutic window as well as the maximum tolerated dose for the compositions of the invention. 
     The XTEN-drug compositions and/or the binding fusion protein-drug compositions and pharmaceutical compositions comprising the BFP-D or XTEN-D can be administered by routes and by methods and dosing schedules appropriate for the given disease, disorder or condition. In certain embodiments, the XTEN-drug compositions and/or the binding fusion protein-drug compositions of the invention are administered as an IV infusion. In other embodiments, the compositions are administered subcutaneously or intramuscularly. In yet other embodiments, the compositions are administered orally. In the case of intravenous infusion, administration may last for any appropriate time period, which is readily determinable and assessable by one of ordinary skill in the art. For example, infusions may last for from about one to about 24 hours, although shorter or longer infusion times all fall within the scope of the invention. In certain embodiments, infusions are administered daily, weekly, every two weeks, every 21 days, or monthly. Appropriate time periods are known by one of skill in the art, and may be determined based upon a variety of factors, including the type of therapy or drug being used in combination with the XTEN-drug conjugate. Clinicians of ordinary skill in the art of medicine will know that the dosage that is administered to a patient will vary according to the age, weight and physical condition of the patient, the route of administration, the specific disease being treated, the stage of disease and the like. For any particular subject, the specific dosage regimens (both dosage and frequency of administration) should be adjusted for that patient by a skilled practitioner. Examples of different ranges of dosage and administration schedules are provided in U.S. Pat. No. 5,670,537. 
     Targeted XTEN-drug conjugate compositions useful in the treatment of cancer include, but are not limited to, compositions comprising one or more targeting moieties against cell surface receptors and tumor-associated antigens (TAA). Tumor-associated antigens are known in the art, and can be prepared for use in generating targeting moieties using methods and information that are well known in the art. Non-limiting examples of tumor-associated polypeptides are contained within Table 2. In preferred embodiments, the targets to which targeting moieties would be directed could include receptors specifically expressed on the surface of one or more particular type(s) of cancer cell as compared to on one or more normal non-cancerous cells. Often, such tumor-associated polypeptides are more abundantly expressed on the surface of the cancer cells as compared to on the surface of the non-cancerous cells; e.g., HER2 in certain breast cancers. The identification of such tumor-associated cell surface antigen polypeptides has given rise to the ability to specifically target cancer cells for destruction via antibody-based therapies. 
     Disorders Mediated by VEGF-Expressing Cells 
     A BFP-D composition that comprises a targeting moiety derived from an anti-VEGF antibody or fragment can be advantageously utilized in a method of treating a VEGF-mediated disease or disorder, such as neovascular disorders. In one embodiment, the invention provides a method of treating a solid tumor disorder in a human patient comprising administering to the patient an effective amount of a BFP-D or pharmaceutical composition wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to human VEGF wherein the binding can inhibit vascularization of the tumor, and the BFP-D further comprises a conjugated cytotoxic drug, such as a drug selected from Table 9, for treating a solid tumor. In yet another embodiment, the solid tumor disorder in the foregoing method is selected from the group consisting of breast carcinomas, lung carcinomas, gastric carcinomas, esophageal carcinomas, colorectal carcinomas, liver carcinomas, ovarian carcinomas, thecomas, arrhenoblastomas, cervical carcinomas, endometrial carcinoma, endometrial hyperplasia, endometriosis, fibrosarcomas, choriocarcinoma, head and neck cancer, nasopharyngeal carcinoma, laryngeal carcinomas, hepatoblastoma, Kaposi&#39;s sarcoma, melanoma, skin carcinomas, hemangioma, cavernous hemangioma, hemangioblastoma, pancreas carcinomas, retinoblastoma, astrocytoma, glioblastoma, Schwannoma, oligodendroglioma, medulloblastoma, neuroblastomas, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, urinary tract carcinomas, thyroid carcinomas, Wilm&#39;s tumor, renal cell carcinoma, prostate carcinoma, abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs&#39; syndrome. 
     In still another embodiment, the invention provides a method of treating an intraocular neovascular disorder in a human patient comprising administering to the patient a therapeutically effective amount of a BFP-D or pharmaceutical composition comprising the BFP-D wherein at least one targeting moiety comprises an antigen binding site that binds to human VEGF and the BFP-D further comprises a conjugated cytotoxic drug, such as a drug selected from Table 9. In a further embodiment, the intraocular neovascular disorder is selected from the group consisting of diabetic and other proliferative retinopathies including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, and age-related macular degeneration. 
     Disorders Mediated by HER2-Expressing Cells 
     In another embodiment, the binding fusion protein is used to treat disorders mediated by HER2-expressing cells. The invention provides a method for treating a human disease mediated by HER2-expressing cells with a binding fusion protein composition that is derived from a parental antibody that binds to HER2. Such compositions have prophylactic and therapeutic applications in a broad spectrum of HER2-expressing cell-mediated disorders, including pathologies supported by the proliferation of cells expressing HER2, such as cancers characterized by over-expression of HER2, in a manner similar to the application of full length anti-Her2 antibodies in the treatment of such disease indications that is known in the art, which treatment indications include HER2-overexpressing breast, ovarian and lung cancers. 
     In one embodiment, the invention provides a method of treating a HER2-expressing cell mediated disorder in a human patient comprising administering to the patient a therapeutically effective amount of a BFP-D or pharmaceutical composition comprising a BFP-D wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to HER2, and the BFP-D further comprises a conjugated cytotoxic drug, such as a drug selected from Table 9. The disorder can be a HER2-expressing cell proliferative disorder, including a benign or malignant tumor characterized by the over-expression of the ErbB2 receptor, e.g. a cancer, such as, breast cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer. In addition, the invention contemplates the use of the foregoing conjugate in place of full-length anti-Her2 antibody in the treatment of HER2-overexpressing cancers as described in U.S. Pat. No. 5,725,856. 
     In one non-limiting exemplary method, the invention provides a method of inhibiting growth of tumor cells by administering to a patient a therapeutically effective amount of anti-HER2 BFP-D composition capable of inhibiting the HER2 receptor function by the targeting moiety component and/or inhibiting or killing the HER2 cell by the drug component, such as, but not limited to epaclitaxel, paclitaxel, docetaxel, doxetaxel, irinotecan, pemetrexed, chloranbucil, or gemcitabine, or a suitable cytotoxic drug selected from Table 9, 
     A further embodiment of the invention relates to administering a therapeutically effective amount of anti-HER2 composition capable of inhibiting growth factor receptor function. Still another object of the invention is to provide methods for the treatment and/or prevention of erbB-2 receptor over-expressing tumors comprising the administration of an anti-tumor effective amount of at least one of the disclosed anti-HER2 BFP-D capable of binding to cancer cells associated by the over-expression of erbB-2 protein. In another embodiment, the invention provides a method for the treatment and/or prevention of erbB-2 receptor over-expressing tumors comprising the administration of therapeutically-effective amounts of anti-Her2 BFP-D comprising a first and a second anti-Her2 binding moiety, which may be the same or which may bind different epitopes of the erbB-2 protein, capable of inhibiting the HER2 receptor function, and one or more drug molecules selected from Table 9. Preferably, such combinations of binding moieties and drug will exhibit better cytotoxic activity than would be expected for the sum of the cytotoxic activity of the individual antibodies and separately administered drugs at the same or lower overall concentrations of the individual components. 
     Disorders Mediated by EGFR-Expressing Cells 
     In one embodiment, the invention provides a method for treating a human disease mediated by EGFR-expressing cells with a BFP-D that is derived from a parental antibody that binds to human EGFR (a.k.a., ErbB-1 or Her1) and further comprises a drug selected from Table 9. Such BFP-D can have prophylactic and therapeutic applications in a broad spectrum of EGFR-expressing cell-mediated disorders, including pathologies supported by the proliferation of cells expressing EGFR, such as cancers characterized by over-expression of EGFR, including cancers of the breast, ovary, head and neck, brain, bladder, pancreas, and lung. 
     In one embodiment, the invention provides a method of treating a cell proliferation disorder in a human patient characterized by over-expression of EGFR comprising administering to the patient a therapeutically effective amount of a BFP-D wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to human EGFR and further comprises a cytotoxic drug known to be effective against EGFR-bearing cells. The disorder can be a benign or malignant tumor characterized by the over-expression of the EGFR, e.g. a cancer, such as, breast cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer. 
     Disorders Mediated by CD20-Expressing Cells 
     In another embodiment, the invention provides a method of treating disorders mediated by CD20-expressing cells. The invention provides a method for treating a human disease mediated by CD20-expressing cells with a BFP-D composition that is derived from a parental antibody that binds to human CD20 and further comprises a cytotoxic drug known to have activity against CD20 expressing cells, such as a drug selected from Table 9. Such compositions have prophylactic and therapeutic applications in a broad spectrum of CD20-expressing cell-mediated disorders, including pathologies supported by the proliferation of CD20-expressing cells, such as cancers of CD20-expressing cells, in a manner similar to the application of full length anti-CD20 antibodies in the treatment of such disease indications known in the art, which treatment indications include B-lymphocytic lymphomas, as described in U.S. Pat. No. 6,682,734. 
     Disorders Mediated by CD18-Expressing Cells 
     In another embodiment, the invention provides a method of treating disorders mediated by CD18-expressing cells. The invention provides a method for treating a human disease mediated by CD18-expressing cells with a BFP-D composition that is derived from a parental antibody that binds to human CD18 and further comprises a cytotoxic drug known to have activity against CD18 expressing cells, such as a drug selected from Table 9. Such compositions have prophylactic and therapeutic applications in a broad spectrum of CD18-expressing cell-mediated disorders, including pathologies supported by leukocyte adhesion, in a manner similar to the application of full length anti-CD18 antibodies in the treatment of such disease indications known in the art, which treatment indications include acute myocardial infarction and stroke. In one embodiment, the invention provides a method of treating a disorder in a human patient mediated by a CD18-expressing cell, comprising administering to the patient a therapeutically effective amount of a BFP-D wherein at least one targeting moiety in the conjugate comprises an antigen binding site that binds to human CD18, and the BFP-D further comprises a conjugated drug known to have beneficial effects in the treatment of myocardial infarction and stroke, such as a drug selected from Table 9. In another embodiment, the CD18-expressing cell-mediated disorder is an inflammatory disorder, such as an ischemic reperfusion disorder, including acute myocardial infarction and stroke. In addition, the invention contemplates the use of the foregoing binding fusion protein in place of full-length anti-CD18 antibody in the treatment of stroke as described in PCT Publication WO 97/26912. 
     In another embodiment, the invention provides a method of treating a LFA-1-mediated disorder in a human, comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the conjugate comprises a targeting moiety that binds to human CD18, and the BFP-D further comprises a conjugated immunosuppressive drug, such as a drug selected from Table 9. In addition, the invention contemplates the use of the foregoing binding fusion protein in place of full-length anti-CD18 antibody in the treatment of an LFA-1-mediated disorder, such as psoriasis and graft rejection, in a human patient as described in U.S. Pat. No. 5,622,700. 
     Disorders Mediated by CD11a-Expressing Cells 
     In another embodiment, the invention provides a method of treating disorders mediated by CD11a-expressing cells. In one embodiment, the invention provides a method for treating a human disease mediated by a CD11a-expressing cell with a binding fusion protein composition that is derived from a parental antibody that binds to human CD11a and further comprises an immunosuppressive or cytotoxic drug known to have activity against CD11a expressing cells. Such compositions have prophylactic and therapeutic applications in a broad spectrum of CD11a-expressing cell-mediated disorders, including pathologies supported by leukocyte adhesion, in a manner similar to the application of full length anti-CD11a antibodies in the treatment of such disease indications known in the art, which treatment indications include psoriasis, asthma, graft rejection, and multiple sclerosis. In another embodiment, the invention provides a method of treating a LFA-1-mediated disorder in a human, comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the conjugate comprises an antigen binding site that binds to human CD11a. In addition, the invention contemplates the use of the foregoing binding fusion protein in place of full-length anti-CD11a antibody in the treatment of an LFA-1-mediated disorder, such as psoriasis and graft rejection, in a human patient as described in U.S. Pat. No. 5,622,700. In another aspect, the invention contemplates the use of the foregoing binding fusion proteins in place of full-length anti-CD11a antibody in the treatment of LFA-1-mediated disorders in a human patient as described in U.S. Pat. No. 6,037,454. 
     Disorders Mediated by CD3-Expressing Cells 
     In one embodiment, the invention provides a method for treating a human disease or disorder mediated by CD3-expressing cells with a binding fusion protein that is derived from a parental antibody that binds to human CD3 and further comprises a cytotoxic or immunosuppressive drug known to have activity against CD3 expressing cells, such as a drug selected from Table 9. Such binding fusion proteins can have prophylactic and therapeutic applications in a broad spectrum of CD3-expressing cell-mediated disorders, including conditions associated with the proliferation or activation of cells expressing CD3, such as immune disorders mediated by T-lymphocytes and graft rejection in transplant recipients. The use of anti-CD3 antibodies to treat diseases and disorders has been described, for example, in U.S. Pat. No. 4,515,893. In another aspect, the invention contemplates the use of the foregoing binding fusion protein in place of full length anti-human CD3 antibody in the treatment of acute allograft rejection in kidney transplant recipients as described for ORTHOCLONE OKT3 muromonab-CD3 in  Physician&#39;s Desk Reference,  52 nd  Edition (1998), pp. 1971-1974. 
     Disorders Mediated by TAC-Expressing Cells 
     In one embodiment, the invention provides a method for treating a human disease mediated by interleukin-2 receptor α-chain (TAC)-expressing cells with a binding fusion protein that is derived from a parental antibody that binds to human TAC and further comprises a cytotoxic drug known to have activity against TAC expressing cells. Such binding fusion proteins can have prophylactic and therapeutic applications in a broad spectrum of TAC-expressing cell-mediated disorders, including conditions created by the proliferation or activation of cells expressing TAC and immune disorders mediated by T-lymphocytes or B-lymphocytes, including graft rejection in transplant recipients. 
     In one embodiment, the invention provides a method of treating a disorder in a human patient mediated by a TAC-expressing cell, comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to human TAC, and the BFP-D further comprises a conjugated immunosuppressive or cytotoxic drug, such as a drug selected from Table 9. In another embodiment, the TAC-expressing cell-mediated disorder is characterized by the activation or proliferation of T-lymphocytes or B-lymphocytes, including immune disorders such as graft rejection in transplant recipients, graft-versus-host disease (GHVD), graft rejection in transplant recipients, such as acute graft rejection in renal transplant recipients, and autoimmune diseases such as Type I diabetes, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and myasthenia gravis. The use of antibodies to treat disorders mediated by interleukin-2 receptor α-chain with antibodies has been described in U.S. Pat. No. 5,693,761. 
     TNF-α-Mediated Disorders 
     In one embodiment, the invention provides a method for treating a TNF-α-mediated disease with a binding fusion protein that is derived from a parental antibody that binds to human TNF-α and further comprises a cytotoxic or anti-inflammatory drug, such as a drug selected from Table 9. Such binding fusion proteins can have prophylactic and therapeutic applications in a broad spectrum of TNF-α-mediated disorders, including inflammatory disorders and immune disorders, in a manner similar to the application of full-length anti-human TNF-α antibodies in the treatment of such disease indications such as Crohn&#39;s disease, inflammatory bowel disease, and rheumatoid arthritis. 
     In one embodiment, the invention provides a method of treating an inflammatory disorder in a human patient comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to human TNF-α. In another embodiment, the inflammatory disorder is Crohn&#39;s disease. In yet another embodiment, the inflammatory disorder is inflammatory bowel disease. In still another embodiment, the inflammatory disorder is rheumatoid arthritis. The use of antibodies that bind to human TNF-α in the treatment of inflammatory conditions have been described, for example, in U.S. Pat. Nos. 5,672,347, 5,656,272, and 5,698,195. 
     Tissue Factor-Mediated Disorders 
     In one embodiment, the invention provides a method for treating a tissue factor-mediated disease with a binding fusion protein derived from a parental antibody that binds to human tissue factor, and the BFP-D further comprises a conjugated anticoagulant or antithrombosis drug, such as a drug selected from Table 9. Such binding fusion proteins can have prophylactic and therapeutic applications in a broad spectrum of tissue factor-mediated disorders, including pathologies supported by blood coagulation and in the treatment of such disease indications as deep vein thrombosis, arterial thrombosis, atherosclerosis, vascular stenosis, myocardial ischemic diseases including acute myocardial infarction, reocclusion following angioplasty or atherectomy or thrombolytic treatment for acute myocardial infarction, angina, cerebral ischemic diseases including stroke, venous thrombophlebitis, and pulmonary embolism. In one embodiment, the invention provides a method of treating a tissue factor-mediated disease or disorder (such as the foregoing) in a human patient comprising administering to the patient a therapeutically effective amount of a binding fusion protein wherein at least one targeting moiety in the binding fusion protein comprises an antigen binding site that binds to human tissue factor. 
     III). The DNA Sequences of the Invention 
     The present invention provides isolated polynucleic acids encoding XTEN and binding fusion protein chimeric polypeptides and sequences complementary to polynucleic acid molecules encoding XTEN and binding fusion protein chimeric polypeptides, including homologous variants. In another aspect, the invention encompasses methods to produce polynucleic acids encoding XTEN and binding fusion protein chimeric polypeptides and sequences complementary to polynucleic acid molecules encoding binding fusion protein chimeric polypeptides, including homologous variants. In general, and as illustrated in  FIGS. 7-9 , the methods of producing a polynucleotide sequence coding for an XTEN or a binding fusion protein and expressing the resulting gene product include assembling nucleotides encoding targeting moieties and XTEN (and any linker sequences, if any), linking the components in frame, incorporating the encoding gene into an appropriate expression vector, transforming an appropriate host cell with the expression vector, and causing the fusion protein to be expressed in the transformed host cell, thereby producing the biologically-active binding fusion protein. Standard recombinant techniques in molecular biology can be used to make the polynucleotides and expression vectors of the present invention. 
     In accordance with the invention, nucleic acid sequences that encode XTEN and binding fusion proteins may be used to generate recombinant DNA molecules that direct the expression of XTEN and binding fusion proteins in appropriate host cells. Several cloning strategies are envisioned to be suitable for performing the present invention, many of which can be used to generate a construct that comprises a gene coding for a binding fusion protein composition of the present invention, or its complement. In one embodiment, the cloning strategy would be used to create a gene that encodes an XTEN polypeptide. In another embodiment, the cloning strategy would be used to create a gene that encodes a monomeric binding fusion protein that comprises at least a first targeting moiety and at least a first XTEN polypeptide, or its complement. In another embodiment, the cloning strategy would be used to create a gene that encodes a monomeric binding fusion protein that comprises a first and a second targeting moiety and at least a first XTEN, or its complement. In another embodiment, the cloning strategy would be used to create a gene that encodes a monomeric binding fusion protein that comprises at least a first and a second targeting moiety, a linker, and at least a first XTEN, or its complement. In the foregoing embodiments, the gene would be used in a suitable expression vector to transform a host cell for expression of the fusion protein. 
     In designing a desired XTEN sequences, it was discovered that the non-repetitive nature of the XTEN of the inventive compositions can be achieved despite use of a “building block” molecular approach in the creation of the XTEN-encoding sequences. This was achieved by the use of a library of polynucleotides encoding sequence motifs that are then multimerized to create the genes encoding the XTEN sequences (see  FIGS. 7 and 8 ). Thus, while the expressed XTEN may consist of multiple units of as few as four different sequence motifs, because the motifs themselves consist of non-repetitive amino acid sequences, the overall XTEN sequence is rendered non-repetitive. Accordingly, in one embodiment, the XTEN-encoding polynucleotides comprise multiple polynucleotides that encode non-repetitive sequences, or motifs, operably linked in frame and in which the resulting expressed XTEN amino acid sequences are non-repetitive. 
     In one approach, a construct is first prepared containing the DNA sequence corresponding to binding fusion protein. DNA encoding the targeting moiety of the compositions may be obtained from a cDNA library prepared using standard methods from tissue or isolated cells believed to possess targeting moiety mRNA and to express it at a detectable level. If necessary, the coding sequence can be obtained using conventional primer extension procedures as described in Sambrook, et al., supra, to detect precursors and processing intermediates of mRNA that may not have been reverse-transcribed into cDNA. Accordingly, DNA can be conveniently obtained from a cDNA library prepared from such sources. The target moiety encoding gene(s) may also be obtained from a genomic library or created by standard synthetic procedures known in the art (e.g., automated nucleic acid synthesis) using DNA sequences obtained from publicly available databases, patents, or literature references. Such procedures are well known in the art and well described in the scientific and patent literature. For example, sequences can be obtained from Chemical Abstracts Services (CAS) Registry Numbers (published by the American Chemical Society) and/or GenBank Accession Numbers (e.g., Locus ID, NM_XXXXX, NP XXXXX, and XP XXXXX) Model Protein identifiers available through the National Center for Biotechnology Information (NCBI) webpage, available on the world wide web at ncbi.nlm.nih.gov that correspond to entries in the CAS Registry or GenBank database that contain an amino acid sequence of the targeting moiety (e.g., an antibody) or of a fragment or variant of the targeting moiety. For such sequence identifiers provided herein, the summary pages associated with each of these CAS and GenBank and GenSeq Accession Numbers as well as the cited journal publications (e.g., PubMed ID number (PMID)) are each incorporated by reference in their entireties, particularly with respect to the amino acid sequences described therein. In one embodiment, the binding fusion protein encoding gene encodes a protein from any one of Tables 25, 38 or 39, or a fragment or variant thereof. 
     A gene or polynucleotide encoding the targeting moiety portion of the subject binding fusion protein, in the case of an expressed fusion protein that will comprise a single targeting moiety, can be then be cloned into a construct, which can be a plasmid or other vector under control of appropriate transcription and translation sequences for high level protein expression in a biological system. In a later step, a second gene or polynucleotide coding for the XTEN is genetically fused to the nucleotides encoding the N- and/or C-terminus of the targeting moiety gene by cloning it into the construct adjacent and in frame with the gene(s) coding for the targeting moiety. This second step can occur through a ligation or multimerization step. In the foregoing embodiments hereinabove described in this paragraph, it is to be understood that the gene constructs that are created can alternatively be the complement of the respective genes that encode the respective fusion proteins. In addition, for binding fusion proteins comprising two or more targeting moieties and linkers, the gene or polynucleotides coding for these components would be cloned into the construct adjacent to and in frame relative to the other components described above, depending on the desired final configuration of the fusion protein. In a particular aspect of the foregoing, it was discovered that use of alternative encoding sequences for multivalent (e.g., two or more) targeting moieties reduces the risk of homologous recombination during expression. Accordingly, for binding fusion proteins that have repeat binding domains or multivalent targeting moieties with the same or very similar sequences, the invention provides encoding polynucleotides for the respective domains that have different DNA sequences. In a non-limiting example of the foregoing, the invention provides a binding fusion protein with dimeric Ig-like targeting moieties wherein the codons for certain amino acids for the encoding gene for each targeting moiety are varied, wherein the incidence of recombination during expression in a transformed host is reduced compared to a comparable host transformed with targeting genes which are identical. 
     The gene encoding for the XTEN can be made in one or more steps, either fully synthetically or by synthesis combined with enzymatic processes, such as restriction enzyme-mediated cloning, PCR and overlap extension. XTEN polypeptides can be constructed such that the XTEN-encoding gene has low repetitiveness. Genes encoding XTEN with non-repetitive sequences can be assembled from oligonucleotides using standard techniques of gene synthesis. The gene design can be performed using algorithms that optimize codon usage and amino acid composition. In one method of the invention, a library of relatively short XTEN-encoding polynucleotide constructs is created and then assembled, as illustrated in  FIGS. 7 and 8 . This can be a pure codon library such that each library member has the same amino acid sequence but many different coding sequences are possible. Such libraries can be assembled from partially randomized oligonucleotides and used to generate large libraries of XTEN segments comprising the sequence motifs. The randomization scheme can be optimized to control amino acid choices for each position as well as codon usage. 
     Polynucleotide Libraries 
     In another aspect, the invention provides libraries of polynucleotides that encode XTEN sequences that can be used to assemble genes that encode XTEN of a desired length and sequence, which are useful for the creation of genes encoding binding fusion proteins. 
     In certain embodiments, the XTEN-encoding library constructs comprise polynucleotides that encode polypeptide segments of a fixed length. As an initial step, a library of oligonucleotides that encode motifs of 9-14 amino acid residues can be assembled. In a preferred embodiment, libraries of oligonucleotides that encode motifs of 12 amino acids are assembled. 
     The XTEN-encoding sequence segments can be dimerized or multimerized into longer encoding sequences. Dimerization or multimerization can be performed by ligation, overlap extension, PCR assembly or similar cloning techniques known in the art. This process of can be repeated multiple times until the resulting XTEN-encoding sequences have reached the organization of sequence and desired length, providing the XTEN-encoding genes. As will be appreciated, a library of polynucleotides that encodes 12 amino acids can be dimerized into a library of polynucleotides that encode 36 amino acids. In turn, the library of polynucleotides that encode 36 amino acids can be serially dimerized into a library containing successively longer lengths of polynucleotides that encode XTEN sequences. In some embodiments, libraries can be assembled of polynucleotides that encode amino acids that are limited to specific sequence XTEN families; e.g., AD, AE, AF, AG, AM, AQ, BC, or BD sequences of Table 3. In other embodiments, libraries can comprises sequences that encode two or more of the motif family sequences from Table 3. The names and sequences of representative, non-limiting polynucleotide sequences of libraries that encode 36mers are presented in Tables 11-14, and the methods used to create them are described more fully in the Examples. The libraries can be used, in turn, for serial dimerization or ligation to achieve polynucleotide sequence libraries that encode XTEN sequences, for example, of 72, 144, 288, 576, 864, 912, 923, 1296 amino acids, or up to a total length of about 3000 amino acids, as well as intermediate lengths. In one embodiment, the polynucleotide library sequences may also include additional bases used as “sequencing islands,” described more fully below. 
       FIG. 8  is a schematic flowchart of representative, non-limiting steps in the assembly of a XTEN polynucleotide construct and a binding fusion protein polynucleotide construct utilized in the XTEN, binding fusion protein and BFP-D embodiments of the invention. Individual oligonucleotides  501  can be annealed into sequence motifs  502  such as a 12 amino acid motif (“12-mer”), which is subsequently ligated with an oligo containing BbsI, and KpnI restriction sites  503 . Additional sequence motifs from a library are annealed to the 12-mer until the desired length of the XTEN gene  504  is achieved. The XTEN gene is cloned into a stuffer vector. The vector can optionally encode a Flag sequence  506  followed by a stuffer sequence that is flanked by BsaI, BbsI, and KpnI sites  507  and, in this case, a single targeting moiety gene (encoding anti-Her2 in this example) 508, resulting in the gene encoding a binding fusion protein comprising a single targeting moiety 500. A non-exhaustive list of the XTEN names and sequences for polynucleotides encoding XTEN and precursor sequences is provided in Table 10. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 DNA sequences of XTEN and precursor sequences 
               
            
           
           
               
               
               
            
               
                   
                   
                 SEQ 
               
               
                 XTEN 
                   
                 ID 
               
               
                 Name 
                 DNA Sequence 
                 NO: 
               
               
                   
               
               
                 AE144 
                 GGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACTTCTGAAAGCGCTAC 
                 202 
               
               
                   
                 TCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCTGGCTCTGAAACCCCAGGTA 
                   
               
               
                   
                 GCCCGGCAGGCTCTCCGACTTCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAG 
                   
               
               
                   
                 GGTAGCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAGGTAGCG 
                   
               
               
                   
                 AACCTGCTACCTCCGGCTCTGAAACTCCAGGTAGCGAACCGGCTACTTCCGGTTCT 
                   
               
               
                   
                 GAAACTCCAGGTACCTCTACCGAACCTTCCGAAGGCAGCGCACCAGGTACTTCTGA 
                   
               
               
                   
                 AAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGA 
                   
               
               
                   
                 CTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA 
                   
               
               
                   
               
               
                 AF144 
                 GGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTACTTCTCCTAGCGGTGA 
                 203 
               
               
                   
                 ATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACTGCTCCAGGTTC 
                   
               
               
                   
                 TACCAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCTACCAGCGAATCCCCGTCTGG 
                   
               
               
                   
                 CACCGCACCAGGTTCTACTAGCTCTACCGCAGAATCTCCGGGTCCAGGTACTTCCC 
                   
               
               
                   
                 CTAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTACTCCGGAAAGCGGCTCCGCA 
                   
               
               
                   
                 TCTCCAGGTTCTACTAGCTCTACTGCTGAATCTCCTGGTCCAGGTACCTCCCCTAGC 
                   
               
               
                   
                 GGCGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCA 
                   
               
               
                   
                 GGTACCTCCCCTAGCGGTGAATCTTCTACCGCACCA 
                   
               
               
                   
               
               
                 AE288 
                 GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTC 
                 204 
               
               
                   
                 CGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTA 
                   
               
               
                   
                 GCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCT 
                   
               
               
                   
                 GAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCC 
                   
               
               
                   
                 TGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAAT 
                   
               
               
                   
                 CCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAA 
                   
               
               
                   
                 AGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGA 
                   
               
               
                   
                 GGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTACCGAAC 
                   
               
               
                   
                 CTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCA 
                   
               
               
                   
                 GGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTAC 
                   
               
               
                   
                 CCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTA 
                   
               
               
                   
                 GCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCAGCAGGCTCTCCGACT 
                   
               
               
                   
                 TCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTC 
                   
               
               
                   
                 TACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCTG 
                   
               
               
                   
                 AAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACT 
                   
               
               
                   
                 GAACCGTCCGAGGGCAGCGCACCA 
                   
               
               
                   
               
               
                 AE576 
                 GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGAAAGCGCTAC 
                 205 
               
               
                   
                 TCCTGAGTCTGGTCCAGGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTA 
                   
               
               
                   
                 GCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAA 
                   
               
               
                   
                 GGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTC 
                   
               
               
                   
                 TGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTG 
                   
               
               
                   
                 AAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCA 
                   
               
               
                   
                 GGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGG 
                   
               
               
                   
                 CCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTACTTCTACCGAAC 
                   
               
               
                   
                 CGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA 
                   
               
               
                   
                 GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCTTC 
                   
               
               
                   
                 TGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTA 
                   
               
               
                   
                 CTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCT 
                   
               
               
                   
                 GAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTC 
                   
               
               
                   
                 TACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGTCTGAAGGTA 
                   
               
               
                   
                 GCGCACCAGGTACTTCTGAAAGCGCAACCCCGGAATCCGGCCCAGGTACCTCTGAA 
                   
               
               
                   
                 AGCGCAACCCCGGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGA 
                   
               
               
                   
                 AGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCA 
                   
               
               
                   
                 ACCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCC 
                   
               
               
                   
                 AGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGT 
                   
               
               
                   
                 CCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGT 
                   
               
               
                   
                 ACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTCTGA 
                   
               
               
                   
                 AGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGC 
                   
               
               
                   
                 CCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGG 
                   
               
               
                   
                 TAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAAC 
                   
               
               
                   
                 CTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCT 
                   
               
               
                   
                 GGTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAG 
                   
               
               
                   
                 CGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCAC 
                   
               
               
                   
                 CAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCT 
                   
               
               
                   
                 CCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGG 
                   
               
               
                   
                 TAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCC 
                   
               
               
                   
                 CGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA 
                   
               
               
                   
               
               
                 AF576 
                 GGTTCTACTAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCCACTAGCTCTACCGCA 
                 206 
               
               
                   
                 GAATCTCCGGGCCCAGGTTCTACTAGCGAATCCCCTTCTGGTACCGCTCCAGGTTCT 
                   
               
               
                   
                 ACTAGCTCTACCGCTGAATCTCCGGGTCCAGGTTCTACCAGCTCTACTGCAGAATCT 
                   
               
               
                   
                 CCTGGCCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGTTCTACCAGC 
                   
               
               
                   
                 GAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCT 
                   
               
               
                   
                 CCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCT 
                   
               
               
                   
                 CCTTCTGGCACCGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGT 
                   
               
               
                   
                 TCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCTTCT 
                   
               
               
                   
                 GGCACCGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTACT 
                   
               
               
                   
                 AGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACTAGCGAATCTCCTTCTGGCACT 
                   
               
               
                   
                 GCACCAGGTTCTACCAGCGAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCCC 
                   
               
               
                   
                 TGAAAGCGGTTCCGCTTCTCCAGGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCC 
                   
               
               
                   
                 AGGTACTTCTACCCCTGAAAGCGGCTCCGCTTCTCCAGGTTCCACTAGCTCTACCGC 
                   
               
               
                   
                 TGAATCTCCGGGTCCAGGTTCTACTAGCTCTACTGCAGAATCTCCTGGCCCAGGTAC 
                   
               
               
                   
                 CTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTACTTCTACCCCTGAAAGCGGTTC 
                   
               
               
                   
                 TGCATCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTACTTCTAC 
                   
               
               
                   
                 CCCGGAAAGCGGCTCTGCTTCTCCAGGTACTTCTACCCCGGAAAGCGGCTCCGCAT 
                   
               
               
                   
                 CTCCAGGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAGGTTCTACCAGCGAAT 
                   
               
               
                   
                 CCCCGTCTGGTACTGCTCCAGGTTCTACCAGCGAATCTCCTTCTGGTACTGCACCAG 
                   
               
               
                   
                 GTTCTACTAGCTCTACTGCAGAATCTCCTGGCCCAGGTACCTCTACTCCGGAAAGC 
                   
               
               
                   
                 GGCTCTGCATCTCCAGGTACTTCTACCCCTGAAAGCGGTTCTGCATCTCCAGGTTCT 
                   
               
               
                   
                 ACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCGTCTGGC 
                   
               
               
                   
                 ACTGCACCAGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGTTCTACTAGC 
                   
               
               
                   
                 GAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCGTCTGGCACTGCA 
                   
               
               
                   
                 CCAGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGTACTTCTCCGAGCGGT 
                   
               
               
                   
                 GAATCTTCTACCGCACCAGGTTCTACTAGCTCTACCGCTGAATCTCCGGGCCCAGGT 
                   
               
               
                   
                 ACTTCTCCGAGCGGTGAATCTTCTACTGCTCCAGGTTCCACTAGCTCTACTGCTGAA 
                   
               
               
                   
                 TCTCCTGGCCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGTTCTACT 
                   
               
               
                   
                 AGCGAATCTCCGTCTGGCACCGCACCAGGTTCTACTAGCTCTACTGCAGAATCTCCT 
                   
               
               
                   
                 GGCCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTACTTCTACCCCT 
                   
               
               
                   
                 GAAAGCGGTTCTGCATCTCCA 
                   
               
               
                   
               
               
                 AM875 
                 GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCAGGTAGCGAACCGGCTACTTC 
                 207 
               
               
                   
                 CGGTTCTGAAACCCCAGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTT 
                   
               
               
                   
                 CTACCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGC 
                   
               
               
                   
                 TCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACT 
                   
               
               
                   
                 AGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCT 
                   
               
               
                   
                 TCTCCAGGTACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACCGGC 
                   
               
               
                   
                 AACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCCGGCC 
                   
               
               
                   
                 CAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGTACCTCTACTGAACCT 
                   
               
               
                   
                 TCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGG 
                   
               
               
                   
                 TACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCG 
                   
               
               
                   
                 AGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACT 
                   
               
               
                   
                 TCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACTTCTACCGAACCTTCCGAGGG 
                   
               
               
                   
                 CAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTG 
                   
               
               
                   
                 AAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACTGAACCTTCCGAAGGCAGC 
                   
               
               
                   
                 GCTCCAGGTACCTCTACCGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTGAAAG 
                   
               
               
                   
                 CGCAACCCCTGAATCCGGTCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTC 
                   
               
               
                   
                 CAGGTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGCCCGGCTGGCTCT 
                   
               
               
                   
                 CCGACCTCCACCGAGGAAGGTAGCTCTACCCCGTCTGGTGCTACTGGTTCTCCAGG 
                   
               
               
                   
                 TACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGC 
                   
               
               
                   
                 TACTGGCTCTCCAGGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT 
                   
               
               
                   
                 CTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCCGGTTCT 
                   
               
               
                   
                 GAAACTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTGAGGAAGGTAGCCCGGC 
                   
               
               
                   
                 TGGTTCTCCGACTTCTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCG 
                   
               
               
                   
                 CTCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTACTTCTGAAAGCGC 
                   
               
               
                   
                 TACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAG 
                   
               
               
                   
                 GTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCT 
                   
               
               
                   
                 GAATCTCCTGGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAGGTAC 
                   
               
               
                   
                 TTCCCCTAGCGGTGAATCTTCTACTGCACCAGGTACCCCTGGCAGCGGTACCGCTTC 
                   
               
               
                   
                 TTCCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCTCCAGGTTCTAGCCC 
                   
               
               
                   
                 GTCTGCATCTACCGGTACCGGCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAA 
                   
               
               
                   
                 CTCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGGTAGCGAACCGGCT 
                   
               
               
                   
                 ACTTCCGGCTCTGAAACCCCAGGTTCCACCAGCTCTACTGCAGAATCTCCGGGCCC 
                   
               
               
                   
                 AGGTTCTACTAGCTCTACTGCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGGCG 
                   
               
               
                   
                 AATCTTCTACCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACTCCAGGT 
                   
               
               
                   
                 AGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGGTACTTCTACTGAACCTTCTGA 
                   
               
               
                   
                 GGGCAGCGCACCAGGTTCTACCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCT 
                   
               
               
                   
                 CTACTCCGGAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCA 
                   
               
               
                   
                 CTGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTACT 
                   
               
               
                   
                 GAACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTCTGAAGGTAGCGC 
                   
               
               
                   
                 ACCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGC 
                   
               
               
                   
                 TTCCACTGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGG 
                   
               
               
                   
                 TAGCGAACCTGCTACCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGCAACTC 
                   
               
               
                   
                 CGGAGTCTGGTCCAGGTAGCCCTGCAGGTTCTCCTACCTCCACTGAGGAAGGTAGC 
                   
               
               
                   
                 TCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGGT 
                   
               
               
                   
                 ACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTACCTCTGA 
                   
               
               
                   
                 AAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCG 
                   
               
               
                   
                 CTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA 
                   
               
               
                   
               
               
                 AE864 
                 GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGAAAGCGCTAC 
                 208 
               
               
                   
                 TCCTGAGTCTGGTCCAGGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTA 
                   
               
               
                   
                 GCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAA 
                   
               
               
                   
                 GGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTC 
                   
               
               
                   
                 TGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTG 
                   
               
               
                   
                 AAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCA 
                   
               
               
                   
                 GGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGG 
                   
               
               
                   
                 CCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTACTTCTACCGAAC 
                   
               
               
                   
                 CGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA 
                   
               
               
                   
                 GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCTTC 
                   
               
               
                   
                 TGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTA 
                   
               
               
                   
                 CTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCT 
                   
               
               
                   
                 GAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTC 
                   
               
               
                   
                 TACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGTCTGAAGGTA 
                   
               
               
                   
                 GCGCACCAGGTACTTCTGAAAGCGCAACCCCGGAATCCGGCCCAGGTACCTCTGAA 
                   
               
               
                   
                 AGCGCAACCCCGGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGA 
                   
               
               
                   
                 AGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCA 
                   
               
               
                   
                 ACCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCC 
                   
               
               
                   
                 AGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGT 
                   
               
               
                   
                 CCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGT 
                   
               
               
                   
                 ACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTCTGA 
                   
               
               
                   
                 AGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGC 
                   
               
               
                   
                 CCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGG 
                   
               
               
                   
                 TAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAAC 
                   
               
               
                   
                 CTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCT 
                   
               
               
                   
                 GGTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAG 
                   
               
               
                   
                 CGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCAC 
                   
               
               
                   
                 CAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCT 
                   
               
               
                   
                 CCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGG 
                   
               
               
                   
                 TAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCC 
                   
               
               
                   
                 CGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTACC 
                   
               
               
                   
                 TCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTC 
                   
               
               
                   
                 TGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC 
                   
               
               
                   
                 CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCT 
                   
               
               
                   
                 GGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGCTGG 
                   
               
               
                   
                 CTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCC 
                   
               
               
                   
                 CAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCT 
                   
               
               
                   
                 ACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGG 
                   
               
               
                   
                 TAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTACCGAACCTTCCG 
                   
               
               
                   
                 AGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT 
                   
               
               
                   
                 TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGA 
                   
               
               
                   
                 ATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAAC 
                   
               
               
                   
                 CGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACT 
                   
               
               
                   
                 GAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGA 
                   
               
               
                   
                 ACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCC 
                   
               
               
                   
                 CAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCG 
                   
               
               
                   
                 TCCGAGGGCAGCGCACCA 
                   
               
               
                   
               
               
                 AF864 
                 GGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCTAGCGGCGA 
                 209 
               
               
                   
                 ATCTTCTACCGCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTC 
                   
               
               
                   
                 TACTAGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTACTCCTGAAAGCGGTTC 
                   
               
               
                   
                 CGCTTCTCCAGGTACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTTCTACCAG 
                   
               
               
                   
                 CGAATCTCCTTCTGGCACCGCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACCGC 
                   
               
               
                   
                 ACCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTTCTACTAGCGAAT 
                   
               
               
                   
                 CTCCGTCTGGCACTGCTCCAGGTACTTCTCCTAGCGGTGAATCTTCTACCGCTCCAG 
                   
               
               
                   
                 GTACTTCCCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTACTAGCTCTACTGCAG 
                   
               
               
                   
                 AATCTCCGGGCCCAGGTACCTCTCCTAGCGGTGAATCTTCTACCGCTCCAGGTACTT 
                   
               
               
                   
                 CTCCGAGCGGTGAATCTTCTACCGCTCCAGGTTCTACTAGCTCTACTGCAGAATCTC 
                   
               
               
                   
                 CTGGCCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTACTTCTACCC 
                   
               
               
                   
                 CTGAAAGCGGTTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCAC 
                   
               
               
                   
                 CAGGTTCTACCAGCGAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCCCTGAA 
                   
               
               
                   
                 AGCGGTTCCGCTTCTCCAGGTTCTACCAGCTCTACCGCAGAATCTCCTGGTCCAGGT 
                   
               
               
                   
                 ACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCT 
                   
               
               
                   
                 GGCACTGCACCAGGTACTTCTCCGAGCGGTGAATCTTCTACCGCACCAGGTTCTAC 
                   
               
               
                   
                 TAGCTCTACCGCTGAATCTCCGGGCCCAGGTACTTCTCCGAGCGGTGAATCTTCTAC 
                   
               
               
                   
                 TGCTCCAGGTACCTCTACTCCTGAAAGCGGTTCTGCATCTCCAGGTTCCACTAGCTC 
                   
               
               
                   
                 TACCGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACTGCTGAATCTCCTGGCCC 
                   
               
               
                   
                 AGGTTCTACTAGCTCTACTGCTGAATCTCCGGGTCCAGGTTCTACCAGCTCTACTGC 
                   
               
               
                   
                 TGAATCTCCTGGTCCAGGTACCTCCCCGAGCGGTGAATCTTCTACTGCACCAGGTTC 
                   
               
               
                   
                 TACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCGTCTGG 
                   
               
               
                   
                 CACTGCACCAGGTACCTCTACCCCTGAAAGCGGTCCXXXXXXXXXXXXTGCAAGC 
                   
               
               
                   
                 GCAAGCGGCGCGCCAAGCACGGGAXXXXXXXXTAGCGAATCTCCTTCTGGTACCG 
                   
               
               
                   
                 CTCCAGGTTCTACCAGCGAATCCCCGTCTGGTACTGCTCCAGGTTCTACCAGCGAAT 
                   
               
               
                   
                 CTCCTTCTGGTACTGCACCAGGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAG 
                   
               
               
                   
                 GTTCTACCAGCGAATCCCCGTCTGGTACTGCTCCAGGTTCTACCAGCGAATCTCCTT 
                   
               
               
                   
                 CTGGTACTGCACCAGGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTACTT 
                   
               
               
                   
                 CTCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTA 
                   
               
               
                   
                 CTGCTCCAGGTTCTACCAGCTCTACTGCTGAATCTCCGGGTCCAGGTACTTCCCCGA 
                   
               
               
                   
                 GCGGTGAATCTTCTACTGCACCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCTC 
                   
               
               
                   
                 CAGGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTTCTACTAGCGAATCCC 
                   
               
               
                   
                 CGTCTGGTACCGCACCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTT 
                   
               
               
                   
                 CTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTACTTCTACCCCGGAAAGCGGC 
                   
               
               
                   
                 TCTGCTTCTCCAGGTACTTCTACCCCGGAAAGCGGCTCCGCATCTCCAGGTTCTACT 
                   
               
               
                   
                 AGCGAATCTCCTTCTGGTACCGCTCCAGGTACTTCTACCCCTGAAAGCGGCTCCGCT 
                   
               
               
                   
                 TCTCCAGGTTCCACTAGCTCTACCGCTGAATCTCCGGGTCCAGGTTCTACCAGCGAA 
                   
               
               
                   
                 TCTCCTTCTGGCACCGCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACCGCACCA 
                   
               
               
                   
                 GGTACTTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTTCTACCAGCTCTACTGCT 
                   
               
               
                   
                 GAATCTCCGGGTCCAGGTACTTCCCCGAGCGGTGAATCTTCTACTGCACCAGGTAC 
                   
               
               
                   
                 TTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGTACCTCCCCTAGCGGCGAATCTTC 
                   
               
               
                   
                 TACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTACCTCCCC 
                   
               
               
                   
                 TAGCGGTGAATCTTCTACCGCACCAGGTTCTACTAGCTCTACTGCTGAATCTCCGGG 
                   
               
               
                   
                 TCCAGGTTCTACCAGCTCTACTGCTGAATCTCCTGGTCCAGGTACCTCCCCGAGCGG 
                   
               
               
                   
                 TGAATCTTCTACTGCACCAGGTTCTAGCCCTTCTGCTTCCACCGGTACCGGCCCAGG 
                   
               
               
                   
                 TAGCTCTACTCCGTCTGGTGCAACTGGCTCTCCAGGTAGCTCTACTCCGTCTGGTGC 
                   
               
               
                   
                 AACCGGCTCCCCA 
                   
               
               
                   
                 XXXX was inserted in two areas where no sequence information is available. 
                   
               
               
                   
               
               
                 AG864 
                 GGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTTCTAGCCCGTCTGCTTCT 
                 210 
               
               
                   
                 ACTGGTACTGGTCCAGGTTCTAGCCCTTCTGCTTCCACTGGTACTGGTCCAGGTACC 
                   
               
               
                   
                 CCGGGTAGCGGTACCGCTTCTTCTTCTCCAGGTAGCTCTACTCCGTCTGGTGCTACC 
                   
               
               
                   
                 GGCTCTCCAGGTTCTAACCCTTCTGCATCCACCGGTACCGGCCCAGGTGCTTCTCCG 
                   
               
               
                   
                 GGCACCAGCTCTACTGGTTCTCCAGGTACCCCGGGCAGCGGTACCGCATCTTCTTCT 
                   
               
               
                   
                 CCAGGTAGCTCTACTCCTTCTGGTGCAACTGGTTCTCCAGGTACTCCTGGCAGCGGT 
                   
               
               
                   
                 ACCGCTTCTTCTTCTCCAGGTGCTTCTCCTGGTACTAGCTCTACTGGTTCTCCAGGTG 
                   
               
               
                   
                 CTTCTCCGGGCACTAGCTCTACTGGTTCTCCAGGTACCCCGGGTAGCGGTACTGCTT 
                   
               
               
                   
                 CTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTC 
                   
               
               
                   
                 CGGGCACCAGCTCTACCGGTTCTCCAGGTACCCCGGGTAGCGGTACCGCTTCTTCTT 
                   
               
               
                   
                 CTCCAGGTAGCTCTACTCCGTCTGGTGCTACCGGCTCTCCAGGTTCTAACCCTTCTG 
                   
               
               
                   
                 CATCCACCGGTACCGGCCCAGGTTCTAGCCCTTCTGCTTCCACCGGTACTGGCCCAG 
                   
               
               
                   
                 GTAGCTCTACCCCTTCTGGTGCTACCGGCTCCCCAGGTAGCTCTACTCCTTCTGGTG 
                   
               
               
                   
                 CAACTGGCTCTCCAGGTGCATCTCCGGGCACTAGCTCTACTGGTTCTCCAGGTGCAT 
                   
               
               
                   
                 CCCCTGGCACTAGCTCTACTGGTTCTCCAGGTGCTTCTCCTGGTACCAGCTCTACTG 
                   
               
               
                   
                 GTTCTCCAGGTACTCCTGGCAGCGGTACCGCTTCTTCTTCTCCAGGTGCTTCTCCTG 
                   
               
               
                   
                 GTACTAGCTCTACTGGTTCTCCAGGTGCTTCTCCGGGCACTAGCTCTACTGGTTCTC 
                   
               
               
                   
                 CAGGTGCTTCCCCGGGCACTAGCTCTACCGGTTCTCCAGGTTCTAGCCCTTCTGCAT 
                   
               
               
                   
                 CTACTGGTACTGGCCCAGGTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGGTG 
                   
               
               
                   
                 CATCTCCGGGCACTAGCTCTACTGGTTCTCCAGGTGCATCCCCTGGCACTAGCTCTA 
                   
               
               
                   
                 CTGGTTCTCCAGGTGCTTCTCCTGGTACCAGCTCTACTGGTTCTCCAGGTAGCTCTA 
                   
               
               
                   
                 CTCCGTCTGGTGCAACCGGTTCCCCAGGTAGCTCTACTCCTTCTGGTGCTACTGGCT 
                   
               
               
                   
                 CCCCAGGTGCATCCCCTGGCACCAGCTCTACCGGTTCTCCAGGTACCCCGGGCAGC 
                   
               
               
                   
                 GGTACCGCATCTTCCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACCGGTTCCCCA 
                   
               
               
                   
                 GGTAGCTCTACCCCGTCTGGTGCAACCGGCTCCCCAGGTAGCTCTACTCCGTCTGGT 
                   
               
               
                   
                 GCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAGGTGCT 
                   
               
               
                   
                 TCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTGCATCCCCGGGTACCAGCTCTACC 
                   
               
               
                   
                 GGTTCTCCAGGTACTCCTGGCAGCGGTACTGCATCTTCCTCTCCAGGTGCTTCTCCG 
                   
               
               
                   
                 GGCACCAGCTCTACTGGTTCTCCAGGTGCATCTCCGGGCACTAGCTCTACTGGTTCT 
                   
               
               
                   
                 CCAGGTGCATCCCCTGGCACTAGCTCTACTGGTTCTCCAGGTGCTTCTCCTGGTACC 
                   
               
               
                   
                 AGCTCTACTGGTTCTCCAGGTACCCCTGGTAGCGGTACTGCTTCTTCCTCTCCAGGT 
                   
               
               
                   
                 AGCTCTACTCCGTCTGGTGCTACCGGTTCTCCAGGTACCCCGGGTAGCGGTACCGC 
                   
               
               
                   
                 ATCTTCTTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGTTCTCCAGGTACTCC 
                   
               
               
                   
                 GGGCAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGG 
                   
               
               
                   
                 CTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCCCCAGGTTCTAGCCCTTC 
                   
               
               
                   
                 TGCATCCACCGGTACCGGTCCAGGTTCTAGCCCGTCTGCATCTACTGGTACTGGTCC 
                   
               
               
                   
                 AGGTGCATCCCCGGGCACTAGCTCTACCGGTTCTCCAGGTACTCCTGGTAGCGGTA 
                   
               
               
                   
                 CTGCTTCTTCTTCTCCAGGTAGCTCTACTCCTTCTGGTGCTACTGGTTCTCCAGGTTC 
                   
               
               
                   
                 TAGCCCTTCTGCATCCACCGGTACCGGCCCAGGTTCTAGCCCGTCTGCTTCTACCGG 
                   
               
               
                   
                 TACTGGTCCAGGTGCTTCTCCGGGTACTAGCTCTACTGGTTCTCCAGGTGCATCTCC 
                   
               
               
                   
                 TGGTACTAGCTCTACTGGTTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTC 
                   
               
               
                   
                 TCCAGGTTCTAGCCCTTCTGCATCTACCGGTACTGGTCCAGGTGCATCCCCTGGTAC 
                   
               
               
                   
                 CAGCTCTACCGGTTCTCCAGGTTCTAGCCCTTCTGCTTCTACCGGTACCGGTCCAGG 
                   
               
               
                   
                 TACCCCTGGCAGCGGTACCGCATCTTCCTCTCCAGGTAGCTCTACTCCGTCTGGTGC 
                   
               
               
                   
                 AACCGGTTCCCCAGGTAGCTCTACTCCTTCTGGTGCTACTGGCTCCCCAGGTGCATC 
                   
               
               
                   
                 CCCTGGCACCAGCTCTACCGGTTCTCCA 
                   
               
               
                   
               
               
                 AM923 
                 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTGCATCCCCGGGCAC 
                 211 
               
               
                   
                 CAGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACCGGCTCTCCAGG 
                   
               
               
                   
                 TAGCTCTACCCCGTCTGGTGCTACTGGCTCTCCAGGTACTTCTACTGAACCGTCTGA 
                   
               
               
                   
                 AGGCAGCGCACCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCCAGGTAGCC 
                   
               
               
                   
                 CAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCAGAATCT 
                   
               
               
                   
                 CCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTTCTACTAGC 
                   
               
               
                   
                 GAATCTCCTTCTGGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACTGCT 
                   
               
               
                   
                 CCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGTACCTCTACTCCGGAA 
                   
               
               
                   
                 AGCGGTTCTGCATCTCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAACCCCAGG 
                   
               
               
                   
                 TACCTCTGAAAGCGCTACTCCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGA 
                   
               
               
                   
                 CTTCCACTGAGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACT 
                   
               
               
                   
                 TCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGAAGG 
                   
               
               
                   
                 TAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAG 
                   
               
               
                   
                 CAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGC 
                   
               
               
                   
                 GCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAG 
                   
               
               
                   
                 CGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGTC 
                   
               
               
                   
                 CAGGTACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCG 
                   
               
               
                   
                 TCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGG 
                   
               
               
                   
                 TACTTCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCGAACCTGCTACTTCTG 
                   
               
               
                   
                 GTTCTGAAACCCCAGGTAGCCCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTAGC 
                   
               
               
                   
                 TCTACCCCGTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTGCTTCT 
                   
               
               
                   
                 TCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTACCTCTACC 
                   
               
               
                   
                 GAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGC 
                   
               
               
                   
                 TCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCT 
                   
               
               
                   
                 CTCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAA 
                   
               
               
                   
                 GGTACTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTGCAAGCGCAAGCGGCGC 
                   
               
               
                   
                 GCCAAGCACGGGAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCC 
                   
               
               
                   
                 CGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT 
                   
               
               
                   
                 ACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCTACTAG 
                   
               
               
                   
                 CGAATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTAGCGGTGAATCTTCTACTGC 
                   
               
               
                   
                 ACCAGGTACCCCTGGCAGCGGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCCGTC 
                   
               
               
                   
                 TGGTGCTACTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCGGTACCGGCCCAGG 
                   
               
               
                   
                 TAGCGAACCGGCAACCTCCGGCTCTGAAACTCCAGGTACTTCTGAAAGCGCTACTC 
                   
               
               
                   
                 CGGAATCCGGCCCAGGTAGCGAACCGGCTACTTCCGGCTCTGAAACCCCAGGTTCC 
                   
               
               
                   
                 ACCAGCTCTACTGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACTGCAGAATC 
                   
               
               
                   
                 TCCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTAGCGAAC 
                   
               
               
                   
                 CGGCAACCTCTGGCTCTGAAACTCCAGGTAGCGAACCTGCAACCTCCGGCTCTGAA 
                   
               
               
                   
                 ACCCCAGGTACTTCTACTGAACCTTCTGAGGGCAGCGCACCAGGTTCTACCAGCTC 
                   
               
               
                   
                 TACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTC 
                   
               
               
                   
                 CAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTACTTCTACCGAACCGT 
                   
               
               
                   
                 CCGAAGGCAGCGCTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT 
                   
               
               
                   
                 ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTAGCTCTACTCCGTCTGGTGC 
                   
               
               
                   
                 AACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAGGTGCTTC 
                   
               
               
                   
                 CCCGGGCACCAGCTCTACTGGTTCTCCAGGTAGCGAACCTGCTACCTCCGGTTCTG 
                   
               
               
                   
                 AAACCCCAGGTACCTCTGAAAGCGCAACTCCGGAGTCTGGTCCAGGTAGCCCTGCA 
                   
               
               
                   
                 GGTTCTCCTACCTCCACTGAGGAAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCC 
                   
               
               
                   
                 CCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAGGTGCTTCCCCGGGCACC 
                   
               
               
                   
                 AGCTCTACTGGTTCTCCAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGG 
                   
               
               
                   
                 TACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCG 
                   
               
               
                   
                 AAGGTAGCGCACCA 
                   
               
               
                   
               
               
                 AE912 
                 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACCCCGGGTAGCGG 
                 212 
               
               
                   
                 TACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGG 
                   
               
               
                   
                 TGCTTCTCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTAC 
                   
               
               
                   
                 CTCTACTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCT 
                   
               
               
                   
                 CTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTCTCCGACTTCC 
                   
               
               
                   
                 ACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTAC 
                   
               
               
                   
                 TGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCTG 
                   
               
               
                   
                 GCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCT 
                   
               
               
                   
                 ACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGA 
                   
               
               
                   
                 AGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGT 
                   
               
               
                   
                 CTGAGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGG 
                   
               
               
                   
                 TAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCG 
                   
               
               
                   
                 AGGGTAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACT 
                   
               
               
                   
                 TCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGAAGG 
                   
               
               
                   
                 TAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAAC 
                   
               
               
                   
                 CGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGC 
                   
               
               
                   
                 GCACCAGGTACTTCTACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAG 
                   
               
               
                   
                 CGCAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGC 
                   
               
               
                   
                 CCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGC 
                   
               
               
                   
                 AACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAG 
                   
               
               
                   
                 GTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGTCT 
                   
               
               
                   
                 GAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTAC 
                   
               
               
                   
                 TTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTACTGAACCTTCCGAGG 
                   
               
               
                   
                 GCAGCGCTCCAGGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCT 
                   
               
               
                   
                 ACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCAC 
                   
               
               
                   
                 CGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTGAA 
                   
               
               
                   
                 AGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGAC 
                   
               
               
                   
                 TCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAA 
                   
               
               
                   
                 CCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA 
                   
               
               
                   
                 GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTAC 
                   
               
               
                   
                 TCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA 
                   
               
               
                   
                 GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGCAGGCTCTCCGACC 
                   
               
               
                   
                 TCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTC 
                   
               
               
                   
                 TACCGAACCGTCTGAGGGCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGT 
                   
               
               
                   
                 CTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAA 
                   
               
               
                   
                 AGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAAC 
                   
               
               
                   
                 CCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAAC 
                   
               
               
                   
                 CGTCCGAGGGCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAA 
                   
               
               
                   
                 GGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACCTC 
                   
               
               
                   
                 CGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTA 
                   
               
               
                   
                 GCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACT 
                   
               
               
                   
                 TCTACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTC 
                   
               
               
                   
                 TGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAAT 
                   
               
               
                   
                 CCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCG 
                   
               
               
                   
                 GCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAAC 
                   
               
               
                   
                 TCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAAC 
                   
               
               
                   
                 CTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA 
                   
               
               
                   
                 GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTAC 
                   
               
               
                   
                 TCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA 
                   
               
               
                   
               
               
                 AM1296 
                 GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCAGGTAGCGAACCGGCTACTTC 
                 213 
               
               
                   
                 CGGTTCTGAAACCCCAGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTT 
                   
               
               
                   
                 CTACCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGC 
                   
               
               
                   
                 TCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACT 
                   
               
               
                   
                 AGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCT 
                   
               
               
                   
                 TCTCCAGGTACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACCGGC 
                   
               
               
                   
                 AACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCCGGCC 
                   
               
               
                   
                 CAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGTACCTCTACTGAACCT 
                   
               
               
                   
                 TCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGG 
                   
               
               
                   
                 TACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCG 
                   
               
               
                   
                 AGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACT 
                   
               
               
                   
                 TCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACTTCTACCGAACCTTCCGAGGG 
                   
               
               
                   
                 CAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTG 
                   
               
               
                   
                 AAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACTGAACCTTCCGAAGGCAGC 
                   
               
               
                   
                 GCTCCAGGTACCTCTACCGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTGAAAG 
                   
               
               
                   
                 CGCAACCCCTGAATCCGGTCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTC 
                   
               
               
                   
                 CAGGTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGCCCGGCTGGCTCT 
                   
               
               
                   
                 CCGACCTCCACCGAGGAAGGTAGCTCTACCCCGTCTGGTGCTACTGGTTCTCCAGG 
                   
               
               
                   
                 TACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGC 
                   
               
               
                   
                 TACTGGCTCTCCAGGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT 
                   
               
               
                   
                 CTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCCGGTTCT 
                   
               
               
                   
                 GAAACTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTGAGGAAGGTAGCCCGGC 
                   
               
               
                   
                 TGGTTCTCCGACTTCTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCG 
                   
               
               
                   
                 CTCCAGGTCCAGAACCAACGGGGCCGGCCCCAAGCGGAGGTAGCGAACCGGCAAC 
                   
               
               
                   
                 CTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCCGGCCCAG 
                   
               
               
                   
                 GTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGTACTTCTGAAAGCGCTACT 
                   
               
               
                   
                 CCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAG 
                   
               
               
                   
                 CCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTGAAAGCGCTACTCCTG 
                   
               
               
                   
                 AGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCG 
                   
               
               
                   
                 GCTGGCTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCCT 
                   
               
               
                   
                 GGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTAG 
                   
               
               
                   
                 CGGTGAATCTTCTACTGCACCAGGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCC 
                   
               
               
                   
                 AGGTTCTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTACTTCTCCTAGCGGCG 
                   
               
               
                   
                 AATCTTCTACCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGT 
                   
               
               
                   
                 ACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCC 
                   
               
               
                   
                 TGAATCCGGTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAGGTACCT 
                   
               
               
                   
                 CTGAAAGCGCTACTCCGGAATCTGGTCCAGGTACTTCTGAAAGCGCTACTCCGGAA 
                   
               
               
                   
                 TCCGGTCCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGA 
                   
               
               
                   
                 AAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCG 
                   
               
               
                   
                 CACCAGGTACCTCCCCTAGCGGCGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCG 
                   
               
               
                   
                 GCGAATCTTCTACCGCTCCAGGTACCTCCCCTAGCGGTGAATCTTCTACCGCACCAG 
                   
               
               
                   
                 GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCT 
                   
               
               
                   
                 ACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTTC 
                   
               
               
                   
                 TAGCCCTTCTGCTTCCACCGGTACCGGCCCAGGTAGCTCTACTCCGTCTGGTGCAAC 
                   
               
               
                   
                 TGGCTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTAGCTCTAC 
                   
               
               
                   
                 CCCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGGTGCAACCGGCTC 
                   
               
               
                   
                 CCCAGGTGCATCCCCGGGTACTAGCTCTACCGGTTCTCCAGGTGCAAGCGCAAGCG 
                   
               
               
                   
                 GCGCGCCAAGCACGGGAGGTACTTCTCCGAGCGGTGAATCTTCTACCGCACCAGGT 
                   
               
               
                   
                 TCTACTAGCTCTACCGCTGAATCTCCGGGCCCAGGTACTTCTCCGAGCGGTGAATCT 
                   
               
               
                   
                 TCTACTGCTCCAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCT 
                   
               
               
                   
                 ACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTAG 
                   
               
               
                   
                 CGCACCAGGTTCTAGCCCTTCTGCATCTACTGGTACTGGCCCAGGTAGCTCTACTCC 
                   
               
               
                   
                 TTCTGGTGCTACCGGCTCTCCAGGTGCTTCTCCGGGTACTAGCTCTACCGGTTCTCC 
                   
               
               
                   
                 AGGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTACTTCTCCTAGCGGTG 
                   
               
               
                   
                 AATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACTGCTCCAGGTA 
                   
               
               
                   
                 CTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGC 
                   
               
               
                   
                 TCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTTCTAC 
                   
               
               
                   
                 CAGCGAATCCCCTTCTGGTACTGCTCCAGGTTCTACCAGCGAATCCCCTTCTGGCAC 
                   
               
               
                   
                 CGCACCAGGTACTTCTACCCCTGAAAGCGGCTCCGCTTCTCCAGGTAGCCCGGCAG 
                   
               
               
                   
                 GCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGC 
                   
               
               
                   
                 CCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTAGCCCTGCTGGCTC 
                   
               
               
                   
                 TCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAG 
                   
               
               
                   
                 GTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTAGCTCTACCCCGTCTGGT 
                   
               
               
                   
                 GCTACCGGTTCCCCAGGTGCTTCTCCTGGTACTAGCTCTACCGGTTCTCCAGGTAGC 
                   
               
               
                   
                 TCTACCCCGTCTGGTGCTACTGGCTCTCCAGGTTCTACTAGCGAATCCCCGTCTGGT 
                   
               
               
                   
                 ACTGCTCCAGGTACTTCCCCTAGCGGTGAATCTTCTACTGCTCCAGGTTCTACCAGC 
                   
               
               
                   
                 TCTACCGCAGAATCTCCGGGTCCAGGTAGCTCTACCCCTTCTGGTGCAACCGGCTCT 
                   
               
               
                   
                 CCAGGTGCATCCCCGGGTACCAGCTCTACCGGTTCTCCAGGTACTCCGGGTAGCGG 
                   
               
               
                   
                 TACCGCTTCTTCCTCTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTGAGGAAGG 
                   
               
               
                   
                 TAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGGTACTTCTACCGAACCTTCCGA 
                   
               
               
                   
                 AGGTAGCGCTCCA 
                   
               
               
                   
               
               
                 BC864 
                 GGTACTTCCACCGAACCATCCGAACCAGGTAGCGCAGGTACTTCCACCGAACCATC 
                 214 
               
               
                   
                 CGAACCTGGCAGCGCAGGTAGCGAACCGGCAACCTCTGGTACTGAACCATCAGGT 
                   
               
               
                   
                 AGCGGCGCATCCGAGCCTACCTCTACTGAACCAGGTAGCGAACCGGCTACCTCCGG 
                   
               
               
                   
                 TACTGAGCCATCAGGTAGCGAACCGGCAACTTCCGGTACTGAACCATCAGGTAGCG 
                   
               
               
                   
                 AACCGGCAACTTCCGGCACTGAACCATCAGGTAGCGGTGCATCTGAGCCGACCTCT 
                   
               
               
                   
                 ACTGAACCAGGTACTTCTACTGAACCATCTGAGCCGGGCAGCGCAGGTAGCGAACC 
                   
               
               
                   
                 AGCTACTTCTGGCACTGAACCATCAGGTACTTCTACTGAACCATCCGAACCAGGTA 
                   
               
               
                   
                 GCGCAGGTAGCGAACCTGCTACCTCTGGTACTGAGCCATCAGGTAGCGAACCGGCT 
                   
               
               
                   
                 ACCTCTGGTACTGAACCATCAGGTACTTCTACCGAACCATCCGAGCCTGGTAGCGC 
                   
               
               
                   
                 AGGTACTTCTACCGAACCATCCGAGCCAGGCAGCGCAGGTAGCGAACCGGCAACC 
                   
               
               
                   
                 TCTGGCACTGAGCCATCAGGTAGCGAACCAGCAACTTCTGGTACTGAACCATCAGG 
                   
               
               
                   
                 TACTAGCGAGCCATCTACTTCCGAACCAGGTGCAGGTAGCGGCGCATCCGAACCTA 
                   
               
               
                   
                 CTTCCACTGAACCAGGTACTAGCGAGCCATCCACCTCTGAACCAGGTGCAGGTAGC 
                   
               
               
                   
                 GAACCGGCAACTTCCGGCACTGAACCATCAGGTAGCGAACCGGCTACCTCTGGTAC 
                   
               
               
                   
                 TGAACCATCAGGTACTTCTACCGAACCATCCGAGCCTGGTAGCGCAGGTACTTCTA 
                   
               
               
                   
                 CCGAACCATCCGAGCCAGGCAGCGCAGGTAGCGGTGCATCCGAGCCGACCTCTACT 
                   
               
               
                   
                 GAACCAGGTAGCGAACCAGCAACTTCTGGCACTGAGCCATCAGGTAGCGAACCAG 
                   
               
               
                   
                 CTACCTCTGGTACTGAACCATCAGGTAGCGAACCGGCTACTTCCGGCACTGAACCA 
                   
               
               
                   
                 TCAGGTAGCGAACCAGCAACCTCCGGTACTGAACCATCAGGTACTTCCACTGAACC 
                   
               
               
                   
                 ATCCGAACCGGGTAGCGCAGGTAGCGAACCGGCAACTTCCGGCACTGAACCATCA 
                   
               
               
                   
                 GGTAGCGGTGCATCTGAGCCGACCTCTACTGAACCAGGTACTTCTACTGAACCATC 
                   
               
               
                   
                 TGAGCCGGGCAGCGCAGGTAGCGAACCTGCAACCTCCGGCACTGAGCCATCAGGT 
                   
               
               
                   
                 AGCGGCGCATCTGAACCAACCTCTACTGAACCAGGTACTTCCACCGAACCATCTGA 
                   
               
               
                   
                 GCCAGGCAGCGCAGGTAGCGGCGCATCTGAACCAACCTCTACTGAACCAGGTAGC 
                   
               
               
                   
                 GAACCAGCAACTTCTGGTACTGAACCATCAGGTAGCGGCGCATCTGAGCCTACTTC 
                   
               
               
                   
                 CACTGAACCAGGTAGCGAACCGGCAACTTCCGGCACTGAACCATCAGGTAGCGGT 
                   
               
               
                   
                 GCATCTGAGCCGACCTCTACTGAACCAGGTACTTCTACTGAACCATCTGAGCCGGG 
                   
               
               
                   
                 CAGCGCAGGTAGCGAACCGGCAACTTCCGGCACTGAACCATCAGGTAGCGGTGCA 
                   
               
               
                   
                 TCTGAGCCGACCTCTACTGAACCAGGTACTTCTACTGAACCATCTGAGCCGGGCAG 
                   
               
               
                   
                 CGCAGGTAGCGAACCAGCTACTTCTGGCACTGAACCATCAGGTACTTCTACTGAAC 
                   
               
               
                   
                 CATCCGAACCAGGTAGCGCAGGTAGCGAACCTGCTACCTCTGGTACTGAGCCATCA 
                   
               
               
                   
                 GGTACTTCTACTGAACCATCCGAGCCGGGTAGCGCAGGTACTTCCACTGAACCATC 
                   
               
               
                   
                 TGAACCTGGTAGCGCAGGTACTTCCACTGAACCATCCGAACCAGGTAGCGCAGGTA 
                   
               
               
                   
                 CTTCTACTGAACCATCCGAGCCGGGTAGCGCAGGTACTTCCACTGAACCATCTGAA 
                   
               
               
                   
                 CCTGGTAGCGCAGGTACTTCCACTGAACCATCCGAACCAGGTAGCGCAGGTACTAG 
                   
               
               
                   
                 CGAACCATCCACCTCCGAACCAGGCGCAGGTAGCGGTGCATCTGAACCGACTTCTA 
                   
               
               
                   
                 CTGAACCAGGTACTTCCACTGAACCATCTGAGCCAGGTAGCGCAGGTACTTCCACC 
                   
               
               
                   
                 GAACCATCCGAACCAGGTAGCGCAGGTACTTCCACCGAACCATCCGAACCTGGCA 
                   
               
               
                   
                 GCGCAGGTAGCGAACCGGCAACCTCTGGTACTGAACCATCAGGTAGCGGTGCATCC 
                   
               
               
                   
                 GAGCCGACCTCTACTGAACCAGGTAGCGAACCAGCAACTTCTGGCACTGAGCCATC 
                   
               
               
                   
                 AGGTAGCGAACCAGCTACCTCTGGTACTGAACCATCAGGTAGCGAACCGGCAACCT 
                   
               
               
                   
                 CTGGCACTGAGCCATCAGGTAGCGAACCAGCAACTTCTGGTACTGAACCATCAGGT 
                   
               
               
                   
                 ACTAGCGAGCCATCTACTTCCGAACCAGGTGCAGGTAGCGAACCTGCAACCTCCGG 
                   
               
               
                   
                 CACTGAGCCATCAGGTAGCGGCGCATCTGAACCAACCTCTACTGAACCAGGTACTT 
                   
               
               
                   
                 CCACCGAACCATCTGAGCCAGGCAGCGCAGGTAGCGAACCTGCAACCTCCGGCAC 
                   
               
               
                   
                 TGAGCCATCAGGTAGCGGCGCATCTGAACCAACCTCTACTGAACCAGGTACTTCCA 
                   
               
               
                   
                 CCGAACCATCTGAGCCAGGCAGCGCA 
                   
               
               
                   
               
               
                 BD864 
                 GGTAGCGAAACTGCTACTTCCGGCTCTGAGACTGCAGGTACTAGTGAATCCGCAAC 
                 215 
               
               
                   
                 TAGCGAATCTGGCGCAGGTAGCACTGCAGGCTCTGAGACTTCCACTGAAGCAGGTA 
                   
               
               
                   
                 CTAGCGAGTCCGCAACCAGCGAATCCGGCGCAGGTAGCGAAACTGCTACCTCTGGC 
                   
               
               
                   
                 TCCGAGACTGCAGGTAGCGAAACTGCAACCTCTGGCTCTGAAACTGCAGGTACTTC 
                   
               
               
                   
                 CACTGAAGCAAGTGAAGGCTCCGCATCAGGTACTTCCACCGAAGCAAGCGAAGGC 
                   
               
               
                   
                 TCCGCATCAGGTACTAGTGAGTCCGCAACTAGCGAATCCGGTGCAGGTAGCGAAAC 
                   
               
               
                   
                 CGCTACCTCTGGTTCCGAAACTGCAGGTACTTCTACCGAGGCTAGCGAAGGTTCTG 
                   
               
               
                   
                 CATCAGGTAGCACTGCTGGTTCCGAGACTTCTACTGAAGCAGGTACTAGCGAATCT 
                   
               
               
                   
                 GCTACTAGCGAATCCGGCGCAGGTACTAGCGAATCCGCTACCAGCGAATCCGGCGC 
                   
               
               
                   
                 AGGTAGCGAAACTGCAACCTCTGGTTCCGAGACTGCAGGTACTAGCGAGTCCGCTA 
                   
               
               
                   
                 CTAGCGAATCTGGCGCAGGTACTTCCACTGAAGCTAGTGAAGGTTCTGCATCAGGT 
                   
               
               
                   
                 AGCGAAACTGCTACTTCTGGTTCCGAAACTGCAGGTAGCGAAACCGCTACCTCTGG 
                   
               
               
                   
                 TTCCGAAACTGCAGGTACTTCTACCGAGGCTAGCGAAGGTTCTGCATCAGGTAGCA 
                   
               
               
                   
                 CTGCTGGTTCCGAGACTTCTACTGAAGCAGGTACTAGCGAGTCCGCTACTAGCGAA 
                   
               
               
                   
                 TCTGGCGCAGGTACTTCCACTGAAGCTAGTGAAGGTTCTGCATCAGGTAGCGAAAC 
                   
               
               
                   
                 TGCTACTTCTGGTTCCGAAACTGCAGGTAGCACTGCTGGCTCCGAGACTTCTACCG 
                   
               
               
                   
                 AAGCAGGTAGCACTGCAGGTTCCGAAACTTCCACTGAAGCAGGTAGCGAAACTGC 
                   
               
               
                   
                 TACCTCTGGCTCTGAGACTGCAGGTACTAGCGAATCTGCTACTAGCGAATCCGGCG 
                   
               
               
                   
                 CAGGTACTAGCGAATCCGCTACCAGCGAATCCGGCGCAGGTAGCGAAACTGCAAC 
                   
               
               
                   
                 CTCTGGTTCCGAGACTGCAGGTACTAGCGAATCTGCTACTAGCGAATCCGGCGCAG 
                   
               
               
                   
                 GTACTAGCGAATCCGCTACCAGCGAATCCGGCGCAGGTAGCGAAACTGCAACCTCT 
                   
               
               
                   
                 GGTTCCGAGACTGCAGGTAGCGAAACCGCTACCTCTGGTTCCGAAACTGCAGGTAC 
                   
               
               
                   
                 TTCTACCGAGGCTAGCGAAGGTTCTGCATCAGGTAGCACTGCTGGTTCCGAGACTT 
                   
               
               
                   
                 CTACTGAAGCAGGTAGCGAAACTGCTACTTCCGGCTCTGAGACTGCAGGTACTAGT 
                   
               
               
                   
                 GAATCCGCAACTAGCGAATCTGGCGCAGGTAGCACTGCAGGCTCTGAGACTTCCAC 
                   
               
               
                   
                 TGAAGCAGGTAGCACTGCTGGTTCCGAAACCTCTACCGAAGCAGGTAGCACTGCAG 
                   
               
               
                   
                 GTTCTGAAACCTCCACTGAAGCAGGTACTTCCACTGAGGCTAGTGAAGGCTCTGCA 
                   
               
               
                   
                 TCAGGTAGCACTGCTGGTTCCGAAACCTCTACCGAAGCAGGTAGCACTGCAGGTTC 
                   
               
               
                   
                 TGAAACCTCCACTGAAGCAGGTACTTCCACTGAGGCTAGTGAAGGCTCTGCATCAG 
                   
               
               
                   
                 GTAGCACTGCAGGTTCTGAGACTTCCACCGAAGCAGGTAGCGAAACTGCTACTTCT 
                   
               
               
                   
                 GGTTCCGAAACTGCAGGTACTTCCACTGAAGCTAGTGAAGGTTCCGCATCAGGTAC 
                   
               
               
                   
                 TAGTGAGTCCGCAACCAGCGAATCCGGCGCAGGTAGCGAAACCGCAACCTCCGGT 
                   
               
               
                   
                 TCTGAAACTGCAGGTACTAGCGAATCCGCAACCAGCGAATCTGGCGCAGGTACTAG 
                   
               
               
                   
                 TGAGTCCGCAACCAGCGAATCCGGCGCAGGTAGCGAAACCGCAACCTCCGGTTCTG 
                   
               
               
                   
                 AAACTGCAGGTACTAGCGAATCCGCAACCAGCGAATCTGGCGCAGGTAGCGAAAC 
                   
               
               
                   
                 TGCTACTTCCGGCTCTGAGACTGCAGGTACTTCCACCGAAGCAAGCGAAGGTTCCG 
                   
               
               
                   
                 CATCAGGTACTTCCACCGAGGCTAGTGAAGGCTCTGCATCAGGTAGCACTGCTGGC 
                   
               
               
                   
                 TCCGAGACTTCTACCGAAGCAGGTAGCACTGCAGGTTCCGAAACTTCCACTGAAGC 
                   
               
               
                   
                 AGGTAGCGAAACTGCTACCTCTGGCTCTGAGACTGCAGGTACTAGCGAATCTGCTA 
                   
               
               
                   
                 CTAGCGAATCCGGCGCAGGTACTAGCGAATCCGCTACCAGCGAATCCGGCGCAGG 
                   
               
               
                   
                 TAGCGAAACTGCAACCTCTGGTTCCGAGACTGCAGGTAGCGAAACTGCTACTTCCG 
                   
               
               
                   
                 GCTCCGAGACTGCAGGTAGCGAAACTGCTACTTCTGGCTCCGAAACTGCAGGTACT 
                   
               
               
                   
                 TCTACTGAGGCTAGTGAAGGTTCCGCATCAGGTACTAGCGAGTCCGCAACCAGCGA 
                   
               
               
                   
                 ATCCGGCGCAGGTAGCGAAACTGCTACCTCTGGCTCCGAGACTGCAGGTAGCGAA 
                   
               
               
                   
                 ACTGCAACCTCTGGCTCTGAAACTGCAGGTACTAGCGAATCTGCTACTAGCGAATC 
                   
               
               
                   
                 CGGCGCAGGTACTAGCGAATCCGCTACCAGCGAATCCGGCGCAGGTAGCGAAACT 
                   
               
               
                   
                 GCAACCTCTGGTTCCGAGACTGCA 
               
               
                   
               
            
           
         
       
     
     One may clone the library of XTEN-encoding genes into one or more expression vectors known in the art. To facilitate the identification of well-expressing library members, one can construct the library as fusion to a reporter protein. Non-limiting examples of suitable reporter genes are green fluorescent protein, luciferace, alkaline phosphatase, and beta-galactosidase. By screening, one can identify short XTEN sequences that can be expressed in high concentration in the host organism of choice. Subsequently, one can generate a library of random XTEN dimers and repeat the screen for high level of expression. Subsequently, one can screen the resulting constructs for a number of properties such as level of expression, protease stability, or binding to antiserum. 
     One aspect of the invention is to provide polynucleotide sequences encoding the components of the fusion protein wherein the creation of the sequence has undergone codon optimization. Of particular interest is codon optimization with the goal of improving expression of the polypeptide compositions and to improve the genetic stability of the encoding gene in the production hosts. For example, codon optimization is of particular importance for XTEN sequences that are rich in glycine or that have repetitive amino acid sequences. Codon optimization can be performed using computer programs (Gustafsson, C., et al. (2004)  Trends Biotechnol,  22: 346-53), some of which minimize ribosomal pausing (Coda Genomics Inc.). In one embodiment, one can perform codon optimization by constructing codon libraries where all members of the library encode the same amino acid sequence but where codon usage is varied. Such libraries can be screened for highly expressing and genetically stable members that are particularly suitable for the large-scale production of XTEN-containing products. When designing XTEN sequences one can consider a number of properties. One can minimize the repetitiveness in the encoding DNA sequences. In addition, one can avoid or minimize the use of codons that are rarely used by the production host (e.g. the AGG and AGA arginine codons and one leucine codon in  E. coli ). In the case of  E. coli , two glycine codons, GGA and GGG, are rarely used in highly expressed proteins. Thus codon optimization of the gene encoding XTEN sequences can be very desirable. DNA sequences that have a high level of glycine tend to have a high GC content that can lead to instability or low expression levels. Thus, when possible, it is preferred to choose codons such that the GC-content of XTEN-encoding sequence is suitable for the production organism that will be used to manufacture the XTEN. 
     Optionally, the full-length XTEN-encoding gene may comprise one or more sequencing islands. In this context, sequencing islands are short-stretch sequences that are distinct from the XTEN library construct sequences and that include a restriction site not present or expected to be present in the full-length XTEN-encoding gene. In one embodiment, a sequencing island is the sequence 5′-AGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGT-3′ (SEQ ID NO: 216). In another embodiment, a sequencing island is the sequence 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 217) 
               
               
                   
                 5′-AGGTCCAGAACCAACGGGGCCGGCCCCAAGCGGAGGT-3′. 
               
            
           
         
       
     
     As an alternative, one can construct codon libraries where all members of the library encode the same amino acid sequence but where codon usage is varied. Such libraries can be screened for highly expressing and genetically stable members that are particularly suitable for the large-scale production of XTEN-containing products. 
     Optionally, one can sequence clones in the library to eliminate isolates that contain undesirable sequences. The initial library of short XTEN sequences can allow some variation in amino acid sequence. For instance one can randomize some codons such that a number of hydrophilic amino acids can occur in a particular position. 
     During the process of iterative multimerization one can screen the resulting library members for other characteristics like solubility or protease resistance in addition to a screen for high-level expression. 
     In one embodiment of a construct encoding a binding fusion protein, once the gene that encodes the XTEN of desired length and properties is selected, it is genetically fused to the nucleotides encoding the N- and/or the C-terminus of the targeting moiety gene(s) by cloning it into the construct adjacent and in frame with the gene coding for the targeting moiety or adjacent to a linker sequence. The invention provides various permutations of the foregoing, depending on the binding fusion protein to be encoded. For example, a gene encoding a binding fusion protein comprising two targeting moieties such as embodied by formula II, as depicted above, would have polynucleotides encoding two targeting moieties, a linker, at least a first XTEN, and optionally a second XTEN. The step of cloning the targeting moiety genes into the XTEN construct can occur through a ligation or multimerization step. As shown in  FIG. 6A - FIG. 6D , the constructs encoding binding fusion proteins can be designed in different configurations of the components; e.g., XTEN  205 , VL  202 , VH  204  and linker sequences  203  or  206 . In one embodiment, as illustrated in  FIG. 6A , the construct comprises polynucleotide sequences complementary to, or those that encode a monomeric polypeptide of components in the following order (5′ to 3′) VL  202 , linker  203 , VH  204 , and XTEN  205 , or the reverse order. As will be apparent to those of skill in the art, in view of the disclosure and  FIG. 6A - FIG. 6D , other permutations or combinations of the foregoing are possible. 
     The invention also encompasses polynucleotides comprising XTEN-encoding polynucleotide variants that have a high percentage of sequence identity to (a) a polynucleotide sequence from Table 10, or (b) sequences that are complementary to the polynucleotides of (a). A polynucleotide with a high percentage of sequence identity is one that has at least about an 80% nucleic acid sequence identity, alternatively at least about 81%, alternatively at least about 82%, alternatively at least about 83%, alternatively at least about 84%, alternatively at least about 85%, alternatively at least about 86%, alternatively at least about 87%, alternatively at least about 88%, alternatively at least about 89%, alternatively at least about 90%, alternatively at least about 91%, alternatively at least about 92%, alternatively at least about 93%, alternatively at least about 94%, alternatively at least about 95%, alternatively at least about 96%, alternatively at least about 97%, alternatively at least about 98%, and alternatively at least about 99% nucleic acid sequence identity to (a) or (b) of the foregoing, or that can hybridize with the target polynucleotide or its complement under stringent conditions. 
     Homology, sequence similarity or sequence identity of nucleotide or amino acid sequences may also be determined conventionally by using known software or computer programs such as the BestFit or Gap pairwise comparison programs (GCG Wisconsin Package, Genetics Computer Group, 575 Science Drive, Madison, Wis. 53711). BestFit uses the local homology algorithm of Smith and Waterman (Advances in Applied Mathematics. 1981. 2: 482-489), to find the best segment of identity or similarity between two sequences. Gap performs global alignments: all of one sequence with all of another similar sequence using the method of Needleman and Wunsch, (Journal of Molecular Biology. 1970. 48:443-453). When using a sequence alignment program such as BestFit, to determine the degree of sequence homology, similarity or identity, the default setting may be used, or an appropriate scoring matrix may be selected to optimize identity, similarity or homology scores. 
     Nucleic acid sequences that are “complementary” are those that are capable of base-pairing according to the standard Watson-Crick complementarity rules. As used herein, the term “complementary sequences” means nucleic acid sequences that are substantially complementary, as may be assessed by the same nucleotide comparison set forth above, or as defined as being capable of hybridizing to the polynucleotides that encode the binding fusion protein sequences under stringent conditions, such as those described herein. 
     The resulting polynucleotides encoding the binding fusion protein chimeric compositions can then be individually cloned into an expression vector. The nucleic acid sequence may be inserted into the vector by a variety of procedures. In general, DNA is inserted into an appropriate restriction endonuclease site(s) using techniques known in the art. Vector components generally include, but are not limited to, one or more of a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Construction of suitable vectors containing one or more of these components employs standard ligation techniques that are known to the skilled artisan. Such techniques are well known in the art and well described in the scientific and patent literature. 
     Various vectors are publicly available. The vector may, for example, be in the form of a plasmid, cosmid, viral particle, or phage. Both expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Such vector sequences are well known for a variety of bacteria, yeast, and viruses. Useful expression vectors that can be used include, for example, segments of chromosomal, non-chromosomal and synthetic DNA sequences. Suitable vectors include, but are not limited to, derivatives of SV40 and pcDNA and known bacterial plasmids such as col EI, pCR1, pBR322, pMal-C2, pET, pGEX as described by Smith, et al.,  Gene  57:31-40 (1988), pMB9 and derivatives thereof, plasmids such as RP4, phage DNAs such as the numerous derivatives of phage I such as NM98 9, as well as other phage DNA such as M13 and filamentous single stranded phage DNA; yeast plasmids such as the 2 micron plasmid or derivatives of the 2 m plasmid, as well as centomeric and integrative yeast shuttle vectors; vectors useful in eukaryotic cells such as vectors useful in insect or mammalian cells; vectors derived from combinations of plasmids and phage DNAs, such as plasmids that have been modified to employ phage DNA or the expression control sequences; and the like. The requirements are that the vectors are replicable and viable in the host cell of choice. Low- or high-copy number vectors may be used as desired. 
     Promoters suitable for use in expression vectors with prokaryotic hosts include the β-lactamase and lactose promoter systems [Chang et al., Nature, 275:615 (1978); Goeddel et al., Nature, 281:544 (1979)], alkaline phosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic Acids Res., 8:4057 (1980); EP 36,776], and hybrid promoters such as the tac promoter [deBoer et al., Proc. Natl. Acad. Sci. USA, 80:21-25 (1983)]. Promoters for use in bacterial systems can also contain a Shine-Dalgarno (S.D.) sequence operably linked to the DNA encoding binding fusion protein. 
     For example, in a baculovirus expression system, both non-fusion transfer vectors, such as, but not limited to pVL941 (BamHI cloning site, available from Summers, et al., Virology 84:390-402 (1978)), pVL1393 (BamHI, Smal, Xbal, EcoRI, IVotl, Xmalll, BgIII and Pstl cloning sites; Invitrogen), pVL1392 (BgIII, Pstl, NotI, XmaIII, EcoRI, Xball, Smal and BamHI cloning site; Summers, et al., Virology 84:390-402 (1978) and Invitrogen) and pBlueBacIII (BamHI, BgIII, Pstl, Ncol and Hindi II cloning site, with blue/white recombinant screening, Invitrogen), and fusion transfer vectors such as, but not limited to, pAc7 00 (BamHI and KpnI cloning sites, in which the BamHI recognition site begins with the initiation codon; Summers, et al.,  Virology  84:390-402 (1978)), pAc701 and pAc70-2 (same as pAc700, with different reading frames), pAc360 [BamHI cloning site 36 base pairs downstream of a polyhedrin initiation codon; Invitrogen (1995)) and pBlueBacHisA, B, C (three different reading frames with BamH I, BgI II, Pstl, Nco 1 and Hind III cloning site, an N-terminal peptide for ProBond purification and blue/white recombinant screening of plaques; Invitrogen ( 220 ) can be used. 
     Schematics of exemplary plasmids containing one or more of the components described above are illustrated in  FIG. 10A - FIG. 10D . 
     Mammalian expression vectors can comprise an origin of replication, a suitable promoter and enhancer, and also any necessary ribosome binding sites, polyadenylation site, splice donor and acceptor sites, transcriptional termination sequences, and 5′ flanking nontranscribed sequences. DNA sequences derived from the SV40 splice, and polyadenylation sites may be used to provide the required nontranscribed genetic elements. Mammalian expression vectors contemplated for use in the invention include vectors with inducible promoters, such as the dihydrofolate reductase promoters, any expression vector with a DHFR expression cassette or a DHFR/methotrexate co-amplification vector such as pED (Pstl, Sail, Sbal, Smal and EcoRI cloning sites, with the vector expressing both the cloned gene and DHFR; Randal J. Kaufman, 1991, Randal J. Kaufman, Current Protocols in Molecular Biology, 16,12 (1991)). Alternatively a glutamine synthetase/methionine sulfoximine co-amplification vector, such as pEE14 (Hindlll, Xball, Smal, Sbal, EcoRI and Sell cloning sites in which the vector expresses glutamine synthetase and the cloned gene; Celltech). A vector that directs episomal expression under the control of the Epstein Barr Virus (EBV) or nuclear antigen (EBNA) can be used such as pREP4 (BamHI r SfH, Xhol, NotI, Nhel, Hindi II, NheI, PvuII and KpnI cloning sites, constitutive RSV-LTR promoter, hygromycin selectable marker; Invitrogen), pCEP4 (BamHI, SfH, Xhol, NotI, Nhel, Hindlll, Nhel, PvuII and KpnI cloning sites, constitutive hCMV immediate early gene promoter, hygromycin selectable marker; Invitrogen), pMEP4 (.KpnI, Pvul, Nhel, Hindlll, NotI, Xhol, Sfil, BamHI cloning sites, inducible methallothionein H a gene promoter, hygromycin selectable marker, Invitrogen), pREP8 (BamHI, Xhol, NotI, Hindlll, Nhel and KpnI cloning sites, RSV-LTR promoter, histidinol selectable marker; Invitrogen), pREP9 (KpnI, Nhel, Hind lll, NotI, Xho l, Sfi l, BamH I cloning sites, RSV-LTR promoter, G418 selectable marker; Invitrogen), and pEBVHis (RSV-LTR promoter, hygromycin selectable marker, N-terminal peptide purifiable via ProBond resin and cleaved by enterokinase; Invitrogen). 
     Selectable mammalian expression vectors for use in the invention include, but are not limited to, pRc/CMV (Hind 111, BstXI, NotI, Sbal and Apal cloning sites, G418 selection, Invitrogen), pRc/RSV (Hind II, Spel, BstXI, NotI, Xbal cloning sites, G418 selection, Invitrogen) and the like. Vaccinia virus mammalian expression vectors (see, for example, Randall J. Kaufman,  Current Protocols in Molecular Biology  16.12 (Frederick M. Ausubel, et al., eds. Wiley 1991) that can be used in the present invention include, but are not limited to, pSC11 (Smal cloning site, TK- and beta-gal selection), pMJ601 (Sal 1, Sma 1, A flI, Narl, BspMII, BamHI, Apal, Nhel, SacII, KpnI and Hindlll cloning sites; TK- and -gal selection), pTKgptFlS (EcoRI, Pstl, SaIII, Accl, HindII, Sbal, BamHI and Hpa cloning sites, TK or XPRT selection) and the like. 
     Yeast expression systems that can also be used in the present invention include, but are not limited to, the non-fusion pYES2 vector (XJbal, Sphl, Shol, NotI, GstXI, EcoRI, BstXI, BamHI, Sad, KpnI and Hindlll cloning sites, Invitrogen), the fusion pYESHisA, B, C (Xball, Sphl, Shol, NotI, BstXI, EcoRI, BamHI, Sad, KpnI and Hindi II cloning sites, N-terminal peptide purified with ProBond resin and cleaved with enterokinase; Invitrogen), pRS vectors and the like. 
     In addition, the expression vector containing the chimeric binding fusion protein-encoding polynucleotide molecule may include drug selection markers. Such markers aid in cloning and in the selection or identification of vectors containing chimeric DNA molecules. For example, genes that confer resistance to neomycin, puromycin, hygromycin, dihydrofolate reductase (DHFR) inhibitor, guanine phosphoribosyl transferase (GPT), zeocin, and histidinol are useful selectable markers. Alternatively, enzymes such as herpes simplex virus thymidine kinase (tk) or chloramphenicol acetyltransferase (CAT) may be employed. Immunologic markers also can be employed. Any known selectable marker may be employed so long as it is capable of being expressed simultaneously with the nucleic acid encoding a gene product. Further examples of selectable markers are well known to one of skill in the art and include reporters such as enhanced green fluorescent protein (EGFP), beta-galactosidase (β-gal) or chloramphenicol acetyltransferase (CAT). 
     In one embodiment, the polynucleotide encoding a binding fusion protein composition can be fused C-terminally to an N-terminal signal sequence appropriate for the expression host system. Signal sequences are typically proteolytically removed from the protein during the translocation and secretion process, generating a defined N-terminus. A wide variety of signal sequences have been described for most expression systems, including bacterial, yeast, insect, and mammalian systems. A non-limiting list of preferred examples for each expression system follows herein. Preferred signal sequences are OmpA, PhoA, and DsbA for  E. coli  expression. Signal peptides preferred for yeast expression are ppL-alpha, DEX4, invertase signal peptide, acid phosphatase signal peptide, CPY, or INU1. For insect cell expression the preferred signal sequences are sexta adipokinetic hormone precursor, CP1, CP2, CP3, CP4, TPA, PAP, or gp67. For mammalian expression the preferred signal sequences are IL2 L, SV40, IgG kappa and IgG lambda. 
     In another embodiment, a leader sequence, potentially comprising a well-expressed, independent protein domain, can be fused to the N-terminus of the binding fusion protein sequence, separated by a protease cleavage site. While any leader peptide sequence that does not inhibit cleavage at the designed proteolytic site can be used, sequences in preferred embodiments will comprise stable, well-expressed sequences such that expression and folding of the overall composition is not significantly adversely affected, and preferably expression, solubility, and/or folding efficiency are significantly improved. A wide variety of suitable leader sequences have been described in the literature. A non-limiting list of suitable sequences includes maltose binding protein, cellulose binding domain, glutathione S-transferase, 6×His tag (SEQ ID NO: 218), FLAG tag, hemaglutinin tag, and green fluorescent protein. The leader sequence can also be further improved by codon optimization, especially in the second codon position following the ATG start codon, by methods well described in the literature and hereinabove. 
     Various in vitro enzymatic methods for cleaving proteins at specific sites are known. Such methods include use of enterokinase (DDDK) (SEQ ID NO: 219), Factor Xa (IDGR) (SEQ ID NO: 880), thrombin (LVPRGS) (SEQ ID NO: 220), PreScission™ (LEVLFQGP) (SEQ ID NO: 221), TEV protease (EQLYFQG) (SEQ ID NO: 222), 3C protease (ETLFQGP) (SEQ ID NO: 223), Sortase A (LPETG) (SEQ ID NO: 224), Granzyme B (D/X, N/X, M/N or S/X), inteins, SUMO, DAPase (TAGZyme™), Aeromonas aminopeptidase, Aminopeptidase M, and carboxypeptidases A and B. Additional methods are disclosed in Arnau, et al., Protein Expression and Purification 48: 1-13 (2006). 
     In other embodiments, an optimized polynucleotide sequence encoding at least about 20 to about 60 amino acids with XTEN characteristics can be included at the N-terminus of the XTEN sequence to promote the initiation of translation to allow for expression of XTEN fusions at the N-terminus of proteins without the presence of a helper domain. In an advantage of the foregoing, the sequence does not require subsequent cleavage, thereby reducing the number of steps to manufacture XTEN-containing compositions. As described in more detail in the Examples, the optimized N-terminal sequence has attributes of an unstructured protein, but may include nucleotide bases encoding amino acids selected for their ability to promote initiation of translation and enhanced expression. In one embodiment of the foregoing, the optimized polynucleotide encodes an XTEN sequence with at least about 90% sequence identity to AE624. In another embodiment of the foregoing, the optimized polynucleotide encodes an XTEN sequence with at least about 90% sequence identity to AE912. In yet another embodiment of the foregoing, the optimized polynucleotide encodes an XTEN sequence with at least about 90% sequence identity to AM923. 
     In another embodiment, the protease site of the leader sequence construct is chosen such that it is recognized by an in vivo protease. In this embodiment, the protein is purified from the expression system while retaining the leader by avoiding contact with an appropriate protease. The full-length construct is then injected into a patient. Upon injection, the construct comes into contact with the protease specific for the cleavage site and is cleaved by the protease. In the case where the uncleaved protein is substantially less active than the cleaved form, this method has the beneficial effect of allowing higher initial doses while avoiding toxicity, as the active form is generated slowly in vivo. Some non-limiting examples of in vivo proteases which are useful for this application include tissue FXIa, FXIIa, kallikrein, FVIIa, FIXa, FXa, FIIa (thrombin), Elastase-2, granzyme B, MMP-12, MMP-13, MMP-17 or MMP-20, or by non-mammalian proteases such as TEV, enterokinase, PreScission™ protease (rhinovirus 3C protease), and sortase A. 
     In this manner, a chimeric DNA molecule coding for a monomeric binding fusion protein is generated within the construct. Optionally, this chimeric DNA molecule may be transferred or cloned into another construct that is a more appropriate expression vector. At this point, a host cell capable of expressing the chimeric DNA molecule can be transformed with the chimeric DNA molecule. The vectors containing the DNA segments of interest can be transferred into the host cell by well-known methods, depending on the type of cellular host. For example, calcium chloride transfection is commonly utilized for prokaryotic cells, whereas calcium phosphate treatment, lipofection, or electroporation may be used for other cellular hosts. Other methods used to transform mammalian cells include the use of polybrene, protoplast fusion, liposomes, electroporation, and microinjection. See, generally, Sambrook, et al., supra. 
     The transformation may occur with or without the utilization of a carrier, such as an expression vector. Then, the transformed host cell is cultured under conditions suitable for expression of the chimeric DNA molecule encoding the binding fusion protein. 
     The present invention also provides a host cell for expressing the monomeric fusion protein compositions disclosed herein. Examples of suitable eukaryotic host cells include, but are not limited to mammalian cells, such as VERO cells, HELA cells such as ATCC No. CCL2, CHO cell lines, COS cells, WI38 cells, BHK cells, HepG2 cells, 3T3 cells, A549 cells, PC12 cells, K562 cells, 293 cells, Sf9 cells and CvI cells. Examples of suitable non-mammalian eukaryotic cells include eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for encoding vectors.  Saccharomyces cerevisiae  is a commonly used lower eukaryotic host microorganism. Others include  Schizosaccharomyces pombe  (Beach and Nurse,  Nature,  290: 140 [1981]; EP 139,383 published 2 May 1985);  Kluyveromyces  hosts (U.S. Pat. No. 4,943,529; Fleer et al., Bio/Technology, 9:968-975 (1991)) such as, e.g.,  K. lactis  (MW98-8C, CBS683, CBS4574; Louvencourt et al., J. Bacteriol., 737 [1983]),  K. fragilis  (ATCC 12,424),  K. bulgaricus  (ATCC 16,045), K wickeramii (ATCC 24,178),  K. waltii  (ATCC 56,500), K  drosophilarum  (ATCC 36,906; Van den Berg et al.,  Bio/Technology,  8:135 (1990)),  K thermotolerans , and  K marxianus; yarrowia  (EP 402,226);  Pichia pastoris  (EP 183,070; Sreekrishna et al.,  J. Basic Microbiol.,  28:265-278 [1988]);  Candida; Trichoderma  reesia (EP 244,234);  Neurospora crassa  (Case et al., Proc. Natl. Acad. Sci. USA, 76:5259-5263 [1979]);  Schwanniomyces  such as  Schwanniomyces occidentalis  (EP 394,538 published 31 Oct. 1990); and filamentous fungi such as, e.g.,  Neurospora, Penicillium, Tolypocladium  (WO 91/00357 published 10 Jan. 1991), and  Aspergillus  hosts such as  A. nidulans  (Ballance et al., Biochem. Biophys. Res. Commun., 112:284-289 [1983]; Tilburn et al., Gene, 26:205-221 [1983]; Yelton et al., Proc. Natl. Acad. Sci. USA, 81: 1470-1474 [1984]) and  A. niger  (Kelly and Hynes, EMBO J., 4:475-479 [1985]). Methylotropic yeasts are suitable herein and include, but are not limited to, yeast capable of growth on methanol selected from the genera consisting of  Hansenula, Candida, Kloeckera, Pichia, Saccharomyces, Torulopsis , and  Rhodotorula . A list of specific species that are exemplary of this class of yeasts may be found in C. Anthony, The Biochemistry of Methylotrophs, 269 (1982). 
     Other suitable cells that can be used in the present invention include, but are not limited to, prokaryotic host cells strains such as  Escherichia coli , (e.g., strain DH5-α),  Bacillus subtilis, Salmonella typhimurium , or strains of the genera of  Pseudomonas, Streptomyces  and  Staphylococcus . Non-limiting examples of suitable prokaryotes include those from the genera:  Actinoplanes; Archaeoglobus; Bdellovibrio; Borrelia; Chloroflexus; Enterococcus; Escherichia; Lactobacillus; Listeria; Oceanobacillus; Paracoccus; Pseudomonas; Staphylococcus; Streptococcus; Streptomyces; Thermoplasma ; and  Vibrio . Non-limiting examples of specific strains include:  Archaeoglobus fulgidus; Bdellovibrio bacteriovorus; Borrelia burgdorferi; Chloroflexus aurantiacus; Enterococcus faecalis; Enterococcus faecium; Lactobacillus johnsonii; Lactobacillus plantarum; Lactococcus lactis; Listeria innocua; Listeria monocytogenes; Oceanobacillus iheyensis; Paracoccus zeaxanthinifaciens; Pseudomonas mevalonii; Staphylococcus aureus; Staphylococcus epidermidis; Staphylococcus haemolyticus; Streptococcus agalactiae; Streptomyces griseolosporeus; Streptococcus mutans; Streptococcus pneumoniae; Streptococcus pyogenes; Thermoplasma acidophilum; Thermoplasma volcanium; Vibrio cholerae; Vibrio parahaemolyticus ; and  Vibrio vulnificus.    
     Host cells containing the polynucleotides of interest can be cultured in conventional nutrient media (e.g., Ham&#39;s nutrient mixture) modified as appropriate for activating promoters, selecting transformants or amplifying genes. The culture conditions, such as temperature, pH and the like, are those previously used with the host cell selected for expression, and will be apparent to the ordinarily skilled artisan. Cells are typically harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification. For compositions secreted by the host cells, supernatant from centrifugation is separated and retained for further purification. Microbial cells employed in expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents, all of which are well known to those skilled in the art. Embodiments that involve cell lysis may entail use of a buffer that contains protease inhibitors that limit degradation after expression of the chimeric DNA molecule. Suitable protease inhibitors include, but are not limited to leupeptin, pepstatin or aprotinin. The supernatant then may be precipitated in successively increasing concentrations of saturated ammonium sulfate. 
     Gene expression may be measured in a sample directly, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA [Thomas, Proc. Natl. Acad. Sci. USA, 77:5201-5205 (1980)], dot blotting (DNA analysis), or in situ hybridization, using an appropriately labeled probe, based on the sequences provided herein. Alternatively, antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected. 
     Gene expression, alternatively, may be measured by immunological of fluorescent methods, such as immunohistochemical staining of cells or tissue sections and assay of cell culture or body fluids or the detection of selectable markers, to quantitate directly the expression of gene product. Antibodies useful for immunohistochemical staining and/or assay of sample fluids may be either monoclonal or polyclonal, and may be prepared in any mammal. Conveniently, the antibodies may be prepared against a native sequence polypeptide or against a synthetic peptide based on the DNA sequences provided herein or against exogenous sequence fused to targeting moieties and encoding a specific epitope. Examples of selectable markers are well known to one of skill in the art and include reporters such as enhanced green fluorescent protein (EGFP), beta-galactosidase (β-gal) or chloramphenicol acetyltransferase (CAT). 
     Expressed binding fusion protein product(s) may be purified via methods known in the art or by methods disclosed herein. Procedures such as gel filtration, affinity purification, salt fractionation, ion exchange chromatography, size exclusion chromatography, hydroxyapatite adsorption chromatography, hydrophobic interaction chromatography and gel electrophoresis may be used; each tailored to recover and purify the fusion protein produced by the respective host cells. Some expressed binding fusion protein may require refolding during isolation and purification. Methods of purification are described in Robert K. Scopes, Protein Purification: Principles and Practice, Charles R. Castor (ed.), Springer-Verlag 1994, and Sambrook, et al., supra. Multi-step purification separations are also described in Baron, et al., Crit. Rev. Biotechnol. 10:179-90 (1990) and Below, et al., J. Chromatogr. A. 679:67-83 (1994). 
     IV). Pharmaceutical Compositions 
     The present invention provides pharmaceutical compositions comprising binding fusion proteins, XTEN-drug conjugates, or BFP-D conjugates. In one embodiment, the pharmaceutical composition comprises the binding fusion protein and at least one pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprises the BFP-D and at least one pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprises the XTEN-drug conjugate and at least one pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the polypeptide is combined in admixture with a pharmaceutically acceptable carrier vehicle, such as aqueous solutions or buffers, pharmaceutically acceptable suspensions and emulsions. Examples of non-aqueous solvents include propyl ethylene glycol, polyethylene glycol and vegetable oils. Therapeutic formulations are prepared for storage by mixing the active ingredient having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers, as described in Remington&#39;s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980), in the form of lyophilized formulations or aqueous solutions. In addition, the pharmaceutical compositions can also contain other pharmaceutically active compounds or a plurality of compositions of the invention. 
     The pharmaceutical compositions may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including transdermal, aerosol, buccal and sublingual), vaginal, parenteral (including subcutaneous, subcutaneous by infusion pump, intramuscular, intravenous and intradermal), intravitreal, and pulmonary. It will also be appreciated that the preferred route will vary with the condition and age of the recipient, and the disease being treated. 
     In preferred embodiments, the pharmaceutical composition is administered parenterally. In this embodiment, the composition may be supplied as a lyophilized powder to be reconstituted prior to administration. The composition may also be supplied in a liquid form, which can be administered directly to a patient. In one embodiment, the composition is supplied as a liquid in a pre-filled syringe such that a patient can easily self-administer the composition. 
     The compositions of the invention may be formulated using a variety of excipients. Suitable excipients include microcrystalline cellulose (e.g. Avicel PH102, Avicel PH101), polymethacrylate, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) (such as Eudragit RS-30D), hydroxypropyl methylcellulose (Methocel KlOOM, Premium CR Methocel KlOOM, Methocel E5, Opadry®), magnesium stearate, talc, triethyl citrate, aqueous ethylcellulose dispersion (Surelease®), and protamine sulfate. The slow release agent may also comprise a carrier, which can comprise, for example, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. Pharmaceutically acceptable salts can also be used in these slow release agents, for example, mineral salts such as hydrochlorides, hydrobromides, phosphates, or sulfates, as well as the salts of organic acids such as acetates, proprionates, malonates, or benzoates. The composition may also contain liquids, such as water, saline, glycerol, and ethanol, as well as substances such as wetting agents, emulsifying agents, or pH buffering agents. Liposomes may also be used as a carrier. 
     For liquid formulations, a desired property is that the formulation be supplied in a form that can pass through a 25, 28, 30, 31, 32 gauge needle for intravenous, intramuscular, intraarticular, or subcutaneous administration. Syringe pumps may also be used to delivery the pharmaceutical compositions of the invention. Such devices are described in U.S. Pat. Nos. 4,976,696; 4,933,185; 5,017,378; 6,309,370; 6,254,573; 4,435,173; 4,398,908; 6,572,585; 5,298,022; 5,176,502; 5,492,534; 5,318,540; and 4,988,337, the contents of which are incorporated herein by reference. One skilled in the art, considering both the disclosure of this invention and the disclosures of these other patents could produce a syringe pump for the extended release of the compositions of the present invention. 
     Administration via transdermal formulations can be performed using methods also known in the art, including those described generally in, e.g., U.S. Pat. Nos. 5,186,938 and 6,183,770, 4,861,800, 6,743,211, 6,945,952, 4,284,444, and WO 89/09051, incorporated herein by reference in their entireties. A transdermal patch is a particularly useful embodiment with polypeptides having absorption problems. Patches can be made to control the release of skin-permeable active ingredients over a 12 hour, 24 hour, 3 day, and 7 day period. In one example, a 2-fold daily excess of a polypeptide of the present invention is placed in a non-volatile fluid. The compositions of the invention are provided in the form of a viscous, non-volatile liquid. The penetration through skin of specific formulations may be measures by standard methods in the art (for example, Franz et al., J. Invest. Derm. 64:194-195 (1975)). Examples of suitable patches are passive transfer skin patches, iontophoretic skin patches, or patches with microneedles such as Nicoderm. 
     In other embodiments, the composition may be delivered via intranasal, buccal, or sublingual routes to the brain to enable transfer of the active agents through the olfactory passages into the CNS and reducing the systemic administration. Devices commonly used for this route of administration are included in U.S. Pat. No. 6,715,485. Compositions delivered via this route may enable increased CNS dosing or reduced total body burden reducing systemic toxicity risks associated with certain drugs. Preparation of a pharmaceutical composition for delivery in a subdermally implantable device can be performed using methods known in the art, such as those described in, e.g., U.S. Pat. Nos. 3,992,518; 5,660,848; and 5,756,115. 
     V). Pharmaceutical Kits 
     In another aspect, the invention provides a kit to facilitate the use of the composition embodiments disclosed herein. In one embodiment, the kit comprises, in at least a first container: (a) an amount of a binding fusion protein composition sufficient to administer in treatment of a subject with a disease, condition or disorder; and (b) an amount of a pharmaceutically acceptable carrier; together in a formulation ready for injection or for reconstitution with sterile water, buffer, or dextrose; together with a label identifying the binding fusion protein drug and storage and handling conditions, and/or a sheet of the approved indications for the drug and instructions for the reconstitution and/or administration of the binding fusion protein drug for the use for the prevention and/or treatment of a approved indication, appropriate dosage and safety information, and information identifying the lot and expiration of the drug. 
     In another embodiment, the kit comprises, in at least a first container: (a) an amount of a binding fusion protein-drug conjugate composition sufficient to administer in treatment of a subject with a disease, condition or disorder; and (b) an amount of a pharmaceutically acceptable carrier; together in a formulation ready for injection or for reconstitution with sterile water, buffer, or dextrose; together with a label identifying the binding fusion protein-drug conjugate and storage and handling conditions, and/or a sheet of the approved indications for the drug and instructions for the reconstitution and/or administration of the compositions for the use for the prevention and/or treatment of a approved indication, appropriate dosage and safety information, and information identifying the lot and expiration of the drug. 
     In another embodiment, the kit comprises, in at least a first container: (a) an amount of an XTEN-drug conjugate composition sufficient to administer in treatment of a subject with a disease, condition or disorder; and (b) an amount of a pharmaceutically acceptable carrier; together in a formulation ready for injection or for reconstitution with sterile water, buffer, or dextrose; together with a label identifying the XTEN-drug conjugate and storage and handling conditions, and/or a sheet of the approved indications for the drug and instructions for the reconstitution and/or administration of the compositions for the use for the prevention and/or treatment of a approved indication, appropriate dosage and safety information, and information identifying the lot and expiration of the drug. 
     In any of the embodiments of the foregoing kits, the kit can comprise a second container that can carry a suitable diluent for the subject composition, which will provide the user with the appropriate concentration of the pharmaceutical composition to be delivered to the subject. 
     Examples 
     Example 1: Construction of XTEN_AD36 Motif Segments 
     The following example describes the construction of a collection of codon-optimized genes encoding motif sequences of 36 amino acids. As a first step, a stuffer vector pCW0359 was constructed based on a pET vector and that includes a T7 promoter. pCW0359 encodes a cellulose binding domain (CBD) and a TEV protease recognition site followed by a stuffer sequence that is flanked by BsaI, BbsI, and KpnI sites. The BsaI and BbsI sites were inserted such that they generate compatible overhangs after digestion. The stuffer sequence is followed by a truncated version of the GFP gene and a His tag. The stuffer sequence contains stop codons and thus  E. coli  cells carrying the stuffer plasmid pCW0359 form non-fluorescent colonies. The stuffer vector pCW0359 was digested with BsaI and KpnI to remove the stuffer segment and the resulting vector fragment was isolated by agarose gel purification. The sequences were designated XTEN_AD36, reflecting the AD family of motifs. Its segments have the amino acid sequence [X] 3  where X is a 12mer peptide with the sequences: GESPGGSSGSES (SEQ ID NO: 2), GSEGSSGPGESS (SEQ ID NO: 3), GSSESGSSEGGP (SEQ ID NO: 4), or GSGGEPSESGSS (SEQ ID NO: 5). The insert was obtained by annealing the following pairs of phosphorylated synthetic oligonucleotide pairs: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 225) 
               
