# Patent

## Title
Growth hormone polypeptides and methods of making and using same

## Abstract

The present invention relates to compositions comprising growth hormone linked to extended recombinant polypeptide (XTEN), isolated nucleic acids encoding the compositions and vectors and host cells containing the same, and methods of making and using such compositions in treatment of growth hormone-related diseases, disorders, and conditions.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a Continuation Application which claims the priority benefit of U.S. application Ser. No. 14/152,692, filed Jan. 10, 2014, now U.S. Pat. No. 9,168,312, which is a Continuation Application which claims the priority benefit of U.S. application Ser. No. 12/796,640, filed Jun. 8, 2010, now U.S. Pat. No. 8,703,717; which claim the benefit of U.S. Provisional Application Ser. No. 61/185,112, filed Jun. 8, 2009; 61/236,836, filed Aug. 25, 2009; and 61/280,955, filed Nov. 10, 2009, and U.S. application Ser. No. 12/699,761, filed Feb. 3, 2010, now U.S. Pat. No. 8,673,860, and PCT Application Serial No. PCT/US10/23106, both filed Feb. 3, 2010 which are hereby incorporated herein by reference in their entirety.
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. 9, 2016 is named 32808-716.303.SeqList.txt and is 1,813,891 bytes in size.


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.


BACKGROUND OF THE INVENTION
Human growth hormone (hGH) is a hormone that participates in the regulation of human growth and development. Growth Hormone (herein after “GH”), also known as somatotrophin, represents a class of proteinaceous hormones produced and secreted by the somatotropic cells of the anterior pituitary. Secretion of GH is stimulated by the growth hormone releasing hormone (GHRH) from the hypothalamus and suppressed by somatostatin. This pituitary hormone exhibits a number of biological effects including somatogenesis, lactation, activation of macrophages, insulin-like and diabetogenic effects among others (Chawla, R, K. (1983) Ann. Rev. Med. 34, 519; Edwards, C. K. et al. (1988) Science 239, 769; Thorner, M. O., et al. (1988) J. Clin. Invest. 81, 745). Human growth hormone is a member of a family of homologous hormones that include placental lactogens, prolactins, and other genetic and species variants of GH. GH regulates the secretion of Insulin-like growth factor (IGF-1, formerly known as somatomedin C), among other peptide hormones known collectively as somatomedins, which accounts for most of its biological activity.
A number of diseases and disorders are associated with the deficiency of GH. A deficiency can be congenital, acquired in childhood or in adult life, and can be partial or complete. In some cases, the deficiency is transient, but more commonly is permanent, and may occur in association with deficiencies of other pituitary hormones. Growth hormone deficiency in children leads to dwarfism, growth failure or short stature. Deficiency in adults is rare, but symptoms can include diminished body mass and poor bone density, and a number of psychological symptoms. Other hormonal or glandular disorders frequently coincide with deficiency of growth hormone.
Stimulating the increase in height in childhood is the most widely known effect of GH, and appears to function by at least two mechanisms: GH directly stimulates division and multiplication of chondrocytes of cartilage, and GH also stimulates production of IGF-1. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it apparently both an endocrine and an autocrine/paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.
Human growth hormone (hGH) plays a key role in somatic growth through its effects on the metabolism of proteins, carbohydrates and lipids. In addition to its effects on somatic growth, hGH has been shown to stimulate blood cells in vitro (Derfalvi et al., 1998; Merchav et al; 1988), to increase erythrocytes and hemoglobin counts (Valerio et al., 1997; Vihervuori et al., 1996), to enhance both proliferation and Ig production in plasma cell lines (Kimata and Yoshida, 1994) and to stimulate CD8+ cell counts and, to a lesser extent CD4+ cell counts (Geffner, 1997).
Injectable forms of GH have been marketed for GH deficiency in children and adults, Turner Syndrome, Prader-Willi Syndrome, and children small for gestational age. In addition, it has seen use in the battle against aging and for weight management, as well as the mobilization of cells capable of regenerating hematopoiesis in the peripheral blood.
The 22 kDA molecular weight of hGH is well below the threshold value for kidney filtration of about 70 kDa (Caliceti (2003) Adv Drug Deliv Rev 55:1261-1277), which contributes to the serum half-life of native hGH being less than 20 minutes in humans. Thus, commercial preparations of hGH must be dosed daily to achieve clinical benefit. A sustained-release form of GH, Nutropin Depot (Genentech and Alkermes) was approved by the FDA in 1999, allowing for fewer injections (every 2 or 4 weeks instead of daily); however, the product was discontinued in 2004.
Chemical modifications to a therapeutic protein can modify its in vivo clearance rate and subsequent serum half-life. One example of a common modification is the addition of a polyethylene glycol (PEG) moiety, typically coupled to the protein via an aldehyde or N-hydroxysuccinimide (NHS) group on the PEG reacting with an amine group (e.g. lysine side chain or the N-terminus). However, the conjugation step can result in the formation of heterogeneous product mixtures that need to be separated, leading to significant product loss and complexity of manufacturing and does not result in a completely chemically-uniform product. Also, the pharmacologic function of GH may be hampered if amino acid side chains in the vicinity of its binding site become modified by the PEGylation process. Other approaches include the genetic fusion of an Fc domain to the therapeutic GH protein. Conjugation of the Fc domain increases the size of the therapeutic protein, hence reducing the rate of clearance through the kidney. Additionally, the Fc domain confers the ability to bind to, and be recycled from lysosomes by, the FcRn receptor, which results in increased pharmacokinetic half-life. Unfortunately, the Fc domain does not fold efficiently during recombinant expression, and tends to form insoluble precipitates known as inclusion bodies. These inclusion bodies must be solubilized and functional protein must be renatured from the misfolded aggregate, a time-consuming, inefficient, and expensive process. Accordingly, there remains a need for growth hormone compositions that can increase the half-life and can be administered less frequently, but are safer and less complicated and costly to produce.
SUMMARY OF THE INVENTION
The present disclosure is directed to compositions and methods that can be useful for or the treatment of any disease, disorder or condition that is improved, ameliorated, or inhibited by the administration of growth hormone. In particular, the present invention provides compositions of fusion proteins comprising one or more extended recombinant polypeptides with a non-repetitive sequence and/or unstructured conformation (XTEN) linked to growth hormone (GH). In part, the present disclosure is directed to pharmaceutical compositions comprising the fusion proteins and the uses thereof for treating growth hormone-related diseases, disorders or conditions.
In one embodiment, the invention provides an isolated fusion protein, comprising a growth hormone that is at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% identical to an amino acid sequence selected from Table 1, wherein said growth hormone is linked to an extended recombinant polypeptide (XTEN) of at least about 100, or at least about 200, or at least about 400, or at least about 800, or at least about 900, or at least about 1000, or at least about 2000, up to about 3000 amino acids residues, wherein the XTEN is characterized in that (a) the XTEN comprises at least about 200 contiguous amino acids that exhibits at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% identical to a comparable length of an amino acid sequence selected from a sequence shown in Table 3; (b) 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 −5, or −6, or −7, or −8, or −9 or greater; (c) 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 even less; and (d) the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues constitutes more than about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of the total amino acid residues of the XTEN. In one embodiment, the growth hormone of the isolated fusion protein is human growth hormone. In another embodiment, the isolated fusion protein comprises at least a second XTEN, wherein the fusion protein adopts a multiple-XTEN configuration shown in Table 5, or a variant thereof.
In another embodiment, the XTEN sequence of the GHXTEN fusion proteins is characterized in that is 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 the Chou-Fasman algorithm.
In another embodiment, the invention provides GHXTEN fusion proteins, wherein the XTEN is 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, the XTEN sequence has less than 5% amino acid residues with a positive charge, 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 the Chou-Fasman algorithm.
In another embodiment, the invention provides GHXTEN fusion proteins, wherein the XTEN is 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 9 to about 14 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 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 some embodiments, no one type of amino acid constitutes more than 30% of the XTEN sequence of the GHXTEN. In other embodiments, the XTEN has a sequence in which no three contiguous amino acids are identical unless the amino acid is serine, in which case no more than three contiguous amino acids are serine residues. In still other embodiments, at least about 80%, or about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or 100% of the XTEN sequence consists of non-overlapping sequence motifs, wherein each of the sequence motifs has 12 amino acid residues. In one embodiment, the XTEN sequence consists of non-overlapping sequence motifs, wherein the sequence motifs are from one or more sequences of Table 2.
In some embodiments, GHXTEN fusion proteins exhibits enhanced pharmacokinetic properties compared to GH not linked to XTEN, wherein the enhanced properties include but are not limited to longer terminal half-life, larger area under the curve, increased time in which the blood concentration remains within the therapeutic window, increased time between consecutive doses, and decreased dose in moles over time. In some embodiments, the terminal half-life of the GHXTEN fusion protein administered to a subject is increased 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, or at least about 40-fold, or at least about 60-fold, or at least about 100-fold, or even higher as compared to GH not linked to XTEN and administered to a subject at a comparable dose. In other embodiments, the enhanced pharmacokinetic property is reflected by the fact that the blood concentrations that remain within the therapeutic window for the GHXTEN fusion protein for a given period are 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 longer, or at least about 20-fold, or at least about 40-fold, or at least about 60-fold, or at least about 100-fold compared to GH not linked to XTEN and administered to a subject at a comparable dose. The increase in half-life and time spent within the therapeutic window permits less frequent dosing and decreased amounts of the fusion protein (in moles equivalent) that are administered to a subject, compared to the corresponding GH not linked to XTEN. In one embodiment, the therapeutically effective dose regimen results in a gain in time of at least two-fold, or at least three-fold, or at least four-fold, or at least five-fold, or at least six-fold, or at least eight-fold, or at least 10-fold, or at least about 20-fold, or at least about 40-fold, or at least about 60-fold, or at least about 100-fold between at least two consecutive Cmax peaks and/or Cmin troughs for blood levels of the fusion protein compared to the corresponding GH not linked to the fusion protein and administered using a comparable dose regimen to a subject.
In some embodiments, the XTEN enhances thermostability of a biologically active protein when linked to the biologically active protein wherein the thermostability is ascertained by measuring the retention of biological activity after exposure to a temperature of about 37° C. for at least about 7 days of the biologically active protein in comparison to the XTEN linked to the biologically active protein. In one embodiment of the foregoing, the retention of biological activity in increased by at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, or about 150%, at least about 200%, at least about 300%, or about 500% longer compared to the GH not linked to the XTEN comprises of the XTEN.
In some embodiments, the isolated fusion protein with at least a first XTEN comprises a GH wherein the GH is human growth hormone. In some embodiments, the isolated fusion protein further comprises a second XTEN, which can be identical or can be different from the first XTEN, and wherein the fusion protein adopts a multiple-XTEN configuration shown in Table 5. In one embodiment of the foregoing, the first and the second XTEN can each be a sequence selected from Table 3, or can exhibit at least 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 Table 3. In another embodiment, the isolated fusion protein comprising a second XTEN sequence adopts a multiple-XTEN configuration shown in Table 5.
In one embodiment, the isolated fusion protein is less immunogenic compared to the GH not linked to the XTEN, wherein immunogenicity is ascertained by, e.g., measuring production of IgG antibodies selectively binding to the biologically active protein after administration of comparable doses to a subject.
In some embodiments, the growth hormone peptide and the XTEN of the fusion protein is linked via a spacer, wherein the spacer sequence comprises between about 1 to about 50 amino acid residues that optionally comprises a cleavage sequence. In one embodiment, the cleavage sequence is susceptible to cleavage by a protease. Non-limiting examples of such protease include FXIa, FXIIa, kallikrein, FVIIa, FIXa, FXa, thrombin, elastase-2, granzyme B, MMP-12, MMP-13, MMP-17 or MMP-20, TEV, enterokinase, rhinovirus 3C protease, and sortase A.
In some embodiments, the isolated fusion protein is configured to have reduced binding affinity for a target receptor of the corresponding GH, as compared to the corresponding GH not linked to the fusion protein. In one embodiment, the GHXTEN fusion protein exhibits binding affinity for a target receptor of the GH in the range of about 0.01%-30%, or about 0.1% to about 20%, or about 1% to about 15%, or about 2% to about 10% of the binding affinity of the corresponding GH that lacks the XTEN. In another embodiment, the GHXTEN fusion protein exhibits binding affinity for a target receptor of the GH that is reduced at least about 3-fold, or at least about 5-fold, or at least about 6-fold, or at least about 7-fold, or at least about 8-fold, or at least about 9-fold, or at least about 10-fold, or at least about 12-fold, or at least about 15-fold, or at least about 17-fold, or at least about 20-fold, or at least about 30-fold, or at least about 50-fold, or at least about 100-fold less binding affinity compared to GH not linked to XTEN. In a related embodiment, a fusion protein with reduced affinity can have reduced receptor-mediated clearance and a corresponding increase in half-life of at least about 3-fold, or at least about 5-fold, or at least about 6-fold, or at least about 7-fold, or at least about 8-fold, or at least about 9-fold, or at least about 10-fold, or at least about 12-fold, or at least about 15-fold, or at least about 17-fold, or at least about 20-fold, or at least about 30-fold, or at least about 50-fold, or at least about 100-fold longer compared to the corresponding GH that is not linked to the fusion protein.
In one embodiment, the invention provides an isolated GHXTEN fusion protein comprising an amino acids 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 Table 35, Table 36, and Table 37.
In some embodiments, the invention provides GHXTEN fusion proteins wherein the GHXTEN exhibits increased solubility of at least three-fold, or at least about four-fold, or at least about five-fold, or at least about six-fold, or at least about seven-fold, or at least about eight-fold, or at least about nine-fold, or at least about ten-fold, or at least about 15-fold, or at least a 20-fold, or at least 40-fold, or at least 60-fold at physiologic conditions compared to the GH not linked to the fusion protein.
In some embodiments, GHXTEN 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, or at least about 150 kD, or at least about 200 kD, or at least about 300 kD, or at least about 400 kD, or at least about 500 kD, or at least about 600 kD, or at least about 700 kD, while the actual molecular weight of each GH component of the fusion protein is less than about 25 kD. Accordingly, the GHXTEN 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 fusion protein. In some cases, the isolated GHXTEN 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.
The invention contemplates GHXTEN fusion proteins compositions comprising, but not limited to GH selected from Table 1 (or fragments or sequence variants thereof), XTEN selected from Table 3 (or sequence variants thereof) that are in a configuration selected from Table 5. Generally, the resulting GHXTEN will retain at least a portion of the biological activity of the corresponding GH not linked to the XTEN. In other cases, the GH component either becomes biologically active or has an increase in activity upon its release from the XTEN by cleavage of an optional cleavage sequence incorporated within spacer sequences into the GHXTEN.
In one embodiment of the GHXTEN composition, the invention provides a fusion protein of formula I:

(XTEN)x-GH-(XTEN)y  I

wherein independently for each occurrence, GH is a is a growth hormone; x is either 0 or 1 and y is either 0 or 1 wherein x+y≧1; and XTEN is an extended recombinant polypeptide.

In some embodiments, the XTEN is fused to the growth hormone on an N- or C-terminus of the growth hormone. In some embodiments, the isolated fusion protein comprises a human growth hormone and a first and a second XTEN selected from AE912, AM923, AE144, and AE288.
In another embodiment of the GHXTEN composition, the invention provides a fusion protein of formula II:

(XTEN)x-(GH)-(S)y-(XTEN)y  II

wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1 and y is either 0 or 1 wherein x+y≧1; and XTEN is an extended recombinant polypeptide.

In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula III:

(GH)-(S)x-(XTEN)-(S)y-(GH)-(S)z-(XTEN)z  III

wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; z is either 0 or 1; and XTEN is an extended recombinant polypeptide.

In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula IV:

(XTEN)x-(S)y-(GH)-(S)z-(XTEN)-(GH)  IV

wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; z is either 0 or 1; and XTEN is an extended recombinant polypeptide.

In another embodiment, the invention provides an isolated fusion growth hormone, wherein the fusion protein is of formula V:

(GH)x-(S)x-(GH)-(S)y-(XTEN)  V

wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; and XTEN is an extended recombinant polypeptide.

In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula VI:

(XTEN)-(S)x-(GH)-(S)y-(GH)  VI

wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; and XTEN is an extended recombinant polypeptide.

In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula VII:

(XTEN)-(S)x-(GH)-(S)y-(GH)-(XTEN)  VII

wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; and XTEN is an extended recombinant polypeptide.

In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula VIII:

((S)m-(GH)x-(S)n-(XTEN)y-(S)o)t  VIII

wherein t is an integer that is greater than 0 (1, 2, 3, etc.); independently each of m, n, o, x, and y is an integer (0, 1, 2, 3, etc.), GH is a is a growth hormone; S is an spacer, optionally comprises a cleavage site; and XTEN is an extended recombinant polypeptide, with the proviso that: (1) x+y>1, (2) when t=1, x>0 and y>0, (3) when there is more than one GH, S, or XTEN, each GH, XTEN, or S are the same or are independently different; and (4) when t>1, each m, n, o, x, or y within each subunit are the same or are independently different.

In some embodiments, administration of a therapeutically effective dose of a fusion protein of an embodiment of formulas I-VIII to a subject in need thereof can result in a gain in time of at least two-fold, or at least three-fold, or at least four-fold, or at least five-fold or more spent within a therapeutic window for the fusion protein compared to the corresponding GH not linked to the XTEN of and administered at a comparable dose to a subject. In other cases, administration of a therapeutically effective dose of a fusion protein of an embodiment of formulas I-VIII to a subject in need thereof can result in a gain in time between consecutive doses necessary to maintain a therapeutically effective dose regimen of at least 48 h, or at least 72 h, or at least about 96 h, or at least about 120 h, or at least about 7 days, or at least about 14 days, or at least about 21 days between consecutive doses compared to a GH not linked to XTEN and administered at a comparable dose.
The fusion proteins can be designed to have different configurations, N- to C-terminus, of a GH, XTEN, and optional spacer sequences, including but not limited to XTEN-GH, GH-XTEN, XTEN-S-GH, GH-S-XTEN, XTEN-GH-XTEN, GH-GH-XTEN, XTEN-GH-GH, GH-S-GH-XTEN, XTEN-GH-S-GH, and multimers thereof. The choice of configuration can, as disclosed herein, confer particular pharmacokinetic, physico/chemical, or pharmacologic properties.
In some embodiments, the isolated fusion protein is characterized in that: (i) it has a longer half-life compared to the corresponding growth hormone that lacks the XTEN; (ii) when a smaller molar amount of the fusion protein is administered to a subject in comparison to the corresponding growth hormone that lacks the XTEN administered to a subject under an otherwise equivalent dose regimen, the fusion protein achieves a comparable area under the curve (AUC) as the corresponding growth hormone that lacks the XTEN; (iii) when a smaller molar amount of the fusion protein is administered to a subject in comparison to the corresponding growth hormone that lacks the XTEN administered to a subject under an otherwise equivalent dose regimen, the fusion protein achieves a comparable therapeutic effect as the corresponding growth hormone that lacks the XTEN; (iv) when the fusion protein is administered to a subject less frequently in comparison to the corresponding growth hormone that lacks the XTEN administered to a subject using an otherwise equivalent molar amount, the fusion protein achieves a comparable area under the curve (AUC) as the corresponding growth hormone that lacks the XTEN; (v) when the fusion protein is administered to a subject less frequently in comparison to the corresponding growth hormone that lacks the XTEN administered to a subject using an otherwise equivalent molar amount, the fusion protein achieves a comparable therapeutic effect as the corresponding growth hormone that lacks the XTEN; (vi) when an accumulatively smaller molar amount of the fusion protein is administered to a subject in comparison to the corresponding growth hormone that lacks the XTEN administered to a subject under an otherwise equivalent dose period, the fusion protein achieves comparable area under the curve (AUC) as the corresponding growth hormone that lacks the XTEN; or (vii) when an accumulatively smaller molar amount of the fusion protein is administered to a subject in comparison to the corresponding growth hormone that lacks the XTEN administered to a subject under an otherwise equivalent dose period, the fusion protein achieves comparable therapeutic effect as the corresponding growth hormone that lacks the XTEN.
In one embodiment, the GHXTEN fusion proteins of formulas I-VIII described above exhibit a biological activity of at least about 0.1%, or at least about 0.1%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 4%, or at least about 5%, or at least about 10%, or at least about 20%, or at least about 30%, or at least 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 biological activity compared to the GH not linked to the fusion protein. In another embodiment, the GHXTEN fusion proteins of formulas I-VIII bind the same receptors or ligands as the corresponding parental biologically active protein that is not covalently linked to the fusion protein.
The invention provides a method of producing a fusion protein comprising a growth hormone fused to one or more extended recombinant polypeptides (XTEN), comprising: (a) providing host cell comprising a recombinant polynucleotide molecule encoding the fusion protein (b) culturing the host cell under conditions permitting the expression of the fusion protein; and (c) recovering the fusion protein. In one embodiment of the method, the growth hormone of the fusion protein has at least 90% sequence identity to human growth hormone or a sequence selected from Table 1. In another embodiment of the method, the one or more XTEN of the expressed fusion protein has 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 sequence selected from Table 3. In another embodiment of the method, the polynucleotide encoding the XTEN is codon optimized for enhanced expression of said fusion protein in the host cell. In another embodiment of the method, the host cell is a prokaryotic cell. In another embodiment of the method, the host cell is E. coli. In another embodiment of the method the isolated fusion protein is recovered from the host cell cytoplasm in substantially soluble form.
The invention provides isolated nucleic acids comprising a polynucleotide sequence selected from (a) a polynucleotide encoding the fusion protein of any of the foregoing embodiments, or (b) the complement of the polynucleotide of (a). In one embodiment, the invention provides an isolated nucleic acid comprising 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 of comparable length selected from Table 35, Table 36, and Table 37; 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. In another embodiment, the host cell is E. coli. In another embodiment, the host cell is a eukaryotic cell.
In one embodiment, the invention provides pharmaceutical compositions comprising the fusion protein of any of the foregoing embodiments and a 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 provides a method of treating a growth-hormone related condition in a subject, comprising administering to the subject a therapeutically effective amount of the fusion protein of any of the foregoing embodiments. In one embodiment of the method, the growth-hormone related condition is selected from growth-hormone deficiency, Turner's Syndrome, Prader-Willi Syndrome, idiopathic short stature, AIDS wasting, multiple sclerosis, Crohn's disease, ulcerative colitis, and muscular dystrophy.
In some embodiments, the composition can be administered subcutaneously, intramuscularly, or intravenously. In one embodiment, the composition is administered at a therapeutically effective amount. In one embodiment, the therapeutically effective amount results in a gain in time spent within a therapeutic window for the fusion protein compared to the corresponding GH of the fusion protein not linked to the fusion protein and administered at a comparable dose to a subject. The gain in time spent within the therapeutic window can at least three-fold longer than the corresponding GH not linked to the fusion protein, or alternatively, at least four-fold, or five-fold, or six-fold, or seven-fold, or eight-fold, or nine-fold, or at least 10-fold, or at least 20-fold, or at least about 30-fold, or at least about 50-fold, or at least about 100-fold longer than the corresponding GH not linked to the fusion protein. In some embodiments of the method of treatment, (i) a smaller molar amount of (e.g. of about two-fold less, or about three-fold less, or about four-fold less, or about five-fold less, or about six-fold less, or about eight-fold less, or about 100 fold-less or greater) the fusion protein is administered in comparison to the corresponding growth hormone that lacks the XTEN under an otherwise same dose regimen, and the fusion protein achieves a comparable area under the curve and/or a comparable therapeutic effect as the corresponding growth hormone that lacks the XTEN; (ii) the fusion protein is administered less frequently (e.g., every two days, about every seven days, about every 14 days, about every 21 days, or about, monthly) in comparison to the corresponding growth hormone that lacks the XTEN under an otherwise same dose amount, and the fusion protein achieves a comparable area under the curve and/or a comparable therapeutic effect as the corresponding growth hormone that lacks the XTEN; or (iii) an accumulative smaller molar amount (e.g. about 5%, or about 10%, or about 20%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90% less) of the fusion protein is administered in comparison to the corresponding growth hormone that lacks the XTEN under the otherwise same dose regimen the fusion protein achieves a comparable area under the curve and/or a comparable therapeutic effect as the corresponding growth hormone that lacks the XTEN. The accumulative smaller molar amount is measure for a period of at least about one week, or about 14 days, or about 21 days, or about one month. In some embodiments of the method, the therapeutic effect is a measured parameter selected from IGF-1 concentrations, IGFBP3 concentration, height velocity, lean body mass, total body fat, trunk fat, response to insulin challenge, rate of division of chondrocytes, chondrocyte numbers, bone density, bone growth, and increase in epiphyseal plate width.
In another embodiment, invention provides a method of treating a disease, disorder or condition, comprising administering the pharmaceutical composition described above to a subject using multiple consecutive doses of the pharmaceutical composition administered using a therapeutically effective dose regimen. In one embodiment of the foregoing, the therapeutically effective dose regimen can result in a gain in time of at least three-fold, or alternatively, at least four-fold, or five-fold, or six-fold, or seven-fold, or eight-fold, or nine-fold, or at least 10-fold, or at least 20-fold, or at least about 30-fold, or at least about 50-fold, or at least about 100-fold longer time between at least two consecutive Cmax peaks and/or Cmin troughs for blood levels of the fusion protein compared to the corresponding GH of the fusion protein not linked to the fusion protein and administered at a comparable dose regimen to a subject. In another embodiment of the foregoing, the administration of the fusion protein results in improvement in at least one measured parameter of a growth hormone-related disease using less frequent dosing or a lower total dosage in moles of the fusion protein of the pharmaceutical composition compared to the corresponding biologically active protein component(s) not linked to the fusion protein and administered to a subject d using a therapeutically effective regimen to a subject.
The invention further provides use of the compositions comprising the fusion protein of any of the foregoing embodiments in the preparation of a medicament for treating a disease, disorder or condition in a subject in need thereof. In one embodiment of the foregoing, the disease, disorder or condition is selected from group consisting of Turner's Syndrome, Prader-Willi Syndrome, idiopathic short stature, AIDS wasting, multiple sclerosis, Crohn's disease, ulcerative colitis, and muscular dystrophy. Any of the disclosed embodiments can be practiced alone or in combination depending on the interested application.
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. 1 shows schematic representations of exemplary GHXTEN fusion proteins (FIGS. 1A-H), all depicted in an N- to C-terminus orientation. FIG. 1A shows two different configurations of GHXTEN fusion proteins (100), each comprising a single growth hormone (GH) and an XTEN, the first of which has an XTEN molecule (102) attached to the C-terminus of a GH (103), and the second of which has an XTEN molecule attached to the N-terminus of a GH (103). FIG. 1B shows two different configurations of GHXTEN fusion proteins (100), each comprising a single GH, a spacer sequence and an XTEN, the first of which has an XTEN molecule (102) attached to the C-terminus of a spacer sequence (104) and the spacer sequence attached to the C-terminus of a GH (103) and the second of which has an XTEN molecule attached to the N-terminus of a spacer sequence (104) and the spacer sequence attached to the N-terminus of a GH (103). FIG. 1C shows two different configurations of GHXTEN fusion proteins (101), each comprising two molecules of a single GH and one molecule of an XTEN, the first of which has an XTEN linked to the C-terminus of a first GH and that GH is linked to the C-terminus of a second GH, and the second of which is in the opposite orientation in which the XTEN is linked to the N-terminus of a first GH and that GH is linked to the N-terminus of a second GH. FIG. 1D shows two different configurations of GHXTEN fusion proteins (101), each comprising two molecules of a single GH, a spacer sequence and one molecule of an XTEN, the first of which has an XTEN linked to the C-terminus of a spacer sequence and the spacer sequence linked to the C-terminus of a first GH which is linked to the C-terminus of a second GH, and the second of which is in the opposite orientation in which the XTEN is linked to the N-terminus of a spacer sequence and the spacer sequence is linked to the N-terminus of a first GH that that GH is linked to the N-terminus of a second GH. FIG. 1E shows two different configurations of GHXTEN fusion proteins (101), each comprising two molecules of a single GH, a spacer sequence and one molecule of an XTEN, the first of which has an XTEN linked to the C-terminus of a first GH and the first GH linked to the C-terminus of a spacer sequence which is linked to the C-terminus of a second GH molecule, and the second of which is in the opposite configuration of XTEN linked to the N-terminus of a first GH which is linked to the N-terminus of a spacer sequence which in turn is linked to the N-terminus of a second molecule of GH. FIG. 1F shows a configuration of GHXTEN fusion protein (105), each comprising one molecule of GH and two molecules of an XTEN linked to the N-terminus and the C-terminus of the GH. FIG. 1G shows a configuration (106) of a single GH linked to two XTEN, with the second XTEN separated from the GH by a spacer sequence. FIG. 1H s a configuration (106) of a two GH linked to two XTEN, with the second XTEN linked to the C-terminus of the first GH and the N-terminus of the second GH, which is at the C-terminus of the GHXTEN.
FIG. 2 is a schematic illustration of exemplary polynucleotide constructs (FIGS. 2A-H) of GHXTEN genes that encode the corresponding GHXTEN polypeptides of FIG. 1; all depicted in a 5′ to 3′ orientation. In these illustrative examples the genes encode GHXTEN fusion proteins with one GH and XTEN (200); or one GH, one spacer sequence and one XTEN (200); two GH and one XTEN (201); or two GH, a spacer sequence and one XTEN (201); one GH and two XTEN (205); or two GH and two XTEN (206). In these depictions, the polynucleotides encode the following components: XTEN (202), GH (203), and spacer amino acids that can include a cleavage sequence (204), with all sequences linked in frame.
FIG. 3 is a schematic illustration of two exemplary monomeric GHXTEN and the ability of the monomeric fusion proteins to bind to a target receptor on a cell surface, with subsequent cell signaling. FIG. 3A shows a GHXTEN fusion protein (100) consisting of a GH (103) and an XTEN (102) and a second GHXTEN fusion protein (105) consisting of a GH linked to two XTEN (105). FIG. 3B shows the interaction of the GHXTEN with the GH on the C-terminus (100) and the GHXTEN with an XTEN on the C-terminus (105) with target receptors (108) to GH on a cell surface (107). In this case, binding to the receptor with high affinity is exhibited when GH has a free C-terminus, while the GHXTEN with a C-terminal XTEN does not bind tightly to the receptor, and disassociates, as seen in FIG. 3C. FIG. 3D shows that the bound GHXTEN (100) with high binding affinity remains bound to the receptor (106) and has been internalized into an endosome (110) within the cell, illustrating receptor-mediated clearance of the bound GH and triggering cell signaling (109), portrayed as stippled cytoplasm.
FIG. 4 is a schematic flowchart of representative steps in the assembly, production and the evaluation of a XTEN.
FIG. 5 is a schematic flowchart of representative steps in the assembly of a GHXTEN polynucleotide construct encoding a fusion protein. Individual oligonucleotides 501 are 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 encodes a Flag sequence 506 followed by a stopper sequence that is flanked by BsaI, BbsI, and KpnI sites 507 and an exendin-4 gene 508, resulting in the gene 500 encoding an XTEN-GH fusion protein.
FIG. 6 is a schematic flowchart of representative steps in the assembly of a gene encoding fusion protein comprising a growth hormone (GH) and XTEN, its expression and recovery as a fusion protein, and its evaluation as a candidate GHXTEN product.
FIG. 7 is a schematic representation of the design of GHXTEN expression vectors with different processing strategies. FIG. 7A shows an exemplary expression vector encoding XTEN fused to the 3′ end of the sequence encoding GH. Note that no additional leader sequences are required in this vector. FIG. 7B depicts an expression vector encoding XTEN fused to the 5′ end of the sequence encoding GH with a CBD leader sequence and a TEV protease site. FIG. 7C depicts an expression vector as in FIG. 7B where the CBD and TEV processing site have been replaced with an optimized N-terminal leader sequence (NTS). FIG. 7D depicts an expression vector encoding an NTS sequence, an XTEN, a sequence encoding GH, and than a second sequence encoding an XTEN.
FIG. 8 is a schematic representation of the step-wise construction of GHXTEN genes that contain N-terminal XTEN encoding sequences linked to hGH and the subsequent linkage of sequences encoding either 144 or 288 XTEN linked to the C-terminus of XTEN, as described in Example 22.
FIG. 9 shows results of expression assays for the indicated constructs comprising GFP and XTEN sequences. The expression cultures were assayed using a fluorescence plate reader (excitation 395 nm, emission 510 nm) to determine the amount of GFP reporter present. 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. The results also show that the libraries starting with amino acids MA had better expression levels than those beginning with ME (see Example 14).
FIG. 10 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 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 the three libraries LCW0569 (SEQ ID NOS 845-846, respectively, in order of appearance), LCW0570 (SEQ ID NOS 847-848, respectively, in order of appearance), and LCW0571 (SEQ ID NOS 849-850, respectively, in order of appearance).
FIG. 11 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.
FIG. 12 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 that resulted in leader sequences that may be a solution for expression of XTEN proteins where the XTEN is N-terminal to the GH.
FIG. 13 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, as described in Example 17.
FIG. 14 shows an SDS-PAGE gel of samples from a stability study of the fusion protein of XTEN_AE864 fused to the N-terminus of GFP (see Example 39). The GFP-XTEN was incubated in cynomolgus plasma and rat kidney lysate for up to 7 days at 37° C. In addition, GFP-XTEN administered to cynomolgus monkeys was also assessed. 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. 15 shows the results of a receptor binding assay for hGH in which the binding activity of hGH fused to K288 polypeptide is compared to free hGH, as described in Example 25.
FIG. 16 shows the results of in vitro binding affinity assay of hGH-AM864 (circles) and AM864-hGH (inverted triangles) to hGHR-Fc, as described in Example 25. Unmodified recombinant hGH (squares) is shown for comparison.
FIG. 17 shows the effects of heat treatment on stability of hGH and AM864-hGH, as described in Example 26. FIG. 17A is an SDS-PAGE gel of the two preparations treated at 25° C. and 80° C. for 15 minutes, while FIG. 17B shows the corresponding percentage of receptor binding activity of the 80° C. sample relative to the 25° C. treatment, indicating that the XTEN conferred heat stability and retention of activity to the hGH and the GHXTEN fusion protein.
FIG. 18 shows results of an ELISA-based assay to determine the ability of addition of a C-terminus XTEN to reduce binding affinity of GHXTEN to bind to GH receptor, as described in Example 25.
FIG. 19 shows SDS-PAGE analysis of hGH fused to K288, with samples from throughout the purification process, as described in Example 19.
FIG. 20 shows SDS-PAGE analysis of 5 μg of final purified protein of hGH fused to Y576 in the configurations of hGH-Y576 and Y576-hGH subjected to both non-reducing and reducing SDS-PAGE, as described in Example 24, using NuPAGE 4-12% Bis-Tris gel from Invitrogen according to manufacturer's specifications.
FIG. 21 shows size exclusion chromatography profiles of two GHXTEN constructs Y576-GH and hGH-Y576 (N- to C-terminus), shown as an overlay, as described in Example 24.
FIG. 22 shows the pharmacokinetic profile of two GHXTEN constructs Y576-GH and hGH-Y576 (N- to C-terminus) following intravenous administration to cynomolgus monkeys, as described in Example 30. The results show that the orientation (N- versus C-terminal) of hGH relative to the XTEN did not affect the clearance of the fusion proteins.
FIG. 23 shows the pharmacokinetic profile after a single dose of 5 mg/kg AM864-hGH administered subcutaneously to cynomolgus monkeys, with the derived equivalent hGH concentration shown (dashed line), as described in Example 30. Terminal half-life was calculated as 33 hours by WinNonLin using a single compartment fit.
FIG. 24 shows the results of IGF-1 secretion in cynomolgus monkeys in response to administration of hGH or the GHXTEN AM864-hGH at the doses indicated, as described in Example 27.
FIG. 25 shows the effects of administration of hGH or AM864-hGH at the indicated doses on body weight in a hypox rat model, as described in Example 28. The results show retention of biologic activity by the GHXTEN constructs that is equivalent in potency to hGH, yet with less frequent dosing.
FIG. 26 shows the comparative effects of administration of placebo, hGH, and AM864-hGH on growth of cartilage in the tibial epiphyseal plate in hypox rats, shown in histologic cross-sections of the tibia after 9 days of treatment, as described in Example 29.
FIG. 27 shows the pharmacokinetic results of four hGH GHTXEN fusion proteins administered to rats by the subcutaneous route, compared to unmodified recombinant hGH, as described in Example 31.
FIG. 28 shows the concentration profiles of three hGH XTEN constructs after subcutaneous administration to cynomolgus monkeys, as described in Example 32.
FIG. 29 shows the results of a pharmacokinetic study of three doses levels of the GHXTEN AE912-hGH-AE144 administered to male and female cynos SC at 0.3 (open circles), 1.5 (squares), and 7.5 mg/kg (triangles), as described in Example 33.
FIG. 30. Shows the results of IGF-1 levels in cynos in response to the administration of AE912-hGH-AE144, as described in Example 33 (same groups as per FIG. 29).
FIG. 31 shows the results of an experiment to compare bioavailability of the GHXTEN AE912-hGH-AE144 administered by three different routes, as described in Example 34. AE912-hGH-AE144 was administered to male and female cynos SC at 1.5 mg/kg via intravenous (triangle), subcutaneous (open circles), and intramuscular (squares) routes, with plasma concentrations of the GHXTEN shown in the figure.
FIG. 32 shows the effects of administration of vehicle (open circles), recombinant hGH dosed at 5 nmol/kg/day (closed circles), the GHXTEN AE912-hGH-AE144 at varying doses and dose frequency (closed triangles=0.5 nmol/kg/day; open triangles=1.5 nmol/day; squares=3 nmol/kg/Q2D) on body weight in hypox rats, as described in Example 35.
FIG. 33 shows results of a modeled projection of the ability of hGH or the GHXTEN to maintain blood levels within a therapeutic window in the hypox rat model, based on results derived from the data portrayed in FIG. 32, using the same dosing groups.
FIG. 34 shows results of a 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 37. The glucagon-XTEN constructs are 1) glucagon-Y288; 2) glucagon Y-144; 3) glucagon-Y72; and 4) glucagon-Y36. The results indicate an increase in apparent molecular weight with increasing length of XTEN moiety.
FIG. 35 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 38. 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. 36 illustrates allometric scaling results for predicted human response to Ex4-XTEN_AE864 based on measured results from four animal species; i.e., mice, rats, cynomolgus monkeys and dogs. FIG. 36A shows measured terminal half-life versus body mass, with a predicted T1/2 in humans of 139 h. FIG. 36B shows measured drug clearance versus body mass, with a predicted clearance rate value of 30 ml/h in humans. FIG. 36C shows measured volume of distribution versus body mass, with a predicted value of 5970 ml in humans.
FIG. 37 shows the near UV circular dichroism spectrum of Ex4-XTEN_AE864, performed as described in Example 42.