               
                   
                 AD1for: AGGTGAATCTCCDGGTGGYTCYAGCGGTTCYGARTC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 226) 
               
               
                   
                 AD1rev: ACCTGAYTCRGAACCGCTRGARCCACCHGGAGATTC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 227) 
               
               
                   
                 AD2for: AGGTAGCGAAGGTTCTTCYGGTCCDGGYGARTCYTC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 228) 
               
               
                   
                 AD2rev: ACCTGARGAYTCRCCHGGACCRGAAGAACCTTCGCT 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 229) 
               
               
                   
                 AD3for: AGGTTCYTCYGAAAGCGGTTCTTCYGARGGYGGTCC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 230) 
               
               
                   
                 AD3rev: ACCTGGACCRCCYTCRGAAGAACCGCTTTCRGARGA 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 231) 
               
               
                   
                 AD4for: AGGTTCYGGTGGYGAACCDTCYGARTCTGGTAGCTC 
               
            
           
         
       
     
     We also annealed the phosphorylated oligonucleotide 3KpnIstopperFor: AGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 232) and the non-phosphorylated oligonucleotide pr_3 KpnIstopperRev: CCTCGAGTGAAGACGA (SEQ ID NO: 233). The annealed oligonucleotide pairs were ligated, which resulted in a mixture of products with varying length that represents the varying number of 12mer repeats ligated to one BbsI/KpnI segment. The products corresponding to the length of 36 amino acids were isolated from the mixture by preparative agarose gel electrophoresis and ligated into the BsaI/KpnI digested stuffer vector pCW0359. Most of the clones in the resulting library designated LCW0401 showed green fluorescence after induction, which shows that the sequence of XTEN_AD36 had been ligated in frame with the GFP gene and that most sequences of XTEN_AD36 had good expression levels. 
     We screened 96 isolates from library LCW0401 for high level of fluorescence by stamping them onto agar plate containing IPTG. The same isolates were evaluated by PCR and 48 isolates were identified that contained segments with 36 amino acids as well as strong fluorescence. These isolates were sequenced and 39 clones were identified that contained correct XTEN_AD36 segments. The file names of the nucleotide and amino acid constructs and the sequences for these segments are listed in Table 11. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 DNA and Amino Acid Sequences for 36-mer motifs 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
                 SEQ 
               
               
                   
                   
                 ID 
                   
                 ID 
               
               
                 File name 
                 Amino acid sequence 
                 NO: 
                 Nucleotide sequence 
                 NO: 
               
               
                   
               
               
                 LCW0401_001_ 
                 GSGGEPSESGSSGESP 
                 234 
                 GGTTCTGGTGGCGAACCGTCCGAGTCTGGTAG 
                 272 
               
               
                 GFP-N_A01.ab1 
                 GGSSGSESGESPGGSS 
                   
                 CTCAGGTGAATCTCCGGGTGGCTCTAGCGGTT 
                   
               
               
                   
                 GSES 
                   
                 CCGAGTCAGGTGAATCTCCTGGTGGTTCCAGC 
                   
               
               
                   
                   
                   
                 GGTTCCGAGTCA 
                   
               
               
                   
               
               
                 LCW0401_002_ 
                 GSEGSSGPGESSGESP 
                 235 
                 GGTAGCGAAGGTTCTTCTGGTCCTGGCGAGTC 
                 273 
               
               
                 GFP-N_B01.ab1 
                 GGSSGSESGSSESGSS 
                   
                 TTCAGGTGAATCTCCTGGTGGTTCCAGCGGTTC 
                   
               
               
                   
                 EGGP 
                   
                 TGAATCAGGTTCCTCCGAAAGCGGTTCTTCCG 
                   
               
               
                   
                   
                   
                 AGGGCGGTCCA 
                   
               
               
                   
               
               
                 LCW0401_003_ 
                 GSSESGSSEGGPGSSE 
                 236 
                 GGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGG 
                 274 
               
               
                 GFP-N_C01.ab1 
                 SGSSEGGPGESPGGSS 
                   
                 TCCAGGTTCCTCTGAAAGCGGTTCTTCTGAGGG 
                   
               
               
                   
                 GSES 
                   
                 TGGTCCAGGTGAATCTCCGGGTGGCTCCAGCG 
                   
               
               
                   
                   
                   
                 GTTCCGAGTCA 
                   
               
               
                   
               
               
                 LCW0401_004_ 
                 GSGGEPSESGSSGSSE 
                 237 
                 GGTTCCGGTGGCGAACCGTCTGAATCTGGTAG 
                 275 
               
               
                 GFP-N_D01.ab1 
                 SGSSEGGPGSGGEPSE 
                   
                 CTCAGGTTCTTCTGAAAGCGGTTCTTCCGAGGG 
                   
               
               
                   
                 SGSS 
                   
                 TGGTCCAGGTTCTGGTGGTGAACCTTCCGAGTC 
                   
               
               
                   
                   
                   
                 TGGTAGCTCA 
                   
               
               
                   
               
               
                 LCW0401_007_ 
                 GSSESGSSEGGPGSEG 
                 238 
                 GGTTCTTCCGAAAGCGGTTCTTCTGAGGGTGGT 
                 276 
               
               
                 GFP-N_F01.ab1 
                 SSGPGESSGSEGSSGP 
                   
                 CCAGGTAGCGAAGGTTCTTCCGGTCCAGGTGA 
                   
               
               
                   
                 GESS 
                   
                 GTCTTCAGGTAGCGAAGGTTCTTCTGGTCCTGG 
                   
               
               
                   
                   
                   
                 TGAATCTTCA 
                   
               
               
                   
               
               
                 LCW0401_008_ 
                 GSSESGSSEGGPGESP 
                 239 
                 GGTTCCTCTGAAAGCGGTTCTTCCGAGGGTGG 
                 277 
               
               
                 GFP-N_G01.ab1 
                 GGSSGSESGSEGSSGP 
                   
                 TCCAGGTGAATCTCCAGGTGGTTCCAGCGGTT 
                   
               
               
                   
                 GESS 
                   
                 CTGAGTCAGGTAGCGAAGGTTCTTCTGGTCCA 
                   
               
               
                   
                   
                   
                 GGTGAATCCTCA 
                   
               
               
                   
               
               
                 LCW0401_012_ 
                 GSGGEPSESGSSGSGG 
                 240 
                 GGTTCTGGTGGTGAACCGTCTGAGTCTGGTAG 
                 278 
               
               
                 GFP-N_H01.ab1 
                 EPSESGSSGSEGSSGP 
                   
                 CTCAGGTTCCGGTGGCGAACCATCCGAATCTG 
                   
               
               
                   
                 GESS 
                   
                 GTAGCTCAGGTAGCGAAGGTTCTTCCGGTCCA 
                   
               
               
                   
                   
                   
                 GGTGAGTCTTCA 
                   
               
               
                   
               
               
                 LCW0401_015_ 
                 GSSESGSSEGGPGSEG 
                 241 
                 GGTTCTTCCGAAAGCGGTTCTTCCGAAGGCGG 
                 279 
               
               
                 GFP-N_A02.ab1 
                 SSGPGESSGESPGGSS 
                   
                 TCCAGGTAGCGAAGGTTCTTCTGGTCCAGGCG 
                   
               
               
                   
                 GSES 
                   
                 AATCTTCAGGTGAATCTCCTGGTGGCTCCAGC 
                   
               
               
                   
                   
                   
                 GGTTCTGAGTCA 
                   
               
               
                   
               
               
                 LCW0401_016_ 
                 GSSESGSSEGGPGSSE 
                 242 
                 GGTTCCTCCGAAAGCGGTTCTTCTGAGGGCGG 
                 280 
               
               
                 GFP-N_B02.ab1 
                 SGSSEGGPGSSESGSS 
                   
                 TCCAGGTTCCTCCGAAAGCGGTTCTTCCGAGG 
                   
               
               
                   
                 EGGP 
                   
                 GCGGTCCAGGTTCTTCTGAAAGCGGTTCTTCCG 
                   
               
               
                   
                   
                   
                 AGGGCGGTCCA 
                   
               
               
                   
               
               
                 LCW0401_020_ 
                 GSGGEPSESGSSGSEG 
                 243 
                 GGTTCCGGTGGCGAACCGTCCGAATCTGGTAG 
                 281 
               
               
                 GFP-N_E02.ab1 
                 SSGPGESSGSSESGSS 
                   
                 CTCAGGTAGCGAAGGTTCTTCTGGTCCAGGCG 
                   
               
               
                   
                 EGGP 
                   
                 AATCTTCAGGTTCCTCTGAAAGCGGTTCTTCTG 
                   
               
               
                   
                   
                   
                 AGGGCGGTCCA 
                   
               
               
                   
               
               
                 LCW0401_022_ 
                 GSGGEPSESGSSGSSE 
                 244 
                 GGTTCTGGTGGTGAACCGTCCGAATCTGGTAG 
                 282 
               
               
                 GFP-N_F02.ab1 
                 SGSSEGGPGSGGEPSE 
                   
                 CTCAGGTTCTTCCGAAAGCGGTTCTTCTGAAGG 
                   
               
               
                   
                 SGSS 
                   
                 TGGTCCAGGTTCCGGTGGCGAACCTTCTGAAT 
                   
               
               
                   
                   
                   
                 CTGGTAGCTCA 
                   
               
               
                   
               
               
                 LCW0401_024_ 
                 GSGGEPSESGSSGSSE 
                 245 
                 GGTTCTGGTGGCGAACCGTCCGAATCTGGTAG 
                 283 
               
               
                 GFP-N_G02.ab1 
                 SGSSEGGPGESPGGSS 
                   
                 CTCAGGTTCCTCCGAAAGCGGTTCTTCTGAAG 
                   
               
               
                   
                 GSES 
                   
                 GTGGTCCAGGTGAATCTCCAGGTGGTTCTAGC 
                   
               
               
                   
                   
                   
                 GGTTCTGAATCA 
                   
               
               
                   
               
               
                 LCW0401_026_ 
                 GSGGEPSESGSSGESP 
                 246 
                 GGTTCTGGTGGCGAACCGTCTGAGTCTGGTAG 
                 284 
               
               
                 GFP-N_H02.ab1 
                 GGSSGSESGSEGSSGP 
                   
                 CTCAGGTGAATCTCCTGGTGGCTCCAGCGGTTC 
                   
               
               
                   
                 GESS 
                   
                 TGAATCAGGTAGCGAAGGTTCTTCTGGTCCTG 
                   
               
               
                   
                   
                   
                 GTGAATCTTCA 
                   
               
               
                   
               
               
                 LCW0401_027_ 
                 GSGGEPSESGSSGESP 
                 247 
                 GGTTCCGGTGGCGAACCTTCCGAATCTGGTAG 
                 285 
               
               
                 GFP-N_A03.ab1 
                 GGSSGSESGSGGEPSE 
                   
                 CTCAGGTGAATCTCCGGGTGGTTCTAGCGGTTC 
                   
               
               
                   
                 SGSS 
                   
                 TGAGTCAGGTTCTGGTGGTGAACCTTCCGAGT 
                   
               
               
                   
                   
                   
                 CTGGTAGCTCA 
                   
               
               
                   
               
               
                 LCW0401_028_ 
                 GSSESGSSEGGPGSSE 
                 248 
                 GGTTCCTCTGAAAGCGGTTCTTCTGAGGGCGG 
                 286 
               
               
                 GFP-N_B03.ab1 
                 SGSSEGGPGSSESGSS 
                   
                 TCCAGGTTCTTCCGAAAGCGGTTCTTCCGAGG 
                   
               
               
                   
                 EGGP 
                   
                 GCGGTCCAGGTTCTTCCGAAAGCGGTTCTTCTG 
                   
               
               
                   
                   
                   
                 AAGGCGGTCCA 
                   
               
               
                   
               
               
                 LCW0401_030_ 
                 GESPGGSSGSESGSEG 
                 249 
                 GGTGAATCTCCGGGTGGCTCCAGCGGTTCTGA 
                 287 
               
               
                 GFP-N_CO3.ab1 
                 SSGPGESSGSEGSSGP 
                   
                 GTCAGGTAGCGAAGGTTCTTCCGGTCCGGGTG 
                   
               
               
                   
                 GESS 
                   
                 AGTCCTCAGGTAGCGAAGGTTCTTCCGGTCCT 
                   
               
               
                   
                   
                   
                 GGTGAGTCTTCA 
                   
               
               
                   
               
               
                 LCW0401_031_ 
                 GSGGEPSESGSSGSGG 
                 250 
                 GGTTCTGGTGGCGAACCTTCCGAATCTGGTAG 
                 288 
               
               
                 GFP-N_D03.ab1 
                 EPSESGSSGSSESGSS 
                   
                 CTCAGGTTCCGGTGGTGAACCTTCTGAATCTGG 
                   
               
               
                   
                 EGGP 
                   
                 TAGCTCAGGTTCTTCTGAAAGCGGTTCTTCCGA 
                   
               
               
                   
                   
                   
                 GGGCGGTCCA 
                   
               
               
                   
               
               
                 LCW0401_033_ 
                 GSGGEPSESGSSGSGG 
                 251 
                 GGTTCCGGTGGTGAACCTTCTGAATCTGGTAG 
                 289 
               
               
                 GFP-N_E03.ab1 
                 EPSESGSSGSGGEPSE 
                   
                 CTCAGGTTCCGGTGGCGAACCATCCGAGTCTG 
                   
               
               
                   
                 SGSS 
                   
                 GTAGCTCAGGTTCCGGTGGTGAACCATCCGAG 
                   
               
               
                   
                   
                   
                 TCTGGTAGCTCA 
                   
               
               
                   
               
               
                 LCW0401_037_ 
                 GSGGEPSESGSSGSSE 
                 252 
                 GGTTCCGGTGGCGAACCTTCTGAATCTGGTAG 
                 290 
               
               
                 GFP-N_F03.ab1 
                 SGSSEGGPGSEGSSGP 
                   
                 CTCAGGTTCCTCCGAAAGCGGTTCTTCTGAGG 
                   
               
               
                   
                 GESS 
                   
                 GCGGTCCAGGTAGCGAAGGTTCTTCTGGTCCG 
                   
               
               
                   
                   
                   
                 GGCGAGTCTTCA 
                   
               
               
                   
               
               
                 LCW0401_038_ 
                 GSGGEPSESGSSGSEG 
                 253 
                 GGTTCCGGTGGTGAACCGTCCGAGTCTGGTAG 
                 291 
               
               
                 GFP-N_G03.ab1 
                 SSGPGESSGSGGEPSE 
                   
                 CTCAGGTAGCGAAGGTTCTTCTGGTCCGGGTG 
                   
               
               
                   
                 SGSS 
                   
                 AGTCTTCAGGTTCTGGTGGCGAACCGTCCGAA 
                   
               
               
                   
                   
                   
                 TCTGGTAGCTCA 
                   
               
               
                   
               
               
                 LCW0401_039_ 
                 GSGGEPSESGSSGESP 
                 254 
                 GGTTCTGGTGGCGAACCGTCCGAATCTGGTAG 
                 292 
               
               
                 GFP-N_H03.ab1 
                 GGSSGSESGSGGEPSE 
                   
                 CTCAGGTGAATCTCCTGGTGGTTCCAGCGGTTC 
                   
               
               
                   
                 SGSS 
                   
                 CGAGTCAGGTTCTGGTGGCGAACCTTCCGAAT 
                   
               
               
                   
                   
                   
                 CTGGTAGCTCA 
                   
               
               
                   
               
               
                 LCW0401_040_ 
                 GSSESGSSEGGPGSGG 
                 255 
                 GGTTCTTCCGAAAGCGGTTCTTCCGAGGGCGG 
                 293 
               
               
                 GFP-N_A04.ab1 
                 EPSESGSSGSSESGSS 
                   
                 TCCAGGTTCCGGTGGTGAACCATCTGAATCTG 
                   
               
               
                   
                 EGGP 
                   
                 GTAGCTCAGGTTCTTCTGAAAGCGGTTCTTCTG 
                   
               
               
                   
                   
                   
                 AAGGTGGTCCA 
                   
               
               
                   
               
               
                 LCW0401_042_ 
                 GSEGSSGPGESSGESP 
                 256 
                 GGTAGCGAAGGTTCTTCCGGTCCTGGTGAGTC 
                 294 
               
               
                 GFP-N_C04.ab1 
                 GGSSGSESGSEGSSGP 
                   
                 TTCAGGTGAATCTCCAGGTGGCTCTAGCGGTTC 
                   
               
               
                   
                 GESS 
                   
                 CGAGTCAGGTAGCGAAGGTTCTTCTGGTCCTG 
                   
               
               
                   
                   
                   
                 GCGAGTCCTCA 
                   
               
               
                   
               
               
                 LCW0401_046_ 
                 GSSESGSSEGGPGSSE 
                 257 
                 GGTTCCTCTGAAAGCGGTTCTTCCGAAGGCGG 
                 295 
               
               
                 GFP-N_D04.ab1 
                 SGSSEGGPGSSESGSS 
                   
                 TCCAGGTTCTTCCGAAAGCGGTTCTTCTGAGGG 
                   
               
               
                   
                 EGGP 
                   
                 CGGTCCAGGTTCCTCCGAAAGCGGTTCTTCTGA 
                   
               
               
                   
                   
                   
                 GGGTGGTCCA 
                   
               
               
                   
               
               
                 LCW0401_047_ 
                 GSGGEPSESGSSGESP 
                 258 
                 GGTTCTGGTGGCGAACCTTCCGAGTCTGGTAG 
                 296 
               
               
                 GFP-N_E04.ab1 
                 GGSSGSESGESPGGSS 
                   
                 CTCAGGTGAATCTCCGGGTGGTTCTAGCGGTTC 
                   
               
               
                   
                 GSES 
                   
                 CGAGTCAGGTGAATCTCCGGGTGGTTCCAGCG 
                   
               
               
                   
                   
                   
                 GTTCTGAGTCA 
                   
               
               
                   
               
               
                 LCW0401_051_ 
                 GSGGEPSESGSSGSEG 
                 259 
                 GGTTCTGGTGGCGAACCATCTGAGTCTGGTAG 
                 297 
               
               
                 GFP-N_F04.ab1 
                 SSGPGESSGESPGGSS 
                   
                 CTCAGGTAGCGAAGGTTCTTCCGGTCCAGGCG 
                   
               
               
                   
                 GSES 
                   
                 AGTCTTCAGGTGAATCTCCTGGTGGCTCCAGC 
                   
               
               
                   
                   
                   
                 GGTTCTGAGTCA 
                   
               
               
                   
               
               
                 LCW0401_053_ 
                 GESPGGSSGSESGESP 
                 260 
                 GGTGAATCTCCTGGTGGTTCCAGCGGTTCCGA 
                 298 
               
               
                 GFP-N_H04.ab1 
                 GGSSGSESGESPGGSS 
                   
                 GTCAGGTGAATCTCCAGGTGGCTCTAGCGGTT 
                   
               
               
                   
                 GSES 
                   
                 CCGAGTCAGGTGAATCTCCTGGTGGTTCTAGC 
                   
               
               
                   
                   
                   
                 GGTTCTGAATCA 
                   
               
               
                   
               
               
                 LCW0401_054_ 
                 GSEGSSGPGESSGSEG 
                 261 
                 GGTAGCGAAGGTTCTTCCGGTCCAGGTGAATC 
                 299 
               
               
                 GFP-N_A05.ab1 
                 SSGPGESSGSGGEPSE 
                   
                 TTCAGGTAGCGAAGGTTCTTCTGGTCCTGGTGA 
                   
               
               
                   
                 SGSS 
                   
                 ATCCTCAGGTTCCGGTGGCGAACCATCTGAAT 
                   
               
               
                   
                   
                   
                 CTGGTAGCTCA 
                   
               
               
                   
               
               
                 LCW0401_059_ 
                 GSGGEPSESGSSGSEG 
                 262 
                 GGTTCTGGTGGCGAACCATCCGAATCTGGTAG 
                 300 
               
               
                 GFP-N_D05.ab1 
                 SSGPGESSGESPGGSS 
                   
                 CTCAGGTAGCGAAGGTTCTTCTGGTCCTGGCG 
                   
               
               
                   
                 GSES 
                   
                 AATCTTCAGGTGAATCTCCAGGTGGCTCTAGC 
                   
               
               
                   
                   
                   
                 GGTTCCGAATCA 
                   
               
               
                   
               
               
                 LCW0401_060_ 
                 GSGGEPSESGSSGSSE 
                 263 
                 GGTTCCGGTGGTGAACCGTCCGAATCTGGTAG 
                 301 
               
               
                 GFP-N_E05.ab1 
                 SGSSEGGPGSGGEPSE 
                   
                 CTCAGGTTCCTCTGAAAGCGGTTCTTCCGAGG 
                   
               
               
                   
                 SGSS 
                   
                 GTGGTCCAGGTTCCGGTGGTGAACCTTCTGAG 
                   
               
               
                   
                   
                   
                 TCTGGTAGCTCA 
                   
               
               
                   
               
               
                 LCW0401_061_ 
                 GSSESGSSEGGPGSGG 
                 264 
                 GGTTCCTCTGAAAGCGGTTCTTCTGAGGGCGG 
                 302 
               
               
                 GFP-N_F05.ab1 
                 EPSESGSSGSEGSSGP 
                   
                 TCCAGGTTCTGGTGGCGAACCATCTGAATCTG 
                   
               
               
                   
                 GESS 
                   
                 GTAGCTCAGGTAGCGAAGGTTCTTCCGGTCCG 
                   
               
               
                   
                   
                   
                 GGTGAATCTTCA 
                   
               
               
                   
               
               
                 LCW0401_063_ 
                 GSGGEPSESGSSGSEG 
                 265 
                 GGTTCTGGTGGTGAACCGTCCGAATCTGGTAG 
                 303 
               
               
                 GFP-N_H05.ab1 
                 SSGPGESSGSEGSSGP 
                   
                 CTCAGGTAGCGAAGGTTCTTCTGGTCCTGGCG 
                   
               
               
                   
                 GESS 
                   
                 AGTCTTCAGGTAGCGAAGGTTCTTCTGGTCCTG 
                   
               
               
                   
                   
                   
                 GTGAATCTTCA 
                   
               
               
                   
               
               
                 LCW0401_066_ 
                 GSGGEPSESGSSGSSE 
                 266 
                 GGTTCTGGTGGCGAACCATCCGAGTCTGGTAG 
                 304 
               
               
                 GFP-N_B06.ab1 
                 SGSSEGGPGSGGEPSE 
                   
                 CTCAGGTTCTTCCGAAAGCGGTTCTTCCGAAG 
                   
               
               
                   
                 SGSS 
                   
                 GCGGTCCAGGTTCTGGTGGTGAACCGTCCGAA 
                   
               
               
                   
                   
                   
                 TCTGGTAGCTCA 
                   
               
               
                   
               
               
                 LCW0401_067_ 
                 GSGGEPSESGSSGESP 
                 267 
                 GGTTCCGGTGGCGAACCTTCCGAATCTGGTAG 
                 305 
               
               
                 GFP-N_C06.ab1 
                 GGSSGSESGESPGGSS 
                   
                 CTCAGGTGAATCTCCGGGTGGTTCTAGCGGTTC 
                   
               
               
                   
                 GSES 
                   
                 CGAATCAGGTGAATCTCCAGGTGGTTCTAGCG 
                   
               
               
                   
                   
                   
                 GTTCCGAATCA 
                   
               
               
                   
               
               
                 LCW0401_069_ 
                 GSGGEPSESGSSGSGG 
                 268 
                 GGTTCCGGTGGTGAACCATCTGAGTCTGGTAG 
                 306 
               
               
                 GFP-N_D06.ab1 
                 EPSESGSSGESPGGSS 
                   
                 CTCAGGTTCCGGTGGCGAACCGTCCGAGTCTG 
                   
               
               
                   
                 GSES 
                   
                 GTAGCTCAGGTGAATCTCCGGGTGGTTCCAGC 
                   
               
               
                   
                   
                   
                 GGTTCCGAATCA 
                   
               
               
                   
               
               
                 LCW0401_070_ 
                 GSEGSSGPGESSGSSE 
                 269 
                 GGTAGCGAAGGTTCTTCTGGTCCGGGCGAATC 
                 307 
               
               
                 GFP-N_E06.ab1 
                 SGSSEGGPGSEGSSGP 
                   
                 CTCAGGTTCCTCCGAAAGCGGTTCTTCCGAAG 
                   
               
               
                   
                 GESS 
                   
                 GTGGTCCAGGTAGCGAAGGTTCTTCCGGTCCT 
                   
               
               
                   
                   
                   
                 GGTGAATCTTCA 
                   
               
               
                   
               
               
                 LCW0401_078_ 
                 GSSESGSSEGGPGESP 
                 270 
                 GGTTCCTCTGAAAGCGGTTCTTCTGAAGGCGG 
                 308 
               
               
                 GFP-N_F06.ab1 
                 GGSSGSESGESPGGSS 
                   
                 TCCAGGTGAATCTCCGGGTGGCTCCAGCGGTT 
                   
               
               
                   
                 GSES 
                   
                 CTGAATCAGGTGAATCTCCTGGTGGCTCCAGC 
                   
               
               
                   
                   
                   
                 GGTTCCGAGTCA 
                   
               
               
                   
               
               
                 LCW0401_079_ 
                 GSEGSSGPGESSGSEG 
                 271 
                 GGTAGCGAAGGTTCTTCTGGTCCAGGCGAGTC 
                 309 
               
               
                 GFP-N_G06.ab1 
                 SSGPGESSGSGGEPSE 
                   
                 TTCAGGTAGCGAAGGTTCTTCCGGTCCTGGCG 
                   
               
               
                   
                 SGSS 
                   
                 AGTCTTCAGGTTCCGGTGGCGAACCGTCCGAA 
                   
               
               
                   
                   
                   
                 TCTGGTAGCTCA 
               
               
                   
               
            
           
         
       
     
     Example 2: Construction of XTEN_AE36 Segments 
     A codon library encoding XTEN sequences of 36 amino acid length was constructed. The XTEN sequence was designated XTEN_AE36. Its segments have the amino acid sequence [X] 3  where X is a 12mer peptide with the sequence: GSPAGSPTSTEE (SEQ ID NO: 6), GSEPATSGSETP (SEQ ID NO: 7), GTSESATPESGP (SEQ ID NO: 8), or GTSTEPSEGSAP (SEQ ID NO: 9). The insert was obtained by annealing the following pairs of phosphorylated synthetic oligonucleotide pairs: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 310) 
               
               
                   
                 AE1for: AGGTAGCCCDGCWGGYTCTCCDACYTCYACYGARGA 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 311) 
               
               
                   
                 AE1rev: ACCTTCYTCRGTRGARGTHGGAGARCCWGCHGGGCT 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 312) 
               
               
                   
                 AE2for: AGGTAGCGAACCKGCWACYTCYGGYTCTGARACYCC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 313) 
               
               
                   
                 AE2rev: ACCTGGRGTYTCAGARCCRGARGTWGCMGGTTCGCT 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 314) 
               
               
                   
                 AE3for: AGGTACYTCTGAAAGCGCWACYCCKGARTCYGGYCC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 315) 
               
               
                   
                 AE3rev: ACCTGGRCCRGAYTCMGGRGTWGCGCTTTCAGARGT 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 316) 
               
               
                   
                 AE4for: AGGTACYTCTACYGAACCKTCYGARGGYAGCGCWCC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 317) 
               
               
                   
                 AE4rev: ACCTGGWGCGCTRCCYTCRGAMGGTTCRGTAGARGT 
               
            
           
         
       
     
     We also annealed the phosphorylated oligonucleotide 3KpnIstopperFor: AGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 232) and the non-phosphorylated oligonucleotide pr_3 KpnIstopperRev: CCTCGAGTGAAGACGA (SEQ ID NO: 233). The annealed oligonucleotide pairs were ligated, which resulted in a mixture of products with varying length that represents the varying number of 12mer repeats ligated to one BbsI/KpnI segment. The products corresponding to the length of 36 amino acids were isolated from the mixture by preparative agarose gel electrophoresis and ligated into the BsaI/KpnI digested stuffer vector pCW0359. Most of the clones in the resulting library designated LCW0402 showed green fluorescence after induction which shows that the sequence of XTEN_AE36 had been ligated in frame with the GFP gene and most sequences of XTEN AE36 show good expression. 
     We screened 96 isolates from library LCW0402 for high level of fluorescence by stamping them onto agar plate containing IPTG. The same isolates were evaluated by PCR and 48 isolates were identified that contained segments with 36 amino acids as well as strong fluorescence. These isolates were sequenced and 37 clones were identified that contained correct XTEN_AE36 segments. The file names of the nucleotide and amino acid constructs and the sequences for these segments are listed in Table 12. 
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 DNA and Amino Acid Sequences for 36-mer motifs 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
                 SEQ 
               
               
                   
                   
                 ID 
                   
                 ID 
               
               
                 File name 
                 Amino acid sequence 
                 NO: 
                 Nucleotide sequence 
                 NO: 
               
               
                   
               
               
                 LCW0402_002_ 
                 GSPAGSPTSTEEGT 
                 318 
                 GGTAGCCCGGCAGGCTCTCCGACCTCTACTGA 
                 355 
               
               
                 GFP-N_A07.ab1 
                 SESATPESGPGTSTE 
                   
                 GGAAGGTACTTCTGAAAGCGCAACCCCGGAGT 
                   
               
               
                   
                 PSEGSAP 
                   
                 CCGGCCCAGGTACCTCTACCGAACCGTCTGAG 
                   
               
               
                   
                   
                   
                 GGCAGCGCACCA 
                   
               
               
                   
               
               
                 LCW0402_003_ 
                 GTSTEPSEGSAPGT 
                 319 
                 GGTACTTCTACCGAACCGTCCGAAGGCAGCGC 
                 356 
               
               
                 GFP-N_B07.ab1 
                 STEPSEGSAPGTSTE 
                   
                 TCCAGGTACCTCTACTGAACCTTCCGAGGGCA 
                   
               
               
                   
                 PSEGSAP 
                   
                 GCGCTCCAGGTACCTCTACCGAACCTTCTGAA 
                   
               
               
                   
                   
                   
                 GGTAGCGCACCA 
                   
               
               
                   
               
               
                 LCW0402_004_ 
                 GTSTEPSEGSAPGT 
                 320 
                 GGTACCTCTACCGAACCGTCTGAAGGTAGCGC 
                 357 
               
               
                 GFP-N_C07.ab1 
                 SESATPESGPGTSES 
                   
                 ACCAGGTACCTCTGAAAGCGCAACTCCTGAGT 
                   
               
               
                   
                 ATPESGP 
                   
                 CCGGTCCAGGTACTTCTGAAAGCGCAACCCCG 
                   
               
               
                   
                   
                   
                 GAGTCTGGCCCA 
                   
               
               
                   
               
               
                 LCW0402_005_ 
                 GTSTEPSEGSAPGT 
                 321 
                 GGTACTTCTACTGAACCGTCTGAAGGTAGCGC 
                 358 
               
               
                 GFP-N_D07.ab1 
                 SESATPESGPGTSES 
                   
                 ACCAGGTACTTCTGAAAGCGCAACCCCGGAAT 
                   
               
               
                   
                 ATPESGP 
                   
                 CCGGCCCAGGTACCTCTGAAAGCGCAACCCCG 
                   
               
               
                   
                   
                   
                 GAGTCCGGCCCA 
                   
               
               
                   
               
               
                 LCW0402_006_ 
                 GSEPATSGSETPGT 
                 322 
                 GGTAGCGAACCGGCAACCTCCGGCTCTGAAAC 
                 359 
               
               
                 GFP-N_E07.ab1 
                 SESATPESGPGSPA 
                   
                 CCCAGGTACCTCTGAAAGCGCTACTCCTGAAT 
                   
               
               
                   
                 GSPTSTEE 
                   
                 CCGGCCCAGGTAGCCCGGCAGGTTCTCCGACT 
                   
               
               
                   
                   
                   
                 TCCACTGAGGAA 
                   
               
               
                   
               
               
                 LCW0402_008_ 
                 GTSESATPESGPGS 
                 323 
                 GGTACTTCTGAAAGCGCAACCCCTGAATCCGG 
                 360 
               
               
                 GFP-N_F07.ab1 
                 EPATSGSETPGTSTE 
                   
                 TCCAGGTAGCGAACCGGCTACTTCTGGCTCTG 
                   
               
               
                   
                 PSEGSAP 
                   
                 AGACTCCAGGTACTTCTACCGAACCGTCCGAA 
                   
               
               
                   
                   
                   
                 GGTAGCGCACCA 
                   
               
               
                   
               
               
                 LCW0402_009_ 
                 GSPAGSPTSTEEGSP 
                 324 
                 GGTAGCCCGGCTGGCTCTCCAACCTCCACTGA 
                 361 
               
               
                 GFP-N_G07.ab1 
                 AGSPTSTEEGSEPA 
                   
                 GGAAGGTAGCCCGGCTGGCTCTCCAACCTCCA 
                   
               
               
                   
                 TSGSETP 
                   
                 CTGAAGAAGGTAGCGAACCGGCTACCTCCGGC 
                   
               
               
                   
                   
                   
                 TCTGAAACTCCA 
                   
               
               
                   
               
               
                 LCW0402_011_ 
                 GSPAGSPTSTEEGT 
                 325 
                 GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAG 
                 362 
               
               
                 GFP-N_A08.ab1 
                 SESATPESGPGTSTE 
                   
                 GAAGGTACTTCTGAAAGCGCTACTCCTGAGTC 
                   
               
               
                   
                 PSEGSAP 
                   
                 TGGTCCAGGTACCTCTACTGAACCGTCCGAAG 
                   
               
               
                   
                   
                   
                 GTAGCGCTCCA 
                   
               
               
                   
               
               
                 LCW0402_012_ 
                 GSPAGSPTSTEEGSP 
                 326 
                 GGTAGCCCTGCTGGCTCTCCGACTTCTACTGAG 
                 363 
               
               
                 GFP-N_B08.ab1 
                 AGSPTSTEEGTSTEP 
                   
                 GAAGGTAGCCCGGCTGGTTCTCCGACTTCTACT 
                   
               
               
                   
                 SEGSAP 
                   
                 GAGGAAGGTACTTCTACCGAACCTTCCGAAGG 
                   
               
               
                   
                   
                   
                 TAGCGCTCCA 
                   
               
               
                   
               
               
                 LCW0402_013_ 
                 GTSESATPESGPGT 
                 327 
                 GGTACTTCTGAAAGCGCTACTCCGGAGTCCGG 
                 364 
               
               
                 GFP-N_C08.ab1 
                 STEPSEGSAPGTSTE 
                   
                 TCCAGGTACCTCTACCGAACCGTCCGAAGGCA 
                   
               
               
                   
                 PSEGSAP 
                   
                 GCGCTCCAGGTACTTCTACTGAACCTTCTGAGG 
                   
               
               
                   
                   
                   
                 GTAGCGCTCCA 
                   
               
               
                   
               
               
                 LCW0402_014_ 
                 GTSTEPSEGSAPGSP 
                 328 
                 GGTACCTCTACCGAACCTTCCGAAGGTAGCGC 
                 365 
               
               
                 GFP-N_D08.ab1 
                 AGSPTSTEEGTSTEP 
                   
                 TCCAGGTAGCCCGGCAGGTTCTCCTACTTCCAC 
                   
               
               
                   
                 SEGSAP 
                   
                 TGAGGAAGGTACTTCTACCGAACCTTCTGAGG 
                   
               
               
                   
                   
                   
                 GTAGCGCACCA 
                   
               
               
                   
               
               
                 LCW0402_015_ 
                 GSEPATSGSETPGSP 
                 329 
                 GGTAGCGAACCGGCTACTTCCGGCTCTGAGAC 
                 366 
               
               
                 GFP-N_E08.ab1 
                 AGSPTSTEEGTSES 
                   
                 TCCAGGTAGCCCTGCTGGCTCTCCGACCTCTAC 
                   
               
               
                   
                 ATPESGP 
                   
                 CGAAGAAGGTACCTCTGAAAGCGCTACCCCTG 
                   
               
               
                   
                   
                   
                 AGTCTGGCCCA 
                   
               
               
                   
               
               
                 LCW0402_016_ 
                 GTSTEPSEGSAPGT 
                 330 
                 GGTACTTCTACCGAACCTTCCGAGGGCAGCGC 
                 367 
               
               
                 GFP-N_F08.ab1 
                 SESATPESGPGTSES 
                   
                 ACCAGGTACTTCTGAAAGCGCTACCCCTGAGT 
                   
               
               
                   
                 ATPESGP 
                   
                 CCGGCCCAGGTACTTCTGAAAGCGCTACTCCT 
                   
               
               
                   
                   
                   
                 GAATCCGGTCCA 
                   
               
               
                   
               
               
                 LCW0402_020_ 
                 GTSTEPSEGSAPGS 
                 331 
                 GGTACTTCTACTGAACCGTCTGAAGGCAGCGC 
                 368 
               
               
                 GFP-N_G08.ab1 
                 EPATSGSETPGSPA 
                   
                 ACCAGGTAGCGAACCGGCTACTTCCGGTTCTG 
                   
               
               
                   
                 GSPTSTE 
                   
                 AAACCCCAGGTAGCCCAGCAGGTTCTCCAACT 
                   
               
               
                   
                   
                   
                 TCTACTGAAGAA 
                   
               
               
                   
               
               
                 LCW0402_023_ 
                 GSPAGSPTSTEEGT 
                 332 
                 GGTAGCCCTGCTGGCTCTCCAACCTCCACCGA 
                 369 
               
               
                 GFP-N_A09.ab1 
                 SESATPESGPGSEPA 
                   
                 AGAAGGTACCTCTGAAAGCGCAACCCCTGAAT 
                   
               
               
                   
                 TSGSETP 
                   
                 CCGGCCCAGGTAGCGAACCGGCAACCTCCGGT 
                   
               
               
                   
                   
                   
                 TCTGAAACCCCA 
                   
               
               
                   
               
               
                 LCW0402_024_ 
                 GTSESATPESGPGSP 
                 333 
                 GGTACTTCTGAAAGCGCTACTCCTGAGTCCGG 
                 370 
               
               
                 GFP-N_B09.ab1 
                 AGSPTSTEEGSPAG 
                   
                 CCCAGGTAGCCCGGCTGGCTCTCCGACTTCCA 
                   
               
               
                   
                 SPTSTEE 
                   
                 CCGAGGAAGGTAGCCCGGCTGGCTCTCCAACT 
                   
               
               
                   
                   
                   
                 TCTACTGAAGAA 
                   
               
               
                   
               
               
                 LCW0402_025_ 
                 GTSTEPSEGSAPGT 
                 334 
                 GGTACCTCTACTGAACCTTCTGAGGGCAGCGC 
                 371 
               
               
                 GFP-N_C09.ab1 
                 SESATPESGPGTSTE 
                   
                 TCCAGGTACTTCTGAAAGCGCTACCCCGGAGT 
                   
               
               
                   
                 PSEGSAP 
                   
                 CCGGTCCAGGTACTTCTACTGAACCGTCCGAA 
                   
               
               
                   
                   
                   
                 GGTAGCGCACCA 
                   
               
               
                   
               
               
                 LCW0402_026_ 
                 GSPAGSPTSTEEGT 
                 335 
                 GGTAGCCCGGCAGGCTCTCCGACTTCCACCGA 
                 372 
               
               
                 GFP-N_D09.ab1 
                 STEPSEGSAPGSEPA 
                   
                 GGAAGGTACCTCTACTGAACCTTCTGAGGGTA 
                   
               
               
                   
                 TSGSETP 
                   
                 GCGCTCCAGGTAGCGAACCGGCAACCTCTGGC 
                   
               
               
                   
                   
                   
                 TCTGAAACCCCA 
                   
               
               
                   
               
               
                 LCW0402_027_ 
                 GSPAGSPTSTEEGT 
                 336 
                 GGTAGCCCAGCAGGCTCTCCGACTTCCACTGA 
                 373 
               
               
                 GFP-N_E09.ab1 
                 STEPSEGSAPGTSTE 
                   
                 GGAAGGTACTTCTACTGAACCTTCCGAAGGCA 
                   
               
               
                   
                 PSEGSAP 
                   
                 GCGCACCAGGTACCTCTACTGAACCTTCTGAG 
                   
               
               
                   
                   
                   
                 GGCAGCGCTCCA 
                   
               
               
                   
               
               
                 LCW0402_032_ 
                 GSEPATSGSETPGT 
                 337 
                 GGTAGCGAACCTGCTACCTCCGGTTCTGAAAC 
                 374 
               
               
                 GFP-N_H09.ab1 
                 SESATPESGPGSPA 
                   
                 CCCAGGTACCTCTGAAAGCGCAACTCCGGAGT 
                   
               
               
                   
                 GSPTSTEE 
                   
                 CTGGTCCAGGTAGCCCTGCAGGTTCTCCTACCT 
                   
               
               
                   
                   
                   
                 CCACTGAGGAA 
                   
               
               
                   
               
               
                 LCW0402_034_ 
                 GTSESATPESGPGT 
                 338 
                 GGTACCTCTGAAAGCGCTACTCCGGAGTCTGG 
                 375 
               
               
                 GFP-N_A10.ab1 
                 STEPSEGSAPGTSTE 
                   
                 CCCAGGTACCTCTACTGAACCGTCTGAGGGTA 
                   
               
               
                   
                 PSEGSAP 
                   
                 GCGCTCCAGGTACTTCTACTGAACCGTCCGAA 
                   
               
               
                   
                   
                   
                 GGTAGCGCACCA 
                   
               
               
                   
               
               
                 LCW0402_036_ 
                 GSPAGSPTSTEEGT 
                 339 
                 GGTAGCCCGGCTGGTTCTCCGACTTCCACCGA 
                 376 
               
               
                 GFP-N_C10.ab1 
                 STEPSEGSAPGTSTE 
                   
                 GGAAGGTACCTCTACTGAACCTTCTGAGGGTA 
                   
               
               
                   
                 PSEGSAP 
                   
                 GCGCTCCAGGTACCTCTACTGAACCTTCCGAA 
                   
               
               
                   
                   
                   
                 GGCAGCGCTCCA 
                   
               
               
                   
               
               
                 LCW0402_039_ 
                 GTSTEPSEGSAPGT 
                 340 
                 GGTACTTCTACCGAACCGTCCGAGGGCAGCGC 
                 377 
               
               
                 GFP-N_E10.ab1 
                 STEPSEGSAPGTSTE 
                   
                 TCCAGGTACTTCTACTGAACCTTCTGAAGGCA 
                   
               
               
                   
                 PSEGSAP 
                   
                 GCGCTCCAGGTACTTCTACTGAACCTTCCGAA 
                   
               
               
                   
                   
                   
                 GGTAGCGCACCA 
                   
               
               
                   
               
               
                 LCW0402_040_ 
                 GSEPATSGSETPGT 
                 341 
                 GGTAGCGAACCTGCAACCTCTGGCTCTGAAAC 
                 378 
               
               
                 GFP-N_F10.ab1 
                 SESATPESGPGTSTE 
                   
                 CCCAGGTACCTCTGAAAGCGCTACTCCTGAAT 
                   
               
               
                   
                 PSEGSAP 
                   
                 CTGGCCCAGGTACTTCTACTGAACCGTCCGAG 
                   
               
               
                   
                   
                   
                 GGCAGCGCACCA 
                   
               
               
                   
               
               
                 LCW0402_041_ 
                 GTSTEPSEGSAPGSP 
                 342 
                 GGTACTTCTACCGAACCGTCCGAGGGTAGCGC 
                 379 
               
               
                 GFP-N_G10.ab1 
                 AGSPTSTEEGTSTEP 
                   
                 ACCAGGTAGCCCAGCAGGTTCTCCTACCTCCA 
                   
               
               
                   
                 SEGSAP 
                   
                 CCGAGGAAGGTACTTCTACCGAACCGTCCGAG 
                   
               
               
                   
                   
                   
                 GGTAGCGCACCA 
                   
               
               
                   
               
               
                 LCW0402_050_ 
                 GSEPATSGSETPGT 
                 343 
                 GGTAGCGAACCGGCAACCTCCGGCTCTGAAAC 
                 380 
               
               
                 GFP-N_A11.ab1 
                 SESATPESGPGSEPA 
                   
                 TCCAGGTACTTCTGAAAGCGCTACTCCGGAAT 
                   
               
               
                   
                 TSGSETP 
                   
                 CCGGCCCAGGTAGCGAACCGGCTACTTCCGGC 
                   
               
               
                   
                   
                   
                 TCTGAAACCCCA 
                   
               
               
                   
               
               
                 LCW0402_051_ 
                 GSEPATSGSETPGT 
                 344 
                 GGTAGCGAACCGGCAACTTCCGGCTCTGAAAC 
                 381 
               
               
                 GFP-N_B11.ab1 
                 SESATPESGPGSEPA 
                   
                 CCCAGGTACTTCTGAAAGCGCTACTCCTGAGT 
                   
               
               
                   
                 TSGSETP 
                   
                 CTGGCCCAGGTAGCGAACCTGCTACCTCTGGC 
                   
               
               
                   
                   
                   
                 TCTGAAACCCCA 
                   
               
               
                   
               
               
                 LCW0402_059_ 
                 GSEPATSGSETPGS 
                 345 
                 GGTAGCGAACCGGCAACCTCTGGCTCTGAAAC 
                 382 
               
               
                 GFP-N_E11.ab1 
                 EPATSGSETPGTSTE 
                   
                 TCCAGGTAGCGAACCTGCAACCTCCGGCTCTG 
                   
               
               
                   
                 PSEGSAP 
                   
                 AAACCCCAGGTACTTCTACTGAACCTTCTGAG 
                   
               
               
                   
                   
                   
                 GGCAGCGCACCA 
                   
               
               
                   
               
               
                 LCW0402_060_ 
                 GTSESATPESGPGS 
                 346 
                 GGTACTTCTGAAAGCGCTACCCCGGAATCTGG 
                 383 
               
               
                 GFP-N_F11.ab1 
                 EPATSGSETPGSEP 
                   
                 CCCAGGTAGCGAACCGGCTACTTCTGGTTCTG 
                   
               
               
                   
                 ATSGSETP 
                   
                 AAACCCCAGGTAGCGAACCGGCTACCTCCGGT 
                   
               
               
                   
                   
                   
                 TCTGAAACTCCA 
                   
               
               
                   
               
               
                 LCW0402_061_ 
                 GTSTEPSEGSAPGT 
                 347 
                 GGTACCTCTACTGAACCTTCCGAAGGCAGCGC 
                 384 
               
               
                 GFP-N_G11.ab1 
                 STEPSEGSAPGTSES 
                   
                 TCCAGGTACCTCTACCGAACCGTCCGAGGGCA 
                   
               
               
                   
                 ATPESGP 
                   
                 GCGCACCAGGTACTTCTGAAAGCGCAACCCCT 
                   
               
               
                   
                   
                   
                 GAATCCGGTCCA 
                   
               
               
                   
               
               
                 LCW0402_065_ 
                 GSEPATSGSETPGT 
                 348 
                 GGTAGCGAACCGGCAACCTCTGGCTCTGAAAC 
                 385 
               
               
                 GFP-N_A12.ab1 
                 SESATPESGPGTSES 
                   
                 CCCAGGTACCTCTGAAAGCGCTACTCCGGAAT 
                   
               
               
                   
                 ATPESGP 
                   
                 CTGGTCCAGGTACTTCTGAAAGCGCTACTCCG 
                   
               
               
                   
                   
                   
                 GAATCCGGTCCA 
                   
               
               
                   
               
               
                 LCW0402_066_ 
                 GSEPATSGSETPGS 
                 349 
                 GGTAGCGAACCTGCTACCTCCGGCTCTGAAAC 
                 386 
               
               
                 GFP-N_B12.ab1 
                 EPATSGSETPGTSTE 
                   
                 TCCAGGTAGCGAACCGGCTACTTCCGGTTCTG 
                   
               
               
                   
                 PSEGSAP 
                   
                 AAACTCCAGGTACCTCTACCGAACCTTCCGAA 
                   
               
               
                   
                   
                   
                 GGCAGCGCACCA 
                   
               
               
                   
               
               
                 LCW0402_067_ 
                 GSEPATSGSETPGT 
                 350 
                 GGTAGCGAACCTGCTACTTCTGGTTCTGAAACT 
                 387 
               
               
                 GFP-N_C12.ab1 
                 STEPSEGSAPGSEPA 
                   
                 CCAGGTACTTCTACCGAACCGTCCGAGGGTAG 
                   
               
               
                   
                 TSGSETP 
                   
                 CGCTCCAGGTAGCGAACCTGCTACTTCTGGTTC 
                   
               
               
                   
                   
                   
                 TGAAACTCCA 
                   
               
               
                   
               
               
                 LCW0402_069_ 
                 GTSTEPSEGSAPGT 
                 351 
                 GGTACCTCTACCGAACCGTCCGAGGGTAGCGC 
                 388 
               
               
                 GFP-N_D12.ab1 
                 STEPSEGSAPGSEPA 
                   
                 ACCAGGTACCTCTACTGAACCGTCTGAGGGTA 
                   
               
               
                   
                 TSGSETP 
                   
                 GCGCTCCAGGTAGCGAACCGGCAACCTCCGGT 
                   
               
               
                   
                   
                   
                 TCTGAAACTCCA 
                   
               
               
                   
               
               
                 LCW0402_073_ 
                 GTSTEPSEGSAPGS 
                 352 
                 GGTACTTCTACTGAACCTTCCGAAGGTAGCGC 
                 389 
               
               
                 GFP-N_F12.ab1 
                 EPATSGSETPGSPA 
                   
                 TCCAGGTAGCGAACCTGCTACTTCTGGTTCTGA 
                   
               
               
                   
                 GSPTSTEE 
                   
                 AACCCCAGGTAGCCCGGCTGGCTCTCCGACCT 
                   
               
               
                   
                   
                   
                 CCACCGAGGAA 
                   
               
               
                   
               
               
                 LCW0402_074_ 
                 GSEPATSGSETPGSP 
                 353 
                 GGTAGCGAACCGGCTACTTCCGGCTCTGAGAC 
                 390 
               
               
                 GFP-N_G12.ab1 
                 AGSPTSTEEGTSES 
                   
                 TCCAGGTAGCCCAGCTGGTTCTCCAACCTCTAC 
                   
               
               
                   
                 ATPESGP 
                   
                 TGAGGAAGGTACTTCTGAAAGCGCTACCCCTG 
                   
               
               
                   
                   
                   
                 AATCTGGTCCA 
                   
               
               
                   
               
               
                 LCW0402_075_ 
                 GTSESATPESGPGS 
                 354 
                 GGTACCTCTGAAAGCGCAACTCCTGAGTCTGG 
                 391 
               
               
                 GFP-N_H12.ab1 
                 EPATSGSETPGTSES 
                   
                 CCCAGGTAGCGAACCTGCTACCTCCGGCTCTG 
                   
               
               
                   
                 ATPESGP 
                   
                 AGACTCCAGGTACCTCTGAAAGCGCAACCCCG 
                   
               
               
                   
                   
                   
                 GAATCTGGTCCA 
               
               
                   
               
            
           
         
       
     
     Example 3: Construction of XTEN_AF36 Segments 
     A codon library encoding sequences of 36 amino acid length was constructed. The sequences were designated XTEN_AF36. Its segments have the amino acid sequence [X] 3  where X is a 12mer peptide with the sequence: GSTSESPSGTAP (SEQ ID NO: 10), GTSTPESGSASP (SEQ ID NO: 11), GTSPSGESSTAP (SEQ ID NO: 12), or GSTSSTAESPGP (SEQ ID NO: 13). The insert was obtained by annealing the following pairs of phosphorylated synthetic oligonucleotide pairs: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 392) 
               
               
                   
                 AF1for: AGGTTCTACYAGCGAATCYCCKTCTGGYACYGCWCC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 393) 
               
               
                   
                 AF1rev: ACCTGGWGCRGTRCCAGAMGGRGATTCGCTRGTAGA 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 394) 
               
               
                   
                 AF2for: AGGTACYTCTACYCCKGAAAGCGGYTCYGCWTCTCC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 395) 
               
               
                   
                 AF2rev: ACCTGGAGAWGCRGARCCGCTTTCMGGRGTAGARGT 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 396) 
               
               
                   
                 AF3for: AGGTACYTCYCCKAGCGGYGAATCTTCTACYGCWCC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 397) 
               
               
                   
                 AF3rev: ACCTGGWGCRGTAGAAGATTCRCCGCTMGGRGARGT 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 398) 
               
               
                   
                 AF4for: AGGTTCYACYAGCTCTACYGCWGAATCTCCKGGYCC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 399) 
               
               
                   
                 AF4rev: ACCTGGRCCMGGAGATTCWGCRGTAGAGCTRGTRGA 
               
            
           
         
       
     
     We also annealed the phosphorylated oligonucleotide 3KpnIstopperFor: AGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 232) and the non-phosphorylated oligonucleotide pr_3 KpnIstopperRev: CCTCGAGTGAAGACGA (SEQ ID NO: 233). The annealed oligonucleotide pairs were ligated, which resulted in a mixture of products with varying length that represents the varying number of 12mer repeats ligated to one BbsI/KpnI segment The products corresponding to the length of 36 amino acids were isolated from the mixture by preparative agarose gel electrophoresis and ligated into the BsaI/KpnI digested stuffer vector pCW0359. Most of the clones in the resulting library designated LCW0403 showed green fluorescence after induction which shows that the sequence of XTEN_AF36 had been ligated in frame with the GFP gene and most sequences of XTEN_AF36 show good expression. 
     We screened 96 isolates from library LCW0403 for high level of fluorescence by stamping them onto agar plate containing IPTG. The same isolates were evaluated by PCR and 48 isolates were identified that contained segments with 36 amino acids as well as strong fluorescence. These isolates were sequenced and 44 clones were identified that contained correct XTEN_AF36 segments. The file names of the nucleotide and amino acid constructs and the sequences for these segments are listed in Table 13. 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 DNA and Amino Acid Sequences for 36-mer motifs 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
                 SEQ 
               
               
                   
                   
                 ID 
                   
                 ID 
               
               
                 File name 
                 Amino acid sequence 
                 NO: 
                 Nucleotide sequence 
                 NO: 
               
               
                   
               
               
                 LCW0403_004_ 
                 GTSTPESGSASPGTS 
                 400 
                 GGTACTTCTACTCCGGAAAGCGGTTCCGCATCT 
                 444 
               
               
                 GFP-N_A01.ab1 
                 PSGESSTAPGTSPSG 
                   
                 CCAGGTACTTCTCCTAGCGGTGAATCTTCTACT 
                   
               
               
                   
                 ESSTAP 
                   
                 GCTCCAGGTACCTCTCCTAGCGGCGAATCTTCT 
                   
               
               
                   
                   
                   
                 ACTGCTCCA 
                   
               
               
                   
               
               
                 LCW0403_005_ 
                 GTSPSGESSTAPGST 
                 401 
                 GGTACTTCTCCGAGCGGTGAATCTTCTACCGCA 
                 445 
               
               
                 GFP-N_B01.ab1 
                 SSTAESPGPGTSPSG 
                   
                 CCAGGTTCTACTAGCTCTACCGCTGAATCTCCG 
                   
               
               
                   
                 ESSTAP 
                   
                 GGCCCAGGTACTTCTCCGAGCGGTGAATCTTCT 
                   
               
               
                   
                   
                   
                 ACTGCTCCA 
                   
               
               
                   
               
               
                 LCW0403_006_ 
                 GSTSSTAESPGPGTS 
                 402 
                 GGTTCCACCAGCTCTACTGCTGAATCTCCTGGT 
                 446 
               
               
                 GFP-N_C01.ab1 
                 PSGESSTAPGTSTPES 
                   
                 CCAGGTACCTCTCCTAGCGGTGAATCTTCTACT 
                   
               
               
                   
                 GSASP 
                   
                 GCTCCAGGTACTTCTACTCCTGAAAGCGGCTCT 
                   
               
               
                   
                   
                   
                 GCTTCTCCA 
                   
               
               
                   
               
               
                 LCW0403_007_ 
                 GSTSSTAESPGPGST 
                 403 
                 GGTTCTACCAGCTCTACTGCAGAATCTCCTGGC 
                 447 
               
               
                 GFP-N_D01.ab1 
                 SSTAESPGPGTSPSG 
                   
                 CCAGGTTCCACCAGCTCTACCGCAGAATCTCCG 
                   
               
               
                   
                 ESSTAP 
                   
                 GGTCCAGGTACTTCCCCTAGCGGTGAATCTTCT 
                   
               
               
                   
                   
                   
                 ACCGCACCA 
                   
               
               
                   
               
               
                 LCW0403_008_ 
                 GSTSSTAESPGPGTS 
                 404 
                 GGTTCTACTAGCTCTACTGCTGAATCTCCTGGCC 
                 448 
               
               
                 GFP-N_E01.ab1 
                 PSGESSTAPGTSTPES 
                   
                 CAGGTACTTCTCCTAGCGGTGAATCTTCTACCG 
                   
               
               
                   
                 GSASP 
                   
                 CTCCAGGTACCTCTACTCCGGAAAGCGGTTCTG 
                   
               
               
                   
                   
                   
                 CATCTCCA 
                   
               
               
                   
               
               
                 LCW0403_010_ 
                 GSTSSTAESPGPGTS 
                 405 
                 GGTTCTACCAGCTCTACCGCAGAATCTCCTGGT 
                 449 
               
               
                 GFP-N_F01.ab1 
                 TPESGSASPGSTSESP 
                   
                 CCAGGTACCTCTACTCCGGAAAGCGGCTCTGCA 
                   
               
               
                   
                 SGTAP 
                   
                 TCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCA 
                   
               
               
                   
                   
                   
                 CTGCACCA 
                   
               
               
                   
               
               
                 LCW0403_011_ 
                 GSTSSTAESPGPGTS 
                 406 
                 GGTTCTACTAGCTCTACTGCAGAATCTCCTGGC 
                 450 
               
               
                 GFP-N_G01.ab1 
                 TPESGSASPGTSTPES 
                   
                 CCAGGTACCTCTACTCCGGAAAGCGGCTCTGCA 
                   
               
               
                   
                 GSASP 
                   
                 TCTCCAGGTACTTCTACCCCTGAAAGCGGTTCT 
                   
               
               
                   
                   
                   
                 GCATCTCCA 
                   
               
               
                   
               
               
                 LCW0403_012_ 
                 GSTSESPSGTAPGTS 
                 407 
                 GGTTCTACCAGCGAATCTCCTTCTGGCACCGCT 
                 451 
               
               
                 GFP-N_H01.ab1 
                 PSGESSTAPGSTSESP 
                   
                 CCAGGTACCTCTCCTAGCGGCGAATCTTCTACC 
                   
               
               
                   
                 SGTAP 
                   
                 GCTCCAGGTTCTACTAGCGAATCTCCTTCTGGC 
                   
               
               
                   
                   
                   
                 ACTGCACCA 
                   
               
               
                   
               
               
                 LCW0403_013_ 
                 GSTSSTAESPGPGST 
                 408 
                 GGTTCCACCAGCTCTACTGCAGAATCTCCGGGC 
                 452 
               
               
                 GFP-N_A02.ab1 
                 SSTAESPGPGTSPSG 
                   
                 CCAGGTTCTACTAGCTCTACTGCAGAATCTCCG 
                   
               
               
                   
                 ESSTAP 
                   
                 GGTCCAGGTACTTCTCCTAGCGGCGAATCTTCT 
                   
               
               
                   
                   
                   
                 ACCGCTCCA 
                   
               
               
                   
               
               
                 LCW0403_014_ 
                 GSTSSTAESPGPGTS 
                 409 
                 GGTTCCACTAGCTCTACTGCAGAATCTCCTGGC 
                 453 
               
               
                 GFP-N_B02.ab1 
                 TPESGSASPGSTSESP 
                   
                 CCAGGTACCTCTACCCCTGAAAGCGGCTCTGCA 
                   
               
               
                   
                 SGTAP 
                   
                 TCTCCAGGTTCTACCAGCGAATCCCCGTCTGGC 
                   
               
               
                   
                   
                   
                 ACCGCACCA 
                   
               
               
                   
               
               
                 LCW0403_015_ 
                 GSTSSTAESPGPGST 
                 410 
                 GGTTCTACTAGCTCTACTGCTGAATCTCCGGGT 
                 454 
               
               
                 GFP-N_C02.ab1 
                 SSTAESPGPGTSPSG 
                   
                 CCAGGTTCTACCAGCTCTACTGCTGAATCTCCT 
                   
               
               
                   
                 ESSTAP 
                   
                 GGTCCAGGTACCTCCCCGAGCGGTGAATCTTCT 
                   
               
               
                   
                   
                   
                 ACTGCACCA 
                   
               
               
                   
               
               
                 LCW0403_017_ 
                 GSTSSTAESPGPGST 
                 411 
                 GGTTCTACCAGCTCTACCGCTGAATCTCCTGGC 
                 455 
               
               
                 GFP-N_D02.ab1 
                 SESPSGTAPGSTSST 
                   
                 CCAGGTTCTACCAGCGAATCCCCGTCTGGCACC 
                   
               
               
                   
                 AESPGP 
                   
                 GCACCAGGTTCTACTAGCTCTACCGCTGAATCT 
                   
               
               
                   
                   
                   
                 CCGGGTCCA 
                   
               
               
                   
               
               
                 LCW0403_018_ 
                 GSTSSTAESPGPGST 
                 412 
                 GGTTCTACCAGCTCTACCGCAGAATCTCCTGGC 
                 456 
               
               
                 GFP-N_E02.ab1 
                 SSTAESPGPGSTSST 
                   
                 CCAGGTTCCACTAGCTCTACCGCTGAATCTCCT 
                   
               
               
                   
                 AESPGP 
                   
                 GGTCCAGGTTCTACTAGCTCTACCGCTGAATCT 
                   
               
               
                   
                   
                   
                 CCTGGTCCA 
                   
               
               
                   
               
               
                 LCW0403_019_ 
                 GSTSESPSGTAPGST 
                 413 
                 GGTTCTACTAGCGAATCCCCTTCTGGTACTGCTC 
                 457 
               
               
                 GFP-N_F02.ab1 
                 SSTAESPGPGSTSST 
                   
                 CAGGTTCCACTAGCTCTACCGCTGAATCTCCTG 
                   
               
               
                   
                 AESPGP 
                   
                 GCCCAGGTTCCACTAGCTCTACTGCAGAATCTC 
                   
               
               
                   
                   
                   
                 CTGGTCCA 
                   
               
               
                   
               
               
                 LCW0403_023_ 
                 GSTSESPSGTAPGST 
                 414 
                 GGTTCTACTAGCGAATCTCCTTCTGGTACCGCTC 
                 458 
               
               
                 GFP-N_H02.ab1 
                 SESPSGTAPGSTSESP 
                   
                 CAGGTTCTACCAGCGAATCCCCGTCTGGTACTG 
                   
               
               
                   
                 SGTAP 
                   
                 CTCCAGGTTCTACCAGCGAATCTCCTTCTGGTA 
                   
               
               
                   
                   
                   
                 CTGCACCA 
                   
               
               
                   
               
               
                 LCW0403_024_ 
                 GSTSSTAESPGPGST 
                 415 
                 GGTTCCACCAGCTCTACTGCTGAATCTCCTGGC 
                 459 
               
               
                 GFP-N_A03.ab1 
                 SSTAESPGPGSTSST 
                   
                 CCAGGTTCTACCAGCTCTACTGCTGAATCTCCG 
                   
               
               
                   
                 AESPGP 
                   
                 GGCCCAGGTTCCACCAGCTCTACCGCTGAATCT 
                   
               
               
                   
                   
                   
                 CCGGGTCCA 
                   
               
               
                   
               
               
                 LCW0403_025_ 
                 GSTSSTAESPGPGST 
                 416 
                 GGTTCCACTAGCTCTACCGCAGAATCTCCTGGT 
                 460 
               
               
                 GFP-N_B03.ab1 
                 SSTAESPGPGTSPSG 
                   
                 CCAGGTTCTACTAGCTCTACTGCTGAATCTCCG 
                   
               
               
                   
                 ESSTAP 
                   
                 GGTCCAGGTACCTCCCCTAGCGGCGAATCTTCT 
                   
               
               
                   
                   
                   
                 ACCGCTCCA 
                   
               
               
                   
               
               
                 LCW0403_028_ 
                 GSSPSASTGTGPGSS 
                 417 
                 GGTTCTAGCCCTTCTGCTTCCACCGGTACCGGC 
                 461 
               
               
                 GFP-N_D03.ab1 
                 TPSGATGSPGSSTPS 
                   
                 CCAGGTAGCTCTACTCCGTCTGGTGCAACTGGC 
                   
               
               
                   
                 GATGSP 
                   
                 TCTCCAGGTAGCTCTACTCCGTCTGGTGCAACC 
                   
               
               
                   
                   
                   
                 GGCTCCCCA 
                   
               
               
                   
               
               
                 LCW0403_029_ 
                 GTSPSGESSTAPGTS 
                 418 
                 GGTACTTCCCCTAGCGGTGAATCTTCTACTGCTC 
                 462 
               
               
                 GFP-N_E03.ab1 
                 TPESGSASPGSTSST 
                   
                 CAGGTACCTCTACTCCGGAAAGCGGCTCCGCAT 
                   
               
               
                   
                 AESPGP 
                   
                 CTCCAGGTTCTACTAGCTCTACTGCTGAATCTCC 
                   
               
               
                   
                   
                   
                 TGGTCCA 
                   
               
               
                   
               
               
                 LCW0403_030_ 
                 GSTSSTAESPGPGST 
                 419 
                 GGTTCTACTAGCTCTACCGCTGAATCTCCGGGT 
                 463 
               
               
                 GFP-N_F03.ab1 
                 SSTAESPGPGTSTPES 
                   
                 CCAGGTTCTACCAGCTCTACTGCAGAATCTCCT 
                   
               
               
                   
                 GSASP 
                   
                 GGCCCAGGTACTTCTACTCCGGAAAGCGGTTCC 
                   
               
               
                   
                   
                   
                 GCTTCTCCA 
                   
               
               
                   
               
               
                 LCW0403_031_ 
                 GTSPSGESSTAPGST 
                 420 
                 GGTACTTCTCCTAGCGGTGAATCTTCTACCGCTC 
                 464 
               
               
                 GFP-N_G03.ab1 
                 SSTAESPGPGTSTPES 
                   
                 CAGGTTCTACCAGCTCTACTGCTGAATCTCCTG 
                   
               
               
                   
                 GSASP 
                   
                 GCCCAGGTACTTCTACCCCGGAAAGCGGCTCCG 
                   
               
               
                   
                   
                   
                 CTTCTCCA 
                   
               
               
                   
               
               
                 LCW0403_033_ 
                 GSTSESPSGTAPGST 
                 421 
                 GGTTCTACTAGCGAATCCCCTTCTGGTACTGCA 
                 465 
               
               
                 GFP-N_H03.ab1 
                 SSTAESPGPGSTSST 
                   
                 CCAGGTTCTACCAGCTCTACTGCTGAATCTCCG 
                   
               
               
                   
                 AESPGP 
                   
                 GGCCCAGGTTCCACCAGCTCTACCGCAGAATCT 
                   
               
               
                   
                   
                   
                 CCTGGTCCA 
                   
               
               
                   
               
               
                 LCW0403_035_ 
                 GSTSSTAESPGPGST 
                 422 
                 GGTTCCACCAGCTCTACCGCTGAATCTCCGGGC 
                 466 
               
               
                 GFP-N_A04.ab1 
                 SESPSGTAPGSTSST 
                   
                 CCAGGTTCTACCAGCGAATCCCCTTCTGGCACT 
                   
               
               
                   
                 AESPGP 
                   
                 GCACCAGGTTCTACTAGCTCTACCGCAGAATCT 
                   
               
               
                   
                   
                   
                 CCGGGCCCA 
                   
               
               
                   
               
               
                 LCW0403_036_ 
                 GSTSSTAESPGPGTS 
                 423 
                 GGTTCTACCAGCTCTACTGCTGAATCTCCGGGT 
                 467 
               
               
                 GFP-N_B04.ab1 
                 PSGESSTAPGTSTPES 
                   
                 CCAGGTACTTCCCCGAGCGGTGAATCTTCTACT 
                   
               
               
                   
                 GSASP 
                   
                 GCACCAGGTACTTCTACTCCGGAAAGCGGTTCC 
                   
               
               
                   
                   
                   
                 GCTTCTCCA 
                   
               
               
                   
               
               
                 LCW0403_039_ 
                 GSTSESPSGTAPGST 
                 424 
                 GGTTCTACCAGCGAATCTCCTTCTGGCACCGCT 
                 468 
               
               
                 GFP-N_C04.ab1 
                 SESPSGTAPGTSPSG 
                   
                 CCAGGTTCTACTAGCGAATCCCCGTCTGGTACC 
                   
               
               
                   
                 ESSTAP 
                   
                 GCACCAGGTACTTCTCCTAGCGGCGAATCTTCT 
                   
               
               
                   
                   
                   
                 ACCGCACCA 
                   
               
               
                   
               
               
                 LCW0403_041_ 
                 GSTSESPSGTAPGST 
                 425 
                 GGTTCTACCAGCGAATCCCCTTCTGGTACTGCT 
                 469 
               
               
                 GFP-N_D04.ab1 
                 SESPSGTAPGTSTPES 
                   
                 CCAGGTTCTACCAGCGAATCCCCTTCTGGCACC 
                   
               
               
                   
                 GSASP 
                   
                 GCACCAGGTACTTCTACCCCTGAAAGCGGCTCC 
                   
               
               
                   
                   
                   
                 GCTTCTCCA 
                   
               
               
                   
               
               
                 LCW0403_044_ 
                 GTSTPESGSASPGST 
                 426 
                 GGTACCTCTACTCCTGAAAGCGGTTCTGCATCT 
                 470 
               
               
                 GFP-N_E04.ab1 
                 SSTAESPGPGSTSST 
                   
                 CCAGGTTCCACTAGCTCTACCGCAGAATCTCCG 
                   
               
               
                   
                 AESPGP 
                   
                 GGCCCAGGTTCTACTAGCTCTACTGCTGAATCT 
                   
               
               
                   
                   
                   
                 CCTGGCCCA 
                   
               
               
                   
               
               
                 LCW0403_046_ 
                 GSTSESPSGTAPGST 
                 427 
                 GGTTCTACCAGCGAATCCCCTTCTGGCACTGCA 
                 471 
               
               
                 GFP-N_F04.ab1 
                 SESPSGTAPGTSPSG 
                   
                 CCAGGTTCTACTAGCGAATCCCCTTCTGGTACC 
                   
               
               
                   
                 ESSTAP 
                   
                 GCACCAGGTACTTCTCCGAGCGGCGAATCTTCT 
                   
               
               
                   
                   
                   
                 ACTGCTCCA 
                   
               
               
                   
               
               
                 LCW0403_047_ 
                 GSTSSTAESPGPGST 
                 428 
                 GGTTCTACTAGCTCTACCGCTGAATCTCCTGGC 
                 472 
               
               
                 GFP-N_G04.ab1 
                 SSTAESPGPGSTSESP 
                   
                 CCAGGTTCCACTAGCTCTACCGCAGAATCTCCG 
                   
               
               
                   
                 SGTAP 
                   
                 GGCCCAGGTTCTACTAGCGAATCCCCTTCTGGT 
                   
               
               
                   
                   
                   
                 ACCGCTCCA 
                   
               
               
                   
               
               
                 LCW0403_049_ 
                 GSTSSTAESPGPGST 
                 429 
                 GGTTCCACCAGCTCTACTGCAGAATCTCCTGGC 
                 473 
               
               
                 GFP-N_H04.ab1 
                 SSTAESPGPGTSTPES 
                   
                 CCAGGTTCTACTAGCTCTACCGCAGAATCTCCT 
                   
               
               
                   
                 GSASP 
                   
                 GGTCCAGGTACCTCTACTCCTGAAAGCGGTTCC 
                   
               
               
                   
                   
                   
                 GCATCTCCA 
                   
               
               
                   
               
               
                 LCW0403_051_ 
                 GSTSSTAESPGPGST 
                 430 
                 GGTTCTACTAGCTCTACTGCTGAATCTCCGGGC 
                 474 
               
               
                 GFP-N_A05.ab1 
                 SSTAESPGPGSTSESP 
                   
                 CCAGGTTCTACTAGCTCTACCGCTGAATCTCCG 
                   
               
               
                   
                 SGTAP 
                   
                 GGTCCAGGTTCTACTAGCGAATCTCCTTCTGGT 
                   
               
               
                   
                   
                   
                 ACCGCTCCA 
                   
               
               
                   
               
               
                 LCW0403_053_ 
                 GTSPSGESSTAPGST 
                 431 
                 GGTACCTCCCCGAGCGGTGAATCTTCTACTGCA 
                 475 
               
               
                 GFP-N_B05.ab1 
                 SESPSGTAPGSTSST 
                   
                 CCAGGTTCTACTAGCGAATCCCCTTCTGGTACT 
                   
               
               
                   
                 AESPGP 
                   
                 GCTCCAGGTTCCACCAGCTCTACTGCAGAATCT 
                   
               
               
                   
                   
                   
                 CCGGGTCCA 
                   
               
               
                   
               
               
                 LCW0403_054_ 
                 GSTSESPSGTAPGTS 
                 432 
                 GGTTCTACTAGCGAATCCCCGTCTGGTACTGCT 
                 476 
               
               
                 GFP-N_C05.ab1 
                 PSGESSTAPGSTSST 
                   
                 CCAGGTACTTCCCCTAGCGGTGAATCTTCTACT 
                   
               
               
                   
                 AESPGP 
                   
                 GCTCCAGGTTCTACCAGCTCTACCGCAGAATCT 
                   
               
               
                   
                   
                   
                 CCGGGTCCA 
                   
               
               
                   
               
               
                 LCW0403_057_ 
                 GSTSSTAESPGPGST 
                 433 
                 GGTTCTACCAGCTCTACCGCTGAATCTCCTGGC 
                 477 
               
               
                 GFP-N_D05.ab1 
                 SESPSGTAPGTSPSG 
                   
                 CCAGGTTCTACTAGCGAATCTCCGTCTGGCACC 
                   
               
               
                   
                 ESSTAP 
                   
                 GCACCAGGTACTTCCCCTAGCGGTGAATCTTCT 
                   
               
               
                   
                   
                   
                 ACTGCACCA 
                   
               
               
                   
               
               
                 LCW0403_058_ 
                 GSTSESPSGTAPGST 
                 434 
                 GGTTCTACTAGCGAATCTCCTTCTGGCACTGCA 
                 478 
               
               
                 GFP-N_E05.ab1 
                 SESPSGTAPGTSTPES 
                   
                 CCAGGTTCTACCAGCGAATCTCCGTCTGGCACT 
                   
               
               
                   
                 GSASP 
                   
                 GCACCAGGTACCTCTACCCCTGAAAGCGGTTCC 
                   
               
               
                   
                   
                   
                 GCTTCTCCA 
                   
               
               
                   
               
               
                 LCW0403_060_ 
                 GTSTPESGSASPGST 
                 435 
                 GGTACCTCTACTCCGGAAAGCGGTTCCGCATCT 
                 479 
               
               
                 GFP-N_F05.ab1 
                 SESPSGTAPGSTSST 
                   
                 CCAGGTTCTACCAGCGAATCCCCGTCTGGCACC 
                   
               
               
                   
                 AESPGP 
                   
                 GCACCAGGTTCTACTAGCTCTACTGCTGAATCT 
                   
               
               
                   
                   
                   
                 CCGGGCCCA 
                   
               
               
                   
               
               
                 LCW0403_063_ 
                 GSTSSTAESPGPGTS 
                 436 
                 GGTTCTACTAGCTCTACTGCAGAATCTCCGGGC 
                 480 
               
               
                 GFP-N_G05.ab1 
                 PSGESSTAPGTSPSG 
                   
                 CCAGGTACCTCTCCTAGCGGTGAATCTTCTACC 
                   
               
               
                   
                 ESSTAP 
                   
                 GCTCCAGGTACTTCTCCGAGCGGTGAATCTTCT 
                   
               
               
                   
                   
                   
                 ACCGCTCCA 
                   
               
               
                   
               
               
                 LCW0403_064_ 
                 GTSPSGESSTAPGTS 
                 437 
                 GGTACCTCCCCTAGCGGCGAATCTTCTACTGCT 
                 481 
               
               
                 GFP-N_H05.ab1 
                 PSGESSTAPGTSPSG 
                   
                 CCAGGTACCTCTCCTAGCGGCGAATCTTCTACC 
                   
               
               
                   
                 ESSTAP 
                   
                 GCTCCAGGTACCTCCCCTAGCGGTGAATCTTCT 
                   
               
               
                   
                   
                   
                 ACCGCACCA 
                   
               
               
                   
               
               
                 LCW0403_065_ 
                 GSTSSTAESPGPGTS 
                 438 
                 GGTTCCACTAGCTCTACTGCTGAATCTCCTGGC 
                 482 
               
               
                 GFP-N_A06.ab1 
                 TPESGSASPGSTSESP 
                   
                 CCAGGTACTTCTACTCCGGAAAGCGGTTCCGCT 
                   
               
               
                   
                 SGTAP 
                   
                 TCTCCAGGTTCTACTAGCGAATCTCCGTCTGGC 
                   
               
               
                   
                   
                   
                 ACCGCACCA 
                   
               
               
                   
               
               
                 LCW0403_066_ 
                 GSTSESPSGTAPGTS 
                 439 
                 GGTTCTACTAGCGAATCTCCGTCTGGCACTGCT 
                 483 
               
               
                 GFP-N_B06.ab1 
                 PSGESSTAPGTSPSG 
                   
                 CCAGGTACTTCTCCTAGCGGTGAATCTTCTACC 
                   
               
               
                   
                 ESSTAP 
                   
                 GCTCCAGGTACTTCCCCTAGCGGCGAATCTTCT 
                   
               
               
                   
                   
                   
                 ACCGCTCCA 
                   
               
               
                   
               
               
                 LCW0403_067_ 
                 GSTSESPSGTAPGTS 
                 440 
                 GGTTCTACTAGCGAATCTCCTTCTGGTACCGCTC 
                 484 
               
               
                 GFP-N_C06.ab1 
                 TPESGSASPGSTSST 
                   
                 CAGGTACTTCTACCCCTGAAAGCGGCTCCGCTT 
                   
               
               
                   
                 AESPGP 
                   
                 CTCCAGGTTCCACTAGCTCTACCGCTGAATCTC 
                   
               
               
                   
                   
                   
                 CGGGTCCA 
                   
               
               
                   
               
               
                 LCW0403_068_ 
                 GSTSSTAESPGPGST 
                 441 
                 GGTTCCACTAGCTCTACTGCTGAATCTCCTGGC 
                 485 
               
               
                 GFP-N_D06.ab1 
                 SSTAESPGPGSTSESP 
                   
                 CCAGGTTCTACCAGCTCTACCGCTGAATCTCCT 
                   
               
               
                   
                 SGTAP 
                   
                 GGCCCAGGTTCTACCAGCGAATCTCCGTCTGGC 
                   
               
               
                   
                   
                   
                 ACCGCACCA 
                   
               
               
                   
               
               
                 LCW0403_069_ 
                 GSTSESPSGTAPGTS 
                 442 
                 GGTTCTACTAGCGAATCCCCGTCTGGTACCGCA 
                 486 
               
               
                 GFP-N_E06.ab1 
                 TPESGSASPGTSTPES 
                   
                 CCAGGTACTTCTACCCCGGAAAGCGGCTCTGCT 
                   
               
               
                   
                 GSASP 
                   
                 TCTCCAGGTACTTCTACCCCGGAAAGCGGCTCC 
                   
               
               
                   
                   
                   
                 GCATCTCCA 
                   
               
               
                   
               
               
                 LCW0403_070_ 
                 GSTSESPSGTAPGTS 
                 443 
                 GGTTCTACTAGCGAATCCCCGTCTGGTACTGCT 
                 487 
               
               
                 GFP-N_F06.ab1 
                 TPESGSASPGTSTPES 
                   
                 CCAGGTACTTCTACTCCTGAAAGCGGTTCCGCT 
                   
               
               
                   
                 GSASP 
                   
                 TCTCCAGGTACCTCTACTCCGGAAAGCGGTTCT 
                   
               
               
                   
                   
                   
                 GCATCTCCA 
               
               
                   
               
            
           
         
       
     
     Example 4: Construction of XTEN_AG36 Segments 
     A codon library encoding sequences of 36 amino acid length was constructed. The sequences were designated XTEN_AG36. Its segments have the amino acid sequence [X] 3  where X is a 12mer peptide with the sequence: GTPGSGTASSSP (SEQ ID NO: 14), GSSTPSGATGSP (SEQ ID NO: 15), GSSPSASTGTGP (SEQ ID NO: 16), or GASPGTSSTGSP (SEQ ID NO: 17). The insert was obtained by annealing the following pairs of phosphorylated synthetic oligonucleotide pairs: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 488) 
               
               
                   
                 AG1for: AGGTACYCCKGGYAGCGGTACYGCWTCTTCYTCTCC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 489) 
               
               
                   
                 AG1rev: ACCTGGAGARGAAGAWGCRGTACCGCTRCCMGGRGT 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 490) 
               
               
                   
                 AG2for: AGGTAGCTCTACYCCKTCTGGTGCWACYGGYTCYCC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 491) 
               
               
                   
                 AG2rev: ACCTGGRGARCCRGTWGCACCAGAMGGRGTAGAGCT 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 492) 
               
               
                   
                 AG3for: AGGTTCTAGCCCKTCTGCWTCYACYGGTACYGGYCC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 493) 
               
               
                   
                 AG3rev: ACCTGGRCCRGTACCRGTRGAWGCAGAMGGGCTAGA 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 494) 
               
               
                   
                 AG4for: AGGTGCWTCYCCKGGYACYAGCTCTACYGGTTCTCC 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 495) 
               
               
                   
                 AG4rev: ACCTGGAGAACCRGTAGAGCTRGTRCCMGGRGAWGC 
               
            
           
         
       
     
     We also annealed the phosphorylated oligonucleotide 3KpnIstopperFor: AGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 232) and the non-phosphorylated oligonucleotide pr_3 KpnIstopperRev: CCTCGAGTGAAGACGA (SEQ ID NO: 233). The annealed oligonucleotide pairs were ligated, which resulted in a mixture of products with varying length that represents the varying number of 12mer repeats ligated to one BbsI/KpnI segment. The products corresponding to the length of 36 amino acids were isolated from the mixture by preparative agarose gel electrophoresis and ligated into the BsaI/KpnI digested stuffer vector pCW0359. Most of the clones in the resulting library designated LCW0404 showed green fluorescence after induction which shows that the sequence of XTEN_AG36 had been ligated in frame with the GFP gene and most sequences of XTEN_AG36 show good expression. 
     We screened 96 isolates from library LCW0404 for high level of fluorescence by stamping them onto agar plate containing IPTG. The same isolates were evaluated by PCR and 48 isolates were identified that contained segments with 36 amino acids as well as strong fluorescence. These isolates were sequenced and 44 clones were identified that contained correct XTEN_AG36 segments. The file names of the nucleotide and amino acid constructs and the sequences for these segments are listed in Table 14. 
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 DNA and Amino Acid Sequences for 36-mer motifs 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
                 SEQ 
               
               
                   
                   
                 ID 
                   
                 ID 
               
               
                 File name 
                 Amino acid sequence 
                 NO: 
                 Nucleotide sequence 
                 NO: 
               
               
                   
               
               
                 LCW0404_001_ 
                 GASPGTSSTGSPGTPG 
                 496 
                 GGTGCATCCCCGGGCACTAGCTCTACCGGTT 
                 540 
               
               
                 GFP-N_A07.ab1 
                 SGTASSSPGSSTPSGA 
                   
                 CTCCAGGTACTCCTGGTAGCGGTACTGCTTC 
                   
               
               
                   
                 TGSP 
                   
                 TTCTTCTCCAGGTAGCTCTACTCCTTCTGGTG 
                   
               
               
                   
                   
                   
                 CTACTGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_003_ 
                 GSSTPSGATGSPGSSP 
                 497 
                 GGTAGCTCTACCCCTTCTGGTGCTACCGGCT 
                 541 
               
               
                 GFP-N_B07.ab1 
                 SASTGTGPGSSTPSGA 
                   
                 CTCCAGGTTCTAGCCCGTCTGCTTCTACCGGT 
                   
               
               
                   
                 TGSP 
                   
                 ACCGGTCCAGGTAGCTCTACCCCTTCTGGTG 
                   
               
               
                   
                   
                   
                 CTACTGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_006_ 
                 GASPGTSSTGSPGSSP 
                 498 
                 GGTGCATCTCCGGGTACTAGCTCTACCGGTT 
                 542 
               
               
                 GFP-N_C07.ab1 
                 SASTGTGPGSSTPSGA 
                   
                 CTCCAGGTTCTAGCCCTTCTGCTTCCACTGGT 
                   
               
               
                   
                 TGSP 
                   
                 ACCGGCCCAGGTAGCTCTACCCCGTCTGGTG 
                   
               
               
                   
                   
                   
                 CTACTGGTTCCCCA 
                   
               
               
                   
               
               
                 LCW0404_007_ 
                 GTPGSGTASSSPGSST 
                 499 
                 GGTACTCCGGGCAGCGGTACTGCTTCTTCCT 
                 543 
               
               
                 GFP-N_D07.ab1 
                 PSGATGSPGASPGTSS 
                   
                 CTCCAGGTAGCTCTACCCCTTCTGGTGCAAC 
                   
               
               
                   
                 TGSP 
                   
                 TGGTTCCCCAGGTGCATCCCCTGGTACTAGC 
                   
               
               
                   
                   
                   
                 TCTACCGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_009_ 
                 GTPGSGTASSSPGASP 
                 500 
                 GGTACCCCTGGCAGCGGTACTGCTTCTTCTTC 
                 544 
               
               
                 GFP-N_E07.ab1 
                 GTSSTGSPGSRPSAST 
                   
                 TCCAGGTGCTTCCCCTGGTACCAGCTCTACC 
                   
               
               
                   
                 GTGP 
                   
                 GGTTCTCCAGGTTCTAGACCTTCTGCATCCAC 
                   
               
               
                   
                   
                   
                 CGGTACTGGTCCA 
                   
               
               
                   
               
               
                 LCW0404_011_ 
                 GASPGTSSTGSPGSST 
                 501 
                 GGTGCATCTCCTGGTACCAGCTCTACCGGTT 
                 545 
               
               
                 GFP-N_F07.ab1 
                 PSGATGSPGASPGTSS 
                   
                 CTCCAGGTAGCTCTACTCCTTCTGGTGCTACT 
                   
               
               
                   
                 TGSP 
                   
                 GGCTCTCCAGGTGCTTCCCCGGGTACCAGCT 
                   
               
               
                   
                   
                   
                 CTACCGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_012_ 
                 GTPGSGTASSSPGSST 
                 502 
                 GGTACCCCGGGCAGCGGTACCGCATCTTCCT 
                 546 
               
               
                 GFP-N_G07.ab1 
                 PSGATGSPGSSTPSGA 
                   
                 CTCCAGGTAGCTCTACCCCGTCTGGTGCTAC 
                   
               
               
                   
                 TGSP 
                   
                 CGGTTCCCCAGGTAGCTCTACCCCGTCTGGT 
                   
               
               
                   
                   
                   
                 GCAACCGGCTCCCCA 
                   
               
               
                   
               
               
                 LCW0404_014_ 
                 GASPGTSSTGSPGASP 
                 503 
                 GGTGCATCTCCGGGCACTAGCTCTACTGGTT 
                 547 
               
               
                 GFP-N_H07.ab1 
                 GTSSTGSPGASPGTSS 
                   
                 CTCCAGGTGCATCCCCTGGCACTAGCTCTAC 
                   
               
               
                   
                 TGSP 
                   
                 TGGTTCTCCAGGTGCTTCTCCTGGTACCAGCT 
                   
               
               
                   
                   
                   
                 CTACTGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_015_ 
                 GSSTPSGATGSPGSSP 
                 504 
                 GGTAGCTCTACTCCGTCTGGTGCAACCGGCT 
                 548 
               
               
                 GFP-N_A08.ab1 
                 SASTGTGPGASPGTSS 
                   
                 CCCCAGGTTCTAGCCCGTCTGCTTCCACTGGT 
                   
               
               
                   
                 TGSP 
                   
                 ACTGGCCCAGGTGCTTCCCCGGGCACCAGCT 
                   
               
               
                   
                   
                   
                 CTACTGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_016_ 
                 GSSTPSGATGSPGSST 
                 505 
                 GGTAGCTCTACTCCTTCTGGTGCTACCGGTTC 
                 549 
               
               
                 GFP-N_B08.ab1 
                 PSGATGSPGTPGSGT 
                   
                 CCCAGGTAGCTCTACTCCTTCTGGTGCTACTG 
                   
               
               
                   
                 ASSSP 
                   
                 GTTCCCCAGGTACTCCGGGCAGCGGTACTGC 
                   
               
               
                   
                   
                   
                 TTCTTCCTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_017_ 
                 GSSTPSGATGSPGSST 
                 506 
                 GGTAGCTCTACTCCGTCTGGTGCAACCGGTT 
                 550 
               
               
                 GFP-N_C08.ab1 
                 PSGATGSPGASPGTSS 
                   
                 CCCCAGGTAGCTCTACTCCTTCTGGTGCTACT 
                   
               
               
                   
                 TGSP 
                   
                 GGCTCCCCAGGTGCATCCCCTGGCACCAGCT 
                   
               
               
                   
                   
                   
                 CTACCGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_018_ 
                 GTPGSGTA SSSPGSSP 
                 507 
                 GGTACTCCTGGTAGCGGTACCGCATCTTCCT 
                 551 
               
               
                 GFP-N_D08.ab1 
                 SASTGTGPGSSTPSGA 
                   
                 CTCCAGGTTCTAGCCCTTCTGCATCTACCGGT 
                   
               
               
                   
                 TGSP 
                   
                 ACCGGTCCAGGTAGCTCTACTCCTTCTGGTG 
                   
               
               
                   
                   
                   
                 CTACTGGCTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_023_ 
                 GASPGTSSTGSPGSSP 
                 508 
                 GGTGCTTCCCCGGGCACTAGCTCTACCGGTT 
                 552 
               
               
                 GFP-N_F08.ab1 
                 SASTGTGPGTPGSGT 
                   
                 CTCCAGGTTCTAGCCCTTCTGCATCTACTGGT 
                   
               
               
                   
                 ASSSP 
                   
                 ACTGGCCCAGGTACTCCGGGCAGCGGTACTG 
                   
               
               
                   
                   
                   
                 CTTCTTCCTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_025_ 
                 GSSTPSGATGSPGSST 
                 509 
                 GGTAGCTCTACTCCGTCTGGTGCTACCGGCT 
                 553 
               
               
                 GFP-N_G08.ab1 
                 PSGATGSPGASPGTSS 
                   
                 CTCCAGGTAGCTCTACCCCTTCTGGTGCAAC 
                   
               
               
                   
                 TGSP 
                   
                 CGGCTCCCCAGGTGCTTCTCCGGGTACCAGC 
                   
               
               
                   
                   
                   
                 TCTACTGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_029_ 
                 GTPGSGTASSSPGSST 
                 510 
                 GGTACCCCTGGCAGCGGTACCGCTTCTTCCT 
                 554 
               
               
                 GFP-N_A09.ab1 
                 PSGATGSPGSSPSAST 
                   
                 CTCCAGGTAGCTCTACCCCGTCTGGTGCTAC 
                   
               
               
                   
                 GTGP 
                   
                 TGGCTCTCCAGGTTCTAGCCCGTCTGCATCTA 
                   
               
               
                   
                   
                   
                 CCGGTACCGGCCCA 
                   
               
               
                   
               
               
                 LCW0404_030_ 
                 GSSTPSGATGSPGTPG 
                 511 
                 GGTAGCTCTACTCCTTCTGGTGCAACCGGCT 
                 555 
               
               
                 GFP-N_B09.ab1 
                 SGTASSSPGTPGSGTA 
                   
                 CCCCAGGTACCCCGGGCAGCGGTACCGCATC 
                   
               
               
                   
                 SSSP 
                   
                 TTCCTCTCCAGGTACTCCGGGTAGCGGTACT 
                   
               
               
                   
                   
                   
                 GCTTCTTCTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_031_ 
                 GTPGSGTASSSPGSST 
                 512 
                 GGTACCCCGGGTAGCGGTACTGCTTCTTCCT 
                 556 
               
               
                 GFP-N_C09.ab1 
                 PSGATGSPGASPGTSS 
                   
                 CTCCAGGTAGCTCTACCCCTTCTGGTGCAAC 
                   
               
               
                   
                 TGSP 
                   
                 CGGCTCTCCAGGTGCTTCTCCGGGCACCAGC 
                   
               
               
                   
                   
                   
                 TCTACCGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_034_ 
                 GSSTPSGATGSPGSST 
                 513 
                 GGTAGCTCTACCCCGTCTGGTGCTACCGGCT 
                 557 
               
               
                 GFP-N_D09.ab1 
                 PSGATGSPGASPGTSS 
                   
                 CTCCAGGTAGCTCTACCCCGTCTGGTGCAAC 
                   
               
               
                   
                 TGSP 
                   
                 CGGCTCCCCAGGTGCATCCCCGGGTACTAGC 
                   
               
               
                   
                   
                   
                 TCTACCGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_035_ 
                 GASPGTSSTGSPGTPG 
                 514 
                 GGTGCTTCTCCGGGCACCAGCTCTACTGGTT 
                 558 
               
               
                 GFP-N_E09.ab1 
                 SGTASSSPGSSTPSGA 
                   
                 CTCCAGGTACCCCGGGCAGCGGTACCGCATC 
                   
               
               