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”, “linked,” “fused,” and “fusion” are used interchangeably herein. These terms refer to the joining together of two or more chemical elements or 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 or 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.
“Ligation” refers to the process of forming phosphodiester bonds between two nucleic acid fragments or genes, linking them together. To ligate the DNA fragments or genes together, the ends of the DNA must be compatible with each other. In some cases, the ends will be directly compatible after endonuclease digestion. However, it may be necessary to first convert the staggered ends commonly produced after endonuclease digestion to blunt ends to make them compatible for ligation.
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, 2nd 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, 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, 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'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'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 “t1/2” as used herein means the terminal half-life calculated as ln(2)/Kel. Kel 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 “t1/2”, “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 is determined using size exclusion chromatography (SEC) and similar methods compared to globular protein standards and is measured in “apparent kD” units. The Apparent Molecular Weight Factor is the ratio between the Apparent Molecular Weight 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'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 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 that 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,” 3rd 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 & Gilman's The Pharmacological Basis of Therapeutics,” 11th Edition, McGraw-Hill, 2005; and Freshney, R. I., “Culture of Animal Cells: A Manual of Basic Technique,” 4th edition, John Wiley & Sons, Somerset, N J, 2000, the contents of which are incorporated in their entirety herein by reference.
II). Growth Hormone
The present invention relates in part to fusion protein compositions of growth hormone (GH), including human growth hormone (hGH).
(a) Growth Hormone Proteins
“Growth Hormone” or “GH” means a growth hormone protein and species and sequence variants thereof, and includes, but is not limited to, the 191 single-chain amino acid sequence of human GH. The GH can be the native, full-length protein or can be a truncated fragment or a sequence variant that retains at least a portion of the biological activity of the native protein. There are two known types of human GH (hereinafter “hGH”) derived from the pituitary gland: one having a molecular weight of about 22,000 daltons (22 kD hGH) and the other having a molecular weight of about 20,000 daltons (20 kD hGH). The 20 kD HGH has an amino acid sequence that corresponds to that of 22 kD hGH consisting of 191 amino acids except that 15 amino acid residues from the 32nd to the 46th of 22 kD hGH are missing. Some reports have shown that the 20 kD hGH has been found to exhibit lower risks and higher activity than 22 kD hGH. The invention contemplates use of the 22 kD, the 20 kD hGH, as well as species and sequence variants and truncated fragments thereof as being appropriate for use as a fusion partner with XTEN disclosed herein for GHXTEN compositions. The cloned gene for hGH has been expressed in a secreted form in Eschericha coli (U.S. Pat. No. 4,898,830; Chang, C. N., et al., Gene 55:189 [1987]) and its DNA and amino acid sequence has been reported (Goeddel, et al. Nature, 281:544 [1979); Gray, et al., Gene 39: 247[1985]).
The invention contemplates inclusion in the GHXTEN compositions sequences with homology to GH sequences, sequence fragments that are natural, such as from humans, non-human primates, mammals (including domestic animals), and non-natural sequence variants which retain at least a portion of the biologic activity or biological function of GH and/or that are useful for preventing, treating, mediating, or ameliorating a GH-related disease, deficiency, disorder or condition. Non-mammalian GH sequences are well-described in the literature. For example, a sequence alignment of fish GHs can be found in Genetics and Molecular Biology 2003 26 p. 295-300. An analysis of the evolution of avian GH sequences is presented in Journal of Evolutionary Biology 2006 19 p. 844-854. In addition, native sequences homologous to human GH may be found by standard homology searching techniques, such as NCBI BLAST.
Effects of GH on the tissues of the body can generally be described as anabolic. Like most other protein hormones, native GH acts by interacting with a specific plasma membrane receptor, referred to as growth hormone receptor. GH acts on the liver and other tissues to stimulate production of IGF-1, which is responsible for the growth promoting effects of GH and also reflects the amount produced. IGF-1, in turn, has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth. In one embodiment, the invention provides a GHXTEN that exhibits at least one of the properties of native GH hereinabove described herein.
In one embodiment, the GH incorporated into the subject compositions is a recombinant polypeptide with a sequence corresponding to a protein found in nature. In another embodiment, the GH is a sequence variant, fragment, homolog, or a mimetics of a natural sequence that retains at least a portion of the biological activity of the corresponding native GH. Table 1 provides a non-limiting list of sequences of GHs from a wide variety of mammalian species that are encompassed by the GHXTEN fusion proteins of the invention. Any of these GH sequences or homologous derivatives constructed by shuffling individual mutations between species or families that retain at least a portion of the biological activity of the native GH may be useful for the fusion proteins of this invention. GH that can be incorporated into a GHXTEN fusion protein can include a protein that exhibits 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 to a sequence selected from Table 1.







TABLE 1







Growth hormone amino acid sequences from animal species









Species GH
SEQ ID NO:
Amino Acid Sequence












Human
1
FPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTSLCFSESIPTP




SNREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVYGASDSNVYDLLKDLEEGI




QTLMGRLEDGSPRTGQIFKQTYSKFDTNSHNDDALLKNYGLLYCFRKDMDKVETFLRI




VQCRSVEGSCGF


 


Pig
2
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCFSETIPA




PTGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDRVYEKLKDLEEG




IQALMRELEDGSPRAGQILKQTYDKFDTNLRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


Alpaca
3
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERTYIPEGQRYSIQNAQAAFCFSETIPAP




TGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDRVYEKLKDLEEGI




QALMRELEDGSPRAGQILRQTYDKFDTNLRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


Camel
4
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERTYIPEGQRYSIQNAQAAFCFSETIPAP




TGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDRVYEKLKDLEEGI




QALMRELEDGSPRAGQILRQTYDKFDTNLRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


Horse
5
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCFSETIPA




PTGKDEAQQRSDMELLRFSLLLIQSWLGPVQLLSRVFTNSLVFGTSDRVYEKLRDLEEG




IQALMRELEDGSPRAGQILKQTYDKFDTNLRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


Elephant
6
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCFSETIPA




PTGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDRVYEKLKDLEEG




IQALMRELEDGSPRPGQVLKQTYDKFDTNMRSDDALLKNYGLLSCFKKDLHKAETYL




RV MKCRRFVESSCAF


 


Red fox
7
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCFSETIPA




PTGKDEAQQRSDVELLRFSLVLIQSWLGPLQFLSRVFTNSLVFGTSDRVYEKLKDLEEG




IQALMRELEDGSPRAGQILKQTYDKFDTNLRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


Dog
8
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCFSETIPA




PTGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDRVYEKLKDLEEG




IQALMRELEDGSPRAGQILKQTYDKFDTNLRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


Cat
9
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCFSETIPA




PTGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDRVYEKLKDLEEG




IQALMRELEDGSPRGGQILKQTYDKFDTNLRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


American
10
FPAMPLSSLFANAVLRAQHLHQLAADTYKDFERAYIPEGQRYSIQNAQAAFCFSETIPA


mink

PTGKDEAQQRSDMELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDRVYEKLKDLEEG




IQALMRELEDGSPRAGPILKQTYDKFDTNLRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


Finback
11
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCFSETIPA


whale

PTGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDRVYEKLKDLEEG




IQALMRELEDGSPRAGQILKQTYDKFDTNMRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


Dolphin
12
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNTQAAFCFSETIPAP




TGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDRVYEKLKDLEEGI




QALMRELEDGSPRAGQILKQTYDKFDTNMRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


Hippo
13
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNTQAAFCFSETIPAP




TGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDRVYEKLKDLEEGI




QALMRELEDGSPRAGQILKQTYDKFDTNMRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


Rabbit
14
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCFSETIPA




PTGKDEAQQRSDMELLRFSLLLIQSWLGPVQFLSRAFTNTLVFGTSDRVYEKLKDLEEG




IQALMRELEDGSPRVGQLLKQTYDKFDTNLRGDDALLKNYGLLSCFKKDLHKAETYL




RV MKCRRFVESSCVF


 


Rat
15
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCFSETIPA




PTGKEEAQQRTDMELLRFSLLLIQSWLGPVQFLSRIFTNSLMFGTSDRVYEKLKDLEEGI




QALMQELEDGSPRIGQILKQTYDKFDANMRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFAESSCAF


 


Mouse
16
FPAMPLSSLFSNAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCFSETIPAP




TGKEEAQQRTDMELLRFSLLLIQSWLGPVQFLSRIFTNSLMFGTSDRVYEKLKDLEEGI




QALMQELEDGSPRVGQILKQTYDKFDANMRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


Hamster
17
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQTAFCFSETIPAP




TGKEEAQQRSDMELLRFSLLLIQSWLGPVQFLSRIFTNSLMFGTSDRVYEKLKDLEEGI




QALMQELEDGSPRVGQILKQTYDKFDTNMRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


Mole rat
18
FPAMPLSNLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCFSETIPA




PTGKEEAQQRSDMELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDRVFLKLKDLEEGI




QALMRELEDGSLRAGQLLKQTYDKFDTNMRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


Guinea pig
19
FPAMPLSSLFGNAVLRAQHLHQLAADTYKEFERTYIPEGQRYSIHNTQTAFCFSETIPAP




TDKEEAQQRSDVELLHFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDRVYEKLKDLEEGI




QALMRELEDGTPRAGQILKQTYDKFDTNLRSNDALLKNYGLLSCFRKDLHRTETYLRV




MKCRRFVESSCAF


 


Ox
20
AFPAMSLSGLFANAVLRAQHLHQLAADTFKEFERTYIPEGQRYSIQNTQVAFCFSETIPA




PTGKNEAQQKSDLELLRISLLLIQSWLGPLQFLSRVFTNSLVFGTSDRVYEKLKDLEEGI




LALMRELEDGTPRAGQILKQTYDKFDTNMRSDDALLKNYGLLSCFRKDLHKTETYLR




V MKCRRFGEASCAF


 


Sheep/Goat
21
AFPAMSLSGLFANAVLRAQHLHQLAADTFKEFERTYIPEGQRYSIQNTQVAFCFSETIPA




PTGKNEAQQKSDLELLRISLLLIQSWLGPLQFLSRVFTNSLVFGTSDRVYEKLKDLEEGI




LALMRELEDVTPRAGQILKQTYDKFDTNMRSDDALLKNYGLLSCFRKDLHKTETYLR




V MKCRRFGEASCAF


 


Red deer
22
FPAMSLSGLFANAVLRAQHLHQLAADTFKEFERTYIPEGQRYSIQNTQVAFCFSETIPAP




TGKNEAQQKSDLELLRISLLLIQSWLGPLQFLSRVFTNSLVFGTSDRVYEKLKDLEEGIL




ALMRELEDGTPRAGQILKQTYDKFDTNMRSDDALLKNYGLLSCFRKDLHKTETYLRV




MKCRRFGEASCAF


 


Giraffe
23
AFPAMSLSGLFANAVLRAQHLHQLAADTFKEFERTYIPEGQRYSIQNTQVAFCFSETIPA




PTGKNEAQQKSDLELLRISLLLIQSWLGPLQFLSRVFSNSLVFGTSDRVYEKLKDLEEGI




LALMRELEDGTPRAGQILKQTYDKFDTNMRSDDALLKNYGLLSCFRKDLHKTETYLR




V MKCRRFGEASCAF


 


Chevrotain-1
24
FPAMSLSGLFANAVLRVQHLHQLAADTFKEFERTYIPEGQRYSIQNTQVAFCFSETIPAP




TGKNEAQQKSDLELLRISLLLIQSWLGPLQFLSRVFTNSLVFGTSDRVYEKLKDLEEGIL




ALMRELEDGPPRAGQILKQTYDKFDTNMRSDDALLKNYGLLSCFRKDLHKTETYLRV




MKCRRFGEASCAF


 


Slow loris
25
FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCFSETIPA




PTGKDEAQQRSDMELLRFSLLLIQSWLGPVQLLSRVFTNSLVLGTSDRVYEKLKDLEEG




IQALMRELEDGSPRVGQILKQTYDKFDTNLRSDDALLKNYGLLSCFKKDLHKAETYLR




V MKCRRFVESSCAF


 


Marmoset
26
FPTIPLSRLLDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTSLCFSESIPTP




ASKKETQQKSNLELLRMSLLLIQSWFEPVQFLRSVFANSLLYGVSDSDVYEYLKDLEEG




IQTLMGRLEDGSPRTGEIFMQTYRKFDVNSQNNDALLKNYGLLYCFRKDMDKVETFL




RI VQCR-SVEGSCGF


 


BrTailed
27
FPAMPLSSLFANAVLRAQHLHQLVADTYKEFERTYIPEAQRHSIQSTQTAFCFSETIPAP


Possum

TGKDEAQQRSDVELLRFSLLLIQSWLSPVQFLSRVFTNSLVFGTSDRVYEKLRDLEEGIQ




ALMQELEDGSSRGGLVLKTTYDKFDTNLRSDEALLKNYGLLSCFKKDLHKAETYLRV




MKCRRFVESSCAF


 


Monkey
28
FPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTSLCFSESIPTP


(rhesus)

SNREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVYGTSYSDVYDLLKDLEEGI




QTLMGRLEDGSSRTGQIFKQTYSKFDTNSHNNDALLKNYGLLYCFRKDMDKIETFLRI




VQCR-SVEGSCGF









III). Growth Hormone Fusion Protein Compositions
The present invention relates in part to fusion protein compositions of growth hormone (GH). In one aspect, the invention provides isolated monomeric fusion proteins of GH comprising the full-length sequence or sequence variants of GH covalently linked to extended recombinant recombinant polypeptides (“XTEN” or “XTENs”). As described more fully below, the fusion proteins optionally include spacer sequences that further comprise cleavage sequences to release the GH from the fusion protein when acted on by a protease, releasing GH from the XTEN sequence(s).
In one aspect, the invention provides an isolated fusion protein comprising at least a first biologically active growth hormone protein covalently linked to one or more extended recombinant polypeptides (“XTEN”), resulting in a growth hormone-XTEN fusion protein composition (hereinafter “GHXTEN”). In one embodiment, the growth hormone is human growth hormone or a sequence variant of hGH. As described more fully below, the fusion proteins optionally include spacer sequences that further comprise cleavage sequences to release the GH from the fusion protein when acted on by a protease.
The term “GHXTEN”, as used herein, is meant to encompass fusion polypeptides that comprise one or more payload regions each comprising a biologically active GH that mediates one or more biological or therapeutic activities associated with growth hormone and at least one other region comprising at least a first XTEN polypeptide that serves as a carrier.
The GH of the subject compositions, particularly those disclosed in Table 1, together with their corresponding nucleic acid and amino acid sequences, are well known in the art and descriptions and sequences are available in public databases such as Chemical Abstracts Services Databases (e.g., the CAS Registry), GenBank, The Universal Protein Resource (UniProt) and subscription provided databases such as GenSeq (e.g., Derwent). Polynucleotide sequences may be a wild type polynucleotide sequence encoding a given GH (e.g., either full length or mature), or in some instances the sequence may be a variant of the wild type polynucleotide sequence (e.g., a polynucleotide which encodes the wild type biologically active protein, wherein the DNA sequence of the polynucleotide has been optimized, for example, for expression in a particular species; or a polynucleotide encoding a variant of the wild type protein, such as a site directed mutant or an allelic variant. It is well within the ability of the skilled artisan to use a wild-type or consensus cDNA sequence or a codon-optimized variant of a GH to create GHXTEN constructs contemplated by the invention using methods known in the art and/or in conjunction with the guidance and methods provided herein, and described more fully in the Examples.
The GH for inclusion in the GHXTEN of the invention include any growth hormone or sequence variant of biologic, therapeutic, prophylactic, or diagnostic interest or function, or that is useful for mediating or preventing or ameliorating a disease, disorder or condition associated with growth, growth hormone deficiency or defect when administered to a subject. Of particular interest are GHXTEN fusion protein compositions for which an increase in a pharmacokinetic parameter, increased solubility, increased stability, or some other enhanced pharmaceutical property compared to native GH is sought, or for which increasing the terminal half-life would improve efficacy, safety, or result in reduce dosing frequency and/or improve patient compliance. Thus, the GHXTEN fusion protein compositions are prepared with various objectives in mind, including improving the therapeutic efficacy of the bioactive GH by, for example, increasing the in vivo exposure or the length that the GHXTEN remains within the therapeutic window when administered to a subject, compared to a GH not linked to XTEN.
In one embodiment, the GH incorporated into the subject compositions can be a recombinant polypeptide with a sequence corresponding to a protein found in nature. In another embodiment, the GH is a sequence variant, fragment, homolog, or mimetic of a natural sequence that retain at least a portion of the biological activity of the native GH. In non-limiting examples, a GH is a sequence that exhibits 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%, or at least about 99%, or 100% sequence identity to a protein sequence selected from Table 1. In one embodiment, a GHXTEN fusion protein comprises a single GH molecule linked to an XTEN (as described more fully below). In another embodiment, the GHXTEN comprises a first GH and a second molecule of the same GH, resulting in a fusion protein comprising the two GH linked to one or more XTEN (for example, or two molecules of hGH). In some cases of the foregoing embodiments, the GH and XTEN components are of an N- to C-terminus configuration selected from Table 5. In another embodiment, the GHXTEN fusion protein comprises a single GH molecule linked to a first and a second XTEN, with an N- to C-terminus configuration of XTEN-GH-XTEN, in which the GH is a sequence that exhibits 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%, or at least about 99%, or 100% sequence identity to a protein sequence selected from Table 1, and the first and/or the second XTEN are sequences that exhibits 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%, or at least about 99%, or 100% sequence identity to a sequence selected from Table 3.
In general, the GH fusion partner component of the GHXTEN exhibits a binding specificity to a given target or another desired biological characteristic when used in vivo or when utilized in an in vitro assay. For example, the GHXTEN is an agonist, having the ability to bind to a transmembrane receptor for growth hormone. In one embodiment, the binding of GHXTEN to growth receptor leads to receptor dimerization and lead to at least a portion of the activation of intercellular signal transduction pathway compared to native growth hormone. In one embodiment, the GHXTEN bound to a transmembrane receptor for growth hormone would exhibit at least about 1%, or about 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or at least about 95% of the activation of intercellular signal transduction pathway compared to native growth hormone not linked to XTEN.
The subject GHXTEN of the present invention exhibits an enhancement of one or more pharmacokinetic parameters, which optionally is enhanced by release of GH from the fusion protein by cleavage of a spacer sequence. The GHXTEN with enhanced pharmacokinetic parameters permits less frequent dosing or an enhanced pharmacologic effect, such as but not limited to maintaining the biologically active GHXTEN within the therapeutic window between the minimum effective dose or blood concentration (Cmin) and the maximum tolerated dose or blood concentration (Cmax). In such cases, the linking of the GH to a fusion protein comprising a select XTEN sequence(s) can result in an improvement in these properties, making them more useful as therapeutic or preventive agents compared to GH not linked to XTEN.
IV). Extended Recombinant Polypeptides
In one aspect, the invention provides XTEN polypeptide compositions that are useful as a fusion protein partner to which GH is linked, resulting in a GHXTEN 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.
XTENs have utility as a fusion protein partners partner in that they serve as a “carrier”, conferring certain desirable pharmacokinetic, physicochemical and pharmaceutical properties when linked to a GH protein to a create a fusion protein. Such desirable properties include but are not limited to enhanced pharmacokinetic parameters and solubility characteristics the compositions, amongst other properties described herein. Such fusion protein compositions have utility to treat certain growth hormone-related diseases, disorders or conditions, as described herein. As used herein, “XTEN” specifically excludes antibodies or antibody fragments such as single-chain antibodies or Fc fragments of a light chain or a heavy chain.
In some embodiments, XTEN are long polypeptides having greater than about 100 to about 3000 amino acid residues, preferably greater than 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. In other embodiments, when used as a linker between fusion protein components or where an increase in half-life of the fusion protein is not needed but where an increase in solubility or other physico/chemical property for the GH fusion partner component is desired, an XTEN sequence shorter than 100 amino acid residues, such as about 96, or about 84, or about 72, or about 60, or about 48, or about 36 amino acid residues are incorporated into a fusion protein composition with the GH to effect the property.
The selection criteria for the XTEN to be linked to the biologically active proteins used to create the inventive fusion proteins compositions generally relate to attributes of physical/chemical properties and conformational structure of the XTEN that is, in turn, used to confer enhanced pharmaceutical and pharmacokinetic properties to the fusion proteins compositions. The XTEN of the present invention 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 make them particularly useful as fusion protein partners. Non-limiting examples of the properties of the fusion proteins comprising GH that is 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 GH not linked to XTEN and administered by a similar route) such that the Cmax is lower, which, in turn, results in reductions in adverse effects of the GH that, collectively, results in an increased period of time that a fusion protein of a GHXTEN 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.
Typically, 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 some embodiments, the invention provides XTEN sequences that, under physiologic conditions, resemble denatured sequences largely devoid in secondary structure. In other cases, the XTEN sequences are 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 methods 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 (Garnier 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 some embodiments, the XTEN sequences used in the inventive fusion protein compositions can have an alpha-helix percentage ranging from 0% to less than about 5% as determined by the Chou-Fasman algorithm. In other cases, 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 some embodiments, 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%. In other cases, 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.
1. Non-Repetitive Sequences
In some embodiments, XTEN sequences of the compositions 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, or 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 be likely to aggregate if the sequences were otherwise repetitive. Typically, the GHXTEN fusion proteins comprise XTEN sequences of greater than about 100 to about 3000 amino acid residues, preferably greater than 400 to about 3000 cumulative residues, wherein the sequences are substantially non-repetitive. In one embodiment, the XTEN sequences have greater than about 100 to about 3000 amino acid residues, preferably greater than 400 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 would be substantially non-repetitive.
The degree of repetitiveness of a polypeptide or a gene are measured by computer programs or algorithms or by other means known in the art. Repetitiveness in a polypeptide sequence can, for example, be assessed by determining the number of times shorter sequences of a given length occur within the polypeptide. For example, a polypeptide of 200 amino acid residues has 192 overlapping 9-amino acid sequences (or 9-mer “frames”) and 198 3-mer frames, but the number of unique 9-mer or 3-mer sequences will depend on the amount of repetitiveness within the sequence. A score is generated (hereinafter “subsequence score”) that is reflective of the degree of repetitiveness of the subsequences in the overall polypeptide sequence. In the context of the present invention, “subsequence score” means 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 44. In some embodiments, the present invention provides GHXTEN each comprising one or more XTEN in which the XTEN have a subsequence score less than 12, more preferably less than 10, more preferably less than 9, more preferably less than 8, more preferably less than 7, more preferably less than 6, and most preferably less than 5. In the embodiments hereinabove described in this paragraph, an XTEN with a subsequence score less than about 10 (i.e., 9, 8, 7, etc.) is “substantially non-repetitive.”
The non-repetitive characteristic of XTEN impart to fusion proteins with GH a greater degree of solubility and less tendency to aggregate compared to polypeptides having repetitive sequences. These properties 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 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 that comprise multiple units of shorter sequences, or motifs, in which the amino acid sequences of the motifs are non-repetitive. In designing XTEN sequences, it was discovered that the non-repetitive criterion may be 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 rendered substantially non-repetitive.
In one embodiment, XTEN have a non-repetitive sequence of greater than about 100 to about 3000 amino acid residues, preferably greater than 400 to about 3000 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 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 100 to about 3000 amino acid residues, preferably greater than 400 to about 3000 residues in length. In some embodiments, XTEN have sequences of greater than about 100 to about 3000 amino acid residues, preferably greater than 400 to about 3000 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 100 to about 3000 amino acid residues, preferably greater than 400 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 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 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 would be substantially non-repetitive.
In some embodiments, the invention provides compositions comprising non-repetitive XTEN sequence(s) of greater than about 100 to about 3000 amino acid residues, of cumulatively greater than 400 to about 3000 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 2. In some embodiments, the XTEN comprises non-overlapping sequence motifs in which 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 two or more non-overlapping sequences selected from a single motif family of Table 2, resulting in a “family” sequence in which the overall sequence remains substantially non-repetitive. Accordingly, in these embodiments, an XTEN sequence comprises multiple units of non-overlapping sequence motifs of the AD motif family, or the AE motif family, or the AF motif family, or the AG motif family, or the AM motif family, or the AQ motif family, or the BC family, or the BD family of sequences of Table 2. In other embodiments, the XTEN comprises motif sequences from two or more of the motif families of Table 2.







TABLE 2







XTEN Sequence Motifs of 12 Amino Acids and Motif


Families









Motif Family*
SEQ ID NO:
MOTIF SEQUENCE





AD
29
GESPGGSSGSES


 


AD
30
GSEGSSGPGESS


 


AD
31
GSSESGSSEGGP


 


AD
32
GSGGEPSESGSS


 


AE, AM
33
GSPAGSPTSTEE


 


AE, AM, AQ
34
GSEPATSGSETP


 


AE, AM, AQ
35
GTSESATPESGP


 


AE, AM, AQ
36
GTSTEPSEGSAP


 


AF, AM
37
GSTSESPSGTAP


 


AF, AM
38
GTSTPESGSASP


 


AF, AM
39
GTSPSGESSTAP


 


AF, AM
40
GSTSSTAESPGP


 


AG, AM
41
GTPGSGTASSSP


 


AG, AM
42
GSSTPSGATGSP


 


AG, AM
43
GSSPSASTGTGP


 


AG, AM
44
GASPGTSSTGSP


 


AQ
45
GEPAGSPTSTSE


 


AQ
46
GTGEPSSTPASE


 


AQ
47
GSGPSTESAPTE


 


AQ
48
GSETPSGPSETA


 


AQ
49
GPSETSTSEPGA


 


AQ
50
GSPSEPTEGTSA


 


BC
51
GSGASEPTSTEP


 


BC
52
GSEPATSGTEPS


 


BC
53
GTSEPSTSEPGA


 


BC
54
GTSTEPSEPGSA


 


BD
55
GSTAGSETSTEA


 


BD
56
GSETATSGSETA


 


BD
57
GTSESATSESGA


 


BD
58
GTSTEASEGSAS





*Denotes individual motif sequences that, when used together in various permutations, results in a “family sequence”






In other embodiments, the GHXTEN composition comprises a non-repetitive XTEN sequence of greater than about 100 to about 3000 amino acid residues, preferably greater than 400 to about 3000 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 8-11.
In those embodiments wherein the XTEN component of the GHXTEN 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 sequence motifs of Table 2, or less than 100% sequence identity with an XTEN from Table 3, 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 GHXTEN 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 few (e.g. less than 5%) 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 GHXTEN 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 of the present invention, the invention encompasses GHXTEN compositions comprising carriers of XTEN polypeptides with extended length sequences. The present invention makes use of the discovery that increasing the length of 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 fixed repeat order of single family sequence motifs (e.g., the four AE motifs of Table 2), result in a sequence with a higher percentage of random coil formation, as determined by GOR algorithm, compared to shorter XTEN lengths. In general, increasing the length of the unstructured polypeptide fusion partner, as described in the Examples, results in a fusion protein with a disproportional increase in terminal half-life compared to fusion proteins with unstructured polypeptide partners with shorter sequence lengths.
Non-limiting examples of XTEN contemplated for inclusion in the GHXTEN of the invention are presented in Table 3. In one embodiment, the invention provides GHXTEN compositions wherein the XTEN sequence length of the fusion protein(s) is greater than about 100 to about 3000 amino acid residues, and in some cases is greater than 400 to about 3000 amino acid residues, wherein the XTEN confers enhanced pharmacokinetic properties on the GHXTEN in comparison to GH not linked to XTEN. In some embodiments, the XTEN sequences of the GHXTEN compositions of the present invention can be 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 100 to 150, about 150 to 250, about 250 to 400, 401 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 one embodiment, the GHXTEN can comprise an XTEN sequence wherein the sequence exhibits 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 to a XTEN selected from Table 3. In some embodiments, the XTEN sequence is designed for optimized expression as the N-terminal component of the GHXTEN by inclusion of encoding nucleotides for an optimized N-terminal leader sequence (NTS) in the XTEN portion of the gene encoding the fusion protein. In one embodiment, the N-terminal XTEN sequence of the expressed GHXTEN has at least 90% sequence identity to the sequence of AE48 or AM48, AE624, or AE912 or AM923. In another embodiment, the XTEN has the N-terminal residues described in Examples 14-17.
In other embodiments, the GHXTEN fusion protein comprises a first and a second XTEN sequence, wherein the cumulative total of the residues in the XTEN sequences is greater than about 400 to about 3000 amino acid residues. In embodiments of the foregoing, the GHXTEN fusion protein comprises a first and a second XTEN sequence wherein the 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 to at least a first or additionally a second XTEN selected from Table 3. Examples where more than one XTEN is used in a GHXTEN composition include, but are not limited to constructs with an XTEN linked to both the N- and C-termini of at least one GH.
As described more fully below, the invention provides methods in which the GHXTEN is designed by selecting the length of the XTEN to confer a target half-life on a fusion protein administered to a subject. In general, XTEN lengths longer that about cumulative 400 residues incorporated into the GHXTEN compositions result in longer half-life compared to shorter cumulative lengths; e.g., shorter than about 280 residues. However, in another embodiment, GHXTEN fusion proteins are designed to comprise XTEN with a longer sequence length that is selected to additionally confer slower rates of systemic absorption after subcutaneous or intramuscular administration to a subject. In such embodiments, the Cmax is reduced in comparison to a comparable dose of a GH not linked to XTEN, thereby contributing to the ability to keep the GHXTEN within the therapeutic window for the composition. Thus, the XTEN confers the property of a depot to the administered GHXTEN, in addition to the other physical/chemical properties described herein.







TABLE 3







XTEN Polypeptides









XTEN
SEQ ID



Name
NO:
Amino Acid Sequence





AE48
59
MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGS


 


AM48
60
MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGS


 


AE144
61
GSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGSEP




ATSGSETPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGSAPGTSESATPESGPGSEPATSG




SETPGTSTEPSEGSAP


 


AF144
62
GTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGSTSESPSGTAPGSTSS




TAESPGPGTSPSGESSTAPGTSTPESGSASPGSTSSTAESPGPGTSPSGESSTAPGTSPSGESST




APGTSPSGESSTAP


 


AE288
63
GTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTST




EPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPT




STEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGP




GSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEP




ATSGSETPGTSESATPESGPGTSTEPSEGSAP


 


AF504
64
GASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSXP




SASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGASPGTS




STGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSS




PGSSTPSGATGSPGSXPSASTGTGPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSPGA




SPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGT




SSTGSPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTG




SPGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGS




STPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSP


 


AF540
65
GSTSSTAESPGPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGSTSSTAESPGPGTSTP




ESGSASPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESST




APGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGS




TSESPSGTAPGTSTPESGSASPGSTSESPSGTAPGTSTPESGSASPGSTSSTAESPGPGSTSSTA




ESPGPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASP




GSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGSTSSTAESPGPGTSTPESGSASPGTSTP




ESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGT




APGTSTPESGSASPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGSTSSTAESPGPGT




STPESGSASPGSTSESPSGTAP


 


AD576
66
GSSESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSSE




SGSSEGGPGSSESGSSEGGPGESPGGSSGSESGSEGSSGPGESSGSSESGSSEGGPGSSESGSS




EGGPGSSESGSSEGGPGSGGEPSESGSSGESPGGSSGSESGESPGGSSGSESGSGGEPSESGS




SGSSESGSSEGGPGSGGEPSESGSSGSGGEPSESGSSGSEGSSGPGESSGESPGGSSGSESGSG




GEPSESGSSGSGGEPSESGSSGSGGEPSESGSSGSSESGSSEGGPGESPGGSSGSESGESPGGS




SGSESGESPGGSSGSESGESPGGSSGSESGESPGGSSGSESGSSESGSSEGGPGSGGEPSESGS




SGSEGSSGPGESSGSSESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSGGEPSESGSSGES




PGGSSGSESGESPGGSSGSESGSSESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSGGEPS




ESGSSGSGGEPSESGSSGESPGGSSGSESGSEGSSGPGESSGSSESGSSEGGPGSEGSSGPGESS


 


AE576
67
GSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTST




EPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATP




ESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAP




GTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTST




EPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSG




SETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAP




GTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEP




ATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATP




ESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAP


 


AF576
68
GSTSSTAESPGPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGSTSSTAESPGPGTSTP




ESGSASPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESST




APGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGS




TSESPSGTAPGTSTPESGSASPGSTSESPSGTAPGTSTPESGSASPGSTSSTAESPGPGSTSSTA




ESPGPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASP




GSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGSTSSTAESPGPGTSTPESGSASPGTSTP




ESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGT




APGTSTPESGSASPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGSTSSTAESPGPGT




STPESGSASPGSTSESPSGTAPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSASP


 


AE624
69
MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTSTEEGT




SESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESA




TPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGS




APGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGT




STEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESA




TPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPES




GPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGT




STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESA




TPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTST




EEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAP


 


AD836
70
GSSESGSSEGGPGSSESGSSEGGPGESPGGSSGSESGSGGEPSESGSSGESPGGSSGSESGESP




GGSSGSESGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGESPGGSSGSESGESPGGSS




GSESGESPGGSSGSESGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGP




GSSESGSSEGGPGSSESGSSEGGPGSGGEPSESGSSGESPGGSSGSESGESPGGSSGSESGSG




GEPSESGSSGSEGSSGPGESSGSSESGSSEGGPGSGGEPSESGSSGSEGSSGPGESSGSSESGS




SEGGPGSGGEPSESGSSGESPGGSSGSESGSGGEPSESGSSGSGGEPSESGSSGSSESGSSEG




GPGSGGEPSESGSSGSGGEPSESGSSGSEGSSGPGESSGESPGGSSGSESGSEGSSGPGESSGS




EGSSGPGESSGSGGEPSESGSSGSSESGSSEGGPGSSESGSSEGGPGESPGGSSGSESGSGGE




PSESGSSGSEGSSGPGESSGESPGGSSGSESGSEGSSGPGSSESGSSEGGPGSGGEPSESGSSG




SEGSSGPGESSGSEGSSGPGESSGSEGSSGPGESSGSGGEPSESGSSGSGGEPSESGSSGESPG




GSSGSESGESPGGSSGSESGSGGEPSESGSSGSEGSSGPGESSGESPGGSSGSESGSSESGSSE




GGPGSSESGSSEGGPGSSESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGESPGGSSGSES




GSGGEPSESGSSGSSESGSSEGGPGESPGGSSGSESGSGGEPSESGSSGESPGGSSGSESGSG




GEPSESGSS


 


AE864
71
GSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTST




EPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATP




ESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAP




GTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTST




EPSEGSAPGTSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSG




SETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAP




GTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEP




ATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATP




ESGPGSPAGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAP




GTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTST




EPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPT




STEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGP




GSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEP




ATSGSETPGTSESATPESGPGTSTEPSEGSAP


 


AF864
72
GSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTP




ESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGTSPSGESST




APGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGT




STPESGSASPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSTSSTA




ESPGPGTSTPESGSASPGSTSESPSGTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAP




GTSTPESGSASPGSTSSTAESPGPGSTSSTAESPGPGSTSSTAESPGPGSTSSTAESPGPGTSPS




GESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGPXXXGASASGAPSTXXXXSESPSG




TAPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPG




TSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPE




SGSASPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGTSTPESGSAS




PGTSTPESGSASPGSTSESPSGTAPGTSTPESGSASPGSTSSTAESPGPGSTSESPSGTAPGSTS




ESPSGTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASPGTSPSGESS




TAPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPG




SSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSP


 


AG864
73
GASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSSP




SASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGASPGTS




STGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSS




PGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSPGAS




PGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTS




STGSPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGS




PGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSS




TPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGT




SSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTG




SPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGS




STPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGTPGS




GTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGPGASPGTSSTGSPGASPGTSST




GSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPG




SSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSP


 


AM875
74
GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTS




ESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATP




ESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAP




GSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTST




EPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPT




STEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAP




GSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGASASGAPSTGGTSES




ATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESS




TAPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSEPATSGSETPGTSESATPESGPG




SEPATSGSETPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSEPATSGSETPGSEPA




TSGSETPGTSTEPSEGSAPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGTSTEPSEGS




APGTSTEPSEGSAPGTSTEPSEGSAPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGS




EPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGT




SSTGSPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAP


 


AE912
75
MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSPAGSPTSTEEGT




SESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESA




TPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGS




APGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGT




STEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESA




TPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPES




GPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGT




STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESA




TPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTST




EEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGS




EPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGS




PTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTST




EEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGS




EPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESA




TPESGPGTSTEPSEGSAP


 


AM923
76
MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGTSTEPSEGSAPGS




EPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGSTSESP




SGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTE




EGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTS




TEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPS




EGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPSGATGS




PGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSP




AGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGASASGAPSTGGTSESATPESGPGSPAGSP




TSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSS




PGSSTPSGATGSPGSSPSASTGTGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGST




SSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSEPATSGSETPGSEPATSGSETPGTSTEPSE




GSAPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGTSTEPSEGSAPGTSTEPSEGSAP




GTSTEPSEGSAPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSE




SATPESGPGSPAGSPTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATP




ESGPGTSTEPSEGSAPGTSTEPSEGSAP


 


AM1318
77
GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSASPGSTS




ESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSGSETPGTSESATP




ESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAP




GSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTST




EPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPT




STEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAP




GSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGPEPTGPAPSGGSEPA




TSGSETPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTS




TEEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPG




TSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGTSTEPSEGSAPGTSESA




TPESGPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSESATPESGPGTSTEPSEGS




APGTSESATPESGPGTSTEPSEGSAPGTSPSGESSTAPGTSPSGESSTAPGTSPSGESSTAPGT




STEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGSSPSASTGTGPGSSTPSGATGSPGSSTPS




GATGSPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASASGAPSTGGTSPSGESST




APGSTSSTAESPGPGTSPSGESSTAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGS




SPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPGTSTPESGSASPGTSPSGESSTAPGTSPSG




ESSTAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGSTSESPSGTAPGSTSESPSGT




APGTSTPESGSASPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGT




SESATPESGPGSEPATSGSETPGSSTPSGATGSPGASPGTSSTGSPGSSTPSGATGSPGSTSES




PSGTAPGTSPSGESSTAPGSTSSTAESPGPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASS




SPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAP


 


BC 864
78
GTSTEPSEPGSAGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGSEPATSGTEPSGSEP




ATSGTEPSGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPATSGTEPSGTSTEPSE




PGSAGSEPATSGTEPSGSEPATSGTEPSGTSTEPSEPGSAGTSTEPSEPGSAGSEPATSGTEPS




GSEPATSGTEPSGTSEPSTSEPGAGSGASEPTSTEPGTSEPSTSEPGAGSEPATSGTEPSGSEP




ATSGTEPSGTSTEPSEPGSAGTSTEPSEPGSAGSGASEPTSTEPGSEPATSGTEPSGSEPATSG




TEPSGSEPATSGTEPSGSEPATSGTEPSGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEP




GTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSGASEPTSTEPGSEP




ATSGTEPSGSGASEPTSTEPGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPATSG




TEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPATSGTEPSGTSTEPSEPGSAGSEPATSGTEPS




GTSTEPSEPGSAGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPSEPGSAGTST




EPSEPGSAGTSEPSTSEPGAGSGASEPTSTEPGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPSE




PGSAGSEPATSGTEPSGSGASEPTSTEPGSEPATSGTEPSGSEPATSGTEPSGSEPATSGTEPS




GSEPATSGTEPSGTSEPSTSEPGAGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSEP




ATSGTEPSGSGASEPTSTEPGTSTEPSEPGSA


 


BD864
79
GSETATSGSETAGTSESATSESGAGSTAGSETSTEAGTSESATSESGAGSETATSGSETAGS




ETATSGSETAGTSTEASEGSASGTSTEASEGSASGTSESATSESGAGSETATSGSETAGTSTE




ASEGSASGSTAGSETSTEAGTSESATSESGAGTSESATSESGAGSETATSGSETAGTSESATS




ESGAGTSTEASEGSASGSETATSGSETAGSETATSGSETAGTSTEASEGSASGSTAGSETST




EAGTSESATSESGAGTSTEASEGSASGSETATSGSETAGSTAGSETSTEAGSTAGSETSTEA




GSETATSGSETAGTSESATSESGAGTSESATSESGAGSETATSGSETAGTSESATSESGAGTS




ESATSESGAGSETATSGSETAGSETATSGSETAGTSTEASEGSASGSTAGSETSTEAGSETA




TSGSETAGTSESATSESGAGSTAGSETSTEAGSTAGSETSTEAGSTAGSETSTEAGTSTEASE




GSASGSTAGSETSTEAGSTAGSETSTEAGTSTEASEGSASGSTAGSETSTEAGSETATSGSE




TAGTSTEASEGSASGTSESATSESGAGSETATSGSETAGTSESATSESGAGTSESATSESGA




GSETATSGSETAGTSESATSESGAGSETATSGSETAGTSTEASEGSASGTSTEASEGSASGST




AGSETSTEAGSTAGSETSTEAGSETATSGSETAGTSESATSESGAGTSESATSESGAGSETA




TSGSETAGSETATSGSETAGSETATSGSETAGTSTEASEGSASGTSESATSESGAGSETATS




GSETAGSETATSGSETAGTSESATSESGAGTSESATSESGAGSETATSGSETA









4. XTEN Segments
In one embodiment, the invention provides an isolated GHXTEN fusion protein wherein the cumulative length of the XTEN component is greater than about 100 to about 3000 amino acid residues containing at least one polypeptide sequence segment selected from Tables 3, 8, 9, 10, 11, and 12 and wherein 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 of the remainder of the XTEN sequence by and large contains hydrophilic amino acids and less than about 2% of the remainder of the XTEN consists of hydrophobic or aromatic amino acids, or cysteine. In some embodiments, the XTEN contains multiple segments wherein the segments are identical or different. In another embodiment, the invention provides an isolated GHXTEN 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 100 to about 923, or at least about 100 to about 875, or at least about 100 to about 576, or at least about 100 to about 288, or at least about 100 to about 144 amino acid residues wherein the sequence segment(s) consists of at least three 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 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 oraromatic amino acids, or cysteine. In another embodiment, the invention provides an isolated GHXTEN 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 200 to about 923, or at least about 200 to about 875, or at least about 200 to about 576, or at least about 200 to about 288 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 the segment is less than 12, more preferably less than 10, more preferably less than 9, more preferably less than 8, more preferably less than 7, more preferably less than 6, and most preferably 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 some embodiments, the invention provides a short-length XTEN sequence incorporated as the N-terminal portion of the GHXTEN fusion protein. The expression of the fusion protein is enhanced in a host cell transformed with a suitable expression vector comprising an optimized N-terminal leader polynucleotide 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 fusion protein compared to the expression of a corresponding fusion protein from a polynucleotide not comprising the NTS, and obviates the need for incorporation of a non-XTEN leader sequence used to enhance expression. In one embodiment, the invention provides GHXTEN 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 GHXTEN fusion protein not comprising the N-terminal XTEN sequence (where the encoding gene lacks the NTS).
In one embodiment, the N-terminal XTEN polypeptide of the GHXTEN 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 amino acid sequences of which are as follows:







AE48:


(SEQ ID NO: 80)


MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGS


 


AM48:


(SEQ ID NO: 81)


MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGS






In another embodiment, the short-length N-terminal XTEN is linked to an XTEN of longer length to form the N-terminal region of the GHXTEN 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 is linked to any of the XTEN disclosed herein (e.g., an XTEN of Table 3) and the resulting XTEN, in turn, is linked to the N-terminal of any of the GH disclosed herein (e.g., a GH of Table 1) as a component of the fusion protein. Alternatively, polynucleotides encoding the short-length XTEN (or its complement) is linked to polynucleotides encoding any of the XTEN (or its complement) disclosed herein and the resulting gene encoding the N-terminal XTEN, in turn, is linked to the 5′ end of polynucleotides encoding any of the GH (or to the 3′ end of its complement) disclosed herein. In some embodiments, the N-terminal XTEN polypeptide with long length 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 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 GESTPA, to accommodate the restriction endonuclease restriction sites that would be employed to join the nucleotides encoding the N-terminal XTEN to the gene encoding the targeting moiety of the fusion protein. 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/or reducing the proportion of 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. In some embodiments, the net charge density of the XTEN of the compositions may be above +0.1 or below −0.1 charges/residue. In other embodiments, the net charge of a 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.
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 is conferred by incorporation of glutamic acid residues. Accordingly, in one embodiment the invention provides XTEN in which the XTEN sequences contain about 8, 10, 15, 20, 25, or even about 30% glutamic acid. Generally, the glutamic residues would be 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 kD 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, enhancing the physicochemical properties of the resulting GHXTEN fusion protein for, example, simplifying purification procedures.
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 growth hormone, plus a chemotherapeutic agent useful in the treatment of growth-related 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.
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 preferred embodiments, the XTEN will have an isoelectric point between 1.5 and 4.5. In these embodiments, the XTEN incorporated into the GHXTEN fusion protein compositions of the present invention carry a net negative charge under physiologic conditions that contribute to the unstructured conformation and reduced binding of the XTEN component to mammalian proteins and tissues.
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 GHXTEN 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 the activation of 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'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 is 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 GHXTEN 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 also reduce the immunogenicity of the GH fusion partner in the GHXTEN 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 is 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 some embodiments, 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 45. The TEPITOPE score of a given peptide frame within a protein is the log of the Kd (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 10e10 Kd to 10e−10 Kd), and can be reduced by avoiding hydrophobic amino acids that 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 GHXTEN does not have a predicted T-cell epitope at a TEPITOPE score of about −5 or greater, or −6 or greater, or −7 or greater, or −8 or greater, or at a TEPITOPE score of −9 or greater. As used herein, a score of “−9 or greater” would encompass TEPITOPE scores of 10 to −9, inclusive, but would not encompass a score of −10, as −10 is less than −9.
In another embodiment, the inventive XTEN sequences, including those incorporated into the subject GHXTEN fusion proteins, are 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 is 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 render the XTEN compositions, including the XTEN of the GHXTEN fusion protein compositions, substantially unable to be bound by mammalian receptors, including those of the immune system. In one embodiment, an XTEN of a GHXTEN fusion protein can have >100 nM Kd binding to a mammalian receptor, or greater than 500 nM Kd, or greater than 1 μM Kd towards a mammalian cell surface or circulating polypeptide receptor.
Additionally, the non-repetitive sequence and corresponding lack of epitopes of XTEN 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. Not being to be bound by any theory, XTENs typically have a much lower tendency to stimulate proliferation of B cells and thus an immune response. In one embodiment, the GHXTEN have reduced immunogenicity as compared to the corresponding GH that is not fused. In one embodiment, the administration of up to three parenteral doses of a GHXTEN to a mammal result in detectable anti-GHXTEN 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 GHXTEN to a mammal result in detectable anti-GH 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 GHXTEN to a mammal 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 is 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 GHXTEN 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 have a high hydrodynamic radius that confers a corresponding increased Apparent Molecular Weight to the GHXTEN fusion protein incorporating the XTEN. As detailed in Example 37, the linking of XTEN to GH sequences results in GHXTEN compositions that can have increased hydrodynamic radii, increased Apparent Molecular Weight, and increased Apparent Molecular Weight Factor compared to a GH 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 GH 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 or 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 37 demonstrate, the addition of increasing lengths of XTEN results in proportional increases in the parameters of hydrodynamic radius, Apparent Molecular Weight, and Apparent Molecular Weight Factor, permitting the tailoring of GHXTEN to desired characteristic cut-off Apparent Molecular Weights or hydrodynamic radii. Accordingly, in certain embodiments, the GHXTEN 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 an GHXTEN 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 GHXTEN to create a fusion protein that 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 GH to result in a GHXTEN 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 GHXTEN 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.
V). GHXTEN Structural Configurations and Properties
The GH of the subject compositions are not limited to native, full-length polypeptides, but also include recombinant versions as well as biologically and/or pharmacologically active variants or fragments thereof. For example, it will be appreciated that various amino acid deletions, insertions and substitutions can be made in the GH to create variants without departing from the spirit of the invention with respect to the biological activity or pharmacologic properties of the GH. Examples of conservative substitutions for amino acids in polypeptide sequences are shown in Table 4. However, in embodiments of the GHXTEN in which the sequence identity of the GH is less than 100% compared to a specific sequence 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 GH, which may be at any position within the sequence of the GH, including adjacent amino acid residues. If any one substitution results in an undesirable change in biological activity, then one of the alternative amino acids can be employed and the construct evaluated by the methods described herein, 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 full-length native amino acid sequence of a GH that retains some if not all of the biological activity of the native peptide.







TABLE 4







Exemplary conservative amino acid substitutions










Original Residue
Exemplary Substitutions






Ala (A)
val; leu; ile



Arg (R)
lys; gin; asn



Asn (N)
gin; his; Iys; arg



Asp (D)
glu



Cys (C)
ser



Gln (Q)
asn



Glu (E)
asp



Gly (G)
pro



His (H)
asn: gin: Iys: arg



xIle (I)
leu; val; met; ala; phe: norleucine



Leu (L)
norleucine: ile: val; met; ala: phe



Lys (K)
arg: gin: asn



Met (M)
leu; phe; ile



Phe (F)
leu: val: ile; 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









(a) GHXTEN Fusion Protein Configurations
The invention provides GHXTEN fusion protein compositions with the GH and XTEN components linked in specific N- to C-terminus configurations. In some embodiments, one or more GHs are linked to one or more XTENs, either at the N-terminus or at the C-terminus, with or without a spacer, to form a block copolymer, and the sequential arrangement of the GHs and the XTENs in the GHXTEN fusion protein are the same as the configuration known in the block copolymer chemistry. When there is more than one GH, XTEN, or spacer, each of the GH, the XTEN, or the spacer have the same or different sequences, and the GHs and/or XTENs are linked either continuously or alternately (regular or irregular). Thus, in all of the formulae provided herein, when there is more than one GH, XTEN, or spacer, each of the GH, XTEN, and spacer are the same or different. In some embodiments, the GHXTEN is a monomeric fusion protein with a GH linked to one XTEN polypeptide. In other embodiments, the GHXTEN is a monomeric fusion protein with a GH linked to two or more XTEN polypeptides. In still other embodiments, the GHXTEN is a monomeric fusion protein with two or more GH linked to one XTEN polypeptide. In still other embodiments, the GHXTEN is a monomeric fusion protein with two or more GH linked to two or more XTEN polypeptide. Table 5 provides non-limiting examples of configurations that are encompassed by the GHXTEN fusion proteins of the invention; numerous other variations will be apparent to the ordinarily skilled artisan, including the incorporation the spacer and cleavage sequences disclosed herein or known in the art.