                   
                 TGSP 
                   
                 TTCTTCTCCAGGTAGCTCTACTCCTTCTGGTG 
                   
               
               
                   
                   
                   
                 CAACTGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_036_ 
                 GSSPSASTGTGPGSST 
                 515 
                 GGTTCTAGCCCGTCTGCTTCCACCGGTACTG 
                 559 
               
               
                 GFP-N_F09.ab1 
                 PSGATGSPGTPGSGT 
                   
                 GCCCAGGTAGCTCTACCCCGTCTGGTGCAAC 
                   
               
               
                   
                 ASSSP 
                   
                 TGGTTCCCCAGGTACCCCTGGTAGCGGTACC 
                   
               
               
                   
                   
                   
                 GCTTCTTCTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_037_ 
                 GASPGTSSTGSPGSSP 
                 516 
                 GGTGCTTCTCCGGGCACCAGCTCTACTGGTT 
                 560 
               
               
                 GFP-N_G09.ab1 
                 SASTGTGPGSSTPSGA 
                   
                 CTCCAGGTTCTAGCCCTTCTGCATCCACCGGT 
                   
               
               
                   
                 TGSP 
                   
                 ACCGGTCCAGGTAGCTCTACCCCTTCTGGTG 
                   
               
               
                   
                   
                   
                 CAACCGGCTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_040_ 
                 GASPGTSSTGSPGSST 
                 517 
                 GGTGCATCCCCGGGCACCAGCTCTACCGGTT 
                 561 
               
               
                 GFP-N_H09.ab1 
                 PSGATGSPGSSTPSGA 
                   
                 CTCCAGGTAGCTCTACCCCGTCTGGTGCTAC 
                   
               
               
                   
                 TGSP 
                   
                 CGGCTCTCCAGGTAGCTCTACCCCGTCTGGT 
                   
               
               
                   
                   
                   
                 GCTACTGGCTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_041_ 
                 GTPGSGTASSSPGSST 
                 518 
                 GGTACCCCTGGTAGCGGTACTGCTTCTTCCTC 
                 562 
               
               
                 GFP-N_A10.ab1 
                 PSGATGSPGTPGSGT 
                   
                 TCCAGGTAGCTCTACTCCGTCTGGTGCTACC 
                   
               
               
                   
                 ASSSP 
                   
                 GGTTCTCCAGGTACCCCGGGTAGCGGTACCG 
                   
               
               
                   
                   
                   
                 CATCTTCTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_043_ 
                 GSSPSASTGTGPGSST 
                 519 
                 GGTTCTAGCCCTTCTGCTTCCACCGGTACTGG 
                 563 
               
               
                 GFP-N_C10.ab1 
                 PSGATGSPGSSTPSGA 
                   
                 CCCAGGTAGCTCTACCCCTTCTGGTGCTACC 
                   
               
               
                   
                 TGSP 
                   
                 GGCTCCCCAGGTAGCTCTACTCCTTCTGGTG 
                   
               
               
                   
                   
                   
                 CAACTGGCTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_045_ 
                 GASPGTSSTGSPGSSP 
                 520 
                 GGTGCTTCTCCTGGCACCAGCTCTACTGGTTC 
                 564 
               
               
                 GFP-N_D10.ab1 
                 SASTGTGPGSSPSAST 
                   
                 TCCAGGTTCTAGCCCTTCTGCTTCTACCGGTA 
                   
               
               
                   
                 GTGP 
                   
                 CTGGTCCAGGTTCTAGCCCTTCTGCATCCACT 
                   
               
               
                   
                   
                   
                 GGTACTGGTCCA 
                   
               
               
                   
               
               
                 LCW0404_047_ 
                 GTPGSGTASSSPGASP 
                 521 
                 GGTACTCCTGGCAGCGGTACCGCTTCTTCTTC 
                 565 
               
               
                 GFP-N_F10.ab1 
                 GTSSTGSPGASPGTSS 
                   
                 TCCAGGTGCTTCTCCTGGTACTAGCTCTACTG 
                   
               
               
                   
                 TGSP 
                   
                 GTTCTCCAGGTGCTTCTCCGGGCACTAGCTCT 
                   
               
               
                   
                   
                   
                 ACTGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_048_ 
                 GSSTPSGATGSPGASP 
                 522 
                 GGTAGCTCTACCCCGTCTGGTGCTACCGGTT 
                 566 
               
               
                 GFP-N_G10.ab1 
                 GTSSTGSPGSSTPSGA 
                   
                 CCCCAGGTGCTTCTCCTGGTACTAGCTCTACC 
                   
               
               
                   
                 TGSP 
                   
                 GGTTCTCCAGGTAGCTCTACCCCGTCTGGTG 
                   
               
               
                   
                   
                   
                 CTACTGGCTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_049_ 
                 GSSTPSGATGSPGTPG 
                 523 
                 GGTAGCTCTACCCCGTCTGGTGCTACTGGTT 
                 567 
               
               
                 GFP-N_H10.ab1 
                 SGTASSSPGSSTPSGA 
                   
                 CTCCAGGTACTCCGGGCAGCGGTACTGCTTC 
                   
               
               
                   
                 TGSP 
                   
                 TTCCTCTCCAGGTAGCTCTACCCCTTCTGGTG 
                   
               
               
                   
                   
                   
                 CTACTGGCTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_050_ 
                 GASPGTSSTGSPGSSP 
                 524 
                 GGTGCATCTCCTGGTACCAGCTCTACTGGTT 
                 568 
               
               
                 GFP-N_A11.ab1 
                 SASTGTGPGSSTPSGA 
                   
                 CTCCAGGTTCTAGCCCTTCTGCTTCTACCGGT 
                   
               
               
                   
                 TGSP 
                   
                 ACCGGTCCAGGTAGCTCTACTCCTTCTGGTG 
                   
               
               
                   
                   
                   
                 CTACCGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_051_ 
                 GSSTPSGATGSPGSST 
                 525 
                 GGTAGCTCTACCCCGTCTGGTGCTACTGGCT 
                 569 
               
               
                 GFP-N_Bll.ab1 
                 PSGATGSPGSSTPSGA 
                   
                 CTCCAGGTAGCTCTACTCCTTCTGGTGCTACT 
                   
               
               
                   
                 TGSP 
                   
                 GGTTCCCCAGGTAGCTCTACCCCGTCTGGTG 
                   
               
               
                   
                   
                   
                 CAACTGGCTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_052_ 
                 GASPGTSSTGSPGTPG 
                 526 
                 GGTGCATCCCCGGGTACCAGCTCTACCGGTT 
                 570 
               
               
                 GFP-N_C11.ab1 
                 SGTASSSPGASPGTSS 
                   
                 CTCCAGGTACTCCTGGCAGCGGTACTGCATC 
                   
               
               
                   
                 TGSP 
                   
                 TTCCTCTCCAGGTGCTTCTCCGGGCACCAGCT 
                   
               
               
                   
                   
                   
                 CTACTGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_053_ 
                 GSSTPSGATGSPGSSP 
                 527 
                 GGTAGCTCTACTCCTTCTGGTGCAACTGGTTC 
                 571 
               
               
                 GFP-N_D11.ab1 
                 SASTGTGPGASPGTSS 
                   
                 TCCAGGTTCTAGCCCGTCTGCATCCACTGGT 
                   
               
               
                   
                 TGSP 
                   
                 ACCGGTCCAGGTGCTTCCCCTGGCACCAGCT 
                   
               
               
                   
                   
                   
                 CTACCGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_057_ 
                 GASPGTSSTGSPGSST 
                 528 
                 GGTGCATCTCCTGGTACTAGCTCTACTGGTTC 
                 572 
               
               
                 GFP-N_E11.ab1 
                 PSGATGSPGSSPSAST 
                   
                 TCCAGGTAGCTCTACTCCGTCTGGTGCAACC 
                   
               
               
                   
                 GTGP 
                   
                 GGCTCTCCAGGTTCTAGCCCTTCTGCATCTAC 
                   
               
               
                   
                   
                   
                 CGGTACTGGTCCA 
                   
               
               
                   
               
               
                 LCW0404_060_ 
                 GTPGSGTASSSPGSST 
                 529 
                 GGTACTCCTGGCAGCGGTACCGCATCTTCCT 
                 573 
               
               
                 GFP-N_F11.ab1 
                 PSGATGSPGASPGTSS 
                   
                 CTCCAGGTAGCTCTACTCCGTCTGGTGCAAC 
                   
               
               
                   
                 TGSP 
                   
                 TGGTTCCCCAGGTGCTTCTCCGGGTACCAGC 
                   
               
               
                   
                   
                   
                 TCTACCGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_062_ 
                 GSSTPSGATGSPGTPG 
                 530 
                 GGTAGCTCTACCCCGTCTGGTGCAACCGGCT 
                 574 
               
               
                 GFP-N_G11.ab1 
                 SGTASSSPGSSTPSGA 
                   
                 CCCCAGGTACTCCTGGTAGCGGTACCGCTTC 
                   
               
               
                   
                 TGSP 
                   
                 TTCTTCTCCAGGTAGCTCTACTCCGTCTGGTG 
                   
               
               
                   
                   
                   
                 CTACCGGCTCCCCA 
                   
               
               
                   
               
               
                 LCW0404_066_ 
                 GSSPSASTGTGPGSSP 
                 531 
                 GGTTCTAGCCCTTCTGCATCCACCGGTACCG 
                 575 
               
               
                 GFP-N_H11.ab1 
                 SASTGTGPGASPGTSS 
                   
                 GCCCAGGTTCTAGCCCGTCTGCTTCTACCGG 
                   
               
               
                   
                 TGSP 
                   
                 TACTGGTCCAGGTGCTTCTCCGGGTACTAGC 
                   
               
               
                   
                   
                   
                 TCTACTGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_067_ 
                 GTPGSGTASSSPGSST 
                 532 
                 GGTACCCCGGGTAGCGGTACCGCTTCTTCTT 
                 576 
               
               
                 GFP-N_A12.ab1 
                 PSGATGSPGSNPSAST 
                   
                 CTCCAGGTAGCTCTACTCCGTCTGGTGCTAC 
                   
               
               
                   
                 GTGP 
                   
                 CGGCTCTCCAGGTTCTAACCCTTCTGCATCCA 
                   
               
               
                   
                   
                   
                 CCGGTACCGGCCCA 
                   
               
               
                   
               
               
                 LCW0404_068_ 
                 GSSPSASTGTGPGSST 
                 533 
                 GGTTCTAGCCCTTCTGCATCTACTGGTACTGG 
                 577 
               
               
                 GFP-N_B12.ab1 
                 PSGATGSPGASPGTSS 
                   
                 CCCAGGTAGCTCTACTCCTTCTGGTGCTACC 
                   
               
               
                   
                 TGSP 
                   
                 GGCTCTCCAGGTGCTTCTCCGGGTACTAGCT 
                   
               
               
                   
                   
                   
                 CTACCGGTTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_069_ 
                 GSSTPSGATGSPGASP 
                 534 
                 GGTAGCTCTACCCCTTCTGGTGCAACCGGCT 
                 578 
               
               
                 GFP-N_C12.ab1 
                 GTSSTGSPGTPGSGTA 
                   
                 CTCCAGGTGCATCCCCGGGTACCAGCTCTAC 
                   
               
               
                   
                 SSSP 
                   
                 CGGTTCTCCAGGTACTCCGGGTAGCGGTACC 
                   
               
               
                   
                   
                   
                 GCTTCTTCCTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_070_ 
                 GSSTPSGATGSPGSST 
                 535 
                 GGTAGCTCTACTCCGTCTGGTGCAACCGGTT 
                 579 
               
               
                 GFP-N_D12.ab1 
                 PSGATGSPGSSTPSGA 
                   
                 CCCCAGGTAGCTCTACCCCTTCTGGTGCAAC 
                   
               
               
                   
                 TGSP 
                   
                 CGGCTCCCCAGGTAGCTCTACCCCTTCTGGT 
                   
               
               
                   
                   
                   
                 GCAACTGGCTCTCCA 
                   
               
               
                   
               
               
                 LCW0404_073_ 
                 GASPGTSSTGSPGTPG 
                 536 
                 GGTGCTTCTCCTGGCACTAGCTCTACCGGTTC 
                  580_ 
               
               
                 GFP-N_E12.ab1 
                 SGTASSSPGSSTPSGA 
                   
                 TCCAGGTACCCCTGGTAGCGGTACCGCATCT 
                   
               
               
                   
                 TGSP 
                   
                 TCCTCTCCAGGTAGCTCTACTCCTTCTGGTGC 
                   
               
               
                   
                   
                   
                 TACTGGTTCCCCA 
                   
               
               
                   
               
               
                 LCW0404_075_ 
                 GSSTPSGATGSPGSSP 
                 537 
                 GGTAGCTCTACCCCGTCTGGTGCTACTGGCT 
                 581 
               
               
                 GFP-N_F12.ab1 
                 SASTGTGPGSSPSAST 
                   
                 CCCCAGGTTCTAGCCCTTCTGCATCCACCGG 
                   
               
               
                   
                 GTGP 
                   
                 TACCGGTCCAGGTTCTAGCCCGTCTGCATCT 
                   
               
               
                   
                   
                   
                 ACTGGTACTGGTCCA 
                   
               
               
                   
               
               
                 LCW0404_080_ 
                 GASPGTSSTGSPGSSP 
                 538 
                 GGTGCTTCCCCGGGCACCAGCTCTACTGGTT 
                 582 
               
               
                 GFP-N_G12.ab1 
                 SASTGTGPGSSPSAST 
                   
                 CTCCAGGTTCTAGCCCGTCTGCTTCTACTGGT 
                   
               
               
                   
                 GTGP 
                   
                 ACTGGTCCAGGTTCTAGCCCTTCTGCTTCCAC 
                   
               
               
                   
                   
                   
                 TGGTACTGGTCCA 
                   
               
               
                   
               
               
                 LCW0404_081_ 
                 GASPGTSSTGSPGSSP 
                 539 
                 GGTGCTTCCCCGGGTACCAGCTCTACCGGTT 
                 583 
               
               
                 GFP-N_H12.ab1 
                 SASTGTGPGTPGSGT 
                   
                 CTCCAGGTTCTAGCCCTTCTGCTTCTACCGGT 
                   
               
               
                   
                 ASSSP 
                   
                 ACCGGTCCAGGTACCCCTGGCAGCGGTACCG 
                   
               
               
                   
                   
                   
                 CATCTTCCTCTCCA 
               
               
                   
               
            
           
         
       
     
     Example 5: Construction of XTEN_AE864 
     XTEN AE864 was constructed from serial dimerization of XTEN AE36 to AE72, 144, 288, 576 and 864. A collection of XTEN AE72 segments was constructed from 37 different segments of XTEN_AE36. Cultures of  E. coli  harboring all 37 different 36-amino acid segments were mixed and plasmid was isolated. This plasmid pool was digested with BsaI/NcoI to generate the small fragment as the insert. The same plasmid pool was digested with BbsI/NcoI to generate the large fragment as the vector. The insert and vector fragments were ligated resulting in a doubling of the length and the ligation mixture was transformed into BL21Gold(DE3) cells to obtain colonies of XTEN_AE72. 
     This library of XTEN_AE72 segments was designated LCW0406. All clones from LCW0406 were combined and dimerized again using the same process as described above yielding library LCW0410 of XTEN_AE144. All clones from LCW0410 were combined and dimerized again using the same process as described above yielding library LCW0414 of XTEN_AE288. Two isolates LCW0414.001 and LCW0414.002 were randomly picked from the library and sequenced to verify the identities. All clones from LCW0414 were combined and dimerized again using the same process as described above yielding library LCW0418 of XTEN_AE576. We screened 96 isolates from library LCW0418 for high level of GFP fluorescence. 8 isolates with right sizes of inserts by PCR and strong fluorescence were sequenced and 2 isolates (LCW0418.018 and LCW0418.052) were chosen for future use based on sequencing and expression data. 
     The specific clone pCW0432 of XTEN_AE864 was constructed by combining LCW0418.018 of XTEN_AE576 and LCW0414.002 of XTEN_AE288 using the same dimerization process as described above. 
     Example 6: Construction of XTEN_AM144 
     A collection of XTEN_AM144 segments was constructed starting from 37 different segments of XTEN_AE36, 44 segments of XTEN_AF36, and 44 segments of XTEN_AG36. 
     Cultures of  E. coli  that harboring all 125 different 36-amino acid segments were mixed and plasmid was isolated. This plasmid pool was digested with BsaI/NcoI to generate the small fragment as the insert. The same plasmid pool was digested with BbsI/NcoI to generate the large fragment as the vector. The insert and vector fragments were ligated resulting in a doubling of the length and the ligation mixture was transformed into BL21Gold(DE3) cells to obtain colonies of XTEN_AM72. 
     This library of XTEN_AM72 segments was designated LCW0461. All clones from LCW0461 were combined and dimerized again using the same process as described above yielding library LCW0462. 1512 Isolates from library LCW0462 were screened for protein expression. Individual colonies were transferred into 96 well plates and cultured overnight as starter cultures. These starter cultures were diluted into fresh autoinduction medium and cultured for 20-30 h. Expression was measured using a fluorescence plate reader with excitation at 395 nm and emission at 510 nm. 192 isolates showed high level expression and were submitted to DNA sequencing. Most clones in library LCW0462 showed good expression and similar physicochemical properties suggesting that most combinations of XTEN_AM36 segments yield useful XTEN sequences. 30 isolates from LCW0462 were chosen as a preferred collection of XTEN_AM144 segments for the construction of multifunctional proteins that contain multiple XTEN segments. The file names of the nucleotide and amino acid constructs and the sequences for these segments are listed in Table 15. 
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 DNA and amino acid sequences for AM144 segments 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
                 SEQ 
               
               
                   
                   
                 ID 
                   
                 ID 
               
               
                 Clone 
                 Sequence Trimmed 
                 NO: 
                 Protein Sequence 
                 NO: 
               
               
                   
               
               
                 LCW462_r1 
                 GGTACCCCGGGCAGCGGTACCGCATCTTCCTCTCCAG 
                 584 
                 GTPGSGTASSSPG 
                 617 
               
               
                   
                 GTAGCTCTACCCCGTCTGGTGCTACCGGTTCCCCAGG 
                   
                 SSTPSGATGSPGS 
                   
               
               
                   
                 TAGCTCTACCCCGTCTGGTGCAACCGGCTCCCCAGGT 
                   
                 STPSGATGSPGSP 
                   
               
               
                   
                 AGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTA 
                   
                 AGSPTSTEEGTSE 
                   
               
               
                   
                 CTTCTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTAC 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 CTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTTCT 
                   
                 PSEGSAPGSSPSA 
                   
               
               
                   
                 AGCCCTTCTGCATCCACCGGTACCGGCCCAGGTTCTA 
                   
                 STGTGPGSSPSAS 
                   
               
               
                   
                 GCCCGTCTGCTTCTACCGGTACTGGTCCAGGTGCTTCT 
                   
                 TGTGPGASPGTSS 
                   
               
               
                   
                 CCGGGTACTAGCTCTACTGGTTCTCCAGGTACCTCTA 
                   
                 TGSPGTSTEPSEG 
                   
               
               
                   
                 CCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTAC 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 TGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAACC 
                   
                 APGSEPATSGSET 
                   
               
               
                   
                 GGCAACCTCCGGTTCTGAAACTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r5 
                 GGTTCTACCAGCGAATCCCCTTCTGGCACTGCACCAG 
                 585 
                 GSTSESPSGTAPG 
                 618 
               
               
                   
                 GTTCTACTAGCGAATCCCCTTCTGGTACCGCACCAGG 
                   
                 STSESPSGTAPGT 
                   
               
               
                   
                 TACTTCTCCGAGCGGCGAATCTTCTACTGCTCCAGGT 
                   
                 SPSGESSTAPGTS 
                   
               
               
                   
                 ACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTA 
                   
                 TEPSEGSAPGTST 
                   
               
               
                   
                 CCTCTACCGAACCGTCCGAGGGCAGCGCACCAGGTAC 
                   
                 EPSEGSAPGTSES 
                   
               
               
                   
                 TTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTGCA 
                   
                 ATPESGPGASPGT 
                   
               
               
                   
                 TCTCCTGGTACCAGCTCTACCGGTTCTCCAGGTAGCTC 
                   
                 SSTGSPGSSTPSG 
                   
               
               
                   
                 TACTCCTTCTGGTGCTACTGGCTCTCCAGGTGCTTCCC 
                   
                 ATGSPGASPGTSS 
                   
               
               
                   
                 CGGGTACCAGCTCTACCGGTTCTCCAGGTTCTACTAG 
                   
                 TGSPGSTSESPSG 
                   
               
               
                   
                 CGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGC 
                   
                 TAPGSTSESPSGT 
                   
               
               
                   
                 GAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCC 
                   
                 APGTSTPESGSAS 
                   
               
               
                   
                 CTGAAAGCGGTTCCGCTTCTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r9 
                 GGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAG 
                 586 
                 GTSTEPSEGSAPG 
                 619 
               
               
                   
                 GTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGG 
                   
                 TSESATPESGPGT 
                   
               
               
                   
                 TACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGT 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 ACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTA 
                   
                 TEPSEGSAPGTSE 
                   
               
               
                   
                 CTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTAC 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 TTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACT 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 TCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCG 
                   
                 SEGSAPGSEPATS 
                   
               
               
                   
                 AACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGCCC 
                   
                 GSETPGSPAGSPT 
                   
               
               
                   
                 GGCTGGCTCTCCGACCTCCACCGAGGAAGGTGCTTCT 
                   
                 STEEGASPGTSST 
                   
               
               
                   
                 CCTGGCACCAGCTCTACTGGTTCTCCAGGTTCTAGCC 
                   
                 GSPGSSPSASTGT 
                   
               
               
                   
                 CTTCTGCTTCTACCGGTACTGGTCCAGGTTCTAGCCCT 
                   
                 GPGSSPSASTGTG 
                   
               
               
                   
                 TCTGCATCCACTGGTACTGGTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r10 
                 GGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAG 
                 587 
                 GSEPATSGSETPG 
                 620 
               
               
                   
                 GTACCTCTGAAAGCGCTACTCCGGAATCTGGTCCAGG 
                   
                 TSESATPESGPGT 
                   
               
               
                   
                 TACTTCTGAAAGCGCTACTCCGGAATCCGGTCCAGGT 
                   
                 SESATPESGPGST 
                   
               
               
                   
                 TCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTT 
                   
                 SESPSGTAPGSTS 
                   
               
               
                   
                 CTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTAC 
                   
                 ESPSGTAPGTSPS 
                   
               
               
                   
                 TTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTGCA 
                   
                 GESSTAPGASPGT 
                   
               
               
                   
                 TCTCCGGGTACTAGCTCTACCGGTTCTCCAGGTTCTAG 
                   
                 SSTGSPGSSPSAS 
                   
               
               
                   
                 CCCTTCTGCTTCCACTGGTACCGGCCCAGGTAGCTCT 
                   
                 TGTGPGSSTPSGA 
                   
               
               
                   
                 ACCCCGTCTGGTGCTACTGGTTCCCCAGGTAGCTCTA 
                   
                 TGSPGSSTPSGAT 
                   
               
               
                   
                 CTCCGTCTGGTGCAACCGGTTCCCCAGGTAGCTCTAC 
                   
                 GSPGSSTPSGATG 
                   
               
               
                   
                 TCCTTCTGGTGCTACTGGCTCCCCAGGTGCATCCCCTG 
                   
                 SPGASPGTSSTGS 
                   
               
               
                   
                 GCACCAGCTCTACCGGTTCTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r15 
                 GGTGCTTCTCCGGGCACCAGCTCTACTGGTTCTCCAG 
                 588 
                 GASPGTSSTGSPG 
                 621 
               
               
                   
                 GTTCTAGCCCTTCTGCATCCACCGGTACCGGTCCAGG 
                   
                 SSPSASTGTGPGS 
                   
               
               
                   
                 TAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGT 
                   
                 STPSGATGSPGTS 
                   
               
               
                   
                 ACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTA 
                   
                 ESATPESGPGSEP 
                   
               
               
                   
                 GCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAG 
                   
                 ATSGSETPGSEPA 
                   
               
               
                   
                 CGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTACT 
                   
                 TSGSETPGTSESA 
                   
               
               
                   
                 TCTGAAAGCGCTACTCCGGAGTCCGGTCCAGGTACCT 
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                 CTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACTTC 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 TACTGAACCTTCTGAGGGTAGCGCTCCAGGTACCTCT 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 ACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTA 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 CTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAACC 
                   
                 APGSEPATSGSET 
                   
               
               
                   
                 GGCAACCTCCGGTTCTGAAACTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r16 
                 GGTACCTCTACCGAACCTTCCGAAGGTAGCGCTCCAG 
                 589 
                 GTSTEPSEGSAPG 
                 622 
               
               
                   
                 GTAGCCCGGCAGGTTCTCCTACTTCCACTGAGGAAGG 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 TACTTCTACCGAACCTTCTGAGGGTAGCGCACCAGGT 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 ACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTA 
                   
                 ESATPESGPGSEP 
                   
               
               
                   
                 GCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTAC 
                   
                 ATSGSETPGTSES 
                   
               
               
                   
                 CTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGC 
                   
                 ATPESGPGSPAGS 
                   
               
               
                   
                 CCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTT 
                   
                 PTSTEEGTSESAT 
                   
               
               
                   
                 CTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCTC 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 TACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCGA 
                   
                 GSAPGSEPATSGS 
                   
               
               
                   
                 ACCTGCTACTTCTGGTTCTGAAACTCCAGGTACTTCTA 
                   
                 ETPGTSTEPSEGS 
                   
               
               
                   
                 CCGAACCGTCCGAGGGTAGCGCTCCAGGTAGCGAAC 
                   
                 APGSEPATSGSET 
                   
               
               
                   
                 CTGCTACTTCTGGTTCTGAAACTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r20 
                 GGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAG 
                 590 
                 GTSTEPSEGSAPG 
                 623 
               
               
                   
                 GTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGG 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 TACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGT 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 ACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTA 
                   
                 TEPSEGSAPGTST 
                   
               
               
                   
                 CCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTAC 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 CTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACT 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 TCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTT 
                   
                 SEGSAPGTSESAT 
                   
               
               
                   
                 CTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTC 
                   
                 PESGPGTSESATP 
                   
               
               
                   
                 TGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCT 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 ACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCGAAC 
                   
                 SAPGSEPATSGSE 
                   
               
               
                   
                 CTGCTACTTCTGGTTCTGAAACCCCAGGTAGCCCGGC 
                   
                 TPGSPAGSPTSTE 
                   
               
               
                   
                 TGGCTCTCCGACCTCCACCGAGGAA 
                   
                 E 
                   
               
               
                   
               
               
                 LCW462_r23 
                 GGTACTTCTACCGAACCGTCCGAGGGCAGCGCTCCAG 
                 591 
                 GTSTEPSEGSAPG 
                 624 
               
               
                   
                 GTACTTCTACTGAACCTTCTGAAGGCAGCGCTCCAGG 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 TACTTCTACTGAACCTTCCGAAGGTAGCGCACCAGGT 
                   
                 STEPSEGSAPGST 
                   
               
               
                   
                 TCTACCAGCGAATCCCCTTCTGGTACTGCTCCAGGTTC 
                   
                 SESPSGTAPGSTS 
                   
               
               
                   
                 TACCAGCGAATCCCCTTCTGGCACCGCACCAGGTACT 
                   
                 ESPSGTAPGTSTP 
                   
               
               
                   
                 TCTACCCCTGAAAGCGGCTCCGCTTCTCCAGGTAGCG 
                   
                 ESGSASPGSEPAT 
                   
               
               
                   
                 AACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTC 
                   
                 SGSETPGTSESAT 
                   
               
               
                   
                 TGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCT 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 ACTGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTA 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 CTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGA 
                   
                 SAPGTSESATPES 
                   
               
               
                   
                 AAGCGCAACCCCGGAATCCGGCCCAGGTACCTCTGA 
                   
                 GPGTSESATPESG 
                   
               
               
                   
                 AAGCGCAACCCCGGAGTCCGGCCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r24 
                 GGTAGCTCTACCCCTTCTGGTGCTACCGGCTCTCCAG 
                 592 
                 GSSTPSGATGSPG 
                 625 
               
               
                   
                 GTTCTAGCCCGTCTGCTTCTACCGGTACCGGTCCAGG 
                   
                 SSPSASTGTGPGS 
                   
               
               
                   
                 TAGCTCTACCCCTTCTGGTGCTACTGGTTCTCCAGGTA 
                   
                 STPSGATGSPGSP 
                   
               
               
                   
                 GCCCTGCTGGCTCTCCGACTTCTACTGAGGAAGGTAG 
                   
                 AGSPTSTEEGSPA 
                   
               
               
                   
                 CCCGGCTGGTTCTCCGACTTCTACTGAGGAAGGTACT 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 TCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTGCTT 
                   
                 PSEGSAPGASPGT 
                   
               
               
                   
                 CCCCGGGCACTAGCTCTACCGGTTCTCCAGGTTCTAG 
                   
                 SSTGSPGSSPSAS 
                   
               
               
                   
                 CCCTTCTGCATCTACTGGTACTGGCCCAGGTACTCCG 
                   
                 TGTGPGTPGSGT 
                   
               
               
                   
                 GGCAGCGGTACTGCTTCTTCCTCTCCAGGTTCTACTAG 
                   
                 ASSSPGSTSSTAE 
                   
               
               
                   
                 CTCTACTGCTGAATCTCCTGGCCCAGGTACTTCTCCTA 
                   
                 SPGPGTSPSGESS 
                   
               
               
                   
                 GCGGTGAATCTTCTACCGCTCCAGGTACCTCTACTCC 
                   
                 TAPGTSTPESGSA 
                   
               
               
                   
                 GGAAAGCGGTTCTGCATCTCCA 
                   
                 SP 
                   
               
               
                   
               
               
                 LCW462_r27 
                 GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAG 
                 593 
                 GTSTEPSEGSAPG 
                 626 
               
               
                   
                 GTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGG 
                   
                 TSESATPESGPGT 
                   
               
               
                   
                 TACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGT 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 ACTTCTACTGAACCGTCTGAAGGTAGCGCACCAGGTA 
                   
                 TEPSEGSAPGTSE 
                   
               
               
                   
                 CTTCTGAAAGCGCAACCCCGGAATCCGGCCCAGGTAC 
                   
                 SATPESGPGTSES 
                   
               
               
                   
                 CTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTACT 
                   
                 ATPESGPGTPGSG 
                   
               
               
                   
                 CCTGGCAGCGGTACCGCTTCTTCTTCTCCAGGTGCTTC 
                   
                 TASSSPGASPGTS 
                   
               
               
                   
                 TCCTGGTACTAGCTCTACTGGTTCTCCAGGTGCTTCTC 
                   
                 STGSPGASPGTSS 
                   
               
               
                   
                 CGGGCACTAGCTCTACTGGTTCTCCAGGTAGCCCTGC 
                   
                 TGSPGSPAGSPTS 
                   
               
               
                   
                 TGGCTCTCCGACTTCTACTGAGGAAGGTAGCCCGGCT 
                   
                 TEEGSPAGSPTST 
                   
               
               
                   
                 GGTTCTCCGACTTCTACTGAGGAAGGTACTTCTACCG 
                   
                 EEGTSTEPSEGSA 
                   
               
               
                   
                 AACCTTCCGAAGGTAGCGCTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r28 
                 GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAG 
                 594 
                 GSPAGSPTSTEEG 
                 627 
               
               
                   
                 GTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGG 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 TACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGT 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 ACCTCTACCGAACCGTCTGAAGGTAGCGCACCAGGTA 
                   
                 TEPSEGSAPGTSE 
                   
               
               
                   
                 CCTCTGAAAGCGCAACTCCTGAGTCCGGTCCAGGTAC 
                   
                 SATPESGPGTSES 
                   
               
               
                   
                 TTCTGAAAGCGCAACCCCGGAGTCTGGCCCAGGTACC 
                   
                 ATPESGPGTPGSG 
                   
               
               
                   
                 CCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCT 
                   
                 TASSSPGSSTPSG 
                   
               
               
                   
                 CTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCT 
                   
                 ATGSPGASPGTSS 
                   
               
               
                   
                 CCGGGCACCAGCTCTACCGGTTCTCCAGGTACCTCTA 
                   
                 TGSPGTSTEPSEG 
                   
               
               
                   
                 CTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGA 
                   
                 SAPGTSESATPES 
                   
               
               
                   
                 AAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACT 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 GAACCGTCCGAAGGTAGCGCACCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r38 
                 GGTAGCGAACCGGCAACCTCCGGCTCTGAAACTCCAG 
                 595 
                 GSEPATSGSETPG 
                 628 
               
               
                   
                 GTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGG 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 TAGCGAACCGGCTACTTCCGGCTCTGAAACCCCAGGT 
                   
                 EPATSGSETPGSS 
                   
               
               
                   
                 AGCTCTACCCCGTCTGGTGCAACCGGCTCCCCAGGTA 
                   
                 TPSGATGSPGTPG 
                   
               
               
                   
                 CTCCTGGTAGCGGTACCGCTTCTTCTTCTCCAGGTAGC 
                   
                 SGTASSSPGSSTP 
                   
               
               
                   
                 TCTACTCCGTCTGGTGCTACCGGCTCCCCAGGTGCAT 
                   
                 SGATGSPGASPGT 
                   
               
               
                   
                 CTCCTGGTACCAGCTCTACCGGTTCTCCAGGTAGCTCT 
                   
                 SSTGSPGSSTPSG 
                   
               
               
                   
                 ACTCCTTCTGGTGCTACTGGCTCTCCAGGTGCTTCCCC 
                   
                 ATGSPGASPGTSS 
                   
               
               
                   
                 GGGTACCAGCTCTACCGGTTCTCCAGGTAGCGAACCT 
                   
                 TGSPGSEPATSGS 
                   
               
               
                   
                 GCTACTTCTGGTTCTGAAACTCCAGGTACTTCTACCG 
                   
                 ETPGTSTEPSEGS 
                   
               
               
                   
                 AACCGTCCGAGGGTAGCGCTCCAGGTAGCGAACCTG 
                   
                 APGSEPATSGSET 
                   
               
               
                   
                 CTACTTCTGGTTCTGAAACTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r39 
                 GGTACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAG 
                 596 
                 GTSTEPSEGSAPG 
                 629 
               
               
                   
                 GTACCTCTACCGAACCGTCCGAGGGCAGCGCACCAG 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 GTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGG 
                   
                 SESATPESGPGSP 
                   
               
               
                   
                 TAGCCCTGCTGGCTCTCCGACTTCTACTGAGGAAGGT 
                   
                 AGSPTSTEEGSPA 
                   
               
               
                   
                 AGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGGTA 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 CTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTAG 
                   
                 PSEGSAPGSPAGS 
                   
               
               
                   
                 CCCGGCTGGTTCTCCGACTTCCACCGAGGAAGGTACC 
                   
                 PTSTEEGTSTEPS 
                   
               
               
                   
                 TCTACTGAACCTTCTGAGGGTAGCGCTCCAGGTACCT 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 CTACTGAACCTTCCGAAGGCAGCGCTCCAGGTGCTTC 
                   
                 GSAPGASPGTSST 
                   
               
               
                   
                 CCCGGGCACCAGCTCTACTGGTTCTCCAGGTTCTAGC 
                   
                 GSPGSSPSASTGT 
                   
               
               
                   
                 CCGTCTGCTTCTACTGGTACTGGTCCAGGTTCTAGCCC 
                   
                 GPGSSPSASTGTG 
                   
               
               
                   
                 TTCTGCTTCCACTGGTACTGGTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r41 
                 GGTAGCTCTACCCCGTCTGGTGCTACCGGTTCCCCAG 
                 597 
                 GSSTPSGATGSPG 
                 630 
               
               
                   
                 GTGCTTCTCCTGGTACTAGCTCTACCGGTTCTCCAGGT 
                   
                 ASPGTSSTGSPGS 
                   
               
               
                   
                 AGCTCTACCCCGTCTGGTGCTACTGGCTCTCCAGGTA 
                   
                 STPSGATGSPGSP 
                   
               
               
                   
                 GCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTAC 
                   
                 AGSPTSTEEGTSE 
                   
               
               
                   
                 CTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGC 
                   
                 SATPESGPGSEPA 
                   
               
               
                   
                 GAACCGGCAACCTCCGGTTCTGAAACCCCAGGTGCAT 
                   
                 TSGSETPGASPGT 
                   
               
               
                   
                 CTCCTGGTACTAGCTCTACTGGTTCTCCAGGTAGCTCT 
                   
                 SSTGSPGSSTPSG 
                   
               
               
                   
                 ACTCCGTCTGGTGCAACCGGCTCTCCAGGTTCTAGCC 
                   
                 ATGSPGSSPSAST 
                   
               
               
                   
                 CTTCTGCATCTACCGGTACTGGTCCAGGTTCTACCAG 
                   
                 GTGPGSTSESPSG 
                   
               
               
                   
                 CGAATCCCCTTCTGGTACTGCTCCAGGTTCTACCAGC 
                   
                 TAPGSTSESPSGT 
                   
               
               
                   
                 GAATCCCCTTCTGGCACCGCACCAGGTACTTCTACCC 
                   
                 APGTSTPESGSAS 
                   
               
               
                   
                 CTGAAAGCGGCTCCGCTTCTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r42 
                 GGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAG 
                 598 
                 GSTSESPSGTAPG 
                 631 
               
               
                   
                 GTTCTACTAGCGAATCCCCGTCTGGTACCGCACCAGG 
                   
                 STSESPSGTAPGT 
                   
               
               
                   
                 TACTTCTCCTAGCGGCGAATCTTCTACCGCACCAGGT 
                   
                 SPSGESSTAPGTS 
                   
               
               
                   
                 ACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTA 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 CCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAC 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 TTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACC 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTT 
                   
                 SEGSAPGTSESAT 
                   
               
               
                   
                 CTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTC 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 TACTGAACCGTCCGAAGGTAGCGCACCAGGTAGCTCT 
                   
                 GSAPGSSTPSGAT 
                   
               
               
                   
                 ACCCCGTCTGGTGCTACCGGTTCCCCAGGTGCTTCTCC 
                   
                 GSPGASPGTSSTG 
                   
               
               
                   
                 TGGTACTAGCTCTACCGGTTCTCCAGGTAGCTCTACC 
                   
                 SPGSSTPSGATGS 
                   
               
               
                   
                 CCGTCTGGTGCTACTGGCTCTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r43 
                 GGTTCTACTAGCTCTACTGCAGAATCTCCGGGCCCAG 
                 599 
                 GSTSSTAESPGPG 
                 632 
               
               
                   
                 GTACCTCTCCTAGCGGTGAATCTTCTACCGCTCCAGG 
                   
                 TSPSGESSTAPGT 
                   
               
               
                   
                 TACTTCTCCGAGCGGTGAATCTTCTACCGCTCCAGGTT 
                   
                 SPSGESSTAPGST 
                   
               
               
                   
                 CTACTAGCTCTACCGCTGAATCTCCGGGTCCAGGTTC 
                   
                 SSTAESPGPGSTS 
                   
               
               
                   
                 TACCAGCTCTACTGCAGAATCTCCTGGCCCAGGTACT 
                   
                 STAESPGPGTSTP 
                   
               
               
                   
                 TCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGTACTT 
                   
                 ESGSASPGTSPSG 
                   
               
               
                   
                 CTCCTAGCGGTGAATCTTCTACCGCTCCAGGTTCTACC 
                   
                 ESSTAPGSTSSTA 
                   
               
               
                   
                 AGCTCTACTGCTGAATCTCCTGGCCCAGGTACTTCTA 
                   
                 ESPGPGTSTPESG 
                   
               
               
                   
                 CCCCGGAAAGCGGCTCCGCTTCTCCAGGTTCTACCAG 
                   
                 SASPGSTSSTAES 
                   
               
               
                   
                 CTCTACCGCTGAATCTCCTGGCCCAGGTTCTACTAGC 
                   
                 PGPGSTSESPSGT 
                   
               
               
                   
                 GAATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTA 
                   
                 APGTSPSGESSTA 
                   
               
               
                   
                 GCGGTGAATCTTCTACTGCACCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r45 
                 GGTACCTCTACTCCGGAAAGCGGTTCCGCATCTCCAG 
                 600 
                 GTSTPESGSASPG 
                 633 
               
               
                   
                 GTTCTACCAGCGAATCCCCGTCTGGCACCGCACCAGG 
                   
                 STSESPSGTAPGS 
                   
               
               
                   
                 TTCTACTAGCTCTACTGCTGAATCTCCGGGCCCAGGT 
                   
                 TSSTAESPGPGTS 
                   
               
               
                   
                 ACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTA 
                   
                 TEPSEGSAPGTST 
                   
               
               
                   
                 CCTCTACCGAACCGTCCGAGGGCAGCGCACCAGGTAC 
                   
                 EPSEGSAPGTSES 
                   
               
               
                   
                 TTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTACC 
                   
                 ATPESGPGTSESA 
                   
               
               
                   
                 TCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCT 
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                 CTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTC 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 TACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 GAAAGCGCTACTCCGGAGTCCGGTCCAGGTACCTCTA 
                   
                 SGPGTSTEPSEGS 
                   
               
               
                   
                 CCGAACCGTCCGAAGGCAGCGCTCCAGGTACTTCTAC 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 TGAACCTTCTGAGGGTAGCGCTCCC 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r47 
                 GGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAG 
                 601 
                 GTSTEPSEGSAPG 
                 634 
               
               
                   
                 GTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGG 
                   
                 TSTEPSEGSAPGS 
                   
               
               
                   
                 TAGCGAACCGGCAACCTCCGGTTCTGAAACTCCAGGT 
                   
                 EPATSGSETPGTS 
                   
               
               
                   
                 ACTTCTACTGAACCGTCTGAAGGTAGCGCACCAGGTA 
                   
                 TEPSEGSAPGTSE 
                   
               
               
                   
                 CTTCTGAAAGCGCAACCCCGGAATCCGGCCCAGGTAC 
                   
                 SATPESGPGTSES 
                   
               
               
                   
                 CTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTGC 
                   
                 ATPESGPGASPGT 
                   
               
               
                   
                 ATCTCCGGGTACTAGCTCTACCGGTTCTCCAGGTTCTA 
                   
                 SSTGSPGSSPSAS 
                   
               
               
                   
                 GCCCTTCTGCTTCCACTGGTACCGGCCCAGGTAGCTC 
                   
                 TGTGPGSSTPSGA 
                   
               
               
                   
                 TACCCCGTCTGGTGCTACTGGTTCCCCAGGTAGCTCT 
                   
                 TGSPGSSTPSGAT 
                   
               
               
                   
                 ACTCCGTCTGGTGCAACCGGTTCCCCAGGTAGCTCTA 
                   
                 GSPGSSTPSGATG 
                   
               
               
                   
                 CTCCTTCTGGTGCTACTGGCTCCCCAGGTGCATCCCCT 
                   
                 SPGASPGTSSTGS 
                   
               
               
                   
                 GGCACCAGCTCTACCGGTTCTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r54 
                 GGTAGCGAACCGGCAACCTCTGGCTCTGAAACTCCAG 
                 602 
                 GSEPATSGSETPG 
                 635 
               
               
                   
                 GTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGG 
                   
                 SEPATSGSETPGT 
                   
               
               
                   
                 TACTTCTACTGAACCTTCTGAGGGCAGCGCACCAGGT 
                   
                 STEPSEGSAPGSE 
                   
               
               
                   
                 AGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTA 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 CCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTAC 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 TTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAGC 
                   
                 PSEGSAPGSSTPS 
                   
               
               
                   
                 TCTACTCCGTCTGGTGCTACCGGCTCTCCAGGTAGCTC 
                   
                 GATGSPGSSTPSG 
                   
               
               
                   
                 TACCCCTTCTGGTGCAACCGGCTCCCCAGGTGCTTCTC 
                   
                 ATGSPGASPGTSS 
                   
               
               
                   
                 CGGGTACCAGCTCTACTGGTTCTCCAGGTAGCTCTAC 
                   
                 TGSPGSSTPSGAT 
                   
               
               
                   
                 CCCGTCTGGTGCTACCGGTTCCCCAGGTGCTTCTCCTG 
                   
                 GSPGASPGTSSTG 
                   
               
               
                   
                 GTACTAGCTCTACCGGTTCTCCAGGTAGCTCTACCCC 
                   
                 SPGSSTPSGATGS 
                   
               
               
                   
                 GTCTGGTGCTACTGGCTCTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r55 
                 GGTACTTCTACCGAACCGTCCGAGGGCAGCGCTCCAG 
                 603 
                 GTSTEPSEGSAPG 
                 636 
               
               
                   
                 GTACTTCTACTGAACCTTCTGAAGGCAGCGCTCCAGG 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 TACTTCTACTGAACCTTCCGAAGGTAGCGCACCAGGT 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 ACTTCTGAAAGCGCTACTCCGGAGTCCGGTCCAGGTA 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 CCTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTAC 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 TTCTACTGAACCTTCTGAGGGTAGCGCTCCAGGTTCT 
                   
                 PSEGSAPGSTSES 
                   
               
               
                   
                 ACTAGCGAATCTCCGTCTGGCACTGCTCCAGGTACTT 
                   
                 PSGTAPGTSPSGE 
                   
               
               
                   
                 CTCCTAGCGGTGAATCTTCTACCGCTCCAGGTACTTCC 
                   
                 SSTAPGTSPSGES 
                   
               
               
                   
                 CCTAGCGGCGAATCTTCTACCGCTCCAGGTAGCCCGG 
                   
                 STAPGSPAGSPTS 
                   
               
               
                   
                 CTGGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGA 
                   
                 TEEGTSESATPES 
                   
               
               
                   
                 AAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACT 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 GAACCGTCCGAAGGTAGCGCTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r57 
                 GGTACTTCTACTGAACCTTCCGAAGGTAGCGCTCCAG 
                 604 
                 GTSTEPSEGSAPG 
                 637 
               
               
                   
                 GTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGG 
                   
                 SEPATSGSETPGS 
                   
               
               
                   
                 TAGCCCGGCTGGCTCTCCGACCTCCACCGAGGAAGGT 
                   
                 PAGSPTSTEEGSP 
                   
               
               
                   
                 AGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTA 
                   
                 AGSPTSTEEGTSE 
                   
               
               
                   
                 CTTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTAC 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 CTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTACC 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 TCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTACCT 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 CTACCGAACCGTCCGAGGGCAGCGCACCAGGTACTTC 
                   
                 EGSAPGTSESATP 
                   
               
               
                   
                 TGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCTCT 
                   
                 ESGPGSSTPSGAT 
                   
               
               
                   
                 ACTCCGTCTGGTGCAACCGGCTCCCCAGGTTCTAGCC 
                   
                 GSPGSSPSASTGT 
                   
               
               
                   
                 CGTCTGCTTCCACTGGTACTGGCCCAGGTGCTTCCCC 
                   
                 GPGASPGTSSTGS 
                   
               
               
                   
                 GGGCACCAGCTCTACTGGTTCTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r61 
                 GGTAGCGAACCGGCTACTTCCGGCTCTGAGACTCCAG 
                 605 
                 GSEPATSGSETPG 
                 638 
               
               
                   
                 GTAGCCCTGCTGGCTCTCCGACCTCTACCGAAGAAGG 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 TACCTCTGAAAGCGCTACCCCTGAGTCTGGCCCAGGT 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 ACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTA 
                   
                 TEPSEGSAPGTST 
                   
               
               
                   
                 CCTCTACCGAACCGTCCGAGGGCAGCGCACCAGGTAC 
                   
                 EPSEGSAPGTSES 
                   
               
               
                   
                 TTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTACC 
                   
                 ATPESGPGTSTPE 
                   
               
               
                   
                 TCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTTCTA 
                   
                 SGSASPGSTSESP 
                   
               
               
                   
                 CCAGCGAATCCCCGTCTGGCACCGCACCAGGTTCTAC 
                   
                 SGTAPGSTSSTAE 
                   
               
               
                   
                 TAGCTCTACTGCTGAATCTCCGGGCCCAGGTACTTCT 
                   
                 SPGPGTSESATPE 
                   
               
               
                   
                 GAAAGCGCTACTCCGGAGTCCGGTCCAGGTACCTCTA 
                   
                 SGPGTSTEPSEGS 
                   
               
               
                   
                 CCGAACCGTCCGAAGGCAGCGCTCCAGGTACTTCTAC 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 TGAACCTTCTGAGGGTAGCGCTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r64 
                 GGTACTTCTACCGAACCGTCCGAGGGCAGCGCTCCAG 
                 606 
                 GTSTEPSEGSAPG 
                 639 
               
               
                   
                 GTACTTCTACTGAACCTTCTGAAGGCAGCGCTCCAGG 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 TACTTCTACTGAACCTTCCGAAGGTAGCGCACCAGGT 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 ACCTCTACCGAACCGTCTGAAGGTAGCGCACCAGGTA 
                   
                 TEPSEGSAPGTSE 
                   
               
               
                   
                 CCTCTGAAAGCGCAACTCCTGAGTCCGGTCCAGGTAC 
                   
                 SATPESGPGTSES 
                   
               
               
                   
                 TTCTGAAAGCGCAACCCCGGAGTCTGGCCCAGGTACT 
                   
                 ATPESGPGTPGSG 
                   
               
               
                   
                 CCTGGCAGCGGTACCGCATCTTCCTCTCCAGGTAGCT 
                   
                 TASSSPGSSTPSG 
                   
               
               
                   
                 CTACTCCGTCTGGTGCAACTGGTTCCCCAGGTGCTTCT 
                   
                 ATGSPGASPGTSS 
                   
               
               
                   
                 CCGGGTACCAGCTCTACCGGTTCTCCAGGTTCCACCA 
                   
                 TGSPGSTSSTAES 
                   
               
               
                   
                 GCTCTACTGCTGAATCTCCTGGTCCAGGTACCTCTCCT 
                   
                 PGPGTSPSGESST 
                   
               
               
                   
                 AGCGGTGAATCTTCTACTGCTCCAGGTACTTCTACTCC 
                   
                 APGTSTPESGSAS 
                   
               
               
                   
                 TGAAAGCGGCTCTGCTTCTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r67 
                 GGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAG 
                 607 
                 GSPAGSPTSTEEG 
                 640 
               
               
                   
                 GTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGG 
                   
                 TSESATPESGPGT 
                   
               
               
                   
                 TACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGT 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 ACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTA 
                   
                 ESATPESGPGSEP 
                   
               
               
                   
                 GCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGTAC 
                   
                 ATSGSETPGTSTE 
                   
               
               
                   
                 TTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTAGC 
                   
                 PSEGSAPGSPAGS 
                   
               
               
                   
                 CCGGCTGGTTCTCCGACTTCCACCGAGGAAGGTACCT 
                   
                 PTSTEEGTSTEPS 
                   
               
               
                   
                 CTACTGAACCTTCTGAGGGTAGCGCTCCAGGTACCTC 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 TACTGAACCTTCCGAAGGCAGCGCTCCAGGTACTTCT 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 ACCGAACCGTCCGAGGGCAGCGCTCCAGGTACTTCTA 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 CTGAACCTTCTGAAGGCAGCGCTCCAGGTACTTCTAC 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 TGAACCTTCCGAAGGTAGCGCACCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r69 
                 GGTACTTCTCCGAGCGGTGAATCTTCTACCGCACCAG 
                 608 
                 GTSPSGESSTAPG 
                 641 
               
               
                   
                 GTTCTACTAGCTCTACCGCTGAATCTCCGGGCCCAGG 
                   
                 STSSTAESPGPGT 
                   
               
               
                   
                 TACTTCTCCGAGCGGTGAATCTTCTACTGCTCCAGGT 
                   
                 SPSGESSTAPGTS 
                   
               
               
                   
                 ACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTA 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 CCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAC 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 TTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTTCT 
                   
                 PSEGSAPGSSPSA 
                   
               
               
                   
                 AGCCCTTCTGCATCTACTGGTACTGGCCCAGGTAGCT 
                   
                 STGTGPGSSTPSG 
                   
               
               
                   
                 CTACTCCTTCTGGTGCTACCGGCTCTCCAGGTGCTTCT 
                   
                 ATGSPGASPGTSS 
                   
               
               
                   
                 CCGGGTACTAGCTCTACCGGTTCTCCAGGTACTTCTA 
                   
                 TGSPGTSTPESGS 
                   
               
               
                   
                 CTCCGGAAAGCGGTTCCGCATCTCCAGGTACTTCTCC 
                   
                 ASPGTSPSGESST 
                   
               
               
                   
                 TAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTCCTA 
                   
                 APGTSPSGESSTA 
                   
               
               
                   
                 GCGGCGAATCTTCTACTGCTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r70 
                 GGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAG 
                 609 
                 GTSESATPESGPG 
                 642 
               
               
                   
                 GTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGG 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 TACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGT 
                   
                 STEPSEGSAPGSP 
                   
               
               
                   
                 AGCCCTGCTGGCTCTCCGACTTCTACTGAGGAAGGTA 
                   
                 AGSPTSTEEGSPA 
                   
               
               
                   
                 GCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGGTAC 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 TTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTTCT 
                   
                 PSEGSAPGSSPSA 
                   
               
               
                   
                 AGCCCTTCTGCTTCCACCGGTACTGGCCCAGGTAGCT 
                   
                 STGTGPGSSTPSG 
                   
               
               
                   
                 CTACCCCTTCTGGTGCTACCGGCTCCCCAGGTAGCTCT 
                   
                 ATGSPGSSTPSGA 
                   
               
               
                   
                 ACTCCTTCTGGTGCAACTGGCTCTCCAGGTAGCGAAC 
                   
                 TGSPGSEPATSGS 
                   
               
               
                   
                 CGGCAACTTCCGGCTCTGAAACCCCAGGTACTTCTGA 
                   
                 ETPGTSESATPES 
                   
               
               
                   
                 AAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAACCT 
                   
                 GPGSEPATSGSET 
                   
               
               
                   
                 GCTACCTCTGGCTCTGAAACCCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r72 
                 GGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAG 
                 610 
                 GTSTEPSEGSAPG 
                 643 
               
               
                   
                 GTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGG 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 TACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGT 
                   
                 STEPSEGSAPGSS 
                   
               
               
                   
                 AGCTCTACCCCGTCTGGTGCTACCGGTTCCCCAGGTG 
                   
                 TPSGATGSPGASP 
                   
               
               
                   
                 CTTCTCCTGGTACTAGCTCTACCGGTTCTCCAGGTAGC 
                   
                 GTSSTGSPGSSTP 
                   
               
               
                   
                 TCTACCCCGTCTGGTGCTACTGGCTCTCCAGGTACTTC 
                   
                 SGATGSPGTSESA 
                   
               
               
                   
                 TGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGA 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 ACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCT 
                   
                 GSETPGTSTEPSE 
                   
               
               
                   
                 ACCGAACCGTCCGAAGGTAGCGCACCAGGTTCTACTA 
                   
                 GSAPGSTSESPSG 
                   
               
               
                   
                 GCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAG 
                   
                 TAPGSTSESPSGT 
                   
               
               
                   
                 CGAATCTCCGTCTGGCACTGCACCAGGTACCTCTACC 
                   
                 APGTSTPESGSAS 
                   
               
               
                   
                 CCTGAAAGCGGTTCCGCTTCTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r73 
                 GGTACCTCTACTCCTGAAAGCGGTTCTGCATCTCCAG 
                 611 
                 GTSTPESGSASPG 
                 644 
               
               
                   
                 GTTCCACTAGCTCTACCGCAGAATCTCCGGGCCCAGG 
                   
                 STSSTAESPGPGS 
                   
               
               
                   
                 TTCTACTAGCTCTACTGCTGAATCTCCTGGCCCAGGTT 
                   
                 TSSTAESPGPGSS 
                   
               
               
                   
                 CTAGCCCTTCTGCATCTACTGGTACTGGCCCAGGTAG 
                   
                 PSASTGTGPGSST 
                   
               
               
                   
                 CTCTACTCCTTCTGGTGCTACCGGCTCTCCAGGTGCTT 
                   
                 PSGATGSPGASPG 
                   
               
               
                   
                 CTCCGGGTACTAGCTCTACCGGTTCTCCAGGTAGCGA 
                   
                 TSSTGSPGSEPAT 
                   
               
               
                   
                 ACCGGCAACCTCCGGCTCTGAAACCCCAGGTACCTCT 
                   
                 SGSETPGTSESAT 
                   
               
               
                   
                 GAAAGCGCTACTCCTGAATCCGGCCCAGGTAGCCCGG 
                   
                 PESGPGSPAGSPT 
                   
               
               
                   
                 CAGGTTCTCCGACTTCCACTGAGGAAGGTTCTACTAG 
                   
                 STEEGSTSESPSG 
                   
               
               
                   
                 CGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGC 
                   
                 TAPGSTSESPSGT 
                   
               
               
                   
                 GAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCC 
                   
                 APGTSTPESGSAS 
                   
               
               
                   
                 CTGAAAGCGGTTCCGCTTCTCCC 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r78 
                 GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAG 
                 612 
                 GSPAGSPTSTEEG 
                 645 
               
               
                   
                 GTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCAGG 
                   
                 TSESATPESGPGT 
                   
               
               
                   
                 TACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGT 
                   
                 STEPSEGSAPGST 
                   
               
               
                   
                 TCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTT 
                   
                 SESPSGTAPGSTS 
                   
               
               
                   
                 CTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTAC 
                   
                 ESPSGTAPGTSPS 
                   
               
               
                   
                 TTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTACC 
                   
                 GESSTAPGTSTEP 
                   
               
               
                   
                 TCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTAGCC 
                   
                 SEGSAPGSPAGSP 
                   
               
               
                   
                 CGGCAGGTTCTCCTACTTCCACTGAGGAAGGTACTTC 
                   
                 TSTEEGTSTEPSE 
                   
               
               
                   
                 TACCGAACCTTCTGAGGGTAGCGCACCAGGTAGCGA 
                   
                 GSAPGSEPATSGS 
                   
               
               
                   
                 ACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCT 
                   
                 ETPGTSESATPES 
                   
               
               
                   
                 GAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTA 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 CTGAACCGTCCGAGGGCAGCGCACCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r79 
                 GGTACCTCTACCGAACCTTCCGAAGGTAGCGCTCCAG 
                 613 
                 GTSTEPSEGSAPG 
                 646 
               
               
                   
                 GTAGCCCGGCAGGTTCTCCTACTTCCACTGAGGAAGG 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 TACTTCTACCGAACCTTCTGAGGGTAGCGCACCAGGT 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 ACCTCCCCTAGCGGCGAATCTTCTACTGCTCCAGGTA 
                   
                 PSGESSTAPGTSP 
                   
               
               
                   
                 CCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTAC 
                   
                 SGESSTAPGTSPS 
                   
               
               
                   
                 CTCCCCTAGCGGTGAATCTTCTACCGCACCAGGTTCT 
                   
                 GESSTAPGSTSES 
                   
               
               
                   
                 ACCAGCGAATCCCCTTCTGGTACTGCTCCAGGTTCTA 
                   
                 PSGTAPGSTSESP 
                   
               
               
                   
                 CCAGCGAATCCCCTTCTGGCACCGCACCAGGTACTTC 
                   
                 SGTAPGTSTPESG 
                   
               
               
                   
                 TACCCCTGAAAGCGGCTCCGCTTCTCCAGGTAGCGAA 
                   
                 SASPGSEPATSGS 
                   
               
               
                   
                 CCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTG 
                   
                 ETPGTSESATPES 
                   
               
               
                   
                 AAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTAC 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 TGAACCGTCCGAGGGCAGCGCACCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r87 
                 GGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAG 
                 614 
                 GSEPATSGSETPG 
                 647 
               
               
                   
                 GTACCTCTGAAAGCGCTACTCCGGAATCTGGTCCAGG 
                   
                 TSESATPESGPGT 
                   
               
               
                   
                 TACTTCTGAAAGCGCTACTCCGGAATCCGGTCCAGGT 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 ACTTCTCCGAGCGGTGAATCTTCTACCGCACCAGGTT 
                   
                 PSGESSTAPGSTS 
                   
               
               
                   
                 CTACTAGCTCTACCGCTGAATCTCCGGGCCCAGGTAC 
                   
                 STAESPGPGTSPS 
                   
               
               
                   
                 TTCTCCGAGCGGTGAATCTTCTACTGCTCCAGGTTCTA 
                   
                 GESSTAPGSTSES 
                   
               
               
                   
                 CTAGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTC 
                   
                 PSGTAPGTSPSGE 
                   
               
               
                   
                 CCCTAGCGGTGAATCTTCTACTGCTCCAGGTTCTACC 
                   
                 SSTAPGSTSSTAE 
                   
               
               
                   
                 AGCTCTACCGCAGAATCTCCGGGTCCAGGTAGCTCTA 
                   
                 SPGPGSSTPSGAT 
                   
               
               
                   
                 CTCCGTCTGGTGCAACCGGTTCCCCAGGTAGCTCTAC 
                   
                 GSPGSSTPSGATG 
                   
               
               
                   
                 CCCTTCTGGTGCAACCGGCTCCCCAGGTAGCTCTACC 
                   
                 SPGSSTPSGANW 
                   
               
               
                   
                 CCTTCTGGTGCAAACTGGCTCTCC 
                   
                 LS 
                   
               
               
                   
               
               
                 LCW462_r88 
                 GGTAGCCCTGCTGGCTCTCCGACTTCTACTGAGGAAG 
                 615 
                 GSPAGSPTSTEEG 
                 648 
               
               
                   
                 GTAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGG 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 TACTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGT 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 ACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTA 
                   
                 TEPSEGSAPGTST 
                   
               
               
                   
                 CCTCTACCGAACCGTCCGAGGGCAGCGCACCAGGTAC 
                   
                 EPSEGSAPGTSES 
                   
               
               
                   
                 TTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTGCA 
                   
                 ATPESGPGASPGT 
                   
               
               
                   
                 TCTCCTGGTACCAGCTCTACCGGTTCTCCAGGTAGCTC 
                   
                 SSTGSPGSSTPSG 
                   
               
               
                   
                 TACTCCTTCTGGTGCTACTGGCTCTCCAGGTGCTTCCC 
                   
                 ATGSPGASPGTSS 
                   
               
               
                   
                 CGGGTACCAGCTCTACCGGTTCTCCAGGTAGCTCTAC 
                   
                 TGSPGSSTPSGAT 
                   
               
               
                   
                 CCCGTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGC 
                   
                 GSPGTPGSGTASS 
                   
               
               
                   
                 AGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCC 
                   
                 SPGSSTPSGATGS 
                   
               
               
                   
                 TTCTGGTGCTACTGGCTCTCCA 
                   
                 P 
                   
               
               
                   
               
               
                 LCW462_r89 
                 GGTAGCTCTACCCCGTCTGGTGCTACTGGTTCTCCAG 
                 616 
                 GSSTPSGATGSPG 
                 649 
               
               
                   
                 GTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGG 
                   
                 TPGSGTASSSPGS 
                   
               
               
                   
                 TAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTA 
                   
                 STPSGATGSPGSP 
                   
               
               
                   
                 GCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTAC 
                   
                 AGSPTSTEEGTSE 
                   
               
               
                   
                 TTCTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACC 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 TCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTACCT 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 CTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGA 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 ACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCT 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 GAAAGCGCAACCCCGGAATCTGGTCCAGGTACTTCTA 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 CTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGA 
                   
                 SAPGTSESATPES 
                   
               
               
                   
                 AAGCGCAACCCCGGAATCCGGCCCAGGTACCTCTGA 
                   
                 GPGTSESATPESG 
                   
               
               
                   
                 AAGCGCAACCCCGGAGTCCGGCCCA 
                   
                 P 
               
               
                   
               
            
           
         
       
     
     Example 7: Construction of XTEN_AM288 
     The entire library LCW0462 was dimerized as described in Example 6 resulting in a library of XTEN_AM288 clones designated LCW0463. 1512 isolates from library LCW0463 were screened using the protocol described in Example 6. 176 highly expressing clones were sequenced and 40 preferred XTEN_AM288 segments were chosen for the construction of multifunctional proteins that contain multiple XTEN segments with 288 amino acid residues. 
     Example 8: Construction of XTEN_AM432 
     We generated a library of XTEN_AM432 segments by recombining segments from library LCW0462 of XTEN_AM144 segments and segments from library LCW0463 of XTEN_AM288 segments. This new library of XTEN_AM432 segment was designated LCW0464. Plasmids were isolated from cultures of  E. coli  harboring LCW0462 and LCW0463, respectively. 1512 isolates from library LCW0464 were screened using the protocol described in Example 6. 176 highly expressing clones were sequenced and 39 preferred XTEN_AM432 segment were chosen for the construction of longer XTENs and for the construction of multifunctional proteins that contain multiple XTEN segments with 432 amino acid residues. 
     In parallel we constructed library LMS0100 of XTEN_AM432 segments using preferred segments of XTEN_AM144 and XTEN_AM288. Screening this library yielded 4 isolates that were selected for further construction 
     Example 9: Construction of XTEN_AM875 
     The stuffer vector pCW0359 was digested with BsaI and KpnI to remove the stuffer segment and the resulting vector fragment was isolated by agarose gel purification. 
     We annealed the phosphorylated oligonucleotide BsaI-AscI-KpnI forP: AGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 650) and the non-phosphorylated oligonucleotide BsaI-AscI-KpnI rev: 
                    (SEQ ID NO: 651)       CCTCGAGTGAAGACGAACCTCCCGTGCTTGGCGCGCCGCTTGCGCTTGC            
for introducing the sequencing island A (SI-A) which encodes amino acids GASASGAPSTG (SEQ ID NO: 652) and has the restriction enzyme AscI recognition nucleotide sequence GGCGCGCC inside. The annealed oligonucleotide pairs were ligated with BsaI and KpnI digested stuffer vector pCW0359 prepared above to yield pCW0466 containing SI-A. We then generated a library of XTEN_AM443 segments by recombining 43 preferred XTEN_AM432 segments from Example 8 and SI-A segments from pCW0466 at C-terminus using the same dimerization process described in Example 5. This new library of XTEN_AM443 segments was designated LCW0479.
 
     We generated a library of XTEN_AM875 segments by recombining segments from library LCW0479 of XTEN_AM443 segments and 43 preferred XTEN_AM432 segments from Example 8 using the same dimerization process described in example 5. This new library of XTEN_AM875 segment was designated LCW0481. 
     Example 10: Construction of XTEN_AM1318 
     We annealed the phosphorylated oligonucleotide BsaI-FseI-KpnI forP: AGGTCCAGAACCAACGGGGCCGGCCCCAAGCGGAGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 653) and the non-phosphorylated oligonucleotide BsaI-FseI-KpnI rev: 
                    (SEQ ID NO: 654)       CCTCGAGTGAAGACGAACCTCCGCTTGGGGCCGGCCCCGTTGGTTCTGG            
for introducing the sequencing island B (SI-B) which encodes amino acids GPEPTGPAPSG (SEQ ID NO: 655) and has the restriction enzyme FseI recognition nucleotide sequence GGCCGGCC inside. The annealed oligonucleotide pairs were ligated with BsaI and KpnI digested stuffer vector pCW0359 as used in Example 9 to yield pCW0467 containing SI-B. We then generated a library of XTEN_AM443 segments by recombining 43 preferred XTEN_AM432 segments from Example 8 and SI-B segments from pCW0467 at C-terminus using the same dimerization process described in example 5. This new library of XTEN_AM443 segments was designated LCW0480.
 
     We generated a library of XTEN_AM1318 segments by recombining segments from library LCW0480 of XTEN_AM443 segments and segments from library LCW0481 of XTEN_AM875 segments using the same dimerization process as in example 5. This new library of XTEN_AM1318 segment was designated LCW0487. 
     Example 11: Construction of XTEN_AD864 
     Using the several consecutive rounds of dimerization, we assembled a collection of XTEN_AD864 sequences starting from segments of XTEN_AD36 listed in Example 1. These sequences were assembled as described in Example 5. Several isolates from XTEN_AD864 were evaluated and found to show good expression and excellent solubility under physiological conditions. One intermediate construct of XTEN_AD576 was sequenced. This clone was evaluated in a PK experiment in cynomolgus monkeys and a half-life of about 20 h was measured. 
     Example 12: Construction of XTEN_AF864 
     Using the several consecutive rounds of dimerization, we assembled a collection of XTEN_AF864 sequences starting from segments of XTEN_AF36 listed in Example 3. These sequences were assembled as described in Example 5. Several isolates from XTEN_AF864 were evaluated and found to show good expression and excellent solubility under physiological conditions. One intermediate construct of XTEN_AF540 was sequenced. This clone was evaluated in a PK experiment in cynomolgus monkeys and a half-life of about 20 h was measured. A full length clone of XTEN_AF864 had excellent solubility and showed half-life exceeding 60 h in cynomolgus monkeys. A second set of XTEN_AF sequences was assembled including a sequencing island as described in Example 9. 
     Example 13: Construction of XTEN_AG864 
     Using the several consecutive rounds of dimerization, we assembled a collection of XTEN_AG864 sequences starting from segments of XTEN_AD36 listed in Example 1. These sequences were assembled as described in Example 5. Several isolates from XTEN_AG864 were evaluated and found to show good expression and excellent solubility under physiological conditions. A full length clone of XTEN_AG864 had excellent solubility and showed half-life exceeding 60 h in cynomolgus monkeys. 
     Example 14: Construction of N-Terminal Extensions of XTEN—Construction and Screening of 12Mer Addition Libraries 
     This example details a step in the optimization of the N-terminus of the XTEN protein to promote the initiation of translation to allow for expression of XTEN fusions at the N-terminus of fusion proteins without the presence of a helper domain. Historically expression of proteins with XTEN at the N-terminus was poor, yielding values that would essentially undetectable in the GFP fluorescence assay (&lt;25% of the expression with the N-terminal CBD helper domain). To create diversity at the codon level, seven amino acid sequences were selected and prepared with a diversity of codons. Seven pairs of oligonucleotides encoding 12 amino acids with codon diversities were designed, annealed and ligated into the NdeI/BsaI restriction enzyme digested stuffer vector pCW0551 (Stuffer-XTEN_AM875-GFP), and transformed into  E. coli  BL21Gold(DE3) competent cells to obtain colonies of seven libraries. The resulting clones have N-terminal XTEN 12mers fused in-frame to XTEN_AM875-GFP to allow use of GFP fluorescence for screening the expression. Individual colonies from the seven created libraries were picked and grown overnight to saturation in 500 μl of super broth media in a 96 deep well plate. The number of colonies picked ranged from approximately half to a third of the theoretical diversity of the library (see Table 16). 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 Theoretical Diversity and Sampling Numbers for 12 mer Addition Libraries. The amino 
               
               
                 acid residues with randomized codons are underlined. 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Motif 
                 Amino Acid 
                 SEQ ID 
                 Theoretical 
                 Number 
               
               
                 Library 
                 Family 
                 Sequence 
                 NO: 
                 Diversity 
                 screened 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 LCW546 
                 AE12 
                 MA SPAG S PTST EE 
                 656 
                 572 
                 2 plates (168) 
               
               
                   
               
               
                 LCW547 
                 AE12 
                 MA TS E SATPES GP 
                 657 
                 1536 
                 5 plates (420) 
               
               
                   
               
               
                 LCW548 
                 AF12 
                 MA TSP S GE SS TA P 
                 658 
                 192 
                 2 plates (168) 
               
               
                   
               
               
                 LCW549 
                 AF12 
                 ME STS S TAE S PG P 
                 659 
                 384 
                 2 plates (168) 
               
               
                   
               
               
                 LCW552 
                 AG12 
                 MA SSTP SG ATGS P 
                 660 
                 384 
                 2 plates (168) 
               
               
                   
               
               
                 LCW553 
                 AG12 
                 ME ASPGT S STG SP 
                 661 
                 384 
                 2 plates (168) 
               
               
                   
               
               
                 LCW554 
                 (CBD-like) 
                 M AS TP E SG S SG 
                 662 
                 32 
                 1 plate (84) 
               
               
                   
               
            
           
         
       
     
     The saturated overnight cultures were used to inoculate fresh 500 μl cultures in auto-induction media in which they were grown overnight at 26° C. These expression cultures were then assayed using a fluorescence plate reader (excitation 395 nm, emission 510 nm) to determine the amount of GFP reporter present (see  FIG. 11  for results of expression assays). The results, graphed as box and whisker plots, indicate that while median expression levels were approximately half of the expression levels compared to the “benchmark” CBD N-terminal helper domain, the best clones from the libraries were much closer to the benchmarks, indicating that further optimization around those sequences was warranted. This is in contrast to previous XTEN versions that were &lt;25% of the expression levels of the CBD N-terminal benchmark. The results also show that the libraries starting with amino acids MA had better expression levels than those beginning with ME. This was most apparent when looking at the best clones, which were closer to the benchmarks as they mostly start with MA. Of the 176 clones within 33% of the CBD-AM875 benchmark, 87% begin with MA, where as only 75% of the sequences in the libraries beginning with MA, a clear over representation of the clones beginning with MA at the highest level of expression. 96 of the best clones were sequenced to confirm identity and twelve sequences (see Table 17), 4 from LCW546, 4 from LCW547 and 4 from LCW552 were selected for further optimization. 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Advanced 12 mer DNA Sequences 
               
            
           
           
               
               
               
            
               
                   
                   
                 SEQ 
               
               
                   
                   
                 ID 
               
               
                 Clone 
                 DNA Sequence 
                 NO: 
               
               
                   
               
               
                 LCW546_02 
                 ATGGCTAGTCCGGCTGGCTCTCCGACCTCCACTGAGGAAGGTACTTCTACT 
                 663 
               
               
                   
               
               
                 LCW546_06 
                 ATGGCTAGTCCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACTTCTACT 
                 664 
               
               
                   
               
               
                 LCW546_07 
                 ATGGCTAGTCCAGCAGGCTCTCCTACCTCCACCGAGGAAGGTACTTCTACT 
                 665 
               
               
                   
               
               
                 LCW546_09 
                 ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTACT 
                 666 
               
               
                   
               
               
                 LCW547_03 
                 ATGGCTACATCCGAAAGCGCAACCCCTGAGTCCGGTCCAGGTACTTCTACT 
                 667 
               
               
                   
               
               
                 LCW547_06 
                 ATGGCTACATCCGAAAGCGCAACCCCTGAATCTGGTCCAGGTACTTCTACT 
                 668 
               
               
                   
               
               
                 LCW547_10 
                 ATGGCTACGTCTGAAAGCGCTACTCCGGAATCTGGTCCAGGTACTTCTACT 
                 669 
               
               
                   
               
               
                 LCW547_17 
                 ATGGCTACGTCCGAAAGCGCTACCCCTGAATCCGGTCCAGGTACTTCTACT 
                 670 
               
               
                   
               
               
                 LCW552_03 
                 ATGGCTAGTTCTACCCCGTCTGGTGCAACCGGTTCCCCAGGTACTTCTACT 
                 671 
               
               
                   
               
               
                 LCW552_05 
                 ATGGCTAGCTCCACTCCGTCTGGTGCTACCGGTTCCCCAGGTACTTCTACT 
                 672 
               
               
                   
               
               
                 LCW552_10 
                 ATGGCTAGCTCTACTCCGTCTGGTGCTACTGGTTCCCCAGGTACTTCTACT 
                 673 
               
               
                   
               
               
                 LCW552_11 
                 ATGGCTAGTTCTACCCCTTCTGGTGCTACTGGTTCTCCAGGTACTTCTACT 
                 674 
               
               
                   
               
            
           
         
       
     
     Example 15: Construction of N-Terminal Extensions of XTEN—Construction and Screening of Libraries Optimizing Codons 3 and 4 
     This example details a step in the optimization of the N-terminus of the XTEN protein to promote the initiation of translation to allow for expression of XTEN fusions at the N-terminus of proteins without the presence of a helper domain. With preferences for the first two codons established (see Example supra), the third and fourth codons were randomized to determine preferences. Three libraries, based upon best clones from LCW546, LCW547 and LCW552, were designed with the third and fourth residues modified such that all combinations of allowable XTEN codons were present at these positions (see  FIG. 12 ). In order to include all the allowable XTEN codons for each library, nine pairs of oligonucleotides encoding 12 amino acids with codon diversities of third and fourth residues were designed, annealed and ligated into the NdeI/BsaI restriction enzyme digested stuffer vector pCW0551 (Stuffer-XTEN_AM875-GFP), and transformed into  E. coli  BL21Gold(DE3) competent cells to obtain colonies of three libraries LCW0569-571. With 24 XTEN codons the theoretical diversity of each library is 576 unique clones. A total of 504 individual colonies from the three created libraries were picked and grown overnight to saturation in 500 μl of super broth media in a 96 deep well plate. This provided sufficient coverage to understand relative library performance and sequence preferences. The saturated overnight cultures were used to inoculate new 500 μl cultures in auto-induction media in which were grown overnight at 26° C. These expression cultures were then assayed using a fluorescence plate reader (excitation 395 nm, emission 510 nm) to determine the amount of GFP reporter present. The top 75 clones from the screen were sequenced and retested for GFP reporter expression versus the benchmark samples (see  FIG. 13 ). 52 clones yielded usable sequencing data and were used for subsequent analysis. The results were broken down by library and indicate that LCW546 was the superior library. The results are presented in Table 18. Surprisingly, it was discovered that base-lined fluorescence readings for the best clones were ˜900 AU, whereas the CBD N-terminal benchmark was only ˜600 AU. This indicates that this library had instituted an approximately 33% improvement over the best clones from the previous library which were approximately equal in expression to the CBD N-terminal benchmark (Example 14). 
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 Third and Fourth Codon Optimization Library Comparison 
               
            
           
           
               
               
               
               
            
               
                   
                 LCW569 
                 LCW570 
                 LCW571 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 N 
                 21 
                 15 
                 16 
               
               
                   
                 Mean 
                 628 
                 491 
                 537 
               
               
                   
                 Fluorescence 
               
               
                   
                 (AU) 
               
               
                   
                 SD 
                 173 
                 71 
                 232 
               
               
                   
                 CV 
                 28% 
                 15% 
                 43% 
               
               
                   
                   
               
            
           
         
       
     
     Further trends were seen in the data showing preferences for particular codons at the third and fourth position. Within the LCW569 library the glutamate codon GAA at the third position and the threonine codon ACT were associated with higher expression as seen in Table 19. 
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 Preferred Third and Fourth Codons in LCW569 
               
            
           
           
               
               
               
               
               
            
               
                   
                 3 = GAA 
                 Rest 
                 4 = ACT 
                 Rest 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 N 
                 8 
                 13 
                 4 
                 17 
               
               
                   
                 Mean 
                 749 
                 554 
                 744 
                 601 
               
               
                   
                 Fluorescence 
               
               
                   
                 (AU) 
               
               
                   
                 SD 
                 234 
                 47 
                 197 
                 162 
               
               
                   
                 CV 
                 31% 
                 9% 
                 26% 
                 27% 
               
               
                   
                   
               
            
           
         
       
     
     Additionally, the retest of the top 75 clones indicated that several were now superior to the benchmark clones. 
     Example 16: Construction of N-Terminal Extensions of XTEN—Construction and Screening of Combinatorial 12Mer and 36Mer Libraries 
     This example details a step in the optimization of the N-terminus of the XTEN protein to promote the initiation of translation to allow for expression of XTEN fusions at the N-terminus of proteins without the presence of a helper domain. With preferences for the first two codons established (see Example supra), the N-terminus was examined in a broader context by combining the 12 selected 12mer sequences (see Example supra) at the very N-terminus followed by 125 previously constructed 36mer segments (see example supra) in a combinatorial manner. This created novel 48mers at the N-terminus of the XTEN protein and enabled the assessment of the impact of longer-range interactions at the N-terminus on expression of the longer sequences ( FIG. 14 ). Similar to the dimerization procedures used to assemble 36mers (see Example infra), the plasmids containing the 125 selected 36mer segments were digested with restriction enzymes BbsI/NcoI and the appropriate fragment was gel-purified. The plasmid from clone AC94 (CBD-XTEN_AM875-GFP) was also digested with BsaI/NcoI and the appropriate fragments were gel-purified. These fragments were ligated together and transformed into  E. coli  BL21Gold(DE3) competent cells to obtain colonies of the library LCW0579, which also served as the vector for further cloning 12 selected 12mers at the very N-terminus. The plasmids of LCW0579 were digested with NdeI/EcoRI/BsaI and the appropriate fragments were gel-purified. 12 pairs of oligonucleotides encoding 12 selected 12mer sequences were designed, annealed and ligated with the NdeI/EcoRI/BsaI digested LCW0579 vector, and transformed into  E. coli  BL21Gold(DE3) competent cells to obtain colonies of the library LCW0580. With a theoretical diversity of 1500 unique clones, a total of 1512 individual colonies from the created library were picked and grown overnight to saturation in 500 μl of super broth media in a 96 deep well plate. This provided sufficient coverage to understand relative library performance and sequence preferences. The saturated overnight cultures were used to inoculate new 500 μl cultures in auto-induction media that were grown overnight at 26° C. These expression cultures were then assayed using a fluorescence plate reader (excitation 395 nm, emission 510 nm) to determine the amount of GFP reporter present. The top 90 clones were sequenced and retested for GFP reporter expression. 83 clones yielded usable sequencing data and were used for subsequent analysis. The sequencing data was used to determine the lead 12mer that was present in each clone and the impact of each 12mer on expression was assessed. Clones LCW546_06 and LCW546_09 stood out as being the superior N-terminus (see Table 20). 
     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 Relative Performance of Clones Starting 
               
               
                 with LCW546_06 and LCW459_09 
               
            
           
           
               
               
               
               
               
            
               
                   
                 LCW546_06 
                 All Others 
                 LCW546_09 
                 All Others 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                 N 
                 11 
                 72 
                 9 
                 74 
               
               
                 Mean 
                 1100 
                 752 
                 988 
                 775 
               
               
                 Fluorescence 
               
               
                 (AU) 
               
               
                 SD 
                 275 
                 154 
                 179 
                 202 
               
               
                 CV 
                 25% 
                 20% 
                 18% 
                 26% 
               
               
                   
               
            
           
         
       
     
     The sequencing and retest also revealed several instances of independent replicates of the same sequence in the data producing similar results, thus increasing confidence in the assay. Additionally, 10 clones with 6 unique sequences were superior to the benchmark clone. They are presented in Table 21. It was noted that these were the only occurrences of these sequences and in no case did one of these sequences occur and fail to beat the bench-mark clone. These six sequences were advanced for further optimization. 
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 Combinatorial 12 mer and 36 mer Clones Superior to Benchmark Clone 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
                   
               
               
                   
                   
                 ID 
                   
                   
               
               
                 Clone Name 
                 First 60 codons 
                 NO: 
                 12 mer Name 
                 36 mer Name 
               
               
                   
               
               
                 LCW580_51 
                 ATGGCTAGTCCTGCTGGCTCTCCAACCTC 
                 675 
                 LCW546_06 
                 LCW0404_040 
               
               
                   
                 CACTGAGGAAGGTGCATCCCCGGGCACC 
                   
                   
                   
               
               
                   
                 AGCTCTACCGGTTCTCCAGGTAGCTCTAC 
                   
                   
                   
               
               
                   
                 CCCGTCTGGTGCTACCGGCTCTCCAGGTA 
                   
                   
                   
               
               
                   
                 GCTCTACCCCGTCTGGTGCTACTGGCTCT 
                   
                   
                   
               
               
                   
                 CCAGGTACTTCTACTGAACCGTCTGAAG 
                   
                   
                   
               
               
                   
                 GCAGCGCA 
                   
                   
                   
               
               
                   
               
               
                 LCW580_81 
                 ATGGCTAGTCCTGCTGGCTCTCCAACCTC 
                 676 
                 LCW546_06 
                 LCW0404_040 
               
               
                   
                 CACTGAGGAAGGTGCATCCCCGGGCACC 
                   
                   
                   
               
               
                   
                 AGCTCTACCGGTTCTCCAGGTAGCTCTAC 
                   
                   
                   
               
               
                   
                 CCCGTCTGGTGCTACCGGCTCTCCAGGTA 
                   
                   
                   
               
               
                   
                 GCTCTACCCCGTCTGGTGCTACTGGCTCT 
                   
                   
                   
               
               
                   
                 CCAGGTACTTCTACTGAACCGTCTGAAG 
                   
                   
                   
               
               
                   
                 GCAGCGCA 
                   
                   
                   
               
               
                   
               
               
                 LCW580_38 
                 ATGGCTAGTCCTGCTGGCTCTCCAACCTC 
                 677 
                 LCW546_06 
                 LCW0402_041 
               
               
                   
                 CACTGAGGAAGGTACTTCTACCGAACCG 
                   
                   
                   
               
               
                   
                 TCCGAGGGTAGCGCACCAGGTAGCCCAG 
                   
                   
                   
               
               
                   
                 CAGGTTCTCCTACCTCCACCGAGGAAGG 
                   
                   
                   
               
               
                   
                 TACTTCTACCGAACCGTCCGAGGGTAGC 
                   
                   
                   
               
               
                   
                 GCACCAGGTACTTCTACTGAACCGTCTG 
                   
                   
                   
               
               
                   
                 AAGGCAGCGCA 
                   
                   
                   
               
               
                   
               
               
                 LCW580_63 
                 ATGGCTAGTCCTGCTGGCTCTCCGACCTC 
                 678 
                 LCW546_09 
                 LCW0402_020 
               
               
                   
                 TACTGAGGAAGGTACTTCTACTGAACCG 
                   
                   
                   
               
               
                   
                 TCTGAAGGCAGCGCACCAGGTAGCGAAC 
                   
                   
                   
               
               
                   
                 CGGCTACTTCCGGTTCTGAAACCCCAGGT 
                   
                   
                   
               
               
                   
                 AGCCCAGCAGGTTCTCCAACTTCTACTGA 
                   
                   
                   
               
               
                   
                 AGAAGGTACTTCTACTGAACCGTCTGAA 
                   
                   
                   
               
               
                   
                 GGCAGCGCA 
                   
                   
                   
               
               
                   
               
               
                 LCW580_06 
                 ATGGCTAGTCCTGCTGGCTCTCCAACCTC 
                 679 
                 LCW546_06 
                 LCW0404_031 
               
               
                   
                 CACTGAGGAAGGTACCCCGGGTAGCGGT 
                   
                   
                   
               
               
                   
                 ACTGCTTCTTCCTCTCCAGGTAGCTCTAC 
                   
                   
                   
               
               
                   
                 CCCTTCTGGTGCAACCGGCTCTCCAGGTG 
                   
                   
                   
               
               
                   
                 CTTCTCCGGGCACCAGCTCTACCGGTTCT 
                   
                   
                   
               
               
                   
                 CCAGGTACTTCTACTGAACCGTCTGAAG 
                   
                   
                   
               
               
                   
                 GCAGCGCA 
                   
                   
                   
               
               
                   
               
               
                 LCW580_35 
                 ATGGCTAGTCCTGCTGGCTCTCCGACCTC 
                 680 
                 LCW546_09 
                 LCW0402_020 
               
               
                   
                 TACTGAGGAAGGTACTTCTACTGAACCG 
                   
                   
                   
               
               
                   
                 TCTGAAGGCAGCGCACCAGGTAGCGAAC 
                   
                   
                   
               
               
                   
                 CGGCTACTTCCGGTTCTGAAACCCCAGGT 
                   
                   
                   
               
               
                   
                 AGCCCAGCAGGTTCTCCAACTTCTACTGA 
                   
                   
                   
               
               
                   
                 AGAAGGTACTTCTACTGAACCGTCTGAA 
                   
                   
                   
               
               
                   
                 GGCAGCGCA 
                   
                   
                   
               
               
                   
               
               
                 LCW580_67 
                 ATGGCTAGTCCTGCTGGCTCTCCGACCTC 
                 681 
                 LCW546_09 
                 LCW0403_064 
               
               
                   
                 TACTGAGGAAGGTACCTCCCCTAGCGGC 
                   
                   
                   
               
               
                   
                 GAATCTTCTACTGCTCCAGGTACCTCTCC 
                   
                   
                   
               
               
                   
                 TAGCGGCGAATCTTCTACCGCTCCAGGT 
                   
                   
                   
               
               
                   
                 ACCTCCCCTAGCGGTGAATCTTCTACCGC 
                   
                   
                   
               
               
                   
                 ACCAGGTACTTCTACTGAACCGTCTGAA 
                   
                   
                   
               
               
                   
                 GGCAGCGCA 
                   
                   
                   
               
               
                   
               
               
                 LCW580_13 
                 ATGGCTAGTCCTGCTGGCTCTCCGACCTC 
                 682 
                 LCW546_09 
                 LCW0403_060 
               
               
                   
                 TACTGAGGAAGGTACCTCTACTCCGGAA 
                   
                   
                   
               
               
                   
                 AGCGGTTCCGCATCTCCAGGTTCTACCAG 
                   
                   
                   
               
               
                   
                 CGAATCCCCGTCTGGCACCGCACCAGGT 
                   
                   
                   
               
               
                   
                 TCTACTAGCTCTACTGCTGAATCTCCGGG 
                   
                   
                   
               
               
                   
                 CCCAGGTACTTCTACTGAACCGTCTGAA 
                   
                   
                   
               
               
                   
                 GGCAGCGCA 
                   
                   
                   
               
               
                   
               
               
                 LCW580_88 
                 ATGGCTAGTCCTGCTGGCTCTCCGACCTC 
                 683 
                 LCW546_09 
                 LCW0403_064 
               
               
                   
                 TACTGAGGAAGGTACCTCCCCTAGCGGC 
                   
                   
                   
               
               
                   
                 GAATCTTCTACTGCTCCAGGTACCTCTCC 
                   
                   
                   
               
               
                   
                 TAGCGGCGAATCTTCTACCGCTCCAGGT 
                   
                   
                   
               
               
                   
                 ACCTCCCCTAGCGGTGAATCTTCTACCGC 
                   
                   
                   
               
               
                   
                 ACCAGGTACTTCTACTGAACCGTCTGAA 
                   
                   
                   
               
               
                   
                 GGCAGCGCA 
                   
                   
                   
               
               
                   
               
               
                 LCW580_11 
                 ATGGCTAGTCCTGCTGGCTCTCCGACCTC 
                 684 
                 LCW546_09 
                 LCW0403_060 
               
               
                   
                 TACTGAGGAAGGTACCTCTACTCCGGAA 
                   
                   
                   
               
               
                   
                 AGCGGTTCCGCATCTCCAGGTTCTACCAG 
                   
                   
                   
               
               
                   
                 CGAATCCCCGTCTGGCACCGCACCAGGT 
                   
                   
                   
               
               
                   
                 TCTACTAGCTCTACTGCTGAATCTCCGGG 
                   
                   
                   
               
               
                   
                 CCCAGGTACTTCTACTGAACCGTCTGAA 
                   
                   
                   
               
               
                   
                 GGCAGCGCA 
               
               
                   
               
            
           
         
       
     
     Example 17: Construction of N-Terminal Extensions of XTEN—Construction and Screening of Combinatorial 12mer and 36mer Libraries for XTEN_AM875 and XTEN-AE864 
     This example details a step in the optimization of the N-terminus of the XTEN protein to promote the initiation of translation to allow for expression of XTEN fusions at the N-terminus of proteins without the presence of a helper domain. With preferences for the first four codons (see Examples supra, and for the best pairing of N-terminal 12mers and 36mers (see Example supra) established, a combinatorial approach was undertaken to examine the union of these preferences. This created novel 48mers at the N-terminus of the XTEN protein and enabled the testing of the confluence of previous conclusions. Additionally, the ability of these leader sequences to be a universal solution for all XTEN proteins was assessed by placing the new 48mers in front of both XTEN-AE864 and XTEN-AM875. Instead of using all 125 clones of 36mer segment, the plasmids from 6 selected clones of 36mer segment with best GFP expression in the combinatorial library were digested with NdeI/EcoRI/BsaI and the appropriate fragments were gel-purified. The plasmids from clones AC94 (CBD-XTEN_AM875-GFP) and AC104 (CBD-XTEN_AE864-GFP) were digested with digested with NdeI/EcoRI/BsaI and the appropriate fragments were gel-purified. These fragments were ligated together and transformed into  E. coli  BL21Gold(DE3) competent cells to obtain colonies of the libraries LCW0585 (-XTEN_AM875-GFP) and LCW0586 (-XTEN_AE864-GFP), which could also serve as the vectors for further cloning 8 selected 12mers at the very N-terminus. The plasmids of LCW0585 and LCW0586 were digested with NdeI/EcoRI/BsaI and the appropriate fragments were gel-purified. 8 pairs of oligonucleotides encoding 8 selected 12mer sequences with best GFP expression in the previous (Generation 2) screening were designed, annealed and ligated with the NdeI/EcoRI/BsaI digested LCW0585 and LCW0586 vectors, and transformed into  E. coli  BL21Gold(DE3) competent cells to obtain colonies of the final libraries LCW0587 (XTEN_AM923-GFP) and LCW0588 (XTEN_AE912-GFP). With a theoretical diversity of 48 unique clones, a total of 252 individual colonies from the created libraries were picked and grown overnight to saturation in 500 μl of super broth media in a 96 deep well plate. This provided sufficient coverage to understand relative library performance and sequence preferences. The saturated overnight cultures were used to inoculate new 500 μl cultures in auto-induction media in which were grown overnight at 26° C. These expression cultures were then assayed using a fluorescence plate reader (excitation 395 nm, emission 510 nm) to determine the amount of GFP reporter present. The top 36 clones were sequenced and retested for GFP reporter expression. 36 clones yielded usable sequencing data and these 36 were used for the subsequent analysis. The sequencing data determined the 12mer, the third codon, the fourth codon and the 36mer present in the clone and revealed that many of the clones were independent replicates of the same sequence. Additionally, the retest results for these clones are close in value, indicating the screening process was robust. Preferences for certain combinations at the N-terminus were seen and were consistently yielding higher fluorescence values approximately 50% greater than the benchmark controls (see Tables 22 and 23). These date support the conclusion that the inclusion of the sequences encoding the optimized N-terminal XTEN into the fusion protein genes conferred a marked enhancement on the expression of the fusion proteins. 
     
       
         
           
               
             
               
                 TABLE 22 
               
             
            
               
                   
               
               
                 Preferred N-terminal Combinations for XTEN-AM875 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Clone 
                 Number of 
                   
                   
                   
                   
                   
               
               
                 Name 
                 Replicates 
                 12mer 
                 36mer 
                 Mean 
                 SD 
                 CV 
               
               
                   
               
               
                 CBD−AM875 
                 NA 
                 NA 
                 NA 
                 1715 
                 418 
                 16% 
               
               
                 LCW587_08 
                 7 
                 LCW546_06_3 = 
                 LCW404_40 
                 2333 
                 572 
                 18% 
               
               
                   
                   
                 GAA 
               
               
                 LCW587_17 
                 5 
                 LCW546_09_3 = 
                 LCW403_64 
                 2172 
                 293 
                 10% 
               
               
                   
                   
                 GAA 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 23 
               
             
            
               
                   
               
               
                 Preferred N-terminal Combinations for XTEN-AE864 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Clone 
                 Number of 
                   
                   
                   
                   
                   
               
               
                 Name 
                 Replicates 
                 12mer 
                 36mer 
                 Mean 
                 SD 
                 CV 
               
               
                   
               
               
                 AC82 
                 NA 
                 NA 
                 NA 
                 1979 
                 679 
                 24% 
               
               
                 LCW588_14 
                 8 
                 LCW546_06_opt3 
                 LCW404_31 
                 2801 
                 240 
                  6% 
               
               
                 LCW588_27 
                 2 
                 LCW546_06_opt34 
                 LCW404_40 
                 2839 
                 556 
                 15% 
               
               
                   
               
            
           
         
       
     
     Notably, the preferred combination of the N-terminal for the XTEN-AM875 and the preferred combination for the XTEN-AE864 are not the same (Tables 22 and 23), indicating more complex interactions further than 150 bases from the initiation site influence expression levels. The sequences for the preferred nucleotide sequences are listed in Table 24 and the preferred clones were analyzed by SDS-PAGE to independently confirm expression (see  FIG. 15 ). The complete sequences of XTEN_AM923 and XTEN_AE912 were selected for further analysis. 
     
       
         
           
               
             
               
                 TABLE 24 
               
             
            
               
                   
               
               
                 Preferred DNA Sequences for first 48 Amino Acid Residues of N-terminal XTEN- 
               
               
                 AM875 and XTEN-AE864 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
               
               
                   
                 XTEN 
                   
                 ID 
               
               
                 Clone Name 
                 Modified 
                 Nucleotide Sequence 
                 NO: 
               
               
                   
               
               
                 LCW587_08 
                 AM875 
                 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTGCATC 
                 685 
               
               
                   
                   
                 CCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTG 
                   
               
               
                   
                   
                 GTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGC 
                   
               
               
                   
                   
                 TCTCCAGGTACTTCTACTGAACCG TCTGAAGGCAGCGCA 
                   
               
               
                   
               
               
                 LCW587_17 
                 AM875 
                 ATGGCTGAACCTGCTGGCTCTCCGACCTCTACTGAGGAAGGTACCTC 
                 686 
               
               
                   
                   
                 CCCTAGCGGCGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCG 
                   
               
               
                   
                   
                 AATCTTCTACCGCTCCAGGTACCTCCCCTAGCGGTGAATCTTCTACC 
                   
               
               
                   
                   
                 GCACCAGGTACTTCTACTGAACCGTCTGAAGGCAGCGCA 
                   
               
               
                   
               
               
                 LCW588_14 
                 AE864 
                 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACCCC 
                 687 
               
               
                   
                   
                 GGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGG 
                   
               
               
                   
                   
                 TGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAGCTCTACCGGTT 
                   
               
               
                   
                   
                 CTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTACTGAG 
                   
               
               
                   
               
               
                 LCW588_27 
                 AE864 
                 ATGGCTGAAACTGCTGGCTCTCCAACCTCCACTGAGGAAGGTGCATC 
                 688 
               
               
                   
                   
                 CCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTG 
                   
               
               
                   
                   
                 GTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGC 
                   
               
               
                   
                   
                 TCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTACTGAG 
               
               
                   
               
            
           
         
       
     
     Example 18: Construction of CTLA4-XTEN Genes and Vectors 
     The CTLA4 dimer genes encoding CTLA4(1-120)-XTEN_AE42-CTLA4(3-120) and CTLA4(1-125)-XTEN_AE42-CTLA4(3-125) were designed and synthesized by GeneArt, which introduced NdeI and BbsI restriction sites that are compatible with the NdeI and BsaI sites that flank CBD (Cellulose Binding Domain) in the CBD-XTEN destination vector. The CBD-XTEN plasmid is a pET30 derivative from Novagen in the format of CBD-XTEN_AE864, where CBD is the stuffer for cloning. Constructs were generated by replacing CBD in CBD-XTEN vector with the CTLA4 dimers-encoding fragments. The CBD-XTEN plasmid features a T7 promoter upstream of the CBD sequence, and an XTEN_AE864 sequence fused in-frame downstream of the CBD sequence. The stuffer CBD was removed by restriction digestion using NdeI and BsaI endonucleases. Restriction endonucleases NdeI and BbsI digested CTLA4 dimer DNA fragments were ligated into the NdeI and BsaI digested CBD-XTEN vector using T4 DNA ligase and electroporated into BL21-Gold(DE3) (Stratagene). Transformants were screened by DNA miniprep and the desired constructs were confirmed by DNA sequencing. The final plasmids yield the CTLA4 dimers with XTEN_AE42 linker fused to XTEN_AE864 genes under the control of a T7 promoter. The resulting DNA are amino acid sequences are listed below. SEQ ID NO: 182 and 184. 
     The linker XTEN_AE42 included in the CTLA4 dimers-XTEN_AE864 plasmids was removed by restriction digestion using the flanking AscI and FseI endonucleases. On the other end, XTEN_AE158 sequence with the same flanking AscI and FseI restriction sites constructed on another plasmid was digested with AscI and FseI endonucleases and ligated into the AscI and FseI digested CTLA4 dimers-XTEN_AE864 plasmids above using T4 DNA ligase and electroporated into BL21-Gold(DE3) (Stratagene). Transformants were screened by DNA miniprep and the desired constructs were confirmed by DNA sequencing. The final plasmids yield the CTLA4 dimers with XTENAE158 linker fused to XTEN_AE864 genes under the control of a T7 promoter. The resulting DNA and amino acid sequences are presented in Table 25 below. 
     Example 19: Construction of aIL6R-XTEN Genes and Vectors 
     DNA ligase and electroporated into BL21-Gold(DE3) (Stratagene). The plasmids yield the aIL6R sscFv-XTEN_AE864 genes under the control of the T7 promoter. The plasmid with one additional BsaI site introduced by PCR was further digested by NdeI and BsaI, ligated with NdeI and BsaI digested XTEN_AE48 fragment using T4 DNA ligase and electroporated into BL21-Gold (DE3). The final plasmid yields the XTEN_AE48-aIL6R scFv-XTEN_AE864 gene under the control of a T7 promoter. All the transformants were screened by DNA miniprep and the desired constructs were confirmed by DNA sequencing. The resulting DNA sequences and encoded final product are provided below. The genes encoding aIL6R scFv at C-terminus were amplified by PCR, which introduced BsaI/HindIII and BsaI/BbsI&amp;HindIII restriction sites that are compatible with the BbsI and HindIII sites that flank GFP (Green Fluorescent Protein) in the XTEN-GFP destination vector. The XTEN-GFP plasmid is a pET30 derivative from Novagen in the format of XTEN_AE912-GFP, where GFP is the stuffer for cloning. Constructs were generated by replacing GFP in XTEN-GFP vector with the aIL6R scFv-encoding PCR fragments. The XTEN-GFP plasmid features a T7 promoter upstream of the XTEN_AE912 sequence and a stuffer GFP sequence fused in-frame downstream of the XTEN_AE912 sequence. The stuffer GFP was removed by restriction digestion using BbsI and HindIII endonucleases. Restriction endonucleases BsaI and HindIII digested aIL6R scFv PCR fragments were ligated into the BbsI and HindIII digested XTEN-GFP vector using T4 DNA ligase and electroporated into BL21-Gold(DE3) (Stratagene). The plasmids yield the XTEN_AE912-aIL6R scFv genes under the control of the T7 promoter. The plasmid with one additional BbsI site introduced by PCR was further digested by BbsI and HindIII, ligated with BsaI and HindIII digested XTEN_AE144 fragment using T4 DNA ligase and electroporated into BL21-Gold (DE3). The final plasmid yields the XTEN_AE912-aIL6R scFv-XTEN_AE144 gene under the control of a T7 promoter. All the transformants were screened by DNA miniprep and the desired constructs were confirmed by DNA sequencing. The resulting DNA sequences and encoded amino acid sequences are provided in Table 25 below. 
     Example 20: Construction Anti-CD40-XTEN and XTEN-Anti-CD40 Genes and Vectors Construction Anti-CD40-XTEN 
     Two genes encoding anti-CD40 were designed by reverse-translation combined with codon optimization. These genes encoding anti-CD40 were synthesized by GeneArt (Regensburg, Germany), which introduced NdeI and BbsI restriction sites that are compatible with the NdeI and BsaI sites that flank the stuffer in the pCBD-XTEN_AE864 destination vector. The pCBD-XTEN_AE864 plasmid is a pET30 derivative from Novagen. Constructs were generated by replacing the CBD sequence in pCBD-XTEN_AE864 with the anti-CD40-encoding fragments. The pCBD-XTEN_AE864 features a T7 promoter upstream of CBD followed by an XTEN sequence fused in-frame. Restriction digested anti-CD40 DNA fragments were ligated into the cleaved pCBD-XTEN_AE864 vector using T4 DNA ligase and electroporated into BL21(DE3) Gold (Stratagene, La Jolla, Calif.). Transformants were screened by DNA miniprep and the desired construct was confirmed by DNA sequencing. The final vectors yield the anti-CD40-XTEN_AE864 gene under the control of a T7 promoter. The resulting constructs are: AC384, pBC0009; AC385, pBC0010. The resulting DNA sequences and encoded amino acid sequences are provided in Table 25 below. 
     Construction of XTEN-anti-CD40 
     Two genes encoding anti-CD40 were amplified by polymerase chain reaction (PCR) using primers anti-CD40forBsaI (anti-CD40_1 forBsaI: ATAAAGGGTCTCCAGGTGAAATTGTTCTGACCCAATCTCC (SEQ ID NO: 689); anti-CD40_2forBsaI: ATAAAGGGTCTCCAGGTGAAATTGTTCTGACTCAATCTCCA (SEQ ID NO: 690)) and anti-CD40revHindIII (anti-CD40_1 revHindIII: AACTCGAAGCTTttaGCTAGACACAGTAACCAGAGT (SEQ ID NO: 691); anti-CD40_2revHindIII: AACTCGAAGCTTttaAGAGGATACGGTCACCAGAGT (SEQ ID NO: 692)), which introduced BsaI and HindIII restriction sites that are compatible with the BbsI and HindIII sites that flank the stuffer in the XTEN_AE912 destination vector. The XTEN_AE912-GFP plasmid is a pET30 derivative from Novagen. Constructs were generated by replacing the GFP sequence in XTENAE912-GFP with the anti-CD40-encoding fragments. The XTEN_AE912-GFP features a T7 promoter upstream of XTEN followed by a GFP sequence fused in-frame. The GFP fragments were removed by restriction digestion using BbsI and HindIII endonucleases. Restriction digested anti-CD40 DNA fragments were ligated into the cleaved XTEN_AE912-GFP vector using T4 DNA ligase and electroporated into BL21(DE3) Gold (Stratagene, La Jolla, Calif.). Transformants were screened by DNA miniprep and the desired construct was confirmed by DNA sequencing. The final vectors yield the XTEN_AE912-anti-CD40 gene under the control of a T7 promoter. The resulting constructs are: AC386, pBC0011; AC387, pBC0012. The resulting DNA sequences and encoded amino acid sequences are provided below. 
     Example 21: Construction of Anti-Her2-XTEN and XTEN-Anti-Her2 Genes and Vectors Construction of Anti-Her2-XTEN 
     The gene encoding scFv anti-Her2 has the format VL-XTEN_Y30-VH, where VL is the light chain of anti-Her2 antibody fragment, VH is the heavy chain of the antibody fragment and XTEN_Y30 is the sequence GSGEGSEGEGGGEGSEGEGSGEGGEGEGSG (SEQ ID NO: 1) flanked by the restriction sites AgeI and KpnI. The gene was synthesized and cloned into a commercial vector for use as the PCR template. The gene encoding scFv anti-Her2 was amplified by polymerase chain reaction (PCR) using primers anti-Her2forNdeI (agatatacatATGGAAGACATTCAGATGACCCAGAGC (SEQ ID NO: 693)) and anti-Her2revBsaI (CCGGGCTACCTGGAGACCCGGAAACAGTTACCAGAGTACC (SEQ ID NO: 694)), which introduced NdeI and BsaI restriction sites that are compatible with the NdeI and BsaI sites that flank the stuffer in the pCBD-XTEN_AE864 destination vector. The pCBD-XTEN_AE864 plasmid is a pET30 derivative from Novagen. Constructs were generated by replacing the CBD sequence in pCBD-XTEN_AE864 with the anti-Her2-encoding fragments. The pCBD-XTEN_AE864 features a T7 promoter upstream of CBD followed by an XTEN sequence fused in-frame. Restriction digested anti-Her2 DNA fragments were ligated into the cleaved pCBD-XTEN_AE864 vector using T4 DNA ligase and electroporated into BL21(DE3) Gold (Stratagene, La Jolla, Calif.). Transformants were screened by DNA miniprep and the desired construct was confirmed by DNA sequencing. The final vectors yield the anti-Her2-XTEN_AE864 gene under the control of a T7 promoter. The resulting constructs is are: pBC0007, SeqID 140. The resulting DNA sequences and encoded amino acid sequences are provided below. 
     Construction of XTEN-Anti-Her2 
     The gene encoding svFV anti-Her2 (described above) was amplified by polymerase chain reaction (PCR) using primers anti-Her2forBbsI (GCACCAGGTTCGTCTTCACTCGACATTCAGATGACCCAGAGC (SEQ ID NO: 695)) and anti-Her2revHindIII (AACTCGAAGCTTTCAGGAAACAGTTACCAGAGTACCTTG (SEQ ID NO: 696)), which introduced BbsI and HindIII restriction sites that are compatible with the BbsI and HindIII sites that flank the stuffer in the XTEN_AE912 destination vector. The XTEN_AE912-GFP plasmid is a pET30 derivative from Novagen. Constructs were generated by replacing the GFP sequence in XTEN_AE912-GFP with the anti-Her2-encoding fragment. The XTEN_AE912-GFP features a T7 promoter upstream of XTEN followed by a GFP sequence fused in-frame. The GFP fragment was removed by restriction digestion using BbsI and HindIII endonucleases. Restriction digested anti-Her2 DNA fragment was ligated into the cleaved XTEN_AE912-GFP vector using T4 DNA ligase and electroporated into BL21(DE3) Gold (Stratagene, La Jolla, Calif.). Transformants were screened by DNA miniprep and the desired construct was confirmed by DNA sequencing. The final vectors yield the XTEN_AE912-anti-Her2 gene under the control of a T7 promoter. The resulting constructs is: pBC0008. The resulting DNA sequences and encoded final product are provided in Table 25 below. 
     Example 22: Construction of Anti-EGFR-XTEN Genes and Vectors 
     The gene encoding anti-EGFR was amplified by polymerase chain reaction (PCR) from a library, which introduced NdeI and BbsI restriction sites that are compatible with the NdeI and BsaI sites that flank the first FLAG tag in the FLAG-Y50-FLAG-His6 (“His6” disclosed as SEQ ID NO: 218) destination vector. Constructs were generated by replacing the FLAG sequence in FLAG-Y50-FLAG-His6 (“His6” disclosed as SEQ ID NO: 218) with the anti-EGFR-encoding fragments. The FLAG-Y50-FLAG-His6 (“His6” disclosed as SEQ ID NO: 218) features a T7 promoter upstream of FLAG followed by the Y50-FLAG-His6 (“His6” disclosed as SEQ ID NO: 218) sequence fused in-frame. Restriction digested anti-EGFR DNA fragments were ligated into the cleaved FLAG-Y50-FLAG-His6 (“His6” disclosed as SEQ ID NO: 218) vector using T4 DNA ligase and electroporated into XL1 Blue. Transformants were screened by DNA miniprep and the desired constructs were confirmed by DNA sequencing. The final vectors yield the anti-EGFR-Y50-FLAG-His6 (“His6” disclosed as SEQ ID NO: 218) gene under the control of a T7 promoter. The resulting construct is: pMS0120. The resulting DNA sequences and encoded amino acid sequences are provided in Table 25 below. 
     Example 23: Construction Anti-CD3-XTEN Genes and Vectors 
     The gene encoding anti-CD3 was amplified by polymerase chain reaction (PCR) from a library, which introduced NdeI and BbsI restriction sites that are compatible with the NdeI and BsaI sites that flank the stuffer in the stuffer-Y288-GFP-His8 (“His8” disclosed as SEQ ID NO: 697) destination vector. Constructs were generated by replacing the stuffer sequence in the stuffer-Y288-GFP-His8 (“His8” disclosed as SEQ ID NO: 697) with the anti-CD3-encoding fragments. Restriction digested anti-CD3 DNA fragments were ligated into the stuffer-Y288-GFP-His8 (“His8” disclosed as SEQ ID NO: 697) vector using T4 DNA ligase and electroporated into BL21(DE3) Gold (Stratagene, La Jolla, Calif.). Transformants were screened by DNA miniprep and the desired constructs were confirmed by DNA sequencing. The final vectors yield the anti-CD3-Y288-GFP-His gene under the control of a T7 promoter. The resulting construct is: pMS0185. The resulting DNA sequences and encoded amino acid sequences are provided below. 
     Example 24: Construction of Genes and Vectors Comprising Multiple scFv 
     Construction of the anti-Her2-Y288-anti-CD3-HA-His6 (“His6” disclosed as SEQ ID NO: 218) and anti-Her2-Y288-anti-EGFR-HA-His6 (“His6” disclosed as SEQ ID NO: 218) genes and vectors 
     The genes encoding anti-CD3 and anti-EGFR were amplified by polymerase chain reaction (PCR), which introduced BbsI restriction sites on both ends of the DNA fragments. A polymerase chain reaction (PCR) was performed to introduce an HA-His6 (“His6” disclosed as SEQ ID NO: 218) tag with a HindIII restriction site on the 3′ end. The anti-CD3-HA-His6 (“His6” disclosed as SEQ ID NO: 218) (or the anti-EGFR-HA-His6 (“His6” disclosed as SEQ ID NO: 218)) fragments were compatible with the BbsI and HindIII sites that flank the GFP-His8 in the anti-Her2-Y288-GFP-His8 (“His8” disclosed as SEQ ID NO: 697) destination vector. Constructs were generated by replacing the GFP-His8 (“His8” disclosed as SEQ ID NO: 697) sequence in the anti-Her2-Y288-GFP-His8 (“His8” disclosed as SEQ ID NO: 697) with the anti-CD3-HA-His6 (“His6” disclosed as SEQ ID NO: 218) or anti-EGFR-HA-His6-encoding fragments (“His6” disclosed as SEQ ID NO: 218). Restriction digested anti-CD3-HA-His6 (“His6” disclosed as SEQ ID NO: 218) or anti-EGFR-HA-His6 (“His6” disclosed as SEQ ID NO: 218) DNA fragments were ligated into the anti-Her2-Y288-GFP-His8 (“His8” disclosed as SEQ ID NO: 697) vector using T4 DNA ligase and electroporated into BL21(DE3) Gold (Stratagene, La Jolla, Calif.). Transformants were screened by DNA miniprep and the desired constructs were confirmed by DNA sequencing. The final vectors yield the anti-Her2-Y288-anti-CD3-HA-His6 (“His6” disclosed as SEQ ID NO: 218) and anti-Her2-Y288-anti-EGFR-HA-His6 (“His6” disclosed as SEQ ID NO: 218) gene under the control of a T7 promoter. The resulting constructs are: pMS0183, AC48 and pMS0184, AC49. The resulting DNA sequences and encoded final product are provided in Table 25 below. 
     Construction of the anti-Her2-Y288-anti-CD3-HA-His8 (“His8” disclosed as SEQ ID NO: 697) genes and vectors 
     The gene encoding anti-CD3 was amplified by polymerase chain reaction (PCR), which introduced BbsI and Spel restriction sites that are compatible with the BbsI and Spel sites that flank the GFP in the anti-Her2-Y288-GFP-HA-His8 (“His8” disclosed as SEQ ID NO: 697) destination vector. Constructs were generated by replacing the GFP sequence in the anti-Her2-Y288-GFP-HA-His8 (“His8” disclosed as SEQ ID NO: 697) with the anti-CD3-encoding fragments. Restriction digested anti-CD3 or DNA fragments were ligated into the anti-Her2-Y288-GFP-HA-His8 (“His8” disclosed as SEQ ID NO: 697) vector using T4 DNA ligase and electroporated into XL1 Blue. Transformants were screened by DNA miniprep and the desired constructs were confirmed by DNA sequencing. The final vectors yield the anti-Her2-Y288-anti-CD3-HA-His8 (“His8” disclosed as SEQ ID NO: 697) gene under the control of a T7 promoter. The resulting construct is: pMS0212, AC69. The resulting DNA sequences and encoded amino acid sequences are provided in Table 25 below. 
     Example 25: Construction of Multivalent aEGFR VHH Binders 
     A library LCW0501 of EGFRVHH-XTENAM144 was constructed by using PCR on four clones of previously codon-optimized library LMS109.005, 020, 038 &amp; 045 with amino acid and DNA sequences designated NdeI_BsaI-EGFR_VHH1-XTEN_AM144-GFP6-229-H8 (LMS109.005); NdeI_BsaI-EGFRVHH1-XTENAM144-GFP6-229-H8 (LMS109.020); NdeI_BsaI-EGFRVHH1-XTENAM144-GFP6-229-H8) (LMS109.038); and NdeI_BsaI-EGFRVHH1-XTENAM144-GFP6-229-H8 (LMS109.045). The amino acid and nucleic acid sequences are provided below. LCW0501 has the gene library of EGFRVHH-XTENAM144 with the flanking restriction sites NdeI &amp;BsaI and BbsI, fused to GFP-8×His-tag (“8×His” disclosed as SEQ ID NO: 697) on a vector of pET30 derivative from Novagen. 
     The plasmid of LCW0501 was digested with BsaI/HindIII to generate the small fragment as the insert and digested with BbsI/HindIII to generate the large fragment as the vector. The insert and vector fragments were ligated and the ligation mixture was electroporated into BL21-Gold (DE3) cells to obtain transformants of LCW0502. LCW0502 is the gene library of EGFR_VHH-XTEN_AM144 dimer with the same flanking restriction sites BsaI and BbsI fused to GFP-8×His-tag (“8×His” disclosed as SEQ ID NO: 697) on the same vector. 
     The plasmid of LCW0502 was digested with BsaI/HindIII to generate the small fragment as the insert and digested with BbsI/HindIII to generate the large fragment as the vector. The insert and vector fragments were ligated and the ligation mixture was electroporated into BL21-Gold (DE3) cells to obtain transformants of LCW0503. LCW0503 is the gene library of EGFR_VHH-XTEN_AM144 tetramer with the same flanking restriction sites BsaI and BbsI fused to GFP-8×His-tag (“8×His” disclosed as SEQ ID NO: 697) on the same vector. 
     The plasmid of LCW0502 was digested with BsaI/HindIII to generate the small fragment as the insert and the plasmid of LCW0503 was digested with BbsI/HindIII to generate the large fragment as the vector. The insert and vector fragments were ligated and the ligation mixture was electroporated into BL21-Gold (DE3) cells to obtain transformants of LCW0504. LCW0504 is the gene library of EGFR_VHH-XTEN_AM144 hexamer with the same flanking restriction sites BsaI and BbsI fused to GFP-8×His-tag (“8×His” disclosed as SEQ ID NO: 697) on the same vector. 
     The plasmid of LCW0503 was digested with BsaI/HindIII to generate the small fragment as the insert and digested with BbsI/HindIII to generate the large fragment as the vector. The insert and vector fragments were ligated and the ligation mixture was electroporated into BL21-Gold (DE3) cells to obtain transformants of LCW0505. LCW0505 is the gene library of EGFR_VHH-XTEN_AM144 octamer with the same flanking restriction sites BsaI and BbsI fused to GFP-8×His-tag (“8×His” disclosed as SEQ ID NO: 697) on the same vector. 
     The LCW501, LCW502, LCW503, LCW504 and LCW505 libraries were screened to determine the best expression candidate for evaluation. The screen was conducted as follows for all of the libraries. Colonies a transformation were picked into 500 μl cultures of LB in 96 deep well plates and grown to saturation overnight. These cultures were stored at 4° C. after 40 μl of these cultures was used to inoculate 500 μl of auto-induction media and these cultures were grown at 26° C. for &gt;24 hours. Following the growth the GFP fluorescence of 100 μl of these auto-induction media cultures was measured using a fluorescence plate reader. The GFP fluorescence is proportional to protein expression and is therefore a read out of total expression. The highest expressing clones were identified, and a new 1 ml overnight was started in SB from the original saturated overnight of that clone. Mini-preps were performed with these new cultures to derived plasmids. The DNA and amino acid sequences are provided in Table 25 below. 
     
       
         
           
               
             
               
                 TABLE 25 
               
             
            
               
                   
               
               
                 DNA and amino acid sequences of binding fusion protein constructs 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
                 SEQ 
               
               
                 Clone 
                   
                 ID 
                 Amino Acid 
                 ID 
               
               
                 Name 
                 DNA Sequence 
                 NO: 
                 Sequence 
                 NO: 
               
               
                   
               
               
                 CTLA4- 
                 ATGGCAATGCATGTTGCACAGCCTGCAGTTGTTCTGGC 
                 698 
                 MAMHVAQPAVV 
                 723 
               
               
                 AE36- 
                 AAGCAGCCGTGGTATTGCCAGCTTTGTTTGTGAATATGC 
                   
                 LASSRGIASFVCE 
                   
               
               
                 CTLA4- 
                 AAGTCCGGGTAAAGCAACCGAAGTTCGTGTTACCGTTC 
                   
                 YASPGKATEVRV 
                   
               
               
                 AE864, 
                 TGAGACAGGCAGATAGCCAGGTTACCGAAGTTTGTGCA 
                   
                 TVLRQADSQVTE 
                   
               
               
                 AC389 
                 GCAACCTATATGATGGGTAATGAACTGACCTTTCTGGA 
                   
                 VCAATYMMGNE 
                   
               
               
                   
                 TGATAGCATTTGTACCGGCACCAGCAGCGGTAATCAGG 
                   
                 LTFLDDSICTGTS 
                   
               
               
                   
                 TTAATCTGACCATTCAGGGTCTGCGTGCAATGGATACC 
                   
                 SGNQVNLTIQGL 
                   
               
               
                   
                 GGTCTGTATATTTGTAAAGTGGAACTGATGTATCCGCCT 
                   
                 RAMDTGLYICKV 
                   
               
               
                   
                 CCGTATTATCTGGGTATTGGTAATGGCACCCAGATTTAT 
                   
                 ELMYPPPYYLGIG 
                   
               
               
                   
                 GTTATTGATCCGGAAGGCGCGCCAGGTACAAGCGAAAG 
                   
                 NGTQIYVIDPEGA 
                   
               
               
                   
                 CGCAACACCGGAAAGCGGTCCGGGTAGCGAACCGGCA 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 ACCAGCGGTAGCGAAACACCGGGTACATCAACCGAAC 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 CGAGCGAAGGTAGCGCACCGGGGCCGGCCATGCATGT 
                   
                 TSTEPSEGSAPGP 
                   
               
               
                   
                 GGCCCAGCCAGCCGTGGTGCTGGCAAGTTCACGCGGTA 
                   
                 AMHVAQPAVVL 
                   
               
               
                   
                 TTGCATCATTTGTGTGCGAATATGCATCACCTGGTAAAG 
                   
                 ASSRGIASFVCEY 
                   
               
               
                   
                 CCACAGAAGTGCGCGTAACAGTACTGCGTCAGGCCGAT 
                   
                 ASPGKATEVRVT 
                   
               
               
                   
                 TCACAGGTGACAGAAGTTTGCGCTGCCACATACATGAT 
                   
                 VLRQADSQVTEV 
                   
               
               
                   
                 GGGCAACGAGCTGACATTCCTGGACGATTCAATTTGTA 
                   
                 CAATYMMGNEL 
                   
               
               
                   
                 CTGGTACAAGCTCAGGCAATCAGGTGAACCTGACAATC 
                   
                 TFLDDSICTGTSS 
                   
               
               
                   
                 CAAGGCCTGAGAGCTATGGACACAGGCCTGTACATCTG 
                   
                 GNQVNLTIQGLR 
                   
               
               
                   
                 CAAAGTTGAGCTGATGTACCCTCCGCCTTATTACTTAGG 
                   
                 AMDTGLYICKVE 
                   
               
               
                   
                 CATTGGCAACGGTACACAGATCTATGTGATCGATCCTG 
                   
                 LMYPPPYYLGIG 
                   
               
               
                   
                 AGGGAGGTAGCCCGGCTGGCTCTCCTACCTCTACTGAG 
                   
                 NGTQIYVIDPEGG 
                   
               
               
                   
                 GAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCC 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 AGGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAG 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 GTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGT 
                   
                 TEPSEGSAPGSPA 
                   
               
               
                   
                 ACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTAC 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 CTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTC 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 TGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAAC 
                   
                 SEGSAPGTSESAT 
                   
               
               
                   
                 CGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCG 
                   
                 PESGPGSEPATSG 
                   
               
               
                   
                 GCTACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCAGG 
                   
                 SETPGSEPATSGS 
                   
               
               
                   
                 CTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCG 
                   
                 ETPGSPAGSPTST 
                   
               
               
                   
                 CAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCG 
                   
                 EEGTSESATPESG 
                   
               
               
                   
                 TCTGAGGGCAGCGCACCAGGTACTTCTACCGAACCGTC 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 CGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTA 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 CCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAG 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 GGTAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGG 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 CAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGT 
                   
                 TEPSEGSAPGTSE 
                   
               
               
                   
                 CCGGTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGC 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 GCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGG 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 TCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTC 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 CAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA 
                   
                 GSETPGTSTEPSE 
                   
               
               
                   
                 GGTACTTCTACTGAACCGTCTGAAGGTAGCGCACCAGG 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 TACTTCTGAAAGCGCAACCCCGGAATCCGGCCCAGGTA 
                   
                 SAPGTSESATPES 
                   
               
               
                   
                 CCTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTAGC 
                   
                 GPGTSESATPESG 
                   
               
               
                   
                 CCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTC 
                   
                 PGSPAGSPTSTEE 
                   
               
               
                   
                 TGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAAC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCTGAA 
                   
                 SEPATSGSETPGT 
                   
               
               
                   
                 AGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGA 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 ACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAAC 
                   
                 TEPSEGSAPGTST 
                   
               
               
                   
                 CGTCCGAAGGTAGCGCACCAGGTACTTCTACCGAACCG 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 TCCGAAGGCAGCGCTCCAGGTACCTCTACTGAACCTTC 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 CGAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTCTG 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 AAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAG 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 GGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTC 
                   
                 GSAPGSPAGSPTS 
                   
               
               
                   
                 CACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTA 
                   
                 TEEGTSTEPSEGS 
                   
               
               
                   
                 GCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCT 
                   
                 APGTSESATPESG 
                   
               
               
                   
                 GGCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGAC 
                   
                 PGSEPATSGSETP 
                   
               
               
                   
                 TCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCA 
                   
                 SEPATSGSETPGT 
                   
               
               
                   
                 GGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGG 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 TACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTA 
                   
                 TEPSEGSAPGTSE 
                   
               
               
                   
                 CTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGC 
                   
                 SATPESGPGSPAG 
                   
               
               
                   
                 CCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCC 
                   
                 SPTSTEEGSPAGS 
                   
               
               
                   
                 GGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGG 
                   
                 PTSTEEGSPAGSP 
                   
               
               
                   
                 CAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAA 
                   
                 TSTEEGTSESATP 
                   
               
               
                   
                 AGCGCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGA 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 ACCGTCTGAGGGCAGCGCACCAGGTACCTCTGAAAGCG 
                   
                 SAPGTSESATPES 
                   
               
               
                   
                 CAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACC 
                   
                 GPGSEPATSGSET 
                   
               
               
                   
                 TCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAAC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 CCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTG 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 GCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCT 
                   
                 TSESATPESGPGT 
                   
               
               
                   
                 GAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG 
                   
                 STEPSEGSAPGSP 
                   
               
               
                   
                 CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCA 
                   
                 AGSPTSTEEGTSE 
                   
               
               
                   
                 CCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCC 
                   
                 SATPESGPGSEPA 
                   
               
               
                   
                 GGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAAC 
                   
                 TSGSETPGTSESA 
                   
               
               
                   
                 CCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCC 
                   
                 TPESGPGSPAGSP 
                   
               
               
                   
                 CAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAA 
                   
                 TSTEEGSPAGSPT 
                   
               
               
                   
                 GGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGG 
                   
                 STEEGTSTEPSEG 
                   
               
               
                   
                 TACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTA 
                   
                 SAPGTSESATPES 
                   
               
               
                   
                 CTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT 
                   
                 GPGTSESATPESG 
                   
               
               
                   
                 TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCT 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 GAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACC 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 GGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGG 
                   
                 SEPATSGSETPGS 
                   
               
               
                   
                 CTACCTCCGGTTCTGAAACTCCAGGTAGCCCAGCAGGC 
                   
                 PAGSPTSTEEGTS 
                   
               
               
                   
                 TCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCT 
                   
                 TEPSEGSAPGTST 
                   
               
               
                   
                 TCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTC 
                   
                 EPSEGSAPGSEPA 
                   
               
               
                   
                 TGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTG 
                   
                 TSGSETPGTSESA 
                   
               
               
                   
                 GCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCT 
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                 GAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG 
                   
                 EGSAPG 
                   
               
               
                   
                 CAGCGCACCAGGTTAA 
                   
                   
                   
               
               
                   
               
               
                 CTLA4- 
                 ATGGCAATGCATGTTGCACAGCCTGCAGTTGTTCTGGC 
                 699 
                 MAMHVAQPAVV 
                 724 
               
               
                 AE36- 
                 AAGCAGCCGTGGTATTGCCAGCTTTGTTTGTGAATATGC 
                   
                 LASSRGIASFVCE 
                   
               
               
                 CTLA4- 
                 AAGTCCGGGTAAAGCAACCGAAGTTCGTGTTACCGTTC 
                   
                 YASPGKAIEVRV 
                   
               
               
                 AE864, 
                 TGAGACAGGCAGATAGCCAGGTTACCGAAGTTTGTGCA 
                   
                 TVLRQADSQVTE 
                   
               
               
                 AC390 
                 GCAACCTATATGATGGGTAATGAACTGACCTTTCTGGA 
                   
                 VCAATYMMGNE 
                   
               
               
                   
                 TGATAGCATTTGTACCGGCACCAGCAGCGGTAATCAGG 
                   
                 LTFLDDSICTGTS 
                   
               
               
                   
                 TTAATCTGACCATTCAGGGTCTGCGTGCAATGGATACC 
                   
                 SGNQVNLTIQGL 
                   
               
               
                   
                 GGTCTGTATATTTGTAAAGTGGAACTGATGTATCCGCCT 
                   
                 RAMDTGLYICKV 
                   
               
               
                   
                 CCGTATTATCTGGGTATTGGTAATGGCACCCAGATTTAT 
                   
                 ELMYPPPYYLGIG 
                   
               
               
                   
                 GTTATTGATCCGGAACCGTGTCCGGATAGCGGCGCGCC 
                   
                 NGTQIYVIDPEPC 
                   
               
               
                   
                 AGGTACAAGCGAAAGCGCAACACCGGAAAGCGGTCCG 
                   
                 PDSGAPGTSESAT 
                   
               
               
                   
                 GGTAGCGAACCGGCAACCAGCGGTAGCGAAACACCGG 
                   
                 PESGPGSEPATSG 
                   
               
               
                   
                 GTACATCAACCGAACCGAGCGAAGGTAGCGCACCGGG 
                   
                 SETPGTSTEPSEG 
                   
               
               
                   
                 GCCGGCCATGCATGTGGCCCAGCCAGCCGTGGTGCTGG 
                   
                 SAPGPAMHVAQP 
                   
               
               
                   
                 CAAGTTCACGCGGTATTGCATCATTTGTGTGCGAATATG 
                   
                 AVVLASSRGIASF 
                   
               
               
                   
                 CATCACCTGGTAAAGCCACAGAAGTGCGCGTAACAGTA 
                   
                 VCEYASPGKATE 
                   
               
               
                   
                 CTGCGTCAGGCCGATTCACAGGTGACAGAAGTTTGCGC 
                   
                 VRVTVLRQADSQ 
                   
               
               
                   
                 TGCCACATACATGATGGGCAACGAGCTGACATTCCTGG 
                   
                 VTEVCAATYMM 
                   
               
               
                   
                 ACGATTCAATTTGTACTGGTACAAGCTCAGGCAATCAG 
                   
                 GNELTFLDDSICT 
                   
               
               
                   
                 GTGAACCTGACAATCCAAGGCCTGAGAGCTATGGACAC 
                   
                 GTSSGNQVNLTIQ 
                   
               
               
                   
                 AGGCCTGTACATCTGCAAAGTTGAGCTGATGTACCCTC 
                   
                 GLRAMDTGLYIC 
                   
               
               
                   
                 CGCCTTATTACTTAGGCATTGGCAACGGTACACAGATC 
                   
                 KVELMYPPPYYL 
                   
               
               
                   
                 TATGTGATCGATCCTGAACCTTGCCCTGATTCAGGAGGT 
                   
                 GIGNGTQIYVIDP 
                   
               
               
                   
                 AGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTAC 
                   
                 EPCPDSGGSPAGS 
                   
               
               
                   
                 TTCTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCTC 
                   
                 PTSTEEGTSESAT 
                   
               
               
                   
                 TACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCCCAG 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 CAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACT 
                   
                 GSAPGSPAGSPTS 
                   
               
               
                   
                 GAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGA 
                   
                 TEEGTSTEPSEGS 
                   
               
               
                   
                 ACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCG 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 CTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACT 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 TCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTC 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 CGGTTCTGAAACTCCAGGTAGCCCGGCAGGCTCTCCGA 
                   
                 SEPATSGSETPGS 
                   
               
               
                   
                 CCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCG 
                   
                 PAGSPTSTEEGTS 
                   
               
               
                   
                 GAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGG 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 CAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTA 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 GCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACC 
                   
                 PSEGSAPGSPAGS 
                   
               
               
                   
                 GAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGC 
                   
                 PTSTEEGTSTEPS 
                   
               
               
                   
                 ACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTC 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 CAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCA 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 GGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGG 
                   
                 SGPGTSTEPSEGS 
                   
               
               
                   
                 TACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTA 
                   
                 APGTSESATPESG 
                   
               
               
                   
                 GCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGTACT 
                   
                 PGSEPATSGSETP 
                   
               
               
                   
                 TCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTC 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 TACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTG 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 AAAGCGCAACCCCGGAATCCGGCCCAGGTACCTCTGAA 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 AGCGCAACCCCGGAGTCCGGCCCAGGTAGCCCTGCTGG 
                   
                 ESATPESGPGSPA 
                   
               
               
                   
                 CTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCG 
                   
                 GSPTSTEEGTSES 
                   
               
               
                   
                 CAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACC 
                   
                 ATPESGPGSEPAT 
                   
               
               
                   
                 TCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGCTAC 
                   
                 SGSETPGTSESAT 
                   
               
               
                   
                 TCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGTCTG 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 AGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGG 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 CAGCGCTCCAGGTACCTCTACTGAACCTTCCGAGGGCA 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 GCGCTCCAGGTACCTCTACCGAACCTTCTGAAGGTAGC 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 GCACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCGC 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 ACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGG 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 AAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGG 
                   
                 ESATPESGPGSEP 
                   
               
               
                   
                 TAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTA 
                   
                 ATSGSETPGTSES 
                   
               
               
                   
                 CCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGC 
                   
                 ATPESGPGSEPAT 
                   
               
               
                   
                 GAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTC 
                   
                 SGSETPGTSESAT 
                   
               
               
                   
                 TGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTA 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 CTGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTGAA 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 AGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGG 
                   
                 SGPGSPAGSPTST 
                   
               
               
                   
                 CTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCT 
                   
                 EEGSPAGSPTSTE 
                   
               
               
                   
                 CTCCAACTTCTACTGAAGAAGGTAGCCCGGCAGGCTCT 
                   
                 EGSPAGSPTSTEE 
                   
               
               
                   
                 CCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAAC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 AGGGCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCT 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 GAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTC 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 TGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAAT 
                   
                 SATPESGPGSEPA 
                   
               
               
                   
                 CTGGTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAA 
                   
                 TSGSETPGTSESA 
                   
               
               
                   
                 ACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGG 
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                 CCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCAC 
                   
                 EGSAPGSPAGSPT 
                   
               
               
                   
                 CAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAA 
                   
                 STEEGTSESATPE 
                   
               
               
                   
                 GGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG 
                   
                 SGPGSEPATSGSE 
                   
               
               
                   
                 TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTA 
                   
                 TPGTSESATPESG 
                   
               
               
                   
                 CTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGC 
                   
                 PGSPAGSPTSTEE 
                   
               
               
                   
                 CCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCC 
                   
                 GSPAGSPTSTEEG 
                   
               
               
                   
                 GGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTAC 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 CGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAA 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 GCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGC 
                   
                 ESATPESGPGTSE 
                   
               
               
                   
                 GCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGC 
                   
                 SATPESGPGSEPA 
                   
               
               
                   
                 TACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTT 
                   
                 TSGSETPGSEPAT 
                   
               
               
                   
                 CTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCC 
                   
                 SGSETPGSPAGSP 
                   
               
               
                   
                 GGTTCTGAAACTCCAGGTAGCCCAGCAGGCTCTCCGAC 
                   
                 TSTEEGTSTEPSE 
                   
               
               
                   
                 TTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAG 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 GCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGC 
                   
                 SAPGSEPATSGSE 
                   
               
               
                   
                 AGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGA 
                   
                 TPGTSESATPESG 
                   
               
               
                   
                 AACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTG 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 GCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCA 
                   
                 G 
                   
               
               
                   
                 CCAGGTTAA 
                   
                   
                   
               
               
                   
               
               
                 CTLA4- 
                 ATGGCAATGCATGTTGCACAGCCTGCAGTTGTTCTGGC 
                 700 
                 MAMHVAQPAVV 
                 725 
               
               
                 AE158- 
                 AAGCAGCCGTGGTATTGCCAGCTTTGTTTGTGAATATGC 
                   
                 LASSRGIASFVCE 
                   
               
               
                 CTLA4- 
                 AAGTCCGGGTAAAGCAACCGAAGTTCGTGTTACCGTTC 
                   
                 YASPGKAIEVRV 
                   
               
               
                 AE864, 
                 TGAGACAGGCAGATAGCCAGGTTACCGAAGTTTGTGCA 
                   
                 TVLRQADSQVTE 
                   
               
               
                 AC391 
                 GCAACCTATATGATGGGTAATGAACTGACCTTTCTGGA 
                   
                 VCAATYMMGNE 
                   
               
               
                   
                 TGATAGCATTTGTACCGGCACCAGCAGCGGTAATCAGG 
                   
                 LTFLDDSICTGTS 
                   
               
               
                   
                 TTAATCTGACCATTCAGGGTCTGCGTGCAATGGATACC 
                   
                 SGNQVNLTIQGL 
                   
               
               
                   
                 GGTCTGTATATTTGTAAAGTGGAACTGATGTATCCGCCT 
                   
                 RAMDTGLYICKV 
                   
               
               
                   
                 CCGTATTATCTGGGTATTGGTAATGGCACCCAGATTTAT 
                   
                 ELMYPPPYYLGIG 
                   
               
               
                   
                 GTTATTGATCCGGAAGGCGCGCCAAGCACGGGAGGTAC 
                   
                 NGTQIYVIDPEGA 
                   
               
               
                   
                 TTCTGAAAGCGCTACTCCGGAGTCCGGTCCAGGTACCT 
                   
                 PSTGGTSESATPE 
                   
               
               
                   
                 CTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACTTCT 
                   
                 SGPGTSTEPSEGS 
                   
               
               
                   
                 ACTGAACCTTCTGAGGGTAGCGCTCCAGGTACTTCTGA 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 AAGCGCTACTCCGGAGTCCGGTCCAGGTACCTCTACCG 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 AACCGTCCGAAGGCAGCGCTCCAGGTACTTCTACTGAA 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 CCTTCTGAGGGTAGCGCTCCAGGTACCTCTGAAAGCGC 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 TACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGT 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 CTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCC 
                   
                 TEPSEGSAPGTST 
                   
               
               
                   
                 GAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGA 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 GGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCT 
                   
                 PSEGSAPGSPAGS 
                   
               
               
                   
                 CCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGT 
                   
                 PTSTEEGTSTEPS 
                   
               
               
                   
                 AGCGCACCAGGTCCAGAACCAACGGGGCCGGCCATGC 
                   
                 EGSAPGPEPTGPA 
                   
               
               
                   
                 ATGTGGCCCAGCCAGCCGTGGTGCTGGCAAGTTCACGC 
                   
                 MHVAQPAVVLA 
                   
               
               
                   
                 GGTATTGCATCATTTGTGTGCGAATATGCATCACCTGGT 
                   
                 SSRGIASFVCEYA 
                   
               
               
                   
                 AAAGCCACAGAAGTGCGCGTAACAGTACTGCGTCAGGC 
                   
                 SPGKATEVRVTV 
                   
               
               
                   
                 CGATTCACAGGTGACAGAAGTTTGCGCTGCCACATACA 
                   
                 LRQADSQVTEVC 
                   
               
               
                   
                 TGATGGGCAACGAGCTGACATTCCTGGACGATTCAATT 
                   
                 AATYMMGNELT 
                   
               
               
                   
                 TGTACTGGTACAAGCTCAGGCAATCAGGTGAACCTGAC 
                   
                 FLDDSICTGTSSG 
                   
               
               
                   
                 AATCCAAGGCCTGAGAGCTATGGACACAGGCCTGTACA 
                   
                 NQVNLTIQGLRA 
                   
               
               
                   
                 TCTGCAAAGTTGAGCTGATGTACCCTCCGCCTTATTACT 
                   
                 MDTGLYICKVEL 
                   
               
               
                   
                 TAGGCATTGGCAACGGTACACAGATCTATGTGATCGAT 
                   
                 MYPPPYYLGIGN 
                   
               
               
                   
                 CCTGAGGGAGGTAGCCCGGCTGGCTCTCCTACCTCTAC 
                   
                 GTQIYVIDPEGGS 
                   
               
               
                   
                 TGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTG 
                   
                 PAGSPTSTEEGTS 
                   
               
               
                   
                 GTCCAGGTACCTCTACTGAACCGTCCGAAGGTAGCGCT 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 CCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA 
                   
                 EPSEGSAPGSPAG 
                   
               
               
                   
                 AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAG 
                   
                 SPTSTEEGTSTEPS 
                   
               
               
                   
                 GTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGT 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 ACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAG 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 CGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCG 
                   
                 SGPGSEPATSGSE 
                   
               
               
                   
                 AACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCG 
                   
                 TPGSEPATSGSET 
                   
               
               
                   
                 GCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGA 
                   
                 PGSPAGSPTSTEE 
                   
               
               
                   
                 AAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCTACCG 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 AACCGTCTGAGGGCAGCGCACCAGGTACTTCTACCGAA 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 CCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTC 
                   
                 STEPSEGSAPGSP 
                   
               
               
                   
                 TCCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGT 
                   
                 AGSPTSTEEGTST 
                   
               
               
                   
                 CCGAGGGTAGCGCACCAGGTACCTCTACTGAACCTTCT 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 GAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCC 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 GGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGAAG 
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                 GTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAA 
                   
                 EGSAPGTSESATP 
                   
               
               
                   
                 TCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGA 
                   
                 ESGPGSEPATSGS 
                   
               
               
                   
                 GACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCG 
                   
                 ETPGTSTEPSEGS 
                   
               
               
                   
                 CACCAGGTACTTCTACTGAACCGTCTGAAGGTAGCGCA 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 CCAGGTACTTCTGAAAGCGCAACCCCGGAATCCGGCCC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 AGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCAG 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 GTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGT 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 ACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAG 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 CGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCT 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 CTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCT 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 ACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTAC 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 TGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACCG 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 AACCGTCCGAAGGCAGCGCTCCAGGTACCTCTACTGAA 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 CCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACC 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 TTCTGAAGGTAGCGCACCAGGTACTTCTACCGAACCGT 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 CCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCT 
                   
                 APGSPAGSPTSTE 
                   
               
               
                   
                 ACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGA 
                   
                 EGTSTEPSEGSAP 
                   
               
               
                   
                 GGGTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTG 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 AGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTCT 
                   
                 SEPATSGSETPGT 
                   
               
               
                   
                 GAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATC 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 TGGTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAA 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 CCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGC 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 CCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACC 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 AGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAG 
                   
                 TPESGPGSPAGSP 
                   
               
               
                   
                 GTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGT 
                   
                 TSTEEGSPAGSPT 
                   
               
               
                   
                 AGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAG 
                   
                 STEEGSPAGSPTS 
                   
               
               
                   
                 CCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTT 
                   
                 TEEGTSESATPES 
                   
               
               
                   
                 CTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCT 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 ACCGAACCGTCTGAGGGCAGCGCACCAGGTACCTCTGA 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 AAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTG 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 CTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGC 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 GCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAAC 
                   
                 EPATSGSETPGTS 
                   
               
               
                   
                 CTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTA 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 CTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCG 
                   
                 EPSEGSAPGSPAG 
                   
               
               
                   
                 AGGGCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACC 
                   
                 SPTSTEEGTSESA 
                   
               
               
                   
                 TCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGA 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 ATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTG 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 AAACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCC 
                   
                 ESGPGSPAGSPTS 
                   
               
               
                   
                 GGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGA 
                   
                 TEEGSPAGSPTST 
                   
               
               
                   
                 GGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAG 
                   
                 EEGTSTEPSEGSA 
                   
               
               
                   
                 AAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCA 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 GGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGG 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 TACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTA 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 CTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGC 
                   
                 EPATSGSETPGSE 
                   
               
               
                   
                 GAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGA 
                   
                 PATSGSETPGSPA 
                   
               
               
                   
                 ACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCAG 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 CAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACT 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 GAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGA 
                   
                 SEGSAPGSEPATS 
                   
               
               
                   
                 ACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAA 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 CCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCC 
                   
                 SAPG 
                   
               
               
                   
                 GAGGGCAGCGCACCAGGTTAA 
                   
                   
                   
               
               
                   
               
               
                 CTLA4- 
                 ATGGCAATGCATGTTGCACAGCCTGCAGTTGTTCTGGC 
                 701 
                 MAMHVAQPAVV 
                 726 
               
               
                 AE158- 
                 AAGCAGCCGTGGTATTGCCAGCTTTGTTTGTGAATATGC 
                   
                 LASSRGIASFVCE 
                   
               
               
                 CTLA4- 
                 AAGTCCGGGTAAAGCAACCGAAGTTCGTGTTACCGTTC 
                   
                 YASPGKATEVRV 
                   
               
               
                 AE864, 
                 TGAGACAGGCAGATAGCCAGGTTACCGAAGTTTGTGCA 
                   
                 TVLRQADSQVTE 
                   
               
               
                 AC392 
                 GCAACCTATATGATGGGTAATGAACTGACCTTTCTGGA 
                   
                 VCAATYMMGNE 
                   
               
               
                   
                 TGATAGCATTTGTACCGGCACCAGCAGCGGTAATCAGG 
                   
                 LTFLDDSICTGTS 
                   
               
               
                   
                 TTAATCTGACCATTCAGGGTCTGCGTGCAATGGATACC 
                   
                 SGNQVNLTIQGL 
                   
               
               
                   
                 GGTCTGTATATTTGTAAAGTGGAACTGATGTATCCGCCT 
                   
                 RAMDTGLYICKV 
                   
               
               
                   
                 CCGTATTATCTGGGTATTGGTAATGGCACCCAGATTTAT 
                   
                 ELMYPPPYYLGIG 
                   
               
               
                   
                 GTTATTGATCCGGAACCGTGTCCGGATAGCGGCGCGCC 
                   
                 NGTQIYVIDPEPC 
                   
               
               
                   
                 AAGCACGGGAGGTACTTCTGAAAGCGCTACTCCGGAGT 
                   
                 PDSGAPSTGGTSE 
                   
               
               
                   
                 CCGGTCCAGGTACCTCTACCGAACCGTCCGAAGGCAGC 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 GCTCCAGGTACTTCTACTGAACCTTCTGAGGGTAGCGCT 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 CCAGGTACTTCTGAAAGCGCTACTCCGGAGTCCGGTCC 
                   
                 SEGSAPGTSESAT 
                   
               
               
                   
                 AGGTACCTCTACCGAACCGTCCGAAGGCAGCGCTCCAG 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 GTACTTCTACTGAACCTTCTGAGGGTAGCGCTCCAGGT 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 ACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTAC 
                   
                 SAPGTSESATPES 
                   
               
               
                   
                 CTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTT 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 CTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 ACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGC 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 AGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCG 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 AACCGTCCGAGGGTAGCGCACCAGGTCCAGAACCAAC 
                   
                 STEPSEGSAPGPE 
                   
               
               
                   
                 GGGGCCGGCCATGCATGTGGCCCAGCCAGCCGTGGTGC 
                   
                 PTGPAMHVAQPA 
                   
               
               
                   
                 TGGCAAGTTCACGCGGTATTGCATCATTTGTGTGCGAAT 
                   
                 VVLASSRGIASFV 
                   
               
               
                   
                 ATGCATCACCTGGTAAAGCCACAGAAGTGCGCGTAACA 
                   
                 CEYASPGKATEV 
                   
               
               
                   
                 GTACTGCGTCAGGCCGATTCACAGGTGACAGAAGTTTG 
                   
                 RVTVLRQADSQV 
                   
               
               
                   
                 CGCTGCCACATACATGATGGGCAACGAGCTGACATTCC 
                   
                 TEVCAATYMMG 
                   
               
               
                   
                 TGGACGATTCAATTTGTACTGGTACAAGCTCAGGCAAT 
                   
                 NELTFLDDSICTG 
                   
               
               
                   
                 CAGGTGAACCTGACAATCCAAGGCCTGAGAGCTATGGA 
                   
                 TSSGNQVNLTIQG 
                   
               
               
                   
                 CACAGGCCTGTACATCTGCAAAGTTGAGCTGATGTACC 
                   
                 LRAMDTGLYICK 
                   
               
               
                   
                 CTCCGCCTTATTACTTAGGCATTGGCAACGGTACACAG 
                   
                 VELMYPPPYYLGI 
                   
               
               
                   
                 ATCTATGTGATCGATCCTGAACCTTGCCCTGATTCAGGA 
                   
                 GNGTQIYVIDPEP 
                   
               
               
                   
                 GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGG 
                   
                 CPDSGGSPAGSPT 
                   
               
               
                   
                 TACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTAC 
                   
                 STEEGTSESATPE 
                   
               
               
                   
                 CTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC 
                   
                 SGPGTSTEPSEGS 
                   
               
               
                   
                 CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCT 
                   
                 APGSPAGSPTSTE 
                   
               
               
                   
                 ACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTAC 
                   
                 EGTSTEPSEGSAP 
                   
               
               
                   
                 TGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAA 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 GCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCT 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 ACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTAC 
                   
                 EPATSGSETPGSE 
                   
               
               
                   
                 CTCCGGTTCTGAAACTCCAGGTAGCCCGGCAGGCTCTC 
                   
                 PATSGSETPGSPA 
                   
               
               
                   
                 CGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACC 
                   
                 GSPTSTEEGTSES 
                   
               
               
                   
                 CCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGA 
                   
                 ATPESGPGTSTEP 
                   
               
               
                   
                 GGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGG 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 GTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCC 
                   
                 EGSAPGSPAGSPT 
                   
               
               
                   
                 ACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAG 
                   
                 STEEGTSTEPSEG 
                   
               
               
                   
                 CGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCG 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 CTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGT 
                   
                 APGTSESATPESG 
                   
               
               
                   
                 CCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACC 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 AGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAG 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 GTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGT 
                   
                 SEPATSGSETPGT 
                   
               
               
                   
                 ACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTAC 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 TTCTACTGAACCGTCTGAAGGTAGCGCACCAGGTACTT 
                   
                 TEPSEGSAPGTSE 
                   
               
               
                   
                 CTGAAAGCGCAACCCCGGAATCCGGCCCAGGTACCTCT 
                   
                 SATPESGPGTSES 
                   
               
               
                   
                 GAAAGCGCAACCCCGGAGTCCGGCCCAGGTAGCCCTGC 
                   
                 ATPESGPGSPAGS 
                   
               
               
                   
                 TGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAA 
                   
                 PTSTEEGTSESAT 
                   
               
               
                   
                 GCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCA 
                   
                 PESGPGSEPATSG 
                   
               
               
                   
                 ACCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGC 
                   
                 SETPGTSESATPE 
                   
               
               
                   
                 TACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGT 
                   
                 SGPGTSTEPSEGS 
                   
               
               
                   
                 CTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCC 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 GAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGA 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 AGGCAGCGCTCCAGGTACCTCTACTGAACCTTCCGAGG 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 GCAGCGCTCCAGGTACCTCTACCGAACCTTCTGAAGGT 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 AGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG 
                   
                 STEPSEGSAPGSP 
                   
               
               
                   
                 CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCG 
                   
                 AGSPTSTEEGTST 
                   
               
               
                   
                 AGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCA 
                   
                 EPSEGSAPGTSES 
                   
               
               
                   
                 CCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCC 
                   
                 ATPESGPGSEPAT 
                   
               
               
                   
                 AGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAG 
                   
                 SGSETPGTSESAT 
                   
               
               
                   
                 GTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGT 
                   
                 PESGPGSEPATSG 
                   
               
               
                   
                 AGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTAC 
                   
                 SETPGTSESATPE 
                   
               
               
                   
                 CTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTC 
                   
                 SGPGTSTEPSEGS 
                   
               
               
                   
                 TACTGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTG 
                   
                 APGTSESATPESG 
                   
               
               
                   
                 AAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCT 
                   
                 PGSPAGSPTSTEE 
                   
               
               
                   
                 GGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGG 
                   
                 GSPAGSPTSTEEG 
                   
               
               
                   
                 CTCTCCAACTTCTACTGAAGAAGGTAGCCCGGCAGGCT 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 CTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTC 
                   
                 TEPSEGSAPGTSE 
                   
               
               
                   
                 TGAGGGCAGCGCACCAGGTACCTCTGAAAGCGCAACTC 
                   
                 SATPESGPGSEPA 
                   
               
               
                   
                 CTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGC 
                   
                 TSGSETPGTSESA 
                   
               
               
                   
                 TCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGA 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 ATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCTCTG 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 AAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCT 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 GGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGC 
                   
                 SAPGSPAGSPTST 
                   
               
               
                   
                 ACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAG 
                   
                 EEGTSESATPESG 
                   
               
               
                   
                 AAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCA 
                   
                 PGSEPATSGSETP 
                   
               
               
                   
                 GGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGG 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 TACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTA 
                   
                 SPAGSPTSTEEGS 
                   
               
               
                   
                 GCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGC 
                   
                 PAGSPTSTEEGTS 
                   
               
               
                   
                 CCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCT 
                   
                 TEPSEGSAPGTSE 
                   
               
               
                   
                 ACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGA 
                   
                 SATPESGPGTSES 
                   
               
               
                   
                 AAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAA 
                   
                 ATPESGPGTSESA 
                   
               
               
                   
                 GCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGC 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 GCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTAC 
                   
                 GSETPGSEPATSG 
                   
               
               
                   
                 TTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCT 
                   
                 SETPGSPAGSPTS 
                   
               
               
                   
                 CCGGTTCTGAAACTCCAGGTAGCCCAGCAGGCTCTCCG 
                   
                 TEEGTSTEPSEGS 
                   
               
               
                   
                 ACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGA 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 AGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGG 
                   
                 PGSEPATSGSETP 
                   
               
               
                   
                 GCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCT 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 GAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATC 
                   
                 TSTEPSEGSAPG 
                   
               
               
                   
                 TGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCG 
                   
                   
                   
               
               
                   
                 CACCAGGTTAA 
                   
                   
                   
               
               
                   
               
               
                 AE912- 
                 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGA 
                 702 
                 MAEPAGSPTSTEE 
                 727 
               
               
                 aIL6R 
                 AGGTACCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGG 
                   
                 GTPGSGTASSSPG 
                   
               
               
                 scFv, 
                 TAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGC 
                   
                 SSTPSGATGSPGA 
                   
               
               
                 AC341 
                 TTCTCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCCC 
                   
                 SPGTSSTGSPGSP 
                   
               
               
                   
                 GGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGA 
                   
                 AGSPTSTEEGTSE 
                   
               
               
                   
                 AAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 AACCGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGC 
                   
                 PSEGSAPGSPAGS 
                   
               
               
                   
                 TCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCT 
                   
                 PTSTEEGTSTEPS 
                   
               
               
                   
                 TCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTC 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 TGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCC 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 CGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGT 
                   
                 SGPGSEPATSGSE 
                   
               
               
                   
                 TCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTC 
                   
                 TPGSEPATSGSET 
                   
               
               
                   
                 TGAAACTCCAGGTAGCCCGGCAGGCTCTCCGACCTCTA 
                   
                 PGSPAGSPTSTEE 
                   
               
               
                   
                 CTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 GGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGC 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 ACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCAC 
                   
                 STEPSEGSAPGSP 
                   
               
               
                   
                 CAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA 
                   
                 AGSPTSTEEGTST 
                   
               
               
                   
                 GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGG 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 TACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTA 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 CTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACT 
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                 TCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTC 
                   
                 EGSAPGTSESATP 
                   
               
               
                   
                 TGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAAC 
                   
                 ESGPGSEPATSGS 
                   
               
               
                   
                 CGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCG 
                   
                 ETPGTSTEPSEGS 
                   
               
               
                   
                 AACCGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAA 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 CCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 AACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAA 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CCCCGGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCA 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 ACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCC 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 TGAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTT 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCGGAG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 TCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAG 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 CGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCG 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 CACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCT 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 CCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCC 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 AGGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCAG 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT 
                   
                 APGSPAGSPTSFE 
                   
               
               
                   
                 AGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTAC 
                   
                 EGTSTEPSEGSAP 
                   
               
               
                   
                 TTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAA 
                   
                 SEPATSGSETPGT 
                   
               
               
                   
                 CCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAA 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 AGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGC 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 AACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 CTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGT 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACT 
                   
                 TPESGPGSPAGSP 
                   
               
               
                   
                 CCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGAC 
                   
                 TSTEEGSPAGSPT 
                   
               
               
                   
                 TTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTT 
                   
                 STEEGSPAGSPTS 
                   
               
               
                   
                 CTACTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCT 
                   
                 TEEGTSESATPES 
                   
               
               
                   
                 ACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTC 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 CGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCG 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 CACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGC 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 CCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCC 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 AGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAG 
                   
                 EPATSGSETPGTS 
                   
               
               
                   
                 GTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGT 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 ACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTAC 
                   
                 EPSEGSAPGSPAG 
                   
               
               
                   
                 TTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCC 
                   
                 SPTSTEEGTSESA 
                   
               
               
                   
                 CTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACC 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 GGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAA 
                   
                 ESGPGSPAGSPTS 
                   
               
               
                   
                 GCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGC 
                   
                 TEEGSPAGSPTST 
                   
               
               
                   
                 TCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTC 
                   
                 EEGTSTEPSEGSA 
                   
               
               
                   
                 TCCAACTTCTACTGAAGAAGGTACTTCTACCGAACCTTC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 CGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCT 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 GAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGA 
                   
                 EPATSGSETPGSE 
                   
               
               
                   
                 ATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTG 
                   
                 PATSGSETPGSPA 
                   
               
               
                   
                 AAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAA 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 ACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGA 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 GGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCAC 
                   
                 SEGSAPGSEPATS 
                   
               
               
                   
                 CAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGG 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 TACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTA 
                   
                 SAPGADIQMTQS 
                   
               
               
                   
                 CTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTGCT 
                   
                 PSSLSASVGDRVT 
                   
               
               
                   
                 GATATTCAAATGACTCAATCTCCTTCTTCTCTGTCCGCA 
                   
                 ITCRASQDISSYL 
                   
               
               
                   
                 TCTGTAGGCGACCGTGTAACCATCACTTGCCGTGCCTCC 
                   
                 NWYQQKPGKAP 
                   
               
               
                   
                 CAGGACATCTCCAGCTACCTGAACTGGTACCAGCAGAA 
                   
                 KLLIYYTSRLHSG 
                   
               
               
                   
                 GCCGGGCAAGGCTCCGAAACTGCTGATTTATTACACTA 
                   
                 VPSRFSGSGSGTD 
                   
               
               
                   
                 GCCGTCTGCATTCTGGTGTTCCGAGCCGCTTCTCCGGTT 
                   
                 FTFTISSLQPEDIA 
                   
               
               
                   
                 CTGGCAGCGGTACCGATTTCACTTTTACTATCTCCAGCC 
                   
                 TYYCQQGNTLPY 
                   
               
               
                   
                 TGCAACCGGAGGACATCGCGACGTACTATTGCCAGCAA 
                   
                 TFGQGTKVEIKT 
                   
               
               
                   
                 GGTAATACCCTGCCGTACACCTTCGGCCAAGGCACGAA 
                   
                 GSGEGSEGEGGG 
                   
               
               
                   
                 AGTTGAAATCAAAACCGGTTCTGGCGAAGGCTCTGAAG 
                   
                 EGSEGEGSGEGG 
                   
               
               
                   
                 GTGAAGGTGGTGGTGAAGGCTCTGAAGGTGAAGGATCT 
                   
                 EGEGSGSQVQLQ 
                   
               
               
                   
                 GGTGAAGGTGGCGAAGGTGAGGGTTCTGGATCCCAAGT 
                   
                 ESGPGLVRPSQTL 
                   
               
               
                   
                 TCAGCTGCAGGAATCTGGTCCGGGTCTGGTTCGTCCGTC 
                   
                 SLTCTVSGYSITS 
                   
               
               
                   
                 TCAGACCCTGTCCCTGACCTGCACGGTGTCCGGCTACTC 
                   
                 DHAWSWVRQPP 
                   
               
               
                   
                 TATTACCTCTGACCATGCGTGGTCCTGGGTCCGTCAGCC 
                   
                 GRGLEWIGYISYS 
                   
               
               
                   
                 ACCGGGTCGCGGTCTGGAGTGGATCGGCTACATCAGCT 
                   
                 GITTYNPSLKSRV 
                   
               
               
                   
                 ACAGCGGCATCACCACTTACAACCCGTCCCTGAAAAGC 
                   
                 TMLRDTSKNQFS 
                   
               
               
                   
                 CGTGTCACCATGCTGCGTGACACCTCCAAAAATCAATT 
                   
                 LRLSSVTAADTA 
                   
               
               
                   
                 CTCCCTGCGCCTGAGCTCTGTGACGGCGGCCGACACTG 
                   
                 VYYCARSLARTT 
                   
               
               
                   
                 CGGTGTACTACTGCGCTCGCAGCCTGGCGCGTACCACT 
                   
                 AMDYWGQGSLV 
                   
               
               
                   
                 GCTATGGATTACTGGGGTCAGGGCAGCCTGGTAACCGT 
                   
                 TVSS 
                   
               
               
                   
                 CAGCAGCTAA 
                   
                   
                   
               
               
                   
               
               
                 aIL6R 
                 ATGGCTGATATTCAAATGACTCAATCTCCTTCTTCTCTG 
                 703 
                 MADIQMTQSPSS 
                 728 
               
               
                 scFv- 
                 TCCGCATCTGTAGGCGACCGTGTAACCATCACTTGCCGT 
                   
                 LSASVGDRVTITC 
                   
               
               
                 AE864, 
                 GCCTCCCAGGACATCTCCAGCTACCTGAACTGGTACCA 
                   
                 RASQDISSYLNW 
                   
               
               
                 AC342 
                 GCAGAAGCCGGGCAAGGCTCCGAAACTGCTGATTTATT 
                   
                 YQQKPGKAPKLL 
                   
               
               
                   
                 ACACTAGCCGTCTGCATTCTGGTGTTCCGAGCCGCTTCT 
                   
                 IYYTSRLHSGVPS 
                   
               
               
                   
                 CCGGTTCTGGCAGCGGTACCGATTTCACTTTTACTATCT 
                   
                 RFSGSGSGTDFTF 
                   
               
               
                   
                 CCAGCCTGCAACCGGAGGACATCGCGACGTACTATTGC 
                   
                 TISSLQPEDIATY 
                   
               
               
                   
                 CAGCAAGGTAATACCCTGCCGTACACCTTCGGCCAAGG 
                   
                 YCQQGNTLPYTF 
                   
               
               
                   
                 CACGAAAGTTGAAATCAAAACCGGTTCTGGCGAAGGCT 
                   
                 GQGTKVEIKTGS 
                   
               
               
                   
                 CTGAAGGTGAAGGTGGTGGTGAAGGCTCTGAAGGTGA 
                   
                 GEGSEGEGGGEG 
                   
               
               
                   
                 AGGATCTGGTGAAGGTGGCGAAGGTGAGGGTTCTGGAT 
                   
                 SEGEGSGEGGEG 
                   
               
               
                   
                 CCCAAGTTCAGCTGCAGGAATCTGGTCCGGGTCTGGTT 
                   
                 EGSGSQVQLQES 
                   
               
               
                   
                 CGTCCGTCTCAGACCCTGTCCCTGACCTGCACGGTGTCC 
                   
                 GPGLVRPSQTLSL 
                   
               
               
                   
                 GGCTACTCTATTACCTCTGACCATGCGTGGTCCTGGGTC 
                   
                 TCTVSGYSITSDH 
                   
               
               
                   
                 CGTCAGCCACCGGGTCGCGGTCTGGAGTGGATCGGCTA 
                   
                 AWSWVRQPPGR 
                   
               
               
                   
                 CATCAGCTACAGCGGCATCACCACTTACAACCCGTCCC 
                   
                 GLEWIGYISYSGI 
                   
               
               
                   
                 TGAAAAGCCGTGTCACCATGCTGCGTGACACCTCCAAA 
                   
                 TTYNPSLKSRVT 
                   
               
               
                   
                 AATCAATTCTCCCTGCGCCTGAGCTCTGTGACGGCGGC 
                   
                 MLRDTSKNQFSL 
                   
               
               
                   
                 CGACACTGCGGTGTACTACTGCGCTCGCAGCCTGGCGC 
                   
                 RLSSVTAADTAV 
                   
               
               
                   
                 GTACCACTGCTATGGATTACTGGGGTCAGGGCAGCCTG 
                   
                 YYCARSLARTTA 
                   
               
               
                   
                 GTAACCGTCAGCAGCGGGTCTCCAGGTAGCCCGGCTGG 
                   
                 MDYWGQGSLVT 
                   
               
               
                   
                 CTCTCCTACCTCTACTGAGGAAGGTACTTCTGAAAGCG 
                   
                 VSSGSPGSPAGSP 
                   
               
               
                   
                 CTACTCCTGAGTCTGGTCCAGGTACCTCTACTGAACCGT 
                   
                 TSTEEGTSESATP 
                   
               
               
                   
                 CCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTCTCCG 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 ACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGA 
                   
                 SAPGSPAGSPTST 
                   
               
               
                   
                 AGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGG 
                   
                 EEGTSTEPSEGSA 
                   
               
               
                   
                 GCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAA 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 TCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGA 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 AACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAA 
                   
                 SEPATSGSETPGS 
                   
               
               
                   
                 CTCCAGGTAGCCCGGCAGGCTCTCCGACCTCTACTGAG 
                   
                 EPATSGSETPGSP 
                   
               
               
                   
                 GAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCC 
                   
                 AGSPTSTEEGTSE 
                   
               
               
                   
                 AGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 AGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTAC 
                   
                 SEGSAPGSPAGSP 
                   
               
               
                   
                 TTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT 
                   
                 TSTEEGTSTEPSE 
                   
               
               
                   
                 CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCT 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 GAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTAC 
                   
                 SAPGTSESATPES 
                   
               
               
                   
                 TGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTGAAA 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 GCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCT 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 ACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCG 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 TCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGTC 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 TGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCC 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 CGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCCG 
                   
                 ESATPESGPGTSE 
                   
               
               
                   
                 GAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTC 
                   
                 SATPESGPGSPAG 
                   
               
               
                   
                 CACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAAT 
                   
                 SPTSTEEGTSESA 
                   
               
               
                   
                 CCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAA 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 ACCCCAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGG 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 CCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTC 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 CAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 GGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGG 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 TACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTA 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 CCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACT 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 TCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCC 
                   
                 TSTEPSEGSAPGS 
                   
               
               
                   
                 AGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTA 
                   
                 PAGSPTSTEEGTS 
                   
               
               
                   
                 CCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTGAA 
                   
                 TEPSEGSAPGTSE 
                   
               
               
                   
                 AGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGC 
                   
                 SATPESGPGSEPA 
                   
               
               
                   
                 TACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCG 
                   
                 TSGSETPGTSESA 
                   
               
               
                   
                 CAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACC 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 TCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTAC 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 TCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGA 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 GGGCAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTG 
                   
                 SAPGTSESATPES 
                   
               
               
                   
                 AGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCC 
                   
                 GPGSPAGSPTSTE 
                   
               
               
                   
                 ACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTAC 
                   
                 EGSPAGSPTSTEE 
                   
               
               
                   
                 TGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCTACTG 
                   
                 GSPAGSPTSTEEG 
                   
               
               
                   
                 AGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGC 
                   
                 TSESATPESGPGT 
                   
               
               
                   
                 CCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACC 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 AGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAG 
                   
                 ESATPESGPGSEP 
                   
               
               
                   
                 GTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT 
                   
                 ATSGSETPGTSES 
                   
               
               
                   
                 ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAG 
                   
                 ATPESGPGSEPAT 
                   
               
               
                   
                 CGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCT 
                   
                 SGSETPGTSESAT 
                   
               
               
                   
                 CTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCT 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 ACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGC 
                   
                 GSAPGSPAGSPTS 
                   
               
               
                   
                 TGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAA 
                   
                 TEEGTSESATPES 
                   
               
               
                   
                 GCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCA 
                   
                 GPGSEPATSGSET 
                   
               
               
                   
                 ACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 TACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC 
                   
                 GSPAGSPTSTEEG 
                   
               
               
                   
                 CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCA 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 ACTTCTACTGAAGAAGGTACTTCTACCGAACCTTCCGA 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 GGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTG 
                   
                 ESATPESGPGTSE 
                   
               
               
                   
                 AGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAA 
                   
                 SATPESGPGTSES 
                   
               
               
                   
                 TCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGAATC 
                   
                 ATPESGPGSEPAT 
                   
               
               
                   
                 TGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAA 
                   
                 SGSETPGSEPATS 
                   
               
               
                   
                 CCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACT 
                   
                 GSETPGSPAGSPT 
                   
               
               
                   
                 CCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA 
                   
                 STEEGTSTEPSEG 
                   
               
               
                   
                 AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAG 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 GTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGT 
                   
                 APGSEPATSGSET 
                   
               
               
                   
                 AGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTAC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 CTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTC 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 TACTGAACCGTCCGAGGGCAGCGCACCAGGTTAA 
                   
                   
                   
               
               
                   
               
               
                 AE912- 
                 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGA 
                 704 
                 MAEPAGSPTSTEE 
                 729 
               
               
                 aIL6R- 
                 AGGTACCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGG 
                   
                 GTPGSGTASSSPG 
                   
               
               
                 AE144, 
                 TAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGC 
                   
                 SSTPSGATGSPGA 
                   
               
               
                 AC361 
                 TTCTCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCCC 
                   
                 SPGTSSTGSPGSP 
                   
               
               
                   
                 GGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGA 
                   
                 AGSPTSTEEGTSE 
                   
               
               
                   
                 AAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 AACCGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGC 
                   
                 PSEGSAPGSPAGS 
                   
               
               
                   
                 TCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCT 
                   
                 PTSTEEGTSTEPS 
                   
               
               
                   
                 TCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTC 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 TGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCC 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 CGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGT 
                   
                 SGPGSEPATSGSE 
                   
               
               
                   
                 TCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTC 
                   
                 TPGSEPATSGSET 
                   
               
               
                   
                 TGAAACTCCAGGTAGCCCGGCAGGCTCTCCGACCTCTA 
                   
                 PGSPAGSPTSTEE 
                   
               
               
                   
                 CTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 GGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGC 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 ACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCAC 
                   
                 STEPSEGSAPGSP 
                   
               
               
                   
                 CAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA 
                   
                 AGSPTSTEEGTST 
                   
               
               
                   
                 GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGG 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 TACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTA 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 CTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACT 
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                 TCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTC 
                   
                 EGSAPGTSESATP 
                   
               
               
                   
                 TGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAAC 
                   
                 ESGPGSEPATSGS 
                   
               
               
                   
                 CGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCG 
                   
                 ETPGTSTEPSEGS 
                   
               
               
                   
                 AACCGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAA 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 CCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 AACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAA 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CCCCGGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCA 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 ACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCC 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 TGAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTT 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCGGAG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 TCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAG 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 CGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCG 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 CACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCT 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 CCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCC 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 AGGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCAG 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT 
                   
                 APGSPAGSPTSFE 
                   
               
               
                   
                 AGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTAC 
                   
                 EGTSTEPSEGSAP 
                   
               
               
                   
                 TTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAA 
                   
                 SEPATSGSETPGT 
                   
               
               
                   
                 CCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAA 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 AGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGC 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 AACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 CTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGT 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACT 
                   
                 TPESGPGSPAGSP 
                   
               
               
                   
                 CCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGAC 
                   
                 TSTEEGSPAGSPT 
                   
               
               
                   
                 TTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTT 
                   
                 STEEGSPAGSPTS 
                   
               
               
                   
                 CTACTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCT 
                   
                 TEEGTSESATPES 
                   
               
               
                   
                 ACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTC 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 CGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCG 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 CACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGC 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 CCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCC 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 AGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAG 
                   
                 EPATSGSETPGTS 
                   
               
               
                   
                 GTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGT 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 ACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTAC 
                   
                 EPSEGSAPGSPAG 
                   
               
               
                   
                 TTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCC 
                   
                 SPTSTEEGTSESA 
                   
               
               
                   
                 CTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACC 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 GGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAA 
                   
                 ESGPGSPAGSPTS 
                   
               
               
                   
                 GCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGC 
                   
                 TEEGSPAGSPTST 
                   
               
               
                   
                 TCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTC 
                   
                 EEGTSTEPSEGSA 
                   
               
               
                   
                 TCCAACTTCTACTGAAGAAGGTACTTCTACCGAACCTTC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 CGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCT 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 GAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGA 
                   
                 EPATSGSETPGSE 
                   
               
               
                   
                 ATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTG 
                   
                 PATSGSETPGSPA 
                   
               
               
                   
                 AAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAA 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 ACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGA 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 GGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCAC 
                   
                 SEGSAPGSEPATS 
                   
               
               
                   
                 CAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGG 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 TACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTA 
                   
                 SAPGADIQMTQS 
                   
               
               
                   
                 CTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTGCT 
                   
                 PSSLSASVGDRVT 
                   
               
               
                   
                 GATATTCAAATGACTCAATCTCCTTCTTCTCTGTCCGCA 
                   
                 ITCRASQDISSYL 
                   
               
               
                   
                 TCTGTAGGCGACCGTGTAACCATCACTTGCCGTGCCTCC 
                   
                 NWYQQKPGKAP 
                   
               
               
                   
                 CAGGACATCTCCAGCTACCTGAACTGGTACCAGCAGAA 
                   
                 KLLIYYTSRLHSG 
                   
               
               
                   
                 GCCGGGCAAGGCTCCGAAACTGCTGATTTATTACACTA 
                   
                 VPSRFSGSGSGTD 
                   
               
               
                   
                 GCCGTCTGCATTCTGGTGTTCCGAGCCGCTTCTCCGGTT 
                   
                 FTFTISSLQPEDIA 
                   
               
               
                   
                 CTGGCAGCGGTACCGATTTCACTTTTACTATCTCCAGCC 
                   
                 TYYCQQGNTLPY 
                   
               
               
                   
                 TGCAACCGGAGGACATCGCGACGTACTATTGCCAGCAA 
                   
                 TFGQGTKVEIKT 
                   
               
               
                   
                 GGTAATACCCTGCCGTACACCTTCGGCCAAGGCACGAA 
                   
                 GSGEGSEGEGGG 
                   
               
               
                   
                 AGTTGAAATCAAAACCGGTTCTGGCGAAGGCTCTGAAG 
                   
                 EGSEGEGSGEGG 
                   
               
               
                   
                 GTGAAGGTGGTGGTGAAGGCTCTGAAGGTGAAGGATCT 
                   
                 EGEGSGSQVQLQ 
                   
               
               
                   
                 GGTGAAGGTGGCGAAGGTGAGGGTTCTGGATCCCAAGT 
                   
                 ESGPGLVRPSQTL 
                   
               
               
                   
                 TCAGCTGCAGGAATCTGGTCCGGGTCTGGTTCGTCCGTC 
                   
                 SLTCTVSGYSITS 
                   
               
               
                   
                 TCAGACCCTGTCCCTGACCTGCACGGTGTCCGGCTACTC 
                   
                 DHAWSWVRQPP 
                   
               
               
                   
                 TATTACCTCTGACCATGCGTGGTCCTGGGTCCGTCAGCC 
                   
                 GRGLEWIGYISYS 
                   
               
               
                   
                 ACCGGGTCGCGGTCTGGAGTGGATCGGCTACATCAGCT 
                   
                 GITTYNPSLKSRV 
                   
               
               
                   
                 ACAGCGGCATCACCACTTACAACCCGTCCCTGAAAAGC 
                   
                 TMLRDTSKNQFS 
                   
               
               
                   
                 CGTGTCACCATGCTGCGTGACACCTCCAAAAATCAATT 
                   
                 LRLSSVTAADTA 
                   
               
               
                   
                 CTCCCTGCGCCTGAGCTCTGTGACGGCGGCCGACACTG 
                   
                 VYYCARSLARTT 
                   
               
               
                   
                 CGGTGTACTACTGCGCTCGCAGCCTGGCGCGTACCACT 
                   
                 AMDYWGQGSLV 
                   
               
               
                   
                 GCTATGGATTACTGGGGTCAGGGCAGCCTGGTAACCGT 
                   
                 TVSSGGTSESATP 
                   
               
               
                   
                 CAGCAGCGGAGGTACTTCTGAAAGCGCTACTCCGGAGT 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 CCGGTCCAGGTACCTCTACCGAACCGTCCGAAGGCAGC 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 GCTCCAGGTACTTCTACTGAACCTTCTGAGGGTAGCGCT 
                   
                 APGTSESATPESG 
                   
               
               
                   
                 CCAGGTACTTCTGAAAGCGCTACTCCGGAGTCCGGTCC 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 AGGTACCTCTACCGAACCGTCCGAAGGCAGCGCTCCAG 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 GTACTTCTACTGAACCTTCTGAGGGTAGCGCTCCAGGT 
                   
                 TSESATPESGPGT 
                   
               
               
                   
                 ACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTAC 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 CTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTT 
                   
                 TEPSEGSAPGTST 
                   
               
               
                   
                 CTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT 
                   
                 EPSEGSAPGSPAG 
                   
               
               
                   
                 ACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGC 
                   
                 SPTSTEEGTSTEPS 
                   
               
               
                   
                 AGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCG 
                   
                 EGSAPG 
                   
               
               
                   
                 AACCGTCCGAGGGTAGCGCACCAGGTTAA 
                   
                   
                   
               
               
                   
               
               
                 AE48- 
                 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGA 
                 705 
                 MAEPAGSPTSTEE 
                 730 
               
               
                 aIL6R- 
                 AGGTACCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGG 
                   
                 GTPGSGTASSSPG 
                   
               
               
                 AE864, 
                 TAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGC 
                   
                 SSTPSGATGSPGA 
                   
               
               
                 AC362 
                 TTCTCCGGGCACCAGCTCTACCGGTTCTCCAgggtctccaggt 
                   
                 SPGTSSTGSPGSP 
                   
               
               
                   
                 GATATTCAAATGACTCAATCTCCTTCTTCTCTGTCCGCA 
                   
                 GDIQMTQSPSSLS 
                   
               
               
                   
                 TCTGTAGGCGACCGTGTAACCATCACTTGCCGTGCCTCC 
                   
                 ASVGDRVTITCR 
                   
               
               
                   
                 CAGGACATCTCCAGCTACCTGAACTGGTACCAGCAGAA 
                   
                 ASQDISSYLNWY 
                   
               
               
                   
                 GCCGGGCAAGGCTCCGAAACTGCTGATTTATTACACTA 
                   
                 QQKPGKAPKLLI 
                   
               
               
                   
                 GCCGTCTGCATTCTGGTGTTCCGAGCCGCTTCTCCGGTT 
                   
                 YYTSRLHSGVPS 
                   
               
               
                   
                 CTGGCAGCGGTACCGATTTCACTTTTACTATCTCCAGCC 
                   
                 RFSGSGSGTDFTF 
                   
               
               
                   
                 TGCAACCGGAGGACATCGCGACGTACTATTGCCAGCAA 
                   
                 TISSLQPEDIATY 
                   
               
               
                   
                 GGTAATACCCTGCCGTACACCTTCGGCCAAGGCACGAA 
                   
                 YCQQGNTLPYTF 
                   
               
               
                   
                 AGTTGAAATCAAAACCGGTTCTGGCGAAGGCTCTGAAG 
                   
                 GQGTKVEIKTGS 
                   
               
               
                   
                 GTGAAGGTGGTGGTGAAGGCTCTGAAGGTGAAGGATCT 
                   
                 GEGSEGEGGGEG 
                   
               
               
                   
                 GGTGAAGGTGGCGAAGGTGAGGGTTCTGGATCCCAAGT 
                   
                 SEGEGSGEGGEG 
                   
               
               
                   
                 TCAGCTGCAGGAATCTGGTCCGGGTCTGGTTCGTCCGTC 
                   
                 EGSGSQVQLQES 
                   
               
               
                   
                 TCAGACCCTGTCCCTGACCTGCACGGTGTCCGGCTACTC 
                   
                 GPGLVRPSQTLSL 
                   
               
               
                   
                 TATTACCTCTGACCATGCGTGGTCCTGGGTCCGTCAGCC 
                   
                 TCTVSGYSITSDH 
                   
               
               
                   
                 ACCGGGTCGCGGTCTGGAGTGGATCGGCTACATCAGCT 
                   
                 AWSWVRQPPGR 
                   
               
               
                   
                 ACAGCGGCATCACCACTTACAACCCGTCCCTGAAAAGC 
                   
                 GLEWIGYISYSGI 
                   
               
               
                   
                 CGTGTCACCATGCTGCGTGACACCTCCAAAAATCAATT 
                   
                 TTYNPSLKSRVT 
                   
               
               
                   
                 CTCCCTGCGCCTGAGCTCTGTGACGGCGGCCGACACTG 
                   
                 MLRDTSKNQFSL 
                   
               
               
                   
                 CGGTGTACTACTGCGCTCGCAGCCTGGCGCGTACCACT 
                   
                 RLSSVTAADTAV 
                   
               
               
                   
                 GCTATGGATTACTGGGGTCAGGGCAGCCTGGTAACCGT 
                   
                 YYCARSLARTTA 
                   
               
               
                   
                 CAGCAGCGGAGGTAGCCCGGCTGGCTCTCCTACCTCTA 
                   
                 MDYWGQGSLVT 
                   
               
               
                   
                 CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCT 
                   
                 VSSGGSPAGSPTS 
                   
               
               
                   
                 GGTCCAGGTACCTCTACTGAACCGTCCGAAGGTAGCGC 
                   
                 TEEGTSESATPES 
                   
               
               
                   
                 TCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGG 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 AAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCA 
                   
                 PGSPAGSPTSTEE 
                   
               
               
                   
                 GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGG 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 TACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTA 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 GCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGC 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 GAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC 
                   
                 PATSGSETPGSEP 
                   
               
               
                   
                 GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTG 
                   
                 ATSGSETPGSPAG 
                   
               
               
                   
                 AAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCTACC 
                   
                 SPTSTEEGTSESA 
                   
               
               
                   
                 GAACCGTCTGAGGGCAGCGCACCAGGTACTTCTACCGA 
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                 ACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTT 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 CTCCTACCTCCACCGAGGAAGGTACTTCTACCGAACCG 
                   
                 GSAPGSPAGSPTS 
                   
               
               
                   
                 TCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCTTC 
                   
                 TEEGTSTEPSEGS 
                   
               
               
                   
                 TGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCC 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 CGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGAA 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 GGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGA 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 ATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTG 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 AGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGC 
                   
                 EPATSGSETPGTS 
                   
               
               
                   
                 GCACCAGGTACTTCTACTGAACCGTCTGAAGGTAGCGC 
                   
                 TEPSEGSAPGTST 
                   
               
               
                   
                 ACCAGGTACTTCTGAAAGCGCAACCCCGGAATCCGGCC 
                   
                 EPSEGSAPGTSES 
                   
               
               
                   
                 CAGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCA 
                   
                 ATPESGPGTSESA 
                   
               
               
                   
                 GGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGG 
                   
                 TPESGPGSPAGSP 
                   
               
               
                   
                 TACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA 
                   
                 TSTEEGTSESATP 
                   
               
               
                   
                 GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACC 
                   
                 ESGPGSEPATSGS 
                   
               
               
                   
                 TCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTC 
                   
                 ETPGTSESATPES 
                   
               
               
                   
                 TACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTA 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 CTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACC 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 GAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTACTGA 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 ACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAAC 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 CTTCTGAAGGTAGCGCACCAGGTACTTCTACCGAACCG 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 TCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCC 
                   
                 TEPSEGSAPGSPA 
                   
               
               
                   
                 TACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCG 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 AGGGTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCT 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 GAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTC 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 TGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAAT 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 CTGGTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAA 
                   
                 ESGPGSEPATSGS 
                   
               
               
                   
                 ACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGG 
                   
                 ETPGTSESATPES 
                   
               
               
                   
                 CCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCAC 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 CAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCA 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 GGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGG 
                   
                 GSPAGSPTSTEEG 
                   
               
               
                   
                 TAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTA 
                   
                 SPAGSPTSTEEGS 
                   
               
               
                   
                 GCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACT 
                   
                 PAGSPTSTEEGTS 
                   
               
               
                   
                 TCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTC 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 TACCGAACCGTCTGAGGGCAGCGCACCAGGTACCTCTG 
                   
                 EPSEGSAPGTSES 
                   
               
               
                   
                 AAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCT 
                   
                 ATPESGPGSEPAT 
                   
               
               
                   
                 GCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAG 
                   
                 SGSETPGTSESAT 
                   
               
               
                   
                 CGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAA 
                   
                 PESGPGSEPATSG 
                   
               
               
                   
                 CCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT 
                   
                 SETPGTSESATPE 
                   
               
               
                   
                 ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCC 
                   
                 SGPGTSTEPSEGS 
                   
               
               
                   
                 GAGGGCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAAC 
                   
                 APGSPAGSPTSTE 
                   
               
               
                   
                 CTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTG 
                   
                 EGTSESATPESGP 
                   
               
               
                   
                 AATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCT 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 GAAACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTC 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 CGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCG 
                   
                 PAGSPTSTEEGSP 
                   
               
               
                   
                 AGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAA 
                   
                 AGSPTSTEEGTST 
                   
               
               
                   
                 GAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACC 
                   
                 EPSEGSAPGTSES 
                   
               
               
                   
                 AGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAG 
                   
                 ATPESGPGTSESA 
                   
               
               
                   
                 GTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGT 
                   
                 TPESGPGTSESAT 
                   
               
               
                   
                 ACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAG 
                   
                 PESGPGSEPATSG 
                   
               
               
                   
                 CGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCG 
                   
                 SETPGSEPATSGS 
                   
               
               
                   
                 AACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCA 
                   
                 ETPGSPAGSPTST 
                   
               
               
                   
                 GCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTAC 
                   
                 EEGTSTEPSEGSA 
                   
               
               
                   
                 TGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTG 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 AACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCA 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 ACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGC 
                   
                 TSESATPESGPGT 
                   
               
               
                   
                 TACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTC 
                   
                 STEPSEGSAPG 
                   
               
               
                   
                 CGAGGGCAGCGCACCAGGTTAA 
                   
                   
                   
               
               
                   
               
               
                 anti- 
                 ATGGCTGAAATTGTTCTGACCCAATCTCCTGCAACTCTG 
                 706 
                 MAEIVLTQSPATL 
                 731 
               
               
                 CD40- 
                 TCTCTGTCTCCAGGTGAACGCGCCACCCTGTCTTGTCGT 
                   
                 SLSPGERATLSCR 
                   
               
               
                 AE864, 
                 GCGTCCCAGTCTATCTCTGATTATCTGCATTGGTATCAG 
                   
                 ASQSISDYLHWY 
                   
               
               
                 AC384 
                 CAGAAACCTGGCCAGGCTCCGCGCCTGCTGATCTATTA 
                   
                 QQKPGQAPRLLI 
                   
               
               
                   
                 CGCCAGCCACAGCATCTCTGGTATCCCGGCTCGCTTCTC 
                   
                 YYASHSISGIPAR 
                   
               
               
                   
                 CGGCTCCGGCAGCGGCACCGACTTCACTCTGACTATTA 
                   
                 FSGSGSGTDFTLT 
                   
               
               
                   
                 GCTCCCTGGAACCGGAGGATTTCGCAGTTTATTACTGTC 
                   
                 ISSLEPEDFAVYY 
                   
               
               
                   
                 AGCACGGTCACTCCTACCCGTGGACCTTTGGTGGCGGC 
                   
                 CQHGHSYPWTFG 
                   
               
               
                   
                 ACCAAAGTTGAAATCAAAACCGGTTCTGGCGAAGGCTC 
                   
                 GGTKVEIKTGSG 
                   
               
               
                   
                 TGAAGGTGAAGGTGGTGGTGAAGGCTCTGAAGGTGAA 
                   
                 EGSEGEGGGEGS 
                   
               
               
                   
                 GGATCTGGTGAAGGTGGCGAAGGTGAGGGATCTGGTAC 
                   
                 EGEGSGEGGEGE 
                   
               
               
                   
                 CCAAGTCCAGCTGGTTCAGTCCGGCTCTGAACTGAAGA 
                   
                 GSGTQVQLVQSG 
                   
               
               
                   
                 AACCGGGCGCTTCTGTTAAAGTTAGCTGCAAAGCAAGC 
                   
                 SELKKPGASVKV 
                   
               
               
                   
                 GGTTATGCCTTTACTACTACTGGTATGCAGTGGGTCCGC 
                   
                 SCKASGYAFTTT 
                   
               
               
                   
                 CAGGCACCGGGTCAGGGCCTGGAGTGGATGGGCTGGAT 
                   
                 GMQWVRQAPGQ 
                   
               
               
                   
                 CAACACCCACTCTGGTGTCCCTAAATACGTTGAAGATTT 
                   
                 GLEWMGWINTH 
                   
               
               
                   
                 CAAAGGCCGTTTCGTGTTCTCCCTGGACACTTCCGTCAG 
                   
                 SGVPKYVEDFKG 
                   
               
               
                   
                 CACCGCGTATCTGCAGATCAGCAGCCTGAAAGCTGAGG 
                   
                 RFVFSLDTSVSTA 
                   
               
               
                   
                 ACACCGCGGTTTATTACTGCGCGCGTAGCGGCAATGGT 
                   
                 YLQISSLKAEDTA 
                   
               
               
                   
                 AACTACGACCTGGCTTATTTCAAATACTGGGGTCAGGG 
                   
                 VYYCARSGNGN 
                   
               
               
                   
                 CACTCTGGTTACTGTGTCTAGCGGAGGTAGCCCGGCTG 
                   
                 YDLAYFKYWGQ 
                   
               
               
                   
                 GCTCTCCTACCTCTACTGAGGAAGGTACTTCTGAAAGC 
                   
                 GTLVTVSSGGSP 
                   
               
               
                   
                 GCTACTCCTGAGTCTGGTCCAGGTACCTCTACTGAACCG 
                   
                 AGSPTSTEEGTSE 
                   
               
               
                   
                 TCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTCTCC 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 GACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCG 
                   
                 PSEGSAPGSPAGS 
                   
               
               
                   
                 AAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAG 
                   
                 PTSTEEGTSTEPS 
                   
               
               
                   
                 GGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGA 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 ATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTG 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 AAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAA 
                   
                 SGPGSEPATSGSE 
                   
               
               
                   
                 ACTCCAGGTAGCCCGGCAGGCTCTCCGACCTCTACTGA 
                   
                 TPGSEPATSGSET 
                   
               
               
                   
                 GGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCC 
                   
                 PGSPAGSPTSTEE 
                   
               
               
                   
                 CAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGG 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 TAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTA 
                   
                 STEPSEGSAPGSP 
                   
               
               
                   
                 CTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACC 
                   
                 AGSPTSTEEGTST 
                   
               
               
                   
                 TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCT 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 GAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTAC 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 TGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTGAAA 
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                 GCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCT 
                   
                 EGSAPGTSESATP 
                   
               
               
                   
                 ACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCG 
                   
                 ESGPGSEPATSGS 
                   
               
               
                   
                 TCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGTC 
                   
                 ETPGTSTEPSEGS 
                   
               
               
                   
                 TGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCC 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 CGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCCG 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 GAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAAT 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 CCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAA 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 ACCCCAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGG 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 CCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTC 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 CAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 GGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGG 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 TACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTA 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 CCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACT 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 TCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCC 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 AGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTA 
                   
                 APGSPAGSPTSTE 
                   
               
               
                   
                 CCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTGAA 
                   
                 EGTSTEPSEGSAP 
                   
               
               
                   
                 AGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 TACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCG 
                   
                 SEPATSGSETPGT 
                   
               
               
                   
                 CAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACC 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 TCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTAC 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 TCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGA 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 GGGCAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTG 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 AGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCC 
                   
                 TPESGPGSPAGSP 
                   
               
               
                   
                 ACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTAC 
                   
                 TSTEEGSPAGSPT 
                   
               
               
                   
                 TGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCTACTG 
                   
                 STEEGSPAGSPTS 
                   
               
               
                   
                 AGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGC 
                   
                 TEEGTSESATPES 
                   
               
               
                   
                 CCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACC 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 AGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAG 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 GTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAG 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 CGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCT 
                   
                 EPATSGSETPGTS 
                   
               
               
                   
                 CTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCT 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 ACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGC 
                   
                 EPSEGSAPGSPAG 
                   
               
               
                   
                 TGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAA 
                   
                 SPTSTEEGTSESA 
                   
               
               
                   
                 GCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCA 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 ACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGC 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 TACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC 
                   
                 ESGPGSPAGSPTS 
                   
               
               
                   
                 CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCA 
                   
                 TEEGSPAGSPTST 
                   
               
               
                   
                 ACTTCTACTGAAGAAGGTACTTCTACCGAACCTTCCGA 
                   
                 EEGTSTEPSEGSA 
                   
               
               
                   
                 GGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTG 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 AGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAA 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 TCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGAATC 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 TGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAA 
                   
                 EPATSGSETPGSE 
                   
               
               
                   
                 CCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACT 
                   
                 PATSGSETPGSPA 
                   
               
               
                   
                 CCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAG 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 GTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGT 
                   
                 SEGSAPGSEPATS 
                   
               
               
                   
                 AGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTAC 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 CTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTC 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 TACTGAACCGTCCGAGGGCAGCGCACCA 
                   
                 SAP 
                   
               
               
                   
               
               
                 anti- 
                 ATGGCTGAAATTGTTCTGACTCAATCTCCAGCAACTCTG 
                 707 
                 MAEIVLTQSPATL 
                 732 
               
               
                 CD40- 
                 TCTCTGTCTCCAGGTGAACGTGCAACCCTGTCTTGCCGT 
                   
                 SLSPGERATLSCR 
                   
               
               
                 AE864, 
                 GCGTCCCAGTCCATCTCCGATTATCTGCATTGGTATCAG 
                   
                 ASQSISDYLHWY 
                   
               
               
                 AC385 
                 CAGAAACCGGGTCAGGCGCCTCGTCTGCTGATCTATTA 
                   
                 QQKPGQAPRLLI 
                   
               
               
                   
                 TGCGTCTCACTCCATTTCCGGTATCCCGGCACGTTTCTC 
                   
                 YYASHSISGIPAR 
                   
               
               
                   
                 TGGCAGCGGCAGCGGCACCGATTTCACCCTGACGATCT 
                   
                 FSGSGSGTDFTLT 
                   
               
               
                   
                 CTTCTCTGGAACCGGAAGATTTCGCAGTCTATTATTGTC 
                   
                 ISSLEPEDFAVYY 
                   
               
               
                   
                 AGCATGGTCACAGCTACCCGTGGACCTTCGGCGGTGGC 
                   
                 CQHGHSYPWTFG 
                   
               
               
                   
                 ACGAAAGTTGAAATCAAGACCGGTTCTGGCGAAGGCTC 
                   
                 GGTKVEIKTGSG 
                   
               
               
                   
                 TGAAGGTGAAGGTGGTGGTGAAGGCTCTGAAGGTGAA 
                   
                 EGSEGEGGGEGS 
                   
               
               
                   
                 GGATCTGGTGAAGGTGGCGAAGGTGAGGGATCTGGTAC 
                   
                 EGEGSGEGGEGE 
                   
               
               
                   
                 CCAGGTCCAGCTGGTTCAAAGCGGCTCTGAACTGAAAA 
                   
                 GSGTQVQLVQSG 
                   
               
               
                   
                 AGCCGGGTGCCTCTGTCAAAGTGTCTTGCAAGGCAAGC 
                   
                 SELKKPGASVKV 
                   
               
               
                   
                 GGCTACGCGTTTACGACCACCGGCATGCAGTGGGTCCG 
                   
                 SCKASGYAFTTT 
                   
               
               
                   
                 TCAGGCCCCGGGCCAGGGTCTGGAATGGATGGGCTGGA 
                   
                 GMQWVRQAPGQ 
                   
               
               
                   
                 TCAACACCCATTCTGGCGTACCGAAATACGTTGAAGAT 
                   
                 GLEWMGWINTH 
                   
               
               
                   
                 TTCAAAGGCCGTTTCGTGTTCTCCCTGGATACGTCCGTT 
                   
                 SGVPKYVEDFKG 
                   
               
               
                   
                 TCCACCGCCTACCTGCAGATCTCTTCCCTGAAAGCAGA 
                   
                 RFVFSLDTSVSTA 
                   
               
               
                   
                 AGATACTGCGGTGTACTATTGCGCACGTAGCGGCAACG 
                   
                 YLQISSLKAEDTA 
                   
               
               
                   
                 GCAACTACGACCTGGCCTACTTCAAATACTGGGGTCAG 
                   
                 VYYCARSGNGN 
                   
               
               
                   
                 GGTACTCTGGTGACCGTATCCTCTGGAGGTAGCCCGGC 
                   
                 YDLAYFKYWGQ 
                   
               
               
                   
                 TGGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGAAA 
                   
                 GTLVTVSSGGSP 
                   
               
               
                   
                 GCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTGAAC 
                   
                 AGSPTSTEEGTSE 
                   
               
               
                   
                 CGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTCT 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 CCGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCC 
                   
                 PSEGSAPGSPAGS 
                   
               
               
                   
                 GAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA 
                   
                 PTSTEEGTSTEPS 
                   
               
               
                   
                 GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGG 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 AATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCT 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 GAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGA 
                   
                 SGPGSEPATSGSE 
                   
               
               
                   
                 AACTCCAGGTAGCCCGGCAGGCTCTCCGACCTCTACTG 
                   
                 TPGSEPATSGSET 
                   
               
               
                   
                 AGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGC 
                   
                 PGSPAGSPTSTEE 
                   
               
               
                   
                 CCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 AGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAG 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 GTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGT 
                   
                 STEPSEGSAPGSP 
                   
               
               
                   
                 ACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAC 
                   
                 AGSPTSTEEGTST 
                   
               
               
                   
                 CTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTC 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 TGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTA 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 CTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTGAA 
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                 AGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGC 
                   
                 EGSAPGTSESATP 
                   
               
               
                   
                 TACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACC 
                   
                 ESGPGSEPATSGS 
                   
               
               
                   
                 GTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGT 
                   
                 ETPGTSTEPSEGS 
                   
               
               
                   
                 CTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAACC 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 CCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCT 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAA 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 TCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGA 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 AACCCCAGGTACCTCTGAAAGCGCTACTCCGGAGTCTG 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 GCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCT 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 CCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACC 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 AGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAG 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 GTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTAC 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 TTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCC 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 CAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCT 
                   
                 APGSPAGSPTSTE 
                   
               
               
                   
                 ACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTGA 
                   
                 EGTSTEPSEGSAP 
                   
               
               
                   
                 AAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTG 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGC 
                   
                 SEPATSGSETPGT 
                   
               
               
                   
                 GCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAAC 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 CTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTA 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 CTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 AGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACTCCT 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 GAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTC 
                   
                 TPESGPGSPAGSP 
                   
               
               
                   
                 CACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTA 
                   
                 TSTEEGSPAGSPT 
                   
               
               
                   
                 CTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCTACT 
                   
                 STEEGSPAGSPTS 
                   
               
               
                   
                 GAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGG 
                   
                 TEEGTSESATPES 
                   
               
               
                   
                 CCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCAC 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 CAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGG 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 TACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTA 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 GCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACC 
                   
                 EPATSGSETPGTS 
                   
               
               
                   
                 TCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCT 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 ACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGC 
                   
                 EPSEGSAPGSPAG 
                   
               
               
                   
                 TGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAA 
                   
                 SPTSTEEGTSESA 
                   
               
               
                   
                 GCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCA 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 ACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGC 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 TACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC 
                   
                 ESGPGSPAGSPTS 
                   
               
               
                   
                 CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCA 
                   
                 TEEGSPAGSPTST 
                   
               
               
                   
                 ACTTCTACTGAAGAAGGTACTTCTACCGAACCTTCCGA 
                   
                 EEGTSTEPSEGSA 
                   
               
               
                   
                 GGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTG 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 AGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAA 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 TCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGAATC 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 TGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAA 
                   
                 EPATSGSETPGSE 
                   
               
               
                   
                 CCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACT 
                   
                 PATSGSETPGSPA 
                   
               
               
                   
                 CCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAG 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 GTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGT 
                   
                 SEGSAPGSEPATS 
                   
               
               
                   
                 AGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTAC 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 CTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTC 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 TACTGAACCGTCCGAGGGCAGCGCACCA 
                   
                 SAP 
                   
               
               
                   
               
               
                 AE912- 
                 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGA 
                 708 
                 MAEPAGSPTSTEE 
                 733 
               
               
                 anti- 
                 AGGTACCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGG 
                   
                 GTPGSGTASSSPG 
                   
               
               
                 CD40, 
                 TAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGC 
                   
                 SSTPSGATGSPGA 
                   
               
               
                 AC386 
                 TTCTCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCCC 
                   
                 SPGTSSTGSPGSP 
                   
               
               
                   
                 GGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGA 
                   
                 AGSPTSTEEGTSE 
                   
               
               
                   
                 AAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 AACCGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGC 
                   
                 PSEGSAPGSPAGS 
                   
               
               
                   
                 TCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCT 
                   
                 PTSTEEGTSTEPS 
                   
               
               
                   
                 TCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTC 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 TGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCC 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 CGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGT 
                   
                 SGPGSEPATSGSE 
                   
               
               
                   
                 TCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTC 
                   
                 TPGSEPATSGSET 
                   
               
               
                   
                 TGAAACTCCAGGTAGCCCGGCAGGCTCTCCGACCTCTA 
                   
                 PGSPAGSPTSTEE 
                   
               
               
                   
                 CTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 GGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGC 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 ACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCAC 
                   
                 STEPSEGSAPGSP 
                   
               
               
                   
                 CAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA 
                   
                 AGSPTSTEEGTST 
                   
               
               
                   
                 GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGG 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 TACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTA 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 CTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACT 
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                 TCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTC 
                   
                 EGSAPGTSESATP 
                   
               
               
                   
                 TGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAAC 
                   
                 ESGPGSEPATSGS 
                   
               
               
                   
                 CGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCG 
                   
                 ETPGTSTEPSEGS 
                   
               
               
                   
                 AACCGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAA 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 CCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 AACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAA 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CCCCGGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCA 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 ACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCC 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 TGAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTT 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCGGAG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 TCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAG 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 CGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCG 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 CACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCT 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 CCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCC 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 AGGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCAG 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT 
                   
                 APGSPAGSPTSFE 
                   
               
               
                   
                 AGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTAC 
                   
                 EGTSTEPSEGSAP 
                   
               
               
                   
                 TTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAA 
                   
                 SEPATSGSETPGT 
                   
               
               
                   
                 CCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAA 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 AGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGC 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 AACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 CTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGT 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACT 
                   
                 TPESGPGSPAGSP 
                   
               
               
                   
                 CCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGAC 
                   
                 TSTEEGSPAGSPT 
                   
               
               
                   
                 TTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTT 
                   
                 STEEGSPAGSPTS 
                   
               
               
                   
                 CTACTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCT 
                   
                 TEEGTSESATPES 
                   
               
               
                   
                 ACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTC 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 CGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCG 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 CACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGC 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 CCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCC 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 AGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAG 
                   
                 EPATSGSETPGTS 
                   
               
               
                   
                 GTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGT 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 ACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTAC 
                   
                 EPSEGSAPGSPAG 
                   
               
               
                   
                 TTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCC 
                   
                 SPTSTEEGTSESA 
                   
               
               
                   
                 CTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACC 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 GGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAA 
                   
                 ESGPGSPAGSPTS 
                   
               
               
                   
                 GCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGC 
                   
                 TEEGSPAGSPTST 
                   
               
               
                   
                 TCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTC 
                   
                 EEGTSTEPSEGSA 
                   
               
               
                   
                 TCCAACTTCTACTGAAGAAGGTACTTCTACCGAACCTTC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 CGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCT 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 GAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGA 
                   
                 EPATSGSETPGSE 
                   
               
               
                   
                 ATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTG 
                   
                 PATSGSETPGSPA 
                   
               
               
                   
                 AAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAA 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 ACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGA 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 GGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCAC 
                   
                 SEGSAPGSEPATS 
                   
               
               
                   
                 CAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGG 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 TACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTA 
                   
                 SAPGEIVLTQSPA 
                   
               
               
                   
                 CTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTGAA 
                   
                 TLSLSPGERATLS 
                   
               
               
                   
                 ATTGTTCTGACCCAATCTCCTGCAACTCTGTCTCTGTCT 
                   
                 CRASQSISDYLH 
                   
               
               
                   
                 CCAGGTGAACGCGCCACCCTGTCTTGTCGTGCGTCCCA 
                   
                 WYQQKPGQAPR 
                   
               
               
                   
                 GTCTATCTCTGATTATCTGCATTGGTATCAGCAGAAACC 
                   
                 LLIYYASHSISGIP 
                   
               
               
                   
                 TGGCCAGGCTCCGCGCCTGCTGATCTATTACGCCAGCC 
                   
                 ARFSGSGSGTDFT 
                   
               
               
                   
                 ACAGCATCTCTGGTATCCCGGCTCGCTTCTCCGGCTCCG 
                   
                 LTISSLEPEDFAV 
                   
               
               
                   
                 GCAGCGGCACCGACTTCACTCTGACTATTAGCTCCCTG 
                   
                 YYCQHGHSYPW 
                   
               
               
                   
                 GAACCGGAGGATTTCGCAGTTTATTACTGTCAGCACGG 
                   
                 TFGGGTKVEIKT 
                   
               
               
                   
                 TCACTCCTACCCGTGGACCTTTGGTGGCGGCACCAAAG 
                   
                 GSGEGSEGEGGG 
                   
               
               
                   
                 TTGAAATCAAAACCGGTTCTGGCGAAGGCTCTGAAGGT 
                   
                 EGSEGEGSGEGG 
                   
               
               
                   
                 GAAGGTGGTGGTGAAGGCTCTGAAGGTGAAGGATCTG 
                   
                 EGEGSGTQVQLV 
                   
               
               
                   
                 GTGAAGGTGGCGAAGGTGAGGGATCTGGTACCCAAGTC 
                   
                 QSGSELKKPGAS 
                   
               
               
                   
                 CAGCTGGTTCAGTCCGGCTCTGAACTGAAGAAACCGGG 
                   
                 VKVSCKASGYAF 
                   
               
               
                   
                 CGCTTCTGTTAAAGTTAGCTGCAAAGCAAGCGGTTATG 
                   
                 TTTGMQWVRQA 
                   
               
               
                   
                 CCTTTACTACTACTGGTATGCAGTGGGTCCGCCAGGCA 
                   
                 PGQGLEWMGWI 
                   
               
               
                   
                 CCGGGTCAGGGCCTGGAGTGGATGGGCTGGATCAACAC 
                   
                 NTHSGVPKYVED 
                   
               
               
                   
                 CCACTCTGGTGTCCCTAAATACGTTGAAGATTTCAAAG 
                   
                 FKGRFVFSLDTSV 
                   
               
               
                   
                 GCCGTTTCGTGTTCTCCCTGGACACTTCCGTCAGCACCG 
                   
                 STAYLQISSLKAE 
                   
               
               
                   
                 CGTATCTGCAGATCAGCAGCCTGAAAGCTGAGGACACC 
                   
                 DTAVYYCARSGN 
                   
               
               
                   
                 GCGGTTTATTACTGCGCGCGTAGCGGCAATGGTAACTA 
                   
                 GNYDLAYFKYW 
                   
               
               
                   
                 CGACCTGGCTTATTTCAAATACTGGGGTCAGGGCACTC 
                   
                 GQGTLVTVS 
                   
               
               
                   
                 TGGTTACTGTGTCTAGC 
                   
                   
                   
               
               
                   
               
               
                 AE912- 
                 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGA 
                 709 
                 MAEPAGSPTSTEE 
                 734 
               
               
                 anti- 
                 AGGTACCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGG 
                   
                 GTPGSGTASSSPG 
                   
               
               
                 CD40, 
                 TAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGC 
                   
                 SSTPSGATGSPGA 
                   
               
               
                 AC387, 
                 TTCTCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCCC 
                   
                 SPGTSSTGSPGSP 
                   
               
               