TABLE 5







GHXTEN configurations










Components*
Configuration**






Single GH; Single XTEN
GH-XTEN




XTEN-GH



Single GH; Multiple XTEN
XTEN-GH-XTEN




GH-XTEN-XTEN




XTEN-XTEN-GH




XTEN-GH-XTEN-XTEN




XTEN-XTEN-GH-XTEN




XTEN-XTEN-GH-XTEN



Multiple GH, Single XTEN
GH-XTEN-GH




XTEN-GH-GH




GH-GH-XTEN




GH-XTEN-GH-GH



Multiple GH; Multiple XTEN
GH-XTEN-GH-XTEN




XTEN-GH-XTEN-GH




XTEN-XTEN-GH-XTEN-GH




XTEN-XTEN-GH-GH




GH-XTEN-XTEN-GH




GH-GH-XTEN-XTEN




GH-GH-XTEN-XTEN-GH




GH-XTEN-GH-XTEN-GH





*Characterized as single for 1 component or multiple for 2 or more of that component


**Reflects N- to C-terminus configuration of the growth factor and XTEN components






The invention contemplates GHXTEN fusion proteins compositions comprising, but not limited to single or multiple GH selected from Table 1 (or fragments or sequence variants thereof), single or multiple XTEN selected from Table 3 (or sequence variants thereof) that are in a configuration shown in Table 5. Generally, the resulting GHXTEN retains at least a portion of the biological activity of the corresponding GH not linked to the XTEN. In other embodiments, the GH component either becomes biologically active or has an increase in activity upon its release from the XTEN by cleavage of an optional cleavage sequence incorporated within spacer sequences into the GHXTEN, described more fully below.
In one embodiment of the GHXTEN composition, the invention provides a fusion protein of formula I:

(XTEN)x-GH-(XTEN)y  I

wherein independently for each occurrence, GH is a is a growth hormone; x is either 0 or 1 and y is either 0 or 1 wherein x+y≧1; and XTEN is an extended recombinant polypeptide.

In another embodiment of the GHXTEN composition, the invention provides a fusion protein of formula II:

(XTEN)x-(GH)-(S)y-(XTEN)y  II

wherein independently for each occurrence, GH is a is a growth hormone a; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1 and y is either 0 or 1 wherein x+y≧1; and XTEN is an extended recombinant polypeptide.

In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula III:

(GH)-(S)x-(XTEN)-(S)y-(GH)-(S)z-(XTEN)z  III

wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; z is either 0 or 1; and XTEN is an extended recombinant polypeptide.

In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula IV:

(XTEN)x-(S)y-(GH)-(S)z-(XTEN)-(GH)  IV

wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; z is either 0 or 1; and XTEN is an extended recombinant polypeptide.

In another embodiment, the invention provides an isolated fusion growth hormone, wherein the fusion protein is of formula V:

(GH)x-(S)x-(GH)-(S)y-(XTEN)  V

wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; and XTEN is an extended recombinant polypeptide.

In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula VI:

(XTEN)-(S)x-(GH)-(S)y-(GH)  VI

wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; and XTEN is an extended recombinant polypeptide.

In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula VII:

(XTEN)-(S)x(GH)-(S)y-(GH)-(XTEN)  VII

wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; and XTEN is an extended recombinant polypeptide.

In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula VIII:

((S)m-(GH)x-(S)n-(XTEN)y-(S)o)t  VIII

wherein t is an integer that is greater than 0 (1, 2, 3, etc.); independently each of m, n, o, x, and y is an integer (0, 1, 2, 3, etc.), GH is a is a growth hormone; S is an spacer, optionally comprising a cleavage site; and XTEN is an extended recombinant polypeptide, with the proviso that: (1) x+y>1, (2) when t=1, x>0 and y>0, (3) when there is more than one GH, S, or XTEN, each GH, XTEN, or S are the same or are independently different; and (4) when t>1, each m, n, o, x, or y within each subunit are the same or are independently different.

In some embodiments, administration of a therapeutically effective amount of a fusion protein of an embodiment of formulas I-VIII to a subject in need thereof results in a gain in time of at least two-fold, or at least three-fold, or at least four-fold, or at least five-fold, or at least 10-fold, or at least 20-fold, or at least 40-fold, or at least 100-fold or more spent within a therapeutic window for the fusion protein compared to the corresponding GH not linked to the XTEN of and administered at a comparable amount administered to a subject. In other embodiments, administration of a therapeutically effective dose of a fusion protein of an embodiment of formulas I-VIII to a subject in need thereof can result in a gain in time between consecutive doses necessary to maintain a therapeutically effective dose regimen of at least 48 h, or at least 72 h, or at least about 96 h, or at least about 120 h, or at least about 7 days, or at least about 14 days, or at least about 21 days between consecutive doses compared to a GH not linked to XTEN and administered at a comparable dose.
Any spacer sequence group is optional in the fusion proteins encompassed by the invention. The spacer is provided to enhance expression of the fusion protein from a host cell or to decrease steric hindrance such that the GH component may assume its desired tertiary structure and/or interact appropriately with its target receptor. 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 comprise hydrophilic amino acids that are sterically unhindered that can include, but not be limited to, glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P). In some cases, the spacer can be polyglycines or polyalanines, or is predominately a mixture of combinations of glycine and alanine residues. The spacer polypeptide exclusive of a cleavage sequence is largely to 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, one or both spacer sequences in a GHXTEN fusion protein composition each further contains a cleavage sequence, which are identical or different, wherein the cleavage sequence may be acted on by a protease to release the GH from the fusion protein.
In some embodiments, the incorporation of the cleavage sequence into the GHXTEN is designed to permit release of a GH that becomes active or more active upon its release from the XTEN. The cleavage sequences are located sufficiently close to the GH sequences, generally within 18, or within 12, or within 6, or within 2 amino acids of the GH sequence terminus, such that any remaining residues attached to the GH after cleavage do not appreciably interfere with the activity (e.g., such as binding to a receptor) of the GH, yet provide sufficient access to the protease to be able to effect cleavage of the cleavage sequence. In some embodiments, the cleavage site is a sequence that can be cleaved by a protease endogenous to the mammalian subject such that the GHXTEN can be cleaved after administration to a subject. In such cases, the GHXTEN can serve as a prodrug or a circulating depot for the GH. 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, 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, PreScissionTM 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 and cut sites within the sequences are presented in Table 6, as well as sequence variants thereof. For example, thrombin (activated clotting factor II) acts on the sequence LTPRSLLV (SEQ ID NO: 82) [Rawlings N. D., et al. (2008) Nucleic Acids Res., 36: D320], which would be cut after the arginine at position 4 in the sequence. Active FIIa is produced by cleavage of FIT by FXa in the presence of phospholipids and calcium and is down stream from factor IX in the coagulation pathway. Once activated its natural role in coagulation is to cleave fibrinogen, which then in turn, begins clot formation. FIIa activity is tightly controlled and only occurs when coagulation is necessary for proper hemostasis. However, as coagulation is an on-going process in mammals, by incorporation of the LTPRSLLV sequence (SEQ ID NO: 83) into the GHXTEN between the GH and the XTEN, the XTEN domain would be removed from the adjoining GH concurrent with activation of either the extrinsic or intrinsic coagulation pathways when coagulation is required physiologically, thereby releasing GH over time. Similarly, incorporation of other sequences into GHXTEN that are acted upon by endogenous proteases would provide for sustained release of GH that, in certain embodiments, provide a higher degree of activity for the GH from the “prodrug” form of the GHXTEN.
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. In other embodiments, the known cleavage sequence 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 GH from the XTEN. Exemplary substitutions are shown in Table 6.







TABLE 6







Protease Cleavage Sequences











Protease Acting
Exemplary 
SEQ ID





Cleavage





Upon Sequence
Sequence
NO:
Minimal Cut Site*














FXIa
KLTR↓VVGG
84
KD/FL/T/R↓VA/VE/GT/GV



FXIIa
TMTR↓IVGG
85
NA



Kallikrein
SPFR↓STGG
86
—/—/FL/RY↓SR/RT/—/—



FVIIa
LQVR↓IVGG
87
NA



FIXa
PLGR↓IVGG
88
—/—/G/R↓—/—/—/—



FXa
IEGR↓TVGG
89
IA/E/GFP/R↓STI/VFS/—/G



FIIa (thrombin)
LTPR↓SLLV
90
—/—/PLA/R↓SAG/—/—/—



Elastase-2
LGPV↓SGVP
91
—/—/—/VIAT↓—/—/—/—



Granzyme-B
VAGD↓SLEE
92
V/—/—/D↓—/—/—/—



MMP-12
GPAG↓LGGA
93
G/PA/—/G↓L/—/G/—
94


MMP-13
GPAG↓LRGA
95
G/P/—/G↓L/—/GA/—
96


MMP-17
APLG↓LRLR
97
—/PS/—/—↓LQ/—/LT/—



MMP-20
PALP↓LVAQ
98
NA



TEV
ENLYFQ↓G
99
ENLYFQ↓G/S
100


Enterokinase
DDDK↓IVGG
101
DDDK↓IVGG
102


Protease 3C
LEVLFQ↓GP
103
LEVLFQ↓GP
104


(PreScission TM)