                   
                 GGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGA 
                   
                 AGSPTSTEEGTSE 
                   
               
               
                   
                 AAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 AACCGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGC 
                   
                 PSEGSAPGSPAGS 
                   
               
               
                   
                 TCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCT 
                   
                 PTSTEEGTSTEPS 
                   
               
               
                   
                 TCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTC 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 TGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCC 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 CGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGT 
                   
                 SGPGSEPATSGSE 
                   
               
               
                   
                 TCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTC 
                   
                 TPGSEPATSGSET 
                   
               
               
                   
                 TGAAACTCCAGGTAGCCCGGCAGGCTCTCCGACCTCTA 
                   
                 PGSPAGSPTSTEE 
                   
               
               
                   
                 CTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 GGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGC 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 ACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCAC 
                   
                 STEPSEGSAPGSP 
                   
               
               
                   
                 CAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA 
                   
                 AGSPTSTEEGTST 
                   
               
               
                   
                 GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGG 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 TACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTA 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 CTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACT 
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                 TCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTC 
                   
                 EGSAPGTSESATP 
                   
               
               
                   
                 TGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAAC 
                   
                 ESGPGSEPATSGS 
                   
               
               
                   
                 CGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCG 
                   
                 ETPGTSTEPSEGS 
                   
               
               
                   
                 AACCGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAA 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 CCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 AACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAA 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CCCCGGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCA 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 ACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCC 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 TGAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTT 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCGGAG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 TCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAG 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 CGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCG 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 CACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCT 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 CCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCC 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 AGGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCAG 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT 
                   
                 APGSPAGSPTSTE 
                   
               
               
                   
                 AGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTAC 
                   
                 EGTSTEPSEGSAP 
                   
               
               
                   
                 TTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAA 
                   
                 SEPATSGSETPGT 
                   
               
               
                   
                 CCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAA 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 AGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGC 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 AACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 CTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGT 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACT 
                   
                 TPESGPGSPAGSP 
                   
               
               
                   
                 CCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGAC 
                   
                 TSTEEGSPAGSPT 
                   
               
               
                   
                 TTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTT 
                   
                 STEEGSPAGSPTS 
                   
               
               
                   
                 CTACTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCT 
                   
                 TEEGTSESATPES 
                   
               
               
                   
                 ACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTC 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 CGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCG 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 CACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGC 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 CCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCC 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 AGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAG 
                   
                 EPATSGSETPGTS 
                   
               
               
                   
                 GTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGT 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 ACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTAC 
                   
                 EPSEGSAPGSPAG 
                   
               
               
                   
                 TTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCC 
                   
                 SPTSTEEGTSESA 
                   
               
               
                   
                 CTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACC 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 GGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAA 
                   
                 ESGPGSPAGSPTS 
                   
               
               
                   
                 GCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGC 
                   
                 TEEGSPAGSPTST 
                   
               
               
                   
                 TCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTC 
                   
                 EEGTSTEPSEGSA 
                   
               
               
                   
                 TCCAACTTCTACTGAAGAAGGTACTTCTACCGAACCTTC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 CGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCT 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 GAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGA 
                   
                 EPATSGSETPGSE 
                   
               
               
                   
                 ATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTG 
                   
                 PATSGSETPGSPA 
                   
               
               
                   
                 AAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAA 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 ACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGA 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 GGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCAC 
                   
                 SEGSAPGSEPATS 
                   
               
               
                   
                 CAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGG 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 TACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTA 
                   
                 SAPGEIVLTQSPA 
                   
               
               
                   
                 CTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTGAA 
                   
                 TLSLSPGERATLS 
                   
               
               
                   
                 ATTGTTCTGACTCAATCTCCAGCAACTCTGTCTCTGTCT 
                   
                 CRASQSISDYLH 
                   
               
               
                   
                 CCAGGTGAACGTGCAACCCTGTCTTGCCGTGCGTCCCA 
                   
                 WYQQKPGQAPR 
                   
               
               
                   
                 GTCCATCTCCGATTATCTGCATTGGTATCAGCAGAAACC 
                   
                 LLIYYASHSISGIP 
                   
               
               
                   
                 GGGTCAGGCGCCTCGTCTGCTGATCTATTATGCGTCTCA 
                   
                 ARFSGSGSGTDFT 
                   
               
               
                   
                 CTCCATTTCCGGTATCCCGGCACGTTTCTCTGGCAGCGG 
                   
                 LTISSLEPEDFAV 
                   
               
               
                   
                 CAGCGGCACCGATTTCACCCTGACGATCTCTTCTCTGGA 
                   
                 YYCQHGHSYPW 
                   
               
               
                   
                 ACCGGAAGATTTCGCAGTCTATTATTGTCAGCATGGTC 
                   
                 TFGGGTKVEIKT 
                   
               
               
                   
                 ACAGCTACCCGTGGACCTTCGGCGGTGGCACGAAAGTT 
                   
                 GSGEGSEGEGGG 
                   
               
               
                   
                 GAAATCAAGACCGGTTCTGGCGAAGGCTCTGAAGGTGA 
                   
                 EGSEGEGSGEGG 
                   
               
               
                   
                 AGGTGGTGGTGAAGGCTCTGAAGGTGAAGGATCTGGTG 
                   
                 EGEGSGTQVQLV 
                   
               
               
                   
                 AAGGTGGCGAAGGTGAGGGATCTGGTACCCAGGTCCA 
                   
                 QSGSELKKPGAS 
                   
               
               
                   
                 GCTGGTTCAAAGCGGCTCTGAACTGAAAAAGCCGGGTG 
                   
                 VKVSCKASGYAF 
                   
               
               
                   
                 CCTCTGTCAAAGTGTCTTGCAAGGCAAGCGGCTACGCG 
                   
                 TTTGMQWVRQA 
                   
               
               
                   
                 TTTACGACCACCGGCATGCAGTGGGTCCGTCAGGCCCC 
                   
                 PGQGLEWMGWI 
                   
               
               
                   
                 GGGCCAGGGTCTGGAATGGATGGGCTGGATCAACACCC 
                   
                 NTHSGVPKYVED 
                   
               
               
                   
                 ATTCTGGCGTACCGAAATACGTTGAAGATTTCAAAGGC 
                   
                 FKGRFVFSLDTSV 
                   
               
               
                   
                 CGTTTCGTGTTCTCCCTGGATACGTCCGTTTCCACCGCC 
                   
                 STAYLQISSLKAE 
                   
               
               
                   
                 TACCTGCAGATCTCTTCCCTGAAAGCAGAAGATACTGC 
                   
                 DTAVYYCARSGN 
                   
               
               
                   
                 GGTGTACTATTGCGCACGTAGCGGCAACGGCAACTACG 
                   
                 GNYDLAYFKYW 
                   
               
               
                   
                 ACCTGGCCTACTTCAAATACTGGGGTCAGGGTACTCTG 
                   
                 GQGTLVTVS 
                   
               
               
                   
                 GTGACCGTATCCTCT 
                   
                   
                   
               
               
                   
               
               
                 anti- 
                 ATGGAAGACATTCAGATGACCCAGAGCCCGTCCTCCCT 
                 710 
                 MEDIQMTQSPSSL 
                 735 
               
               
                 Her2- 
                 GAGCGCTTCTGTTGGCGACCGCGTGACCATCACCTGCC 
                   
                 SASVGDRVTITCR 
                   
               
               
                 AE864 
                 GTGCTTCCCAGGATGTTAACACCGCTGTAGCTTGGTATC 
                   
                 ASQDVNTAVAW 
                   
               
               
                   
                 AACAGAAACCGGGCAAAGCACCGAAACTGCTGATCTA 
                   
                 YQQKPGKAPKLL 
                   
               
               
                   
                 CTCTGCTTCCTTTCTGTATAGCGGTGTTCCGTCTCGTTTC 
                   
                 IYSASFLYSGVPS 
                   
               
               
                   
                 AGCGGCTCTCGTAGCGGTACGGATTTTACTCTGACGAT 
                   
                 RFSGSRSGTDFTL 
                   
               
               
                   
                 CAGCTCTCTGCAGCCGGAGGACTTCGCTACCTACTACT 
                   
                 TISSLQPEDFATY 
                   
               
               
                   
                 GCCAGCAGCACTACACCACCCCGCCTACCTTTGGTCAG 
                   
                 YCQQHYTTPPTF 
                   
               
               
                   
                 GGCACCAAAGTGGAAATCAAGACCGGTTCTGGCGAAG 
                   
                 GQGTKVEIKTGS 
                   
               
               
                   
                 GCTCTGAAGGTGAAGGTGGTGGTGAAGGCTCTGAAGGT 
                   
                 GEGSEGEGGGEG 
                   
               
               
                   
                 GAAGGATCTGGTGAAGGTGGCGAAGGTGAGGGATCTG 
                   
                 SEGEGSGEGGEG 
                   
               
               
                   
                 GTACCGAGGTCCAGCTGGTTGAGTCTGGCGGCGGTCTG 
                   
                 EGSGTEVQLVES 
                   
               
               
                   
                 GTCCAACCTGGTGGCTCCCTGCGCCTGTCTTGCGCAGCG 
                   
                 GGGLVQPGGSLR 
                   
               
               
                   
                 TCCGGCTTTAATATCAAAGATACGTACATTCACTGGGTC 
                   
                 LSCAASGFNIKDT 
                   
               
               
                   
                 CGCCAGGCACCGGGCAAAGGCCTGGAATGGGTTGCTCG 
                   
                 YIHWVRQAPGKG 
                   
               
               
                   
                 TATCTACCCGACTAACGGTTATACCCGTTATGCAGACA 
                   
                 LEWVARIYPTNG 
                   
               
               
                   
                 GCGTAAAGGGTCGCTTCACGATCTCCGCGGATACCTCC 
                   
                 YTRYADSVKGRF 
                   
               
               
                   
                 AAAAACACCGCATACCTGCAAATGAACTCTCTGCGTGC 
                   
                 TISADTSKNTAYL 
                   
               
               
                   
                 GGAAGATACTGCCGTGTACTACTGCTCTCGCTGGGGCG 
                   
                 QMNSLRAEDTAV 
                   
               
               
                   
                 GTGACGGTTTCTATGCAATGGACTACTGGGGTCAAGGT 
                   
                 YYCSRWGGDGF 
                   
               
               
                   
                 ACTCTGGTAACTGTTTCCGGGTCTCCAGGTAGCCCGGCT 
                   
                 YAMDYWGQGTL 
                   
               
               
                   
                 GGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGAAAG 
                   
                 VTVSGSPGSPAGS 
                   
               
               
                   
                 CGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTGAACC 
                   
                 PTSTEEGTSESAT 
                   
               
               
                   
                 GTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTCTC 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 CGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCC 
                   
                 GSAPGSPAGSPTS 
                   
               
               
                   
                 GAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA 
                   
                 TEEGTSTEPSEGS 
                   
               
               
                   
                 GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGG 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 AATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCT 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 GAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGA 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 AACTCCAGGTAGCCCGGCAGGCTCTCCGACCTCTACTG 
                   
                 SEPATSGSETPGS 
                   
               
               
                   
                 AGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGC 
                   
                 PAGSPTSTEEGTS 
                   
               
               
                   
                 CCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACC 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 AGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAG 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 GTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGT 
                   
                 PSEGSAPGSPAGS 
                   
               
               
                   
                 ACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAC 
                   
                 PTSTEEGTSTEPS 
                   
               
               
                   
                 CTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTC 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 TGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTA 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 CTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTGAA 
                   
                 SGPGTSTEPSEGS 
                   
               
               
                   
                 AGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGC 
                   
                 APGTSESATPESG 
                   
               
               
                   
                 TACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACC 
                   
                 PGSEPATSGSETP 
                   
               
               
                   
                 GTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGT 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 CTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAACC 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 CCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCT 
                   
                 ESATPESGPGSPA 
                   
               
               
                   
                 CCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAA 
                   
                 GSPTSTEEGTSES 
                   
               
               
                   
                 TCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGA 
                   
                 ATPESGPGSEPAT 
                   
               
               
                   
                 AACCCCAGGTACCTCTGAAAGCGCTACTCCGGAGTCTG 
                   
                 SGSETPGTSESAT 
                   
               
               
                   
                 GCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCT 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 CCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACC 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 AGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAG 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 GTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTAC 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 TTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCC 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 CAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCT 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 ACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTGA 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 AAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTG 
                   
                 ESATPESGPGSEP 
                   
               
               
                   
                 CTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGC 
                   
                 ATSGSETPGTSES 
                   
               
               
                   
                 GCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAAC 
                   
                 ATPESGPGSEPAT 
                   
               
               
                   
                 CTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTA 
                   
                 SGSETPGTSESAT 
                   
               
               
                   
                 CTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCG 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 AGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACTCCT 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 GAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTC 
                   
                 SGPGSPAGSPTST 
                   
               
               
                   
                 CACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTA 
                   
                 EEGSPAGSPTSTE 
                   
               
               
                   
                 CTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCTACT 
                   
                 EGSPAGSPTSTEE 
                   
               
               
                   
                 GAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGG 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCAC 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 CAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGG 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 TACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTA 
                   
                 SATPESGPGSEPA 
                   
               
               
                   
                 GCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACC 
                   
                 TSGSETPGTSESA 
                   
               
               
                   
                 TCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCT 
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                 ACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGC 
                   
                 EGSAPGSPAGSPT 
                   
               
               
                   
                 TGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAA 
                   
                 STEEGTSESATPE 
                   
               
               
                   
                 GCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCA 
                   
                 SGPGSEPATSGSE 
                   
               
               
                   
                 ACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGC 
                   
                 TPGTSESATPESG 
                   
               
               
                   
                 TACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC 
                   
                 PGSPAGSPTSTEE 
                   
               
               
                   
                 CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCA 
                   
                 GSPAGSPTSTEEG 
                   
               
               
                   
                 ACTTCTACTGAAGAAGGTACTTCTACCGAACCTTCCGA 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 GGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTG 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 AGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAA 
                   
                 ESATPESGPGTSE 
                   
               
               
                   
                 TCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGAATC 
                   
                 SATPESGPGSEPA 
                   
               
               
                   
                 TGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAA 
                   
                 TSGSETPGSEPAT 
                   
               
               
                   
                 CCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACT 
                   
                 SGSETPGSPAGSP 
                   
               
               
                   
                 CCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA 
                   
                 TSTEEGTSTEPSE 
                   
               
               
                   
                 AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAG 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 GTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGT 
                   
                 SAPGSEPATSGSE 
                   
               
               
                   
                 AGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTAC 
                   
                 TPGTSESATPESG 
                   
               
               
                   
                 CTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTC 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 TACTGAACCGTCCGAGGGCAGCGCACCA 
                   
                   
                   
               
               
                   
               
               
                 anti- 
                 ATGGAAGACATTCAGATGACCCAGAGCCCGTCCTCCCT 
                 711 
                 MEDIQMTQSPSSL 
                 736 
               
               
                 Her2- 
                 GAGCGCTTCTGTTGGCGACCGCGTGACCATCACCTGCC 
                   
                 SASVGDRVTITCR 
                   
               
               
                 AE576 
                 GTGCTTCCCAGGATGTTAACACCGCTGTAGCTTGGTATC 
                   
                 ASQDVNTAVAW 
                   
               
               
                   
                 AACAGAAACCGGGCAAAGCACCGAAACTGCTGATCTA 
                   
                 YQQKPGKAPKLL 
                   
               
               
                   
                 CTCTGCTTCCTTTCTGTATAGCGGTGTTCCGTCTCGTTTC 
                   
                 IYSASFLYSGVPS 
                   
               
               
                   
                 AGCGGCTCTCGTAGCGGTACGGATTTTACTCTGACGAT 
                   
                 RFSGSRSGTDFTL 
                   
               
               
                   
                 CAGCTCTCTGCAGCCGGAGGACTTCGCTACCTACTACT 
                   
                 TISSLQPEDFATY 
                   
               
               
                   
                 GCCAGCAGCACTACACCACCCCGCCTACCTTTGGTCAG 
                   
                 YCQQHYTTPPTF 
                   
               
               
                   
                 GGCACCAAAGTGGAAATCAAGACCGGTTCTGGCGAAG 
                   
                 GQGTKVEIKTGS 
                   
               
               
                   
                 GCTCTGAAGGTGAAGGTGGTGGTGAAGGCTCTGAAGGT 
                   
                 GEGSEGEGGGEG 
                   
               
               
                   
                 GAAGGATCTGGTGAAGGTGGCGAAGGTGAGGGATCTG 
                   
                 SEGEGSGEGGEG 
                   
               
               
                   
                 GTACCGAGGTCCAGCTGGTTGAGTCTGGCGGCGGTCTG 
                   
                 EGSGTEVQLVES 
                   
               
               
                   
                 GTCCAACCTGGTGGCTCCCTGCGCCTGTCTTGCGCAGCG 
                   
                 GGGLVQPGGSLR 
                   
               
               
                   
                 TCCGGCTTTAATATCAAAGATACGTACATTCACTGGGTC 
                   
                 LSCAASGFNIKDT 
                   
               
               
                   
                 CGCCAGGCACCGGGCAAAGGCCTGGAATGGGTTGCTCG 
                   
                 YIHWVRQAPGKG 
                   
               
               
                   
                 TATCTACCCGACTAACGGTTATACCCGTTATGCAGACA 
                   
                 LEWVARIYPTNG 
                   
               
               
                   
                 GCGTAAAGGGTCGCTTCACGATCTCCGCGGATACCTCC 
                   
                 YTRYADSVKGRF 
                   
               
               
                   
                 AAAAACACCGCATACCTGCAAATGAACTCTCTGCGTGC 
                   
                 TISADTSKNTAYL 
                   
               
               
                   
                 GGAAGATACTGCCGTGTACTACTGCTCTCGCTGGGGCG 
                   
                 QMNSLRAEDTAV 
                   
               
               
                   
                 GTGACGGTTTCTATGCAATGGACTACTGGGGTCAAGGT 
                   
                 YYCSRWGGDGF 
                   
               
               
                   
                 ACTCTGGTAACTGTTTCCGGGTCTCCAGGTAGCCCGGCT 
                   
                 YAMDYWGQGTL 
                   
               
               
                   
                 GGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGAAAG 
                   
                 VTVSGSPGSPAGS 
                   
               
               
                   
                 CGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTGAACC 
                   
                 PTSTEEGTSESAT 
                   
               
               
                   
                 GTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTCTC 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 CGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCC 
                   
                 GSAPGSPAGSPTS 
                   
               
               
                   
                 GAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA 
                   
                 TEEGTSTEPSEGS 
                   
               
               
                   
                 GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGG 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 AATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCT 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 GAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGA 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 AACTCCAGGTAGCCCGGCAGGCTCTCCGACCTCTACTG 
                   
                 SEPATSGSETPGS 
                   
               
               
                   
                 AGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGC 
                   
                 PAGSPTSTEEGTS 
                   
               
               
                   
                 CCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACC 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 AGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAG 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 GTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGT 
                   
                 PSEGSAPGSPAGS 
                   
               
               
                   
                 ACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAC 
                   
                 PTSTEEGTSTEPS 
                   
               
               
                   
                 CTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTC 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 TGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTA 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 CTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTGAA 
                   
                 SGPGTSTEPSEGS 
                   
               
               
                   
                 AGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGC 
                   
                 APGTSESATPESG 
                   
               
               
                   
                 TACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACC 
                   
                 PGSEPATSGSETP 
                   
               
               
                   
                 GTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGT 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 CTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAACC 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 CCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCT 
                   
                 ESATPESGPGSPA 
                   
               
               
                   
                 CCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAA 
                   
                 GSPTSTEEGTSES 
                   
               
               
                   
                 TCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGA 
                   
                 ATPESGPGSEPAT 
                   
               
               
                   
                 AACCCCAGGTACCTCTGAAAGCGCTACTCCGGAGTCTG 
                   
                 SGSETPGTSESAT 
                   
               
               
                   
                 GCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCT 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 CCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACC 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 AGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAG 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 GTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTAC 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 TTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCC 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 CAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCT 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 ACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTGA 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 AAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTG 
                   
                 ESATPESGPGSEP 
                   
               
               
                   
                 CTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGC 
                   
                 ATSGSETPGTSES 
                   
               
               
                   
                 GCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAAC 
                   
                 ATPESGPGSEPAT 
                   
               
               
                   
                 CTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTA 
                   
                 SGSETPGTSESAT 
                   
               
               
                   
                 CTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCG 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 AGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACTCCT 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 GAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTC 
                   
                 SGPGSPAGSPTST 
                   
               
               
                   
                 CACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTA 
                   
                 EEGSPAGSPTSTE 
                   
               
               
                   
                 CTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCTACT 
                   
                 EGSPAGSPTSTEE 
                   
               
               
                   
                 GAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGG 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCAC 
                   
                 TSTEPSEGSAP 
                   
               
               
                   
                 CA 
                   
                   
                   
               
               
                   
               
               
                 anti- 
                 ATGGAAGACATTCAGATGACCCAGAGCCCGTCCTCCCT 
                 712 
                 MEDIQMTQSPSSL 
                 737 
               
               
                 Her2- 
                 GAGCGCTTCTGTTGGCGACCGCGTGACCATCACCTGCC 
                   
                 SASVGDRVTITCR 
                   
               
               
                 AE288 
                 GTGCTTCCCAGGATGTTAACACCGCTGTAGCTTGGTATC 
                   
                 ASQDVNTAVAW 
                   
               
               
                   
                 AACAGAAACCGGGCAAAGCACCGAAACTGCTGATCTA 
                   
                 YQQKPGKAPKLL 
                   
               
               
                   
                 CTCTGCTTCCTTTCTGTATAGCGGTGTTCCGTCTCGTTTC 
                   
                 IYSASFLYSGVPS 
                   
               
               
                   
                 AGCGGCTCTCGTAGCGGTACGGATTTTACTCTGACGAT 
                   
                 RFSGSRSGTDFTL 
                   
               
               
                   
                 CAGCTCTCTGCAGCCGGAGGACTTCGCTACCTACTACT 
                   
                 TISSLQPEDFATY 
                   
               
               
                   
                 GCCAGCAGCACTACACCACCCCGCCTACCTTTGGTCAG 
                   
                 YCQQHYTTPPTF 
                   
               
               
                   
                 GGCACCAAAGTGGAAATCAAGACCGGTTCTGGCGAAG 
                   
                 GQGTKVEIKTGS 
                   
               
               
                   
                 GCTCTGAAGGTGAAGGTGGTGGTGAAGGCTCTGAAGGT 
                   
                 GEGSEGEGGGEG 
                   
               
               
                   
                 GAAGGATCTGGTGAAGGTGGCGAAGGTGAGGGATCTG 
                   
                 SEGEGSGEGGEG 
                   
               
               
                   
                 GTACCGAGGTCCAGCTGGTTGAGTCTGGCGGCGGTCTG 
                   
                 EGSGTEVQLVES 
                   
               
               
                   
                 GTCCAACCTGGTGGCTCCCTGCGCCTGTCTTGCGCAGCG 
                   
                 GGGLVQPGGSLR 
                   
               
               
                   
                 TCCGGCTTTAATATCAAAGATACGTACATTCACTGGGTC 
                   
                 LSCAASGFNIKDT 
                   
               
               
                   
                 CGCCAGGCACCGGGCAAAGGCCTGGAATGGGTTGCTCG 
                   
                 YIHWVRQAPGKG 
                   
               
               
                   
                 TATCTACCCGACTAACGGTTATACCCGTTATGCAGACA 
                   
                 LEWVARIYPTNG 
                   
               
               
                   
                 GCGTAAAGGGTCGCTTCACGATCTCCGCGGATACCTCC 
                   
                 YTRYADSVKGRF 
                   
               
               
                   
                 AAAAACACCGCATACCTGCAAATGAACTCTCTGCGTGC 
                   
                 TISADTSKNTAYL 
                   
               
               
                   
                 GGAAGATACTGCCGTGTACTACTGCTCTCGCTGGGGCG 
                   
                 QMNSLRAEDTAV 
                   
               
               
                   
                 GTGACGGTTTCTATGCAATGGACTACTGGGGTCAAGGT 
                   
                 YYCSRWGGDGF 
                   
               
               
                   
                 ACTCTGGTAACTGTTTCCGGGTCTCCAGGTACCTCTGAA 
                   
                 YAMDYWGQGTL 
                   
               
               
                   
                 AGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGC 
                   
                 VTVSGSPGTSESA 
                   
               
               
                   
                 TACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCG 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 CAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACC 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 TCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTAC 
                   
                 ESGPGSEPATSGS 
                   
               
               
                   
                 TCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGA 
                   
                 ETPGTSESATPES 
                   
               
               
                   
                 GGGCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCT 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 CCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAA 
                   
                 PGSPAGSPTSTEE 
                   
               
               
                   
                 TCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGA 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 AACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCG 
                   
                 SEPATSGSETPGT 
                   
               
               
                   
                 GCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAG 
                   
                 SESATPESGPGSP 
                   
               
               
                   
                 GAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGA 
                   
                 AGSPTSTEEGSPA 
                   
               
               
                   
                 AGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAG 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 GTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGT 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 ACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTAC 
                   
                 TPESGPGTSESAT 
                   
               
               
                   
                 TTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCG 
                   
                 PESGPGTSESATP 
                   
               
               
                   
                 AACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAA 
                   
                 ESGPGSEPATSGS 
                   
               
               
                   
                 CCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCAGC 
                   
                 ETPGSEPATSGSE 
                   
               
               
                   
                 AGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTG 
                   
                 TPGSPAGSPTSTE 
                   
               
               
                   
                 AACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAA 
                   
                 EGTSTEPSEGSAP 
                   
               
               
                   
                 CCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAAC 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 CTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTA 
                   
                 SEPATSGSETPGT 
                   
               
               
                   
                 CTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCG 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 AGGGCAGCGCACCA 
                   
                 TEPSEGSAP 
                   
               
               
                   
               
               
                 AE912- 
                 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGA 
                 713 
                 MAEPAGSPTSTEE 
                 738 
               
               
                 anti-Her2 
                 AGGTACCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGG 
                   
                 GTPGSGTASSSPG 
                   
               
               
                   
                 TAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGC 
                   
                 SSTPSGATGSPGA 
                   
               
               
                   
                 TTCTCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCCC 
                   
                 SPGTSSTGSPGSP 
                   
               
               
                   
                 GGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGA 
                   
                 AGSPTSTEEGTSE 
                   
               
               
                   
                 AAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 AACCGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGC 
                   
                 PSEGSAPGSPAGS 
                   
               
               
                   
                 TCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCT 
                   
                 PTSTEEGTSTEPS 
                   
               
               
                   
                 TCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTC 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 TGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCC 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 CGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGT 
                   
                 SGPGSEPATSGSE 
                   
               
               
                   
                 TCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTC 
                   
                 TPGSEPATSGSET 
                   
               
               
                   
                 TGAAACTCCAGGTAGCCCGGCAGGCTCTCCGACCTCTA 
                   
                 PGSPAGSPTSTEE 
                   
               
               
                   
                 CTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 GGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGC 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 ACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCAC 
                   
                 STEPSEGSAPGSP 
                   
               
               
                   
                 CAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA 
                   
                 AGSPTSTEEGTST 
                   
               
               
                   
                 GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGG 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 TACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTA 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 CTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACT 
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                 TCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTC 
                   
                 EGSAPGTSESATP 
                   
               
               
                   
                 TGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAAC 
                   
                 ESGPGSEPATSGS 
                   
               
               
                   
                 CGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCG 
                   
                 ETPGTSTEPSEGS 
                   
               
               
                   
                 AACCGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAA 
                   
                 APGTSTEPSEGSA 
                   
               
               
                   
                 CCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 AACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAA 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CCCCGGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCA 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 ACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCC 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 TGAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTT 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCGGAG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 TCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAG 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 CGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCG 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 CACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCT 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 CCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCC 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 AGGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCAG 
                   
                 SAPGTSTEPSEGS 
                   
               
               
                   
                 GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT 
                   
                 APGSPAGSPTSTE 
                   
               
               
                   
                 AGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTAC 
                   
                 EGTSTEPSEGSAP 
                   
               
               
                   
                 TTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAA 
                   
                 SEPATSGSETPGT 
                   
               
               
                   
                 CCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAA 
                   
                 SESATPESGPGSE 
                   
               
               
                   
                 AGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGC 
                   
                 PATSGSETPGTSE 
                   
               
               
                   
                 AACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCG 
                   
                 SATPESGPGTSTE 
                   
               
               
                   
                 CTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGT 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACT 
                   
                 TPESGPGSPAGSP 
                   
               
               
                   
                 CCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGAC 
                   
                 TSTEEGSPAGSPT 
                   
               
               
                   
                 TTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTT 
                   
                 STEEGSPAGSPTS 
                   
               
               
                   
                 CTACTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCT 
                   
                 TEEGTSESATPES 
                   
               
               
                   
                 ACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTC 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 CGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCG 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 CACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGC 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 CCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCC 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 AGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAG 
                   
                 EPATSGSETPGTS 
                   
               
               
                   
                 GTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGT 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 ACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTAC 
                   
                 EPSEGSAPGSPAG 
                   
               
               
                   
                 TTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCC 
                   
                 SPTSTEEGTSESA 
                   
               
               
                   
                 CTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACC 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 GGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAA 
                   
                 ESGPGSPAGSPTS 
                   
               
               
                   
                 GCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGC 
                   
                 TEEGSPAGSPTST 
                   
               
               
                   
                 TCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTC 
                   
                 EEGTSTEPSEGSA 
                   
               
               
                   
                 TCCAACTTCTACTGAAGAAGGTACTTCTACCGAACCTTC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 CGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCC 
                   
                 GTSESATPESGPG 
                   
               
               
                   
                 CTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCT 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 GAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGA 
                   
                 EPATSGSETPGSE 
                   
               
               
                   
                 ATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTG 
                   
                 PATSGSETPGSPA 
                   
               
               
                   
                 AAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAA 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 ACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGA 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 GGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCAC 
                   
                 SEGSAPGSEPATS 
                   
               
               
                   
                 CAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA 
                   
                 GSETPGTSESATP 
                   
               
               
                   
                 GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGG 
                   
                 ESGPGTSTEPSEG 
                   
               
               
                   
                 TACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTA 
                   
                 SAPGSSSLDIQMT 
                   
               
               
                   
                 CTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTTCG 
                   
                 QSPSSLSASVGDR 
                   
               
               
                   
                 TCTTCACTCGACATTCAGATGACCCAGAGCCCGTCCTCC 
                   
                 VTITCRASQDVN 
                   
               
               
                   
                 CTGAGCGCTTCTGTTGGCGACCGCGTGACCATCACCTG 
                   
                 TAVAWYQQKPG 
                   
               
               
                   
                 CCGTGCTTCCCAGGATGTTAACACCGCTGTAGCTTGGTA 
                   
                 KAPKLLIYSASFL 
                   
               
               
                   
                 TCAACAGAAACCGGGCAAAGCACCGAAACTGCTGATCT 
                   
                 YSGVPSRFSGSRS 
                   
               
               
                   
                 ACTCTGCTTCCTTTCTGTATAGCGGTGTTCCGTCTCGTTT 
                   
                 GTDFTLTISSLQP 
                   
               
               
                   
                 CAGCGGCTCTCGTAGCGGTACGGATTTTACTCTGACGA 
                   
                 EDFATYYCQQHY 
                   
               
               
                   
                 TCAGCTCTCTGCAGCCGGAGGACTTCGCTACCTACTACT 
                   
                 TTPPTFGQGTKVE 
                   
               
               
                   
                 GCCAGCAGCACTACACCACCCCGCCTACCTTTGGTCAG 
                   
                 IKTGSGEGSEGEG 
                   
               
               
                   
                 GGCACCAAAGTGGAAATCAAGACCGGTTCTGGCGAAG 
                   
                 GGEGSEGEGSGE 
                   
               
               
                   
                 GCTCTGAAGGTGAAGGTGGTGGTGAAGGCTCTGAAGGT 
                   
                 GGEGEGSGTEVQ 
                   
               
               
                   
                 GAAGGATCTGGTGAAGGTGGCGAAGGTGAGGGATCTG 
                   
                 LVESGGGLVQPG 
                   
               
               
                   
                 GTACCGAGGTCCAGCTGGTTGAGTCTGGCGGCGGTCTG 
                   
                 GSLRLSCAASGF 
                   
               
               
                   
                 GTCCAACCTGGTGGCTCCCTGCGCCTGTCTTGCGCAGCG 
                   
                 NIKDTYIHWVRQ 
                   
               
               
                   
                 TCCGGCTTTAATATCAAAGATACGTACATTCACTGGGTC 
                   
                 APGKGLEWVARI 
                   
               
               
                   
                 CGCCAGGCACCGGGCAAAGGCCTGGAATGGGTTGCTCG 
                   
                 YPTNGYTRYADS 
                   
               
               
                   
                 TATCTACCCGACTAACGGTTATACCCGTTATGCAGACA 
                   
                 VKGRFTISADTSK 
                   
               
               
                   
                 GCGTAAAGGGTCGCTTCACGATCTCCGCGGATACCTCC 
                   
                 NTAYLQMNSLRA 
                   
               
               
                   
                 AAAAACACCGCATACCTGCAAATGAACTCTCTGCGTGC 
                   
                 EDTAVYYCSRW 
                   
               
               
                   
                 GGAAGATACTGCCGTGTACTACTGCTCTCGCTGGGGCG 
                   
                 GGDGFYAMDYW 
                   
               
               
                   
                 GTGACGGTTTCTATGCAATGGACTACTGGGGTCAAGGT 
                   
                 GQGTLVTVS 
                   
               
               
                   
                 ACTCTGGTAACTGTTTCC 
                   
                   
                   
               
               
                   
               
               
                 anti- 
                 ATGGAGGATATTCTGCTGACGCAAAGCCCTGTTATTCT 
                 714 
                 MEDILLTQSPVIL 
                 739 
               
               
                 EGFR- 
                 GTCTGTTAGCCCGGGTGAGCGCGTTAGCTTCAGCTGCC 
                   
                 SVSPGERVSFSCR 
                   
               
               
                 Y576- 
                 GTGCATCTCAGAGCATTGGCACGAACATTCATTGGTAT 
                   
                 ASQSIGTNIHWY 
                   
               
               
                 FLAG- 
                 CAACAACGTACCAACGGTAGCCCGCGTCTGCTGATTAA 
                   
                 QQRTNGSPRLLIK 
                   
               
               
                 HI56 
                 ATACGCATCCGAATCTATCTCTGGTATCCCGTCTCGCTT 
                   
                 YASESISGIPSRFS 
                   
               
               
                 (“His6” 
                 CAGCGGTTCTGGTAGCGGCACCGACTTTACCCTGAGCA 
                   
                 GSGSGTDFTLSIN 
                   
               
               
                 disclosed 
                 TTAACTCTGTAGAAAGCGAAGATATTGCGGATTACTAC 
                   
                 SVESEDIADYYC 
                   
               
               
                 as SEQ ID 
                 TGCCAGCAGAACAACAACTGGCCGACTACTTTTGGTGC 
                   
                 QQNNNWPTTFGA 
                   
               
               
                 NO: 218) 
                 AGGTACTAAACTGGAACTGAAAACCGGTTCTGGCGAAG 
                   
                 GTKLELKTGSGE 
                   
               
               
                   
                 GCTCTGAAGGTGAAGGTGGTGGTGAAGGCTCTGAAGGT 
                   
                 GSEGEGGGEGSE 
                   
               
               
                   
                 GAAGGATCTGGTGAAGGTGGCGAAGGTGAGGGATCTG 
                   
                 GEGSGEGGEGEG 
                   
               
               
                   
                 GTACCCAAGTGCAGCTGAAACAGAGCGGTCCGGGTCTG 
                   
                 SGTQVQLKQSGP 
                   
               
               
                   
                 GTGCAACCATCCCAGTCTCTGTCTATTACCTGTACCGTT 
                   
                 GLVQPSQSLSITC 
                   
               
               
                   
                 AGCGGTTTCTCCCTGACCAACTACGGTGTTCACTGGGTT 
                   
                 TVSGFSLTNYGV 
                   
               
               
                   
                 CGCCAGTCCCCAGGCAAAGGCCTGGAATGGCTGGGCGT 
                   
                 HWVRQSPGKGLE 
                   
               
               
                   
                 TATTTGGTCCGGCGGCAATACGGATTATAACACCCCGT 
                   
                 WLGVIWSGGNTD 
                   
               
               
                   
                 TCACCTCTCGTCTGTCTATCAACAAAGATAATTCTAAAA 
                   
                 YNTPFTSRLSINK 
                   
               
               
                   
                 GCCAGGTATTCTTCAAGATGAACTCTCTGCAGAGCAAT 
                   
                 DNSKSQVFFKMN 
                   
               
               
                   
                 GACACCGCCATCTACTATTGCGCTCGTGCCCTGACTTAC 
                   
                 SLQSNDTAIYYC 
                   
               
               
                   
                 TACGATTACGAGTTCGCATATTGGGGCCAGGGCACTCT 
                   
                 ARALTYYDYEFA 
                   
               
               
                   
                 GGTGACCGTTTCCGGAGGTGAGGGTTCTGGCGAAGGTT 
                   
                 YWGQGTLVTVS 
                   
               
               
                   
                 CCGAAGGTGAGGGCTCCGAAGGATCTGGCGAAGGTGA 
                   
                 GGEGSGEGSEGE 
                   
               
               
                   
                 GGGTTCCGAAGGTTCTGGCGAAGGTGAAGGCGGTTCTG 
                   
                 GSEGSGEGEGSE 
                   
               
               
                   
                 AGGGATCCGAAGGTGAAGGCTCCGAAGGATCTGGCGA 
                   
                 GSGEGEGGSEGS 
                   
               
               
                   
                 AGGTGAAGGTGGTGAAGGTTCTGGCGAAGGTGAGGGA 
                   
                 EGEGSEGSGEGE 
                   
               
               
                   
                 TCTGGCGAAGGCTCTGAAGGTGAAGGTGGTGGTGAAGG 
                   
                 GGEGSGEGEGSG 
                   
               
               
                   
                 CTCTGAAGGTGAAGGATCTGGTGAAGGTGGCGAAGGTG 
                   
                 EGSEGEGGGEGS 
                   
               
               
                   
                 AGGGATCTGAAGGCGGCTCCGAAGGTGAAGGCGGATC 
                   
                 EGEGSGEGGEGE 
                   
               
               
                   
                 TGAAGGCGGCGAAGGTGAAGGTTCCGAAGGTTCTGGTG 
                   
                 GSEGGSEGEGGS 
                   
               
               
                   
                 AAGGTGAAGGATCTGAAGGTGGCTCCGAAGGTGAAGG 
                   
                 EGGEGEGSEGSG 
                   
               
               
                   
                 ATCTGAAGGCGGTTCCGAAGGTGAGGGCTCTGAAGGTT 
                   
                 EGEGSEGGSEGE 
                   
               
               
                   
                 CTGGCGAAGGTGAAGGCTCTGAAGGATCTGGTGAAGGT 
                   
                 GSEGGSEGEGSE 
                   
               
               
                   
                 GAAGGTTCCGAAGGTTCTGGTGAAGGTGAAGGTTCCGA 
                   
                 GSGEGEGSEGSG 
                   
               
               
                   
                 AGGTTCTGGCGAAGGTGAAGGTTCTGAAGGTGGCTCTG 
                   
                 EGEGSEGSGEGE 
                   
               
               
                   
                 AAGGTGAAGGCGGCTCTGAAGGATCCGAAGGTGAAGG 
                   
                 GSEGSGEGEGSE 
                   
               
               
                   
                 TTCTGGTGAAGGCTCTGAAGGTGAAGGCGGCTCTGAGG 
                   
                 GGSEGEGGSEGS 
                   
               
               
                   
                 GTTCCGAAGGTGAAGGCGGAGGCGAAGGTTCTGAAGG 
                   
                 EGEGSGEGSEGE 
                   
               
               
                   
                 TGAGGGATCTGGTGAAGGTTCTGAAGGTGAAGGCGGTT 
                   
                 GGSEGSEGEGGG 
                   
               
               
                   
                 CTGAAGGTTCCGAAGGTGAAGGTGGCTCTGAGGGATCC 
                   
                 EGSEGEGSGEGSE 
                   
               
               
                   
                 GAAGGTGAAGGTGGCGAAGGATCTGGTGAAGGTGAAG 
                   
                 GEGGSEGSEGEG 
                   
               
               
                   
                 GTTCTGAAGGTTCTGGCGAAGGTGAGGGTTCTGGCGAA 
                   
                 GSEGSEGEGGEG 
                   
               
               
                   
                 GGTTCCGAAGGTGAGGGCTCCGAAGGATCTGGCGAAG 
                   
                 SGEGEGSEGSGE 
                   
               
               
                   
                 GTGAGGGTTCCGAAGGTTCTGGCGAAGGTGAAGGCGGT 
                   
                 GEGSGEGSEGEG 
                   
               
               
                   
                 TCTGAGGGATCCGAAGGTGAGGGTTCTGGCGAAGGTTC 
                   
                 SEGSGEGEGSEGS 
                   
               
               
                   
                 CGAAGGTGAGGGCTCCGAAGGATCTGGCGAAGGTGAG 
                   
                 GEGEGGSEGSEG 
                   
               
               
                   
                 GGTTCCGAAGGTTCTGGCGAAGGTGAAGGCGGTTCTGA 
                   
                 EGSGEGSEGEGSE 
                   
               
               
                   
                 GGGATCCGAAGGTGAAGGCGGTTCTGAAGGTTCCGAAG 
                   
                 GSGEGEGSEGSG 
                   
               
               
                   
                 GTGAAGGTGGCTCTGAGGGATCCGAAGGTGAAGGTGG 
                   
                 EGEGGSEGSEGE 
                   
               
               
                   
                 CGAAGGATCTGGTGAAGGTGAAGGTTCTGAAGGTTCTG 
                   
                 GGSEGSEGEGGS 
                   
               
               
                   
                 GCGAAGGTGAGGGTTCTGGCGAAGGTTCCGAAGGTGA 
                   
                 EGSEGEGGEGSG 
                   
               
               
                   
                 GGGCTCCGAAGGATCTGGCGAAGGTGAGGGTTCCGAA 
                   
                 EGEGSEGSGEGE 
                   
               
               
                   
                 GGTTCTGGCGAAGGTGAAGGCGGTTCTGAGGGATCCGA 
                   
                 GSGEGSEGEGSE 
                   
               
               
                   
                 AGGTGAAGGCTCCGAAGGATCTGGCGAAGGTGAAGGT 
                   
                 GSGEGEGSEGSG 
                   
               
               
                   
                 GGTGAAGGTTCTGGCGAAGGTGAGGGATCTGGCGAAG 
                   
                 EGEGGSEGSEGE 
                   
               
               
                   
                 GCTCTGAAGGTGAAGGTGGTGGTGAAGGCTCTGAAGGT 
                   
                 GSEGSGEGEGGE 
                   
               
               
                   
                 GAAGGTTCCGAAGGTTCTGGTGAAGGTGAAGGTTCCGA 
                   
                 GSGEGEGSGEGS 
                   
               
               
                   
                 AGGTTCTGGCGAAGGTGAAGGTTCTGAAGGTGGCTCTG 
                   
                 EGEGGGEGSEGE 
                   
               
               
                   
                 AAGGTGAAGGCGGCTCTGAAGGATCCGAAGGTGAAGG 
                   
                 GSEGSGEGEGSE 
                   
               
               
                   
                 ATCTGAAGGTGGCTCCGAAGGTGAAGGATCTGAAGGCG 
                   
                 GSGEGEGSEGGS 
                   
               
               
                   
                 GTTCCGAAGGTGAGGGCTCTGAAGGTTCTGGCGAAGGT 
                   
                 EGEGGSEGSEGE 
                   
               
               
                   
                 GAAGGCTCTGAAGGATCTGGTGAAGGTGAAGGATCTGG 
                   
                 GSEGGSEGEGSE 
                   
               
               
                   
                 CGAAGGCTCCGAAGGTGAAGGCGGTTCTGAAGGTGGC 
                   
                 GGSEGEGSEGSG 
                   
               
               
                   
                 GAAGGTGAAGGATCTGAAGGTGGTTCCGAAGGTGAGG 
                   
                 EGEGSEGSGEGE 
                   
               
               
                   
                 GATCTGAAGGTGGCTCTGAAGGTGAAGGTGGCGAAGGT 
                   
                 GSGEGSEGEGGS 
                   
               
               
                   
                 TCTGGCGAAGGTGAAGGTGGAGGCGAAGGTTCTGAAG 
                   
                 EGGEGEGSEGGS 
                   
               
               
                   
                 GTGAAGGTTCCGAAGGTTCTGGTGAAGGTGAGGGATCT 
                   
                 EGEGSEGGSEGE 
                   
               
               
                   
                 GGCGAAGGTTCTGAAGGTGATTATAAAGACGATGACGA 
                   
                 GGEGSGEGEGGG 
                   
               
               
                   
                 TAAAGGTGGTTCTCATCACCATCACCATCACTAA 
                   
                 EGSEGEGSEGSGE 
                   
               
               
                   
                   
                   
                 GEGSGEGSEGDY 
                   
               
               
                   
                   
                   
                 KDDDDKGGSHH 
                   
               
               
                   
                   
                   
                 HHHH 
                   
               
               
                   
               
               
                 anti-CD3- 
                 ATGAAAGACATCCAGATGACCCAGTCTCCTTCCTCTCTG 
                 715 
                 MKDIQMTQSPSS 
                 740 
               
               
                 Y288- 
                 TCCGCGTCCGTGGGCGACCGTGTTACTATCACCTGCTCC 
                   
                 LSASVGDRVTITC 
                   
               
               
                 GFP- 
                 GCCTCCTCTTCTGTCAGCTACATGAACTGGTATCAGCAG 
                   
                 SASSSVSYMNWY 
                   
               
               
                 HIS8(“Hi 
                 ACTCCTGGCAAAGCTCCAAAACGTTGGATTTACGATAC 
                   
                 QQTPGKAPKRWI 
                   
               
               
                 s8” 
                 GTCCAAGCTGGCCTCCGGCGTACCAAGCCGTTTCTCTG 
                   
                 YDTSKLASGVPS 
                   
               
               
                 disclosed 
                 GCTCTGGCAGCGGCACGGATTACACCTTCACTATTTCTA 
                   
                 RFSGSGSGTDYTF 
                   
               
               
                 as SEQ ID 
                 GCCTGCAGCCTGAAGATATTGCCACCTATTACTGCCAA 
                   
                 TISSLQPEDIATY 
                   
               
               
                 NO: 697) 
                 CAATGGTCCTCCAATCCTTTTACCTTTGGTCAGGGCACT 
                   
                 YCQQWSSNPFTF 
                   
               
               
                   
                 AAGCTGCAGATTACTCGCACCGGTTCTGGCGAAGGCTC 
                   
                 GQGTKLQITRTGS 
                   
               
               
                   
                 TGAAGGTGAAGGTGGTGGTGAAGGCTCTGAAGGTGAA 
                   
                 GEGSEGEGGGEG 
                   
               
               
                   
                 GGATCTGGTGAAGGTGGCGAAGGTGAGGGATCTGGTAC 
                   
                 SEGEGSGEGGEG 
                   
               
               
                   
                 CCAGGTCCAACTGGTTCAATCCGGCGGCGGTGTAGTTC 
                   
                 EGSGTQVQLVQS 
                   
               
               
                   
                 AACCGGGTCGCTCTCTGCGTCTTTCCTGCAAGGCGTCCG 
                   
                 GGGVVQPGRSLR 
                   
               
               
                   
                 GTTACACTTTCACGCGTTACACCATGCACTGGGTCCGTC 
                   
                 LSCKASGYTFTR 
                   
               
               
                   
                 AGGCTCCTGGTAAAGGTCTGGAATGGATTGGCTATATC 
                   
                 YTMHWVRQAPG 
                   
               
               
                   
                 AACCCGTCTCGCGGCTATACCAACTATAACCAGAAATT 
                   
                 KGLEWIGYINPSR 
                   
               
               
                   
                 CAAAGATCGTTTTACGATTTCCACTGATAAATCCAAAA 
                   
                 GYTNYNQKFKDR 
                   
               
               
                   
                 GCACCGCATTCCTCCAAATGGACAGCCTGCGTCCGGAA 
                   
                 FTISTDKSKSTAF 
                   
               
               
                   
                 GACACGGCGGTTTATTATTCCGCCCGTTACTACGATGAC 
                   
                 LQMDSLRPEDTA 
                   
               
               
                   
                 CACTACTGCCTGGATTATTGGGGCCAAGGCACTCCAGT 
                   
                 VYYSARYYDDH 
                   
               
               
                   
                 AACCGTGAGCAGCGGAGGTGAGGGTTCTGGCGAAGGTT 
                   
                 YCLDYWGQGTP 
                   
               
               
                   
                 CCGAAGGTGAGGGCTCCGAAGGATCTGGCGAAGGTGA 
                   
                 VTVSSGGEGSGE 
                   
               
               
                   
                 GGGTTCCGAAGGTTCTGGCGAAGGTGAAGGCGGTTCTG 
                   
                 GSEGEGSEGSGE 
                   
               
               
                   
                 AGGGATCCGAAGGTGAAGGCGGTTCTGAGGGATCTGA 
                   
                 GEGSEGSGEGEG 
                   
               
               
                   
                 AGGTGAAGGTGGCTCTGAAGGATCTGAAGGTGAGGGA 
                   
                 GSEGSEGEGGSE 
                   
               
               
                   
                 TCTGGTGAAGGTTCTGAAGGTGAAGGCGGCTCTGAGGG 
                   
                 GSEGEGGSEGSE 
                   
               
               
                   
                 TTCTGAAGGTGAAGGATCTGGTGAAGGTTCCGAAGGTG 
                   
                 GEGSGEGSEGEG 
                   
               
               
                   
                 AGGGTTCTGAAGGTGGTTCTGAAGGTGAAGGCGGTTCT 
                   
                 GSEGSEGEGSGE 
                   
               
               
                   
                 GAGGGTTCTGAAGGTGAGGGTTCTGGCGAAGGTTCCGA 
                   
                 GSEGEGSEGGSE 
                   
               
               
                   
                 AGGTGAAGGCGGCGAAGGTGGATCTGAAGGTGAGGGC 
                   
                 GEGGSEGSEGEG 
                   
               
               
                   
                 TCCGAAGGATCTGGCGAAGGTGAAGGTTCTGGCGAAGG 
                   
                 SGEGSEGEGGEG 
                   
               
               
                   
                 TTCCGAAGGTGAAGGTTCTGAAGGATCTGGCGAAGGTG 
                   
                 GSEGEGSEGSGE 
                   
               
               
                   
                 AGGGTTCTGGCGAAGGTTCCGAAGGTGAGGGCTCCGAA 
                   
                 GEGSGEGSEGEG 
                   
               
               
                   
                 GGATCTGGCGAAGGTGAGGGTTCCGAAGGTTCTGGCGA 
                   
                 SEGSGEGEGSGE 
                   
               
               
                   
                 AGGTGAAGGCGGTTCTGAGGGATCCGAAGGTGAAGGC 
                   
                 GSEGEGSEGSGE 
                   
               
               
                   
                 TCCGAAGGATCTGGCGAAGGTGAAGGTGGTGAAGGTTC 
                   
                 GEGSEGSGEGEG 
                   
               
               
                   
                 TGGCGAAGGTGAGGGATCTGGCGAAGGCTCTGAAGGT 
                   
                 GSEGSEGEGSEGS 
                   
               
               
                   
                 GAAGGTGGTGGTGAAGGCTCTGAAGGTGAAGGATCTG 
                   
                 GEGEGGEGSGEG 
                   
               
               
                   
                 GTGAAGGTGGCGAAGGTGAGGGATCTGAAGGCGGCTC 
                   
                 EGSGEGSEGEGG 
                   
               
               
                   
                 CGAAGGTGAAGGCGGATCTGAAGGCGGCGAAGGTGAA 
                   
                 GEGSEGEGSGEG 
                   
               
               
                   
                 GGTTCCGAAGGTTCTGGTGAAGGTGAAGGATCTGAAGG 
                   
                 GEGEGSEGGSEG 
                   
               
               
                   
                 TGGCTCCGAAGGTGAAGGATCTGAAGGCGGTTCCGAAG 
                   
                 EGGSEGGEGEGS 
                   
               
               
                   
                 GTGAGGGCTCTGAAGGTTCTGGCGAAGGTGAAGGCTCT 
                   
                 EGSGEGEGSEGG 
                   
               
               
                   
                 GAAGGATCTGGTGAAGGTTCGTCTTCACTCGAGGGTAC 
                   
                 SEGEGSEGGSEGE 
                   
               
               
                   
                 CGAACTTTTCACTGGAGTTGTCCCAATTCTTGTTGAATT 
                   
                 GSEGSGEGEGSE 
                   
               
               
                   
                 AGATGGTGATGTTAATGGGCACAAATTTTCTGTCAGTG 
                   
                 GSGEGSSSLEGTE 
                   
               
               
                   
                 GAGAGGGTGAAGGTGATGCAACATACGGAAAACTTAC 
                   
                 LFTGVVPILVELD 
                   
               
               
                   
                 CCTTAAATTTATTTGCACTACTGGAAAACTACCTGTTCC 
                   
                 GDVNGHKFSVSG 
                   
               
               
                   
                 ATGGCCAACACTTGTCACTACTTTCTCTTATGGTGTTCA 
                   
                 EGEGDATYGKLT 
                   
               
               
                   
                 ATGCTTTTCCCGTTATCCGGATCACATGAAACGGCATG 
                   
                 LKFICTTGKLPVP 
                   
               
               
                   
                 ACTTTTTCAAGAGTGCCATGCCCGAAGGTTATGTACAG 
                   
                 WPTLVTTFSYGV 
                   
               
               
                   
                 GAACGCACTATATCTTTCAAAGATGACGGGAACTACAA 
                   
                 QCFSRYPDHMKR 
                   
               
               
                   
                 GACGCGTGCTGAAGTCAAGTTTGAAGGTGATACCCTTG 
                   
                 HDFFKSAMPEGY 
                   
               
               
                   
                 TTAATCGTATCGAGTTAAAAGGTATTGATTTTAAAGAA 
                   
                 VQERTISFKDDG 
                   
               
               
                   
                 GATGGAAACATTCTCGGACACAAACTCGAGTACAACTA 
                   
                 NYKTRAEVKFEG 
                   
               
               
                   
                 TAACTCACACAATGTATACATCACGGCAGACAAACAAA 
                   
                 DTLVNRIELKGID 
                   
               
               
                   
                 AGAATGGAATCAAAGCTAACTTCAAAATTCGCCACAAC 
                   
                 FKEDGNILGHKL 
                   
               
               
                   
                 ATTGAAGATGGATCCGTTCAACTAGCAGACCATTATCA 
                   
                 EYNYNSHNVYIT 
                   
               
               
                   
                 ACAAAATACTCCAATTGGCGATGGCCCTGTCCTTTTACC 
                   
                 ADKQKNGIKANF 
                   
               
               
                   
                 AGACAACCATTACCTGTCGACACAATCTGCCCTTTCGA 
                   
                 KIRHNIEDGSVQL 
                   
               
               
                   
                 AAGATCCCAACGAAAAGCGTGACCACATGGTCCTTCTT 
                   
                 ADHYQQNTPIGD 
                   
               
               
                   
                 GAGTTTGTAACTGCTGCTGGGATTGGTGGCTCTCATCAC 
                   
                 GPVLLPDNHYLS 
                   
               
               
                   
                 CATCACCATCACCATCACTAA 
                   
                 TQSALSKDPNEK 
                   
               
               
                   
                   
                   
                 RDHMVLLEFVTA 
                   
               
               
                   
                   
                   
                 AGIGGSHHHHHH 
                   
               
               
                   
                   
                   
                 HH 
                   
               
               
                   
               
               
                 anti- 
                 ATGGAGGACATTCAGATGACCCAGAGCCCGTCCTCCCT 
                 716 
                 MEDIQMTQSPSSL 
                 741 
               
               
                 Her2- 
                 GAGCGCTTCTGTTGGCGACCGCGTGACCATCACCTGCC 
                   
                 SASVGDRVTITCR 
                   
               
               
                 Y288- 
                 GTGCTTCCCAGGATGTTAACACCGCTGTAGCTTGGTATC 
                   
                 ASQDVNTAVAW 
                   
               
               
                 anti-CD3- 
                 AACAGAAACCGGGCAAAGCACCGAAACTGCTGATCTA 
                   
                 YQQKPGKAPKLL 
                   
               
               
                 HA-His6, 
                 CTCTGCTTCCTTTCTGTATAGCGGTGTTCCGTCTCGTTTC 
                   
                 IYSASFLYSGVPS 
                   
               
               
                 AC48 
                 AGCGGCTCTCGTAGCGGTACGGATTTTACTCTGACGAT 
                   
                 RFSGSRSGTDFTL 
                   
               
               
                 (“His6” 
                 CAGCTCTCTGCAGCCGGAGGACTTCGCTACCTACTACT 
                   
                 TISSLQPEDFATY 
                   
               
               
                 disclosed 
                 GCCAGCAGCACTACACCACCCCGCCTACCTTTGGTCAG 
                   
                 YCQQHYTTPPTF 
                   
               
               
                 as SEQ ID 
                 GGCACCAAAGTGGAAATCAAGACCGGTTCTGGCGAAG 
                   
                 GQGTKVEIKTGS 
                   
               
               
                 NO: 218) 
                 GCTCTGAAGGTGAAGGTGGTGGTGAAGGCTCTGAAGGT 
                   
                 GEGSEGEGGGEG 
                   
               
               
                   
                 GAAGGATCTGGTGAAGGTGGCGAAGGTGAGGGATCTG 
                   
                 SEGEGSGEGGEG 
                   
               
               
                   
                 GTACCGAGGTCCAGCTGGTTGAGTCTGGCGGCGGTCTG 
                   
                 EGSGTEVQLVES 
                   
               
               
                   
                 GTCCAACCTGGTGGCTCCCTGCGCCTGTCTTGCGCAGCG 
                   
                 GGGLVQPGGSLR 
                   
               
               
                   
                 TCCGGCTTTAATATCAAAGATACGTACATTCACTGGGTC 
                   
                 LSCAASGFNIKDT 
                   
               
               
                   
                 CGCCAGGCACCGGGCAAAGGCCTGGAATGGGTTGCTCG 
                   
                 YIHWVRQAPGKG 
                   
               
               
                   
                 TATCTACCCGACTAACGGTTATACCCGTTATGCAGACA 
                   
                 LEWVARIYPTNG 
                   
               
               
                   
                 GCGTAAAGGGTCGCTTCACGATCTCCGCGGATACCTCC 
                   
                 YTRYADSVKGRF 
                   
               
               
                   
                 AAAAACACCGCATACCTGCAAATGAACTCTCTGCGTGC 
                   
                 TISADTSKNTAYL 
                   
               
               
                   
                 GGAAGATACTGCCGTGTACTACTGCTCTCGCTGGGGCG 
                   
                 QMNSLRAEDTAV 
                   
               
               
                   
                 GTGACGGTTTCTATGCAATGGACTACTGGGGTCAAGGT 
                   
                 YYCSRWGGDGF 
                   
               
               
                   
                 ACTCTGGTAACTGTTTCCGGAGGTGAGGGTTCTGGCGA 
                   
                 YAMDYWGQGTL 
                   
               
               
                   
                 AGGTTCCGAAGGTGAGGGCTCCGAAGGATCTGGCGAA 
                   
                 VTVSGGEGSGEG 
                   
               
               
                   
                 GGTGAGGGTTCCGAAGGTTCTGGCGAAGGTGAAGGCG 
                   
                 SEGEGSEGSGEGE 
                   
               
               
                   
                 GTTCTGAGGGATCCGAAGGTGAAGGCGGTTCTGAGGGA 
                   
                 GSEGSGEGEGGS 
                   
               
               
                   
                 TCTGAAGGTGAAGGTGGCTCTGAAGGATCTGAAGGTGA 
                   
                 EGSEGEGGSEGSE 
                   
               
               
                   
                 GGGATCTGGTGAAGGTTCTGAAGGTGAAGGCGGCTCTG 
                   
                 GEGGSEGSEGEG 
                   
               
               
                   
                 AGGGTTCTGAAGGTGAAGGATCTGGTGAAGGTTCCGAA 
                   
                 SGEGSEGEGGSE 
                   
               
               
                   
                 GGTGAGGGTTCTGAAGGTGGTTCTGAAGGTGAAGGCGG 
                   
                 GSEGEGSGEGSE 
                   
               
               
                   
                 TTCTGAGGGTTCTGAAGGTGAGGGTTCTGGCGAAGGTT 
                   
                 GEGSEGGSEGEG 
                   
               
               
                   
                 CCGAAGGTGAAGGCGGCGAAGGTGGATCTGAAGGTGA 
                   
                 GSEGSEGEGSGE 
                   
               
               
                   
                 GGGCTCCGAAGGATCTGGCGAAGGTGAAGGTTCTGGCG 
                   
                 GSEGEGGEGGSE 
                   
               
               
                   
                 AAGGTTCCGAAGGTGAAGGTTCTGAAGGATCTGGCGAA 
                   
                 GEGSEGSGEGEG 
                   
               
               
                   
                 GGTGAGGGTTCTGGCGAAGGTTCCGAAGGTGAGGGCTC 
                   
                 SGEGSEGEGSEGS 
                   
               
               
                   
                 CGAAGGATCTGGCGAAGGTGAGGGTTCCGAAGGTTCTG 
                   
                 GEGEGSGEGSEG 
                   
               
               
                   
                 GCGAAGGTGAAGGCGGTTCTGAGGGATCCGAAGGTGA 
                   
                 EGSEGSGEGEGSE 
                   
               
               
                   
                 AGGCTCCGAAGGATCTGGCGAAGGTGAAGGTGGTGAA 
                   
                 GSGEGEGGSEGS 
                   
               
               
                   
                 GGTTCTGGCGAAGGTGAGGGATCTGGCGAAGGCTCTGA 
                   
                 EGEGSEGSGEGE 
                   
               
               
                   
                 AGGTGAAGGTGGTGGTGAAGGCTCTGAAGGTGAAGGA 
                   
                 GGEGSGEGEGSG 
                   
               
               
                   
                 TCTGGTGAAGGTGGCGAAGGTGAGGGATCTGAAGGCG 
                   
                 EGSEGEGGGEGS 
                   
               
               
                   
                 GCTCCGAAGGTGAAGGCGGATCTGAAGGCGGCGAAGG 
                   
                 EGEGSGEGGEGE 
                   
               
               
                   
                 TGAAGGTTCCGAAGGTTCTGGTGAAGGTGAAGGATCTG 
                   
                 GSEGGSEGEGGS 
                   
               
               
                   
                 AAGGTGGCTCCGAAGGTGAAGGATCTGAAGGCGGTTCC 
                   
                 EGGEGEGSEGSG 
                   
               
               
                   
                 GAAGGTGAGGGCTCTGAAGGTTCTGGCGAAGGTGAAG 
                   
                 EGEGSEGGSEGE 
                   
               
               
                   
                 GCTCTGAAGGATCTGGTGAAGGTGACATCCAGATGACC 
                   
                 GSEGGSEGEGSE 
                   
               
               
                   
                 CAGTCTCCTTCCTCTCTGTCCGCGTCCGTGGGCGACCGT 
                   
                 GSGEGEGSEGSG 
                   
               
               
                   
                 GTTACTATCACCTGCTCCGCCTCCTCTTCTGTCAGCTAC 
                   
                 EGDIQMTQSPSSL 
                   
               
               
                   
                 ATGAACTGGTATCAGCAGACTCCTGGCAAAGCTCCAAA 
                   
                 SASVGDRVTITCS 
                   
               
               
                   
                 ACGTTGGATTTACGATACGTCCAAGCTGGCCTCCGGCG 
                   
                 ASSSVSYMNWY 
                   
               
               
                   
                 TACCAAGCCGTTTCTCTGGCTCTGGCAGCGGCACGGAT 
                   
                 QQTPGKAPKRWI 
                   
               
               
                   
                 TACACCTTCACTATTTCTAGCCTGCAGCCTGAAGATATT 
                   
                 YDTSKLASGVPS 
                   
               
               
                   
                 GCCACCTATTACTGCCAACAATGGTCCTCCAATCCTTTT 
                   
                 RFSGSGSGTDYTF 
                   
               
               
                   
                 ACCTTTGGTCAGGGCACTAAGCTGCAGATTACTCGCAC 
                   
                 TISSLQPEDIATY 
                   
               
               
                   
                 CGGTTCTGGCGAAGGCTCTGAAGGTGAAGGTGGTGGTG 
                   
                 YCQQWSSNPFTF 
                   
               
               
                   
                 AAGGCTCTGAAGGTGAAGGATCTGGTGAAGGTGGCGA 
                   
                 GQGTKLQITRTGS 
                   
               
               
                   
                 AGGTGAGGGATCTGGTACCCAGGTCCAACTGGTTCAAT 
                   
                 GEGSEGEGGGEG 
                   
               
               
                   
                 CCGGCGGCGGTGTAGTTCAACCGGGTCGCTCTCTGCGT 
                   
                 SEGEGSGEGGEG 
                   
               
               
                   
                 CTTTCCTGCAAGGCGTCCGGTTACACTTTCACGCGTTAC 
                   
                 EGSGTQVQLVQS 
                   
               
               
                   
                 ACCATGCACTGGGTCCGTCAGGCTCCTGGTAAAGGTCT 
                   
                 GGGVVQPGRSLR 
                   
               
               
                   
                 GGAATGGATTGGCTATATCAACCCGTCTCGCGGCTATA 
                   
                 LSCKASGYTFTR 
                   
               
               
                   
                 CCAACTATAACCAGAAATTCAAAGATCGTTTTACGATT 
                   
                 YTMHWVRQAPG 
                   
               
               
                   
                 TCCACTGATAAATCCAAAAGCACCGCATTCCTCCAAAT 
                   
                 KGLEWIGYINPSR 
                   
               
               
                   
                 GGACAGCCTGCGTCCGGAAGACACGGCGGTTTATTATT 
                   
                 GYTNYNQKFKDR 
                   
               
               
                   
                 CCGCCCGTTACTACGATGACCACTACTGCCTGGATTATT 
                   
                 FTISTDKSKSTAF 
                   
               
               
                   
                 GGGGCCAAGGCACTCCAGTAACCGTGAGCAGCGGCGG 
                   
                 LQMDSLRPEDTA 
                   
               
               
                   
                 TTATCCTTATGATGTTCCAGACTATGCAGGTGGCTCTCA 
                   
                 VYYSARYYDDH 
                   
               
               
                   
                 TCACCATCACCATCACTGA 
                   
                 YCLDYWGQGTP 
                   
               
               
                   
                   
                   
                 VTVSSGGYPYDV 
                   
               
               
                   
                   
                   
                 PDYAGGSHHHHH 
                   
               
               
                   
                   
                   
                 H 
                   
               
               
                   
               
               
                 anti- 
                 ATGGAGGACATTCAGATGACCCAGAGCCCGTCCTCCCT 
                 717 
                 MEDIQMTQSPSSL 
                 742 
               
               
                 Her2- 
                 GAGCGCTTCTGTTGGCGACCGCGTGACCATCACCTGCC 
                   
                 SASVGDRVTITCR 
                   
               
               
                 Y288- 
                 GTGCTTCCCAGGATGTTAACACCGCTGTAGCTTGGTATC 
                   
                 ASQDVNTAVAW 
                   
               
               
                 anti- 
                 AACAGAAACCGGGCAAAGCACCGAAACTGCTGATCTA 
                   
                 YQQKPGKAPKLL 
                   
               
               
                 EGFR- 
                 CTCTGCTTCCTTTCTGTATAGCGGTGTTCCGTCTCGTTTC 
                   
                 IYSASFLYSGVPS 
                   
               
               
                 HA-His6, 
                 AGCGGCTCTCGTAGCGGTACGGATTTTACTCTGACGAT 
                   
                 RFSGSRSGTDFTL 
                   
               
               
                 AC49 
                 CAGCTCTCTGCAGCCGGAGGACTTCGCTACCTACTACT 
                   
                 TISSLQPEDFATY 
                   
               
               
                 (“His6” 
                 GCCAGCAGCACTACACCACCCCGCCTACCTTTGGTCAG 
                   
                 YCQQHYTTPPTF 
                   
               
               
                 disclosed 
                 GGCACCAAAGTGGAAATCAAGACCGGTTCTGGCGAAG 
                   
                 GQGTKVEIKTGS 
                   
               
               
                 as SEQ ID 
                 GCTCTGAAGGTGAAGGTGGTGGTGAAGGCTCTGAAGGT 
                   
                 GEGSEGEGGGEG 
                   
               
               
                 NO: 218) 
                 GAAGGATCTGGTGAAGGTGGCGAAGGTGAGGGATCTG 
                   
                 SEGEGSGEGGEG 
                   
               
               
                   
                 GTACCGAGGTCCAGCTGGTTGAGTCTGGCGGCGGTCTG 
                   
                 EGSGTEVQLVES 
                   
               
               
                   
                 GTCCAACCTGGTGGCTCCCTGCGCCTGTCTTGCGCAGCG 
                   
                 GGGLVQPGGSLR 
                   
               
               
                   
                 TCCGGCTTTAATATCAAAGATACGTACATTCACTGGGTC 
                   
                 LSCAASGFNIKDT 
                   
               
               
                   
                 CGCCAGGCACCGGGCAAAGGCCTGGAATGGGTTGCTCG 
                   
                 YIHWVRQAPGKG 
                   
               
               
                   
                 TATCTACCCGACTAACGGTTATACCCGTTATGCAGACA 
                   
                 LEWVARIYPTNG 
                   
               
               
                   
                 GCGTAAAGGGTCGCTTCACGATCTCCGCGGATACCTCC 
                   
                 YTRYADSVKGRF 
                   
               
               
                   
                 AAAAACACCGCATACCTGCAAATGAACTCTCTGCGTGC 
                   
                 TISADTSKNTAYL 
                   
               
               
                   
                 GGAAGATACTGCCGTGTACTACTGCTCTCGCTGGGGCG 
                   
                 QMNSLRAEDTAV 
                   
               
               
                   
                 GTGACGGTTTCTATGCAATGGACTACTGGGGTCAAGGT 
                   
                 YYCSRWGGDGF 
                   
               
               
                   
                 ACTCTGGTAACTGTTTCCGGAGGTGAGGGTTCTGGCGA 
                   
                 YAMDYWGQGTL 
                   
               
               
                   
                 AGGTTCCGAAGGTGAGGGCTCCGAAGGATCTGGCGAA 
                   
                 VTVSGGEGSGEG 
                   
               
               
                   
                 GGTGAGGGTTCCGAAGGTTCTGGCGAAGGTGAAGGCG 
                   
                 SEGEGSEGSGEGE 
                   
               
               
                   
                 GTTCTGAGGGATCCGAAGGTGAAGGCGGTTCTGAGGGA 
                   
                 GSEGSGEGEGGS 
                   
               
               
                   
                 TCTGAAGGTGAAGGTGGCTCTGAAGGATCTGAAGGTGA 
                   
                 EGSEGEGGSEGSE 
                   
               
               
                   
                 GGGATCTGGTGAAGGTTCTGAAGGTGAAGGCGGCTCTG 
                   
                 GEGGSEGSEGEG 
                   
               
               
                   
                 AGGGTTCTGAAGGTGAAGGATCTGGTGAAGGTTCCGAA 
                   
                 SGEGSEGEGGSE 
                   
               
               
                   
                 GGTGAGGGTTCTGAAGGTGGTTCTGAAGGTGAAGGCGG 
                   
                 GSEGEGSGEGSE 
                   
               
               
                   
                 TTCTGAGGGTTCTGAAGGTGAGGGTTCTGGCGAAGGTT 
                   
                 GEGSEGGSEGEG 
                   
               
               
                   
                 CCGAAGGTGAAGGCGGCGAAGGTGGATCTGAAGGTGA 
                   
                 GSEGSEGEGSGE 
                   
               
               
                   
                 GGGCTCCGAAGGATCTGGCGAAGGTGAAGGTTCTGGCG 
                   
                 GSEGEGGEGGSE 
                   
               
               
                   
                 AAGGTTCCGAAGGTGAAGGTTCTGAAGGATCTGGCGAA 
                   
                 GEGSEGSGEGEG 
                   
               
               
                   
                 GGTGAGGGTTCTGGCGAAGGTTCCGAAGGTGAGGGCTC 
                   
                 SGEGSEGEGSEGS 
                   
               
               
                   
                 CGAAGGATCTGGCGAAGGTGAGGGTTCCGAAGGTTCTG 
                   
                 GEGEGSGEGSEG 
                   
               
               
                   
                 GCGAAGGTGAAGGCGGTTCTGAGGGATCCGAAGGTGA 
                   
                 EGSEGSGEGEGSE 
                   
               
               
                   
                 AGGCTCCGAAGGATCTGGCGAAGGTGAAGGTGGTGAA 
                   
                 GSGEGEGGSEGS 
                   
               
               
                   
                 GGTTCTGGCGAAGGTGAGGGATCTGGCGAAGGCTCTGA 
                   
                 EGEGSEGSGEGE 
                   
               
               
                   
                 AGGTGAAGGTGGTGGTGAAGGCTCTGAAGGTGAAGGA 
                   
                 GGEGSGEGEGSG 
                   
               
               
                   
                 TCTGGTGAAGGTGGCGAAGGTGAGGGATCTGAAGGCG 
                   
                 EGSEGEGGGEGS 
                   
               
               
                   
                 GCTCCGAAGGTGAAGGCGGATCTGAAGGCGGCGAAGG 
                   
                 EGEGSGEGGEGE 
                   
               
               
                   
                 TGAAGGTTCCGAAGGTTCTGGTGAAGGTGAAGGATCTG 
                   
                 GSEGGSEGEGGS 
                   
               
               
                   
                 AAGGTGGCTCCGAAGGTGAAGGATCTGAAGGCGGTTCC 
                   
                 EGGEGEGSEGSG 
                   
               
               
                   
                 GAAGGTGAGGGCTCTGAAGGTTCTGGCGAAGGTGAAG 
                   
                 EGEGSEGGSEGE 
                   
               
               
                   
                 GCTCTGAAGGATCTGGTGAAGGTGAGGATATTCTGCTG 
                   
                 GSEGGSEGEGSE 
                   
               
               
                   
                 ACGCAAAGCCCTGTTATTCTGTCTGTTAGCCCGGGTGA 
                   
                 GSGEGEGSEGSG 
                   
               
               
                   
                 GCGCGTTAGCTTCAGCTGCCGTGCATCTCAGAGCATTG 
                   
                 EGEDILLTQSPVIL 
                   
               
               
                   
                 GCACGAACATTCATTGGTATCAACAACGTACCAACGGT 
                   
                 SVSPGERVSFSCR 
                   
               
               
                   
                 AGCCCGCGTCTGCTGATTAAATACGCATCCGAATCTAT 
                   
                 ASQSIGTNIHWY 
                   
               
               
                   
                 CTCTGGTATCCCGTCTCGCTTCAGCGGTTCTGGTAGCGG 
                   
                 QQRTNGSPRLLIK 
                   
               
               
                   
                 CACCGACTTTACCCTGAGCATTAACTCTGTAGAAAGCG 
                   
                 YASESISGIPSRFS 
                   
               
               
                   
                 AAGATATTGCGGATTACTACTGCCAGCAGAACAACAAC 
                   
                 GSGSGTDFTLSIN 
                   
               
               
                   
                 TGGCCGACTACTTTTGGTGCAGGTACTAAACTGGAACT 
                   
                 SVESEDIADYYC 
                   
               
               
                   
                 GAAAACCGGTTCTGGCGAAGGCTCTGAAGGTGAAGGTG 
                   
                 QQNNNWPTTFGA 
                   
               
               
                   
                 GTGGTGAAGGCTCTGAAGGTGAAGGATCTGGTGAAGGT 
                   
                 GTKLELKTGSGE 
                   
               
               
                   
                 GGCGAAGGTGAGGGATCTGGTACCCAAGTGCAGCTGA 
                   
                 GSEGEGGGEGSE 
                   
               
               
                   
                 AACAGAGCGGTCCGGGTCTGGTGCAACCATCCCAGTCT 
                   
                 GEGSGEGGEGEG 
                   
               
               
                   
                 CTGTCTATTACCTGTACCGTTAGCGGTTTCTCCCTGACC 
                   
                 SGTQVQLKQSGP 
                   
               
               
                   
                 AACTACGGTGTTCACTGGGTTCGCCAGTCCCCAGGCAA 
                   
                 GLVQPSQSLSITC 
                   
               
               
                   
                 AGGCCTGGAATGGCTGGGCGTTATTTGGTCCGGCGGCA 
                   
                 TVSGFSLTNYGV 
                   
               
               
                   
                 ATACGGATTATAACACCCCGTTCACCTCTCGTCTGTCTA 
                   
                 HWVRQSPGKGLE 
                   
               
               
                   
                 TCAACAAAGATAATTCTAAAAGCCAGGTATTCTTCAAG 
                   
                 WLGVIWSGGNTD 
                   
               
               
                   
                 ATGAACTCTCTGCAGAGCAATGACACCGCCATCTACTA 
                   
                 YNTPFTSRLSINK 
                   
               
               
                   
                 TTGCGCTCGTGCCCTGACTTACTACGATTACGAGTTCGC 
                   
                 DNSKSQVFFKMN 
                   
               
               
                   
                 ATATTGGGGCCAGGGCACTCTGGTGACCGTTTCCGGCG 
                   
                 SLQSNDTAIYYC 
                   
               
               
                   
                 GTTATCCTTATGATGTTCCAGACTATGCAGGTGGCTCTC 
                   
                 ARALTYYDYEFA 
                   
               
               
                   
                 ATCACCATCACCATCACTGA 
                   
                 YWGQGTLVTVS 
                   
               
               
                   
                   
                   
                 GGYPYDVPDYAG 
                   
               
               
                   
                   
                   
                 GSHHHHHH 
                   
               
               
                   
               
               
                 anti- 
                 ATGGAGGACATTCAGATGACCCAGAGCCCGTCCTCCCT 
                 718 
                 MEDIQMTQSPSSL 
                 743 
               
               
                 Her2- 
                 GAGCGCTTCTGTTGGCGACCGCGTGACCATCACCTGCC 
                   
                 SASVGDRVTITCR 
                   
               
               
                 Y288- 
                 GTGCTTCCCAGGATGTTAACACCGCTGTAGCTTGGTATC 
                   
                 ASQDVNTAVAW 
                   
               
               
                 anti-CD3- 
                 AACAGAAACCGGGCAAAGCACCGAAACTGCTGATCTA 
                   
                 YQQKPGKAPKLL 
                   
               
               
                 HA-His8, 
                 CTCTGCTTCCTTTCTGTATAGCGGTGTTCCGTCTCGTTTC 
                   
                 IYSASFLYSGVPS 
                   
               
               
                 AC69 
                 AGCGGCTCTCGTAGCGGTACGGATTTTACTCTGACGAT 
                   
                 RFSGSRSGTDFTL 
                   
               
               
                 (“His8” 
                 CAGCTCTCTGCAGCCGGAGGACTTCGCTACCTACTACT 
                   
                 TISSLQPEDFATY 
                   
               
               
                 disclosed 
                 GCCAGCAGCACTACACCACCCCGCCTACCTTTGGTCAG 
                   
                 YCQQHYTTPPTF 
                   
               
               
                 as SEQ ID 
                 GGCACCAAAGTGGAAATCAAGACCGGTTCTGGCGAAG 
                   
                 GQGTKVEIKTGS 
                   
               
               
                 NO: 697) 
                 GCTCTGAAGGTGAAGGTGGTGGTGAAGGCTCTGAAGGT 
                   
                 GEGSEGEGGGEG 
                   
               
               
                   
                 GAAGGATCTGGTGAAGGTGGCGAAGGTGAGGGATCTG 
                   
                 SEGEGSGEGGEG 
                   
               
               
                   
                 GTACCGAGGTCCAGCTGGTTGAGTCTGGCGGCGGTCTG 
                   
                 EGSGTEVQLVES 
                   
               
               
                   
                 GTCCAACCTGGTGGCTCCCTGCGCCTGTCTTGCGCAGCG 
                   
                 GGGLVQPGGSLR 
                   
               
               
                   
                 TCCGGCTTTAATATCAAAGATACGTACATTCACTGGGTC 
                   
                 LSCAASGFNIKDT 
                   
               
               
                   
                 CGCCAGGCACCGGGCAAAGGCCTGGAATGGGTTGCTCG 
                   
                 YIHWVRQAPGKG 
                   
               
               
                   
                 TATCTACCCGACTAACGGTTATACCCGTTATGCAGACA 
                   
                 LEWVARIYPTNG 
                   
               
               
                   
                 GCGTAAAGGGTCGCTTCACGATCTCCGCGGATACCTCC 
                   
                 YTRYADSVKGRF 
                   
               
               
                   
                 AAAAACACCGCATACCTGCAAATGAACTCTCTGCGTGC 
                   
                 TISADTSKNTAYL 
                   
               
               
                   
                 GGAAGATACTGCCGTGTACTACTGCTCTCGCTGGGGCG 
                   
                 QMNSLRAEDTAV 
                   
               
               
                   
                 GTGACGGTTTCTATGCAATGGACTACTGGGGTCAAGGT 
                   
                 YYCSRWGGDGF 
                   
               
               
                   
                 ACTCTGGTAACTGTTTCCGGGTCTCCAGGTGAGGGTTCT 
                   
                 YAMDYWGQGTL 
                   
               
               
                   
                 GGCGAAGGTTCCGAAGGTGAGGGCTCCGAAGGATCTG 
                   
                 VTVSGSPGEGSG 
                   
               
               
                   
                 GCGAAGGTGAGGGTTCCGAAGGTTCTGGCGAAGGTGA 
                   
                 EGSEGEGSEGSGE 
                   
               
               
                   
                 AGGCGGTTCTGAGGGATCCGAAGGTGAAGGCGGTTCTG 
                   
                 GEGSEGSGEGEG 
                   
               
               
                   
                 AGGGATCTGAAGGTGAAGGTGGCTCTGAAGGATCTGAA 
                   
                 GSEGSEGEGGSE 
                   
               
               
                   
                 GGTGAGGGATCTGGTGAAGGTTCTGAAGGTGAAGGCG 
                   
                 GSEGEGGSEGSE 
                   
               
               
                   
                 GCTCTGAGGGTTCTGAAGGTGAAGGATCTGGTGAAGGT 
                   
                 GEGSGEGSEGEG 
                   
               
               
                   
                 TCCGAAGGTGAGGGTTCTGAAGGTGGTTCTGAAGGTGA 
                   
                 GSEGSEGEGSGE 
                   
               
               
                   
                 AGGCGGTTCTGAGGGTTCTGAAGGTGAGGGTTCTGGCG 
                   
                 GSEGEGSEGGSE 
                   
               
               
                   
                 AAGGTTCCGAAGGTGAAGGCGGCGAAGGTGGATCTGA 
                   
                 GEGGSEGSEGEG 
                   
               
               
                   
                 AGGTGAGGGCTCCGAAGGATCTGGCGAAGGTGAAGGT 
                   
                 SGEGSEGEGGEG 
                   
               
               
                   
                 TCTGGCGAAGGTTCCGAAGGTGAAGGTTCTGAAGGATC 
                   
                 GSEGEGSEGSGE 
                   
               
               
                   
                 TGGCGAAGGTGAGGGTTCTGGCGAAGGTTCCGAAGGTG 
                   
                 GEGSGEGSEGEG 
                   
               
               
                   
                 AGGGCTCCGAAGGATCTGGCGAAGGTGAGGGTTCCGA 
                   
                 SEGSGEGEGSGE 
                   
               
               
                   
                 AGGTTCTGGCGAAGGTGAAGGCGGTTCTGAGGGATCCG 
                   
                 GSEGEGSEGSGE 
                   
               
               
                   
                 AAGGTGAAGGCTCCGAAGGATCTGGCGAAGGTGAAGG 
                   
                 GEGSEGSGEGEG 
                   
               
               
                   
                 TGGTGAAGGTTCTGGCGAAGGTGAGGGATCTGGCGAAG 
                   
                 GSEGSEGEGSEGS 
                   
               
               
                   
                 GCTCTGAAGGTGAAGGTGGTGGTGAAGGCTCTGAAGGT 
                   
                 GEGEGGEGSGEG 
                   
               
               
                   
                 GAAGGATCTGGTGAAGGTGGCGAAGGTGAGGGATCTG 
                   
                 EGSGEGSEGEGG 
                   
               
               
                   
                 AAGGCGGCTCCGAAGGTGAAGGCGGATCTGAAGGCGG 
                   
                 GEGSEGEGSGEG 
                   
               
               
                   
                 CGAAGGTGAAGGTTCCGAAGGTTCTGGTGAAGGTGAAG 
                   
                 GEGEGSEGGSEG 
                   
               
               
                   
                 GATCTGAAGGTGGCTCCGAAGGTGAAGGATCTGAAGGC 
                   
                 EGGSEGGEGEGS 
                   
               
               
                   
                 GGTTCCGAAGGTGAGGGCTCTGAAGGTTCTGGCGAAGG 
                   
                 EGSGEGEGSEGG 
                   
               
               
                   
                 TGAAGGCTCTGAAGGATCTGGTGAAGGTTCGTCTTCAC 
                   
                 SEGEGSEGGSEGE 
                   
               
               
                   
                 TCGAGGGTACCAAAGACATCCAGATGACCCAGTCTCCT 
                   
                 GSEGSGEGEGSE 
                   
               
               
                   
                 TCCTCTCTGTCCGCGTCCGTGGGCGACCGTGTTACTATC 
                   
                 GSGEGSSSLEGTK 
                   
               
               
                   
                 ACCTGCTCCGCCTCCTCTTCTGTCAGCTACATGAACTGG 
                   
                 DIQMTQSPSSLSA 
                   
               
               
                   
                 TATCAGCAGACTCCTGGCAAAGCTCCAAAACGTTGGAT 
                   
                 SVGDRVTITCSAS 
                   
               
               
                   
                 TTACGATACGTCCAAGCTGGCCTCCGGCGTACCAAGCC 
                   
                 SSVSYMNWYQQ 
                   
               
               
                   
                 GTTTCTCTGGCTCTGGCAGCGGCACGGATTACACCTTCA 
                   
                 TPGKAPKRWIYD 
                   
               
               
                   
                 CTATTTCTAGCCTGCAGCCTGAAGATATTGCCACCTATT 
                   
                 TSKLASGVPSRFS 
                   
               
               
                   
                 ACTGCCAACAATGGTCCTCCAATCCTTTTACCTTTGGTC 
                   
                 GSGSGTDYTFTIS 
                   
               
               
                   
                 AGGGCACTAAGCTGCAGATTACTCGCACCGGTTCTGGC 
                   
                 SLQPEDIATYYCQ 
                   
               
               
                   
                 GAAGGCTCTGAAGGTGAAGGTGGTGGTGAAGGCTCTGA 
                   
                 QWSSNPFTFGQG 
                   
               
               
                   
                 AGGTGAAGGATCTGGTGAAGGTGGCGAAGGTGAGGGA 
                   
                 TKLQITRTGSGEG 
                   
               
               
                   
                 TCTGGTACCCAGGTCCAACTGGTTCAATCCGGCGGCGG 
                   
                 SEGEGGGEGSEG 
                   
               
               
                   
                 TGTAGTTCAACCGGGTCGCTCTCTGCGTCTTTCCTGCAA 
                   
                 EGSGEGGEGEGS 
                   
               
               
                   
                 GGCGTCCGGTTACACTTTCACGCGTTACACCATGCACTG 
                   
                 GTQVQLVQSGGG 
                   
               
               
                   
                 GGTCCGTCAGGCTCCTGGTAAAGGTCTGGAATGGATTG 
                   
                 VVQPGRSLRLSC 
                   
               
               
                   
                 GCTATATCAACCCGTCTCGCGGCTATACCAACTATAAC 
                   
                 KASGYTFTRYTM 
                   
               
               
                   
                 CAGAAATTCAAAGATCGTTTTACGATTTCCACTGATAA 
                   
                 HWVRQAPGKGL 
                   
               
               
                   
                 ATCCAAAAGCACCGCATTCCTCCAAATGGACAGCCTGC 
                   
                 EWIGYINPSRGYT 
                   
               
               
                   
                 GTCCGGAAGACACGGCGGTTTATTATTCCGCCCGTTACT 
                   
                 NYNQKFKDRFTIS 
                   
               
               
                   
                 ACGATGACCACTACTGCCTGGATTATTGGGGCCAAGGC 
                   
                 TDKSKSTAFLQM 
                   
               
               
                   
                 ACTCCAGTAACCGTGAGCAGCACTAGTGGCGGTTATCC 
                   
                 DSLRPEDTAVYY 
                   
               
               
                   
                 TTATGATGTTCCAGACTATGCAGGTGGCTCTCATCACCA 
                   
                 SARYYDDHYCLD 
                   
               
               
                   
                 TCACCATCACCACCATTGA 
                   
                 YWGQGTPVTVSS 
                   
               
               
                   
                   
                   
                 TSGGYPYDVPDY 
                   
               
               
                   
                   
                   
                 AGGSHHHHHHH 
                   
               
               
                   
                   
                   
                 H 
                   
               
               
                   
               
               
                 EGFR_V 
                 ATGAAAGGGTCTCCAGGTGAAGTACAGCTTCAAGAATC 
                 719 
                 MKGSPGEVQLQE 
                 744 
               
               
                 HH1- 
                 TGGTGGTGGTCTTGTCCAGGCGGGCGATTCCCTGCGCCT 
                   
                 SGGGLVQAGDSL 
                   
               
               
                 AM144- 
                 GTCTTGTCTGGTCTCTGGTCGTTCATTTAACAGCTATAC 
                   
                 RLSCLVSGRSFNS 
                   
               
               
                 GFP6~22 
                 CATGGGCTGGTTCCGCCAAGCACCGGGCAAGGAACGTG 
                   
                 YTMGWFRQAPG 
                   
               
               
                 9-H8, 
                 AATTCGTAGCAGCTATTCTCTGGTCCGGTCCTACGACCT 
                   
                 KEREFVAAILWS 
                   
               
               
                 LM5109. 
                 ACTATGCTGACTCTGTAAAAGGTCGCTTCACCATCTCCC 
                   
                 GPTTYYADSVKG 
                   
               
               
                 005 
                 GTGATAACGCCAAAAACACCGTATATCTTCAGATGAAC 
                   
                 RFTISRDNAKNTV 
                   
               
               
                   
                 TCTCTGAAACCGGAGGACACGGCCGTGTACTATTGTGC 
                   
                 YLQMNSLKPEDT 
                   
               
               
                   
                 CGCTGCGCTGGGTGTACTGGTGCTAGCGCCTGGTAATG 
                   
                 AVYYCAAALGV 
                   
               
               
                   
                 TCTACAGCTATTGGGGTCAAGGTACCCAGGTCACGGTA 
                   
                 LVLAPGNVYSYW 
                   
               
               
                   
                 AGCTCCGCGCATCATGGAGGTACCCCGGGCAGCGGTAC 
                   
                 GQGTQVTVSSAH 
                   
               
               
                   
                 CGCATCTTCCTCTCCAGGTAGCTCTACCCCGTCTGGTGC 
                   
                 HGGTPGSGTASSS 
                   
               
               
                   
                 TACCGGTTCCCCAGGTAGCTCTACCCCGTCTGGTGCAAC 
                   
                 PGSSTPSGATGSP 
                   
               
               
                   
                 CGGCTCCCCAGGTAGCCCGGCTGGCTCTCCTACCTCTAC 
                   
                 GSSTPSGATGSPG 
                   
               
               
                   
                 TGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTG 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 GTCCAGGTACCTCTACTGAACCGTCCGAAGGTAGCGCT 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 CCAGGTTCTAGCCCTTCTGCATCCACCGGTACCGGCCCA 
                   
                 TEPSEGSAPGSSP 
                   
               
               
                   
                 GGTTCTAGCCCGTCTGCTTCTACCGGTACTGGTCCAGGT 
                   
                 SASTGTGPGSSPS 
                   
               
               
                   
                 GCTTCTCCGGGTACTAGCTCTACTGGTTCTCCAGGTACC 
                   
                 ASTGTGPGASPG 
                   
               
               
                   
                 TCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTC 
                   
                 TSSTGSPGTSTEP 
                   
               
               
                   
                 TACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAAC 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 CGGCAACCTCCGGTTCTGAAACTCCAGGTTCGTCTTCAC 
                   
                 EGSAPGSEPATSG 
                   
               
               
                   
                 TCGAGGGTACCGAACTTTTCACTGGAGTTGTCCCAATTC 
                   
                 SETPGSSSLEGIL 
                   
               
               
                   
                 TTGTTGAATTAGATGGTGATGTTAATGGGCACAAATTTT 
                   
                 LFTGVVPILVELD 
                   
               
               
                   
                 CTGTCAGTGGAGAGGGTGAAGGTGATGCAACATACGG 
                   
                 GDVNGHKFSVSG 
                   
               
               
                   
                 AAAACTTACCCTTAAATTTATTTGCACTACTGGAAAACT 
                   
                 EGEGDATYGKLT 
                   
               
               
                   
                 ACCTGTTCCATGGCCAACACTTGTCACTACTTTCTCTTA 
                   
                 LKFICTTGKLPVP 
                   
               
               
                   
                 TGGTGTTCAATGCTTTTCCCGTTATCCGGATCACATGAA 
                   
                 WPTLVTTFSYGV 
                   
               
               
                   
                 ACGGCATGACTTTTTCAAGAGTGCCATGCCCGAAGGTT 
                   
                 QCFSRYPDHMKR 
                   
               
               
                   
                 ATGTACAGGAACGCACTATATCTTTCAAAGATGACGGG 
                   
                 HDFFKSAMPEGY 
                   
               
               
                   
                 AACTACAAGACGCGTGCTGAAGTCAAGTTTGAAGGTGA 
                   
                 VQERTISFKDDG 
                   
               
               
                   
                 TACCCTTGTTAATCGTATCGAGTTAAAAGGTATTGATTT 
                   
                 NYKTRAEVKFEG 
                   
               
               
                   
                 TAAAGAAGATGGAAACATTCTCGGACACAAACTCGAGT 
                   
                 DTLVNRIELKGID 
                   
               
               
                   
                 ACAACTATAACTCACACAATGTATACATCACGGCAGAC 
                   
                 FKEDGNILGHKL 
                   
               
               
                   
                 AAACAAAAGAATGGAATCAAAGCTAACTTCAAAATTCG 
                   
                 EYNYNSHNVYIT 
                   
               
               
                   
                 CCACAACATTGAAGATGGATCCGTTCAACTAGCAGACC 
                   
                 ADKQKNGIKANF 
                   
               
               
                   
                 ATTATCAACAAAATACTCCAATTGGCGATGGCCCTGTC 
                   
                 KIRHNIEDGSVQL 
                   
               
               
                   
                 CTTTTACCAGACAACCATTACCTGTCGACACAATCTGCC 
                   
                 ADHYQQNTPIGD 
                   
               
               
                   
                 CTTTCGAAAGATCCCAACGAAAAGCGTGACCACATGGT 
                   
                 GPVLLPDNHYLS 
                   
               
               
                   
                 CCTTCTTGAGTTTGTAACTGCTGCTGGGATTGGTGGCTC 
                   
                 TQSALSKDPNEK 
                   
               
               
                   
                 TCATCACCATCACCATCACCATCACTAA 
                   
                 RDHMVLLEFVTA 
                   
               
               
                   
                   
                   
                 AGIGGSHHHHHH 
                   
               
               
                   
                   
                   
                 HH 
                   
               
               
                   
               
               
                 EGFR_V 
                 ATGAAAGGGTCTCCAGGTGAAGTGCAGCTTCAAgAATC 
                 720 
                 MKGSPGEVQLQE 
                 745 
               
               
                 HH1- 
                 TGGTGGTGGTCTGGTACAAGCCGGTGATTCTCTGCGCCT 
                   
                 SGGGLVQAGDSL 
                   
               
               
                 AM144- 
                 GTCTTGTCTGGTCTCCGGTCGCTCTTTTAACAGCTATAC 
                   
                 RLSCLVSGRSFNS 
                   
               
               
                 GFP6~22 
                 CATGGGCTGGTTCCGCCAGGCACCAGGCAAAGAGCGTG 
                   
                 YTMGWFRQAPG 
                   
               
               
                 9-H8, 
                 AATTCGTAGCAGCTATCCTGTGGTCTGGTCCGACTACCT 
                   
                 KEREFVAAILWS 
                   
               
               
                 LMS109. 
                 ACTATGCTGACTCTGTAAAGGGTCGCTTCACGATTTCCC 
                   
                 GPTTYYADSVKG 
                   
               
               
                 020 
                 GTGATAACGCCAAAAACACGGTGTATCTACAAATGAAT 
                   
                 RFTISRDNAKNTV 
                   
               
               
                   
                 TCTCTGAAACCGGAGGACACTGCCGTTTACTATTGTGCC 
                   
                 YLQMNSLKPEDT 
                   
               
               
                   
                 GCTGCGCTGGGTGTACTGGTGCTTGCCCCTGGTAATGTA 
                   
                 AVYYCAAALGV 
                   
               
               
                   
                 TACAGCTATTGGGGTCAAGGTACGCAAGTTACCGTGAG 
                   
                 LVLAPGNVYSYW 
                   
               
               
                   
                 CTCTGCGCATCATGGAGGTACTTCTACCGAACCGTCCG 
                   
                 GQGTQVTVSSAH 
                   
               
               
                   
                 AGGGCAGCGCTCCAGGTACTTCTACTGAACCTTCTGAA 
                   
                 HGGTSTEPSEGSA 
                   
               
               
                   
                 GGCAGCGCTCCAGGTACTTCTACTGAACCTTCCGAAGG 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 TAGCGCACCAGGTTCTACCAGCGAATCCCCTTCTGGTA 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 CTGCTCCAGGTTCTACCAGCGAATCCCCTTCTGGCACCG 
                   
                 STSESPSGTAPGS 
                   
               
               
                   
                 CACCAGGTACTTCTACCCCTGAAAGCGGCTCCGCTTCTC 
                   
                 TSESPSGTAPGTS 
                   
               
               
                   
                 CAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCA 
                   
                 TPESGSASPGSEP 
                   
               
               
                   
                 GGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGG 
                   
                 ATSGSETPGTSES 
                   
               
               
                   
                 TACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTA 
                   
                 ATPESGPGTSTEP 
                   
               
               
                   
                 CTTCTACTGAACCGTCTGAAGGTAGCGCACCAGGTACT 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 TCTGAAAGCGCAACCCCGGAATCCGGCCCAGGTACCTC 
                   
                 EGSAPGTSESATP 
                   
               
               
                   
                 TGAAAGCGCAACCCCGGAGTCCGGCCCAGGTTCGTCTT 
                   
                 ESGPGTSESATPE 
                   
               
               
                   
                 CACTCGAGGGTACCGAACTTTTCACTGGAGTTGTCCCA 
                   
                 SGPGSSSLEGILL 
                   
               
               
                   
                 ATTCTTGTTGAATTAGATGGTGATGTTAATGGGCACAA 
                   
                 FTGVVPILVELDG 
                   
               
               
                   
                 ATTTTCTGTCAGTGGAGAGGGTGAAGGTGATGCAACAT 
                   
                 DVNGHKFSVSGE 
                   
               
               
                   
                 ACGGAAAACTTACCCTTAAATTTATTTGCACTACTGGA 
                   
                 GEGDATYGKLTL 
                   
               
               
                   
                 AAACTACCTGTTCCATGGCCAACACTTGTCACTACTTTC 
                   
                 KFICTTGKLPVPW 
                   
               
               
                   
                 TCTTATGGTGTTCAATGCTTTTCCCGTTATCCGGATCAC 
                   
                 PTLVTTFSYGVQ 
                   
               
               
                   
                 ATGAAACGGCATGACTTTTTCAAGAGTGCCATGCCCGA 
                   
                 CFSRYPDHMKRH 
                   
               
               
                   
                 AGGTTATGTACAGGAACGCACTATATCTTTCAAAGATG 
                   
                 DFFKSAMPEGYV 
                   
               
               
                   
                 ACGGGAACTACAAGACGCGTGCTGAAGTCAAGTTTGAA 
                   
                 QERTISFKDDGN 
                   
               
               
                   
                 GGTGATACCCTTGTTAATCGTATCGAGTTAAAAGGTATT 
                   
                 YKTRAEVKFEGD 
                   
               
               
                   
                 GATTTTAAAGAAGATGGAAACATTCTCGGACACAAACT 
                   
                 TLVNRIELKGIDF 
                   
               
               
                   
                 CGAGTACAACTATAACTCACACAATGTATACATCACGG 
                   
                 KEDGNILGHKLE 
                   
               
               
                   
                 CAGACAAACAAAAGAATGGAATCAAAGCTAACTTCAA 
                   
                 YNYNSHNVYITA 
                   
               
               
                   
                 AATTCGCCACAACATTGAAGATGGATCCGTTCAACTAG 
                   
                 DKQKNGIKANFK 
                   
               
               
                   
                 CAGACCATTATCAACAAAATACTCCAATTGGCGATGGC 
                   
                 IRHNIEDGSVQLA 
                   
               
               
                   
                 CCTGTCCTTTTACCAGACAACCATTACCTGTCGACACAA 
                   
                 DHYQQNTPIGDG 
                   
               
               
                   
                 TCTGCCCTTTCGAAAGATCCCAACGAAAAGCGTGACCA 
                   
                 PVLLPDNHYLST 
                   
               
               
                   
                 CATGGTCCTTCTTGAGTTTGTAACTGCTGCTGGGATTGG 
                   
                 QSALSKDPNEKR 
                   
               
               
                   
                 TGGCTCTCATCACCATCACCATCACCATCACTAA 
                   
                 DHMVLLEFVTAA 
                   
               
               
                   
                   
                   
                 GIGGSHHHHHHH 
                   
               
               
                   
                   
                   
                 H 
                   
               
               
                   
               
               
                 EGFR_V 
                 ATGAAAGGGTCTCCAGGTGAGGTTCAACTTCaAgAATCT 
                 721 
                 MKGSPGEVQLQE 
                 746 
               
               
                 HH1- 
                 GGTGGTGGTCTAGTACAAGCCGGCGACTCCCTGCGCCT 
                   
                 SGGGLVQAGDSL 
                   
               
               
                 AM144- 
                 GTCTTGTCTGGTCTCCGGTCGTTCTTTTAACAGCTATAC 
                   
                 RLSCLVSGRSFNS 
                   
               
               
                 GFP6~22 
                 CATGGGCTGGTTCCGCCAAGCTCCGGGCAAAGAACGTG 
                   
                 YTMGWFRQAPG 
                   
               
               
                 9-H8, 
                 AATTCGTAGCAGCTATTCTCTGGTCTGGTCCTACCACCT 
                   
                 KEREFVAAILWS 
                   
               
               
                 LMS109. 
                 ACTATGCTGACTCTGTAAAGGGCCGTTTCACTATCTCCC 
                   
                 GPTTYYADSVKG 
                   
               
               
                 038 
                 GTGATAACGCCAAAAACACTGTCTATCTGCAGATGAAT 
                   
                 RFTISRDNAKNTV 
                   
               
               
                   
                 TCTCTGAAACCGGAGGACACCGCAGTATACTATTGCGC 
                   
                 YLQMNSLKPEDT 
                   
               
               
                   
                 AGCTGCGCTGGGTGTACTGGTGCTCGCTCCAGGTAATG 
                   
                 AVYYCAAALGV 
                   
               
               
                   
                 TATACAGCTATTGGGGTCAAGGTACGCAAGTCACGGTA 
                   
                 LVLAPGNVYSYW 
                   
               
               
                   
                 AGCTCTGCGCATCATGGAGGTACCCCGGGCAGCGGTAC 
                   
                 GQGTQVTVSSAH 
                   
               
               
                   
                 CGCATCTTCCTCTCCAGGTAGCTCTACCCCGTCTGGTGC 
                   
                 HGGTPGSGTASSS 
                   
               
               
                   
                 TACCGGTTCCCCAGGTAGCTCTACCCCGTCTGGTGCAAC 
                   
                 PGSSTPSGATGSP 
                   
               
               
                   
                 CGGCTCCCCAGGTAGCCCGGCTGGCTCTCCTACCTCTAC 
                   
                 GSSTPSGATGSPG 
                   
               
               
                   
                 TGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTG 
                   
                 SPAGSPTSTEEGT 
                   
               
               
                   
                 GTCCAGGTACCTCTACTGAACCGTCCGAAGGTAGCGCT 
                   
                 SESATPESGPGTS 
                   
               
               
                   
                 CCAGGTTCTAGCCCTTCTGCATCCACCGGTACCGGCCCA 
                   
                 TEPSEGSAPGSSP 
                   
               
               
                   
                 GGTTCTAGCCCGTCTGCTTCTACCGGTACTGGTCCAGGT 
                   
                 SASTGTGPGSSPS 
                   
               
               
                   
                 GCTTCTCCGGGTACTAGCTCTACTGGTTCTCCAGGTACC 
                   
                 ASTGTGPGASPG 
                   
               
               
                   
                 TCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTC 
                   
                 TSSTGSPGTSTEP 
                   
               
               
                   
                 TACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAAC 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 CGGCAACCTCCGGTTCTGAAACTCCAGGTTCGTCTTCAC 
                   
                 EGSAPGSEPATSG 
                   
               
               
                   
                 TCGAGGGTACCGAACTTTTCACTGGAGTTGTCCCAATTC 
                   
                 SETPGSSSLEGTE 
                   
               
               
                   
                 TTGTTGAATTAGATGGTGATGTTAATGGGCACAAATTTT 
                   
                 LFTGVVPILVELD 
                   
               
               
                   
                 CTGTCAGTGGAGAGGGTGAAGGTGATGCAACATACGG 
                   
                 GDVNGHKFSVSG 
                   
               
               
                   
                 AAAACTTACCCTTAAATTTATTTGCACTACTGGAAAACT 
                   
                 EGEGDATYGKLT 
                   
               
               
                   
                 ACCTGTTCCATGGCCAACACTTGTCACTACTTTCTCTTA 
                   
                 LKFICTTGKLPVP 
                   
               
               
                   
                 TGGTGTTCAATGCTTTTCCCGTTATCCGGATCACATGAA 
                   
                 WPTLVTTFSYGV 
                   
               
               
                   
                 ACGGCATGACTTTTTCAAGAGTGCCATGCCCGAAGGTT 
                   
                 QCFSRYPDHMKR 
                   
               
               
                   
                 ATGTACAGGAACGCACTATATCTTTCAAAGATGACGGG 
                   
                 HDFFKSAMPEGY 
                   
               
               
                   
                 AACTACAAGACGCGTGCTGAAGTCAAGTTTGAAGGTGA 
                   
                 VQERTISFKDDG 
                   
               
               
                   
                 TACCCTTGTTAATCGTATCGAGTTAAAAGGTATTGATTT 
                   
                 NYKTRAEVKFEG 
                   
               
               
                   
                 TAAAGAAGATGGAAACATTCTCGGACACAAACTCGAGT 
                   
                 DTLVNRIELKGID 
                   
               
               
                   
                 ACAACTATAACTCACACAATGTATACATCACGGCAGAC 
                   
                 FKEDGNILGHKL 
                   
               
               
                   
                 AAACAAAAGAATGGAATCAAAGCTAACTTCAAAATTCG 
                   
                 EYNYNSHNVYIT 
                   
               
               
                   
                 CCACAACATTGAAGATGGATCCGTTCAACTAGCAGACC 
                   
                 ADKQKNGIKANF 
                   
               
               
                   
                 ATTATCAACAAAATACTCCAATTGGCGATGGCCCTGTC 
                   
                 KIRHNIEDGSVQL 
                   
               
               
                   
                 CTTTTACCAGACAACCATTACCTGTCGACACAATCTGCC 
                   
                 ADHYQQNTPIGD 
                   
               
               
                   
                 CTTTCGAAAGATCCCAACGAAAAGCGTGACCACATGGT 
                   
                 GPVLLPDNHYLS 
                   
               
               
                   
                 CCTTCTTGAGTTTGTAACTGCTGCTGGGATTGGTGGCTC 
                   
                 TQSALSKDPNEK 
                   
               
               
                   
                 TCATCACCATCACCATCACCATCACTAA 
                   
                 RDHMVLLEFVTA 
                   
               
               
                   
                   
                   
                 AGIGGSHHHHHH 
                   
               
               
                   
                   
                   
                 HH 
                   
               
               
                   
               
               
                 EGFR_V 
                 ATGAAAGGGTCTCCAGGTGAAGTGCAACttcaAgAATCTG 
                 722 
                 MKGSPGEVQLQE 
                 747 
               
               
                 HH1- 
                 GTGGTGGTCTGGTACAAGCTGGTGACTCTCTGCGCCTGT 
                   
                 SGGGLVQAGDSL 
                   
               
               
                 AM144- 
                 CTTGTCTGGTCTCCGGTCGTTCCTTCAATAGCTATACCA 
                   
                 RLSCLVSGRSFNS 
                   
               
               
                 GFP6~22 
                 TGGGCTGGTTCCGCCAAGCGCCTGGCAAAGAGCGTGAA 
                   
                 YTMGWFRQAPG 
                   
               
               
                 9-H8, 
                 TTCGTAGCAGCAATCCTTTGGTCCGGTCCAACTACCTAC 
                   
                 KEREFVAAILWS 
                   
               
               
                 LMS109. 
                 TATGCTGACTCTGTAAAAGGTCGCTTCACCATCTCCCGT 
                   
                 GPTTYYADSVKG 
                   
               
               
                 045 
                 GATAACGCCAAAAACACTGTTTATCTACAAATGAATTC 
                   
                 RFTISRDNAKNTV 
                   
               
               
                   
                 TCTGAAACCGGAGGACACGGCTGTTTACTACTGTGCTG 
                   
                 YLQMNSLKPEDT 
                   
               
               
                   
                 CCGCGCTGGGTGTACTGGTGCTCGCACCAGGTAATGTG 
                   
                 AVYYCAAALGV 
                   
               
               
                   
                 TACAGCTATTGGGGTCAAGGTACCCAGGTGACGGTCAG 
                   
                 LVLAPGNVYSYW 
                   
               
               
                   
                 CTCTGCGCATCATGGAGGTAGCCCGGCAGGCTCTCCGA 
                   
                 GQGTQVTVSSAH 
                   
               
               
                   
                 CCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCG 
                   
                 HGGSPAGSPTSTE 
                   
               
               
                   
                 GAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGG 
                   
                 EGTSESATPESGP 
                   
               
               
                   
                 CAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAAT 
                   
                 GTSTEPSEGSAPG 
                   
               
               
                   
                 CCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAG 
                   
                 TSESATPESGPGS 
                   
               
               
                   
                 ACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGC 
                   
                 EPATSGSETPGTS 
                   
               
               
                   
                 ACCAGGTAGCCCGGCTGGTTCTCCGACTTCCACCGAGG 
                   
                 TEPSEGSAPGSPA 
                   
               
               
                   
                 AAGGTACCTCTACTGAACCTTCTGAGGGTAGCGCTCCA 
                   
                 GSPTSTEEGTSTE 
                   
               
               
                   
                 GGTACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGG 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 TACTTCTACCGAACCGTCCGAGGGCAGCGCTCCAGGTA 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 CTTCTACTGAACCTTCTGAAGGCAGCGCTCCAGGTACTT 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 CTACTGAACCTTCCGAAGGTAGCGCACCAGGTTCGTCT 
                   
                 GSAPGTSTEPSEG 
                   
               
               
                   
                 TCACTCGAGGGTACCGAACTTTTCACTGGAGTTGTCCCA 
                   
                 SAPGSSSLEGTEL 
                   
               
               
                   
                 ATTCTTGTTGAATTAGATGGTGATGTTAATGGGCACAA 
                   
                 FTGVVPILVELDG 
                   
               
               
                   
                 ATTTTCTGTCAGTGGAGAGGGTGAAGGTGATGCAACAT 
                   
                 DVNGHKFSVSGE 
                   
               
               
                   
                 ACGGAAAACTTACCCTTAAATTTATTTGCACTACTGGA 
                   
                 GEGDATYGKLTL 
                   
               
               
                   
                 AAACTACCTGTTCCATGGCCAACACTTGTCACTACTTTC 
                   
                 KFICTTGKLPVPW 
                   
               
               
                   
                 TCTTATGGTGTTCAATGCTTTTCCCGTTATCCGGATCAC 
                   
                 PTLVTTFSYGVQ 
                   
               
               
                   
                 ATGAAACGGCATGACTTTTTCAAGAGTGCCATGCCCGA 
                   
                 CFSRYPDHMKRH 
                   
               
               
                   
                 AGGTTATGTACAGGAACGCACTATATCTTTCAAAGATG 
                   
                 DFFKSAMPEGYV 
                   
               
               
                   
                 ACGGGAACTACAAGACGCGTGCTGAAGTCAAGTTTGAA 
                   
                 QERTISFKDDGN 
                   
               
               
                   
                 GGTGATACCCTTGTTAATCGTATCGAGTTAAAAGGTATT 
                   
                 YKTRAEVKFEGD 
                   
               
               
                   
                 GATTTTAAAGAAGATGGAAACATTCTCGGACACAAACT 
                   
                 TLVNRIELKGIDF 
                   
               
               
                   
                 CGAGTACAACTATAACTCACACAATGTATACATCACGG 
                   
                 KEDGNILGHKLE 
                   
               
               
                   
                 CAGACAAACAAAAGAATGGAATCAAAGCTAACTTCAA 
                   
                 YNYNSHNVYITA 
                   
               
               
                   
                 AATTCGCCACAACATTGAAGATGGATCCGTTCAACTAG 
                   
                 DKQKNGIKANFK 
                   
               
               
                   
                 CAGACCATTATCAACAAAATACTCCAATTGGCGATGGC 
                   
                 IRHNIEDGSVQLA 
                   
               
               
                   
                 CCTGTCCTTTTACCAGACAACCATTACCTGTCGACACAA 
                   
                 DHYQQNTPIGDG 
                   
               
               
                   
                 TCTGCCCTTTCGAAAGATCCCAACGAAAAGCGTGACCA 
                   
                 PVLLPDNHYLST 
                   
               
               
                   
                 CATGGTCCTTCTTGAGTTTGTAACTGCTGCTGGGATTGG 
                   
                 QSALSKDPNEKR 
                   
               
               
                   
                 TGGCTCTCATCACCATCACCATCACCATCACTAA 
                   
                 DHMVLLEFVTAA 
                   
               
               
                   
                   
                   
                 GIGGSHHHHHHH 
                   
               
               
                   
                   
                   
                 H 
               
               
                   
               
            
           
         
       
     
     Example 26: Purification of aIL6R-XTEN 
       E. coli  from a single colony containing either: AC341, AC342, AC361, or AC362 were grown to saturation in 2×YT media. 10 mL of this saturated overnight culture was used to inoculate a 500 ml of 2×YT media and this culture was grown to an OD600 between 0.4 and 0.5 at 37° C., transferred to 26° C. and induced with 1 mM IPTG. The culture was then grown overnight (15-17 hours) and harvested by centrifugation at 10,000 rpm in a Sorvall SLA-3000 rotor. The pellets were stored until use at −80° C. Cell paste was resuspended in 25 ml of lysis buffer (20 mM sodium acetate, 50 mM sodium chloride, pH 4.5), lysed by sonication, and clarified by spinning at 10,000 rpm at 4° C. in a Sorvall SS34 rotor. The samples were further acidified by the addition of acetic acid. The sample was further clarified by centrifugation and the supernatant loaded onto a 15 mL DE52 column equilibrated with 20 mM sodium acetate, 50 mM sodium chloride, pH 4.5. The column was washed with 2 columns volumes of 20 mM sodium acetate, 50 mM sodium chloride, pH 4.5, washed with four columns volumes of 20 mM sodium acetate, 100 mM sodium chloride, pH 4.5, and eluted with four columns volumes of 20 mM sodium acetate, 150 mM sodium chloride, pH 4.5. Sodium sulfate was added to the elution fractions to a final concentration of 1M and the sample loaded onto a phenyl HIC column. The column was washed with five column volumes of 20 mM sodium acetate, 1M sodium sulfate pH 4.5, and eluted with four column volumes of 20 mM sodium acetate, 0.5M sodium sulfate pH 4.5. The samples were exchanged in to assay buffer, assigned lots numbers AP342, AP343, AP344 and AP345 and stored frozen at −80° C. 
     Example 27: Purification of aHER2-XTEN-GFP 
     AC62 was grown to saturation overnight in 2×YT+kanamycin. Two 500 mL flasks of 2×YT were inoculated with 3 ml of this saturated overnight and grown to an OD600 of −0.8 at 37° C. The culture was brought to 25° C. and then induced with 1 mM IPTG. The culture was induced overnight. The cell pellet was harvested by centrifugation at 5000 rpm, in a Sorvall SLA-3000 at 4° C. as pellet EP52. The cell pellet was then resuspended in 30 mM Tris pH 8.0, 500 mM NaCl, 20 mM imidazole. The cells were lysed by sonication and then clarified by centrifugation at 15,000 rpm in a Sorvall SS34 rotor. The supernatant was loaded onto a 5 ml Ni-NTA column, washed with 20 column volumes of 30 mM Tris pH 8.0, 500 mM NaCl, 20 mM imidazole, and eluted with 30 mM Tris pH 8.0, 500 mM NaCl, 600 mM imidazole. The elution fractions were diluted 1:2 with 20 mM histidine pH 5.6, and loaded onto an anion exchange column equilibrated with 20 mM histidine pH 5.6. The column was washed with 20 mM histidine pH 5.6, 20 column volumes of 20 mM histidine pH 5.6, 150 mM NaCl, 20 column volumes of 20 mM histidine pH 5.6, 300 mM NaCl, and then eluted with 20 mM histidine pH 5.6, 600 mM NaCl. This protein was assigned lot # AP60 and stored frozen. 
     Example 28: Purification of aCD3-XTEN-GFP 
     AC50 was grown to saturation overnight in 2×YT+kanamycin. A 500 mL flask of 2×YT was inoculated with 3 ml of this saturated overnight and grown to an OD600 of ˜0.8 at 37° C. The culture was brought to 25° C. and then induced with 0.2 mM IPTG. The culture was induced overnight. The cell pellet was harvested by centrifugation at 5000 rpm, in a Sorvall SLA-3000 at 4° C. The cell pellet was then resuspended in 30 mM Tris pH 8.0, 500 mM NaCl, 20 mM imidazole. The cells were lysed by sonication and then clarified by centrifugation at 15,000 rpm in a Sorvall SS34 rotor. The supernatant was loaded onto Ni-NTA column, washed with 10 column volumes of 30 mM Tris pH 8.0, 500 mM NaCl, 20 mM imidazole, and eluted with 30 mM Tris pH 8.0, 500 mM NaCl, 600 mM imidazole. This protein was assigned lot # AP43. 
     Example 29: Purification of aHER2-XTEN-aEGFR 
     AC49 was grown to saturation overnight in 2×YT+kanamycin. A 500 mL flask of 2×YT was inoculated with 3 ml of this saturated overnight and grown to an OD600 of −0.8 at 37° C. The culture was brought to 25° C. and then induced with 0.2 mM IPTG. The culture was induced overnight. The cell pellet was harvested by centrifugation at 5000 rpm, in a Sorvall SLA-3000 at 4° C. as pellet EP36. The cell pellet was then resuspended in 30 mM Tris pH 8.0, 500 mM NaCl, 20 mM imidazole. The cells were lysed by sonication and then clarified by centrifugation at 15,000 rpm in a Sorvall SS34 rotor. The supernatant was loaded onto a 5 ml Ni-NTA column, washed with 10 column volumes of 30 mM Tris pH 8.0, 500 mM NaCl, 20 mM imidazole, and eluted with 30 mM Tris pH 8.0, 500 mM NaCl, 600 mM imidazole. The elution fractions were diluted 1:3 with 20 mM histidine pH 5.6, and loaded onto a 1 mL DEAE column equilibrated with 20 mM histidine pH 5.6, 200 mM NaCl. The column was washed with five column volumes of 20 mM histidine pH 5.6, 400 mM NaCl and five column volumes of 20 mM histidine pH 5.6, 600 mM NaCl, and then eluted with 20 mM histidine pH 5.6, 700 mM NaCl. This protein was assigned lot # AP41. The final purified aHER2-XTEN-aEGFR protein were subjected to non-reducing SDS-PAGE using NuPAGE 4-12% Bis-Tris gel from Invitrogen according to manufacturer&#39;s specifications. The results, as shown in Lane 3 of FIG. 17B (compared to aHER2-XTEN-aHER2-XTEN in Lane 2) demonstrate that the protein was recovered at &gt;95% purity by the process detailed above. Results of SEC analysis of the purified material, performed as described in Example 36, are shown in  FIG. 17C , and demonstrate that the binding fusion protein was recovered in monomeric form and has an apparent molecular weight of approximately 500 kDa, far in excess of its actual molecular weight. 
     Example 30: Purification of aCD3-XTEN-aHER2 
     AC59 was grown to saturation overnight in 2×YT+kanamycin. A 10 L culture of 2×YT in wavebag was inoculated with this saturated overnight and grown to an OD600 of 1.3 at 37° C. The culture was brought to 25° C. and then induced with 1 mM IPTG. The culture was induced overnight. The cell pellet was harvested by centrifugation at 5000 rpm, in a Sorvall SLA-3000 at 4° C. and stored as pellet EP50. The cell pellet was then resuspended in 20 mM Tris pH 8.0, 50 mM NaCl, plus Roche complete protease inhibitors. The cells were lysed by sonication and then clarified by centrifugation at 15,000 rpm in a Sorvall SSR-15 rotor. The supernatant was loaded onto a 60 ml Ni-NTA column, washed with 11 column volumes of 20 mM Tris pH 8.0, 50 mM NaCl; 10 column volumes of 20 mM Tris pH 8.0, 500 mM NaCl; 10 column volumes of 20 mM Tris pH 8.0, 1% triton X-114; 10 column volumes of 20 mM Tris pH 8.0, 5 mM imidazole; 10 column volumes of 20 mM Tris pH 8.0, 50 mM NaCl, 10 mM imidazole, and eluted with 20 mM Tris pH 8.0, 50 mM NaCl, 200 mM imidazole. The elution fractions were diluted with 20 mM histidine pH 6.2, and triton-X114 extracted to remove endotoxin as follows: bring to 5% detergent on ice, warm to 37° C. to cloud, phase separate by centrifugation at room temp at 3000 rpm in a Sorvall bench top centrifuge, transfer top aqueous phase, repeat process 3 times. The final aqueous layer was diluted with 20 mM histidine pH 6.2 and loaded onto a 7.5 mL Q-sepharose FF column equilibrated with 20 mM histidine pH 6.2, 20 mM NaCl. The column was washed with 11 column volumes of 20 mM histidine pH 6.2, 20 mM NaCl, 10 column volumes of 20 mM histidine pH 6.2, 50 mM NaCl, and 10 column volumes of 20 mM histidine pH 6.2, 100 mM NaCl, then eluted with 20 mM histidine pH 5.6, 600 mM NaCl. The protein was then further purified by running a mono-Q column on an AKTA purifier system. The column and system were sanitized with 10 column volumes of 0.5 NaOH and the protein loaded in 20 mM histidine pH 6.0 and eluted with a linear salt gradient. The viable fractions were pooled and triton extracted as above, to further reduce endotoxin. This protein was assigned lot # AP58. 
     Example 31: Purification of aHER2-XTEN-aHER2 
     AC47 was grown to saturation overnight in 2×YT+kanamycin. A 500 mL flask of 2×YT was inoculated with 3 ml of this saturated overnight and grown to an OD600 of −0.8 at 37° C. The culture was brought to 25° C. and then induced with 1 mM IPTG. The culture was induced overnight. The cell pellet was harvested by centrifugation at 5000 rpm, in a Sorvall SLA-3000 at 4° C. and stored as EP35. The cell pellet was then resuspended in 30 mM Tris pH 8.0, 500 mM NaCl, 20 mM imidazole. The cells were lysed by sonication and then clarified by centrifugation at 15,000 rpm in a Sorvall SS34 rotor. The supernatant was loaded onto a 5 ml Ni-NTA column, washed with 10 column volumes of 30 mM Tris pH 8.0, 500 mM NaCl, 20 mM imidazole, and eluted with 30 mM Tris pH 8.0, 500 mM NaCl, 600 mM imidazole. The elution fractions were diluted 1:3 with 20 mM histidine pH 5.6, and loaded onto a 1 mL DEAE column equilibrated with 20 mM histidine pH 5.6, 200 mM NaCl. The column was washed with five column volumes of 20 mM histidine pH 5.6, 400 mM NaCl and five column volumes of 20 mM histidine pH 5.6, 600 mM NaCl, and then eluted with 20 mM histidine pH 5.6, 700 mM NaCl. This protein was assigned lot # AP40. 
     Example 32: Purification of Multivalent aEGFR Vhh Binders 
     Protein from constructs LCW501.001, LCW502.009, LCW503.004, LCW504.004, and LCW505.002 were expressed as follows: Nine 96 well plates with 0.5 ml in each well were grown for each construct. Plates were filled by inoculating 40 ml of saturated overnight in SB into 1 L of auto induction media and then using the Q-fill to load the plates. The samples were sealed with a breathable membrane and then placed at 26 C overnight shaking at 300 rpm. The plates were then pooled into one large bucket and poured into a single centrifuge bottle for harvesting. The cultures were spun at 10,000 rpm in the Sorvall RC-5B centrifuge for 20 mins (GS-3 rotor) to pellet the cells. Approximately 15 g of cell mass was obtained. The cells were resuspended in lysis buffer (20 mM phosphate pH 7.4, 500 mM NaCl, 5 mM imidazole, 0.5 mM EDTA and 1 complete Roche protease mini tablet per 10 ml). The samples were then lysed by sonication (5×20 seconds on, 40 seconds off at power setting 8 with the large probe). The samples were kept on ice, but still warmed to ˜25 during the process. The lysates were then spun at 15,000 rpm in the SS-34 rotor using a Sorvall RC-5B centrifuge to clarify. 
     2 mL Ni-NTA columns were equilibrated in 10 CV&#39;s of lysis buffer and then the lysates from LCW503, LCW504 and LCW505 were loaded. The columns were washed with 10 CV&#39;s of lysis buffer, 3 CV&#39;s of PBS+5 mM imidazole to reduce salt, and then were eluted with PBS+300 mM imidazole. The elution was tracked by GFP such that all of the fluorescence was captured in on fraction. The elutions were held overnight. The following day 3×3 ml (LCW503, LCW504, LCW505) and 2×5 ml (LCW501 and LCW502) Ni-NTA columns were equilibrated in 10 CV&#39;s of lysis buffer and then the lysates from LCW503, LCW504 and LCW505 were loaded. The columns were washed with 50 ml of lysis buffer, 15 ml of PBS+5 mM imidazole to reduce salt, and then were eluted with PBS+300 mM imidazole. The elution was tracked by GFP such that all of the fluorescence was captured in on fraction. The elutions from day one for 503, 504 and 505 were pooled with the second day elutions. 
     The samples were then purified with anion exchange chromatography. A 1 ml mono Q column was used for all of the preps. Buffer A was always 20 mM Tris pH 8.0 and buffer B was always 20 mM Tris pH 8.0 and 1M NaCl. The AKTA purifier system was used with a 10 ml super loop. All runs involved loading with 12 ml injection (regardless of sample volume), washing with 2 CV&#39;s of buffer A, a gradient to 50% B over 20 CV&#39;s, and finally Then a 5 CV washout with 100% B. The column was then re-equilibrated with buffer A between runs. The super loop was disassembled and clean and the tubing flushed to avoid carry over between runs. The fractions were pooled and stored overnight at 4C. The next day the samples concentrated in an Amicon ultra 30,000 MWCO concentrator at 4000 rpm in the Sorvall T21. The concentrated sample was loaded on gel filtration columns. The columns were TSK3000 for LCW501 and LCW502 and TSK4000 for LCW503, LCW504 and LCW505. Fractions were pooled, concentrated and frozen for storage at −80° C. 
     Example 33: Characterization of aIL6R-XTEN 
       E. coli  from a single colony of AC342 was grown to saturation in 2×YT media. 10 mL of this saturated overnight culture was used to inoculate a 500 ml of 2×YT media and this culture was grown to an OD600 between 0.4 and 0.5 at 37° C., transferred to 26° C. and induced with 1 mM IPTG. The culture was then grown overnight (15-17 hours) and harvested by centrifugation at 10,000 rpm in a Sorvall SLA-3000 rotor. The pellets were stored until use at −80° C. Cell paste was resuspended in 25 ml of lysis buffer (20 mM sodium acetate, 50 mM sodium chloride, pH 4.5), lysed by sonication, and clarified by spinning at 10,000 rpm at 4° C. in a Sorvall SS34 rotor. The samples were further acidified by the addition of acetic acid. The sample was further clarified by centrifugation and the supernatant loaded onto a 15 mL DE52 column equilibrated with 20 mM sodium acetate, 50 mM sodium chloride, pH 4.5. The column was washed with 2 columns volumes of 20 mM sodium acetate, 50 mM sodium chloride, pH 4.5, washed with four columns volumes of 20 mM sodium acetate, 100 mM sodium chloride, pH 4.5, and eluted with four columns volumes of 20 mM sodium acetate, 150 mM sodium chloride, pH 4.5. Uniformity was assessed by SEC, which showed a monodispersed peak with minimal contamination ( FIG. 28A ). IL6R binding was assessed in an ELISA as follows: the plates were coated with either 100 ng/well of human IL6R for 1 hour at 37° C., blocked with 3% BSA in PBS for one hour at 37° C., bound by adding the AC342 dilution series to the plate and incubating for one hour at room temperature, washed 3 times with PBST, detected with biotinylated anti-XTEN antibody for one hour at room temperature, washed three times with PBST, amplified with streptavidin-HRP for one hour at room temperature, washed three times with PBST, developed with TMB substrate and read at 405 nm using a plate reader. The ELISA values were plotted versus concentration (log scale), which provided determination of an EC50 value of 5 nM ( FIG. 28B ). 
     Example 34: Characterization of aCD40-XTEN 
     Two aCD40-XTEN constructs, AC384 and AC385, were expressed by growing a culture to saturation in 2×YT and then using this culture to inoculate a 500 ml flask of 2×YT. This second flask was grown to an OD600 of between 0.6 and 1.0 at 37° C., transferred to 26° C., and induced with 1 mM IPTG. The induction was left overnight and cell paste harvested by centrifugation the flowing morning. These pellets were stored as EP220 and EP221. Small samples were taken from the pellet, lysed using bugbuster, and clarified using a microcentrifuge. These cleared lysates were the serially diluted by a factor of three in PBST, for using in a binding ELISA. The ELISA was performed as follows: The plates were coated with either 100 ng/well of human CD40-Fc fusion for 1 hour at 37° C., blocked with 3% BSA in PBS for one hour at 37° C., bound by adding the AC384 or AC385 dilution series to the plate and incubating for one hour at room temperature, washed 3 times with PBST, detected with biotinylated anti-XTEN antibody for one hour at room temperature, washed three times with PBST, amplified with streptavidin-HRP for one hour at room temperature, washed three times with PBST, developed with TMB substrate and read at 405 nm using a plate reader. The ELISA values were plotted versus dilution of lysate plotted on a log scale and an EC50 value determined, with nearly identical results ( FIG. 27 ). Combining this with an estimate concentration of 10 μM in the lysate, the aCD40-XTEN constructs have a Kd of approximately 50 nM for human CD40. 
     Example 35: Characterization of aHER2-XTEN-aHER2 
     Binding of the aHER2-XTEN-aHER2 protein to human HER2 was assessed by ELISA as follows: The plates were coated with either 100 ng/well of human HER2-Fc fusion overnight at 4° C., blocked with 1% BSA in PBS for one hour at room temperature, bound by adding a dilution series of aHER2-XTEN-aHER2 to the plate and incubating for one hour at room temperature, washed 3 times with PBST, detected with anti-HA antibody with HRP conjugation for one hour at room temperature, washed three times with PBST, washed three times with PBST, developed with ABTS substrate and read at 405 nm using a plate reader. The ELISA values were plotted versus concentration plotted on a log scale and an EC50 of 0.5 nM determined ( FIG. 18 ). 
     Example 36: Characterization of aCD3-XTEN-aHER2 
     To confirm the binding specificity of expressed and purified binding fusion proteins with scFv targeting moieties, two preparations directed to the targets HER2 or CD3 were evaluated. Binding fusion proteins of aHER2 linked to the N-terminus of XTEN, with GFP linked to the C-terminus of the XTEN (“aHER2-XTEN-GFP”), and aCD3 linked to the N-terminus of XTEN, with GFP linked to the C-terminus of the XTEN (“aCD3-XTEN-GFP”) were the test articles that were evaluated for their ability to bind their respective targets on Jurkat cells bearing CD3 and SK-BR-3 cells bearing HER2. Jurkat cells and SK-BR3 cells were incubated with the indicated scFv-XTEN-GFP fusion proteins. Bound aCD3-XTEN-GFP and aHER2-XTEN-GFP were detected with a polyclonal anti-GFP antibody specific for the GFP fused to the construct, and an appropriate FITC-conjugated secondary antibody using flow cytometry. The flow cytometry results, shown graphically in  FIG. 19B , demonstrate specific binding of the aCD3-XTEN-GFP to Jurkat cells and specific binding of the aHER2-XTEN-GFP to SK-BR-3 cells, respectively, while there was no non-specific binding detected in the opposite configuration, indicating lack of cross-reactivity by the constructs. 
     A bispecific binding fusion protein with scFv targeting moieties to both HER2 and CD3 (“aCD3-XTEN-aHER2”, matching the N- to C-terminus configuration of the fusion protein components) was recovered by the purification process detailed above and the protein characterized. The aCD3-XTEN-aHER2 protein was subjected to non-reducing SDS-PAGE using NuPAGE 4-12% Bis-Tris gel from Invitrogen according to manufacturer&#39;s specifications. The results, shown in  FIG. 20A  demonstrate that the protein was &gt;95% pure, as judged by SDS-PAGE.  FIG. 20B  shows the output of a size exclusion chromatography (SEC) analysis of the aHER2-aCD3-XTEN compared to molecular weight standards, and demonstrates that no dimers or other higher-order oligomers are formed and that the protein has an approximate apparent molecular weight of approximately 500 kDa, approximately five-fold higher than that derived from the SDS-PAGE assay. 
     An ELISA assay to detect direct binding of the aCD3-XTEN-aHER2 to HER2-Fc-coated wells was performed as follows. The extracellular domain of HER2 fused to the Fc domain of human IgG was coated on to the wells of a microtiter plate. A dilution series of the aCD3-XTEN-aHER2 was then applied to the coated wells. After two hours the unbound aCD3-XTEN-aHER2 was washed away and any bound protein detected with an HRP-conjugated anti-HA antibody. The results of the binding assays are shown in  FIG. 21A . The control fusion protein with N-terminal aHER2 binds to HER2-Fc with an apparent Kd of 80 pM, while the C-terminal fusion of the aCD3-XTEN-aHER2 binds with an apparent Kd of 3.4 nM. Thus, the anti-Her2 component of the aCD3-XTEN-aHER2 construct still retains good binding affinity, although it is lower than the N-terminal construct. 
     Flow cytometry analysis of aHER2-XTEN ( FIG. 19A - FIG. 19B ) and aCD3-XTEN-aHER2 ( FIG. 21C ) show binding to HER2-expressing SK-BR-3 cells. Detection was via an anti-HA antibody and appropriate secondary antibody. The binding of aCD3-XTEN-GFP to CD3-positive Jurkat cells was measured by flow cytometry, using anti-GFP antibody detection, in the presence of a 10-fold molar excess of aHER2-aCD3-XTEN. The results clearly demonstrate that excess bispecific aCD3-XTEN-aHER2 competitively displaces the monospecific aCD3-XTEN-GFP protein and eliminates the observed MFI shift ( FIG. 22 ). Thus, we have engineered a aCD3-XTEN-aHER2 bispecific binding fusion protein that interacts with HER2-expressing tumor cells and CD3-positive T-cells. 
     To demonstrate the ability of the aCD3-XTEN-aHER2 binding fusion protein to target and kill cancer cells, an assay was performed using the construct to direct the cytotoxic activity of T-cells towards tumor cells. Here, we tested the efficacy of the candidate aCD3-XTEN-aHER2 using M21 melanoma and SK-BR-3 breast cancer cells. Tumor cells, expressing the target receptor, were labeled with a membrane permeable fluorophore, DiOC 18 . Fresh peripheral blood mononuclear cells (PBMCs) were then mixed with the labeled tumor cells (Effector cell:Tumor cell ratio 10:1) and the aCD3-XTEN-aHER2 binding fusion protein. After 24 hours the cell suspensions were collected by centrifugation and dead cells were labeled with propidium iodide. The cells were analyzed on a Zeiss Axiovert 100 microscope. Images of target (DiOC 18 ) and dead cells (propidium iodide) were captured with a SPOT CCD camera using appropriate excitation and emission filter sets. Image analysis was conducted using the program ImageJ. The number of target cells per image was determined by using the analyze particles command using the green (DiOC 18 ) fluorescence channel image. The fraction of these cells that were dead was determined by overlapping the red (propidium iodide) fluorescence channel using the co-localization plugin and counting the number green cells that were also red. The proportion of dead tumor cells, as a function of aHER2-aCD3-XTEN concentration is shown in  FIG. 23 . A general linear model with a logit link function was fit to the data with concentration of aCD3-XTEN-aHER2 fusion protein as the independent variable. The model found aCD3-XTEN-aHER2 concentration to be a significant predictor of tumor cell death at a p-value of &lt;0.001 for both M21 and SK-BR-3 target cells. The results support the conclusion that binding fusion proteins with targeting moieties directed to tumor associated antigens can have activity against tumor cells. 
     Example 37: Characterization of aHER2-XTEN-aEGFR 
     Size exclusion chromatography was performed on recovered aHER2-XTEN-aEGFR to assess its monomeric characteristics. Results from the SEC analysis demonstrate that the aHER2-XTEN-aEGFR ( FIG. 17C ) did not dimerize or form other higher order oligomers. As shown in  FIG. 17C , the apparent molecular weight is approximately five-fold larger than its calculated mass (approximately 107 kDa) or the mass estimated from the SDS PAGE of  FIG. 17B , due to the XTEN component; here the elution volume of aHER2-XTEN-aEGFR is compared a set of globular molecular weight standards (from left to right: 670, 158, 44, 17, and 1.4 kDa). The binding activity of aHER2-XTEN-aEGFR to its respective targets was tested in a ELISA format. The extracellular domains of either HER2 or EGFR fused to the Fc domain of human IgG were coated on to the wells of a microtiter plate. A dilution series of the aHER2-XTEN-aEGFR was then applied to the coated wells. After two hours the unbound aHER2-XTEN-aEGFR was washed away and any bound protein detected with an HRP-conjugated Anti-HA antibody. The result indicate that the bifunctional BPXTEN construct was able to bind each target at essentially equivalent concentrations. ( FIG. 18 ). 
     Example 38: Characterization of Multivalent aEGFR Vhh Binding Fusion Proteins 
     Characterization of domain binding fusion proteins was performed on aEGFR-XTEN Vhh constructs that had increasing numbers of targeting moieties, as depicted schematically in  FIG. 24A . SDS-PAGE and SEC were performed with four constructs; LCW501.001, LCW502.009, LCW503.004, and LCW504.004. A clear laddering across constructs in the SDS-PAGE analysis, shown in  FIG. 24B , demonstrates the increasing length of the protein as the number of anti-EGFR binding domains increases. This is mirrored by the SEC that, in  FIG. 25 , shows an increase in the hydrodynamic radius of the proteins as the number of anti-EGFR domains increases. The derived values for apparent molecular weight factor, apparent molecular weight factor and hydrodynamic radii are presented in Table 26. Note that these hydrodynamic radii are characteristically large for a protein of this molecular weight due to the unstructured nature of the XTEN linker domains, resulting in an increased apparent molecular weight for each of the domain binding fusion proteins. 
     LCW501.001, LCW502.009, LCW503.004, and LCW504.004 were also characterized in two different ELISA experiments. In the first Costar 3690 plates were coated with 100 ng of EGFR-Fc in 50 μl of PBS overnight at 4° C., blocked with 3% BSA in PBS for 1 hour, bound with multivalent aEGFR Vhh binders from 1 μM downward using 5-fold dilutions in binding buffer (1% BSA in PBST) for 2 hours at RT with shaking at 80 rpm, washed three times with PBST, detected with a 1:5000 dilution of goat anti-GFP-HRP for 1 hour at room temperature with shaking at 80 rpm, washed five times with PBST, developed with ABTS-H 2 O 2  substrate and read at 405 nm. Binding curves were determined for each of the different multimer species. All of the higher order multimers showed tighter binding than the monomer indicating an avidity effect and that multiple binding sites were active in the multivalent molecules ( FIG. 26A ). The second ELISA based characterization was as follows: Costar 3690 plate were coated with 200 ng of goat anti-GFP in 50 μl of PBS overnight at 4° C., blocked with 3% BSA in PBS for 1 hour, bound with multivalent aEGFR Vhh binders from 3 μM downward using 5-fold dilutions in binding buffer (1% BSA in PBST) for 2 hours at RT with shaking at 80 rpm, washed three times with PBST, detected with 100 ng/well (˜20 nM) of biotinylated EGFR-Fc for 1 hour at room temperature with shaking at 80 rpm, washed three times with PBST, amplified with 1:5000 dilution of streptavidin-HRP in binding buffer and developed with ABTS-H 2 O 2  substrate and read at 405 nm. The higher order multimers showed and increased capacity for EGFR-Fc binding ( FIG. 26B ) indicating that increasing the number of EGFR binding modules in the protein increases the number of available binding sites within the protein. These data suggest that all of the binding sites in the binding fusion proteins, including the higher order tetramers and hexamers, are active and capable of binding EGFR. 
     Example 39: Purification of aHER2-XTEN 
     AC51 was grown to saturation overnight in 2×YT+kanamycin. A 500 mL flask of 2×YT was inoculated with 3 ml of this saturated overnight and grown to an OD600 of −0.8 at 37° C. The culture was brought to 25° C. and then induced with 0.2 mM IPTG. The culture was induced overnight. The cell pellet was harvested by centrifugation at 5000 rpm, in a Sorvall SLA-3000 at 4° C. The cell pellet was then resuspended in 30 mM Tris pH 8.0, 500 mM NaCl, 20 mM imidazole. The cells were lysed by sonication and then clarified by centrifugation at 15,000 rpm in a Sorvall centrifuge. The supernatant was loaded onto Ni-NTA column, washed with 10 column volumes of 30 mM Tris pH 8.0, 500 mM NaCl, 20 mM imidazole, and eluted with 30 mM Tris pH 8.0, 500 mM NaCl, 600 mM imidazole. This protein was assigned lot # AP44. 
     Example 40: Analytical Size Exclusion Chromatography of XTEN Fusion Proteins 
     Size exclusion chromatography analysis was performed on binding fusion proteins containing various targeting moieties and unstructured recombinant proteins of varying length to determine the effect on XTEN on increasing the apparent molecular weight. An exemplary assay used a TSKGel-G4000 SWXL (7.8 mm×30 cm) column in which 40 μg of purified glucagon fusion protein at a concentration of 1 mg/ml was separated at a flow rate of 0.6 ml/min in 20 mM phosphate pH 6.8, 114 mM NaCl. Chromatogram profiles were monitored using OD214 nm and OD280 nm. Column calibration for all assays were performed using a size exclusion calibration standard from BioRad; the markers include thyroglobulin (670 kDa), bovine gamma-globulin (158 kDa), chicken ovalbumin (44 kDa), equine myoglobuin (17 kDa) and vitamin B12 (1.35 kDa). Representative SEC profiles of binding fusion proteins are shown as overlays in  FIGS. 17C, 20 and 25 . Based on the SEC analyses for all constructs evaluated, the apparent molecular weight factors, the apparent molecular weight factor (expressed as the ratio of apparent molecular weight factor to the calculated molecular weight) and the hydrodynamic radius (R H  in nm) are shown in Table 26. The data show that the apparent molecular weight of each compound is proportional to the length of the attached XTEN sequence. This is particularly evident in the case of the EGFR Vhh constructs that included increasing units of EGRF_VHH-AM144_XTEN, going from monomer to dimer to tetramer to hexamer, and showed increases in apparent molecular weight factor as the cumulative length of XTEN increased with each addition of the AM144 linkers. The data also show that the apparent molecular weight of each construct is significantly larger than that expected for a globular protein (as shown by comparison to the standard proteins run in the same assay). Additionally, the incorporation of XTEN fusion partners with 244 total amino acids or more into fusion proteins with targeting moieties resulted with a hydrodynamic radius of 7 nm or greater; well beyond the glomerular pore size of approximately 3-5 nm. Accordingly, it is concluded that binding fusion proteins comprising targeting moieties and XTEN would have reduced renal clearance, contributing to increased terminal half-life and improving the therapeutic or biologic effect relative to a corresponding un-fused targeting moiety proteins. 
     
       
         
           
               
             
               
                 TABLE 26 
               
             
            
               
                   
               
               
                 SEC analysis of various polypeptides 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 Apparent 
                   
               
               
                   
                 XTEN or 
                   
                 Actual 
                 Apparent 
                 Molecular 
               
               
                 Construct 
                 fusion 
                 Therapeutic 
                 MW 
                 MW 
                 Weight 
                 R H   
               
               
                 Name 
                 partner 
                 Protein 
                 (KDa) 
                 (kDa) 
                 Factor 
                 (nm) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 XTEN_AE912- 
                 AE912 
                 Anti-IL6R 
                 111 
                 883 
                 7.9 
                 8.7 
               
               
                 aIL6R scFv 
               
               
                 aHER2- 
                 Y288 
                 Anti-HER2 
                 83 
                 419 
                 5.0 
                 7.4 
               
               
                 XTEN Y288- 
               
               
                 aHER2 
               
               
                 EGFR_Vhh- 
                 AM144 
                 Anti-EGFR 
                 54 
                 107 
                 2 
                 4.9 
               
               
                 XTEN 
               
               
                 monomer 
               
               
                 EGFR_Vhh- 
                 AM144 X2 
                 Anti-EGFR 
                 81 
                 329 
                 4.1 
                 7.0 
               
               
                 XTEN dimer 
               
               
                 EGFR_Vhh- 
                 AM144 X4 
                 Anti-EGFR 
                 135 
                 1022 
                 7.5 
                 9.1 
               
               
                 XTEN 
               
               
                 tetramer 
               
               
                 EGFR_Vhh- 
                 AM144 X6 
                 Anti-EGFR 
                 189 
                 1802 
                 9.5 
                 10.1 
               
               
                 XTEN 
               
               
                 hexamer 
               
               
                   
               
            
           
         
       
     
     Example 41: Creation, Purification and Characterization of Binding Fusion Protein-Conjugates-aHer2-XTEN Constructs with Conjugated AF680 Fluorophore 
     To test the feasibility and utility of binding fusion protein-drug conjugates, binding fusion proteins were conjugated with a fluorophore that was then characterized for binding affinity and utilized in preclinical animal models to evaluate the ability of the conjugates to systemically distribute after injection and bind target tumor tissue. 
     aHer2-XTEN(AE864-Cys)-AF680 
     The  E. coli  containing the AC452 gene on a plasmid were grown in liquid culture to saturation overnight and then 90 ml of this culture was used to inoculate 4.5 L pho induction media, divided evenly between 9 4 L flasks. Cultures were grown at 26° C. in the presence of 10 μg/ml tetracycline and were induced as phosphate was depleted from the media. Protein was trafficked to the periplasm of the host cells via an STII signal sequence fused to the N-terminus of the encoded protein that was subsequently removed by post-translational modification in the cells. The cell pellet was harvested by centrifugation for 20 min at 4000 rpm in a SLA-3000 rotor. Some of the cell pellet (45 of 90 total g) was resuspended in 121 ml of PBS plus 10 mM imidizole and 13.5 ml of BugBuster and DNase were added. The cells were lysed by vortexing periodically over a 90 minute period. The lysate was then clarified by centrifugation at 15,000 rpm for 30 minutes. The clarified lysate was then loaded on to an 85 ml toyopearl chelate column charged with 100 mM NiSO4, and equilibrated with PBS plus 10 mM imidizole. The column was washed with 5 column volumes of PBS plus 10 mM imidizole, and the protein eluted with 3 column volumes of PBS plus 250 mM imidizole and then stripped with 1.2 column volumes of PBS plus 500 mM imidizole. The eluate was reduced with 0.3 mM TCEP and then labeled for 3 hours at room temperature with Alexa Fluor 680 at a ratio of 0.1 mg of dye per mg of protein. The sample was then transferred to 4° C. for overnight storage. The sample was then diluted 2.7 fold with water to reduce the conductivity and loaded on to a macrocapQ column, previously sanitized with NaOH and equilibrated with 20 mM Tris pH 7.5, 50 mM NaCl. The column was washed with 5 column volumes of 20 mM Tris pH 7.5, 50 mM NaCl and eluted with a 10 column volume linear gradient from 150 mM NaCl to 300 mM NaCl both with 20 mM Tris pH 7.5 as the buffer. The pooled elution fractions were concentrated using an Amicon ultra concentrator with a 10,000 MWCO membrane and stored at −80° C., assigned lot # AP502. 
     aHer2-XTEN(AE576-Cys)-AF680 
     The  E. coli  containing the AC451 gene on a plasmid were grown in liquid culture to saturation overnight and then 90 ml of this culture was used to inoculate 10 L pho induction media, divided evenly between 20 4 L flasks. Cultures were grown at 26° C. in the presence of 10 μg/ml tetracycline and were induced as phosphate was depleted from the media. Protein was trafficked to the periplasm of the host cells via an STII signal sequence fused to the N-terminus of the encoded protein that was subsequently removed by post-translational modification in the cells. The cell pellet was harvested by centrifugation for 20 min at 4000 rpm in a SLA-3000 rotor. The cell pellet (39 g) was resuspended in 96.3 ml of PBS plus 10 mM imidizole and 10.7 ml of BugBuster and DNase were added. The cells were lysed by vortexing periodically over a 55 minute period. The lysate was then clarified by centrifugation at 15,000 rpm for 25 minutes. The clarified lysate was then loaded on to an 85 ml toyopearl chelate column charged with 100 mM NiSO4, and equilibrated with PBS plus 10 mM imidizole. The column was washed with 5 column volumes of PBS plus 10 mM imidizole, and the protein eluted with 3 column volumes of PBS plus 250 mM imidizole and then stripped with 1.2 column volumes of PBS plus 500 mM imidizole. The eluate was reduced with 0.3 mM TCEP and then labeled for 3 hours at room temperature with Alexa Fluor 680 at a ratio of 0.1 mg of dye per mg of protein. The sample was then transferred to 4° C. for overnight storage. The sample was then diluted 2.7 fold with water to reduce the conductivity and loaded on to a macrocapQ column, previously sanitized with NaOH and equilibrated with 20 mM Tris pH 7.5, 50 mM NaCl. The column was washed with 5 column volumes of 20 mM Tris pH 7.5, 50 mM NaCl and eluted with a 10 column volume linear gradient from 150 mM NaCl to 300 mM NaCl both with 20 mM Tris pH 7.5 as the buffer. The pooled elution fractions were concentrated using an Amicon ultra concentrator with a 10,000 MWCO membrane and stored at −80° C., assigned lot # AP486. 
     aHer2-XTEN(AE288-Cys)-AF680 
     The  E. coli  containing the AC450 gene on a plasmid were grown in liquid culture to saturation overnight and then 90 ml of this culture was used to inoculate 10 L pho induction media, divided evenly between 20 4 L flasks. Cultures were grown at 26° C. in the presence of 10 μg/ml tetracycline and were induced as phosphate was depleted from the media. Protein was trafficked to the periplasm of the host cells via an STII signal sequence fused to the N-terminus of the encoded protein that was subsequently removed by post-translational modification in the cells. The cell pellet was harvested by centrifugation for 60 min at 4000 rpm in a SLA-3000 rotor. The cell pellet (36 g) was resuspended in 97 ml of PBS plus 10 mM imidizole and 10.7 ml of BugBuster and DNase were added. The cells were lysed by vortexing periodically over a 55 minute period. The lysate was then clarified by centrifugation at 15,000 rpm for 25 minutes. The clarified lysate was then loaded on to an 85 ml toyopearl chelate column charged with 100 mM NiSO4, and equilibrated with PBS plus 10 mM imidizole. The column was washed with 5 column volumes of PBS plus 10 mM imidizole, and the protein eluted with 3 column volumes of PBS plus 250 mM imidizole and then stripped with 1.2 column volumes of PBS plus 500 mM imidizole. The eluate was reduced with 0.3 mM TCEP and then labeled for 3 hours at room temperature with Alexa Fluor 680 at a ratio of 0.1 mg of dye per mg of protein. The sample was then transferred to 4° C. for overnight storage. The sample was then diluted 2.7 fold with water to reduce the conductivity and loaded on to a macrocapQ column, previously sanitized with NaOH and equilibrated with 20 mM Tris pH 7.5, 50 mM NaCl. The column was washed with 5 column volumes of 20 mM Tris pH 7.5, 50 mM NaCl and eluted with a 10 column volume linear gradient from 150 mM NaCl to 300 mM NaCl both with 20 mM Tris pH 7.5 as the buffer. The pooled elution fractions were concentrated using an Amicon ultra concentrator with a 10,000 MWCO membrane and stored at −80° C., assigned lot # AP481. 
     SEC Analysis of aHer2-XTEN(AE288-Cys)-AF680, aHer2-XTEN(AE576-Cys)-AF680, aHer2-XTEN(AE576-Cys)-AF680 
     Confirmation that the Alexa Fluor 680 was conjugated to the XTEN proteins was provided by analytical size exclusion chromatography. The characteristic 690 nm absorbance of the dye would elute very late in the SEC chromatogram if it were free in solution, whereas if it were conjugated to the XTEN protein it would elute earlier at the characteristic volume of the XTEN. The three constructs were assayed using a BioSep S4000 (7.8×6000 mm, phenomenex) run on an Akta purifier system and the chromatogram for each of the three constructs was monitored at 280 ( FIG. 33 , solid lines) and 690 nm ( FIG. 33 , dotted lines). For each of the all three constructs, the 690 nm absorbance peaks co-eluted with the 280 nm peak, indicating that the Alex Fluor 680 was conjugated to the XTEN fusion protein. No free dye was noted at the expected elution time of approximately 52 minutes. The chromatograms also reflect elutions proportional to the increase in apparent mass contributed by the length of the respective XTEN components. 
     Flow Cytometry Analysis of aHer2-XTEN Conjugates 
     Specific binding of a binding fusion protein to a tumor cell line was evaluated using the constructs of anti-HER2 targeting moiety linked to different lengths of XTEN, with a fluorophore AF680 covalently linked to XTEN, as described above. The aHer2-XTEN-Cys-AF680 constructs binding to Her2 were assessed by flow cytometry on the Her2+ tumor cell line, SKOV3, as follows: SKOV3 cells were grown from frozen stocks and passaged 2-3 times. Cells were resuspended into 31 tubes and incubated at 1×10 6  cells/tube with Fc block (BD BioSciences) for 10 minutes on ice. Fifteen tubes were preincubated with 1000 nM unlabeled Herceptin (to block binding as a control) for 20 minutes on ice. All tubes (15 incubated with unlabeled Herceptin, 15 not incubated with unlabeled Herceptin) were then incubated with the 100 nM of the appropriately labeled aHer2-XTEN-AE-288-Cys-AF680, aHer2-XTEN-AE-576-Cys-AF680, and aHer2-XTEN-AE-864-Cys-AF680 conjugate or the labeled isotype control for 20 minutes on ice, washed twice with flow buffer, the pellets were resuspended in 0.2 mL of flow buffer and then were run on an Accuro C6 Flow Cytometer. Data were collected for forward and side scatter and side scatter vs. FL4 for Alexa680. Data ( FIG. 34A - FIG. 34C ) are presented as histograms of each aHer2-XTEN-AE-864-Cys-AF680 ( FIG. 34A ), aHer2-XTEN-AE-576-Cys-AF680 ( FIG. 34B ), and aHer2-XTEN-AE-288-Cys-AF680 conjugate ( FIG. 34C ) overlayed with blocked and unblocked Herceptin. The data show that Herceptin completely blocked the binding of the aHer2-XTEN-AE-288-Cys-AF680, aHer2-XTEN-AE-576-Cys-AF680, and aHer2-XTEN-AE-864-Cys-AF680 conjugate to Her2+SKOV3 cells in vitro, demonstrating the specific binding of the conjugate constructs for the Her2 target on the tumor cells. 
     In Vivo and Ex Vivo Imaging of aHer2-XTEN Conjugates 
     Targeting and biodistribution of the aHer2-XTEN-Cys-AF680 constructs, prepared as described above, to Her2+ tumor was assessed using in vivo, followed by ex vivo, fluorescence imaging. Control groups included mice injected with fluorescently tagged Herceptin-Alexa 680 and mice injected with aHer2-XTEN-864-Alexa 680 but blocked with Herceptin one hour prior to injection. 
     Female nu/nu mice bearing SKOV3 tumor cells were given a single injection of high or low dose aHer2-XTEN-AE-288-Cys-AF680, aHer2-XTEN-AE-576-Cys-AF680, aHer2-XTEN-AE-864-Cys-AF680 or Herceptin-AF680 control. Whole body scans were acquired pre-injection and then at approximately 8, 24, 48 and 72 hours post-injection. Following the 72 hour time point all high dose groups were euthanized and tumors, liver, lung, heart, spleen and kidneys were ex vivo imaged using ex vivo fluorescence imaging. Fluorescence imaging was performed using an IVIS 50 optical imaging system (Caliper Life Sciences, Hopkinton, Mass.). Cy5.5 excitation (615-665 nm) and emission (695-770 nm) filters were selected to match the fluorescence agents&#39; wavelengths. Small and medium binning of the CCD chip was used and the exposure time was between 5-20 seconds to obtain at least several thousand counts from the signals that were observable in each mouse in the image and to avoid saturation of the CCD chip. To normalize images for quantification, a background fluorescence image was acquired using background excitation and emission filters for the Cy5.5 spectral region. 
     In vivo imaging data are shown in  FIG. 35  and Table 27. Several of the groups showed specific fluorescent signals in the tumor, above the level of the autofluorescent background. Significant signals were evident in most of the higher dosage level (6.7 nmol/mouse) aHer2-XTEN test agent groups (Groups 1, 3 and 5) as well as the positive control group dosed with tagged herceptin (Group 7). In addition, there were minor trends suggesting detection of the agents in the tumors for some of the groups where the lower dosage levels were administered. The data also showed a 50% higher peak value for aHer2-XTEN-864-Alexa 680 (Group 1), compared with aHer2-XTEN-576-Alexa 680 (Group 3) and aHer2-XTEN-288-Alexa 680 (Group 5). While the tagged herceptin showed peak tumor binding 8 h post-administration, the test agents generally showed later peak binding approximately 24-48 h post-administration. aHer2-XTEN-288-Alexa 680 showed the most rapid targeting kinetics, as well as the most rapid clearance. 
     Ex vivo imaging data shown in  FIG. 36  and Table 28 summarizes the mean total fluorescence signals measured by group and tissue type. Imaging of tumors in Groups 2 and 9 demonstrated approximately 6-fold higher total fluorescence signal in Group 2 (0.67 nmol aHer2-XTEN-864-Alexa 680) compared with Group 9 (0.67 nmol aHer2-XTEN-864-Alexa 680+100× excess unlabeled Herceptin administered 1 hour prior) indicating specific Her2+ tumor targeting. Results from the extended tissue set (tumor, heart, lungs, spleen, liver, kidneys) indicated that Group 7 (3.3 nmol Herceptin-Alexa680) showed the greatest signals in most tissues, but that Group 1 (6.7 nmol aHer2-XTEN-864-Alexa 680), with the longest XTEN molecule, showed nearly comparable total signals in most cases except for the liver, in which the Herceptin Group 7 had approximately double the fluorescent signal compared to the aHer2-XTEN-864 Group 1. Group 3 (6.7 nmol aHer2-XTEN-576-Alexa 680) and Group 5 (6.7 nmol aHer2-XTEN-864-Alexa 680) showed lower signals in all tissues than Groups 1 and 7. 
     
       
         
           
               
             
               
                 TABLE 27 
               
             
            
               
                   
               
               
                 In vivo fluorescence by group of mean peak signals and signal at 72 h 
               
            
           
           
               
               
               
            
               
                   
                   
                 Average Fluorescence Efficiency 
               
               
                   
                   
                 (group mean normalized to 
               
               
                   
                 Dosage Level 
                 pre-treatment values) 
               
            
           
           
               
               
               
               
               
               
            
               
                 Group # 
                 Test Material 
                 (nmol/mouse) 
                 Peak 
                 Peak Time 
                 Level at 72 h 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Group 1 
                 aHer2-XTEN-864- 
                 6.7 
                 20.3 
                 24 
                 h 
                 11.2 
               
               
                   
                 Alexa 680 
               
               
                 Group 2 
                 aHer2-XTEN-864- 
                 0.67 
                 5.3 
                 48 
                 h 
                 3.5 
               
               
                   
                 Alexa 680 
               
               
                 Group 3 
                 aHer2-XTEN-576- 
                 6.7 
                 14.0 
                 24 
                 h 
                 6.9 
               
               
                   
                 Alexa 680 
               
               
                 Group 4 
                 aHer2-XTEN-576- 
                 0.67 
                 3.6 
                 48 
                 h 
                 3.4 
               
               
                   
                 Alexa 680 
               
               
                 Group 5 
                 aHer2-XTEN-288- 
                 6.7 
                 13.4 
                 8 
                 h 
                 4.2 
               
               
                   
                 Alexa 680 
               
               
                 Group 6 
                 aHer2-XTEN-288- 
                 0.67 
                 3.5 
                 48 
                 h 
                 3.1 
               
               
                   
                 Alexa 680 
               
               
                 Group 7 
                 Herceptin-Alexa680 
                 3.3 
                 40.3 
                 8 
                 h 
                 18.6 
               
               
                   
                 Control 
               
               
                 Group 8 
                 Herceptin-Alexa680 
                 0.33 
                 5.3 
                 48 
                 h 
                 4.4 
               
               
                   
                 Control 
               
               
                 Group 9 
                 aHer2-XTEN-864- 
                 0.67 + 100x 
                 6.0 
                 72 
                 h 
                 6.0 
               
               
                   
                 Alexa 680 + 
                 excess 1 h 
               
               
                   
                 unlabeled Herceptin 
                 before 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 28 
               
             
            
               
                   
               
               
                 Summary by group of mean total signals in tissues imaged ex vivo. 
               
            
           
           
               
               
               
            
               
                   
                   
                 Total Fluorescence Efficiency 
               
               
                   
                 Dosage Level 
                 (group mean) (×10 6 ) 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Group # 
                 Test Material 
                 (nmol/mouse) 
                 Tumor 
                 Heart 
                 Lungs 
                 Spleen 
                 Liver 
                 Kidneys 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Group 1 
                 aHer2-XTEN- 
                 6.7 
                 42 
                 28 
                 130 
                 16 
                 180 
                 120 
               
               
                   
                 864-Alexa 680 
               
               
                 Group 2 
                 aHer2-XTEN- 
                 0.67 
                 4.2 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                   
                 864-Alexa 680 
               
               
                 Group 3 
                 aHer2-XTEN- 
                 6.7 
                 27 
                 6.8 
                 24 
                 3.4 
                 48 
                 31 
               
               
                   
                 576-Alexa 680 
               
               
                 Group 5 
                 aHer2-XTEN- 
                 6.7 
                 7.2 
                 1.9 
                 5.6 
                 2.1 
                 20 
                 34 
               
               
                   
                 288−Alexa 680 
               
               
                 Group 7 
                 Herceptin- 
                 3.3 
                 69 
                 32 
                 150 
                 25 
                 370 
                 110 
               
               
                   
                 Alexa680 
               
               
                   
                 Control 
               
               
                 Group 9 
                 aHer2-XTEN- 
                 0.67 + 100x 
                 0.7 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                   
                 864-Alexa 680 + 
                 excess 1 h 
               
               
                   
                 unlabeled 
                 before 
               
               
                   
                 Herceptin 
               
               
                   
               
            
           
         
       
     
     Example 42: Pharmacokinetic Analysis of CTLA4-XTEN 
     The in vivo pharmacokinetics of CTLA4-XTEN constructs can be assessed using standard methods for protein compositions. Pharmacokinetics is assessed in multiple species, however mice, rats, cynomolgus monkeys, and dogs are preferred due to their common usage in predicting human pharmacokinetics. Compositions of CTLA4-XTEN constructs, or CTLA4 as a comparator, are typically provided in an aqueous buffer compatible with in vivo administration (for example: phosphate-buffered saline or Tris-buffered saline). The compositions would be administered at appropriate doses and via multiple routes: most preferably via intravenous or subcutaneous routes. Blood samples would collected at appropriate time points ranging from 0.08 to 504 hours, and processed into plasma. Plasma samples can be analyzed for concentration of test articles by ELISA assay. Analysis is typically performed using a sandwich ELISA format. Rabbit polyclonal anti-XTEN antibodies or anti-targeting moiety are coated onto wells of an ELISA plate. The wells are blocked, washed and plasma samples are then incubated in the wells at varying dilutions to allow capture of the compound by the coated antibodies. Wells are then washed extensively, and bound protein detected using a biotinylated preparation of a polyclonal anti CTLA4 antibody or anti-XTEN antibody and streptavidin HRP. Concentrations of test article are then calculated at each time point by comparing the colorimetric response at each serum dilution to a standard curve. Pharmacokinetic parameters are then calculated using the WinNonLin software package. It is expected that the results would support the finding that addition of an XTEN to CTLA4 can greatly increase the terminal half-life compared to the targeting moiety not linked to XTEN, and enhance other pharmacokinetic properties as well. 
     Example 43: Pharmacokinetic Analysis of IL6R-XTEN 
     The in vivo pharmacokinetics of IL6R-XTEN constructs can be assessed using standard methods for protein compositions. Pharmacokinetics is assessed in multiple species, however mice, rats, cynomolgus monkeys, and dogs are preferred due to their common usage in predicting human pharmacokinetics. Compositions of IL6R-XTEN constructs, or IL6R as comparator, are typically provided in an aqueous buffer compatible with in vivo administration (for example: phosphate-buffered saline or Tris-buffered saline). The compositions would be administered at appropriate doses and via multiple routes: most preferably via intravenous or subcutaneous routes. Blood samples would be collected at appropriate time points ranging from 0.08 to 504 hours, and processed into plasma. Plasma samples are analyzed for concentration of test articles by ELISA assay. Analysis is typically performed using a sandwich ELISA format. Rabbit polyclonal anti-XTEN antibodies or antibodies to the targeting moiety are coated onto wells of an ELISA plate. The wells are blocked, washed and plasma samples are then incubated in the wells at varying dilutions to allow capture of the compound by the coated antibodies. Wells are then washed extensively, and bound protein detected using a biotinylated preparation of a polyclonal anti-IL6R antibody or anti-XTEN antibody and streptavidin HRP. Concentrations of test article are then calculated at each time point by comparing the colorimetric response at each serum dilution to a standard curve. Pharmacokinetic parameters are then calculated using the WinNonLin software package. It is expected that the results would support the finding that addition of an XTEN to IL6R can greatly increase the terminal half-life compared to the targeting moiety not linked to XTEN, and enhance other pharmacokinetic parameters, as well. 
     Example 44: Pharmacokinetic Analysis of CD40-XTEN 
     The in vivo pharmacokinetics of CD40-XTEN constructs can be assessed using standard methods for protein compositions. Pharmacokinetics is assessed in multiple species, however mice, rats, cynomolgus monkeys, and dogs are preferred due to their common usage in predicting human pharmacokinetics. Compositions of CD40-XTEN constructs, or CD40 as comparator, are typically provided in an aqueous buffer compatible with in vivo administration (for example: phosphate-buffered saline or Tris-buffered saline). The compositions would be administered at appropriate doses and via multiple routes: most preferably via intravenous or subcutaneous routes. Blood samples would be collected at appropriate time points ranging from 0.08 to 504 hours, and processed into plasma. Plasma samples are analyzed for concentration of test articles by ELISA assay. Analysis is typically performed using a sandwich ELISA format. Rabbit polyclonal anti-XTEN antibodies or antibodies to targeting moiety are coated onto wells of an ELISA plate. The wells are blocked, washed and plasma samples are then incubated in the wells at varying dilutions to allow capture of the compound by the coated antibodies. Wells are then washed extensively, and bound protein detected using a biotinylated preparation of a polyclonal anti CD40 antibody or anti-XTEN antibody and streptavidin HRP. Concentrations of test article are then calculated at each time point by comparing the colorimetric response at each serum dilution to a standard curve. Pharmacokinetic parameters are then calculated using the WinNonLin software package. It is expected that the results would support the finding that addition of an XTEN to CD40 can greatly increase the terminal half-life compared to the targeting moiety not linked to XTEN, and enhance other pharmacokinetic parameters, as well. 
     Example 45: Preclinical Analysis of CTLA4-XTEN 
     CTLA4 is involved in delivery of the second co-stimulatory signal required for optimal activation of T cells. As such, the in vivo pharmacologic activity of CTLA4-XTEN constructs can be assessed using preclinical models of human autoimmune inflammatory diseases. Appropriate models for preclinical efficacy testing include but are not limited to collagen induced arthritis, a model for human rheumatoid arthritis, systemic lupus erythematosus, a model for human lupus, and experimental allergic encephalomyelitis, a model for human multiple sclerosis. Preclinical efficacy testing can also be done in transplantation models such as solid organ allograft or islet transplant. These models can be developed in multiple species using methods equivalent to those used for abatacept. CTLA4-XTEN compositions are provided in an aqueous buffer compatible with in vivo administration (for example: phosphate-buffered saline or Tris-buffered saline). The compositions would be administered at appropriate doses, dosing frequency, dosing schedule and route of administration as optimized for the particular model. Efficacy readouts for inflammation could include joint measurements, inhibition of primary and secondary humoral immune response, infiltration of immune cells as measured by histopathology, proteinuria among others. It is expected that the results would support the finding that the CTLA4-XTEN constructs may be more efficacious at inhibiting the inflammatory response as compared to CTLA4 and/or equivalent in potency to comparable dosage CTLA4 with less frequent or more convenient dosing. 
     Example 46: Preclinical Analysis of Anti-IL6R-XTEN 
     IL6 plays an important role in the pathogenesis of rheumatoid arthritis. Anti-IL6R inhibits binding of IL6 to its receptor and neutralizes the actions of IL6. As such, the in vivo pharmacologic activity of anti-IL6R-XTEN constructs can be assessed using preclinical models of human autoimmune inflammatory diseases, in particular, rheumatoid arthritis. Appropriate models for preclinical efficacy testing include but are not limited to non human primate collagen induced arthritis, a model for human rheumatoid arthritis. These models can be developed using methods equivalent to those used for tocilizumab. Anti-IL6R-XTEN compositions are provided in an aqueous buffer compatible with in vivo administration (for example: phosphate-buffered saline or Tris-buffered saline). The compositions would be administered at appropriate doses, dosing frequency, dosing schedule and route of administration as optimized for the particular model. Efficacy readouts for inflammation could include joint measurements, swelling, inhibition of primary and secondary humoral immune response, infiltration of immune cells as measured by histopathology, blood chemistry, among others. It is expected that the results would support the finding that the anti-IL6R4-XTEN constructs may be more efficacious at inhibiting the inflammatory response as compared to anti-IL6R and/or equivalent in potency to comparable dosage anti-IL6R with less frequent or more convenient dosing. 
     Example 47: Preclinical Analysis of Anti-CD40-XTEN 
     Dysregulation of the CD40-CD40 L costimulation pathway plays an important role in the pathogenesis of human inflammatory and autoimmune disease. As such, the in vivo pharmacologic activity of anti-CD40-XTEN constructs can be assessed using preclinical models of human autoimmune inflammatory diseases. Appropriate models for preclinical efficacy testing include but are not limited to collagen induced arthritis, a model for human rheumatoid arthritis, systemic lupus erythematosus, a model for human lupus, and experimental allergic encephalomyelitis, a model for human multiple sclerosis. Preclinical efficacy testing can also be done in transplantation models such as solid organ allograft or islet transplant. These models can be developed using methods equivalent to those used for other CD40 or CD40 L targeting therapies. Anti-CD40-XTEN compositions can be provided in an aqueous buffer compatible with in vivo administration (for example: phosphate-buffered saline or Tris-buffered saline). The compositions can be administered at appropriate doses, dosing frequency, dosing schedule and route of administration as optimized for the particular model. Efficacy readouts for inflammation could include joint measurements, inhibition of primary and secondary humoral immune response, infiltration of immune cells as measured by histopathology, proteinuria among others. It is expected that the results would support the finding that the anti-CD40-XTEN constructs may be more efficacious at inhibiting the inflammatory response as compared to anti-CD40 and/or equivalent in potency to comparable dosage anti-CD40 with less frequent or more convenient dosing. 
     Example 48: Clinical Applications of CTLA4-XTEN 
     CTLA4 is involved in delivery of the second co-stimulatory signal required for optimal activation of T cells. CTLA4-XTEN can be used to treat T cell mediated autoimmune diseases such as rheumatoid arthritis and psoriasis in clinical trials using similar methodology to Orencia. Fusion of XTEN to CTLA4 to create a binding fusion protein composition is expected to improve the half-life of the recombinant protein, thus enabling a lower overall dose per patient with subsequent improvements in convenience (allowing for subcutaneous dosing, reducing dosing frequency, etc) and cost (reduced drug required per dose). 
     Clinical trials could be conducted in patients suffering from rheumatoid arthritis. Clinical trials can be designed such that the efficacy and advantages of the CTLA4-XTEN compositions can be verified in humans. Such studies in patients would comprise three phases. First, a Phase I safety and pharmacokinetics study in adult patients would be conducted to determine the maximum tolerated dose and pharmacokinetics and pharmacodynamics in humans. These initial studies could be performed in patients with rheumatoid arthritis and would define potential toxicities and adverse events to be tracked in future studies. The scheme of the study would be to use single escalating doses of CTLA4-XTEN compositions and measure the biochemical, PK, and clinical parameters. This would permit the determination of the maximum tolerated dose and establish the threshold and maximum concentrations in dosage and circulating drug that constitute the therapeutic window to be used in subsequent Phase II and Phase III trials conducted in target indications to determine efficacy and tolerability of the CTLA4-XTEN compositions. 
     A phase II clinical study of human patients would be conducted in arthritis patients administered CTLA4-XTEN or a suitable anti-inflammatory protein to determine an appropriate dose to relieve at least one symptom associated with rheumatoid arthritis, including reducing joint swelling, joint tenderness, inflammation, morning stiffness, and pain, or at least one biological surrogate marker associated with rheumatoid arthritis, including reducing erythrocyte sedimentation rates, and serum levels of C-reactive protein and/or IL2 receptor. In addition, safety data related to adverse events would be collected. A phase III efficacy study would be conducted wherein arthritis patients would be administered either the CTLA4-XTEN, a positive control, or a placebo daily, bi-weekly, or weekly (or other dosing schedule deemed appropriate given the pharmacokinetic and pharmacodynamic properties of the compound) for an extended period of time. Patients would be evaluated for baseline symptoms of disease activity prior to receiving any treatments, including joint swelling, joint tenderness, inflammation, morning stiffness, disease activity evaluated by patient and physician as well as disability evaluated by, for example, a standardized Health Questionnaire Assessment (HAQ), and pain. Additional baseline evaluations could include erythrocyte sedimentation rates (ESR), serum levels of C-reactive protein (CRP) and soluble IL-2 receptor (IL-2r). The clinical response to treatment could be assessed using the criteria established by the American College of Rheumatology (ACR), such as the ACR20 criterion; i.e., if there was a 20 percent improvement in tender and swollen joint counts and 20 percent improvement in three of the five remaining symptoms measured, such as patient and physician global disease changes, pain, disability, and an acute phase reactant (Felson, D. T., et al., 1993 Arthritis and Rheumatism 36:729-740; Felson, D. T., et al., 1995 Arthritis and Rheumatism 38:1-9). Similarly, a subject would satisfy the ACR50 or ACR70 criterion if there was a 50 or 70 percent improvement, respectively, in tender and swollen joint counts and 50 or 70 percent improvement, respectively, in three of the five remaining symptoms measured, such as patient and physician global disease changes, pain, physical disability, and an acute phase reactant such as CRP or ESR. In addition, potential biomarkers of disease activity could be measured, including rheumatoid factor, CRP, ESR, soluble IL-2R, soluble ICAM-1, soluble E-selectin, and MMP-3. Efficacy outcomes would be determined using standard statistical methods. Toxicity and adverse event markers would also be followed in this study to verify that the compound is safe when used in the manner described. 
     Example 49: Clinical Applications of IL6R-XTEN 
     IL6 plays an important role in the pathogenesis of rheumatoid arthritis. Anti-IL6R inhibits binding of IL6 to its receptor and neutralizes the actions of IL6. Anti-IL6R-XTEN can be used to treat T cell mediated autoimmune diseases such as rheumatoid arthritis in clinical trials using similar methodology to Actemra. Fusion of XTEN to anti-IL6R to create a binding fusion protein is expected to improve the half-life of the recombinant protein, thus enabling a lower overall dose per patient with subsequent improvements in convenience (allowing for subcutaneous dosing, reducing dosing frequency, etc) and cost (reduced drug required per dose). Anti-IL6R-XTEN may also provide a safety advantage over the existing anti-IL6R therapy. 
     Clinical trials could be conducted in patients suffering from rheumatoid arthritis. Clinical trials can be designed such that the efficacy and advantages of the anti-IL6R-XTEN compositions can be verified in humans. Such studies in patients would comprise three phases. First, a Phase I safety and pharmacokinetics study in adult patients would be conducted to determine the maximum tolerated dose and pharmacokinetics and pharmacodynamics in humans. These initial studies could be performed in patients with rheumatoid arthritis and would define potential toxicities and adverse events to be tracked in future studies. The scheme of the study would be to use single escalating doses of anti-IL6R-XTEN compositions and measure the biochemical, PK, and clinical parameters. This would permit the determination of the maximum tolerated dose and establish the threshold and maximum concentrations in dosage and circulating drug that constitute the therapeutic window to be used in subsequent Phase II and Phase III trials conducted in target indications to determine efficacy and tolerability of the anti-IL6R-XTEN compositions. 
     A phase II clinical study of human patients would be conducted in arthritis patients administered anti-IL6R-XTEN or a suitable anti-inflammatory protein to determine an appropriate dose to relieve at least one symptom associated with rheumatoid arthritis, including reducing joint swelling, joint tenderness, inflammation, morning stiffness, and pain, or at least one biological surrogate marker associated with rheumatoid arthritis, including reducing erythrocyte sedimentation rates, and serum levels of C-reactive protein and/or IL2 receptor. In addition, safety data related to adverse events would be collected. A phase III efficacy study would be conducted wherein arthritis patients would be administered either the anti-IL6R-XTEN, a positive control, or a placebo daily, bi-weekly, or weekly (or other dosing schedule deemed appropriate given the pharmacokinetic and pharmacodynamic properties of the compound) for an extended period of time. Patients would be evaluated for baseline symptoms of disease activity prior to receiving any treatments, including joint swelling, joint tenderness, inflammation, morning stiffness, disease activity evaluated by patient and physician as well as disability evaluated by, for example, a standardized Health Questionnaire Assessment (HAQ), and pain. Additional baseline evaluations could include erythrocyte sedimentation rates (ESR), serum levels of C-reactive protein (CRP) and soluble IL-2 receptor (IL-2r). The clinical response to treatment could be assessed using the criteria established by the American College of Rheumatology (ACR), such as the ACR20 criterion; i.e., if there was a 20 percent improvement in tender and swollen joint counts and 20 percent improvement in three of the five remaining symptoms measured, such as patient and physician global disease changes, pain, disability, and an acute phase reactant (Felson, D. T., et al., 1993 Arthritis and Rheumatism 36:729-740; Felson, D. T., et al., 1995 Arthritis and Rheumatism 38:1-9). Similarly, a subject would satisfy the ACR50 or ACR70 criterion if there was a 50 or 70 percent improvement, respectively, in tender and swollen joint counts and 50 or 70 percent improvement, respectively, in three of the five remaining symptoms measured, such as patient and physician global disease changes, pain, physical disability, and an acute phase reactant such as CRP or ESR. In addition, potential biomarkers of disease activity could be measured, including rheumatoid factor, CRP, ESR, soluble IL-2R, soluble ICAM-1, soluble E-selectin, and MMP-3. Efficacy outcomes would be determined using standard statistical methods. Toxicity and adverse event markers would also be followed in this study to verify that the compound is safe when used in the manner described. 
     Example 50: Clinical Applications of Anti-CD40-XTEN 
     Dysregulation of the CD40-CD40 L costimulation pathway plays an important role in the pathogenesis of human inflammatory and autoimmune disease. CD40 is over-expressed on antigen presenting cells in a variety of autoimmune conditions including rheumatoid arthritis, psoriasis, inflammatory bowel disease, and type 1 diabetes, and its ligand, CD154, is over-expressed on T cells in many of these same autoimmune diseases. A binding fusion protein of anti-CD40-XTEN could be used to evaluate efficacy in autoimmune inflammatory diseases and its ability to induce transplantation tolerance in clinical trials using similar methodology to the anti-CD40 antibodies currently in clinical trials. Fusion of XTEN to anti-CD40 to create a binding fusion protein is expected to improve the half-life of the recombinant protein, thus enabling a lower overall dose per patient with subsequent improvements in convenience (reduced dosing frequency, etc) and cost (reduced drug required per dose). 
     Clinical trials could be conducted in patients suffering from any a variety of inflammatory and autoimmune conditions such as but not limited to rheumatoid arthritis, lupus erythematosus, psoriasis, inflammatory bowel disease, multiple sclerosis, etc. or for transplantation. Clinical trials can be designed such that the efficacy and advantages of the anti-CD40-XTEN compositions can be verified in humans. Such studies in patients would comprise three phases. First, a Phase I safety and pharmacokinetics study in adult patients would be conducted to determine the maximum tolerated dose and pharmacokinetics and pharmacodynamics in humans. These studies would define potential toxicities and adverse events to be tracked in future studies. The scheme of the study would be to use single escalating doses of anti-CD40-XTEN compositions and measure the biochemical, PK, and clinical parameters. This would permit the determination of the maximum tolerated dose and establish the threshold and maximum concentrations in dosage and circulating drug that constitute the therapeutic window to be used in subsequent Phase II and Phase III trials conducted in target indications to determine efficacy and tolerability of the anti-CD40-XTEN compositions. 
     A phase II clinical study of human patients would be conducted in arthritis patients administered anti-CD40-XTEN or a suitable anti-inflammatory protein to determine an appropriate dose to relieve at least one symptom associated with rheumatoid arthritis, including reducing joint swelling, joint tenderness, inflammation, morning stiffness, and pain, or at least one biological surrogate marker associated with rheumatoid arthritis, including reducing erythrocyte sedimentation rates, and serum levels of C-reactive protein and/or IL2 receptor. In addition, safety data related to adverse events would be collected. A phase III efficacy study would be conducted wherein arthritis patients would be administered either the anti-CD40-XTEN, a positive control, or a placebo daily, bi-weekly, or weekly (or other dosing schedule deemed appropriate given the pharmacokinetic and pharmacodynamic properties of the compound) for an extended period of time. Patients would be evaluated for baseline symptoms of disease activity prior to receiving any treatments, including joint swelling, joint tenderness, inflammation, morning stiffness, disease activity evaluated by patient and physician as well as disability evaluated by, for example, a standardized Health Questionnaire Assessment (HAQ), and pain. Additional baseline evaluations could include erythrocyte sedimentation rates (ESR), serum levels of C-reactive protein (CRP) and soluble IL-2 receptor (IL-2r). The clinical response to treatment could be assessed using the criteria established by the American College of Rheumatology (ACR), such as the ACR20 criterion; i.e., if there was a 20 percent improvement in tender and swollen joint counts and 20 percent improvement in three of the five remaining symptoms measured, such as patient and physician global disease changes, pain, disability, and an acute phase reactant (Felson, D. T., et al., 1993 Arthritis and Rheumatism 36:729-740; Felson, D. T., et al., 1995 Arthritis and Rheumatism 38:1-9). Similarly, a subject would satisfy the ACR50 or ACR70 criterion if there was a 50 or 70 percent improvement, respectively, in tender and swollen joint counts and 50 or 70 percent improvement, respectively, in three of the five remaining symptoms measured, such as patient and physician global disease changes, pain, physical disability, and an acute phase reactant such as CRP or ESR. In addition, potential biomarkers of disease activity could be measured, including rheumatoid factor, CRP, ESR, soluble IL-2R, soluble ICAM-1, soluble E-selectin, and MMP-3. Efficacy outcomes would be determined using standard statistical methods. Toxicity and adverse event markers would also be followed in this study to verify that the compound is safe when used in the manner described. 
     Example 51: Clinical Applications of aHER2-XTEN-aCD3 
     Her2 antigen is over-expressed on a large number of solid malignancies. Expression is particularly high on many breast cancer cells. Herceptin has been approved for the treatment of HER2-positive breast cancers. A binding fusion protein of anti-Her2-XTEN-anti-CD3 could be evaluated for efficacy in the treatment of the same patient population. Clinical trials can be designed such that the efficacy and advantages of the aHER2-XTEN-aCD3 compositions can be verified in humans. Such studies in patients would comprise three phases. First, a Phase I safety and pharmacokinetics study in adult patients would be conducted to determine the maximum tolerated dose and pharmacokinetics and pharmacodynamics in humans. These studies would define potential toxicities and adverse events to be tracked in future studies. The scheme of the study would be to use single escalating doses of aHER2-XTEN-aCD3 compositions and measure the biochemical, PK, and clinical parameters. This would permit the determination of the maximum tolerated dose and establish the threshold and maximum concentrations in dosage and circulating drug that constitute the therapeutic window to be used in subsequent Phase II and Phase III trials conducted in target indications to determine efficacy and tolerability of the aHER2-XTEN-aCD3 compositions. 
     Example 52: Characterization of Secondary Structure of Fusion Protein Comprising XTEN 
     A fusion protein consisting of the XTEN_AE864 linked to a payload of exenatide was evaluated for degree of secondary structure by circular dichroism spectroscopy. CD spectroscopy was performed on a Jasco J-715 (Jasco Corporation, Tokyo, Japan) spectropolarimeter equipped with Jasco Peltier temperature controller (TPC-348WI). The concentration of protein was adjusted to 0.2 mg/mL in 20 mM sodium phosphate pH 7.0, 50 mM NaCl. The experiments were carried out using HELLMA quartz cells with an optical path-length of 0.1 cm. The CD spectra were acquired at 5°, 25°, 45°, and 65° C. and processed using the J-700 version 1.08.01 (Build 1) Jasco software for Windows. The samples were equilibrated at each temperature for 5 min before performing CD measurements. All spectra were recorded in duplicate from 300 nm to 185 nm using a bandwidth of 1 nm and a time constant of 2 sec, at a scan speed of 100 nm/min. The CD spectrum shown in  FIG. 30  shows no evidence of stable secondary structure and is consistent with an unstructured polypeptide. 
     Example 53: Pharmacokinetics of Extended Polypeptides Fused to GFP in Cynomolgus Monkeys 
     The pharmacokinetics of GFP-L288, GFP-L576, GFP-XTEN_AF576, GFP-XTEN_Y576 and XTENAD836-GFP were tested in cynomolgus monkeys to determine the effect of composition and length of the unstructured polypeptides on PK parameters. Blood samples were analyzed at various times after injection and the concentration of GFP in plasma was measured by ELISA using a polyclonal antibody against GFP for capture and a biotinylated preparation of the same polyclonal antibody for detection. Results are summarized in  FIG. 31 . They show a surprising increase of half-life with increasing length of the XTEN sequence. For example, a half-life of 10 h was determined for GFP-XTEN_L288 (with 288 amino acid residues in the XTEN). Doubling the length of the unstructured polypeptide fusion partner to 576 amino acids increased the half-life to 20-22 h for multiple fusion protein constructs; i.e., GFP-XTEN_L576, GFP-XTEN_AF576, GFP-XTEN_Y576. A further increase of the unstructured polypeptide fusion partner length to 836 residues resulted in a half-life of 72-75 h for XTEN_AD836-GFP. Thus, increasing the polymer length by 288 residues from 288 to 576 residues increased in vivo half-life by about 10 h. However, increasing the polypeptide length by 260 residues from 576 residues to 836 residues increased half-life by more than 50 h. These results show that there is a surprising threshold of unstructured polypeptide length that results in a greater than proportional gain in in vivo half-life. Thus, fusion proteins comprising extended, unstructured polypeptides are expected to have the property of enhanced pharmacokinetics compared to polypeptides of shorter lengths. 
     Example 54: Increasing Solubility and Stability of a Peptide Payload by Linking to XTEN 
     In order to evaluate the ability of XTEN to enhance the physicochemical properties of solubility and stability, fusion proteins of glucagon plus shorter-length XTEN were prepared and evaluated. The test articles were prepared in Tris-buffered saline at neutral pH and characterization of the Gcg-XTEN solution was by reverse-phase HPLC and size exclusion chromatography to affirm that the protein was homogeneous and non-aggregated in solution. The data are presented in Table 29. For comparative purposes, the solubility limit of unmodified glucagon in the same buffer was measured at 60 μM (0.2 mg/mL), and the result demonstrate that for all lengths of XTEN added, a substantial increase in solubility was attained. Importantly, in most cases the glucagon-XTEN fusion proteins were prepared to achieve target concentrations and were not evaluated to determine the maximum solubility limits for the given construct. However, in the case of glucagon linked to the AF-144 XTEN, the limit of solubility was determined, with the result that a 60-fold increase in solubility was achieved, compared to glucagon not linked to XTEN. In addition, the glucagon-AF144 CFXTEN was evaluated for stability, and was found to be stable in liquid formulation for at least 6 months under refrigerated conditions and for approximately one month at 37° C. (data not shown). 
     The data support the conclusion that the linking of short-length XTEN polypeptides to a biologically active protein such as glucagon can markedly enhance the solubility properties of the protein by the resulting fusion protein, as well as confer stability at the higher protein concentrations. 
     
       
         
           
               
             
               
                 TABLE 29 
               
             
            
               
                   
               
               
                 Solubility of Glucagon-XTEN constructs 
               
            
           
           
               
               
               
            
               
                   
                 Test Article 
                 Solubility 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Glucagon 
                 60 
                 μM 
               
               
                   
                 Glucagon-Y36 
                 &gt;370 
                 μM 
               
               
                   
                 Glucagon-Y72 
                 &gt;293 
                 μM 
               
               
                   
                 Glucagon-AF108 
                 &gt;145 
                 μM 
               
               
                   
                 Glucagon-AF120 
                 &gt;160 
                 μM 
               
               
                   
                 Glucagon-Y144 
                 &gt;497 
                 μM 
               
               
                   
                 Glucagon-AE144 
                 &gt;467 
                 μM 
               
               
                   
                 Glucagon-AF144 
                 &gt;3600 
                 μM 
               
               
                   
                 Glucagon-Y288 
                 &gt;163 
                 μM 
               
               
                   
                   
               
            
           
         
       
     
     Example 55: Binding Fusion Proteins with Cleavage Sequences 
     C-Terminal XTEN Releasable by FXIa 
     A fusion protein consisting of an XTEN protein fused to the C-terminus of a targeting moiety can be created with a XTEN release site cleavage sequence placed in between the targeting moiety and XTEN components. In this case, the release site cleavage sequence can be incorporated into the XTEN that contains an amino acid sequence that is recognized and cleaved by the FXIa protease (EC 3.4.21.27, Uniprot P03951). Specifically the amino acid sequence KLTRAET (SEQ ID NO: 748) is cut after the arginine of the sequence by FXIa protease. FXI is the pro-coagulant protease located immediately before FVIII in the intrinsic or contact activated coagulation pathway. Active FXIa is produced from FXI by proteolytic cleavage of the zymogen by FXIIa. Production of FXIa is tightly controlled and only occurs when coagulation is necessary for proper hemostasis. Therefore, by incorporation of the KLTRAET (SEQ ID NO: 748) cleavage sequence, the XTEN domain is removed from targeting moiety concurrent with activation of the intrinsic coagulation pathway in proximity to the targeting moiety-XTEN. This creates a situation where the targeting moiety-XTEN fusion protein is processed in one additional manner during the activation of the intrinsic pathway. 
     C-Terminal XTEN Releasable by Elastase-2 
     A fusion protein consisting of an XTEN protein fused to the C-terminus of a targeting moiety can be created with a XTEN release site cleavage sequence placed in between the targeting moiety and XTEN components. In this case, the release site contains an amino acid sequence that is recognized and cleaved by the elastase-2 protease (EC 3.4.21.37, Uniprot P08246). Specifically the sequence LGPVSGVP (SEQ ID NO: 749) [Rawlings N. D., et al. (2008)  Nucleic Acids Res.,  36: D320], is cut after position 4 in the sequence. Elastase is constitutively expressed by neutrophils and is present at all times in the circulation, but particularly during acute inflammation. Therefore as the long lived targeting moiety-XTEN circulates, a fraction of it is cleaved, particularly locally during inflammatory responses, creating a pool of shorter-lived targeting moiety to be used at the site of inflammation. 
     C-Terminal XTEN Releasable by MMP-12 
     A fusion protein consisting of an XTEN protein fused to the C-terminus of a targeting moiety can be created with a XTEN release site cleavage sequence placed in between the targeting moiety and XTEN components. In this case, the release site contains an amino acid sequence that is recognized and cleaved by the MMP-12 protease (EC 3.4.24.65, Uniprot P39900). Specifically the sequence GPAGLGGA (SEQ ID NO: 750) [Rawlings N. D., et al. (2008)  Nucleic Acids Res.,  36: D320], is cut after position 4 of the sequence. MMP-12 is constitutively expressed in whole blood. Therefore as the long lived AAT-XTEN circulates, a fraction of it is cleaved, creating a pool of shorter-lived AAT to be used. In a desirable feature of the inventive composition, this creates a circulating pro-drug depot that constantly releases a prophylactic amount of targeting moiety, with higher amounts released during an inflammatory response. 
     C-Terminal XTEN Releasable by MMP-13 
     A fusion protein consisting of an XTEN protein fused to the C-terminus of a targeting moiety can be created with a XTEN release site cleavage sequence placed in between the targeting moiety and XTEN components. In this case, the release site contains an amino acid sequence that is recognized and cleaved by the MMP-13 protease (EC 3.4.24-, Uniprot P45452). Specifically the sequence GPAGLRGA (SEQ ID NO: 751) [Rawlings N. D., et al. (2008)  Nucleic Acids Res.,  36: D320], is cut after position 4. MMP-13 is constitutively expressed in whole blood. Therefore as the long lived targeting moiety-XTEN circulates, a fraction of it is cleaved, creating a pool of shorter-lived AAT to be used. In a desirable feature of the inventive composition, this creates a circulating pro-drug depot that constantly releases a prophylactic amount of targeting moiety, with higher amounts released during an inflammatory response. 
     C-Terminal XTEN Releasable by MMP-17 
     A fusion protein consisting of an XTEN protein fused to the C-terminus of a targeting moiety can be created with a XTEN release site cleavage sequence placed in between the targeting moiety and XTEN components. In this case, the release site contains an amino acid sequence that is recognized and cleaved by the MMP-20 protease (EC.3.4.24-, Uniprot Q9ULZ9). Specifically the sequence APLGLRLR (SEQ ID NO: 752) [Rawlings N. D., et al. (2008)  Nucleic Acids Res.,  36: D320], is cut after position 4 in the sequence. MMP-17 is constitutively expressed in whole blood. Therefore as the long lived targeting moiety-XTEN circulates, a fraction of it is cleaved, creating a pool of shorter-lived targeting moiety to be used. In a desirable feature of the inventive composition, this creates a circulating pro-drug depot that constantly releases a prophylactic amount of targeting moiety, with higher amounts released during an inflammatory response. 
     C-Terminal XTEN Releasable by MMP-20 
     A fusion protein consisting of an XTEN protein fused to the C-terminus of a targeting moiety can be created with a XTEN release site cleavage sequence placed in between the targeting moiety and XTEN components. In this case, the release site contains an amino acid sequence that is recognized and cleaved by the MMP-20 protease (EC.3.4.24-, Uniprot 060882). Specifically the sequence PALPLVAQ (SEQ ID NO: 753) [Rawlings N. D., et al. (2008)  Nucleic Acids Res.,  36: D320], is cut after position 4 (depicted by the arrow). MMP-20 is constitutively expressed in whole blood. Therefore as the long lived targeting moiety-XTEN circulates, a fraction of it is cleaved, creating a pool of shorter-lived targeting moiety to be used. In a desirable feature of the inventive composition, this creates a circulating pro-drug depot that constantly releases a prophylactic amount of targeting moiety, with higher amounts released during an inflammatory response. 
     Example 56: Serum Stability of XTEN 
     A fusion protein containing XTEN_AE864 fused to the N-terminus of GFP was incubated in monkey plasma and rat kidney lysate for up to 7 days at 37° C. Samples were withdrawn at time 0, Day 1 and Day 7 and analyzed by SDS PAGE followed by detection using Western analysis and detection with antibodies against GFP as shown in  FIG. 16A - FIG. 16C . The sequence of XTEN_AE864 showed negligible signs of degradation over 7 days in plasma. However, XTEN_AE864 was rapidly degraded in rat kidney lysate over 3 days. The in vivo stability of the fusion protein was tested in plasma samples wherein the GFP_AE864 was immunoprecipitated and analyzed by SDS PAGE as described above. Samples that were withdrawn up to 7 days after injection showed very few signs of degradation. The results demonstrate the resistance of binding fusion protein to degradation due to serum proteases; a factor in the enhancement of pharmacokinetic properties of the binding fusion proteins. 
     Example 57: Analysis of Sequences for Secondary Structure by Prediction Algorithms 
     Amino acid sequences can be assessed for secondary structure via certain computer programs or algorithms, such as the well-known Chou-Fasman algorithm (Chou, P. Y., et al. (1974)  Biochemistry,  13: 222-45) and the Garnier-Osguthorpe-Robson, or “GOR” method (Gamier J, Gibrat J F, Robson B. (1996). GOR method for predicting protein secondary structure from amino acid sequence. Methods Enzymol 266:540-553). For a given sequence, the algorithms can predict whether there exists some or no secondary structure at all, expressed as total and/or percentage of residues of the sequence that form, for example, alpha-helices or beta-sheets or the percentage of residues of the sequence predicted to result in random coil formation. 
     Several representative sequences from XTEN “families” have been assessed using two algorithm tools for the Chou-Fasman and GOR methods to assess the degree of secondary structure in these sequences. The Chou-Fasman tool was provided by William R. Pearson and the University of Virginia, at the “Biosupport” internet site, URL located on the World Wide Web at fasta.bioch.virginia.edu/fasta_www2/fasta_www.cgi?rm=miscl as it existed on Jun. 19, 2009. The GOR tool was provided by Pole Informatique Lyonnais at the Network Protein Sequence Analysis internet site, URL located on the World Wide Web at .npsa-pbilibcp.fr/cgi-bin/secpred_gor4.pl as it existed on Jun. 19, 2008. 
     As a first step in the analyses, a single XTEN sequence was analyzed by the two algorithms. The AE864 composition is a XTEN with 864 amino acid residues created from multiple copies of four 12 amino acid sequence motifs consisting of the amino acids G, S, T, E, P, and A. The sequence motifs are characterized by the fact that there is limited repetitiveness within the motifs and within the overall sequence in that the sequence of any two consecutive amino acids is not repeated more than twice in any one 12 amino acid motif, and that no three contiguous amino acids of full-length the XTEN are identical. Successively longer portions of the AF 864 sequence from the N-terminus were analyzed by the Chou-Fasman and GOR algorithms (the latter requires a minimum length of 17 amino acids). The sequences were analyzed by entering the FASTA format sequences into the prediction tools and running the analysis. The results from the analyses are presented in Table 30. 
     The results indicate that, by the Chou-Fasman calculations, short XTEN of the AE and AG families, up to at least 288 amino acid residues, have no alpha-helices or beta sheets, but amounts of predicted percentage of random coil by the GOR algorithm vary from 78-99%. With increasing XTEN lengths of 504 residues to greater than 1300, the XTEN analyzed by the Chou-Fasman algorithm had predicted percentages of alpha-helices or beta sheets of 0 to about 2%, while the calculated percentages of random coil increased to from 94-99%. Those XTEN with alpha-helices or beta sheets were those sequences with one or more instances of three contiguous serine residues, which resulted in predicted beta-sheet formation. However, even these sequences still had approximately 99% random coil formation. 
     The analysis supports the conclusion that: 1) XTEN created from multiple sequence motifs of G, S, T, E, P, and A that have limited repetitiveness as to contiguous amino acids are predicted to have very low amounts of alpha-helices and beta-sheets; 2) that increasing the length of the XTEN does not appreciably increase the probability of alpha-helix or beta-sheet formation; and 3) that progressively increasing the length of the XTEN sequence by addition of non-repetitive 12-mers consisting of the amino acids G, S, T, E, P, and A results in increased percentage of random coil formation. Based on the numerous sequences evaluated by these methods, it is concluded that XTEN created from sequence motifs of G, S, T, E, P, and A that have limited repetitiveness (defined as no more than two identical contiguous amino acids in any one motif) are expected to have very limited secondary structure. With the exception of motifs containing three contiguous serines, it is believed that any order or combination of sequence motifs from Table 3 can be used to create an XTEN polypeptide that will result in an XTEN sequence that is substantially devoid of secondary structure, and that the effects of three contiguous serines is ameliorated by increasing the length of the XTEN. Such sequences are expected to have the characteristics described in the CFXTEN embodiments of the invention disclosed herein. 
     