Sortase A
LPKT↓GSES
105
L/P/KEAD/T↓G/—/EKS/S
106





↓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






In one embodiment, a GH incorporated into a GHXTEN fusion protein have a sequence that exhibits at least about 80% sequence identity to a sequence from Table 1, alternatively at least about 81%, or about 82%, or about 83%, or about 84%, or about 85%, or about 86%, or about 87%, or about 88%, or about 89%, or 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% sequence identity as compared with a sequence from Table 1. The GH of the foregoing embodiment can be evaluated for activity using assays or measured or determined parameters as described herein, and those sequences that retain at least about 40%, or about 50%, or about 55%, or about 60%, or about 70%, or about 80%, or about 90%, or about 95% or more activity compared to the corresponding native GH sequence would be considered suitable for inclusion in the subject GHXTEN. The GH found to retain a suitable level of activity can be linked to one or more XTEN polypeptides described hereinabove. In one embodiment, a GH found to retain a suitable level of activity can be linked to one or more XTEN polypeptides having at least about 80% sequence identity to a sequence from Table 3, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 100% sequence identity as compared with a sequence of Table 3, resulting in a chimeric fusion protein.
Non-limiting examples of sequences of fusion proteins containing a single GH linked to a single XTEN are presented in Table 35. In one embodiment, a GHXTEN composition would comprise a fusion protein having at least about 80% sequence identity to a GHXTEN from Table 35, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 100% sequence identity as compared with a GHXTEN from Table 35. Non-limiting examples of sequences of fusion proteins containing two molecules of XTEN linked to one or more GH are presented in Table 36, but the invention also contemplates substitution of other GH with sequences exhibiting at least about 90% sequence identity to a sequence selected from Table 1 linked to one or two XTEN, which may be the same or different, exhibiting at least about 90% sequence identity selected from Table 3. In the foregoing fusion proteins hereinabove described in this paragraph, the GHXTEN fusion protein can further comprise a cleavage sequence from Table 6; the cleavage sequence being located between the GH and the XTEN or between adjacent GH (if more than one GH is included in the GHXTEN). In some cases, the GHXTEN comprising the cleavage sequences will also have one or more spacer sequence amino acids between the GH and the cleavage sequence or the XTEN and the cleavage sequence to facilitate access of the protease; the spacer amino acids comprising any natural amino acid, including glycine and alanine as preferred amino acids. Non-limiting examples of GHXTEN comprising GH, XTEN, cleavage sequence(s) and spacer amino acids are presented in Table 37. However, the invention also contemplates substitution of any of the GH sequences of Table 1 for a GH sequence of Table 37, substitution of any XTEN sequence of Table 3 for an XTEN sequence of Table 37, and substitution of any cleavage sequence of Table 6 for a cleavage sequence of Table 37.
(b) Pharmacokinetic Properties of GHXTEN
The invention provides GHXTEN fusion proteins with enhanced pharmacokinetics compared to the GH not linked to XTEN that, when used at the dose determined for the composition by the methods described herein, can achieve a circulating concentration resulting in a pharmacologic effect, yet stay within the safety range for biologically active component of the composition for an extended period of time compared to a comparable dose of the GH not linked to XTEN. In such cases, the GHXTEN remains within the therapeutic window for the fusion protein composition for the extended period of time. As used herein, a “comparable dose” means a dose with an equivalent moles/kg for the active GH pharmacophore that is administered to a subject in a comparable fashion. It will be understood in the art that a “comparable dosage” of GHXTEN fusion protein would represent a greater weight of agent but would have essentially the same mole-equivalents of GH in the dose of the fusion protein and/or would have the same approximate molar concentration relative to the GH.
The pharmacokinetic properties of a GH that can be enhanced by linking a given XTEN to the GH include terminal half-life, area under the curve (AUC), Cmax volume of distribution, and bioavailability providing enhanced utility in the treatment of growth hormone-related disorders, diseases and related conditions. The GH of the GHXTEN compositions can be a sequence that exhibits 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 to a protein sequence selected from Table 1, linked to one or more XTEN that 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 to a protein sequence selected from Table 3.
As described more fully in the Examples pertaining to pharmacokinetic characteristics of fusion proteins comprising XTEN, it was surprisingly discovered that increasing the length of the XTEN sequence confers a disproportionate increase in the terminal half-life of a fusion protein comprising the XTEN. Accordingly, the invention provides GHXTEN fusion proteins comprising XTEN wherein the XTEN is selected to provide a targeted half-life for the GHXTEN composition administered to a subject. In some embodiments, the invention provides monomeric fusion proteins comprising XTEN wherein the XTEN is selected to confer an increase in the terminal half-life for the GHXTEN administered to a subject, compared to the corresponding GH not linked to the fusion protein and administered at a comparable dose, of at least about two-fold longer, 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 seven-fold, or at least about eight-fold, or at least about nine-fold, or at least about ten-fold, or at least about 15-fold, or at least a 20-fold, or at least a 40-fold, or at least a 80-fold, or at least a 100-fold or greater an increase in terminal half-life compared to the GH not linked to the fusion protein. Exogenously administered human growth hormone has been reported to have a terminal half-life in humans of less than 15 minutes (Hindmarch, P. C., et al., Clinical Endocrinology (2008) 30(4): 443-450), whereas various GHXTEN compositions disclosed herein that have been experimentally administered to various animals species, as described in the Examples, have resulted in terminal half-life values of several hours. Similarly, the GHXTEN fusion proteins can have an increase in AUC of 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 a 100%, or at least about 150%, or at least about 200%, or at least about 300%, or at least about 500%, or at least about 1000%, or at least about a 2000% increase in AUC compared to the corresponding GH not linked to the fusion protein and administered to a subject at a comparable dose. The pharmacokinetic parameters of a GHXTEN can be determined by standard methods involving dosing, the taking of blood samples at times intervals, and the assaying of the protein using ELISA, HPLC, radioassay, or other methods known in the art or as described herein, followed by standard calculations of the data to derive the half-life and other PK parameters.
The invention further provides GHXTEN comprising a first and a second GH molecule, optionally separated by a spacer sequence that may further comprise a cleavage sequence, or separated by a second XTEN sequence. In one embodiment, the GH has less activity when linked to the fusion protein compared to a corresponding GH not linked to the fusion protein. In such case, as illustrated in FIG. 38, the GHXTEN is designed such that upon administration to a subject, the GH component is gradually released by cleavage of the cleavage sequence(s), whereupon it regains activity or the ability to bind to its target receptor or ligand. Accordingly, the GHXTEN of the foregoing serves as a prodrug or a circulating depot, resulting in a longer terminal half-life compared to GH not linked to the fusion protein.
(c) Pharmacology and Pharmaceutical Properties of GHXTEN
The present invention provides GHXTEN compositions comprising GH covalently linked to XTEN that can have enhanced properties compared to GH not linked to XTEN, as well as methods to enhance the therapeutic and/or biologic activity or effect of the respective two GH components of the compositions. In addition, the invention provides GHXTEN compositions with enhanced properties compared to those art-known fusion proteins containing immunoglobulin polypeptide partners, polypeptides of shorter length and/or polypeptide partners with repetitive sequences. In addition, GHXTEN fusion proteins provide significant advantages over chemical conjugates, such as pegylated constructs, notably the fact that recombinant GHXTEN fusion proteins can be made in bacterial cell expression systems, which can reduce time and cost at both the research and development and manufacturing stages of a product, as well as result in a more homogeneous, defined product with less toxicity for both the product and metabolites of the GHXTEN compared to pegylated conjugates.
As therapeutic agents, the GHXTEN possesses a number of advantages over therapeutics not comprising XTEN including one or more of the following non-limiting exemplary enhance properties; increased solubility, increased thermal stability, reduced immunogenicity, increased apparent molecular weight, reduced renal clearance, reduced proteolysis, reduced metabolism, enhanced therapeutic efficiency, a lower effective therapeutic dose, increased bioavailability, increased time between dosages capable of maintain blood levels within the therapeutic window for the GH, a “tailored” rate of absorption, enhanced lyophilization stability, enhanced serum/plasma stability, increased terminal half-life, increased solubility in blood stream, decreased binding by neutralizing antibodies, decreased receptor-mediated clearance, reduced side effects, retention of receptor/ligand binding affinity or receptor/ligand activation, stability to degradation, stability to freeze-thaw, stability to proteases, stability to ubiquitination, ease of administration, compatibility with other pharmaceutical excipients or carriers, persistence in the subject, increased stability in storage (e.g., increased shelf-life), reduced toxicity in an organism or environment and the like. The net effect of the enhanced properties is that the GHXTEN results in enhanced therapeutic and/or biologic effect or improved patient compliance when administered to a subject with a growth hormone-related disease or disorder.
Specific assays and methods for measuring the physical and structural properties of expressed proteins are known in the art, including methods for determining properties such as protein aggregation, solubility, secondary and tertiary structure, melting properties, contamination and water content, etc. 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 a particular feature of the invention, XTEN as a fusion partner increases the solubility of the GH payload, particularly in the expression of GH, which is typically expressed as insoluble inclusion bodies in transformed host cells, such as E. coli (see, e.g., Singh, S. M., et al. (2005) J Biosci Bioeng, 99: 303; Patra, A. K., et al. (2000) Protein Expr Purif, 18: 182). Accordingly, where enhancement of the pharmaceutical or physicochemical properties of the GH is desirable, such as the degree of aqueous solubility or stability, the length and/or the motif family composition of the first and the second XTEN sequences of the first and the second fusion protein may each be selected to confer a different degree of solubility and/or stability on the respective fusion proteins such that the overall pharmaceutical properties of the GHXTEN composition are enhanced. The GHXTEN fusion proteins can be constructed and assayed, using methods described herein, to confirm the physicochemical properties and the XTEN adjusted, as needed, to result in the desired properties. In one embodiment, the XTEN sequence of the GHXTEN is selected such that the fusion protein has an aqueous solubility that is within at least about 25% greater compared to a GH not linked to the fusion protein, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 75%, or at least about 100%, or at least about 200%, or at least about 300%, or at least about 400%, or at least about 500%, or at least about 1000% greater than the corresponding GH not linked to the fusion protein.
The invention provides methods to produce and recover expressed GHXTEN from a host cell with enhanced solubility and ease of recovery compared to GH not linked to XTEN. In some embodiments, the method includes the steps of transforming a prokaryotic host cell (e.g, E. coli) with a polynucleotide encoding a GHXTEN with one or more XTEN components of cumulative sequence length greater than about 800, or greater than about 900, or greater than about 1000, or greater than about 1100 amino acid residues, expressing the GHXTEN fusion protein in the host cell, lysing the host cell to recover cytoplasmic contents, and acidifying the host cell cytoplasmic contents wherein the GH can remain in soluble form while the majority of host cell proteins are precipitated to insoluble form. In one embodiment of the foregoing, the post-expression crude host cell lysates can be acidified to a pH of less than about 5.0, or to a pH of less than about 4.7, or to a pH of less than about 4.5, or to a pH of less than about 4.2 and greater than about 50%, or about 60%, or about 70%, or about 80% or more of the expressed GH can be recovered in soluble form. In a feature of the foregoing embodiment, enriched GHXTEN can be separated from precipitated from host cell protein contaminants by centrifugation of the acidified lysate, a reflection of the increased solubility imparted to the GH by fusion to the XTEN carrier. In the embodiments hereinabove described in this paragraph, the XTEN of the GHXTEN fusion proteins can have at least about 80% sequence identity, or 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 one or more XTEN selected from Table 3 and the GH can have at least about 80% sequence identity, or 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 100% sequence identity to a GH selected from Table 1 and the GHXTEN components can be in an N- to C-terminus configuration selected from Table 5.
In one embodiment, the invention provides GHXTEN compositions and methods to produce the compositions that can maintain the GH component within a therapeutic window for a greater period of time compared to comparable dosages of the corresponding GH not linked to XTEN. It will be understood in the art that a “comparable dosage” of GHXTEN fusion protein would represent a greater weight of agent but would have the same approximate mole-equivalents of GH in the dose of the fusion protein and/or would have the same approximate molar concentration relative to the GH. The method to produce the compositions that can maintain the GH component within a therapeutic window includes the steps of selecting the XTEN appropriate for conjugation to a GH to provide the desired pharmacokinetic properties in view of a given dose and dose regiment, followed by assays to verify the pharmacokinetic properties, the activity of the GHXTEN fusion protein, and the safety of the administered composition. By the methods, GHXTEN can be produced that enables increased efficacy of the administered composition by maintaining the circulating concentrations of the GH within the therapeutic window for an enhanced period of time. As used herein, “therapeutic window” means that the amount of drug or biologic as a blood or plasma concentration range, which provides efficacy or a desired pharmacologic effect over time for the disease or condition without unacceptable toxicity, i.e. the range of the circulating blood concentrations between the minimal amount to achieve any positive therapeutic effect and the maximum amount which results in a response that is the response immediately before toxicity to the subject (at a higher dose or concentration). Additionally, therapeutic window generally encompasses an aspect of time; the maximum and minimum concentration that results in a desired pharmacologic effect over time that does not result in unacceptable toxicity or adverse events. A dosed composition that stays within the therapeutic window for the subject could also be said to be within the “safety range.”
The characteristics of GHXTEN compositions of the invention, including functional characteristics or biologic and pharmacologic activity and parameters that result, are determined by any suitable screening assay known in the art for measuring the desired characteristic. The invention provides methods to assay the GHXTEN fusion proteins of differing composition or configuration in order to provide GHXTEN with the desired degree of biologic and/or therapeutic activity, as well as safety profile. Specific in vivo and ex vivo biological assays are used to assess the activity of each configured GHXTEN and/or GH component to be incorporated into GHXTEN, including but not limited to the assays of the Examples, those assays of Table 34, as well as the following assays or other such assays known in the art for assaying the properties and effects of GH. Assays can be conducted that allow determination of binding characteristics of the GHXTEN for GH receptors or a ligand, including binding constant (Kd), EC50 values, as well as their half-life of dissociation of the ligand-receptor complex (T1/2). Binding affinity can be measured, for example, by a competition-type binding assay that detects changes in the ability to specifically bind to a receptor or ligand (see, e.g., Examples). Additionally, techniques such as flow cytometry or surface plasmon resonance can be used to detect binding events. The assays may comprise soluble 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. Other possible assays may determine receptor binding of expressed polypeptides, wherein the assay may comprise soluble receptor molecules, or may determine the binding to cell-expressed receptors. The binding affinity of a GHXTEN for the target receptors or ligands of the corresponding GH 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. In addition, GH sequence variants (assayed as single components or as GHXTEN fusion proteins) can be compared to the native GH using a competitive ELISA binding assay to determine whether they have the same binding specificity and affinity as the native GH, or some fraction thereof such that they are suitable for inclusion in GHXTEN. Functional assays can include the increase of IGF-1 secretion and/or generation within target cells as a result of exposure to GHXTEN, and/or the resulting stimulatory effects of IGF-1 on osteoblast and chondrocyte activity to promote bone growth; all are suitable parameters to assess the activity of GH for inclusion in the GHXTEN fusion protein or the resulting GHXTEN. In addition, human growth hormone (hGH) is known to play a role in somatic growth through its effects on the metabolism of proteins, carbohydrates and lipids, as well as the stimulation of the production of blood cells in vitro (Derfalvi et al., 1998; Merchav et al; 1988), to increase numbers of erythrocytes and hemoglobin content in blood (Valerio et al., 1997; Vihervuori et al., 1996), as wells as the enhancement of proliferation of and Ig production in plasma cell lines (Kimata and Yoshida, 1994), the stimulation of CD8+ cell counts and, to a lesser extent CD4+ cell counts (Geffner, 1997). Parameters that can be measured chronically include velocity of growth, physical maturation, and comparative bone rate of growth. All of the foregoing can be used to assess the activity of GH components to be incorporated into GHXTEN and the resulting GHXTEN.
Dose optimization is important for all drugs, especially for those with a narrow therapeutic window. For example, a standardized single dose of GH for all patients presenting with a diverse symptoms or abnormal clinical parameters may not always be effective. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically or pharmacologically effective amount of the GHXTEN, versus that amount that would result in unacceptable toxicity and place it outside of the safety range, or insufficient potency such that clinical improvement is not achieved.
In many cases, the therapeutic window for GH in subjects of different ages or degree of disease have been established and are available in published literature or are stated on the drug label for approved products containing the GH. In other cases, the therapeutic window can be established for new compositions, including those GHXTEN of the disclosure. The methods for establishing the therapeutic window for a given composition are known to those of skill in the art (see, e.g., Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition, McGraw-Hill (2005)). For example, by using dose-escalation studies in subjects with the target disease or disorder to determine efficacy or a desirable pharmacologic effect, appearance of adverse events, and determination of circulating blood levels, the therapeutic window for a given subject or population of subjects can be determined for a given drug or biologic, or combinations of biologics or drugs. The dose escalation studies can evaluate the activity of a GHXTEN through metabolic studies in a subject or group of subjects that monitor physiological or biochemical parameters, as known in the art or as described herein for one or more parameters associated with the metabolic disease or disorder, or clinical parameters associated with a beneficial outcome for the particular indication, together with observations and/or measured parameters to determine the no effect dose, adverse events, maximum tolerated dose and the like, together with measurement of pharmacokinetic parameters that establish the determined or derived circulating blood levels. The results can then be correlated with the dose administered and the blood concentrations of the therapeutic that are coincident with the foregoing determined parameters or effect levels. By these methods, a range of doses and blood concentrations can be correlated to the minimum effective dose as well as the maximum dose and blood concentration at which a desired effect occurs and above which toxicity occurs, thereby establishing the therapeutic window for the dosed therapeutic. Blood concentrations of the fusion protein (or as measured by the GH component) above the maximum would be considered outside the therapeutic window or safety range. Thus, by the foregoing methods, a Cmin blood level would be established, below which the GHXTEN fusion protein would not have the desired pharmacologic effect, and a Cmax blood level would be established that would represent the highest circulating concentration before reaching a concentration that would elicit unacceptable side effects, toxicity or adverse events, placing it outside the safety range for the GHXTEN. With such concentrations established, the frequency of dosing and the dosage can be further refined by measurement of the Cmax and Cmin to provide the appropriate dose and dose frequency to keep the fusion protein(s) within the therapeutic window. One of skill in the art can, by the means disclosed herein or by other methods known in the art, confirm that the administered GHXTEN remains in the therapeutic window for the desired interval or requires adjustment in dose or length or sequence of XTEN. Further, the determination of the appropriate dose and dose frequency to keep the GHXTEN within the therapeutic window establishes the therapeutically effective dose regimen; the schedule for administration of multiple consecutive doses using a therapeutically effective dose of the fusion protein to a subject in need thereof resulting in consecutive Cmax peaks and/or Cmin troughs that remain within the therapeutic window and results in an improvement in at least one measured parameter relevant for the target disease, disorder or condition. In some cases, the GHXTEN administered at an appropriate dose to a subject results in blood concentrations of the GHXTEN fusion protein that remains within the therapeutic window for a period at least about two-fold longer compared to the corresponding GH not linked to XTEN and administered at a comparable dose; alternatively at least about three-fold longer; alternatively at least about four-fold longer; alternatively at least about five-fold longer; alternatively at least about six-fold longer; alternatively at least about seven-fold longer; alternatively at least about eight-fold longer; alternatively at least about nine-fold longer or at least about ten-fold longer or greater compared to the corresponding GH not linked to XTEN and administered at a comparable dose. As used herein, an “appropriate dose” means a dose of a drug or biologic that, when administered to a subject, would result in a desirable therapeutic or pharmacologic effect and a blood concentration within the therapeutic window.
In one embodiment, the GHXTEN administered at a therapeutically effective dose regimen results in a gain in time of at least about three-fold longer; alternatively at least about four-fold longer; alternatively at least about five-fold longer; alternatively at least about six-fold longer; alternatively at least about seven-fold longer; alternatively at least about eight-fold longer; alternatively at least about nine-fold longer or at least about ten-fold longer between at least two consecutive Cmax peaks and/or Cmin troughs for blood levels of the fusion protein compared to the corresponding biologically active protein of the fusion protein not linked to the fusion protein and administered at a comparable dose regimen to a subject. In another embodiment, the GHXTEN administered at a therapeutically effective dose regimen results in a comparable improvement in one, or two, or three or more measured parameter using less frequent dosing or a lower total dosage in moles of the fusion protein of the pharmaceutical composition compared to the corresponding biologically active protein component(s) not linked to the fusion protein and administered to a subject using a therapeutically effective dose regimen for the GH. The measured parameters include any of the clinical, biochemical, or physiological parameters disclosed herein, or others known in the art for assessing subjects with growth hormone-related disorders.
The invention provides isolated GHXTEN in which the binding affinity for GH target receptors or ligands by the GHXTEN can be 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 100% or more of the affinity of a native GH not bound to XTEN for the target receptor or ligand. In some cases, the binding affinity Kd between the subject GHXTEN and a native receptor or ligand of the GHXTEN is at least about 10−4 M, alternatively at least about 10−5M, alternatively at least about 10−6M, or at least about 10−7M, or at least about 10−8M, or at least about 10−9M of the affinity between the GHXTEN and a native receptor or ligand.
In other embodiments, the invention provides isolated GHXTEN fusion proteins specifically designed to have reduced binding affinity to the GH receptor. In one embodiments, such as fusion proteins comprising an XTEN fused to the C-terminus of the GH 1 about 97% sequence identity, or at least about 99% sequence identity to GH fusion proteins selected from AE912-hGH-AE144, AE912-hGH-AF144, AE912-hGH-AE288, AM923-hGH-AE144, AM923-hGH-AF144, AM923-hGH-AE288, and the sequences of Tables 36-37.
In some embodiments, the GHXTEN fusion proteins of the invention retain at least about 0.05%, or about 0.1%, or 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 98%, or or about 99% percent of the biological activity of the corresponding GH not linked to the fusion protein with regard to an in vitro biologic activity or pharmacologic effect known or associated with the use of the native GH in the treatment and prevention of growth hormone-related diseases, disorder and conditions. Non-limiting examples of activities or pharmacologic effects that can be assayed to assess the retained activity of the GHXTEN fusion proteins include signal transduction markers in cells with GH receptors, elicited IGF-1 concentrations, elicited IGFBP3 concentrations, changes in height velocity, lean body mass, total body fat, trunk fat, parameters associated with insulin resistance syndrome, measurement of division and multiplication rates of chondrocytes, changes in bone density, and bone growth (e.g. increase in epiphyseal plate width). In some embodiments, the activity of the GH component is manifest by the intact GHXTEN fusion protein, while in other cases the activity of the GH component would be primarily manifested upon cleavage and release of the GH from the fusion protein by action of a protease that acts on a cleavage sequence incorporated into the GHXTEN fusion protein. In the foregoing, the GHXTEN is designed to reduce the binding affinity of the GH component for the receptor or ligand when linked to the XTEN but have restored or increased affinity when released from XTEN through the cleavage of cleavage sequence(s) incorporated into the GHXTEN sequence, as described more fully above.