       
         
           
               
             
               
                 TABLE 30 
               
             
            
               
                   
               
               
                 CHOU-FASMAN and GOR prediction calculations of polypeptide sequences 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
                   
                   
               
               
                 SEQ 
                   
                 ID 
                 No. 
                 Chou-Fasman 
                 GOR 
               
               
                 NAME 
                 Sequence 
                 NO: 
                 Residues 
                 Calculation 
                 Calculation 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 AE36: 
                 GSPAGSPTSTEEGTSESATPES 
                 754 
                 36 
                 Residue totals: H: 0 E: 0 
                 94.44% 
               
               
                 LCW0402 
                 GPGTSTEPSEGSAP 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                 _002 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AE36: 
                 GTSTEPSEGSAPGTSTEPSEGS 
                 755 
                 36 
                 Residue totals: H: 0 E: 0 
                 94.44% 
               
               
                 LCW0402 
                 APGTSTEPSEGSAP 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                 _003 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AG36: 
                 GASPGTSSTGSPGTPGSGTASS 
                 756 
                 36 
                 Residue totals: H: 0 E: 0 
                 77.78% 
               
               
                 LCW0404 
                 SPGSSTPSGATGSP 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                 _001 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AG36: 
                 GSSTPSGATGSPGSSPSASTGT 
                 757 
                 36 
                 Residue totals: H: 0 E: 0 
                 83.33 % 
               
               
                 LCW0404 
                 GPGSSTPSGATGSP 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                 _003 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AE42_1 
                 TEPSEGSAPGSPAGSPTSTEEG 
                 758 
                 42 
                 Residue totals: H: 0 E: 0 
                 90.48% 
               
               
                   
                 TSESATPESGPGSEPATSGS 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                   
               
               
                 AE42_1 
                 TEPSEGSAPGSPAGSPTSTEEG 
                 759 
                 42 
                 Residue totals: H: 0 E: 0 
                 90.48% 
               
               
                   
                 TSESATPESGPGSEPATSGS 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                   
               
               
                 AG42_1 
                 GAPSPSASTGTGPGTPGSGTAS 
                 760 
                 42 
                 Residue totals: H: 0 E: 0 
                 88.10% 
               
               
                   
                 SSPGSSTPSGATGSPGPSGP 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                   
               
               
                 AG42_2 
                 GPGTPGSGTASSSPGSSTPSGA 
                 761 
                 42 
                 Residue totals: H: 0 E: 0 
                 88.10% 
               
               
                   
                 TGSPGSSPSASTGTGPGASP 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                   
               
               
                 AE144 
                 GSEPATSGSETPGTSESATPES 
                 762 
                 144 
                 Residue totals: H: 0 E: 0 
                 98.61% 
               
               
                   
                 GPGSEPATSGSETPGSPAGSPT 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                   
                 STEEGTSTEPSEGSAPGSEPATS 
                   
                   
                   
                   
               
               
                   
                 GSETPGSEPATSGSETPGSEPA 
                   
                   
                   
                   
               
               
                   
                 TSGSETPGTSTEPSEGSAPGTSE 
                   
                   
                   
                   
               
               
                   
                 SATPESGPGSEPATSGSETPGTS 
                   
                   
                   
                   
               
               
                   
                 TEPSEGSAP 
                   
                   
                   
                   
               
               
                   
               
               
                 AG144_1 
                 PGSSPSASTGTGPGSSPSASTGT 
                 763 
                 144 
                 Residue totals: H: 0 E: 0 
                 91.67% 
               
               
                   
                 GPGTPGSGTASSSPGSSTPSGA 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                   
                 TGSPGSSPSASTGTGPGASPGT 
                   
                   
                   
                   
               
               
                   
                 SSTGSPGTPGSGTASSSPGSSTP 
                   
                   
                   
                   
               
               
                   
                 SGATGSPGTPGSGTASSSPGAS 
                   
                   
                   
                   
               
               
                   
                 PGTSSTGSPGASPGTSSTGSPG 
                   
                   
                   
                   
               
               
                   
                 TPGSGTASSS 
                   
                   
                   
                   
               
               
                   
               
               
                 AE288 
                 GTSESATPESGPGSEPATSGSE 
                 764 
                 288 
                 Residue totals: H: 0 E: 0 
                 99.31% 
               
               
                   
                 TPGTSESATPESGPGSEPATSGS 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                   
                 ETPGTSESATPESGPGTSTEPSE 
                   
                   
                   
                   
               
               
                   
                 GSAPGSPAGSPTSTEEGTSESA 
                   
                   
                   
                   
               
               
                   
                 TPESGPGSEPATSGSETPGTSES 
                   
                   
                   
                   
               
               
                   
                 ATPESGPGSPAGSPTSTEEGSP 
                   
                   
                   
                   
               
               
                   
                 AGSPTSTEEGTSTEPSEGSAPG 
                   
                   
                   
                   
               
               
                   
                 TSESATPESGPGTSESATPESGP 
                   
                   
                   
                   
               
               
                   
                 GTSESATPESGPGSEPATSGSE 
                   
                   
                   
                   
               
               
                   
                 TPGSEPATSGSETPGSPAGSPTS 
                   
                   
                   
                   
               
               
                   
                 TEEGTSTEPSEGSAPGTSTEPSE 
                   
                   
                   
                   
               
               
                   
                 GSAPGSEPATSGSETPGTSESA 
                   
                   
                   
                   
               
               
                   
                 TPESGPGTSTEPSEGSAP 
                   
                   
                   
                   
               
               
                   
               
               
                 AG288_2 
                 GSSPSASTGTGPGSSPSASTGT 
                 765 
                 288 
                 Residue totals: H: 0 E: 0 
                 92.71 
               
               
                   
                 GPGTPGSGTASSSPGSSTPSGA 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                   
                 TGSPGSSPSASTGTGPGASPGT 
                   
                   
                   
                   
               
               
                   
                 SSTGSPGTPGSGTASSSPGSSTP 
                   
                   
                   
                   
               
               
                   
                 SGATGSPGTPGSGTASSSPGAS 
                   
                   
                   
                   
               
               
                   
                 PGTSSTGSPGASPGTSSTGSPG 
                   
                   
                   
                   
               
               
                   
                 TPGSGTASSSPGSSTPSGATGSP 
                   
                   
                   
                   
               
               
                   
                 GASPGTSSTGSPGTPGSGTASS 
                   
                   
                   
                   
               
               
                   
                 SPGSSTPSGATGSPGSSPSASTG 
                   
                   
                   
                   
               
               
                   
                 TGPGSSPSASTGTGPGSSTPSG 
                   
                   
                   
                   
               
               
                   
                 ATGSPGSSTPSGATGSPGASPG 
                   
                   
                   
                   
               
               
                   
                 TSSTGSPGASPGTSSTGSPGASP 
                   
                   
                   
                   
               
               
                   
                 GTSSTGSPGTPGSGTASSSP 
                   
                   
                   
                   
               
               
                   
               
               
                 AF504 
                 GASPGTSSTGSPGSSPSASTGT 
                 766 
                 504 
                 Residue totals: H: 0 E: 0 
                 94.44% 
               
               
                   
                 GPGSSPSASTGTGPGTPGSGTA 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                   
                 SSSPGSSTPSGATGSPGSNPSAS 
                   
                   
                   
                   
               
               
                   
                 TGTGPGASPGTSSTGSPGTPGS 
                   
                   
                   
                   
               
               
                   
                 GTASSSPGSSTPSGATGSPGTP 
                   
                   
                   
                   
               
               
                   
                 GSGTASSSPGASPGTSSTGSPG 
                   
                   
                   
                   
               
               
                   
                 ASPGTSSTGSPGTPGSGTASSSP 
                   
                   
                   
                   
               
               
                   
                 GSSTPSGATGSPGASPGTSSTG 
                   
                   
                   
                   
               
               
                   
                 SPGTPGSGTASSSPGSSTPSGAT 
                   
                   
                   
                   
               
               
                   
                 GSPGSNPSASTGTGPGSSPSAS 
                   
                   
                   
                   
               
               
                   
                 TGTGPGSSTPSGATGSPGSSTP 
                   
                   
                   
                   
               
               
                   
                 SGATGSPGASPGTSSTGSPGAS 
                   
                   
                   
                   
               
               
                   
                 PGTSSTGSPGASPGTSSTGSPG 
                   
                   
                   
                   
               
               
                   
                 TPGSGTASSSPGASPGTSSTGSP 
                   
                   
                   
                   
               
               
                   
                 GASPGTSSTGSPGASPGTSSTG 
                   
                   
                   
                   
               
               
                   
                 SPGSSPSASTGTGPGTPGSGTA 
                   
                   
                   
                   
               
               
                   
                 SSSPGASPGTSSTGSPGASPGTS 
                   
                   
                   
                   
               
               
                   
                 STGSPGASPGTSSTGSPGSSTPS 
                   
                   
                   
                   
               
               
                   
                 GATGSPGSSTPSGATGSPGASP 
                   
                   
                   
                   
               
               
                   
                 GTSSTGSPGTPGSGTASSSPGSS 
                   
                   
                   
                   
               
               
                   
                 TPSGATGSPGSSTPSGATGSPG 
                   
                   
                   
                   
               
               
                   
                 SSTPSGATGSPGSSPSASTGTGP 
                   
                   
                   
                   
               
               
                   
                 GASPGTSSTGSP 
                   
                   
                   
                   
               
               
                   
               
               
                 AD 576 
                 GSSESGSSEGGPGSGGEPSESG 
                 767 
                 576 
                 Residue totals: H: 7 E: 0 
                 99.65% 
               
               
                   
                 SSGSSESGSSEGGPGSSESGSSE 
                   
                   
                   
                   
               
               
                   
                 GGPGSSESGSSEGGPGSSESGS 
                   
                   
                   
                   
               
               
                   
                 SEGGPGSSESGSSEGGPGESPG 
                   
                   
                   
                   
               
               
                   
                 GSSGSESGSEGSSGPGESSGSSE 
                   
                   
                   
                   
               
               
                   
                 SGSSEGGPGSSESGSSEGGPGS 
                   
                   
                   
                   
               
               
                   
                 SESGSSEGGPGSGGEPSESGSS 
                   
                   
                   
                   
               
               
                   
                 GESPGGSSGSESGESPGGSSGS 
                   
                   
                   
                   
               
               
                   
                 ESGSGGEPSESGSSGSSESGSSE 
                   
                   
                   
                   
               
               
                   
                 GGPGSGGEPSESGSSGSGGEPS 
                   
                   
                   
                   
               
               
                   
                 ESGSSGSEGSSGPGESSGESPG 
                   
                   
                   
                   
               
               
                   
                 GSSGSESGSGGEPSESGSSGSG 
                   
                   
                   
                   
               
               
                   
                 GEPSESGSSGSGGEPSESGSSGS 
                   
                   
                   
                   
               
               
                   
                 SESGSSEGGPGESPGGSSGSES 
                   
                   
                   
                   
               
               
                   
                 GESPGGSSGSESGESPGGSSGS 
                   
                   
                   
                   
               
               
                   
                 ESGESPGGSSGSESGESPGGSS 
                   
                   
                   
                   
               
               
                   
                 GSESGSSESGSSEGGPGSGGEP 
                   
                   
                   
                   
               
               
                   
                 SESGSSGSEGSSGPGESSGSSES 
                   
                   
                   
                   
               
               
                   
                 GSSEGGPGSGGEPSESGSSGSS 
                   
                   
                   
                   
               
               
                   
                 ESGSSEGGPGSGGEPSESGSSG 
                   
                   
                   
                   
               
               
                   
                 ESPGGSSGSESGESPGGSSGSES 
                   
                   
                   
                   
               
               
                   
                 GSSESGSSEGGPGSGGEPSESG 
                   
                   
                   
                   
               
               
                   
                 SSGSSESGSSEGGPGSGGEPSES 
                   
                   
                   
                   
               
               
                   
                 GSSGSGGEPSESGSSGESPGGS 
                   
                   
                   
                   
               
               
                   
                 SGSESGSEGSSGPGESSGSSESG 
                   
                   
                   
                   
               
               
                   
                 SSEGGPGSEGSSGPGESS 
                   
                   
                   
                   
               
               
                   
               
               
                 AE576 
                 GSPAGSPTSTEEGTSESATPES 
                 768 
                 576 
                 Residue totals: H: 2 E: 0 
                 99.65% 
               
               
                   
                 GPGTSTEPSEGSAPGSPAGSPT 
                   
                   
                 percent: H: 0.4 E: 0.0 
                   
               
               
                   
                 STEEGTSTEPSEGSAPGTSTEPS 
                   
                   
                   
                   
               
               
                   
                 EGSAPGTSESATPESGPGSEPA 
                   
                   
                   
                   
               
               
                   
                 TSGSETPGSEPATSGSETPGSPA 
                   
                   
                   
                   
               
               
                   
                 GSPTSTEEGTSESATPESGPGTS 
                   
                   
                   
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGS 
                   
                   
                   
                   
               
               
                   
                 PAGSPTSTEEGTSTEPSEGSAP 
                   
                   
                   
                   
               
               
                   
                 GTSTEPSEGSAPGTSESATPES 
                   
                   
                   
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATP 
                   
                   
                   
                   
               
               
                   
                 ESGPGSEPATSGSETPGTSTEPS 
                   
                   
                   
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGTSES 
                   
                   
                   
                   
               
               
                   
                 ATPESGPGTSESATPESGPGSP 
                   
                   
                   
                   
               
               
                   
                 AGSPTSTEEGTSESATPESGPG 
                   
                   
                   
                   
               
               
                   
                 SEPATSGSETPGTSESATPESGP 
                   
                   
                   
                   
               
               
                   
                 GTSTEPSEGSAPGTSTEPSEGS 
                   
                   
                   
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSE 
                   
                   
                   
                   
               
               
                   
                 GSAPGTSTEPSEGSAPGTSTEPS 
                   
                   
                   
                   
               
               
                   
                 EGSAPGSPAGSPTSTEEGTSTE 
                   
                   
                   
                   
               
               
                   
                 PSEGSAPGTSESATPESGPGSEP 
                   
                   
                   
                   
               
               
                   
                 ATSGSETPGTSESATPESGPGS 
                   
                   
                   
                   
               
               
                   
                 EPATSGSETPGTSESATPESGP 
                   
                   
                   
                   
               
               
                   
                 GTSTEPSEGSAPGTSESATPES 
                   
                   
                   
                   
               
               
                   
                 GPGSPAGSPTSTEEGSPAGSPT 
                   
                   
                   
                   
               
               
                   
                 STEEGSPAGSPTSTEEGTSESAT 
                   
                   
                   
                   
               
               
                   
                 PESGPGTSTEPSEGSAP 
                   
                   
                   
                   
               
               
                   
               
               
                 AG576 
                 PGTPGSGTASSSPGSSTPSGAT 
                 769 
                 576 
                 Residue totals: H: 0 E: 3 
                 99.31% 
               
               
                   
                 GSPGSSPSASTGTGPGSSPSAST 
                   
                   
                 percent: H: 0.4 E: 0.5 
                   
               
               
                   
                 GTGPGSSTPSGATGSPGSSTPS 
                   
                   
                   
                   
               
               
                   
                 GATGSPGASPGTSSTGSPGASP 
                   
                   
                   
                   
               
               
                   
                 GTSSTGSPGASPGTSSTGSPGT 
                   
                   
                   
                   
               
               
                   
                 PGSGTASSSPGASPGTSSTGSP 
                   
                   
                   
                   
               
               
                   
                 GASPGTSSTGSPGASPGTSSTG 
                   
                   
                   
                   
               
               
                   
                 SPGSSPSASTGTGPGTPGSGTA 
                   
                   
                   
                   
               
               
                   
                 SSSPGASPGTSSTGSPGASPGTS 
                   
                   
                   
                   
               
               
                   
                 STGSPGASPGTSSTGSPGSSTPS 
                   
                   
                   
                   
               
               
                   
                 GATGSPGSSTPSGATGSPGASP 
                   
                   
                   
                   
               
               
                   
                 GTSSTGSPGTPGSGTASSSPGSS 
                   
                   
                   
                   
               
               
                   
                 TPSGATGSPGSSTPSGATGSPG 
                   
                   
                   
                   
               
               
                   
                 SSTPSGATGSPGSSPSASTGTGP 
                   
                   
                   
                   
               
               
                   
                 GASPGTSSTGSPGASPGTSSTG 
                   
                   
                   
                   
               
               
                   
                 SPGTPGSGTASSSPGASPGTSST 
                   
                   
                   
                   
               
               
                   
                 GSPGASPGTSSTGSPGASPGTS 
                   
                   
                   
                   
               
               
                   
                 STGSPGASPGTSSTGSPGTPGS 
                   
                   
                   
                   
               
               
                   
                 GTASSSPGSSTPSGATGSPGTP 
                   
                   
                   
                   
               
               
                   
                 GSGTASSSPGSSTPSGATGSPG 
                   
                   
                   
                   
               
               
                   
                 TPGSGTASSSPGSSTPSGATGSP 
                   
                   
                   
                   
               
               
                   
                 GSSTPSGATGSPGSSPSASTGT 
                   
                   
                   
                   
               
               
                   
                 GPGSSPSASTGTGPGASPGTSS 
                   
                   
                   
                   
               
               
                   
                 TGSPGTPGSGTASSSPGSSTPSG 
                   
                   
                   
                   
               
               
                   
                 ATGSPGSSPSASTGTGPGSSPS 
                   
                   
                   
                   
               
               
                   
                 ASTGTGPGASPGTSSTGS 
                   
                   
                   
                   
               
               
                   
               
               
                 AF540 
                 GSTSSTAESPGPGSTSSTAESPG 
                 770 
                 540 
                 Residue totals: H: 2 E: 0 
                 99.65 
               
               
                   
                 PGSTSESPSGTAPGSTSSTAESP 
                   
                   
                 percent: H: 0.4 E: 0.0 
                   
               
               
                   
                 GPGSTSSTAESPGPGTSTPESGS 
                   
                   
                   
                   
               
               
                   
                 ASPGSTSESPSGTAPGTSPSGES 
                   
                   
                   
                   
               
               
                   
                 STAPGSTSESPSGTAPGSTSESP 
                   
                   
                   
                   
               
               
                   
                 SGTAPGTSPSGESSTAPGSTSES 
                   
                   
                   
                   
               
               
                   
                 PSGTAPGSTSESPSGTAPGTSPS 
                   
                   
                   
                   
               
               
                   
                 GESSTAPGSTSESPSGTAPGSTS 
                   
                   
                   
                   
               
               
                   
                 ESPSGTAPGSTSESPSGTAPGTS 
                   
                   
                   
                   
               
               
                   
                 TPESGSASPGSTSESPSGTAPGT 
                   
                   
                   
                   
               
               
                   
                 STPESGSASPGSTSSTAESPGPG 
                   
                   
                   
                   
               
               
                   
                 STSSTAESPGPGTSTPESGSASP 
                   
                   
                   
                   
               
               
                   
                 GTSTPESGSASPGSTSESPSGTA 
                   
                   
                   
                   
               
               
                   
                 PGTSTPESGSASPGTSTPESGSA 
                   
                   
                   
                   
               
               
                   
                 SPGSTSESPSGTAPGSTSESPSG 
                   
                   
                   
                   
               
               
                   
                 TAPGSTSESPSGTAPGSTSSTAE 
                   
                   
                   
                   
               
               
                   
                 SPGPGTSTPESGSASPGTSTPES 
                   
                   
                   
                   
               
               
                   
                 GSASPGSTSESPSGTAPGSTSES 
                   
                   
                   
                   
               
               
                   
                 PSGTAPGTSTPESGSASPGSTSE 
                   
                   
                   
                   
               
               
                   
                 SPSGTAPGSTSESPSGTAPGTST 
                   
                   
                   
                   
               
               
                   
                 PESGSASPGTSPSGESSTAPGST 
                   
                   
                   
                   
               
               
                   
                 SSTAESPGPGTSPSGESSTAPGS 
                   
                   
                   
                   
               
               
                   
                 TSSTAESPGPGTSTPESGSASPG 
                   
                   
                   
                   
               
               
                   
                 STSESPSGTAP 
                   
                   
                   
                   
               
               
                   
               
               
                 AD836 
                 GSSESGSSEGGPGSSESGSSEG 
                 771 
                 836 
                 Residue totals: H: 0 E: 0 
                 98.44% 
               
               
                   
                 GPGESPGGSSGSESGSGGEPSE 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                   
                 SGSSGESPGGSSGSESGESPGG 
                   
                   
                   
                   
               
               
                   
                 SSGSESGSSESGSSEGGPGSSES 
                   
                   
                   
                   
               
               
                   
                 GSSEGGPGSSESGSSEGGPGES 
                   
                   
                   
                   
               
               
                   
                 PGGSSGSESGESPGGSSGSESG 
                   
                   
                   
                   
               
               
                   
                 ESPGGSSGSESGSSESGSSEGGP 
                   
                   
                   
                   
               
               
                   
                 GSSESGSSEGGPGSSESGSSEG 
                   
                   
                   
                   
               
               
                   
                 GPGSSESGSSEGGPGSSESGSSE 
                   
                   
                   
                   
               
               
                   
                 GGPGSSESGSSEGGPGSGGEPS 
                   
                   
                   
                   
               
               
                   
                 ESGSSGESPGGSSGSESGESPG 
                   
                   
                   
                   
               
               
                   
                 GSSGSESGSGGEPSESGSSGSE 
                   
                   
                   
                   
               
               
                   
                 GSSGPGESSGSSESGSSEGGPG 
                   
                   
                   
                   
               
               
                   
                 SGGEPSESGSSGSEGSSGPGESS 
                   
                   
                   
                   
               
               
                   
                 GSSESGSSEGGPGSGGEPSESG 
                   
                   
                   
                   
               
               
                   
                 SSGESPGGSSGSESGSGGEPSES 
                   
                   
                   
                   
               
               
                   
                 GSSGSGGEPSESGSSGSSESGSS 
                   
                   
                   
                   
               
               
                   
                 EGGPGSGGEPSESGSSGSGGEP 
                   
                   
                   
                   
               
               
                   
                 SESGSSGSEGSSGPGESSGESPG 
                   
                   
                   
                   
               
               
                   
                 GSSGSESGSEGSSGPGESSGSE 
                   
                   
                   
                   
               
               
                   
                 GSSGPGESSGSGGEPSESGSSG 
                   
                   
                   
                   
               
               
                   
                 SSESGSSEGGPGSSESGSSEGGP 
                   
                   
                   
                   
               
               
                   
                 GESPGGSSGSESGSGGEPSESG 
                   
                   
                   
                   
               
               
                   
                 SSGSEGSSGPGESSGESPGGSS 
                   
                   
                   
                   
               
               
                   
                 GSESGSEGSSGPGSSESGSSEG 
                   
                   
                   
                   
               
               
                   
                 GPGSGGEPSESGSSGSEGSSGP 
                   
                   
                   
                   
               
               
                   
                 GESSGSEGSSGPGESSGSEGSS 
                   
                   
                   
                   
               
               
                   
                 GPGESSGSGGEPSESGSSGSGG 
                   
                   
                   
                   
               
               
                   
                 EPSESGSSGESPGGSSGSESGES 
                   
                   
                   
                   
               
               
                   
                 PGGSSGSESGSGGEPSESGSSG 
                   
                   
                   
                   
               
               
                   
                 SEGSSGPGESSGESPGGSSGSES 
                   
                   
                   
                   
               
               
                   
                 GSSESGSSEGGPGSSESGSSEG 
                   
                   
                   
                   
               
               
                   
                 GPGSSESGSSEGGPGSGGEPSE 
                   
                   
                   
                   
               
               
                   
                 SGSSGSSESGSSEGGPGESPGG 
                   
                   
                   
                   
               
               
                   
                 SSGSESGSGGEPSESGSSGSSES 
                   
                   
                   
                   
               
               
                   
                 GSSEGGPGESPGGSSGSESGSG 
                   
                   
                   
                   
               
               
                   
                 GEPSESGSSGESPGGSSGSESGS 
                   
                   
                   
                   
               
               
                   
                 GGEPSESGSS 
                   
                   
                   
                   
               
               
                   
               
               
                 AE864 
                 GSPAGSPTSTEEGTSESATPES 
                 772 
                 864 
                 Residue totals: H: 2 E: 3 
                 99.77% 
               
               
                   
                 GPGTSTEPSEGSAPGSPAGSPT 
                   
                   
                 percent: H: 0.2 E: 0.4 
                   
               
               
                   
                 STEEGTSTEPSEGSAPGTSTEPS 
                   
                   
                   
                   
               
               
                   
                 EGSAPGTSESATPESGPGSEPA 
                   
                   
                   
                   
               
               
                   
                 TSGSETPGSEPATSGSETPGSPA 
                   
                   
                   
                   
               
               
                   
                 GSPTSTEEGTSESATPESGPGTS 
                   
                   
                   
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGS 
                   
                   
                   
                   
               
               
                   
                 PAGSPTSTEEGTSTEPSEGSAP 
                   
                   
                   
                   
               
               
                   
                 GTSTEPSEGSAPGTSESATPES 
                   
                   
                   
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATP 
                   
                   
                   
                   
               
               
                   
                 ESGPGSEPATSGSETPGTSTEPS 
                   
                   
                   
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGTSES 
                   
                   
                   
                   
               
               
                   
                 ATPESGPGTSESATPESGPGSP 
                   
                   
                   
                   
               
               
                   
                 AGSPTSTEEGTSESATPESGPG 
                   
                   
                   
                   
               
               
                   
                 SEPATSGSETPGTSESATPESGP 
                   
                   
                   
                   
               
               
                   
                 GTSTEPSEGSAPGTSTEPSEGS 
                   
                   
                   
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSE 
                   
                   
                   
                   
               
               
                   
                 GSAPGTSTEPSEGSAPGTSTEPS 
                   
                   
                   
                   
               
               
                   
                 EGSAPGSPAGSPTSTEEGTSTE 
                   
                   
                   
                   
               
               
                   
                 PSEGSAPGTSESATPESGPGSEP 
                   
                   
                   
                   
               
               
                   
                 ATSGSETPGTSESATPESGPGS 
                   
                   
                   
                   
               
               
                   
                 EPATSGSETPGTSESATPESGP 
                   
                   
                   
                   
               
               
                   
                 GTSTEPSEGSAPGTSESATPES 
                   
                   
                   
                   
               
               
                   
                 GPGSPAGSPTSTEEGSPAGSPT 
                   
                   
                   
                   
               
               
                   
                 STEEGSPAGSPTSTEEGTSESAT 
                   
                   
                   
                   
               
               
                   
                 PESGPGTSTEPSEGSAPGTSESA 
                   
                   
                   
                   
               
               
                   
                 TPESGPGSEPATSGSETPGTSES 
                   
                   
                   
                   
               
               
                   
                 ATPESGPGSEPATSGSETPGTS 
                   
                   
                   
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGS 
                   
                   
                   
                   
               
               
                   
                 PAGSPTSTEEGTSESATPESGP 
                   
                   
                   
                   
               
               
                   
                 GSEPATSGSETPGTSESATPES 
                   
                   
                   
                   
               
               
                   
                 GPGSPAGSPTSTEEGSPAGSPT 
                   
                   
                   
                   
               
               
                   
                 STEEGTSTEPSEGSAPGTSESAT 
                   
                   
                   
                   
               
               
                   
                 PESGPGTSESATPESGPGTSESA 
                   
                   
                   
                   
               
               
                   
                 TPESGPGSEPATSGSETPGSEPA 
                   
                   
                   
                   
               
               
                   
                 TSGSETPGSPAGSPTSTEEGTST 
                   
                   
                   
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGSE 
                   
                   
                   
                   
               
               
                   
                 PATSGSETPGTSESATPESGPG 
                   
                   
                   
                   
               
               
                   
                 TSTEPSEGSAP 
                   
                   
                   
                   
               
               
                   
               
               
                 AF864 
                 GSTSESPSGTAPGTSPSGESSTA 
                 773 
                 875 
                 Residue totals: H: 2 E: 0 
                 95.20% 
               
               
                   
                 PGSTSESPSGTAPGSTSESPSGT 
                   
                   
                 percent: H: 0.2 E: 0.0 
                   
               
               
                   
                 APGTSTPESGSASPGTSTPESGS 
                   
                   
                   
                   
               
               
                   
                 ASPGSTSESPSGTAPGSTSESPS 
                   
                   
                   
                   
               
               
                   
                 GTAPGTSPSGESSTAPGSTSESP 
                   
                   
                   
                   
               
               
                   
                 SGTAPGTSPSGESSTAPGTSPS 
                   
                   
                   
                   
               
               
                   
                 GESSTAPGSTSSTAESPGPGTSP 
                   
                   
                   
                   
               
               
                   
                 SGESSTAPGTSPSGESSTAPGST 
                   
                   
                   
                   
               
               
                   
                 SSTAESPGPGTSTPESGSASPGT 
                   
                   
                   
                   
               
               
                   
                 STPESGSASPGSTSESPSGTAPG 
                   
                   
                   
                   
               
               
                   
                 STSESPSGTAPGTSTPESGSASP 
                   
                   
                   
                   
               
               
                   
                 GSTSSTAESPGPGTSTPESGSAS 
                   
                   
                   
                   
               
               
                   
                 PGSTSESPSGTAPGTSPSGESST 
                   
                   
                   
                   
               
               
                   
                 APGSTSSTAESPGPGTSPSGESS 
                   
                   
                   
                   
               
               
                   
                 TAPGTSTPESGSASPGSTSSTAE 
                   
                   
                   
                   
               
               
                   
                 SPGPGSTSSTAESPGPGSTSSTA 
                   
                   
                   
                   
               
               
                   
                 ESPGPGSTSSTAESPGPGTSPSG 
                   
                   
                   
                   
               
               
                   
                 ESSTAPGSTSESPSGTAPGSTSE 
                   
                   
                   
                   
               
               
                   
                 SPSGTAPGTSTPESGPXXXGAS 
                   
                   
                   
                   
               
               
                   
                 ASGAPSTXXXXSESPSGTAPGS 
                   
                   
                   
                   
               
               
                   
                 TSESPSGTAPGSTSESPSGTAPG 
                   
                   
                   
                   
               
               
                   
                 STSESPSGTAPGSTSESPSGTAP 
                   
                   
                   
                   
               
               
                   
                 GSTSESPSGTAPGTSTPESGSAS 
                   
                   
                   
                   
               
               
                   
                 PGTSPSGESSTAPGTSPSGESST 
                   
                   
                   
                   
               
               
                   
                 APGSTSSTAESPGPGTSPSGESS 
                   
                   
                   
                   
               
               
                   
                 TAPGTSTPESGSASPGSTSESPS 
                   
                   
                   
                   
               
               
                   
                 GTAPGSTSESPSGTAPGTSPSG 
                   
                   
                   
                   
               
               
                   
                 ESSTAPGSTSESPSGTAPGTSTP 
                   
                   
                   
                   
               
               
                   
                 ESGSASPGTSTPESGSASPGSTS 
                   
                   
                   
                   
               
               
                   
                 ESPSGTAPGTSTPESGSASPGST 
                   
                   
                   
                   
               
               
                   
                 SSTAESPGPGSTSESPSGTAPGS 
                   
                   
                   
                   
               
               
                   
                 TSESPSGTAPGTSPSGESSTAPG 
                   
                   
                   
                   
               
               
                   
                 STSSTAESPGPGTSPSGESSTAP 
                   
                   
                   
                   
               
               
                   
                 GTSTPESGSASPGTSPSGESSTA 
                   
                   
                   
                   
               
               
                   
                 PGTSPSGESSTAPGTSPSGESST 
                   
                   
                   
                   
               
               
                   
                 APGSTSSTAESPGPGSTSSTAES 
                   
                   
                   
                   
               
               
                   
                 PGPGTSPSGESSTAPGSSPSAST 
                   
                   
                   
                   
               
               
                   
                 GTGPGSSTPSGATGSPGSSTPS 
                   
                   
                   
                   
               
               
                   
                 GATGSP 
                   
                   
                   
                   
               
               
                   
               
               
                 AG864 
                 GASPGTSSTGSPGSSPSASTGT 
                 774 
                 864 
                 Residue totals: H: 0 E: 0 
                 94.91% 
               
               
                   
                 GPGSSPSASTGTGPGTPGSGTA 
                   
                   
                 percent: H: 0.0 E: 0.0 
                   
               
               
                   
                 SSSPGSSTPSGATGSPGSSPSAS 
                   
                   
                   
                   
               
               
                   
                 TGTGPGASPGTSSTGSPGTPGS 
                   
                   
                   
                   
               
               
                   
                 GTASSSPGSSTPSGATGSPGTP 
                   
                   
                   
                   
               
               
                   
                 GSGTASSSPGASPGTSSTGSPG 
                   
                   
                   
                   
               
               
                   
                 ASPGTSSTGSPGTPGSGTASSSP 
                   
                   
                   
                   
               
               
                   
                 GSSTPSGATGSPGASPGTSSTG 
                   
                   
                   
                   
               
               
                   
                 SPGTPGSGTASSSPGSSTPSGAT 
                   
                   
                   
                   
               
               
                   
                 GSPGSSPSASTGTGPGSSPSAST 
                   
                   
                   
                   
               
               
                   
                 GTGPGSSTPSGATGSPGSSTPS 
                   
                   
                   
                   
               
               
                   
                 GATGSPGASPGTSSTGSPGASP 
                   
                   
                   
                   
               
               
                   
                 GTSSTGSPGASPGTSSTGSPGT 
                   
                   
                   
                   
               
               
                   
                 PGSGTASSSPGASPGTSSTGSP 
                   
                   
                   
                   
               
               
                   
                 GASPGTSSTGSPGASPGTSSTG 
                   
                   
                   
                   
               
               
                   
                 SPGSSPSASTGTGPGTPGSGTA 
                   
                   
                   
                   
               
               
                   
                 SSSPGASPGTSSTGSPGASPGTS 
                   
                   
                   
                   
               
               
                   
                 STGSPGASPGTSSTGSPGSSTPS 
                   
                   
                   
                   
               
               
                   
                 GATGSPGSSTPSGATGSPGASP 
                   
                   
                   
                   
               
               
                   
                 GTSSTGSPGTPGSGTASSSPGSS 
                   
                   
                   
                   
               
               
                   
                 TPSGATGSPGSSTPSGATGSPG 
                   
                   
                   
                   
               
               
                   
                 SSTPSGATGSPGSSPSASTGTGP 
                   
                   
                   
                   
               
               
                   
                 GASPGTSSTGSPGASPGTSSTG 
                   
                   
                   
                   
               
               
                   
                 SPGTPGSGTASSSPGASPGTSST 
                   
                   
                   
                   
               
               
                   
                 GSPGASPGTSSTGSPGASPGTS 
                   
                   
                   
                   
               
               
                   
                 STGSPGASPGTSSTGSPGTPGS 
                   
                   
                   
                   
               
               
                   
                 GTASSSPGSSTPSGATGSPGTP 
                   
                   
                   
                   
               
               
                   
                 GSGTASSSPGSSTPSGATGSPG 
                   
                   
                   
                   
               
               
                   
                 TPGSGTASSSPGSSTPSGATGSP 
                   
                   
                   
                   
               
               
                   
                 GSSTPSGATGSPGSSPSASTGT 
                   
                   
                   
                   
               
               
                   
                 GPGSSPSASTGTGPGASPGTSS 
                   
                   
                   
                   
               
               
                   
                 TGSPGTPGSGTASSSPGSSTPSG 
                   
                   
                   
                   
               
               
                   
                 ATGSPGSSPSASTGTGPGSSPS 
                   
                   
                   
                   
               
               
                   
                 ASTGTGPGASPGTSSTGSPGAS 
                   
                   
                   
                   
               
               
                   
                 PGTSSTGSPGSSTPSGATGSPGS 
                   
                   
                   
                   
               
               
                   
                 SPSASTGTGPGASPGTSSTGSP 
                   
                   
                   
                   
               
               
                   
                 GSSPSASTGTGPGTPGSGTASS 
                   
                   
                   
                   
               
               
                   
                 SPGSSTPSGATGSPGSSTPSGAT 
                   
                   
                   
                   
               
               
                   
                 GSPGASPGTSSTGSP 
                   
                   
                   
                   
               
               
                   
               
               
                 AM875 
                 GTSTEPSEGSAPGSEPATSGSE 
                 775 
                 875 
                 Residue totals: H: 7 E: 3 
                 98.63% 
               
               
                   
                 TPGSPAGSPTSTEEGSTSSTAES 
                   
                   
                 percent: H: 0.8 E: 0.3 
                   
               
               
                   
                 PGPGTSTPESGSASPGSTSESPS 
                   
                   
                   
                   
               
               
                   
                 GTAPGSTSESPSGTAPGTSTPES 
                   
                   
                   
                   
               
               
                   
                 GSASPGTSTPESGSASPGSEPA 
                   
                   
                   
                   
               
               
                   
                 TSGSETPGTSESATPESGPGSPA 
                   
                   
                   
                   
               
               
                   
                 GSPTSTEEGTSTEPSEGSAPGTS 
                   
                   
                   
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPG 
                   
                   
                   
                   
               
               
                   
                 TSTEPSEGSAPGSPAGSPTSTEE 
                   
                   
                   
                   
               
               
                   
                 GTSTEPSEGSAPGTSTEPSEGS 
                   
                   
                   
                   
               
               
                   
                 APGTSESATPESGPGTSESATP 
                   
                   
                   
                   
               
               
                   
                 ESGPGTSTEPSEGSAPGTSTEPS 
                   
                   
                   
                   
               
               
                   
                 EGSAPGTSESATPESGPGTSTE 
                   
                   
                   
                   
               
               
                   
                 PSEGSAPGSEPATSGSETPGSP 
                   
                   
                   
                   
               
               
                   
                 AGSPTSTEEGSSTPSGATGSPG 
                   
                   
                   
                   
               
               
                   
                 TPGSGTASSSPGSSTPSGATGSP 
                   
                   
                   
                   
               
               
                   
                 GTSTEPSEGSAPGTSTEPSEGS 
                   
                   
                   
                   
               
               
                   
                 APGSEPATSGSETPGSPAGSPT 
                   
                   
                   
                   
               
               
                   
                 STEEGSPAGSPTSTEEGTSTEPS 
                   
                   
                   
                   
               
               
                   
                 EGSAPGASASGAPSTGGTSESA 
                   
                   
                   
                   
               
               
                   
                 TPESGPGSPAGSPTSTEEGSPA 
                   
                   
                   
                   
               
               
                   
                 GSPTSTEEGSTSSTAESPGPGST 
                   
                   
                   
                   
               
               
                   
                 SESPSGTAPGTSPSGESSTAPGT 
                   
                   
                   
                   
               
               
                   
                 PGSGTASSSPGSSTPSGATGSP 
                   
                   
                   
                   
               
               
                   
                 GSSPSASTGTGPGSEPATSGSE 
                   
                   
                   
                   
               
               
                   
                 TPGTSESATPESGPGSEPATSGS 
                   
                   
                   
                   
               
               
                   
                 ETPGSTSSTAESPGPGSTSSTAE 
                   
                   
                   
                   
               
               
                   
                 SPGPGTSPSGESSTAPGSEPATS 
                   
                   
                   
                   
               
               
                   
                 GSETPGSEPATSGSETPGTSTEP 
                   
                   
                   
                   
               
               
                   
                 SEGSAPGSTSSTAESPGPGTSTP 
                   
                   
                   
                   
               
               
                   
                 ESGSASPGSTSESPSGTAPGTST 
                   
                   
                   
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGTS 
                   
                   
                   
                   
               
               
                   
                 TEPSEGSAPGSSTPSGATGSPG 
                   
                   
                   
                   
               
               
                   
                 SSPSASTGTGPGASPGTSSTGSP 
                   
                   
                   
                   
               
               
                   
                 GSEPATSGSETPGTSESATPES 
                   
                   
                   
                   
               
               
                   
                 GPGSPAGSPTSTEEGSSTPSGA 
                   
                   
                   
                   
               
               
                   
                 TGSPGSSPSASTGTGPGASPGT 
                   
                   
                   
                   
               
               
                   
                 SSTGSPGTSESATPESGPGTSTE 
                   
                   
                   
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAP 
                   
                   
                   
                   
               
               
                   
               
               
                 AM1318 
                 GTSTEPSEGSAPGSEPATSGSE 
                 776 
                 1318 
                 Residue totals: H: 7 E: 0 
                 99.17% 
               
               
                   
                 TPGSPAGSPTSTEEGSTSSTAES 
                   
                   
                 percent: H: 0.7 E: 0.0 
                   
               
               
                   
                 PGPGTSTPESGSASPGSTSESPS 
                   
                   
                   
                   
               
               
                   
                 GTAPGSTSESPSGTAPGTSTPES 
                   
                   
                   
                   
               
               
                   
                 GSASPGTSTPESGSASPGSEPA 
                   
                   
                   
                   
               
               
                   
                 TSGSETPGTSESATPESGPGSPA 
                   
                   
                   
                   
               
               
                   
                 GSPTSTEEGTSTEPSEGSAPGTS 
                   
                   
                   
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPG 
                   
                   
                   
                   
               
               
                   
                 TSTEPSEGSAPGSPAGSPTSTEE 
                   
                   
                   
                   
               
               
                   
                 GTSTEPSEGSAPGTSTEPSEGS 
                   
                   
                   
                   
               
               
                   
                 APGTSESATPESGPGTSESATP 
                   
                   
                   
                   
               
               
                   
                 ESGPGTSTEPSEGSAPGTSTEPS 
                   
                   
                   
                   
               
               
                   
                 EGSAPGTSESATPESGPGTSTE 
                   
                   
                   
                   
               
               
                   
                 PSEGSAPGSEPATSGSETPGSP 
                   
                   
                   
                   
               
               
                   
                 AGSPTSTEEGSSTPSGATGSPG 
                   
                   
                   
                   
               
               
                   
                 TPGSGTASSSPGSSTPSGATGSP 
                   
                   
                   
                   
               
               
                   
                 GTSTEPSEGSAPGTSTEPSEGS 
                   
                   
                   
                   
               
               
                   
                 APGSEPATSGSETPGSPAGSPT 
                   
                   
                   
                   
               
               
                   
                 STEEGSPAGSPTSTEEGTSTEPS 
                   
                   
                   
                   
               
               
                   
                 EGSAPGPEPTGPAPSGGSEPAT 
                   
                   
                   
                   
               
               
                   
                 SGSETPGTSESATPESGPGSPA 
                   
                   
                   
                   
               
               
                   
                 GSPTSTEEGTSESATPESGPGSP 
                   
                   
                   
                   
               
               
                   
                 AGSPTSTEEGSPAGSPTSTEEG 
                   
                   
                   
                   
               
               
                   
                 TSESATPESGPGSPAGSPTSTEE 
                   
                   
                   
                   
               
               
                   
                 GSPAGSPTSTEEGSTSSTAESPG 
                   
                   
                   
                   
               
               
                   
                 PGSTSESPSGTAPGTSPSGESST 
                   
                   
                   
                   
               
               
                   
                 APGSTSESPSGTAPGSTSESPSG 
                   
                   
                   
                   
               
               
                   
                 TAPGTSPSGESSTAPGTSTEPSE 
                   
                   
                   
                   
               
               
                   
                 GSAPGTSESATPESGPGTSESA 
                   
                   
                   
                   
               
               
                   
                 TPESGPGSEPATSGSETPGTSES 
                   
                   
                   
                   
               
               
                   
                 ATPESGPGTSESATPESGPGTS 
                   
                   
                   
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPG 
                   
                   
                   
                   
               
               
                   
                 TSTEPSEGSAPGTSPSGESSTAP 
                   
                   
                   
                   
               
               
                   
                 GTSPSGESSTAPGTSPSGESSTA 
                   
                   
                   
                   
               
               
                   
                 PGTSTEPSEGSAPGSPAGSPTST 
                   
                   
                   
                   
               
               
                   
                 EEGTSTEPSEGSAPGSSPSASTG 
                   
                   
                   
                   
               
               
                   
                 TGPGSSTPSGATGSPGSSTPSG 
                   
                   
                   
                   
               
               
                   
                 ATGSPGSSTPSGATGSPGSSTPS 
                   
                   
                   
                   
               
               
                   
                 GATGSPGASPGTSSTGSPGASA 
                   
                   
                   
                   
               
               
                   
                 SGAPSTGGTSPSGESSTAPGST 
                   
                   
                   
                   
               
               
                   
                 SSTAESPGPGTSPSGESSTAPGT 
                   
                   
                   
                   
               
               
                   
                 SESATPESGPGTSTEPSEGSAPG 
                   
                   
                   
                   
               
               
                   
                 TSTEPSEGSAPGSSPSASTGTGP 
                   
                   
                   
                   
               
               
                   
                 GSSTPSGATGSPGASPGTSSTG 
                   
                   
                   
                   
               
               
                   
                 SPGTSTPESGSASPGTSPSGESS 
                   
                   
                   
                   
               
               
                   
                 TAPGTSPSGESSTAPGTSESATP 
                   
                   
                   
                   
               
               
                   
                 ESGPGSEPATSGSETPGTSTEPS 
                   
                   
                   
                   
               
               
                   
                 EGSAPGSTSESPSGTAPGSTSES 
                   
                   
                   
                   
               
               
                   
                 PSGTAPGTSTPESGSASPGSPA 
                   
                   
                   
                   
               
               
                   
                 GSPTSTEEGTSESATPESGPGTS 
                   
                   
                   
                   
               
               
                   
                 TEPSEGSAPGSPAGSPTSTEEG 
                   
                   
                   
                   
               
               
                   
                 TSESATPESGPGSEPATSGSETP 
                   
                   
                   
                   
               
               
                   
                 GSSTPSGATGSPGASPGTSSTG 
                   
                   
                   
                   
               
               
                   
                 SPGSSTPSGATGSPGSTSESPSG 
                   
                   
                   
                   
               
               
                   
                 TAPGTSPSGESSTAPGSTSSTAE 
                   
                   
                   
                   
               
               
                   
                 SPGPGSSTPSGATGSPGASPGT 
                   
                   
                   
                   
               
               
                   
                 SSTGSPGTPGSGTASSSPGSPA 
                   
                   
                   
                   
               
               
                   
                 GSPTSTEEGSPAGSPTSTEEGTS 
                   
                   
                   
                   
               
               
                   
                 TEPSEGSAP 
                   
                   
                   
                   
               
               
                   
               
               
                 AM923 
                 MAEPAGSPTSTEEGASPGTSST 
                 777 
                 924 
                 Residue totals: H: 4 E: 3 
                 98.70% 
               
               
                   
                 GSPGSSTPSGATGSPGSSTPSG 
                   
                   
                 percent: H: 0.4 E: 0.3 
                   
               
               
                   
                 ATGSPGTSTEPSEGSAPGSEPA 
                   
                   
                   
                   
               
               
                   
                 TSGSETPGSPAGSPTSTEEGSTS 
                   
                   
                   
                   
               
               
                   
                 STAESPGPGTSTPESGSASPGST 
                   
                   
                   
                   
               
               
                   
                 SESPSGTAPGSTSESPSGTAPGT 
                   
                   
                   
                   
               
               
                   
                 STPESGSASPGTSTPESGSASPG 
                   
                   
                   
                   
               
               
                   
                 SEPATSGSETPGTSESATPESGP 
                   
                   
                   
                   
               
               
                   
                 GSPAGSPTSTEEGTSTEPSEGS 
                   
                   
                   
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSE 
                   
                   
                   
                   
               
               
                   
                 GSAPGTSTEPSEGSAPGSPAGS 
                   
                   
                   
                   
               
               
                   
                 PTSTEEGTSTEPSEGSAPGTSTE 
                   
                   
                   
                   
               
               
                   
                 PSEGSAPGTSESATPESGPGTSE 
                   
                   
                   
                   
               
               
                   
                 SATPESGPGTSTEPSEGSAPGTS 
                   
                   
                   
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPG 
                   
                   
                   
                   
               
               
                   
                 TSTEPSEGSAPGSEPATSGSETP 
                   
                   
                   
                   
               
               
                   
                 GSPAGSPTSTEEGSSTPSGATG 
                   
                   
                   
                   
               
               
                   
                 SPGTPGSGTASSSPGSSTPSGAT 
                   
                   
                   
                   
               
               
                   
                 GSPGTSTEPSEGSAPGTSTEPSE 
                   
                   
                   
                   
               
               
                   
                 GSAPGSEPATSGSETPGSPAGS 
                   
                   
                   
                   
               
               
                   
                 PTSTEEGSPAGSPTSTEEGTSTE 
                   
                   
                   
                   
               
               
                   
                 PSEGSAPGASASGAPSTGGTSE 
                   
                   
                   
                   
               
               
                   
                 SATPESGPGSPAGSPTSTEEGSP 
                   
                   
                   
                   
               
               
                   
                 AGSPTSTEEGSTSSTAESPGPGS 
                   
                   
                   
                   
               
               
                   
                 TSESPSGTAPGTSPSGESSTAPG 
                   
                   
                   
                   
               
               
                   
                 TPGSGTASSSPGSSTPSGATGSP 
                   
                   
                   
                   
               
               
                   
                 GSSPSASTGTGPGSEPATSGSE 
                   
                   
                   
                   
               
               
                   
                 TPGTSESATPESGPGSEPATSGS 
                   
                   
                   
                   
               
               
                   
                 ETPGSTSSTAESPGPGSTSSTAE 
                   
                   
                   
                   
               
               
                   
                 SPGPGTSPSGESSTAPGSEPATS 
                   
                   
                   
                   
               
               
                   
                 GSETPGSEPATSGSETPGTSTEP 
                   
                   
                   
                   
               
               
                   
                 SEGSAPGSTSSTAESPGPGTSTP 
                   
                   
                   
                   
               
               
                   
                 ESGSASPGSTSESPSGTAPGTST 
                   
                   
                   
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGTS 
                   
                   
                   
                   
               
               
                   
                 TEPSEGSAPGSSTPSGATGSPG 
                   
                   
                   
                   
               
               
                   
                 SSPSASTGTGPGASPGTSSTGSP 
                   
                   
                   
                   
               
               
                   
                 GSEPATSGSETPGTSESATPES 
                   
                   
                   
                   
               
               
                   
                 GPGSPAGSPTSTEEGSSTPSGA 
                   
                   
                   
                   
               
               
                   
                 TGSPGSSPSASTGTGPGASPGT 
                   
                   
                   
                   
               
               
                   
                 SSTGSPGTSESATPESGPGTSTE 
                   
                   
                   
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAP 
                   
                   
                   
                   
               
               
                   
               
               
                 AE912 
                 MAEPAGSPTSTEEGTPGSGTAS 
                 778 
                 913 
                 Residue totals: H: 8 E: 3 
                 99.45% 
               
               
                   
                 SSPGSSTPSGATGSPGASPGTSS 
                   
                   
                 percent: H: 0.9 E: 0.3 
                   
               
               
                   
                 TGSPGSPAGSPTSTEEGTSESA 
                   
                   
                   
                   
               
               
                   
                 TPESGPGTSTEPSEGSAPGSPA 
                   
                   
                   
                   
               
               
                   
                 GSPTSTEEGTSTEPSEGSAPGTS 
                   
                   
                   
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGS 
                   
                   
                   
                   
               
               
                   
                 EPATSGSETPGSEPATSGSETP 
                   
                   
                   
                   
               
               
                   
                 GSPAGSPTSTEEGTSESATPES 
                   
                   
                   
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSE 
                   
                   
                   
                   
               
               
                   
                 GSAPGSPAGSPTSTEEGTSTEPS 
                   
                   
                   
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGTSES 
                   
                   
                   
                   
               
               
                   
                 ATPESGPGTSTEPSEGSAPGTS 
                   
                   
                   
                   
               
               
                   
                 ESATPESGPGSEPATSGSETPG 
                   
                   
                   
                   
               
               
                   
                 TSTEPSEGSAPGTSTEPSEGSAP 
                   
                   
                   
                   
               
               
                   
                 GTSESATPESGPGTSESATPES 
                   
                   
                   
                   
               
               
                   
                 GPGSPAGSPTSTEEGTSESATP 
                   
                   
                   
                   
               
               
                   
                 ESGPGSEPATSGSETPGTSESA 
                   
                   
                   
                   
               
               
                   
                 TPESGPGTSTEPSEGSAPGTSTE 
                   
                   
                   
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGTST 
                   
                   
                   
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGTS 
                   
                   
                   
                   
               
               
                   
                 TEPSEGSAPGSPAGSPTSTEEG 
                   
                   
                   
                   
               
               
                   
                 TSTEPSEGSAPGTSESATPESGP 
                   
                   
                   
                   
               
               
                   
                 GSEPATSGSETPGTSESATPES 
                   
                   
                   
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATP 
                   
                   
                   
                   
               
               
                   
                 ESGPGTSTEPSEGSAPGTSESA 
                   
                   
                   
                   
               
               
                   
                 TPESGPGSPAGSPTSTEEGSPA 
                   
                   
                   
                   
               
               
                   
                 GSPTSTEEGSPAGSPTSTEEGTS 
                   
                   
                   
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPG 
                   
                   
                   
                   
               
               
                   
                 TSESATPESGPGSEPATSGSETP 
                   
                   
                   
                   
               
               
                   
                 GTSESATPESGPGSEPATSGSE 
                   
                   
                   
                   
               
               
                   
                 TPGTSESATPESGPGTSTEPSEG 
                   
                   
                   
                   
               
               
                   
                 SAPGSPAGSPTSTEEGTSESATP 
                   
                   
                   
                   
               
               
                   
                 ESGPGSEPATSGSETPGTSESA 
                   
                   
                   
                   
               
               
                   
                 TPESGPGSPAGSPTSTEEGSPA 
                   
                   
                   
                   
               
               
                   
                 GSPTSTEEGTSTEPSEGSAPGTS 
                   
                   
                   
                   
               
               
                   
                 ESATPESGPGTSESATPESGPG 
                   
                   
                   
                   
               
               
                   
                 TSESATPESGPGSEPATSGSETP 
                   
                   
                   
                   
               
               
                   
                 GSEPATSGSETPGSPAGSPTSTE 
                   
                   
                   
                   
               
               
                   
                 EGTSTEPSEGSAPGTSTEPSEGS 
                   
                   
                   
                   
               
               
                   
                 APGSEPATSGSETPGTSESATP 
                   
                   
                   
                   
               
               
                   
                 ESGPGTSTEPSEGSAP 
                   
                   
                   
                   
               
               
                   
               
               
                 BC 864 
                 GTSTEPSEPGSAGTSTEPSEPGS 
                 779 
                   
                 Residue totals: H: 0 E: 0 
                 99.77% 
               
               
                   
                 AGSEPATSGTEPSGSGASEPTS 
                   
                   
                 percent: H: 0 E: 0 
                   
               
               
                   
                 TEPGSEPATSGTEPSGSEPATS 
                   
                   
                   
                   
               
               
                   
                 GTEPSGSEPATSGTEPSGSGAS 
                   
                   
                   
                   
               
               
                   
                 EPTSTEPGTSTEPSEPGSAGSEP 
                   
                   
                   
                   
               
               
                   
                 ATSGTEPSGTSTEPSEPGSAGS 
                   
                   
                   
                   
               
               
                   
                 EPATSGTEPSGSEPATSGTEPS 
                   
                   
                   
                   
               
               
                   
                 GTSTEPSEPGSAGTSTEPSEPGS 
                   
                   
                   
                   
               
               
                   
                 AGSEPATSGTEPSGSEPATSGT 
                   
                   
                   
                   
               
               
                   
                 EPSGTSEPSTSEPGAGSGASEPT 
                   
                   
                   
                   
               
               
                   
                 STEPGTSEPSTSEPGAGSEPATS 
                   
                   
                   
                   
               
               
                   
                 GTEPSGSEPATSGTEPSGTSTEP 
                   
                   
                   
                   
               
               
                   
                 SEPGSAGTSTEPSEPGSAGSGA 
                   
                   
                   
                   
               
               
                   
                 SEPTSTEPGSEPATSGTEPSGSE 
                   
                   
                   
                   
               
               
                   
                 PATSGTEPSGSEPATSGTEPSGS 
                   
                   
                   
                   
               
               
                   
                 EPATSGTEPSGTSTEPSEPGSA 
                   
                   
                   
                   
               
               
                   
                 GSEPATSGTEPSGSGASEPTST 
                   
                   
                   
                   
               
               
                   
                 EPGTSTEPSEPGSAGSEPATSG 
                   
                   
                   
                   
               
               
                   
                 TEPSGSGASEPTSTEPGTSTEPS 
                   
                   
                   
                   
               
               
                   
                 EPGSAGSGASEPTSTEPGSEPA 
                   
                   
                   
                   
               
               
                   
                 TSGTEPSGSGASEPTSTEPGSEP 
                   
                   
                   
                   
               
               
                   
                 ATSGTEPSGSGASEPTSTEPGT 
                   
                   
                   
                   
               
               
                   
                 STEPSEPGSAGSEPATSGTEPSG 
                   
                   
                   
                   
               
               
                   
                 SGASEPTSTEPGTSTEPSEPGSA 
                   
                   
                   
                   
               
               
                   
                 GSEPATSGTEPSGTSTEPSEPGS 
                   
                   
                   
                   
               
               
                   
                 AGSEPATSGTEPSGTSTEPSEP 
                   
                   
                   
                   
               
               
                   
                 GSAGTSTEPSEPGSAGTSTEPS 
                   
                   
                   
                   
               
               
                   
                 EPGSAGTSTEPSEPGSAGTSTE 
                   
                   
                   
                   
               
               
                   
                 PSEPGSAGTSTEPSEPGSAGTSE 
                   
                   
                   
                   
               
               
                   
                 PSTSEPGAGSGASEPTSTEPGTS 
                   
                   
                   
                   
               
               
                   
                 TEPSEPGSAGTSTEPSEPGSAG 
                   
                   
                   
                   
               
               
                   
                 TSTEPSEPGSAGSEPATSGTEPS 
                   
                   
                   
                   
               
               
                   
                 GSGASEPTSTEPGSEPATSGTE 
                   
                   
                   
                   
               
               
                   
                 PSGSEPATSGTEPSGSEPATSGT 
                   
                   
                   
                   
               
               
                   
                 EPSGSEPATSGTEPSGTSEPSTS 
                   
                   
                   
                   
               
               
                   
                 EPGAGSEPATSGTEPSGSGASE 
                   
                   
                   
                   
               
               
                   
                 PTSTEPGTSTEPSEPGSAGSEPA 
                   
                   
                   
                   
               
               
                   
                 TSGTEPSGSGASEPTSTEPGTST 
                   
                   
                   
                   
               
               
                   
                 EPSEPGSA 
               
               
                   
               
               
                 * H: alpha-helix E: beta-sheet 
               
            
           
         
       
     
     Example 58: Analysis of Polypeptide Sequences for Repetitiveness 
     Polypeptide amino acid sequences can be assessed for repetitiveness by quantifying the number of times a shorter subsequence appears within the overall polypeptide. For example, a polypeptide of 200 amino acid residues has 192 overlapping 9-amino acid subsequences (or 9-mer “frames”), but the number of unique 9-mer subsequences will depend on the amount of repetitiveness within the sequence. In the present analysis, different sequences were assessed for repetitiveness by summing the occurrence of all unique 3-mer subsequences for each 3-amino acid frame across the first 200 amino acids of the polymer portion divided by the absolute number of unique 3-mer subsequences within the 200 amino acid sequence. The resulting subsequence score is a reflection of the degree of repetitiveness within the polypeptide. The sequences of Table 31 were analyzed by the algorithm SegScore ( FIG. 37 ), which applies Equation I to the first 200 amino acids of a polypeptide. The results, shown in Table 31, indicate that the unstructured polypeptides consisting of 2 or 3 amino acid types have high subsequence scores, while those of consisting of 12 amino acids motifs of the six amino acids G, S, T, E, P, and A with a low degree of internal repetitiveness, have subsequence scores of less than 10, and in some cases, less than 5. For example, the L288 sequence has two amino acid types and has short, highly repetitive sequences, resulting in a subsequence score of 50.0. The polypeptide J288 has three amino acid types but also has short, repetitive sequences, resulting in a subsequence score of 33.3. Y576 also has three amino acid types, but is not made of internal repeats, reflected in the subsequence score of 15.7 over the first 200 amino acids. W576 consists of four types of amino acids, but has a higher degree of internal repetitiveness, e.g., “GGSG” (SEQ ID NO: 780), resulting in a subsequence score of 23.4. The AD576 consists of four types of 12 amino acid motifs, each consisting of four types of amino acids. Because of the low degree of internal repetitiveness of the individual motifs, the overall subsequence score over the first 200 amino acids is 13.6. In contrast, XTEN&#39;s consisting of four motifs contains six types of amino acids, each with a low degree of internal repetitiveness have lower subsequence scores; i.e., AE864 (6.1), AF864 (7.5), and AM875 (4.5). 
     Conclusions: The results indicate that the combination of 12 amino acid subsequence motifs, each consisting of four to six amino acid types that are essentially non-repetitive, into a longer XTEN polypeptide results in an overall sequence that is non-repetitive. This is despite the fact that each subsequence motif may be used multiple times across the sequence. In contrast, polymers created from smaller numbers of amino acid types resulted in higher subsequence scores, although the actual sequence can be tailored to reduce the degree of repetitiveness to result in lower subsequence scores. 
     
       
         
           
               
             
               
                 TABLE 31 
               
             
            
               
                   
               
               
                 Subsequence score calculations of polypeptide sequences 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
               
               
                 Seq 
                   
                 ID 
                   
               
               
                 Name 
                 Amino Acid Sequence 
                 NO: 
                 Score 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 J288 
                 GSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEG 
                 781 
                 33.3 
               
               
                   
                 GSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEG 
                   
                   
               
               
                   
                 GSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEG 
                   
                   
               
               
                   
                 GSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEG 
                   
                   
               
               
                   
                 GSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEG 
                   
                   
               
               
                   
                 GSGGEGGSGGEGGSGGEG 
                   
                   
               
               
                   
               
               
                 K288 
                 GEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGE 
                 782 
                 46.9 
               
               
                   
                 GGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGG 
                   
                   
               
               
                   
                 EGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGG 
                   
                   
               
               
                   
                 GEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEG 
                   
                   
               
               
                   
                 GGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGE 
                   
                   
               
               
                   
                 GGGEGGEGEGGGEGGEGEGGGEG 
                   
                   
               
               
                   
               
               
                 L288 
                 SSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSES 
                 783 
                 50.0 
               
               
                   
                 SESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESS 
                   
                   
               
               
                   
                 SSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSES 
                   
                   
               
               
                   
                 SSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSES 
                   
                   
               
               
                   
                 SESSSSESSSESSESSSSESSSESSESSSSES 
                   
                   
               
               
                   
               
               
                 Y288 
                 GEGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEGGSEGSEGEGGSEGSEGE 
                 784 
                 26.8 
               
               
                   
                 GSGEGSEGEGGSEGSEGEGSGEGSEGEGSEGGSEGEGGSEGSEGEGSGEGSEGEGG 
                   
                   
               
               
                   
                 EGGSEGEGSEGSGEGEGSGEGSEGEGSEGSGEGEGSGEGSEGEGSEGSGEGEGSEG 
                   
                   
               
               
                   
                 SGEGEGGSEGSEGEGSEGSGEGEGGEGSGEGEGSGEGSEGEGGGEGSEGEGSGEG 
                   
                   
               
               
                   
                 GEGEGSEGGSEGEGGSEGGEGEGSEGSGEGEGSEGGSEGEGSEGGSEGEGSEGSGE 
                   
                   
               
               
                   
                 GEGSEGSGE 
                   
                   
               
               
                   
               
               
                 Q576 
                 GGKPGEGGKPEGGGGKPGGKPEGEGEGKPGGKPEGGGKPGGGEGGKPEGGKPEG 
                 785 
                 18.5 
               
               
                   
                 EGKPGGGEGKPGGKPEGGGGKPEGEGKPGGGGGKPGGKPEGEGKPGGGEGGKPE 
                   
                   
               
               
                   
                 GKPGEGGEGKPGGKPEGGGEGKPGGGKPGEGGKPGEGKPGGGEGGKPEGGKPEG 
                   
                   
               
               
                   
                 EGKPGGGEGKPGGKPGEGGKPEGGGEGKPGGKPGEGGEGKPGGGKPEGEGKPGG 
                   
                   
               
               
                   
                 GKPGGGEGGKPEGEGKPGGKPEGGGEGKPGGKPEGGGKPEGGGEGKPGGGKPGE 
                   
                   
               
               
                   
                 GGKPGEGEGKPGGKPEGEGKPGGEGGGKPEGKPGGGEGGKPEGGKPGEGGKPEG 
                   
                   
               
               
                   
                 GKPGEGGEGKPGGGKPGEGGKPEGGGKPEGEGKPGGGGKPGEGGKPEGGKPEGG 
                   
                   
               
               
                   
                 GEGKPGGGKPEGEGKPGGGEGKPGGKPEGGGGKPGEGGKPEGGKPGGEGGGKPE 
                   
                   
               
               
                   
                 GEGKPGGKPGEGGGGKPGGKPEGEGKPGEGGEGKPGGKPEGGGEGKPGGKPEGG 
                   
                   
               
               
                   
                 GEGKPGGGKPGEGGKPEGGGKPGEGGKPGEGGKPEGEGKPGGGEGKPGGKPGEG 
                   
                   
               
               
                   
                 GKPEGGGEGKPGGKPGGEGGGKPEGGKPGEGGKPEG 
                   
                   
               
               
                   
               
               
                 U576 
                 GEGKPGGKPGSGGGKPGEGGKPGSGEGKPGGKPGSGGSGKPGGKPGEGGKPEGG 
                 786 
                 18.1 
               
               
                   
                 SGGKPGGGGKPGGKPGGEGSGKPGGKPEGGGKPEGGSGGKPGGKPEGGSGGKPG 
                   
                   
               
               
                   
                 GKPGSGEGGKPGGGKPGGEGKPGSGKPGGEGSGKPGGKPEGGSGGKPGGKPEGG 
                   
                   
               
               
                   
                 SGGKPGGSGKPGGKPGEGGKPEGGSGGKPGGSGKPGGKPEGGGSGKPGGKPGEG 
                   
                   
               
               
                   
                 GKPGSGEGGKPGGGKPGGEGKPGSGKPGGEGSGKPGGKPGSGGEGKPGGKPEGG 
                   
                   
               
               
                   
                 SGGKPGGGKPGGEGKPGSGGKPGEGGKPGSGGGKPGGKPGGEGEGKPGGKPGEG 
                   
                   
               
               
                   
                 GKPGGEGSGKPGGGGKPGGKPGGEGGKPEGSGKPGGGSGKPGGKPEGGGGKPEG 
                   
                   
               
               
                   
                 SGKPGGGGKPEGSGKPGGGKPEGGSGGKPGGSGKPGGKPGEGGGKPEGSGKPGG 
                   
                   
               
               
                   
                 GSGKPGGKPEGGGKPEGGSGGKPGGKPEGGSGGKPGGKPGGEGSGKPGGKPGSG 
                   
                   
               
               
                   
                 EGGKPGGKPGEGSGGKPGGKPEGGSGGKPGGSGKPGGKPEGGGSGKPGGKPGEG 
                   
                   
               
               
                   
                 GKPGGEGSGKPGGSGKPG 
                   
                   
               
               
                   
               
               
                 W576 
                 GGSGKPGKPGGSGSGKPGSGKPGGGSGKPGSGKPGGGSGKPGSGKPGGGSGKPGS 
                 787 
                 23.4 
               
               
                   
                 GKPGGGGKPGSGSGKPGGGKPGGSGGKPGGGSGKPGKPGSGGSGKPGSGKPGGG 
                   
                   
               
               
                   
                 SGGKPGKPGSGGSGGKPGKPGSGGGSGKPGKPGSGGSGGKPGKPGSGGSGGKPG 
                   
                   
               
               
                   
                 KPGSGGSGKPGSGKPGGGSGKPGSGKPGSGGSGKPGKPGSGGSGKPGSGKPGSGS 
                   
                   
               
               
                   
                 GKPGSGKPGGGSGKPGSGKPGSGGSGKPGKPGSGGGKPGSGSGKPGGGKPGSGSG 
                   
                   
               
               
                   
                 KPGGGKPGGSGGKPGGSGGKPGKPGSGGGSGKPGKPGSGGGSGKPGKPGGSGSG 
                   
                   
               
               
                   
                 KPGSGKPGGGSGKPGSGKPGSGGSGKPGKPGSGGSGGKPGKPGSGGGKPGSGSGK 
                   
                   
               
               
                   
                 PGGGKPGSGSGKPGGGKPGSGSGKPGGGKPGSGSGKPGGSGKPGSGKPGGGSGG 
                   
                   
               
               
                   
                 KPGKPGSGGSGKPGSGKPGSGGSGKPGKPGGSGSGKPGSGKPGGGSGKPGSGKPG 
                   
                   
               
               
                   
                 GGSGKPGSGKPGGGSGKPGSGKPGGGGKPGSGSGKPGGSGGKPGKPGSGGSGGK 
                   
                   
               
               
                   
                 PGKPGSGGSGKPGSGKPGGGSGGKPGKPGSGG 
                   
                   
               
               
                   
               
               
                 Y576 
                 GEGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEGSEGSGEGEGGEGSGEGE 
                 788 
                 15.7 
               
               
                   
                 GSGEGSEGEGGGEGSEGEGSGEGGEGEGSEGGSEGEGGSEGGEGEGSEGSGEGEG 
                   
                   
               
               
                   
                 SEGGSEGEGSEGGSEGEGSEGSGEGEGSEGSGEGEGSEGSGEGEGSEGSGEGEGSE 
                   
                   
               
               
                   
                 GGSEGEGGSEGSEGEGSGEGSEGEGGSEGSEGEGGGEGSEGEGSGEGSEGEGGSEG 
                   
                   
               
               
                   
                 SEGEGGSEGSEGEGGEGSGEGEGSEGSGEGEGSGEGSEGEGSEGSGEGEGSEGSGE 
                   
                   
               
               
                   
                 GEGGSEGSEGEGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEGGSEGSEGE 
                   
                   
               
               
                   
                 GGSEGSEGEGGEGSGEGEGSEGSGEGEGSGEGSEGEGSEGSGEGEGSEGSGEGEGG 
                   
                   
               
               
                   
                 SEGSEGEGSEGSGEGEGGEGSGEGEGSGEGSEGEGGGEGSEGEGSEGSGEGEGSEG 
                   
                   
               
               
                   
                 SGEGEGSEGGSEGEGGSEGSEGEGSEGGSEGEGSEGGSEGEGSEGSGEGEGSEGSG 
                   
                   
               
               
                   
                 EGEGSGEGSEGEGGSEGGEGEGSEGGSEGEGSEGGSEGEGGEGSGEGEGGGEGSE 
                   
                   
               
               
                   
                 GEGSEGSGEGEGSGEGSE 
                   
                   
               
               
                   
               
               
                 AD576 
                 GSSESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGG 
                 789 
                 13.6 
               
               
                   
                 PGSSESGSSEGGPGSSESGSSEGGPGESPGGSSGSESGSEGSSGPGESSGSSESGSSEG 
                   
                   
               
               
                   
                 GPGSSESGSSEGGPGSSESGSSEGGPGSGGEPSESGSSGESPGGSSGSESGESPGGSS 
                   
                   
               
               
                   
                 GSESGSGGEPSESGSSGSSESGSSEGGPGSGGEPSESGSSGSGGEPSESGSSGSEGSSG 
                   
                   
               
               
                   
                 PGESSGESPGGSSGSESGSGGEPSESGSSGSGGEPSESGSSGSGGEPSESGSSGSSESG 
                   
                   
               
               
                   
                 SSEGGPGESPGGSSGSESGESPGGSSGSESGESPGGSSGSESGESPGGSSGSESGESPG 
                   
                   
               
               
                   
                 GSSGSESGSSESGSSEGGPGSGGEPSESGSSGSEGSSGPGESSGSSESGSSEGGPGSG 
                   
                   
               
               
                   
                 GEPSESGSSGSSESGSSEGGPGSGGEPSESGSSGESPGGSSGSESGESPGGSSGSESGS 
                   
                   
               
               
                   
                 SESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSGGEPSESGSSGSGGEPSESGSSG 
                   
                   
               
               
                   
                 ESPGGSSGSESGSEGSSGPGESSGSSESGSSEGGPGSEGSSGPGESS 
                   
                   
               
               
                   
               
               
                 AE576 
                 AGSPAGSPTSTLEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 
                 790 
                 6.1 
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTS 
                   
                   
               
               
                   
                 TEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSE 
                   
                   
               
               
                   
                 GSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATS 
                   
                   
               
               
                   
                 GSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGS 
                   
                   
               
               
                   
                 PTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTE 
                   
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPA 
                   
                   
               
               
                   
                 GSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSE 
                   
                   
               
               
                   
                 PATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGS 
                   
                   
               
               
                   
                 PAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAP 
                   
                   
               
               
                   
               
               
                 AF540 
                 GSTSSTAESPGPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGSTSSTAESPGP 
                 791 
                 8.8 
               
               
                   
                 GTSTPESGSASPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAP 
                   
                   
               
               
                   
                 GTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAP 
                   
                   
               
               
                   
                 GSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSTSESPSGTAPGTSTPESGSASP 
                   
                   
               
               
                   
                 GSTSSTAESPGPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAP 
                   
                   
               
               
                   
                 GTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAP 
                   
                   
               
               
                   
                 GSTSSTAESPGPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAP 
                   
                   
               
               
                   
                 GTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSPSGESSTAP 
                   
                   
               
               
                   
                 GSTSSTAESPGPGTSPSGESSTAPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAP 
                   
                   
               
               
                   
               
               
                 AF504 
                 GASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGS 
                 792 
                 7.0 
               
               
                   
                 PGSNPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTAS 
                   
                   
               
               
                   
                 SSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGASPGTSS 
                   
                   
               
               
                   
                 TGSPGTPGSGTASSSPGSSTPSGATGSPGSNPSASTGTGPGSSPSASTGTGPGSSTPSG 
                   
                   
               
               
                   
                 ATGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGTPGS 
                   
                   
               
               
                   
                 GTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSPSASTGTGPGTPG 
                   
                   
               
               
                   
                 SGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSS 
                   
                   
               
               
                   
                 TPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGS 
                   
                   
               
               
                   
                 STPSGATGSPGSSPSASTGTGPGASPGTSSTGSP 
                   
                   
               
               
                   
               
               
                 AE864 
                 GSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSA 
                 793 
                 6.1 
               
               
                   
                 PGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTST 
                   
                   
               
               
                   
                 EEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEG 
                   
                   
               
               
                   
                 SAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSG 
                   
                   
               
               
                   
                 SETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSP 
                   
                   
               
               
                   
                 TSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEP 
                   
                   
               
               
                   
                 SEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAG 
                   
                   
               
               
                   
                 SPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEP 
                   
                   
               
               
                   
                 ATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSP 
                   
                   
               
               
                   
                 AGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGS 
                   
                   
               
               
                   
                 EPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPG 
                   
                   
               
               
                   
                 SPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEE 
                   
                   
               
               
                   
                 GSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESG 
                   
                   
               
               
                   
                 PGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAP 
                   
                   
               
               
                   
               
               
                 AF864 
                 GSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASP 
                 794 
                 7.5 
               
               
                   
                 GTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAP 
                   
                   
               
               
                   
                 GTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSPSGESSTAP 
                   
                   
               
               
                   
                 GSTSSTAESPGPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAP 
                   
                   
               
               
                   
                 GTSTPESGSASPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGTSPSGESSTAP 
                   
                   
               
               
                   
                 GSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASPGSTSSTAESPGPGSTSSTAESPGP 
                   
                   
               
               
                   
                 GSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAP 
                   
                   
               
               
                   
                 GTSTPESGPXXXGASASGAPSTXXXXSESPSGTAPGSTSESPSGTAPGSTSESPSGTA 
                   
                   
               
               
                   
                 PGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSPSGESSTA 
                   
                   
               
               
                   
                 PGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASPGSTSESPSGTA 
                   
                   
               
               
                   
                 PGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSAS 
                   
                   
               
               
                   
                 PGSTSESPSGTAPGTSTPESGSASPGSTSSTAESPGPGSTSESPSGTAPGSTSESPSGTA 
                   
                   
               
               
                   
                 PGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASPGTSPSGESSTA 
                   
                   
               
               
                   
                 PGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTA 
                   
                   
               
               
                   
                 PGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSP 
                   
                   
               
               
                   
               
               
                 AG868 
                 GGSPGASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSG 
                 795 
                 7.5 
               
               
                   
                 ATGSPGSNPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGS 
                   
                   
               
               
                   
                 GTASSSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGASP 
                   
                   
               
               
                   
                 GTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSNPSASTGTGPGSSPSASTGTGPGSS 
                   
                   
               
               
                   
                 TPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPG 
                   
                   
               
               
                   
                 TPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSPSASTGTGP 
                   
                   
               
               
                   
                 GTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGS 
                   
                   
               
               
                   
                 PGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATG 
                   
                   
               
               
                   
                 SPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTAS 
                   
                   
               
               
                   
                 SSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTA 
                   
                   
               
               
                   
                 SSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSG 
                   
                   
               
               
                   
                 ATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGTPGS 
                   
                   
               
               
                   
                 GTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGASP 
                   
                   
               
               
                   
                 GTSSTGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSSPSASTGTGPGTP 
                   
                   
               
               
                   
                 GSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSP 
                   
                   
               
               
                   
               
               
                 AM875 
                 GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSAS 
                 796 
                 4.5 
               
               
                   
                 PGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSE 
                   
                   
               
               
                   
                 TPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEG 
                   
                   
               
               
                   
                 SAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATP 
                   
                   
               
               
                   
                 ESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPS 
                   
                   
               
               
                   
                 EGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPS 
                   
                   
               
               
                   
                 GATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPA 
                   
                   
               
               
                   
                 GSPTSTEEGTSTEPSEGSAPGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSP 
                   
                   
               
               
                   
                 AGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGS 
                   
                   
               
               
                   
                 STPSGATGSPGSSPSASTGTGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPG 
                   
                   
               
               
                   
                 STSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETP 
                   
                   
               
               
                   
                 GTSTEPSEGSAPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSA 
                   
                   
               
               
                   
                 PGTSTEPSEGSAPGTSTEPSEGSAPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTG 
                   
                   
               
               
                   
                 SPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSSTPSGATGSPGSSPSASTG 
                   
                   
               
               
                   
                 TGPGASPGTSSTGSPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAP 
                   
                   
               
               
                   
               
               
                 AM1318 
                 GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSAS 
                 797 
                 4.5 
               
               
                   
                 PGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSE 
                   
                   
               
               
                   
                 TPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEG 
                   
                   
               
               
                   
                 SAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATP 
                   
                   
               
               
                   
                 ESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPS 
                   
                   
               
               
                   
                 EGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPS 
                   
                   
               
               
                   
                 GATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPA 
                   
                   
               
               
                   
                 GSPTSTEEGTSTEPSEGSAPGPEPTGPAPSGGSEPATSGSETPGTSESATPESGPGSPA 
                   
                   
               
               
                   
                 GSPTSTEEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSP 
                   
                   
               
               
                   
                 AGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESSTAPGS 
                   
                   
               
               
                   
                 TSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGTSTEPSEGSAPGTSESATPESGPG 
                   
                   
               
               
                   
                 TSESATPESGPGSEPATSGSETPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAP 
                   
                   
               
               
                   
                 GTSESATPESGPGTSTEPSEGSAPGTSPSGESSTAPGTSPSGESSTAPGTSPSGESSTA 
                   
                   
               
               
                   
                 PGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGSSPSASTGTGPGSSTPSGATG 
                   
                   
               
               
                   
                 SPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASASGAP 
                   
                   
               
               
                   
                 STGGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSESATPESGPGTSTEPSE 
                   
                   
               
               
                   
                 GSAPGTSTEPSEGSAPGSSPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPGTSTPES 
                   
                   
               
               
                   
                 GSASPGTSPSGESSTAPGTSPSGESSTAPGTSESATPESGPGSEPATSGSETPGTSTEP 
                   
                   
               
               
                   
                 SEGSAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSPAGSPTSTEEGTSES 
                   
                   
               
               
                   
                 ATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGSST 
                   
                   
               
               
                   
                 PSGATGSPGASPGTSSTGSPGSSTPSGATGSPGSTSESPSGTAPGTSPSGESSTAPGST 
                   
                   
               
               
                   
                 SSTAESPGPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSPAGSPTSTEEGS 
                   
                   
               
               
                   
                 PAGSPTSTEEGTSTEPSEGSAP 
               
               
                   
               
            
           
         
       
     
     Example 59: Calculation of TEPITOPE Scores 
     TEPITOPE scores of 9mer peptide sequence can be calculated by adding pocket potentials as described by Sturniolo [Sturniolo, T., et al. (1999) Nat Biotechnol, 17: 555]. In the present Example, separate Tepitope scores were calculated for individual HLA alleles. Table 32 shows as an example the pocket potentials for HLA*0101B, which occurs in high frequency in the Caucasian population. To calculate the TEPITOPE score of a peptide with sequence P1-P2-P3-P4-P5-P6-P7-P8-P9, the corresponding individual pocket potentials in Table 32 were added. The HLA*0101B score of a 9mer peptide with the sequence FDKLPRTSG (SEQ ID NO: 798) would be the sum of 0, −1.3, 0, 0.9, 0, −1.8, 0.09, 0, 0. 
     To evaluate the TEPITOPE scores for long peptides one can repeat the process for all 9mer subsequences of the sequences. This process can be repeated for the proteins encoded by other HLA alleles. Tables 33-36 give pocket potentials for the protein products of HLA alleles that occur with high frequency in the Caucasian population. 
     TEPITOPE scores calculated by this method range from approximately −10 to +10. However, 9mer peptides that lack a hydrophobic amino acid (FKLMVWY (SEQ ID NO: 799)) in P1 position have calculated TEPITOPE scores in the range of −1009 to −989. This value is biologically meaningless and reflects the fact that a hydrophobic amino acid serves as an anchor residue for HLA binding and peptides lacking a hydrophobic residue in P1 are considered non binders to HLA. Because most XTEN sequences lack hydrophobic residues, all combinations of 9mer subsequences will have TEPITOPEs in the range in the range of −1009 to −989. This method confirms that XTEN polypeptides may have few or no predicted T-cell epitopes. 
     
       
         
           
               
             
               
                 TABLE 32 
               
             
            
               
                   
               
               
                 Pocket potential for HLA*0101B allele. 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Amino 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Acid 
                 P1 
                 P2 
                 P3 
                 P4 
                 P5 
                 P6 
                 P7 
                 P8 
                 P9 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 A 
                 −999 
                 0 
                 0 
                 0 
                 — 
                 0 
                 0 
                 — 
                 0 
               
               
                 C 
                 −999 
                 0 
                 0 
                 0 
                 — 
                 0 
                 0 
                 — 
                 0 
               
               
                 D 
                 −999 
                 −1.3 
                 −1.3 
                 −2.4 
                 — 
                 −2.7 
                 −2 
                 — 
                 −1.9 
               
               
                 E 
                 −999 
                 0.1 
                 −1.2 
                 −0.4 
                 — 
                 −2.4 
                 −0.6 
                 — 
                 −1.9 
               
               
                 F 
                 0 
                 0.8 
                 0.8 
                 0.08 
                 — 
                 −2.1 
                 0.3 
                 — 
                 −0.4 
               
               
                 G 
                 −999 
                 0.5 
                 0.2 
                 −0.7 
                 — 
                 −0.3 
                 −1.1 
                 — 
                 −0.8 
               
               
                 H 
                 −999 
                 0.8 
                 0.2 
                 −0.7 
                 — 
                 −2.2 
                 0.1 
                 — 
                 −1.1 
               
               
                 I 
                 −1 
                 1.1 
                 1.5 
                 0.5 
                 — 
                 −1.9 
                 0.6 
                 — 
                 0.7 
               
               
                 K 
                 −999 
                 1.1 
                 0 
                 −2.1 
                 — 
                 −2 
                 −0.2 
                 — 
                 −1.7 
               
               
                 L 
                 −1 
                 1 
                 1 
                 0.9 
                 — 
                 −2 
                 0.3 
                 — 
                 0.5 
               
               
                 M 
                 −1 
                 1.1 
                 1.4 
                 0.8 
                 — 
                 −1.8 
                 0.09 
                 — 
                 0.08 
               
               
                 N 
                 −999 
                 0.8 
                 0.5 
                 0.04 
                 — 
                 −1.1 
                 0.1 
                 — 
                 −1.2 
               
               
                 P 
                 −999 
                 −0.5 
                 0.3 
                 −1.9 
                 — 
                 −0.2 
                 0.07 
                 — 
                 −1.1 
               
               
                 Q 
                 −999 
                 1.2 
                 0 
                 0.1 
                 — 
                 −1.8 
                 0.2 
                 — 
                 −1.6 
               
               
                 R 
                 −999 
                 2.2 
                 0.7 
                 −2.1 
                 — 
                 −1.8 
                 0.09 
                 — 
                 −1 
               
               
                 S 
                 −999 
                 −0.3 
                 0.2 
                 −0.7 
                 — 
                 −0.6 
                 −0.2 
                 — 
                 −0.3 
               
               
                 T 
                 −999 
                 0 
                 0 
                 −1 
                 — 
                 −1.2 
                 0.09 
                 — 
                 −0.2 
               
               
                 V 
                 −1 
                 2.1 
                 0.5 
                 −0.1 
                 — 
                 −1.1 
                 0.7 
                 — 
                 0.3 
               
               
                 W 
                 0 
                 −0.1 
                 0 
                 −1.8 
                 — 
                 −2.4 
                 −0.1 
                 — 
                 −1.4 
               
               
                 Y 
                 0 
                 0.9 
                 0.8 
                 −1.1 
                 — 
                 −2 
                 0.5 
                 — 
                 −0.9 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 33 
               
             
            
               
                   
               
               
                 Pocket potential for HLA*0301B allele. 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Amino 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 acid 
                 P1 
                 P2 
                 P3 
                 P4 
                 P5 
                 P6 
                 P7 
                 P8 
                 P9 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 A 
                 −999 
                 0 
                 0 
                 0 
                 — 
                 0 
                 0 
                 — 
                 0 
               
               
                 C 
                 −999 
                 0 
                 0 
                 0 
                 — 
                 0 
                 0 
                 — 
                 0 
               
               
                 D 
                 −999 
                 −1.3 
                 −1.3 
                 2.3 
                 — 
                 −2.4 
                 −0.6 
                 — 
                 −0.6 
               
               
                 E 
                 −999 
                 0.1 
                 −1.2 
                 −1 
                 — 
                 −1.4 
                 −0.2 
                 — 
                 −0.3 
               
               
                 F 
                 −1 
                 0.8 
                 0.8 
                 −1 
                 — 
                 −1.4 
                 0.5 
                 — 
                 0.9 
               
               
                 G 
                 −999 
                 0.5 
                 0.2 
                 0.5 
                 — 
                 −0.7 
                 0.1 
                 — 
                 0.4 
               
               
                 H 
                 −999 
                 0.8 
                 0.2 
                 0 
                 — 
                 −0.1 
                 −0.8 
                 — 
                 −0.5 
               
               
                 I 
                 0 
                 1.1 
                 1.5 
                 0.5 
                 — 
                 0.7 
                 0.4 
                 — 
                 0.6 
               
               
                 K 
                 −999 
                 1.1 
                 0 
                 −1 
                 — 
                 1.3 
                 −0.9 
                 — 
                 −0.2 
               
               
                 L 
                 0 
                 1 
                 1 
                 0 
                 — 
                 0.2 
                 0.2 
                 — 
                 −0 
               
               
                 M 
                 0 
                 1.1 
                 1.4 
                 0 
                 — 
                 −0.9 
                 1.1 
                 — 
                 1.1 
               
               
                 N 
                 −999 
                 0.8 
                 0.5 
                 0.2 
                 — 
                 −0.6 
                 −0.1 
                 — 
                 −0.6 
               
               
                 P 
                 −999 
                 −0.5 
                 0.3 
                 −1 
                 — 
                 0.5 
                 0.7 
                 — 
                 −0.3 
               
               
                 Q 
                 −999 
                 1.2 
                 0 
                 0 
                 — 
                 −0.3 
                 −0.1 
                 — 
                 −0.2 
               
               
                 R 
                 −999 
                 2.2 
                 0.7 
                 −1 
                 — 
                 1 
                 −0.9 
                 — 
                 0.5 
               
               
                 S 
                 −999 
                 −0.3 
                 0.2 
                 0.7 
                 — 
                 −0.1 
                 0.07 
                 — 
                 1.1 
               
               
                 T 
                 −999 
                 0 
                 0 
                 −1 
                 — 
                 0.8 
                 −0.1 
                 — 
                 −0.5 
               
               
                 V 
                 0 
                 2.1 
                 0.5 
                 0 
                 — 
                 1.2 
                 0.2 
                 — 
                 0.3 
               
               
                 W 
                 −1 
                 −0.1 
                 0 
                 −1 
                 — 
                 −1.4 
                 −0.6 
                 — 
                 −1 
               
               
                 Y 
                 −1 
                 0.9 
                 0.8 
                 −1 
                 — 
                 −1.4 
                 −0.1 
                 — 
                 0.3 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 34 
               
             
            
               
                   
               
               
                 Pocket potential for HLA*0401B allele. 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Amino 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 acid 
                 P1 
                 P2 
                 P3 
                 P4 
                 P5 
                 P6 
                 P7 
                 P8 
                 P9 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 A 
                 −999 
                 0 
                 0 
                 0 
                 — 
                 0 
                 0 
                 — 
                 0 
               
               
                 C 
                 −999 
                 0 
                 0 
                 0 
                 — 
                 0 
                 0 
                 — 
                 0 
               
               
                 D 
                 −999 
                 −1.3 
                 −1.3 
                 1.4 
                 — 
                 −1.1 
                 −0.3 
                 — 
                 −1.7 
               
               
                 E 
                 −999 
                 0.1 
                 −1.2 
                 1.5 
                 — 
                 −2.4 
                 0.2 
                 — 
                 −1.7 
               
               
                 F 
                 0 
                 0.8 
                 0.8 
                 −0.9 
                 — 
                 −1.1 
                 −1 
                 — 
                 −1 
               
               
                 G 
                 −999 
                 0.5 
                 0.2 
                 −1.6 
                 — 
                 −1.5 
                 −1.3 
                 — 
                 −1 
               
               
                 H 
                 −999 
                 0.8 
                 0.2 
                 1.1 
                 — 
                 −1.4 
                 0 
                 — 
                 0.08 
               
               
                 I 
                 −1 
                 1.1 
                 1.5 
                 0.8 
                 — 
                 −0.1 
                 0.08 
                 — 
                 −0.3 
               
               
                 K 
                 −999 
                 1.1 
                 0 
                 −1.7 
                 — 
                 −2.4 
                 −0.3 
                 — 
                 −0.3 
               
               
                 L 
                 −1 
                 1 
                 1 
                 0.8 
                 — 
                 −1.1 
                 0.7 
                 — 
                 −1 
               
               
                 M 
                 −1 
                 1.1 
                 1.4 
                 0.9 
                 — 
                 −1.1 
                 0.8 
                 — 
                 −0.4 
               
               
                 N 
                 −999 
                 0.8 
                 0.5 
                 0.9 
                 — 
                 1.3 
                 0.6 
                 — 
                 −1.4 
               
               
                 P 
                 −999 
                 −0.5 
                 0.3 
                 −1.6 
                 — 
                 0 
                 −0.7 
                 — 
                 −1.3 
               
               
                 Q 
                 −999 
                 1.2 
                 0 
                 0.8 
                 — 
                 −1.5 
                 0 
                 — 
                 0.5 
               
               
                 R 
                 −999 
                 2.2 
                 0.7 
                 −1.9 
                 — 
                 −2.4 
                 −1.2 
                 — 
                 −1 
               
               
                 S 
                 −999 
                 −0.3 
                 0.2 
                 0.8 
                 — 
                 1 
                 −0.2 
                 — 
                 0.7 
               
               
                 T 
                 −999 
                 0 
                 0 
                 0.7 
                 — 
                 1.9 
                 −0.1 
                 — 
                 −1.2 
               
               
                 V 
                 −1 
                 2.1 
                 0.5 
                 −0.9 
                 — 
                 0.9 
                 0.08 
                 — 
                 −0.7 
               
               
                 W 
                 0 
                 −0.1 
                 0 
                 −1.2 
                 — 
                 −1 
                 −1.4 
                 — 
                 −1 
               
               
                 Y 
                 0 
                 0.9 
                 0.8 
                 −1.6 
                 — 
                 −1.5 
                 −1.2 
                 — 
                 −1 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 35 
               
             
            
               
                   
               
               
                 Pocket potential for HLA*0701B allele. 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Amino 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 acid 
                 P1 
                 P2 
                 P3 
                 P4 
                 P5 
                 P6 
                 P7 
                 P8 
                 P9 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 A 
                 −999 
                 0 
                 0 
                 0 
                 — 
                 0 
                 0 
                 — 
                 0 
               
               
                 C 
                 −999 
                 0 
                 0 
                 0 
                 — 
                 0 
                 0 
                 — 
                 0 
               
               
                 D 
                 −999 
                 −1.3 
                 −1.3 
                 −1.6 
                 — 
                 −2.5 
                 −1.3 
                 — 
                 −1.2 
               
               
                 E 
                 −999 
                 0.1 
                 −1.2 
                 −1.4 
                 — 
                 −2.5 
                 0.9 
                 — 
                 −0.3 
               
               
                 F 
                 0 
                 0.8 
                 0.8 
                 0.2 
                 — 
                 −0.8 
                 2.1 
                 — 
                 2.1 
               
               
                 G 
                 −999 
                 0.5 
                 0.2 
                 −1.1 
                 — 
                 −0.6 
                 0 
                 — 
                 −0.6 
               
               
                 H 
                 −999 
                 0.8 
                 0.2 
                 0.1 
                 — 
                 −0.8 
                 0.9 
                 — 
                 −0.2 
               
               
                 I 
                 −1 
                 1.1 
                 1.5 
                 1.1 
                 — 
                 −0.5 
                 2.4 
                 — 
                 3.4 
               
               
                 K 
                 −999 
                 1.1 
                 0 
                 −1.3 
                 — 
                 −1.1 
                 0.5 
                 — 
                 −1.1 
               
               
                 L 
                 −1 
                 1 
                 1 
                 −0.8 
                 — 
                 −0.9 
                 2.2 
                 — 
                 3.4 
               
               
                 M 
                 −1 
                 1.1 
                 1.4 
                 −0.4 
                 — 
                 −0.8 
                 1.8 
                 — 
                 2 
               
               
                 N 
                 −999 
                 0.8 
                 0.5 
                 −1.1 
                 — 
                 −0.6 
                 1.4 
                 — 
                 −0.5 
               
               
                 P 
                 −999 
                 −0.5 
                 0.3 
                 −1.2 
                 — 
                 −0.5 
                 −0.2 
                 — 
                 −0.6 
               
               
                 Q 
                 −999 
                 1.2 
                 0 
                 −1.5 
                 — 
                 −1.1 
                 1.1 
                 — 
                 −0.9 
               
               
                 R 
                 −999 
                 2.2 
                 0.7 
                 −1.1 
                 — 
                 −1.1 
                 0.7 
                 — 
                 −0.8 
               
               
                 S 
                 −999 
                 −0.3 
                 0.2 
                 1.5 
                 — 
                 0.6 
                 0.4 
                 — 
                 −0.3 
               
               
                 T 
                 −999 
                 0 
                 0 
                 1.4 
                 — 
                 −0.1 
                 0.9 
                 — 
                 0.4 
               
               
                 V 
                 −1 
                 2.1 
                 0.5 
                 0.9 
                 — 
                 0.1 
                 1.6 
                 — 
                 2 
               
               
                 W 
                 0 
                 −0.1 
                 0 
                 −1.1 
                 — 
                 −0.9 
                 1.4 
                 — 
                 0.8 
               
               
                 Y 
                 0 
                 0.9 
                 0.8 
                 −0.9 
                 — 
                 −1 
                 1.7 
                 — 
                 1.1 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 36 
               
             
            
               
                   
               
               
                 Pocket potential for HLA*1501B allele. 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Amino 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 acid 
                 P1 
                 P2 
                 P3 
                 P4 
                 P5 
                 P6 
                 P7 
                 P8 
                 P9 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 A 
                 −999 
                 0 
                 0 
                 0 
                 — 
                 0 
                 0 
                 — 
                 0 
               
               
                 C 
                 −999 
                 0 
                 0 
                 0 
                 — 
                 0 
                 0 
                 — 
                 0 
               
               
                 D 
                 −999 
                 −1.3 
                 −1.3 
                 −0.4 
                 — 
                 −0.4 
                 −0.7 
                 — 
                 −1.9 
               
               
                 E 
                 −999 
                 0.1 
                 −1.2 
                 −0.6 
                 — 
                 −1 
                 −0.7 
                 — 
                 −1.9 
               
               
                 F 
                 −1 
                 0.8 
                 0.8 
                 2.4 
                 — 
                 −0.3 
                 1.4 
                 — 
                 −0.4 
               
               
                 G 
                 −999 
                 0.5 
                 0.2 
                 0 
                 — 
                 0.5 
                 0 
                 — 
                 −0.8 
               
               
                 H 
                 −999 
                 0.8 
                 0.2 
                 1.1 
                 — 
                 −0.5 
                 0.6 
                 — 
                 −1.1 
               
               
                 I 
                 0 
                 1.1 
                 1.5 
                 0.6 
                 — 
                 0.05 
                 1.5 
                 — 
                 0.7 
               
               
                 K 
                 −999 
                 1.1 
                 0 
                 −0.7 
                 — 
                 −0.3 
                 −0.3 
                 — 
                 −1.7 
               
               
                 L 
                 0 
                 1 
                 1 
                 0.5 
                 — 
                 0.2 
                 1.9 
                 — 
                 0.5 
               
               
                 M 
                 0 
                 1.1 
                 1.4 
                 1 
                 — 
                 0.1 
                 1.7 
                 — 
                 0.08 
               
               
                 N 
                 −999 
                 0.8 
                 0.5 
                 −0.2 
                 — 
                 0.7 
                 0.7 
                 — 
                 −1.2 
               
               
                 P 
                 −999 
                 −0.5 
                 0.3 
                 −0.3 
                 — 
                 −0.2 
                 0.3 
                 — 
                 −1.1 
               
               
                 Q 
                 −999 
                 1.2 
                 0 
                 −0.8 
                 — 
                 −0.8 
                 −0.3 
                 — 
                 −1.6 
               
               
                 R 
                 −999 
                 2.2 
                 0.7 
                 0.2 
                 — 
                 1 
                 −0.5 
                 — 
                 −1 
               
               
                 S 
                 −999 
                 −0.3 
                 0.2 
                 −0.3 
                 — 
                 0.6 
                 0.3 
                 — 
                 −0.3 
               
               
                 T 
                 −999 
                 0 
                 0 
                 −0.3 
                 — 
                 −0 
                 0.2 
                 — 
                 −0.2 
               
               
                 V 
                 0 
                 2.1 
                 0.5 
                 0.2 
                 — 
                 −0.3 
                 0.3 
                 — 
                 0.3 
               
               
                 W 
                 −1 
                 −0.1 
                 0 
                 0.4 
                 — 
                 −0.4 
                 0.6 
                 — 
                 −1.4 
               
               
                 Y 
                 −1 
                 0.9 
                 0.8 
                 2.5 
                 — 
                 0.4 
                 0.7 
                 — 
                 −0.9 
               
               
                   
               
            
           
         
       
     
     Example 60: Analytical Size Exclusion Chromatography of XTEN Fusion Proteins with Diverse Payloads 
     Size exclusion chromatography analyses were performed on fusion proteins containing various therapeutic proteins and unstructured recombinant proteins of increasing length. An exemplary assay used a TSKGel-G4000 SWXL (7.8 mm×30 cm) column in which 40 μg of purified glucagon fusion protein at a concentration of 1 mg/ml was separated at a flow rate of 0.6 ml/min in 20 mM phosphate pH 6.8, 114 mM NaCl. Chromatogram profiles were monitored using OD214 nm and OD280 nm. Column calibration for all assays were performed using a size exclusion calibration standard from BioRad; the markers include thyroglobulin (670 kDa), bovine gamma-globulin (158 kDa), chicken ovalbumin (44 kDa), equine myoglobuin (17 kDa) and vitamin B12 (1.35 kDa). Representative chromatographic profiles of Glucagon-Y288, Glucagon-Y144, Glucagon-Y72, Glucagon-Y36 are shown as an overlay in  FIG. 32 . The data show that the apparent molecular weight of each compound is proportional to the length of the attached XTEN sequence. However, the data also show that the apparent molecular weight of each construct is significantly larger than that expected for a globular protein (as shown by comparison to the standard proteins run in the same assay). Based on the SEC analyses for all constructs evaluated, the apparent molecular weights, the apparent molecular weight factor (expressed as the ratio of apparent molecular weight to the calculated molecular weight) and the hydrodynamic radius (RH in nm) are shown in Table 37. The results indicate that incorporation of different XTENs of 576 amino acids or greater confers an apparent molecular weight for the fusion protein of approximately 339 kDa to 760, and that XTEN of 864 amino acids or greater confers an apparent molecular weight greater than approximately 800 kDA. The results of proportional increases in apparent molecular weight to actual molecular weight were consistent for fusion proteins created with XTEN from several different motif families; i.e., AD, AE, AF, AG, and AM, with increases of at least four-fold and ratios as high as about 17-fold. Additionally, the incorporation of XTEN fusion partners with 576 amino acids or more into fusion proteins with the various payloads (and 288 residues in the case of glucagon fused to Y288) resulted with a hydrodynamic radius of 7 nm or greater; well beyond the glomerular pore size of approximately 3-5 nm. Accordingly, it is expected that fusion proteins comprising growth and XTEN have reduced renal clearance, contributing to increased terminal half-life and improving the therapeutic or biologic effect relative to a corresponding un-fused biologic payload protein. 
     
       
         
           
               
             
               
                 TABLE 37 
               
             
            
               
                   
               
               
                 SEC analysis of various polypeptides 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 XTEN 
                   
                   
                   
                 Apparent 
                   
               
               
                 Con- 
                 or 
                 Thera- 
                 Actual 
                 Apparent 
                 Molecular 
               
               
                 struct 
                 fusion 
                 peutic 
                 MW 
                 MW 
                 Weight 
                 R H   
               
               
                 Name 
                 partner 
                 Protein 
                 (kDa) 
                 (kDa) 
                 Factor 
                 (nm) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 AC14 
                 Y288 
                 Glucagon 
                 28.7 
                 370 
                 12.9 
                 7.0 
               
               
                 AC28 
                 Y144 
                 Glucagon 
                 16.1 
                 117 
                 7.3 
                 5.0 
               
               
                 AC34 
                 Y72 
                 Glucagon 
                 9.9 
                 58.6 
                 5.9 
                 3.8 
               
               
                 AC33 
                 Y36 
                 Glucagon 
                 6.8 
                 29.4 
                 4.3 
                 2.6 
               
               
                 AC89 
                 AF120 
                 Glucagon 
                 14.1 
                 76.4 
                 5.4 
                 4.3 
               
               
                 AC88 
                 AF108 
                 Glucagon 
                 13.1 
                 61.2 
                 4.7 
                 3.9 
               
               
                 AC73 
                 AF144 
                 Glucagon 
                 16.3 
                 95.2 
                 5.8 
                 4.7 
               
               
                 AC53 
                 AG576 
                 GFP 
                 74.9 
                 339 
                 4.5 
                 7.0 
               
               
                 AC39 
                 AD576 
                 GFP 
                 76.4 
                 546 
                 7.1 
                 7.7 
               
               
                 AC41 
                 AE576 
                 GFP 
                 80.4 
                 760 
                 9.5 
                 8.3 
               
               
                 AC52 
                 AF576 
                 GFP 
                 78.3 
                 526 
                 6.7 
                 7.6 
               
               
                 AC398 
                 AE288 
                 FVII 
                 76.3 
                 650 
                 8.5 
                 8.2 
               
               
                 AC404 
                 AE864 
                 FVII 
                 129 
                 1900 
                 14.7 
                 10.1 
               
               
                 AC85 
                 AE864 
                 Exendin-4 
                 83.6 
                 938 
                 11.2 
                 8.9 
               
               
                 AC114 
                 AM875 
                 Exendin-4 
                 82.4 
                 1344 
                 16.3 
                 9.4 
               
               
                 AC143 
                 AM875 
                 hGH 
                 100.6 
                 846 
                 8.4 
                 8.7 
               
               
                 AC227 
                 AM875 
                 IL-1ra 
                 95.4 
                 1103 
                 11.6 
                 9.2 
               
               
                 AC228 
                 AM1318 
                 IL-1ra 
                 134.8 
                 2286 
                 17.0 
                 10.5 
               
               
                   
               
            
           
         
       
     
     Example 61: Construction of CBD-XTEN-Cys, a Cysteine-Engineered XTEN 
     A Cysteine Island (CysIsland) encoding the amino acid sequence GGSPAGSCTSP (SEQ ID NO: 174) containing one cysteine was introduced by annealed oligos in the CBD-stuffer-GFP vector to obtain CBD-CysIsland-GFP, where CysIsland is flanked by the restriction sites BsaI and BbsI. The CBD-stuffer-GFP vector is a pET30 derivative from Novagen with TEV protease recognition site between CBD and the stuffer. Constructs were previously generated by replacing the stuffer in CBD-stuffer-GFP vector with genes encoding XTEN_AE288 and XTEN_AE576. The plasmid of CBD-XTEN_AE288-GFP was digested with BsaI/NcoI to generate the small fragment as the insert. The plasmid of CBD-CysIsland-GFP was digested with BbsI/NcoI to generate the large fragment as the vector. The insert and vector fragments were ligated and the ligation mixture was electroporated into BL21-Gold (DE3) cells to obtain transformants of CBD-CysIsland-XTENAE288-GFP. Similarly, the plasmid of CBD-CysIsland-XTENAE288-GFP was digested with BsaI/NcoI to generate the small fragment as the insert. The plasmid of CBD-XTEN_AE576-GFP was digested with BbsI/NcoI to generate the large fragment as the vector. The insert and vector fragments were ligated and the ligation mixture was electroporated into BL21-Gold (DE3) cells to obtain transformants of CBD-XTENAE576-CysIsland-XTENAE288-GFP. Finally, the plasmid of CBD-XTENAE576-CysIsland-XTEN_AE288-GFP was digested with BbsI/HindIII to remove GFP and ligate with annealed oligos for the stop codon, and the ligation mixture was electroporated into BL21-Gold (DE3) cells to obtain transformants of CBD-XTEN_AE576-Cyslsland-XTEN_AE288, which has the DNA and encoded amino acid sequences that follow in Table 38. Additional constructs can be created with cysteines inserted at different locations within the XTEN sequence by the selection of restriction sites appropriate for the given location, including multiple insertions. The method could also be utilized to create lysine-engineered XTEN by substitution of codons encoding lysine for those encoding cysteine in the oligonucleotides. 
     
       
         
           
               
             
               
                 TABLE 38 
               
             
            
               
                   
               
               
                 DNA and amino acid sequence of Cys-engineered XTEN 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
                 SEQ 
               
               
                 Clone 
                   
                 ID 
                 Amino Acid 
                 ID 
               
               
                 Name 
                 DNA Sequence 
                 NO: 
                 Sequence 
                 NO: 
               
               
                   
               
               
                 CBD-TEV- 
                 ATGGCAAATACACCGGTATCAGGCAATTTGAAGGTTGAA 
                 800 
                 MANTPVSGNLKV 
                 801 
               
               
                 AE576- 
                 TTCTACAACAGCAATCCTTCAGATACTACTAACTCAATCA 
                   
                 EFYNSNPSDTTNS 
                   
               
               
                 CysIsland- 
                 ATCCTCAGTTCAAGGTTACTAATACCGGAAGCAGTGCAA 
                   
                 INPQFKVTNTGSS 
                   
               
               
                 AE288 
                 TTGATTTGTCCAAACTCACATTGAGATATTATTATACAGT 
                   
                 AIDLSKLTLRYYY 
                   
               
               
                   
                 AGACGGACAGAAAGATCAGACCTTCTGGGCTGACCATGC 
                   
                 TVDGQKDQTFW 
                   
               
               
                   
                 TGCAATAATCGGCAGTAACGGCAGCTACAACGGAATTAC 
                   
                 ADHAAIIGSNGSY 
                   
               
               
                   
                 TTCAAATGTAAAAGGAACATTTGTAAAAATGAGTTCCTC 
                   
                 NGITSNVKGTFV 
                   
               
               
                   
                 AACAAATAACGCAGACACCTACCTTGAAATCAGCTTTAC 
                   
                 KMSSSTNNADTY 
                   
               
               
                   
                 AGGCGGAACTCTTGAACCGGGTGCACATGTTCAGATACA 
                   
                 LEISFTGGTLEPG 
                   
               
               
                   
                 AGGTAGATTTGCAAAGAATGACTGGAGTAACTATACACA 
                   
                 AHVQIQGRFAKN 
                   
               
               
                   
                 GTCAAATGACTACTCATTCAAGTCTGCTTCACAGTTTGTT 
                   
                 DWSNYTQSNDYS 
                   
               
               
                   
                 GAATGGGATCAGGTAACAGCATACTTGAACGGTGTTCTT 
                   
                 FKSASQFVEWDQ 
                   
               
               
                   
                 GTATGGGGTAAAGAACCCGGTGGCAGTGTAGTAGGTTCA 
                   
                 VTAYLNGVLVW 
                   
               
               
                   
                 GGTTCAGGATCCGAAAATCTGTATTTTCAGGGTGGGTCTC 
                   
                 GKEPGGSVVGSG 
                   
               
               
                   
                 CAGGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAG 
                   
                 SGSENLYFQGGSP 
                   
               
               
                   
                 GTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTAC 
                   
                 GSPAGSPTSTEEG 
                   
               
               
                   
                 CTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCCC 
                   
                 TSESATPESGPGT 
                   
               
               
                   
                 AGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACT 
                   
                 STEPSEGSAPGSP 
                   
               
               
                   
                 GAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAA 
                   
                 AGSPTSTEEGTST 
                   
               
               
                   
                 CCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTA 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 CCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTG 
                   
                 PSEGSAPGTSESA 
                   
               
               
                   
                 GTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTC 
                   
                 TPESGPGSEPATS 
                   
               
               
                   
                 TGAAACTCCAGGTAGCCCGGCAGGCTCTCCGACCTCTACT 
                   
                 GSETPGSEPATSG 
                   
               
               
                   
                 GAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGC 
                   
                 SETPGSPAGSPTS 
                   
               
               
                   
                 CCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA 
                   
                 TEEGTSESATPES 
                   
               
               
                   
                 GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT 
                   
                 GPGTSTEPSEGSA 
                   
               
               
                   
                 AGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTT 
                   
                 PGTSTEPSEGSAP 
                   
               
               
                   
                 CTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTA 
                   
                 GSPAGSPTSTEEG 
                   
               
               
                   
                 CTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAA 
                   
                 TSTEPSEGSAPGT 
                   
               
               
                   
                 GCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACC 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 GTCCGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAAC 
                   
                 ESATPESGPGTST 
                   
               
               
                   
                 CCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGC 
                   
                 EPSEGSAPGTSES 
                   
               
               
                   
                 TCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTA 
                   
                 ATPESGPGSEPAT 
                   
               
               
                   
                 GCGCACCAGGTACTTCTACTGAACCGTCTGAAGGTAGCG 
                   
                 SGSETPGTSTEPS 
                   
               
               
                   
                 CACCAGGTACTTCTGAAAGCGCAACCCCGGAATCCGGCC 
                   
                 EGSAPGTSTEPSE 
                   
               
               
                   
                 CAGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCAG 
                   
                 GSAPGTSESATPE 
                   
               
               
                   
                 GTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTA 
                   
                 SGPGTSESATPES 
                   
               
               
                   
                 CCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCG 
                   
                 GPGSPAGSPTSTE 
                   
               
               
                   
                 AACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCTG 
                   
                 EGTSESATPESGP 
                   
               
               
                   
                 AAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTG 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 AACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACC 
                   
                 TSESATPESGPGT 
                   
               
               
                   
                 GTCCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTC 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 CGAAGGCAGCGCTCCAGGTACCTCTACTGAACCTTCCGA 
                   
                 TEPSEGSAPGTST 
                   
               
               
                   
                 GGGCAGCGCTCCAGGTACCTCTACCGAACCTTCTGAAGG 
                   
                 EPSEGSAPGTSTE 
                   
               
               
                   
                 TAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG 
                   
                 PSEGSAPGTSTEP 
                   
               
               
                   
                 CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGA 
                   
                 SEGSAPGTSTEPS 
                   
               
               
                   
                 GGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACC 
                   
                 EGSAPGSPAGSPT 
                   
               
               
                   
                 AGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGG 
                   
                 STEEGTSTEPSEG 
                   
               
               
                   
                 TAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACC 
                   
                 SAPGTSESATPES 
                   
               
               
                   
                 TCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAA 
                   
                 GPGSEPATSGSET 
                   
               
               
                   
                 CCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAA 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 GCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACC 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 GTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTAC 
                   
                 TSESATPESGPGT 
                   
               
               
                   
                 TCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACT 
                   
                 STEPSEGSAPGTS 
                   
               
               
                   
                 TCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTA 
                   
                 ESATPESGPGSPA 
                   
               
               
                   
                 CTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCTACTG 
                   
                 GSPTSTEEGSPAG 
                   
               
               
                   
                 AGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCC 
                   
                 SPTSTEEGSPAGS 
                   
               
               
                   
                 CAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAG 
                   
                 PTSTEEGTSESAT 
                   
               
               
                   
                 GTGGTAGCCCGGCTGGCTCTTGTACCTCTCCAGGTACCTC 
                   
                 PESGPGTSTEPSE 
                   
               
               
                   
                 TGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACC 
                   
                 GSAPGGSPAGSC 
                   
               
               
                   
                 TGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGC 
                   
                 TSPGTSESATPES 
                   
               
               
                   
                 GCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACC 
                   
                 GPGSEPATSGSET 
                   
               
               
                   
                 TCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTC 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 CTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACC 
                   
                 TSESATPESGPGT 
                   
               
               
                   
                 GAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGC 
                   
                 STEPSEGSAPGSP 
                   
               
               
                   
                 CCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCA 
                   
                 AGSPTSTEEGTSE 
                   
               
               
                   
                 GGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTA 
                   
                 SATPESGPGSEPA 
                   
               
               
                   
                 GCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCC 
                   
                 TSGSETPGTSESA 
                   
               
               
                   
                 CGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTAC 
                   
                 TPESGPGSPAGSP 
                   
               
               
                   
                 CGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAG 
                   
                 TSTEEGSPAGSPT 
                   
               
               
                   
                 CGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCT 
                   
                 STEEGTSTEPSEG 
                   
               
               
                   
                 ACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCC 
                   
                 SAPGTSESATPES 
                   
               
               
                   
                 CGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTC 
                   
                 GPGTSESATPESG 
                   
               
               
                   
                 TGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGA 
                   
                 PGTSESATPESGP 
                   
               
               
                   
                 AACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGA 
                   
                 GSEPATSGSETPG 
                   
               
               
                   
                 GGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACC 
                   
                 SEPATSGSETPGS 
                   
               
               
                   
                 AGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGT 
                   
                 PAGSPTSTEEGTS 
                   
               
               
                   
                 AGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACC 
                   
                 TEPSEGSAPGTST 
                   
               
               
                   
                 TCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTA 
                   
                 EPSEGSAPGSEPA 
                   
               
               
                   
                 CTGAACCGTCCGAGGGCAGCGCACCAGGTTAA 
                   
                 TSGSETPGTSESA 
                   
               
               
                   
                   
                   
                 TPESGPGTSTEPS 
                   
               
               
                   
                   
                   
                 EGSAPG 
               
               
                   
               
            
           
         
       
     
     Example 62: Purification of CBD-XTEN-Cys 
       E. coli  containing AC292 on a plasmid were grown to saturation overnight in 2×YT and then 200 ml of this culture was used to inoculate a 25 L culture of 2×YT media in a wavebag. Both cultures were in the presence of 50 μg/ml kanamycin. The second culture was grown to an OD600 of −1.0 at 37° C., chilled to 26° C., and induced with 12 ml of 1M IPTG overnight. The cell pellet was harvested at 4000 rpm in a SLA-3000 rotor spinning for 20 minutes. The cell pellet (184 g) was resuspended in 736 ml of 20 mM Tris pH 6.8, 50 mM NaCl. The resuspended cells were lysed with a microfluidizer at 20,000 psi and then heated to 75° C. for 15 minutes, followed by rapid cooling on ice for 30 minutes. The lysate was then clarified by centrifugation. The clarified lysate was then loaded on to a DE52 column, previously sanitized with NaOH and equilibrated with 20 mM Tris pH 6.8, 50 mM NaCl. The column was washed with 5 column volumes of 20 mM Tris pH 6.8, 50 mM NaCl, 5 column volumes of 20 mM Tris pH 6.8, 150 mM NaCl and eluted with 5 column volumes of 20 mM Tris pH 6.8, 250 mM NaCl. The pooled elution fractions. were then loaded on to a macrocapQ column, previously sanitized with NaOH and equilibrated with 20 mM Tris pH 6.8, 50 mM NaCl. The column was washed with 9 column volumes of 20 mM Tris pH 6.8, 50 mM NaCl, 9 column volumes of 20 mM Tris pH 6.8, 100 mM NaCl and eluted with 9 column volumes of 20 mM Tris pH 6.8, 250 mM NaCl. The pooled elution fractions were adjusted to a 15% w/v sodium sulfate and then loaded on to a octyl sepharose FF column column, previously sanitized with NaOH and equilibrated with Tris pH 7.5. The column was washed with 4 column volumes of 20 mM Tris pH 7.5 15% w/v sodium sulfate, and eluted with 4 column volumes of 20 mM Tris pH 7.5, 5% w/v sodium sulfate. The sample was stored at 4° C. and given the lot # AP197. The purified cysteine-engineered XTEN could then serve as a suitable reactant for conjugation with a drug, such as a drug from Table 5, resulting in an XTEN-drug conjugate. 
     Example 63: Conjugation and Purification of FITC-X-XTEN 
     Purified protein derived from AC272, lot # AP197, was labeled with FITC maleimide. The sample was reduced by incubating at room temperature with 5 mM TCEP for 1 hour. The sample was then desalted into PBS using DG-10 columns. The sample was labeled by adding a 25-fold molar excess of FITC-maleimide in DMSO and incubating at room temperature for 2 hours. Note that the volume adjusted such that the DMSO concentration was &lt;5% of total solvent. The reaction was quenched by adding 2 mM DTT and then the sample was digested overnight with TEV protease. The sample was diluted two fold with 20 mM Tris pH 7.5 and loaded onto a macrocapQ column, previously sanitized with NaOH and equilibrated with 20 mM Tris pH 7.5. The column was washed with 5 column volumes of 20 mM Tris pH 7.5, 135 mM NaCl, 5 column volumes of 20 mM Tris pH 7.5, 175 mM NaCl and eluted with 5 column volumes of 20 mM Tris pH 7.5, 250 mM NaCl. The pooled elution fractions were then digested with TEV over 60 hours at 4C to complete the digestion. The digested samples were then twice passed over a 1 ml perloza column previously sanitized with NaOH and equilibrated with 20 mM Tris pH 7.5, 135 mM NaCl. To remove any free FITC the sample was then dialyzed against 20 mM Tris pH 7.5, 135 mM NaCl using a 10,000 MWCO membrane. Co-migration of the OD214 protein signal and OD495 FITC signal in a SEC column indicate successful conjugation of the XTEN with the label, with minimal free dye contamination ( FIG. 42B ). The successful conjugation is also indicated by apparent large MW of the protein with FITC fluorescence in SDS PAGE ( FIG. 42A ). 
     Example 64: Purification of GFP-X-XTEN 
     GFP (AC219) was chemically cross-linked to XTEN by a bifunctional cross-linker with an amine reactive group to couple to the GFP lysines and a cysteine reactive group to couple to the free cysteine engineered into the XTEN in AC292. GFP was labeled with bi-functional cross linker sulfo-SMCC by incubating at room temperature for 2 hours. The protein was desalted into PBS using DG-10 columns to remove free sulfo-SMCC. Purified protein derived from AC272, lot # AP197 was reduced and desalted into PBS on DG-10 columns and mixed with the labeled GFP to allow for crosslinking. The crosslinking reaction was quenched with 2 mM DTT and TEV added to remove the CBD domain in a overnight incubation at 4° C. The following day additional TEV was added to complete the digestion with an additional 60 hour 4° C. incubation. Following TEV digestion the sample was dilute to 100 ml in 20 mM Tris pH 7.5 and loaded onto a macrocapQ column, previously sanitized with NaOH and equilibrated with 20 mM Tris pH 7.5. The column was washed with 5 column volumes of 20 mM Tris pH 7.5, 5 column volumes of 20 mM Tris pH 7.5, 50 mM NaCl, 5 column volumes of 20 mM Tris pH 7.5, 100 mM NaCl, 5 column volumes of 20 mM Tris pH 7.5, 150 mM NaCl, 5 column volumes of 20 mM Tris pH 7.5, 200 mM NaCl, 5 column volumes of 20 mM Tris pH 7.5, 250 mM NaCl, 5 column volumes of 20 mM Tris pH 7.5, 300 mM NaCl, and 5 column volumes of 20 mM Tris pH 7.5, 500 mM NaCl. The peak elution fractions were pooled and stored at 4° C. Crosslinking was confirm by co-migration of the OD214 protein signal and OD395 GFP signal in a SEC column, with the SEC output shown as overlays in  FIG. 43 . 
     Example 65: Pharmacokinetics of GFP-XTEN and FITC-XTEN Conjugates 
     The pharmacokinetics of the GFP-XTEN and FITC-XTEN cross-linked conjugates prepared as described in the Examples above were tested in cynomolgus monkeys. GFP-XTEN and FITC-XTEN were administered to male cynos IV at 2 mg/kg and dose volumes of 0.77 and 0.68 mL respectively. Blood samples (1.0 mL) were collected into prechilled heparinized tubes at predose, 2, 4, 8, 24, 48, 72, 96, 120, 168, 216, 264, 336, 388, 432, 504 hour time points, and processed into plasma. Quantitation was performed by ELISA assay using the anti-XTEN antibody for both capture and detection in the case of GFP-XTEN and anti-XTEN capture and anti-FITC detection in the case of FITC-XTEN. A non-compartmental analysis was performed in WinNonLin with all time points included in the fit to determine the PK parameters. The pharmacokinetic results are summarized in Table 39 and  FIG. 44 . The data show XTEN can extend the half-life of molecules to which it is chemically conjugated in a manner comparable to genetic fusions to payloads of similar size. 
     
       
         
           
               
             
               
                 TABLE 39 
               
             
            
               
                   
               
               
                 PK parameters: 
               
            
           
           
               
               
               
               
            
               
                 Construct 
                 Cmax (ng/mL) 
                 AUC (hr*ng/mL) 
                 T ½ (hrs) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 GFP-X-XTEN (AP197d) 
                 52800 
                 8220000 
                 107 
               
               
                 FITC-X-XTEN AP197e 
                 18900 
                 3930000 
                 84.2 
               
               
                   
               
            
           
         
       
     
     Example 66: Preparation of Anti-Her2-XTEN-Paclitaxel BFP-D Conjugate 
     The conjugation process that can be employed is generically illustrated in  FIG. 45 . Drugs can be conjugated to XTEN using the methods of the disclosure or those, e.g., of US Patent publication No. 2009/0074704. By the methods, paclitaxel can first be reacted with an activated linker to a suitable functional group, as shown in  FIG. 45 . The resulting conjugate can be purified by suitable, standard methods known in the art, including HPLC, size exclusion chromatography, gel filtration, ion exchange chromatography, or combinations thereof. Subsequently, the activated paclitaxel conjugate would be incubated with aHer2-XTEN-Cys that was expressed and purified as described in Example 24, using at least a 25-fold excess of paclitaxel conjugate to ensure all reactive cysteine sites on the XTEN are conjugated. The conjugation could be performed essentially as described in Example 64. Excess paclicaxel would be removed from the reaction mixture by dialysis and the final purified product would be concentrated and stored for subsequent use. 
     Example 67: Clinical Applications of Anti-Her2-XTEN-Pactlitaxel Compositions 
     Her2 antigen is overexpressed on a large number of solid malignancies. Expression is particularly high on many breast cancer cells. Herceptin has been approved for the treatment of Her2-positive breast cancers. The invention contemplates that anti-Her2-XTEN-paclitaxel can be used for the treatment of the same patient population. Clinical trials can be designed such that the efficacy and advantages of the anti-Her2-XTEN-paclitaxel compositions can be verified in humans. Such studies in patients would comprise three phases. First, a Phase I safety and pharmacokinetics study in adult patients would be conducted to determine the maximum tolerated dose and pharmacokinetics and pharmacodynamics in humans. These studies define potential toxicities and adverse events to be tracked in future studies. The scheme of the study would be to use single escalating doses of aHer2-XTEN-paclitaxel compositions and measure the biochemical, PK, and clinical parameters. This would permit the determination of the maximum tolerated dose and establish the threshold and maximum concentrations in dosage and circulating drug that constitute the therapeutic window to be used in subsequent Phase II and Phase III trials trials conducted in target indications to determine efficacy and tolerability of the aHER2-XTEN-paclitaxel compositions. 
     
       
         
           
               
             
               
                 TABLE 40 
               
             
            
               
                   
               
               
                 Binding fusion proteins with targeting moieties to single targets 
               
            
           
           
               
               
               
            
               
                   
                   
                 SEQ 
               
               
                   
                   
                 ID 
               
               
                 Name* 
                 Protein Sequence 
                 NO: 
               
               
                   
               
               
                 CTLA4_4- 
                 MHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMM 
                 802 
               
               
                 AM875 
                 GNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQ 
                   
               
               
                   
                 IYVIDPEGGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTST 
                   
               
               
                   
                 PESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEP 
                   
               
               
                   
                 ATSGSETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTST 
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSE 
                   
               
               
                   
                 SATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTST 
                   
               
               
                   
                 EPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSST 
                   
               
               
                   
                 PSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPA 
                   
               
               
                   
                 GSPTSTEEGTSTEPSEGSAPGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPA 
                   
               
               
                   
                 GSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSST 
                   
               
               
                   
                 PSGATGSPGSSPSASTGTGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSTS 
                   
               
               
                   
                 STAESPGPGSTSSTAESPGPGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTST 
                   
               
               
                   
                 EPSEGSAPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTST 
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEP 
                   
               
               
                   
                 ATSGSETPGTSESATPESGPGSPAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGAS 
                   
               
               
                   
                 PGTSSTGSPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAP 
                   
               
               
                   
               
               
                 AE912- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTST 
                 803 
               
               
                 CTLA4 
                 EEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQAD 
                   
               
               
                   
                 SQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELM 
                   
               
               
                   
                 YPPPYYLGIGNGTQIYVIDPEG 
                   
               
               
                   
               
               
                 CTLA4- 
                 MAMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATY 
                 804 
               
               
                 AE36- 
                 MMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGN 
                   
               
               
                 CTLA4- 
                 GTQIYVIDPEGAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGPAMHVAQP 
                   
               
               
                 AE864 
                 AVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFL 
                   
               
               
                   
                 DDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPE 
                   
               
               
                   
                 GGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSA 
                   
               
               
                   
                 PGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTE 
                   
               
               
                   
                 EGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSA 
                   
               
               
                   
                 PGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSET 
                   
               
               
                   
                 PGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTE 
                   
               
               
                   
                 EGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSA 
                   
               
               
                   
                 PGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTE 
                   
               
               
                   
                 EGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSET 
                   
               
               
                   
                 PGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTE 
                   
               
               
                   
                 EGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSET 
                   
               
               
                   
                 PGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTE 
                   
               
               
                   
                 EGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTE 
                   
               
               
                   
                 EGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSET 
                   
               
               
                   
                 PGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSET 
                   
               
               
                   
                 PGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 CTLA4- 
                 MAMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATY 
                 805 
               
               
                 AE158- 
                 MMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGN 
                   
               
               
                 CTLA4- 
                 GTQIYVIDPEGAPSTGGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATP 
                   
               
               
                 AE864 
                 ESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSE 
                   
               
               
                   
                 GSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGPEPTGPAMHVAQPAVVL 
                   
               
               
                   
                 ASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSIC 
                   
               
               
                   
                 TGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEGGSPA 
                   
               
               
                   
                 GSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTST 
                   
               
               
                   
                 EPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSE 
                   
               
               
                   
                 SATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTST 
                   
               
               
                   
                 EPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTST 
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSE 
                   
               
               
                   
                 SATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTST 
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTST 
                   
               
               
                   
                 EPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSE 
                   
               
               
                   
                 SATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPA 
                   
               
               
                   
                 GSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSE 
                   
               
               
                   
                 SATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSE 
                   
               
               
                   
                 SATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTST 
                   
               
               
                   
                 EPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEP 
                   
               
               
                   
                 ATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSE 
                   
               
               
                   
                 SATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 CTLA4- 
                 MAMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATY 
                 806 
               
               
                 AE158- 
                 MMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGN 
                   
               
               
                 CTLA4- 
                 GTQIYVIDPEPCPDSGAPSTGGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTS 
                   
               
               
                 AE864 
                 ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGPEPTGPAMHVAQP 
                   
               
               
                   
                 AVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFL 
                   
               
               
                   
                 DDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEP 
                   
               
               
                   
                 CPDSGG 
                   
               
               
                   
                 SPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEG 
                   
               
               
                   
                 TSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEG 
                   
               
               
                   
                 TSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEG 
                   
               
               
                   
                 TSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEG 
                   
               
               
                   
                 SPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEG 
                   
               
               
                   
                 TSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEG 
                   
               
               
                   
                 TSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPG 
                   
               
               
                   
                 SEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE912- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTST 
                 807 
               
               
                 aIL6R 
                 EEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTLEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGADIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPG 
                   
               
               
                   
                 KAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFG 
                   
               
               
                   
                 QGTKVEIKTGSGEGSEGEGGGEGSEGEGSGEGGEGEGSGSQVQLQESGPGLVRPSQ 
                   
               
               
                   
                 TLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRD 
                   
               
               
                   
                 TSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSS 
                   
               
               
                   
               
               
                 aIL6R- 
                 MADIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLH 
                 808 
               
               
                 AE864 
                 SGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKTGSGEG 
                   
               
               
                   
                 SEGEGGGEGSEGEGSGEGGEGEGSGSQVQLQESGPGLVRPSQTLSLTCTVSGYSITS 
                   
               
               
                   
                 DHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTA 
                   
               
               
                   
                 ADTAVYYCARSLARTTAMDYWGQGSLVTVSSGSPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSE 
                   
               
               
                   
                 TPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSE 
                   
               
               
                   
                 TPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSE 
                   
               
               
                   
                 TPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPES 
                   
               
               
                   
                 GPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTST 
                   
               
               
                   
                 EEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 APG 
                   
               
               
                   
               
               
                 AE912- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTST 
                 809 
               
               
                 aIL6R- 
                 EEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                 AE144 
                 APGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGADIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPG 
                   
               
               
                   
                 KAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFG 
                   
               
               
                   
                 QGTKVEIKTGSGEGSEGEGGGEGSEGEGSGEGGEGEGSGSQVQLQESGPGLVRPSQ 
                   
               
               
                   
                 TLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRD 
                   
               
               
                   
                 TSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSGGTSESATPE 
                   
               
               
                   
                 SGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEG 
                   
               
               
                   
                 SAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
               
               
                 AE48-aIL6R- 
                 MAEPAGSPTSTLEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPGDIQMT 
                 810 
               
               
                 AE864 
                 QSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFS 
                   
               
               
                   
                 GSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKTGSGEGSEGEGGGE 
                   
               
               
                   
                 GSEGEGSGEGGEGEGSGSQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWV 
                   
               
               
                   
                 RQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYY 
                   
               
               
                   
                 CARSLARTTAMDYWGQGSLVTVSSGGSPAGSPTSTEEGTSESATPESGPGTSTEPSE 
                   
               
               
                   
                 GSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGSEPATS 
                   
               
               
                   
                 GSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPS 
                   
               
               
                   
                 EGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPS 
                   
               
               
                   
                 EGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESAT 
                   
               
               
                   
                 PESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESAT 
                   
               
               
                   
                 PESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPS 
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATS 
                   
               
               
                   
                 GSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESAT 
                   
               
               
                   
                 PESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPS 
                   
               
               
                   
                 EGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESAT 
                   
               
               
                   
                 PESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESAT 
                   
               
               
                   
                 PESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESAT 
                   
               
               
                   
                 PESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 aIL6R_VL- 
                 DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSG 
                 811 
               
               
                 AF144- 
                 VPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKGGTSTPESG 
                   
               
               
                 aIL6R_VH- 
                 SASPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAE 
                   
               
               
                 AM875 
                 SPGPGTSPSGESSTAPGTSTPESGSASPGSTSSTAESPGPGTSPSGESSTAPGTSPSGES 
                   
               
               
                   
                 STAPGTSPSGESSTAPGQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQ 
                   
               
               
                   
                 PPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCA 
                   
               
               
                   
                 RSLARTTAMDYWGQGSLVTVSSGGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTST 
                   
               
               
                   
                 EEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSA 
                   
               
               
                   
                 SPGTSTPESGSASPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPSGAT 
                   
               
               
                   
                 GSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGS 
                   
               
               
                   
                 ETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGASASGAPSTGGTSESATPE 
                   
               
               
                   
                 SGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESS 
                   
               
               
                   
                 TAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSEPATSGSETPGTSESATP 
                   
               
               
                   
                 ESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSEPATSG 
                   
               
               
                   
                 SETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESPGPGTSTPESGSASPGSTSESPS 
                   
               
               
                   
                 GTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSSTPSGATGSPGSSPSAST 
                   
               
               
                   
                 GTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSSTPSG 
                   
               
               
                   
                 ATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPGTSTEPSEGSAPGTSTEPS 
                   
               
               
                   
                 EGSAPG 
                   
               
               
                   
               
               
                 AM923- 
                 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGTSTEPSEGS 
                 812 
               
               
                 aIL6R_VH- 
                 APGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGT 
                   
               
               
                 AF144- 
                 APGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPES 
                   
               
               
                 aIL6R_VL 
                 GPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESP 
                   
               
               
                   
                 GPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESP 
                   
               
               
                   
                 GPGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESP 
                   
               
               
                   
                 GPGTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSPAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGQVQLQESGPGLVRPSQTLSLTCTVSGYSITSD 
                   
               
               
                   
                 HAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAA 
                   
               
               
                   
                 DTAVYYCARSLARTTAMDYWGQGSLVTVSSGGTSTPESGSASPGTSPSGESSTAPG 
                   
               
               
                   
                 TSPSGESSTAPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGTSPSGESSTAPG 
                   
               
               
                   
                 TSTPESGSASPGSTSSTAESPGPGTSPSGESSTAPGTSPSGESSTAPGTSPSGESSTAPG 
                   
               
               
                   
                 DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSG 
                   
               
               
                   
                 VPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKG 
                   
               
               
                   
               
               
                 aIL6R_VL- 
                 DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSG 
                 813 
               
               
                 Linker_AE42 
                 VPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKGGAPGTSE 
                   
               
               
                 -aIL6R_VH- 
                 SATPESGPGSEPATSGSETPGTSTEPSEGSAPGPAGQVQLQESGPGLVRPSQTLSLTC 
                   
               
               
                 AD576 
                 TVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQF 
                   
               
               
                   
                 SLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSGGSSESGSSEGGPGSG 
                   
               
               
                   
                 GEPSESGSSGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSS 
                   
               
               
                   
                 ESGSSEGGPGESPGGSSGSESGSEGSSGPGESSGSSESGSSEGGPGSSESGSSEGGPGS 
                   
               
               
                   
                 SESGSSEGGPGSGGEPSESGSSGESPGGSSGSESGESPGGSSGSESGSGGEPSESGSSG 
                   
               
               
                   
                 SSESGSSEGGPGSGGEPSESGSSGSGGEPSESGSSGSEGSSGPGESSGESPGGSSGSES 
                   
               
               
                   
                 GSGGEPSESGSSGSGGEPSESGSSGSGGEPSESGSSGSSESGSSEGGPGESPGGSSGSE 
                   
               
               
                   
                 SGESPGGSSGSESGESPGGSSGSESGESPGGSSGSESGESPGGSSGSESGSSESGSSEG 
                   
               
               
                   
                 GPGSGGEPSESGSSGSEGSSGPGESSGSSESGSSEGGPGSGGEPSESGSSGSSESGSSE 
                   
               
               
                   
                 GGPGSGGEPSESGSSGESPGGSSGSESGESPGGSSGSESGSSESGSSEGGPGSGGEPSE 
                   
               
               
                   
                 SGSSGSSESGSSEGGPGSGGEPSESGSSGSGGEPSESGSSGESPGGSSGSESGSEGSSG 
                   
               
               
                   
                 PGESSGSSESGSSEGGPGSEGSSGPGESSG 
                   
               
               
                   
               
               
                 AM923- 
                 MAEPAGSPTSTLEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGTSTEPSEGS 
                 814 
               
               
                 aIL6R_VH- 
                 APGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGT 
                   
               
               
                 Linker_AM1 
                 APGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPES 
                   
               
               
                 50- 
                 GPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                 aIL6R_VH 
                 APGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESP 
                   
               
               
                   
                 GPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESP 
                   
               
               
                   
                 GPGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESP 
                   
               
               
                   
                 GPGTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSPAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGQVQLQESGPGLVRPSQTLSLTCTVSGYSITSD 
                   
               
               
                   
                 HAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAA 
                   
               
               
                   
                 DTAVYYCARSLARTTAMDYWGQGSLVTVSSGGAPSTGGTSESATPESGPGTSTEPS 
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESAT 
                   
               
               
                   
                 PESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGPEPTGPAGQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPG 
                   
               
               
                   
                 RGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSL 
                   
               
               
                   
                 ARTTAMDYWGQGSLVTVSSG 
                   
               
               
                   
               
               
                 aIL6R_VL- 
                 DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSG 
                 815 
               
               
                 AE42- 
                 VPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKGGAPGTSE 
                   
               
               
                 aIL6R_VH- 
                 SATPESGPGSEPATSGSETPGTSTEPSEGSAPGPAGQVQLQESGPGLVRPSQTLSLTC 
                   
               
               
                 AM875 
                 TVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQF 
                   
               
               
                   
                 SLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSGGTSTEPSEGSAPGSE 
                   
               
               
                   
                 PATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGST 
                   
               
               
                   
                 SESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPESGPGSP 
                   
               
               
                   
                 AGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSP 
                   
               
               
                   
                 AGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSP 
                   
               
               
                   
                 AGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGSAPGT 
                   
               
               
                   
                 STEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGA 
                   
               
               
                   
                 SASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGST 
                   
               
               
                   
                 SESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSE 
                   
               
               
                   
                 PATSGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESPGPGTS 
                   
               
               
                   
                 PSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESPGPGTS 
                   
               
               
                   
                 TPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSS 
                   
               
               
                   
                 TPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGSP 
                   
               
               
                   
                 AGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPGT 
                   
               
               
                   
                 STEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AM923- 
                 MAEPAGSPTSTLEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGTSTEPSEGS 
                 816 
               
               
                 aIL6R_VH- 
                 APGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGT 
                   
               
               
                 AE42- 
                 APGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPES 
                   
               
               
                 aCD40_VL 
                 GPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESP 
                   
               
               
                   
                 GPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESP 
                   
               
               
                   
                 GPGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESP 
                   
               
               
                   
                 GPGTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSPAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGQVQLQESGPGLVRPSQTLSLTCTVSGYSITSD 
                   
               
               
                   
                 HAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAA 
                   
               
               
                   
                 DTAVYYCARSLARTTAMDYWGQGSLVTVSSGGAPGTSESATPESGPGSEPATSGSE 
                   
               
               
                   
                 TPGTSTEPSEGSAPGPAGMAEIVLTQSPATLSLSPGERATLSCRASQSISDYLHWYQQ 
                   
               
               
                   
                 KPGQAPRLLIYYASHSISGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHGHSYPW 
                   
               
               
                   
                 TFGGGTKVEIKG 
                   
               
               
                   
               
               
                 aIL6R_VL- 
                 DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSG 
                 817 
               
               
                 Y32- 
                 VPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKGTGSGEGS 
                   
               
               
                 aIL6R_VH- 
                 EGEGGGEGSEGEGSGEGGEGEGSGSGQVQLQESGPGLVRPSQTLSLTCTVSGYSITS 
                   
               
               
                 AM1296 
                 DHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTA 
                   
               
               
                   
                 ADTAVYYCARSLARTTAMDYWGQGSLVTVSSGGTSTEPSEGSAPGSEPATSGSETP 
                   
               
               
                   
                 GSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAP 
                   
               
               
                   
                 GTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAP 
                   
               
               
                   
                 GTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEE 
                   
               
               
                   
                 GSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAP 
                   
               
               
                   
                 GSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGPEPTGPAPSG 
                   
               
               
                   
                 GSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEE 
                   
               
               
                   
                 GSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGP 
                   
               
               
                   
                 GSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAP 
                   
               
               
                   
                 GTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGTSESATPESGP 
                   
               
               
                   
                 GTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSPSGESSTAP 
                   
               
               
                   
                 GTSPSGESSTAPGTSPSGESSTAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAP 
                   
               
               
                   
                 GSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGS 
                   
               
               
                   
                 PGASPGTSSTGSPGASASGAPSTGGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTA 
                   
               
               
                   
                 PGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSSPSASTGTGPGSSTPSGATGS 
                   
               
               
                   
                 PGASPGTSSTGSPGTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGTSESATPESG 
                   
               
               
                   
                 PGSEPATSGSETPGTSTEPSEGSAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSAS 
                   
               
               
                   
                 PGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESG 
                   
               
               
                   
                 PGSEPATSGSETPGSSTPSGATGSPGASPGTSSTGSPGSSTPSGATGSPGSTSESPSGTA 
                   
               
               
                   
                 PGTSPSGESSTAPGSTSSTAESPGPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSS 
                   
               
               
                   
                 PGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 aCD40- 
                 MAEIVLTQSPATLSLSPGERATLSCRASQSISDYLHWYQQKPGQAPRLLIYYASHSIS 
                 818 
               
               
                 AE864 
                 GIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHGHSYPWTFGGGTKVEIKTGSGEGS 
                   
               
               
                   
                 EGEGGGEGSEGEGSGEGGEGEGSGTQVQLVQSGSELKKPGASVKVSCKASGYAFTT 
                   
               
               
                   
                 TGMQWVRQAPGQGLEWMGWINTHSGVPKYVEDFKGRFVFSLDTSVSTAYLQISSL 
                   
               
               
                   
                 KAEDTAVYYCARSGNGNYDLAYFKYWGQGTLVTVSSGGSPAGSPTSTEEGTSESA 
                   
               
               
                   
                 TPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESA 
                   
               
               
                   
                 TPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESA 
                   
               
               
                   
                 TPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPAT 
                   
               
               
                   
                 SGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESA 
                   
               
               
                   
                 TPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEP 
                   
               
               
                   
                 SEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESA 
                   
               
               
                   
                 TPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPAT 
                   
               
               
                   
                 SGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPAT 
                   
               
               
                   
                 SGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESA 
                   
               
               
                   
                 TPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGS 
                   
               
               
                   
                 PTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEP 
                   
               
               
                   
                 SEGSAP 
                   
               
               
                   
               
               
                 AE912- 
                 MAEPAGSPTSTLEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTST 
                 819 
               
               
                 aCD40 
                 EEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGEIVLTQSPATLSLSPGERATLSCRASQSISDYLHWYQQKPGQA 
                   
               
               
                   
                 PRLLIYYASHSISGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHGHSYPWTFGGGT 
                   
               
               
                   
                 KVEIKTGSGEGSEGEGGGEGSEGEGSGEGGEGEGSGTQVQLVQSGSELKKPGASVK 
                   
               
               
                   
                 VSCKASGYAFTTTGMQWVRQAPGQGLEWMGWINTHSGVPKYVEDFKGRFVFSLD 
                   
               
               
                   
                 TSVSTAYLQISSLKAEDTAVYYCARSGNGNYDLAYFKYWGQGTLVTVS 
                   
               
               
                   
               
               
                 AE912- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTST 
                 820 
               
               
                 aCD40_VH- 
                 EEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                 AF144- 
                 APGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                 aCD40_VL 
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGQVQLVQSGSELKKPGASVKVSCKASGYAFTTTGMQWVRQA 
                   
               
               
                   
                 PGQGLEWMGWINTHSGVPKYVEDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYC 
                   
               
               
                   
                 ARSGNGNYDLAYFKYWGQGTLVTVSSGGTSTPESGSASPGTSPSGESSTAPGTSPSG 
                   
               
               
                   
                 ESSTAPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPE 
                   
               
               
                   
                 SGSASPGSTSSTAESPGPGTSPSGESSTAPGTSPSGESSTAPGTSPSGESSTAPGMAEIV 
                   
               
               
                   
                 LTQSPATLSLSPGERATLSCRASQSISDYLHWYQQKPGQAPRLLIYYASHSISGIPARF 
                   
               
               
                   
                 SGSGSGTDFTLTISSLEPEDFAVYYCQHGHSYPWTFGGGTKVEIKG 
                   
               
               
                   
               
               
                 aCD40_VL- 
                 MAEIVLTQSPATLSLSPGERATLSCRASQSISDYLHWYQQKPGQAPRLLIYYASHSIS 
                 821 
               
               
                 AE144- 
                 GIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHGHSYPWTFGGGTKVEIKGGSEPAT 
                   
               
               
                 aCD40_VH- 
                 SGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGSEPAT 
                   
               
               
                 AE576 
                 SGSETPGSEPATSGSETPGSEPATSGSETPGTSILPSEGSAPGTSESATPESGPGSEPAT 
                   
               
               
                   
                 SGSETPGTSTEPSEGSAPGQVQLVQSGSELKKPGASVKVSCKASGYAFTTTGMQWV 
                   
               
               
                   
                 RQAPGQGLEWMGWINTHSGVPKYVEDFKGRFVFSLDTSVSTAYLQISSLKAEDTAV 
                   
               
               
                   
                 YYCARSGNGNYDLAYFKYWGQGTLVTVSSGGSPAGSPTSTEEGTSESATPESGPGT 
                   
               
               
                   
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGS 
                   
               
               
                   
                 EPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                   
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGT 
                   
               
               
                   
                 STEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGT 
                   
               
               
                   
                 SESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGT 
                   
               
               
                   
                 SESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGT 
                   
               
               
                   
                 STEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGS 
                   
               
               
                   
                 EPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                   
                 SESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGT 
                   
               
               
                   
                 STEPSEGSAPG 
                   
               
               
                   
               
               
                 aCD40_VL- 
                 MAEIVLTQSPATLSLSPGERATLSCRASQSISDYLHWYQQKPGQAPRLLIYYASHSIS 
                 822 
               
               
                 AE42- 
                 GIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHGHSYPWTFGGGTKVEIKGGAPGTS 
                   
               
               
                 aCD40_VH- 
                 ESATPESGPGSEPATSGSETPGTSTEPSEGSAPGPAGQVQLVQSGSELKKPGASVKVS 
                   
               
               
                 BC864 
                 CKASGYAFTTTGMQWVRQAPGQGLEWMGWINTHSGVPKYVEDFKGRFVFSLDTS 
                   
               
               
                   
                 VSTAYLQISSLKAEDTAVYYCARSGNGNYDLAYFKYWGQGTLVTVSSGGTSTEPSE 
                   
               
               
                   
                 PGSAGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGSEPATSGTEPSGSEPATS 
                   
               
               
                   
                 GTEPSGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPATSGTEPSGTSTEPS 
                   
               
               
                   
                 EPGSAGSEPATSGTEPSGSEPATSGTEPSGTSTEPSEPGSAGTSTEPSEPGSAGSEPATS 
                   
               
               
                   
                 GTEPSGSEPATSGTEPSGTSEPSTSEPGAGSGASEPTSTEPGTSEPSTSEPGAGSEPATS 
                   
               
               
                   
                 GTEPSGSEPATSGTEPSGTSTEPSEPGSAGTSTEPSEPGSAGSGASEPTSTEPGSEPATS 
                   
               
               
                   
                 GTEPSGSEPATSGTEPSGSEPATSGTEPSGSEPATSGTEPSGTSTEPSEPGSAGSEPATS 
                   
               
               
                   
                 GTEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGTSTEPS 
                   
               
               
                   
                 EPGSAGSGASEPTSTEPGSEPATSGTEPSGSGASEPTSTEPGSEPATSGTEPSGSGASE 
                   
               
               
                   
                 PTSTEPGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPAT 
                   
               
               
                   
                 SGTEPSGTSTEPSEPGSAGSEPATSGTEPSGTSTEPSEPGSAGTSTEPSEPGSAGTSTEP 
                   
               
               
                   
                 SEPGSAGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPSEPGSAGTSEPSTSEPGAGSGAS 
                   
               
               
                   
                 EPTSTEPGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPSEPGSAGSEPATSGTEPSGSGAS 
                   
               
               
                   
                 EPTSTEPGSEPATSGTEPSGSEPATSGTEPSGSEPATSGTEPSGSEPATSGTEPSGTSEP 
                   
               
               
                   
                 STSEPGAGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPATSGTEPSGSGA 
                   
               
               
                   
                 SEPTSTEPGTSTEPSEPGSAG 
                   
               
               
                   
               
               
                 AM923- 
                 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGTSILPSEGS 
                 823 
               
               
                 aCD40_VH- 
                 APGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGT 
                   
               
               
                 AE42-BD864 
                 APGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESP 
                   
               
               
                   
                 GPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESP 
                   
               
               
                   
                 GPGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESP 
                   
               
               
                   
                 GPGTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSPAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGQVQLVQSGSELKKPGASVKVSCKASGYAFT 
                   
               
               
                   
                 TTGMQWVRQAPGQGLEWMGWINTHSGVPKYVEDFKGRFVFSLDTSVSTAYLQISS 
                   
               
               
                   
                 LKAEDTAVYYCARSGNGNYDLAYFKYWGQGTLVTVSSGGAPGTSESATPESGPGS 
                   
               
               
                   
                 EPATSGSETPGTSTEPSEGSAPGPAGGSETATSGSETAGTSESATSESGAGSTAGSETS 
                   
               
               
                   
                 TEAGTSESATSESGAGSETATSGSETAGSETATSGSETAGTSTEASEGSASGTSTEAS 
                   
               
               
                   
                 EGSASGTSESATSESGAGSETATSGSETAGTSTEASEGSASGSTAGSETSTEAGTSES 
                   
               
               
                   
                 ATSESGAGTSESATSESGAGSETATSGSETAGTSESATSESGAGTSTEASEGSASGSE 
                   
               
               
                   
                 TATSGSETAGSETATSGSETAGTSTEASEGSASGSTAGSETSTEAGTSESATSESGAG 
                   
               
               
                   
                 TSTEASEGSASGSETATSGSETAGSTAGSETSTEAGSTAGSETSTEAGSETATSGSET 
                   
               
               
                   
                 AGTSESATSESGAGTSESATSESGAGSETATSGSETAGTSESATSESGAGTSESATSES 
                   
               
               
                   
                 GAGSETATSGSETAGSETATSGSETAGTSTEASEGSASGSTAGSETSTEAGSETATSG 
                   
               
               
                   
                 SETAGTSESATSESGAGSTAGSETSTEAGSTAGSETSTEAGSTAGSETSTEAGTSILA 
                   
               
               
                   
                 SEGSASGSTAGSETSTEAGSTAGSETSTEAGTSTEASEGSASGSTAGSETSTEAGSET 
                   
               
               
                   
                 ATSGSETAGTSTEASEGSASGTSESATSESGAGSETATSGSETAGTSESATSESGAGT 
                   
               
               
                   
                 SESATSESGAGSETATSGSETAGTSESATSESGAGSETATSGSETAGTSTEASEGSAS 
                   
               
               
                   
                 GTSTEASEGSASGSTAGSETSTEAGSTAGSETSTEAGSETATSGSETAGTSESATSES 
                   
               
               
                   
                 GAGTSESATSESGAGSETATSGSETAGSETATSGSETAGSETATSGSETAGTSTEASE 
                   
               
               
                   
                 GSASGTSESATSESGAGSETATSGSETAGSETATSGSETAGTSESATSESGAGTSESA 
                   
               
               
                   
                 TSESGAGSETATSGSETAG 
                   
               
               
                   
               
               
                 aCD40_VL- 
                 MAEIVLTQSPATLSLSPGERATLSCRASQSISDYLHWYQQKPGQAPRLLIYYASHSIS 
                 824 
               
               
                 Y32- 
                 GIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHGHSYPWTFGGGTKVEIKGTGSGEG 
                   
               
               
                 aCD40_VH- 
                 SEGEGGGEGSEGEGSGEGGEGEGSGSGQVQLVQSGSELKKPGASVKVSCKASGYAF 
                   
               
               
                 AE576 
                 TTTGMQWVRQAPGQGLEWMGWINTHSGVPKYVEDFKGRFVFSLDTSVSTAYLQIS 
                   
               
               
                   
                 SLKAEDTAVYYCARSGNGNYDLAYFKYWGQGTLVTVSSGGSPAGSPTSTEEGTSES 
                   
               
               
                   
                 ATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSES 
                   
               
               
                   
                 ATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSES 
                   
               
               
                   
                 ATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPA 
                   
               
               
                   
                 TSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSES 
                   
               
               
                   
                 ATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSES 
                   
               
               
                   
                 ATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE912- 
                 MAEPAGSPTSILEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTST 
                 825 
               
               
                 aCD40_VH- 
                 EEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                 AF144- 
                 APGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                 aCD40_VL 
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGQVQLVQSGSELKKPGASVKVSCKASGYAFTTTGMQWVRQA 
                   
               
               
                   
                 PGQGLEWMGWINTHSGVPKYVEDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYC 
                   
               
               
                   
                 ARSGNGNYDLAYFKYWGQGTLVTVSSGGTSTPESGSASPGTSPSGESSTAPGTSPSG 
                   
               
               
                   
                 ESSTAPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPE 
                   
               
               
                   
                 SGSASPGSTSSTAESPGPGTSPSGESSTAPGTSPSGESSTAPGTSPSGESSTAPGMAEIV 
                   
               
               
                   
                 LTQSPATLSLSPGERATLSCRASQSISDYLHWYQQKPGQAPRLLIYYASHSISGIPARF 
                   
               
               
                   
                 SGSGSGTDFTLTISSLEPEDFAVYYCQHGHSYPWTFGGGTKVEIKG 
                   
               
               
                   
               
               
                 aCD40_VL- 
                 MAEIVLTQSPATLSLSPGERATLSCRASQSISDYLHWYQQKPGQAPRLLIYYASHSIS 
                 826 
               
               
                 AE144- 
                 GIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHGHSYPWTFGGGTKVEIKGGSEPAT 
                   
               
               
                 aCD40_VH- 
                 SGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGSEPAT 
                   
               
               
                 AE576 
                 SGSETPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGSEPAT 
                   
               
               
                   
                 SGSETPGTSTEPSEGSAPGQVQLVQSGSELKKPGASVKVSCKASGYAFTTTGMQWV 
                   
               
               
                   
                 RQAPGQGLEWMGWINTHSGVPKYVEDFKGRFVFSLDTSVSTAYLQISSLKAEDTAV 
                   
               
               
                   
                 YYCARSGNGNYDLAYFKYWGQGTLVTVSSGGSPAGSPTSTEEGTSESATPESGPGT 
                   
               
               
                   
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGS 
                   
               
               
                   
                 EPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                   
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGT 
                   
               
               
                   
                 STEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGT 
                   
               
               
                   
                 SESATPESGPGTSESATPESGPGSPAGSPTSTLEGTSESATPESGPGSEPATSGSETPGT 
                   
               
               
                   
                 SESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGT 
                   
               
               
                   
                 STEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGS 
                   
               
               
                   
                 EPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                   
                 SESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGT 
                   
               
               
                   
                 STEPSEGSAPG 
                   
               
               
                   
               
               
                 aHER2- 
                 MEDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFL 
                 827 
               
               
                 AE864 
                 YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKTGSGE 
                   
               
               
                   
                 GSEGEGGGEGSEGEGSGEGGEGEGSGTEVQLVESGGGLVQPGGSLRLSCAASGFNI 
                   
               
               
                   
                 KDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMN 
                   
               
               
                   
                 SLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSGSPGSPAGSPTSTEEGTSES 
                   
               
               
                   
                 ATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSES 
                   
               
               
                   
                 ATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSES 
                   
               
               
                   
                 ATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPA 
                   
               
               
                   
                 TSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSES 
                   
               
               
                   
                 ATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSES 
                   
               
               
                   
                 ATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPA 
                   
               
               
                   
                 TSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPA 
                   
               
               
                   
                 TSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSES 
                   
               
               
                   
                 ATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPA 
                   
               
               
                   
                 GSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTST 
                   
               
               
                   
                 EPSEGSAP 
                   
               
               
                   
               
               
                 AE912- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTST 
                 828 
               
               
                 aHER2 
                 EEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGSSSLDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQ 
                   
               
               
                   
                 KPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPT 
                   
               
               
                   
                 FGQGTKVEIKTGSGEGSEGEGGGEGSEGEGSGEGGEGEGSGTEVQLVESGGGLVQP 
                   
               
               
                   
                 GGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI 
                   
               
               
                   
                 SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVS 
                   
               
               
                   
               
               
                 aHer2_VL- 
                 MEDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFL 
                 829 
               
               
                 AE42- 
                 YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGAPG 
                   
               
               
                 aHer2_VH- 
                 TSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGPAGEVQLVESGGGLVQPGGSLR 
                   
               
               
                 AM1296 
                 LSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTS 
                   
               
               
                   
                 KNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSGGTSTEPSEG 
                   
               
               
                   
                 SAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSG 
                   
               
               
                   
                 TAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPE 
                   
               
               
                   
                 SGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEG 
                   
               
               
                   
                 SAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPE 
                   
               
               
                   
                 SGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGS 
                   
               
               
                   
                 ETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEG 
                   
               
               
                   
                 SAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEG 
                   
               
               
                   
                 SAPGPEPTGPAPSGGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGT 
                   
               
               
                   
                 APGTSPSGESSTAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSEPATSGSE 
                   
               
               
                   
                 TPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 APGTSPSGESSTAPGTSPSGESSTAPGTSPSGESSTAPGTSTEPSEGSAPGSPAGSPTST 
                   
               
               
                   
                 EEGTSTEPSEGSAPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGAT 
                   
               
               
                   
                 GSPGSSTPSGATGSPGASPGTSSTGSPGASASGAPSTGGTSPSGESSTAPGSTSSTAES 
                   
               
               
                   
                 PGPGTSPSGESSTAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSSPSASTG 
                   
               
               
                   
                 TGPGSSTPSGATGSPGASPGTSSTGSPGTSTPESGSASPGTSPSGESSTAPGTSPSGESS 
                   
               
               
                   
                 TAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGSTSESPSGTAPGSTSESPSG 
                   
               
               
                   
                 TAPGTSTPESGSASPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTS 
                   
               
               
                   
                 TEEGTSESATPESGPGSEPATSGSETPGSSTPSGATGSPGASPGTSSTGSPGSSTPSGAT 
                   
               
               
                   
                 GSPGSTSESPSGTAPGTSPSGESSTAPGSTSSTAESPGPGSSTPSGATGSPGASPGTSST 
                   
               
               
                   
                 GSPGTPGSGTASSSPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE912- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTST 
                 830 
               
               
                 aHER2_VL- 
                 EEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                 AF144- 
                 APGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                 aHER2_VH 
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGMEDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQK 
                   
               
               
                   
                 PGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTF 
                   
               
               
                   
                 GQGTKVEIKGGTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPG 
                   
               
               
                   
                 STSESPSGTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASPGSTSSTAESPGPG 
                   
               
               
                   
                 TSPSGESSTAPGTSPSGESSTAPGTSPSGESSTAPGEVQLVESGGGLVQPGGSLRLSC 
                   
               
               
                   
                 AASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNT 
                   
               
               
                   
                 AYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSG 
                   
               
               
                   
               
               
                 AE48- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGEVQLVESG 
                 831 
               
               
                 aHER2_VH- 
                 GGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARTYPTNGYTRYADS 
                   
               
               
                 AE144- 
                 VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVT 
                   
               
               
                 aHER2_VL- 
                 VSGGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEG 
                   
               
               
                 AE576 
                 SAPGSEPATSGSETPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGSEPATSGSETPGTSTEPSEGSAPGMEDIQMTQSPSSLSASVGDRVTITCRASQD 
                   
               
               
                   
                 VNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFAT 
                   
               
               
                   
                 YYCQQHYTTPPTFGQGTKVEIKGGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSA 
                   
               
               
                   
                 PGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSET 
                   
               
               
                   
                 PGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSA 
                   
               
               
                   
                 PGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSA 
                   
               
               
                   
                 PGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESG 
                   
               
               
                   
                 PGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESG 
                   
               
               
                   
                 PGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSA 
                   
               
               
                   
                 PGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSET 
                   
               
               
                   
                 PGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESG 
                   
               
               
                   
                 PGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSA 
                   
               
               
                   
                 PG 
                   
               
               
                   
               
               
                 aHer2_VH_1 
                 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNG 
                 832 
               
               
                 -AE288- 
                 YTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYW 
                   
               
               
                 aHer2_VL_1- 
                 GQGTLVTVSGGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPG 
                   
               
               
                 AF576 
                 TSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPG 
                   
               
               
                   
                 TSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEG 
                   
               
               
                   
                 TSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
                 MEDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFL 
                   
               
               
                   
                 YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGSTS 
                   
               
               
                   
                 STAESPGPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGSTSSTAESPGPGTST 
                   
               
               
                   
                 PESGSASPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSP 
                   
               
               
                   
                 SGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTS 
                   
               
               
                   
                 ESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSTSESPSGTAPGTSTPESGSASPGSTS 
                   
               
               
                   
                 STAESPGPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGTST 
                   
               
               
                   
                 PESGSASPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGSTS 
                   
               
               
                   
                 STAESPGPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTST 
                   
               
               
                   
                 PESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSPSGESSTAPGSTS 
                   
               
               
                   
                 STAESPGPGTSPSGESSTAPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGSTS 
                   
               
               
                   
                 STAESPGPGTSTPESGSASPGTSTPESGSASPG 
                   
               
               
                   
               
               
                 aEGFR-Y576 
                 MEDILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGI 
                 833 
               
               
                   
                 PSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKTGSGEGSE 
                   
               
               
                   
                 GEGGGEGSEGEGSGEGGEGEGSGTQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYG 
                   
               
               
                   
                 VHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSN 
                   
               
               
                   
                 DTAIYYCARALTYYDYEFAYWGQGTLVTVSGGEGSGEGSEGEGSEGSGEGEGSEGS 
                   
               
               
                   
                 GEGEGGSEGSEGEGSEGSGEGEGGEGSGEGEGSGEGSEGEGGGEGSEGEGSGEGGE 
                   
               
               
                   
                 GEGSEGGSEGEGGSEGGEGEGSEGSGEGEGSEGGSEGEGSEGGSEGEGSEGSGEGE 
                   
               
               
                   
                 GSEGSGEGEGSEGSGEGEGSEGSGEGEGSEGGSEGEGGSEGSEGEGSGEGSEGEGGS 
                   
               
               
                   
                 EGSEGEGGGEGSEGEGSGEGSEGEGGSEGSEGEGGSEGSEGEGGEGSGEGEGSEGS 
                   
               
               
                   
                 GEGEGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEGSGEGSEGEGSEGSGEG 
                   
               
               
                   
                 EGSEGSGEGEGGSEGSEGEGGSEGSEGEGGSEGSEGEGGEGSGEGEGSEGSGEGEGS 
                   
               
               
                   
                 GEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEGSEGSGEGEGGEGSGEGEGSGE 
                   
               
               
                   
                 GSEGEGGGEGSEGEGSEGSGEGEGSEGSGEGEGSEGGSEGEGGSEGSEGEGSEGGSE 
                   
               
               
                   
                 GEGSEGGSEGEGSEGSGEGEGSEGSGEGEGSGEGSEGEGGSEGGEGEGSEGGSEGE 
                   
               
               
                   
                 GSEGGSEGEGGEGSGEGEGGGEGSEGEGSEGSGEGEGSGEGSEG 
                   
               
               
                   
               
               
                 aEGFR_VL- 
                 MEDILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGI 
                 834 
               
               
                 AE42- 
                 PSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKGGAPGTSE 
                   
               
               
                 aEGFR_VH- 
                 SATPESGPGSEPATSGSETPGTSTEPSEGSAPGPAGQVQLKQSGPGLVQPSQSLSITCT 
                   
               
               
                 AD836 
                 VSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVF 
                   
               
               
                   
                 FKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSGGSSESGSSEGGPGSSE 
                   
               
               
                   
                 SGSSEGGPGESPGGSSGSESGSGGEPSESGSSGESPGGSSGSESGESPGGSSGSESGSS 
                   
               
               
                   
                 ESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGESPGGSSGSESGESPGGSSGSESGE 
                   
               
               
                   
                 SPGGSSGSESGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPG 
                   
               
               
                   
                 SSESGSSEGGPGSSESGSSEGGPGSGGEPSESGSSGESPGGSSGSESGESPGGSSGSES 
                   
               
               
                   
                 GSGGEPSESGSSGSEGSSGPGESSGSSESGSSEGGPGSGGEPSESGSSGSEGSSGPGES 
                   
               
               
                   
                 SGSSESGSSEGGPGSGGEPSESGSSGESPGGSSGSESGSGGEPSESGSSGSGGEPSESG 
                   
               
               
                   
                 SSGSSESGSSEGGPGSGGEPSESGSSGSGGEPSESGSSGSEGSSGPGESSGESPGGSSG 
                   
               
               
                   
                 SESGSEGSSGPGESSGSEGSSGPGESSGSGGEPSESGSSGSSESGSSEGGPGSSESGSSE 
                   
               
               
                   
                 GGPGESPGGSSGSESGSGGEPSESGSSGSEGSSGPGESSGESPGGSSGSESGSEGSSGP 
                   
               
               
                   
                 GSSESGSSEGGPGSGGEPSESGSSGSEGSSGPGESSGSEGSSGPGESSGSEGSSGPGES 
                   
               
               
                   
                 SGSGGEPSESGSSGSGGEPSESGSSGESPGGSSGSESGESPGGSSGSESGSGGEPSESG 
                   
               
               
                   
                 SSGSEGSSGPGESSGESPGGSSGSESGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEG 
                   
               
               
                   
                 GPGSGGEPSESGSSGSSESGSSEGGPGESPGGSSGSESGSGGEPSESGSSGSSESGSSE 
                   
               
               
                   
                 GGPGESPGGSSGSESGSGGEPSESGSSGESPGGSSGSESGSGGEPSESGSSG 
                   
               
               
                   
               
               
                 AM923- 
                 MAEPAGSPTSILEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGTSILPSEGS 
                 835 
               
               
                 aEGFR_VL- 
                 APGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGT 
                   
               
               
                 AM150- 
                 APGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPES 
                   
               
               
                 aEGFR_VH_ 
                 GPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                 1 
                 APGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESP 
                   
               
               
                   
                 GPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESP 
                   
               
               
                   
                 GPGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESP 
                   
               
               
                   
                 GPGTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSPAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGMEDILLTQSPVILSVSPGERVSFSCRASQSIGT 
                   
               
               
                   
                 NIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQ 
                   
               
               
                   
                 NNNWPTTFGAGTKLELKGGAPSTGGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGPEPTGPAG 
                   
               
               
                   
                 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGN 
                   
               
               
                   
                 TDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQG 
                   
               
               
                   
                 TLVTVSG 
                   
               
               
                   
               
               
                 aEGFR_VH- 
                 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGN 
                 836 
               
               
                 AF144- 
                 TDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQG 
                   
               
               
                 aEGFR_VL- 
                 TLVTVSGGTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGSTSE 
                   
               
               
                 AF864 
                 SPSGTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASPGSTSSTAESPGPGTSPS 
                   
               
               
                   
                 GESSTAPGTSPSGESSTAPGTSPSGESSTAPGMEDILLTQSPVILSVSPGERVSFSCRAS 
                   
               
               
                   
                 QSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADY 
                   
               
               
                   
                 YCQQNNNWPTTFGAGTKLELKGGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAP 
                   
               
               
                   
                 GSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAP 
                   
               
               
                   
                 GTSPSGESSTAPGSTSESPSGTAPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGP 
                   
               
               
                   
                 GTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSASP 
                   
               
               
                   
                 GSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSTSSTAESPGPGTSTPESGSASP 
                   
               
               
                   
                 GSTSESPSGTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASP 
                   
               
               
                   
                 GSTSSTAESPGPGSTSSTAESPGPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAP 
                   
               
               
                   
                 GSTSESPSGTAPGSTSESPSGTAPGTSTPESGPXXXGASASGAPSTXXXXSESPSGTAP 
                   
               
               
                   
                 GSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAP 
                   
               
               
                   
                 GTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAP 
                   
               
               
                   
                 GTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAP 
                   
               
               
                   
                 GTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGTSTPESGSASPGSTSSTAESPGP 
                   
               
               
                   
                 GSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAP 
                   
               
               
                   
                 GTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGP 
                   
               
               
                   
                 GSTSSTAESPGPGTSPSGESSTAPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSP 
                   
               
               
                   
                 G 
                   
               
               
                   
               
               
                 AE912- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTST 
                 837 
               
               
                 aEGFR_VH- 
                 EEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                 Y32- 
                 APGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                 aEGFR_VL 
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPG 
                   
               
               
                   
                 KGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARA 
                   
               
               
                   
                 LTYYDYEFAYWGQGTLVTVSGTGSGEGSEGEGGGEGSEGEGSGEGGEGEGSGSGM 
                   
               
               
                   
                 EDILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIP 
                   
               
               
                   
                 SRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKG 
                   
               
               
                   
               
               
                 aEGFR_VL- 
                 MEDILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGI 
                 838 
               
               
                 Linker Y32- 
                 PSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKGTGSGEGS 
                   
               
               
                 aEGFR_VH- 
                 EGEGGGEGSEGEGSGEGGEGEGSGSGQVQLKQSGPGLVQPSQSLSITCTVSGFSLTN 
                   
               
               
                 BC864 
                 YGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQ 
                   
               
               
                   
                 SNDTAIYYCARALTYYDYEFAYWGQGTLVTVSGGTSTEPSEPGSAGTSTEPSEPGSA 
                   
               
               
                   
                 GSEPATSGTEPSGSGASEPTSTEPGSEPATSGTEPSGSEPATSGTEPSGSEPATSGTEPS 
                   
               
               
                   
                 GSGASEPTSTEPGTSTEPSEPGSAGSEPATSGTEPSGTSTEPSEPGSAGSEPATSGTEPS 
                   
               
               
                   
                 GSEPATSGTEPSGTSTEPSEPGSAGTSTEPSEPGSAGSEPATSGTEPSGSEPATSGTEPS 
                   
               
               
                   
                 GTSEPSTSEPGAGSGASEPTSTEPGTSEPSTSEPGAGSEPATSGTEPSGSEPATSGTEPS 
                   
               
               
                   
                 GTSTEPSEPGSAGTSTEPSEPGSAGSGASEPTSTEPGSEPATSGTEPSGSEPATSGTEPS 
                   
               
               
                   
                 GSEPATSGTEPSGSEPATSGTEPSGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEP 
                   
               
               
                   
                 GTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSGASEPTSTEP 
                   
               
               
                   
                 GSEPATSGTEPSGSGASEPTSTEPGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSA 
                   
               
               
                   
                 GSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPATSGTEPSGTSTEPSEPGSA 
                   
               
               
                   
                 GSEPATSGTEPSGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPSEPGSA 
                   
               
               
                   
                 GTSTEPSEPGSAGTSTEPSEPGSAGTSEPSTSEPGAGSGASEPTSTEPGTSTEPSEPGSA 
                   
               
               
                   
                 GTSTEPSEPGSAGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGSEPATSGTEPS 
                   
               
               
                   
                 GSEPATSGTEPSGSEPATSGTEPSGSEPATSGTEPSGTSEPSTSEPGAGSEPATSGTEPS 
                   
               
               
                   
                 GSGASEPTSTEPGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSA 
                   
               
               
                   
                 G 
                   
               
               
                   
               
               
                 aEGFR_VH- 
                 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGN 
                 839 
               
               
                 AE288- 
                 TDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQG 
                   
               
               
                 aEGFR_VL- 
                 TLVTVSGGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSE 
                   
               
               
                 BD864 
                 SATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSE 
                   
               
               
                   
                 SATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSE 
                   
               
               
                   
                 SATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTST 
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGME 
                   
               
               
                   
                 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPS 
                   
               
               
                   
                 RFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKGGSETATSGS 
                   
               
               
                   
                 ETAGTSESATSESGAGSTAGSETSTEAGTSESATSESGAGSETATSGSETAGSETATS 
                   
               
               
                   
                 GSETAGTSTEASEGSASGTSTEASEGSASGTSESATSESGAGSETATSGSETAGTSTE 
                   
               
               
                   
                 ASEGSASGSTAGSETSTEAGTSESATSESGAGTSESATSESGAGSETATSGSETAGTS 
                   
               
               
                   
                 ESATSESGAGTSTEASEGSASGSETATSGSETAGSETATSGSETAGTSTEASEGSASG 
                   
               
               
                   
                 STAGSETSTEAGTSESATSESGAGTSTEASEGSASGSETATSGSETAGSTAGSETSTE 
                   
               
               
                   
                 AGSTAGSETSTEAGSETATSGSETAGTSESATSESGAGTSESATSESGAGSETATSGS 
                   
               
               
                   
                 ETAGTSESATSESGAGTSESATSESGAGSETATSGSETAGSETATSGSETAGTSTEAS 
                   
               
               
                   
                 EGSASGSTAGSETSTEAGSETATSGSETAGTSESATSESGAGSTAGSETSTEAGSTAG 
                   
               
               
                   
                 SETSTEAGSTAGSETSTEAGTSTEASEGSASGSTAGSETSTEAGSTAGSETSTEAGTST 
                   
               
               
                   
                 EASEGSASGSTAGSETSTEAGSETATSGSETAGTSTEASEGSASGTSESATSESGAGS 
                   
               
               
                   
                 ETATSGSETAGTSESATSESGAGTSESATSESGAGSETATSGSETAGTSESATSESGA 
                   
               
               
                   
                 GSETATSGSETAGTSTEASEGSASGTSTEASEGSASGSTAGSETSTEAGSTAGSETST 
                   
               
               
                   
                 EAGSETATSGSETAGTSESATSESGAGTSESATSESGAGSETATSGSETAGSETATSG 
                   
               
               
                   
                 SETAGSETATSGSETAGTSTEASEGSASGTSESATSESGAGSETATSGSETAGSETAT 
                   
               
               
                   
                 SGSETAGTSESATSESGAGTSESATSESGAGSETATSGSETAG 
                   
               
               
                   
               
               
                 aCD3-Y288 
                 MKDIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLA 
                 840 
               
               
                   
                 SGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITRTGSGE 
                   
               
               
                   
                 GSEGEGGGEGSEGEGSGEGGEGEGSGTQVQLVQSGGGVVQPGRSLRLSCKASGYTF 
                   
               
               
                   
                 TRYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQKFKDRFTISTDKSKSTAFLQMDS 
                   
               
               
                   
                 LRPEDTAVYYSARYYDDHYCLDYWGQGTPVTVSSGGEGSGEGSEGEGSEGSGEGE 
                   
               
               
                   
                 GSEGSGEGEGGSEGSEGEGGSEGSEGEGGSEGSEGEGSGEGSEGEGGSEGSEGEGSG 
                   
               
               
                   
                 EGSEGEGSEGGSEGEGGSEGSEGEGSGEGSEGEGGEGGSEGEGSEGSGEGEGSGEGS 
                   
               
               
                   
                 EGEGSEGSGEGEGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEGSEGSGEGE 
                   
               
               
                   
                 GGEGSGEGEGSGEGSEGEGGGEGSEGEGSGEGGEGEGSEGGSEGEGGSEGGEGEGS 
                   
               
               
                   
                 EGSGEGEGSEGGSEGEGSEGGSEGEGSEGSGEGEGSEGSGEGS 
                   
               
               
                   
               
               
                 aCD3_VL- 
                 MKDIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLA 
                 841 
               
               
                 AF144- 
                 SGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITRGGTST 
                   
               
               
                 aCD3_VH- 
                 PESGSASPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGSTSESPSGTAPGSTS 
                   
               
               
                 AE576 
                 STAESPGPGTSPSGESSTAPGTSTPESGSASPGSTSSTAESPGPGTSPSGESSTAPGTSP 
                   
               
               
                   
                 SGESSTAPGTSPSGESSTAPGQVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMH 
                   
               
               
                   
                 WVRQAPGKGLEWIGYINPSRGYTNYNQKFKDRFTISTDKSKSTAFLQMDSLRPEDT 
                   
               
               
                   
                 AVYYSARYYDDHYCLDYWGQGTPVTVSSGGSPAGSPTSTEEGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGSE 
                   
               
               
                   
                 PATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 TEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 ESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSE 
                   
               
               
                   
                 PATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 ESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPG 
                   
               
               
                   
               
               
                 AM923- 
                 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGTSTEPSEGS 
                 842 
               
               
                 aCD3_VH- 
                 APGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGT 
                   
               
               
                 AM150- 
                 APGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPES 
                   
               
               
                 aCD3_VL 
                 GPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESP 
                   
               
               
                   
                 GPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESP 
                   
               
               
                   
                 GPGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESP 
                   
               
               
                   
                 GPGTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSPAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGQVQLVQSGGGVVQPGRSLRLSCKASGYTFT 
                   
               
               
                   
                 RYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQKFKDRFTISTDKSKSTAFLQMDSL 
                   
               
               
                   
                 RPEDTAVYYSARYYDDHYCLDYWGQGTPVTVSSGGAPSTGGTSESATPESGPGTST 
                   
               
               
                   
                 EPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSE 
                   
               
               
                   
                 SATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTST 
                   
               
               
                   
                 EPSEGSAPGPEPTGPAGMKDIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQT 
                   
               
               
                   
                 PGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFT 
                   
               
               
                   
                 FGQGTKLQITRG 
                   
               
               
                   
               
               
                 aCD3_VL- 
                 MKDIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLA 
                 843 
               
               
                 Linker_AE42 
                 SGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITRGGAPG 
                   
               
               
                 -aCD3_VH- 
                 TSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGPAGQVQLVQSGGGVVQPGRSLR 
                   
               
               
                 AM875 
                 LSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQKFKDRFTISTDKS 
                   
               
               
                   
                 KSTAFLQMDSLRPEDTAVYYSARYYDDHYCLDYWGQGTPVTVSSGGTSTEPSEGS 
                   
               
               
                   
                 APGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGT 
                   
               
               
                   
                 APGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESP 
                   
               
               
                   
                 GPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGT 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESP 
                   
               
               
                   
                 GPGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESP 
                   
               
               
                   
                 GPGTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSPAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE912- 
                 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTST 
                 844 
               
               
                 aCD3_VL- 
                 EEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                 AE144- 
                 APGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSIEEGTSESATPES 
                   
               
               
                 aCD3_VH 
                 GPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTST 
                   
               
               
                   
                 EEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGS 
                   
               
               
                   
                 APGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSE 
                   
               
               
                   
                 TPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPES 
                   
               
               
                   
                 GPGTSTEPSEGSAPGMKDIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPG 
                   
               
               
                   
                 KAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFG 
                   
               
               
                   
                 QGTKLQITRGGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEG 
                   
               
               
                   
                 TSTEPSEGSAPGSEPATSGSETPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPG 
                   
               
               
                   
                 TSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGQVQLVQSGGGVVQPGRSLRLSC 
                   
               
               
                   
                 KASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQKFKDRFTISTDKSKST 
                   
               
               
                   
                 AFLQMDSLRPEDTAVYYSARYYDDHYCLDYWGQGTPVTVSSG 
                   
               
               
                   
               
               
                 AE48- 
                 MAEPAGSPTSIEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGQVQLVQSG 
                 845 
               
               
                 aCD3_VH- 
                 GGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQK 
                   
               
               
                 Linker Y32- 
                 FKDRFTISTDKSKSTAFLQMDSLRPEDTAVYYSARYYDDHYCLDYWGQGTPVTVSS 
                   
               
               
                 aCD3_VL- 
                 GTGSGEGSEGEGGGEGSEGEGSGEGGEGEGSGSGMKDIQMTQSPSSLSASVGDRVT 
                   
               
               
                 AE864 
                 ITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSL 
                   
               
               
                   
                 QPEDIATYYCQQWSSNPFTFGQGTKLQITRGGSPAGSPTSTEEGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGSE 
                   
               
               
                   
                 PATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 TEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 ESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSE 
                   
               
               
                   
                 PATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 ESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTS 
                   
               
               
                   
                 ESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTS 
                   
               
               
                   
                 ESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTS 
                   
               
               
                   
                 ESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTS 
                   
               
               
                   
                 TEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AM48- 
                 MAEPAGSPTSILEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGMKDIQMTQ 
                 846 
               
               
                 aCD3_VL- 
                 SPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGVPSRFSG 
                   
               
               
                 Linker_AE42 
                 SGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITRGGAPGTSESATPES 
                   
               
               
                 -aCD3_VH- 
                 GPGSEPATSGSETPGTSTEPSEGSAPGPAGQVQLVQSGGGVVQPGRSLRLSCKASGY 
                   
               
               
                 AM875 
                 TFTRYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQKFKDRFTISTDKSKSTAFLQM 
                   
               
               
                   
                 DSLRPEDTAVYYSARYYDDHYCLDYWGQGTPVTVSSGGTSTEPSEGSAPGSEPATS 
                   
               
               
                   
                 GSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGSTSESP 
                   
               
               
                   
                 SGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPESGPGSPAGSP 
                   
               
               
                   
                 TSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSP 
                   
               
               
                   
                 TSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPS 
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSP 
                   
               
               
                   
                 TSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGSAPGTSTEPS 
                   
               
               
                   
                 EGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGASASG 
                   
               
               
                   
                 APSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESP 
                   
               
               
                   
                 SGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSEPAT 
                   
               
               
                   
                 SGSETPGTSESATPESGPGSEPATSGSETPGSTSSTAESPGPGSTSSTAESPGPGTSPSG 
                   
               
               
                   
                 ESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGSTSSTAESPGPGTSTPE 
                   
               
               
                   
                 SGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSSTPS 
                   
               
               
                   
                 GATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGSPAG 
                   
               
               
                   
                 SPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 aEGRF_VHH 
                 EVQLQESGGGLVQAGDSLRLSCLVSGRSFNSYTMGWFRQAPGKEREFVAAILWSGP 
                 847 
               
               
                 -Linker_Y32- 
                 TTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAALGVLVLAPGNVY 
                   
               
               
                 aEGRF_VHH 
                 SYWGQGTQVTVSSAHHGTGSGEGSEGEGGGEGSEGEGSGEGGEGEGSGSGEVQLQ 
                   
               
               
                 1-BC864 
                 ESGGGLVQAGDSLRLSCLVSGRSFNSYTMGWFRQAPGKEREFVAAILWSGPTTYYA 
                   
               
               
                   
                 DSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAALGVLVLAPGNVYSYWG 
                   
               
               
                   
                 QGTQVTVSSAHHGGTSTEPSEPGSAGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTS 
                   
               
               
                   
                 TEPGSEPATSGTEPSGSEPATSGTEPSGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEP 
                   
               
               
                   
                 GSAGSEPATSGTEPSGTSTEPSEPGSAGSEPATSGTEPSGSEPATSGTEPSGTSTEPSEP 
                   
               
               
                   
                 GSAGTSTEPSEPGSAGSEPATSGTEPSGSEPATSGTEPSGTSEPSTSEPGAGSGASEPT 
                   
               
               
                   
                 STEPGTSEPSTSEPGAGSEPATSGTEPSGSEPATSGTEPSGTSTEPSEPGSAGTSTEPSE 
                   
               
               
                   
                 PGSAGSGASEPTSTEPGSEPATSGTEPSGSEPATSGTEPSGSEPATSGTEPSGSEPATS 
                   
               
               
                   
                 GTEPSGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPATS 
                   
               
               
                   
                 GTEPSGSGASEPTSTEPGTSTEPSEPGSAGSGASEPTSTEPGSEPATSGTEPSGSGASEP 
                   
               
               
                   
                 TSTEPGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPATSGTEPSGSGASEP 
                   
               
               
                   
                 TSTEPGTSTEPSEPGSAGSEPATSGTEPSGTSTEPSEPGSAGSEPATSGTEPSGTSTEPS 
                   
               
               
                   
                 EPGSAGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPS 
                   
               
               
                   
                 EPGSAGTSEPSTSEPGAGSGASEPTSTEPGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPS 
                   
               
               
                   
                 EPGSAGSEPATSGTEPSGSGASEPTSTEPGSEPATSGTEPSGSEPATSGTEPSGSEPATS 
                   
               
               
                   
                 GTEPSGSEPATSGTEPSGTSEPSTSEPGAGSEPATSGTEPSGSGASEPTSTEPGTSTEPS 
                   
               
               
                   
                 EPGSAGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAG 
                   
               
               
                   
               
               
                 aEGRF_VHH 
                 EVQLQESGGGLVQAGDSLRLSCLVSGRSFNSYTMGWFRQAPGKEREFVAAILWSGP 
                 848 
               
               
                 -AE144- 
                 TTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAALGVLVLAPGNVY 
                   
               
               
                 aEGRF_VHH 
                 SYWGQGTQVTVSSAHHGGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPA 
                   
               
               
                 -BD864 
                 GSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSEPATSGSETPGSEPATSGSETPGTST 
                   
               
               
                   
                 EPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGEVQLQESGGGLVQ 
                   
               
               
                   
                 AGDSLRLSCLVSGRSFNSYTMGWFRQAPGKEREFVAAILWSGPTTYYADSVKGRFT 
                   
               
               
                   
                 ISRDNAKNTVYLQMNSLKPEDTAVYYCAAALGVLVLAPGNVYSYWGQGTQVTVS 
                   
               
               
                   
                 SAHHGGSETATSGSETAGTSESATSESGAGSTAGSETSTEAGTSESATSESGAGSETA 
                   
               
               
                   
                 TSGSETAGSETATSGSETAGTSTEASEGSASGTSTEASEGSASGTSESATSESGAGSE 
                   
               
               
                   
                 TATSGSETAGTSTEASEGSASGSTAGSETSTEAGTSESATSESGAGTSESATSESGAG 
                   
               
               
                   
                 SETATSGSETAGTSESATSESGAGTSTEASEGSASGSETATSGSETAGSETATSGSET 
                   
               
               
                   
                 AGTSTEASEGSASGSTAGSETSTEAGTSESATSESGAGTSTEASEGSASGSETATSGS 
                   
               
               
                   
                 ETAGSTAGSETSTEAGSTAGSETSTEAGSETATSGSETAGTSESATSESGAGTSESAT 
                   
               
               
                   
                 SESGAGSETATSGSETAGTSESATSESGAGTSESATSESGAGSETATSGSETAGSETA 
                   
               
               
                   
                 TSGSETAGTSTEASEGSASGSTAGSETSTEAGSETATSGSETAGTSESATSESGAGST 
                   
               
               
                   
                 AGSETSTEAGSTAGSETSTEAGSTAGSETSTEAGTSTEASEGSASGSTAGSETSFLAG 
                   
               
               
                   
                 STAGSETSTEAGTSTEASEGSASGSTAGSETSTEAGSETATSGSETAGTSTEASEGSA 
                   
               
               
                   
                 SGTSESATSESGAGSETATSGSETAGTSESATSESGAGTSESATSESGAGSETATSGSE 
                   
               
               
                   
                 TAGTSESATSESGAGSETATSGSETAGTSTEASEGSASGTSTEASEGSASGSTAGSET 
                   
               
               
                   
                 STEAGSTAGSETSTEAGSETATSGSETAGTSESATSESGAGTSESATSESGAGSETAT 
                   
               
               
                   
                 SGSETAGSETATSGSETAGSETATSGSETAGTSTEASEGSASGTSESATSESGAGSET 
                   
               
               
                   
                 ATSGSETAGSETATSGSETAGTSESATSESGAGTSESATSESGAGSETATSGSETAG 
                   
               
               
                   
               
               
                 aEGRF_VHH 
                 EVQLQESGGGLVQAGDSLRLSCLVSGRSFNSYTMGWFRQAPGKEREFVAAILWSGP 
                 849 
               
               
                 -AF144- 
                 TTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAALGVLVLAPGNVY 
                   
               
               
                 aEGRF_VHH 
                 SYWGQGTQVTVSSAHHGGTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGSTSS 
                   
               
               
                 -AE576 
                 TAESPGPGSTSESPSGTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASPGSTSS 
                   
               
               
                   
                 TAESPGPGTSPSGESSTAPGTSPSGESSTAPGTSPSGESSTAPGEVQLQESGGGLVQA 
                   
               
               
                   
                 GDSLRLSCLVSGRSFNSYTMGWFRQAPGKEREFVAAILWSGPTTYYADSVKGRFTI 
                   
               
               
                   
                 SRDNAKNTVYLQMNSLKPEDTAVYYCAAALGVLVLAPGNVYSYWGQGTQVTVSS 
                   
               
               
                   
                 AHHGGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSP 
                   
               
               
                   
                 TSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPS 
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATS 
                   
               
               
                   
                 GSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSP 
                   
               
               
                   
                 TSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPS 
                   
               
               
                   
                 EGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSP 
                   
               
               
                   
                 TSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATS 
                   
               
               
                   
                 GSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAGSP 
                   
               
               
                   
                 TSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 aEGRF_VHH 
                 EVQLQESGGGLVQAGDSLRLSCLVSGRSFNSYTMGWFRQAPGKEREFVAAILWSGP 
                 850 
               
               
                 - 
                 TTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAALGVLVLAPGNVY 
                   
               
               
                 Linker_AE42 
                 SYWGQGTQVTVSSAHHGGAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPG 
                   
               
               
                 - 
                 PAGEVQLQESGGGLVQAGDSLRLSCLVSGRSFNSYTMGWFRQAPGKEREFVAAIL 
                   
               
               
                 aEGRF_VHH 
                 WSGPTTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAALGVLVLAP 
                   
               
               
                 -AM875 
                 GNVYSYWGQGTQVTVSSAHHGGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEE 
                   
               
               
                   
                 GSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASP 
                   
               
               
                   
                 GTSTPESGSASPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAP 
                   
               
               
                   
                 GTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAP 
                   
               
               
                   
                 GTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAP 
                   
               
               
                   
                 GTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPSGATGSP 
                   
               
               
                   
                 GTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETP 
                   
               
               
                   
                 GSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGASASGAPSTGGTSESATPESGP 
                   
               
               
                   
                 GSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESSTAP 
                   
               
               
                   
                 GTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSEPATSGSETPGTSESATPESGP 
                   
               
               
                   
                 GSEPATSGSETPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSEPATSGSETP 
                   
               
               
                   
                 GSEPATSGSETPGTSTEPSEGSAPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAP 
                   
               
               
                   
                 GTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSSTPSGATGSPGSSPSASTGTGP 
                   
               
               
                   
                 GASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSSTPSGATGSP 
                   
               
               
                   
                 GSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAP 
                   
               
               
                   
                 G 
                   
               
               
                   
               
               
                 aEGRF_VHH 
                 EVQLQESGGGLVQAGDSLRLSCLVSGRSFNSYTMGWFRQAPGKEREFVAAILWSGP 
                 851 
               
               
                 - 
                 TTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAALGVLVLAPGNVY 
                   
               
               
                 Linker_AM1 
                 SYWGQGTQVTVSSAHHGGAPSTGGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                 50- 
                 APGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGS 
                   
               
               
                 aEGRF_VHH 
                 APGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGPEPTGPAG 
                   
               
               
                 -AM1296 
                 EVQLQESGGGLVQAGDSLRLSCLVSGRSFNSYTMGWFRQAPGKEREFVAAILWSGP 
                   
               
               
                   
                 TTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAALGVLVLAPGNVY 
                   
               
               
                   
                 SYWGQGTQVTVSSAHHGGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSS 
                   
               
               
                   
                 TAESPGPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTP 
                   
               
               
                   
                 ESGSASPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSES 
                   
               
               
                   
                 ATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSES 
                   
               
               
                   
                 ATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGS 
                   
               
               
                   
                 GTASSSPGSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPA 
                   
               
               
                   
                 GSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGPEPTGPAPSGGSEPATSGSETPGTSES 
                   
               
               
                   
                 ATPESGPGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSES 
                   
               
               
                   
                 ATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPS 
                   
               
               
                   
                 GESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGTSTEPSEGSAPGTSES 
                   
               
               
                   
                 ATPESGPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSESATPESGPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSPSGESSTAPGTSPSGESSTAPGTSPS 
                   
               
               
                   
                 GESSTAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGSSPSASTGTGPGSSTP 
                   
               
               
                   
                 SGATGSPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASA 
                   
               
               
                   
                 SGAPSTGGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSESATPESGPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGSSPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPGTSTP 
                   
               
               
                   
                 ESGSASPGTSPSGESSTAPGTSPSGESSTAPGTSESATPESGPGSEPATSGSETPGTSTE 
                   
               
               
                   
                 PSEGSAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSPAGSPTSTEEGTSES 
                   
               
               
                   
                 ATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGSSTP 
                   
               
               
                   
                 SGATGSPGASPGTSSTGSPGSSTPSGATGSPGSTSESPSGTAPGTSPSGESSTAPGSTSS 
                   
               
               
                   
                 TAESPGPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSPAGSPTSTEEGSPA 
                   
               
               
                   
                 GSPTSTEEGTSTEPSEGSAPG 
               
               
                   
               
               
                 *“a” before target protein name = anti 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 41 
               
             
            
               
                   
               
               
                 Binding fusion proteins with targeting moieties to different targets 
               
            
           
           
               
               
               
            
               
                   
                   
                 SEQ 
               
               
                   
                   
                 ID 
               
               
                 Name* 
                 Protein Sequence 
                 NO: 
               
               
                   
               
               
                 aHer2- 
                 MEDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSG 
                 852 
               
               
                 Y288- 
                 SRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKTGSGEGSEGEGGGEGSEGEGSGEG 
                   
               
               
                 aEGFR 
                 GEGEGSGTEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGY 
                   
               
               
                   
                 TRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSGG 
                   
               
               
                   
                 EGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEGGSEGSEGEGGSEGSEGEGSGEGSEGEGGS 
                   
               
               
                   
                 EGSEGEGSGEGSEGEGSEGGSEGEGGSEGSEGEGSGEGSEGEGGEGGSEGEGSEGSGEGEGSGEGSE 
                   
               
               
                   
                 GEGSEGSGEGEGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEGSEGSGEGEGGEGSGEGEGS 
                   
               
               
                   
                 GEGSEGEGGGEGSEGEGSGEGGEGEGSEGGSEGEGGSEGGEGEGSEGSGEGEGSEGGSEGEGSEGGS 
                   
               
               
                   
                 EGEGSEGSGEGEGSEGSGEGEDILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLL 
                   
               
               
                   
                 IKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKTGSGEGSE 
                   
               
               
                   
                 GEGGGEGSEGEGSGEGGEGEGSGTQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPG 
                   
               
               
                   
                 KGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFA 
                   
               
               
                   
                 YWGQGTLVTVS 
                   
               
               
                   
               
               
                 aHer2- 
                 MEDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSG 
                 853 
               
               
                 Y288- 
                 SRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKTGSGEGSEGEGGGEGSEGEGSGEG 
                   
               
               
                 aCD3 
                 GEGEGSGTEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGY 
                   
               
               
                   
                 TRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSGS 
                   
               
               
                   
                 PGEGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEGGSEGSEGEGGSEGSEGEGSGEGSEGEG 
                   
               
               
                   
                 GSEGSEGEGSGEGSEGEGSEGGSEGEGGSEGSEGEGSGEGSEGEGGEGGSEGEGSEGSGEGEGSGEG 
                   
               
               
                   
                 SEGEGSEGSGEGEGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEGSEGSGEGEGGEGSGEGE 
                   
               
               
                   
                 GSGEGSEGEGGGEGSEGEGSGEGGEGEGSEGGSEGEGGSEGGEGEGSEGSGEGEGSEGGSEGEGSEG 
                   
               
               
                   
                 GSEGEGSEGSGEGEGSEGSGEGSSSLEGTKDIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQ 
                   
               
               
                   
                 TPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKL 
                   
               
               
                   
                 QITRTGSGEGSEGEGGGEGSEGEGSGEGGEGEGSGTQVQLVQSGGGVVQPGRSLRLSCKASGYTFT 
                   
               
               
                   
                 RYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQKFKDRFTISTDKSKSTAFLQMDSLRPEDTAVY 
                   
               
               
                   
                 YSARYYDDHYCLDYWGQGTPVTVSSTSG 
                   
               
               
                   
               
               
                 aCD3_VL_ 
                 MKDIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGV 
                 854 
               
               
                 1-AE48- 
                 PSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITRGMAEPAGSPTS 
                   
               
               
                 aCD3_VH- 
                 TEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGQVQLVQSGGGVVQPGRSLRLS 
                   
               
               
                 AE144- 
                 CKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQKFKDRFTISTDKSKSTAF 
                   
               
               
                 aHer2_VL- 
                 LQMDSLRPEDTAVYYSARYYDDHYCLDYWGQGTPVTVSSGGSEPATSGSETPGTSESA 
                   
               
               
                 AE48- 
                 TPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSEPATSGS 
                   
               
               
                 aHer2_VH- 
                 ETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAP 
                   
               
               
                 AE864 
                 GMEDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYS 
                   
               
               
                   
                 GVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGMAEPAGSPT 
                   
               
               
                   
                 STEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGEVQLVESGGGLVQPGGSLRL 
                   
               
               
                   
                 SCAASGFNIKDTYIHWVRQAPGKGLEWVARTYPTNGYTRYADSVKGRFTISADTSKNTA 
                   
               
               
                   
                 YLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSGGSPAGSPTSTEEGTSE 
                   
               
               
                   
                 SATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESAT 
                   
               
               
                   
                 PESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSE 
                   
               
               
                   
                 SATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESAT 
                   
               
               
                   
                 PESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPG 
                   
               
               
                   
                 TSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPA 
                   
               
               
                   
                 GSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESAT 
                   
               
               
                   
                 PESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 APGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEG 
                   
               
               
                   
                 SPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEP 
                   
               
               
                   
                 ATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATS 
                   
               
               
                   
                 GSETPGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 aCD3_VH- 
                 QVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRGYT 
                 855 
               
               
                 AE48- 
                 NYNQKFKDRFTISTDKSKSTAFLQMDSLRPEDTAVYYSARYYDDHYCLDYWGQGTPVT 
                   
               
               
                 aCD3_VL- 
                 VSSGMAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGMKDIQMT 
                   
               
               
                 AE144- 
                 QSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGVPSRFSGSG 
                   
               
               
                 aHer2_VH- 
                 SGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITRGGSEPATSGSETPGTSESA 
                   
               
               
                 AE48- 
                 TPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGSEPATSGSETPGSEPATSGS 
                   
               
               
                 aHer2_VL- 
                 ETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAP 
                   
               
               
                 AE864 
                 GEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGY 
                   
               
               
                   
                 TRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQG 
                   
               
               
                   
                 TLVTVSGMAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGMEDI 
                   
               
               
                   
                 QMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSR 
                   
               
               
                   
                 FSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGSPAGSPTSTEEGT 
                   
               
               
                   
                 SESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSES 
                   
               
               
                   
                 ATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSE 
                   
               
               
                   
                 GSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESG 
                   
               
               
                   
                 PGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGT 
                   
               
               
                   
                 SESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSES 
                   
               
               
                   
                 ATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSE 
                   
               
               
                   
                 GSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSET 
                   
               
               
                   
                 PGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGS 
                   
               
               
                   
                 PAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSES 
                   
               
               
                   
                 ATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSE 
                   
               
               
                   
                 GSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTE 
                   
               
               
                   
                 EGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGS 
                   
               
               
                   
                 EPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPA 
                   
               
               
                   
                 TSGSETPGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 aHer2_VL- 
                 MEDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSG 
                 856 
               
               
                 AM48- 
                 VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGMAEPAGSPTS 
                   
               
               
                 aHer2_VH- 
                 TEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGEVQLVESGGGLVQPGGSLRLS 
                   
               
               
                 AF144- 
                 CAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTA 
                   
               
               
                 aCD3_VL- 
                 YLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSGGTSTPESGSASPGTSP 
                   
               
               
                 AM48- 
                 SGESSTAPGTSPSGESSTAPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGTSPSGE 
                   
               
               
                 aCD3_VH- 
                 SSTAPGTSTPESGSASPGSTSSTAESPGPGTSPSGESSTAPGTSPSGESSTAPGTSPSGESST 
                   
               
               
                 AM1296 
                 APGMKDIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLA 
                   
               
               
                   
                 SGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITRGMAEPAGS 
                   
               
               
                   
                 PTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGQVQLVQSGGGVVQPGRSL 
                   
               
               
                   
                 RLSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQKFKDRFTISTDKSKS 
                   
               
               
                   
                 TAFLQMDSLRPEDTAVYYSARYYDDHYCLDYWGQGTPVTVSSGGTSTEPSEGSAPGSE 
                   
               
               
                   
                 PATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGSTSES 
                   
               
               
                   
                 PSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPESGPGSPAGSPTS 
                   
               
               
                   
                 TEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEE 
                   
               
               
                   
                 GTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTS 
                   
               
               
                   
                 TEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPS 
                   
               
               
                   
                 GATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSG 
                   
               
               
                   
                 SETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGPEPTGPAPSGGSEPATSGSETP 
                   
               
               
                   
                 GTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTS 
                   
               
               
                   
                 ESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSG 
                   
               
               
                   
                 ESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAP 
                   
               
               
                   
                 GTSESATPESGPGTSTEPSEGSAPGTSPSGESSTAPGTSPSGESSTAPGTSPSGESSTAPGTS 
                   
               
               
                   
                 TEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGSSPSASTGTGPGSSTPSGATGSPGSSTPS 
                   
               
               
                   
                 GATGSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASASGAPSTGGTSPSGESS 
                   
               
               
                   
                 TAPGSTSSTAESPGPGTSPSGESSTAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAP 
                   
               
               
                   
                 GSSPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPGTSTPESGSASPGTSPSGESSTAPGTS 
                   
               
               
                   
                 PSGESSTAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGSTSESPSGTAPGSTSES 
                   
               
               
                   
                 PSGTAPGTSTPESGSASPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTS 
                   
               
               
                   
                 TEEGTSESATPESGPGSEPATSGSETPGSSTPSGATGSPGASPGTSSTGSPGSSTPSGATGSP 
                   
               
               
                   
                 GSTSESPSGTAPGTSPSGESSTAPGSTSSTAESPGPGSSTPSGATGSPGASPGTSSTGSPGTP 
                   
               
               
                   
                 GSGTASSSPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 aHer2_VH- 
                 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYT 
                 857 
               
               
                 AM48- 
                 RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGT 
                   
               
               
                 aHer2_VL- 
                 LVTVSGMAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGMEDIQ 
                   
               
               
                 AF144- 
                 MTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF 
                   
               
               
                 aCD3_VH- 
                 SGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGTSTPESGSASPGTSP 
                   
               
               
                 AM48- 
                 SGESSTAPGTSPSGESSTAPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGTSPSGE 
                   
               
               
                 aCD3_VL- 
                 SSTAPGTSTPESGSASPGSTSSTAESPGPGTSPSGESSTAPGTSPSGESSTAPGTSPSGESST 
                   
               
               
                 AM875 
                 APGQVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSR 
                   
               
               
                   
                 GYTNYNQKFKDRFTISTDKSKSTAFLQMDSLRPEDTAVYYSARYYDDHYCLDYWGQG 
                   
               
               
                   
                 TPVTVSSGMAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGMKD 
                   
               
               
                   
                 IQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGVPSRF 
                   
               
               
                   
                 SGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITRGGTSTEPSEGSAPGS 
                   
               
               
                   
                 EPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGSTSE 
                   
               
               
                   
                 SPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPESGPGSPAGSPT 
                   
               
               
                   
                 STEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTE 
                   
               
               
                   
                 EGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGT 
                   
               
               
                   
                 STEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTP 
                   
               
               
                   
                 SGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATS 
                   
               
               
                   
                 GSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGASASGAPSTGGTSESATPES 
                   
               
               
                   
                 GPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESSTAPG 
                   
               
               
                   
                 TPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSEPATSGSETPGTSESATPESGPGSEP 
                   
               
               
                   
                 ATSGSETPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSEPATSGSETPGSEPATS 
                   
               
               
                   
                 GSETPGTSTEPSEGSAPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSTEPSEGSAPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSP 
                   
               
               
                   
                 GSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGA 
                   
               
               
                   
                 SPGTSSTGSPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 aHer2_VL- 
                 MEDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSG 
                 858 
               
               
                 Linker_AE 
                 VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGAPGTSESAT 
                   
               
               
                 42- 
                 PESGPGSEPATSGSETPGTSTEPSEGSAPGPAGEVQLVESGGGLVQPGGSLRLSCAASGFN 
                   
               
               
                 aHer2_VH- 
                 IKDTYIHWVRQAPGKGLEWVARTYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSL 
                   
               
               
                 AE288- 
                 RAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSGGTSESATPESGPGSEPATSGSETP 
                   
               
               
                 aEGFR_V 
                 GTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTS 
                   
               
               
                 L- 
                 ESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEP 
                   
               
               
                 Linker_A 
                 SEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGS 
                   
               
               
                 M150- 
                 ETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGP 
                   
               
               
                 aEGFR_V 
                 GTSTEPSEGSAPGMEDILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLL 
                   
               
               
                 H-AD576 
                 IKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKG 
                   
               
               
                   
                 GAPSTGGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSILPSE 
                   
               
               
                   
                 GSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSA 
                   
               
               
                   
                 PGSPAGSPTSTEEGTSTEPSEGSAPGPEPTGPAGQVQLKQSGPGLVQPSQSLSITCTVSGFS 
                   
               
               
                   
                 LTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQ 
                   
               
               
                   
                 SNDTAIYYCARALTYYDYEFAYWGQGTLVTVSGGSSESGSSEGGPGSGGEPSESGSSGS 
                   
               
               
                   
                 SESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGESP 
                   
               
               
                   
                 GGSSGSESGSEGSSGPGESSGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSGGEP 
                   
               
               
                   
                 SESGSSGESPGGSSGSESGESPGGSSGSESGSGGEPSESGSSGSSESGSSEGGPGSGGEPSES 
                   
               
               
                   
                 GSSGSGGEPSESGSSGSEGSSGPGESSGESPGGSSGSESGSGGEPSESGSSGSGGEPSESGS 
                   
               
               
                   
                 SGSGGEPSESGSSGSSESGSSEGGPGESPGGSSGSESGESPGGSSGSESGESPGGSSGSESG 
                   
               
               
                   
                 ESPGGSSGSESGESPGGSSGSESGSSESGSSEGGPGSGGEPSESGSSGSEGSSGPGESSGSSE 
                   
               
               
                   
                 SGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSGGEPSESGSSGESPGGSSGSESGESPGG 
                   
               
               
                   
                 SSGSESGSSESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSGGEPSESGSSGSGGEPSES 
                   
               
               
                   
                 GSSGESPGGSSGSESGSEGSSGPGESSGSSESGSSEGGPGSEGSSGPGESSG 
                   
               
               
                   
               
               
                 aHer2_VH- 
                 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYT 
                 859 
               
               
                 Linker_A 
                 RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGT 
                   
               
               
                 M150- 
                 LVTVSGGAPSTGGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGT 
                   
               
               
                 aHer2_VL- 
                 STEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTE 
                   
               
               
                 AE288- 
                 PSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGPEPTGPAGMEDIQMTQSPSSLSASVGDRV 
                   
               
               
                 aEGFR_V 
                 TITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQP 
                   
               
               
                 H- 
                 EDFATYYCQQHYTTPPTFGQGTKVEIKGGTSESATPESGPGSEPATSGSETPGTSESATPE 
                   
               
               
                 Linker_AE 
                 SGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGP 
                   
               
               
                 42- 
                 GSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTS 
                   
               
               
                 aEGFR_V 
                 ESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGS 
                   
               
               
                 L-AE576 
                 PTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEG 
                   
               
               
                   
                 SAPGQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGG 
                   
               
               
                   
                 NTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGT 
                   
               
               
                   
                 LVTVSGGAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGPAGMEDILLTQSPVIL 
                   
               
               
                   
                 SVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLS 
                   
               
               
                   
                 INSVESEDIADYYCQQNNNWPTTFGAGTKLELKGGSPAGSPTSTEEGTSESATPESGPGT 
                   
               
               
                   
                 STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGSEPA 
                   
               
               
                   
                 TSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSE 
                   
               
               
                   
                 GSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSA 
                   
               
               
                   
                 PGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGT 
                   
               
               
                   
                 SESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTE 
                   
               
               
                   
                 PSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSE 
                   
               
               
                   
                 GSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESG 
                   
               
               
                   
                 PGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGS 
                   
               
               
                   
                 PAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                   
               
               
                 AE624- 
                 MAEPAGSPTSTLEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTSTEEG 
                 860 
               
               
                 aHer2_VL- 
                 TSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSE 
                   
               
               
                 Linker_AE 
                 SATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPS 
                   
               
               
                 42- 
                 EGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPES 
                   
               
               
                 aHer2 VH- 
                 GPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                 AE288- 
                 TSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSE 
                   
               
               
                 aEGFR_V 
                 SATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPS 
                   
               
               
                 L- 
                 EGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSE 
                   
               
               
                 Linker_A 
                 TPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPG 
                   
               
               
                 M150- 
                 SPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGME 
                   
               
               
                 aEGFR_V 
                 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVP 
                   
               
               
                 H 
                 SRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGAPGTSESATPE 
                   
               
               
                   
                 SGPGSEPATSGSETPGTSTEPSEGSAPGPAGEVQLVESGGGLVQPGGSLRLSCAASGFNIK 
                   
               
               
                   
                 DTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRA 
                   
               
               
                   
                 EDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSGGTSESATPESGPGSEPATSGSETPGT 
                   
               
               
                   
                 SESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSES 
                   
               
               
                   
                 ATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSE 
                   
               
               
                   
                 GSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSET 
                   
               
               
                   
                 PGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGT 
                   
               
               
                   
                 STEPSEGSAPGMEDILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK 
                   
               
               
                   
                 YASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKGGA 
                   
               
               
                   
                 PSTGGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSA 
                   
               
               
                   
                 PGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGS 
                   
               
               
                   
                 PAGSPTSTEEGTSTEPSEGSAPGPEPTGPAGQVQLKQSGPGLVQPSQSLSITCTVSGFSLTN 
                   
               
               
                   
                 YGVHWVRQSPGKGLEWLVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSND 
                   
               
               
                   
                 TAIYYCARALTYYDYEFAYWGQGTLVTVSG 
                   
               
               
                   
               
               
                 AE912- 
                 MAEPAGSPTSTLEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTSTEEG 
                 861 
               
               
                 aHer2_VH- 
                 TSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSE 
                   
               
               
                 Linker_A 
                 SATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPS 
                   
               
               
                 M150- 
                 EGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPES 
                   
               
               
                 aHer2_VL- 
                 GPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                 AE288- 
                 TSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSE 
                   
               
               
                 aEGFR_V 
                 SATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPS 
                   
               
               
                 H- 
                 EGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSE 
                   
               
               
                 Linker_AE 
                 TPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPG 
                   
               
               
                 42- 
                 SPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSE 
                   
               
               
                 aEGFR_V 
                 SATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPS 
                   
               
               
                 L 
                 EGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTST 
                   
               
               
                   
                 EEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPG 
                   
               
               
                   
                 SEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEP 
                   
               
               
                   
                 ATSGSETPGTSESATPESGPGTSTEPSEGSAPGEVQLVESGGGLVQPGGSLRLSCAASGFN 
                   
               
               
                   
                 IKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSL 
                   
               
               
                   
                 RAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSGGAPSTGGTSESATPESGPGTSIEP 
                   
               
               
                   
                 SEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPE 
                   
               
               
                   
                 SGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAP 
                   
               
               
                   
                 GPEPTGPAGMEDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLI 
                   
               
               
                   
                 YSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGG 
                   
               
               
                   
                 TSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTST 
                   
               
               
                   
                 EPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSP 
                   
               
               
                   
                 TSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPES 
                   
               
               
                   
                 GPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPG 
                   
               
               
                   
                 SEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGQVQLKQSGPGLVQPSQSLSITCTVSG 
                   
               
               
                   
                 FSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNS 
                   
               
               
                   
                 LQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSGGAPGTSESATPESGPGSEPATSGS 
                   
               
               
                   
                 ETPGTSTEPSEGSAPGPAGMEDILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRT 
                   
               
               
                   
                 NGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGT 
                   
               
               
                   
                 KLELKG 
                   
               
               
                   
               
               
                 AM923- 
                 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGTSTEPSEGSAPG 
                 862 
               
               
                 aEGFR_V 
                 SEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGSTS 
                   
               
               
                 L- 
                 ESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPESGPGSPAGSP 
                   
               
               
                 Linker_A 
                 TSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTST 
                   
               
               
                 M150- 
                 EEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPG 
                   
               
               
                 aEGFR_V 
                 TSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSST 
                   
               
               
                 H-AF144- 
                 PSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPAT 
                   
               
               
                 aHer2_VH- 
                 SGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGASASGAPSTGGTSESATPE 
                   
               
               
                 Linker_A 
                 SGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESSTAP 
                   
               
               
                 M150- 
                 GTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSEPATSGSETPGTSESATPESGPGS 
                   
               
               
                 aHer2_VL 
                 EPATSGSETPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSEPATSGSETPGSEPA 
                   
               
               
                   
                 TSGSETPGTSTEPSEGSAPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGTSTEPSE 
                   
               
               
                   
                 GSAPGTSTEPSEGSAPGTSTEPSEGSAPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTG 
                   
               
               
                   
                 SPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPG 
                   
               
               
                   
                 ASPGTSSTGSPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGMEDILLTQSPVILSV 
                   
               
               
                   
                 SPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSIN 
                   
               
               
                   
                 SVESEDIADYYCQQNNNWPTTFGAGTKLELKGGAPSTGGTSESATPESGPGTSTEPSEGS 
                   
               
               
                   
                 APGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPG 
                   
               
               
                   
                 TSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGPEP 
                   
               
               
                   
                 TGPAGQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWS 
                   
               
               
                   
                 GGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQ 
                   
               
               
                   
                 GTLVTVSGGTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGSTSESP 
                   
               
               
                   
                 SGTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASPGSTSSTAESPGPGTSPSGESST 
                   
               
               
                   
                 APGTSPSGESSTAPGTSPSGESSTAPGEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYI 
                   
               
               
                   
                 HWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDT 
                   
               
               
                   
                 AVYYCSRWGGDGFYAMDYWGQGTLVTVSGGAPSTGGTSESATPESGPGTSTEPSEGSA 
                   
               
               
                   
                 PGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGT 
                   
               
               
                   
                 STEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGPEPT 
                   
               
               
                   
                 GPAGMEDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASF 
                   
               
               
                   
                 LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKG 
               
               
                   
               
               
                 *“a” before target moiety protein name = anti