In other cases, the GHXTEN can be designed to reduce the binding affinity of the GH component to the GH receptor to increase the terminal half-life of GHXTEN administered to a subject by reducing receptor-mediated clearance; e.g., by adding an XTEN to the C-terminus of the GH component of the fusion protein. In other cases, the GHXTEN are designed to reduce the binding affinity of the GH component to the GH receptor to reduce toxicity or side effects due to the administered composition.
Accordingly, the invention provides a method for increasing the terminal half-life of a GHXTEN by producing a single-chain fusion protein construct with a specific N- to C-terminus configuration of the components comprising at least a first GH and a first and a second XTEN, wherein the fusion protein in a first N- to C-terminus configuration of the GH and XTEN components has reduced receptor-mediated clearance (RMC) and a corresponding increase in terminal half-life compared to a GHXTEN in a second N- to C-terminus configuration. In one embodiment of the foregoing, the GHXTEN is configured, N- to C-terminus as XTEN-GH-XTEN, which has reduced receptor binding compared to a GHXTEN configures, N- to C-terminus XTEN-GH. In another embodiment of the foregoing, the GHXTEN is configured GH-XTEN. In the foregoing embodiments, the two XTEN molecules can be identical or they can be of a different sequence composition or length. Non-limiting examples of the foregoing embodiment with two XTEN linked to a single GH include the constructs AE912-hGH-AE144, AE912-hGH-AE288, AE864-hGH-AE144, AM923-hGH-AE144, and AM923-hGH-AE288. The invention contemplates other such constructs in which a GH from Table 1 and XTEN from Table 3 are substituted for the respective components of the foregoing examples, and are produced, for example, in a configuration from Table 5 such that the construct has reduced receptor mediated clearance compared to an alternative configuration of the respective components. In some embodiments, the foregoing method for increasing the terminal half-life provides configured GHXTEN that can result in an increase in the terminal half-life of at least about 30%, or about 50%, or about 75%, or about 100%, or about 150%, or about 200%, or about 300%, or about 400% or more compared to the half-life of a GHXTEN in a second configuration where receptor binding is not reduced. The invention takes advantage of the fact that certain ligands wherein reduced binding affinity to a receptor, either as a result of a decreased on-rate or an increased off-rate, may be effected by the obstruction of either the N- or C-terminus (as shown in FIG. 3), and using that terminus as the linkage to another polypeptide of the composition, whether another molecule of a GH, an XTEN, or a spacer sequence results in the reduced binding affinity. The choice of the particular configuration of the GHXTEN fusion protein reduces the degree of binding affinity to the receptor such that a reduced rate of receptor-mediated clearance is achieved. Generally, activation of the receptor is coupled to RMC such that binding of a polypeptide to its receptor without activation does not lead to RMC, while activation of the receptor leads to RMC. However, in some cases, particularly where the ligand has an increased off rate, the ligand may nevertheless be able to bind sufficiently to initiate cell signaling without triggering receptor mediated clearance, with the net result that the GHXTEN remains bioavailable. In such cases, the configured GHXTEN has an increased half-life compared to those configurations that lead to a higher degree of RMC.
In cases where a reduction in binding affinity to the growth hormone receptor is desired in order to reduce receptor-mediated clearance but retention of at least a portion of the biological activity is also desired, sufficient binding affinity to obtain the desired receptor activation must nevertheless be maintained e.g., by initiation of signal transduction. Thus, in one embodiment, the invention provides a GHXTEN configured such that the binding affinity of the GHXTEN for a target receptor is in the range of about 0.01%-40%, or about 0.01%-30%, or about 0.01%-20% of the binding affinity compared to a corresponding GHXTEN in a configuration wherein the binding affinity is not reduced. The binding affinity of the configured BXTEN is thus preferably reduced by 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 99.99% as compared to the binding affinity of a corresponding GHXTEN in a configuration wherein the binding affinity of the GH component to the target receptor is not reduced or compared to the GH not linked to the fusion protein, determined under comparable conditions. Expressed differently, the GH component of the configured GHXTEN has a binding affinity that is as small as about 0.01%, or at least about 0.1%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 4%, or at least about 5%, or at least about 10%, or at least about 20%, or at least about 30%, or at least 40% of that of the corresponding GH component of a GHXTEN in a configuration wherein the binding affinity of the GH component is not reduced. In the foregoing embodiments, the binding affinity of the configured GHXTEN for the target receptor are “substantially reduced” compared to a corresponding native GH or a GHXTEN with a configuration in which the binding affinity of the corresponding GH component is not reduced. Accordingly, the present invention provides compositions and methods to produce compositions with reduced RMC by configuring the GHXTEN, examples of which are provided above, so as to be able to bind and activate a sufficient number of receptors to obtain a desired in vivo biological response yet avoid activation of more receptors than is required for obtaining such response. The increased half-life permits higher dosages and reduced frequency of dosing compared to GH not linked to XTEN or compared to GHXTEN configurations wherein the GH component retains sufficient biological or pharmacological activity to result in a composition with clinical efficacy maintained despite reduced dosing frequency.
VI). Uses of the Compositions of the Present Invention
In another aspect, the invention provides a method for achieving a beneficial effect in a disease, disorder or condition mediated by GH. The present invention addresses disadvantages and/or limitations of GH that have a relatively short terminal half-life and/or a narrow therapeutic window.
Most processes involved in growth of the body are regulated by multiple peptides and hormones, and such peptides and hormones, as well as analogues thereof, have found utility in the treatment of growth hormone-related diseases, disorders and conditions. However, the use of commercially-avaiable growth hormones, has met with less than optimal success in the management of subjects afflicted with such diseases, disorders and conditions. In particular, dose optimization and frequency of dosing is important for peptide and hormone biologics used in the treatment of growth hormone-related diseases and disorders. The fact that growth hormone has a short half-life, necessitates frequent dosing in order to achieve clinical benefit, which results in difficulties in the management of such patients.
In one embodiment, the invention provides a method for achieving a beneficial affect in a subject with a growth hormone-related disease, disorder or condition comprising the step of administering to the subject a therapeutically- or prophylactically-effective amount of a GHXTEN wherein said administration results in the improvement of one or more biochemical or physiological parameters or clinical endpoints associated with a growth hormone-related disease, disorder or condition. The effective amount produces 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 growth hormone-related disease, disorder or condition. In some cases, the method for achieving a beneficial effect includes administering a therapeutically effective amount of a GHXTEN fusion protein composition to treat a subject with a growth hormone-related disease, disorder, or condition, including, but not limited to, congenital or acquired GH deficiency in adults and children, Turner's Syndrome, Prader-Willi Syndrome, chronic renal failure, intrauterine growth retardation, idiopathic short stature, AIDS wasting, obesity, multiple sclerosis, aging, fibromyalgia, Crohn's disease, ulcerative colitis, muscular dystrophy, low muscle mass (e.g. bodybuilding), low bone density, or any other indication for which GH can be utilized (but for which endogenous growth hormone levels in a subject are not necessarily deficient).
In another embodiment, the invention provides a method of stimulating IGF-1 production in individuals with GH deficiency. The method comprises the step of administering therapeutically effective amount of GHXTEN to a subject that results in the increased blood levels and/or duration in increased blood levels of IGF-1 compared to a subject receiving a GH not linked to an XTEN and administered at a comparable dose. In some cases, the increase in IGF-1 is at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 75%, or at least about 100%, or at least about 200%, or at least about 300%. In another embodiment, the invention provides a method of stimulating the division and numbers of chrondrocytes. The method comprises the step of administering therapeutically effective amount of GHXTEN that results in the increased production of chrondrocytes by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 75%, or at least about 100%, or at least about 200%, or at least about 300% compared to a subject receiving a GH not linked to an XTEN and administered at a comparable dose. In another embodiment, the invention provides a method comprising the step of administering therapeutically effective amount of GHXTEN that results in increased bone growth as measured by increase in epiphyseal plate width by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 75%, or at least about 100%, or at least about 200%, or at least about 300% compared to a subject receiving a GH not linked to an XTEN and administered at a comparable dose.
As a result of the enhanced PK parameters of GHXTEN, as described herein, the GH is administered using longer intervals between doses compared to the corresponding GH not linked to XTEN to prevent, treat, alleviate, reverse or ameliorate symptoms or clinical abnormalities of the growth hormone-related disease, disorder or condition or prolong the survival of the subject being treated.
The methods of the invention includes administration of consecutive doses of a therapeutically effective amount of the GHXTEN 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 GHXTEN; i.e., the schedule for consecutively administered doses of the fusion protein composition, 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. In one embodiment, the method comprises administering a therapeutically-effective amount of a pharmaceutical composition comprising a GHXTEN fusion protein composition comprising a GH linked to an XTEN sequence(s) and at least one pharmaceutically acceptable carrier to a subject in need thereof that results in greater improvement in at least one parameter, physiologic condition, or clinical outcome mediated by the GH component(s) (non-limiting examples of which are described above) compared to the effect mediated by administration of a pharmaceutical composition comprising a GH not linked to XTEN and administered at a comparable dose. In one embodiment, the pharmaceutical composition is administered at a therapeutically effective dose. In another embodiment, the pharmaceutical composition is administered using multiple consecutive doses using a therapeutically effective dose regimen (as defined herein) for the length of the dosing period.
A therapeutically effective amount of the GHXTEN varies 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 GHXTEN are outweighed by the therapeutically beneficial effects. A prophylactically effective amount refers to an amount of GHXTEN required for the period of time necessary to achieve the desired prophylactic result.
For the inventive methods, longer acting GHXTEN 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 GHXTEN 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 composition compared to the corresponding GH component(s) 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, or at least about 80-fold, or at least about 100-fold longer, compared to the corresponding GH component 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 GHXTEN administered using a therapeutically effective dose regimen to a subject in need thereof results in a gain in time between consecutive Cmax peaks and/or Cmin troughs for blood levels of the fusion protein compared to the corresponding GH not linked to the fusion protein and administered using a dose regimen established for that GH. In the foregoing embodiment, the gain in time spent between consecutive Cmax peaks and/or Cmin troughs 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 or at least about 80-fold, or at least about 100-fold longer, compared to the corresponding GH component not linked to the fusion protein and administered using a dose regimen established for that GH. In the embodiments hereinabove described in this paragraph the administration of the fusion protein results in an improvement in at least one of the parameters (disclosed herein as being useful for assessing the subject diseases, conditions or disorders) using a lower unit dose in moles of fusion protein compared to the corresponding GH component not linked to the fusion protein and administered at a comparable unit dose or dose regimen to a subject.
The method of treatment comprises administration of a GHXTEN using a therapeutically effective dose regimen to effect improvements in one or more parameters associated with growth hormone diseases, disorders or conditions. In some embodiments, administration of the GHXTEN to a subject results in an improvement in one or more of the biochemical, physiologic, or clinical parameters that is of greater magnitude than that of the corresponding GH component not linked to XTEN, determined using the same assay or based on a measured clinical parameter. In other embodiments, administration of the GHXTEN to a subject using a therapeutically effective dose regimen results in activity in one or more of the biochemical, physiologic, or clinical parameters that is of longer duration than the activity of one of the single GH components not linked to XTEN, determined using that same assay or based on a measured clinical parameter. In one embodiment of the foregoing, the administration of the GHXTEN to a subject using a therapeutically effective dose regimen results in an improvement in peak concentrations and area under the curve of blood IGF-1 levels of at least 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 100% or more in the subject compared to a comparable dose of GH not linked to XTEN administered to a subject. In another embodiment of the foregoing, the administration of the GHXTEN to a subject using a therapeutically effective dose regimen results in increased weight gain in the subject of at least about 10%, or about 20%, or about 30%, or about 40%, or about 50% or more compared to a comparable dose regimen of GH not linked to XTEN administered to a subject.
The invention further contemplates that GHXTEN used in accordance with the methods provided herein is administered in conjunction with other treatment methods and pharmaceutical compositions useful for treating growth hormone-related diseases, disorders, and conditions, or conditions for which growth hormone is adjunctive therapy; e.g., insulin resistance and poor glycemic control. Such compositions, include for example, DPP-IV inhibitors, insulin, insulin analogues, PPAR gamma agonists, dual-acting PPAR agonists, GLP-1 agonists or analogues, PTP1B inhibitors, SGLT inhibitors, insulin secretagogues, RXR agonists, glycogen synthase kinase-3 inhibitors, insulin sensitizers, immune modulators, beta-3 adrenergic receptor agonists, Pan-PPAR agonists, 11beta-HSD1 inhibitors, biguanides, alpha-glucosidase inhibitors, meglitinides, thiazolidinediones, sulfonylureas and other diabetes medicants known in the art, or anti-hypertensive drugs, calcium channel blockers, and related products. In some embodiments, the administration of a GHXTEN permits use of lower dosages of the co-administered pharmaceutical composition to achieve a comparable clinical effect or measured parameter for the disease, disorder or condition in the subject.
In another aspect, the invention provides a method of designing the GHXTEN compositions with desired pharmacologic or pharmaceutical properties. The GHXTEN fusion proteins are designed and prepared with various objectives in mind (compared to the GH components not linked to the fusion protein), including improving the therapeutic efficacy for the treatment of growth hormone-related diseases, disorders, and conditions, enhancing the pharmacokinetic characteristics of the fusion proteins compared to the GH, lowering the dose or frequency of dosing required to achieve a pharmacologic effect, enhancing the pharmaceutical properties, and to enhance the ability of the GH components to remain within the therapeutic window for an extended period of time.
In general, the steps in the design and production of the fusion proteins and the inventive compositions, as illustrated in FIGS. 4-6, include: (1) the selection of GHs (e.g., native proteins, analogs or derivatives with activity) to treat the particular disease, disorder or condition; (2) selecting the XTEN that will confer the desired PK and physicochemical characteristics on the resulting GHXTEN (e.g., the administration of the composition to a subject results in the fusion protein being maintained within the therapeutic window for a greater period compared to GH not linked to XTEN); (3) establishing a desired N- to C-terminus configuration of the GHXTEN to achieve the desired efficacy or PK parameters; (4) establishing the design of the expression vector encoding the configured GHXTEN; (5) transforming a suitable host with the expression vector; and (6) expression and recovery of the resultant fusion protein. For those GHXTEN for which an increase in half-life (greater than 24 h) or an increased period of time spent within a therapeutic window is desired, the XTEN chosen for incorporation generally has at least about 500, or about 576, or about 864, or about 875, or about 912, or about 923 amino acid residues where a single XTEN is to be incorporated into the GHXTEN. In another embodiment, the GHXTEN comprises a first XTEN of the foregoing lengths, and a second XTEN of about 144, or about 288, or about 576, or about 864, or about 875, or about 912, or about 923 amino acid residues.
In other embodiments, where an increase in half-life is not required, but an increase in a pharmaceutical property (e.g., solubility) is desired, a GHXTEN is designed to include XTEN of shorter lengths. In some embodiments of the foregoing, the GHXTEN comprises a GH linked to an XTEN having at least about 24, or about 36, or about 48, or about 60, or about 72, or about 84, or about 96 amino acid residues, in which the solubility of the fusion protein under physiologic conditions is at least three-fold greater than the corresponding GH not linked to XTEN, or alternatively, at least four-fold, or five-fold, or six-fold, or seven-fold, or eight-fold, or nine-fold, or at least 10-fold, or at least 20-fold, or at least 30-fold, or at least 50-fold, or at least 60-fold or greater than GH not linked to XTEN. In one embodiment of the foregoing, the GH is human growth hormone.
In another aspect, the invention provides methods of making GHXTEN compositions to improve ease of manufacture, result in increased stability, increased water solubility, and/or ease of formulation, as compared to the native GH. In one embodiment, the invention includes a method of increasing the water solubility of a GH comprising the step of linking the GH to one or more XTEN such that a higher concentration in soluble form of the resulting GHXTEN can be achieved, under physiologic conditions, compared to the GH in an un-fused state. Factors that contribute to the property of XTEN to confer increased water solubility of GHs when incorporated into a fusion protein include the high solubility of the XTEN fusion partner and the low degree of self-aggregation between molecules of XTEN in solution. In some embodiments, the method results in a GHXTEN fusion protein wherein the water solubility is at least about 20%, or at least about 30% greater, or at least about 50% greater, or at least about 75% greater, or at least about 90% greater, or at least about 100% greater, or at least about 150% greater, or at least about 200% greater, or at least about 400% greater, or at least about 600% greater, or at least about 800% greater, or at least about 1000% greater, or at least about 2000% greater, or at least about 4000% greater, or at least about 6000% greater under physiologic conditions, compared to the un-fused GH.
In another embodiment, the invention includes a method of increasing the shelf-life of a GH comprising the step of linking the GH with one or more XTEN selected such that the shelf-life of the resulting GHXTEN is extended compared to the GH in an un-fused state. As used herein, shelf-life refers to the period of time over which the functional activity of a GH or GHXTEN that is in solution or in some other storage formulation remains stable without undue loss of activity. As used herein, “functional activity” refers to a pharmacologic effect or biological activity, such as the ability to bind a receptor or ligand, or an enzymatic activity, or to display one or more known functional activities associated with a GH, as known in the art. A GH that degrades or aggregates generally has reduced functional activity or reduced bioavailability compared to one that remains in solution. Factors that contribute to the ability of the method to extend the shelf life of GHs when incorporated into a fusion protein include increased water solubility, reduced self-aggregation in solution, and increased heat stability of the XTEN fusion partner. In particular, the low tendency of XTEN to aggregate facilitates methods of formulating pharmaceutical preparations containing higher drug concentrations of GHs, and the heat-stability of XTEN contributes to the property of GHXTEN fusion proteins to remain soluble and functionally active for extended periods. In one embodiment, the method results in GHXTEN fusion proteins with “prolonged” or “extended” shelf-life that exhibit greater activity relative to a standard that has been subjected to the same storage and handling conditions. The standard may be the un-fused full-length GH. In one embodiment, the method includes the step of formulating the isolated GHXTEN with one or more pharmaceutically acceptable excipients that enhance the ability of the XTEN to retain its unstructured conformation and for the GHXTEN to remain soluble in the formulation for a time that is greater than that of the corresponding un-fused GH. In one embodiment, the method comprises linking a GH to one or more XTEN to create a GHXTEN fusion protein results in a solution that retains greater than about 100% of the functional activity, or greater than about 105%, 110%, 120%, 130%, 150% or 200% of the functional activity of a standard when compared at a given time point and when subjected to the same storage and handling conditions as the standard, thereby increasing its shelf-life.
Shelf-life may also be assessed in terms of functional activity remaining after storage, normalized to functional activity when storage began. GHXTEN fusion proteins of the invention with prolonged or extended shelf-life as exhibited by prolonged or extended functional activity retains about 50% more functional activity, or about 60%, 70%, 80%, or 90% more of the functional activity of the equivalent GH not linked to XTEN when subjected to the same conditions for the same period of time. For example, a GHXTEN fusion protein of the invention comprising human growth hormone fused to one or more XTEN sequences retains about 80% or more of its original activity in solution for periods of up to 2 weeks, or 4 weeks, or 6 weeks or longer under various temperature conditions. In some embodiments, the GHXTEN retains at least about 50%, or about 60%, or at least about 70%, or at least about 80%, and most preferably at least about 90% or more of its original activity in solution when heated at 80° C. for 10 min. In other embodiments, the GHXTEN retains at least about 50%, preferably at least about 60%, or at least about 70%, or at least about 80%, or alternatively at least about 90% or more of its original activity in solution when heated or maintained at 37° C. for about 7 days. In another embodiment, GHXTEN fusion protein retains at least about 80% or more of its functional activity after exposure to a temperature of about 30° C. to about 70° C. over a period of time of about one hour to about 18 hours. In the foregoing embodiments hereinabove described in this paragraph, the retained activity of the GHXTEN is 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 greater at a given time point than that of the corresponding GH not linked to the fusion protein.
VII). The Nucleic Acids Sequences of the Invention
The present invention provides isolated polynucleic acids encoding GHXTEN chimeric fusion proteins and sequences complementary to polynucleic acid molecules encoding GHXTEN chimeric fusion proteins, including homologous variants thereof. In another aspect, the invention encompasses methods to produce polynucleic acids encoding GHXTEN chimeric fusion proteins and sequences complementary to polynucleic acid molecules encoding GHXTEN chimeric fusion protein, including homologous variants thereof. In general, and as illustrated in FIGS. 4-6, the methods of producing a polynucleotide sequence coding for a GHXTEN fusion protein and expressing the resulting gene product include assembling nucleotides encoding GH and XTEN, ligating the components in frame, incorporating the encoding gene into an expression vector appropriate for a host cell, transforming the appropriate host cell with the expression vector, and culturing the host cell under conditions causing or permitting the fusion protein to be expressed in the transformed host cell, thereby producing the biologically-active GHXTEN polypeptide, which is recovered as an isolated fusion protein by standard protein purification methods known in the art. Standard recombinant techniques in molecular biology is used to make the polynucleotides and expression vectors of the present invention.
In accordance with the invention, nucleic acid sequences that encode GHXTEN (or its complement) is used to generate recombinant DNA molecules that direct the expression of GHXTEN fusion proteins in appropriate host cells. Several cloning strategies are suitable for performing the present invention, many of which is used to generate a construct that comprises a gene coding for a fusion protein of the GHXTEN composition of the present invention, or its complement. In some embodiments, the cloning strategy is used to create a gene that encodes a monomeric GHXTEN that comprises at least a first GH and at least a first XTEN polypeptide, or their complement. In one embodiment of the foregoing, the gene comprises a sequence encoding a hGH or sequence variant. In other embodiments, the cloning strategy is used to create a gene that encodes a monomeric GHXTEN that comprises nucleotides encoding at least a first molecule of GH or its complement and a first and at least a second XTEN or their complement that is used to transform a host cell for expression of the fusion protein of the GHXTEN composition. In the foregoing embodiments hereinabove described in this paragraph, the genes can further comprise nucleotides encoding spacer sequences that also encodes cleavage sequence(s).
In designing a desired XTEN sequences, it was discovered that the non-repetitive nature of the XTEN of the inventive compositions is 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 peptide sequence motifs, described above, that are then ligated and/or multimerized to create the genes encoding the XTEN sequences (see FIGS. 4 and 5 and Examples). Thus, while the XTEN(s) of the expressed fusion protein 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 GHXTEN fusion protein. DNA encoding the GH of the compositions is obtained from a cDNA library prepared using standard methods from tissue or isolated cells believed to possess GH mRNA and to express it at a detectable level. Libraries is screened with probes containing, for example, about 20 to 100 bases designed to identify the GH gene of interest by hybridization using conventional molecular biology techniques. The best candidates for probes are those that represent sequences that are highly homologous for human growth hormone, and should be of sufficient length and sufficiently unambiguous that false positives are minimized, but may be degenerate at one or more positions. 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. One can then use polymerase chain reaction (PCR) methodology to amplify the target DNA or RNA coding sequence to obtain sufficient material for the preparation of the GHXTEN constructs containing the GH gene(s). Assays can then be conducted to confirm that hybridizing full-length genes are the desired GH gene(s). By these conventional methods, DNA can be conveniently obtained from a cDNA library prepared from such sources. The GH encoding gene(s) is also be obtained from a genomic library or created by standard synthetic procedures known in the art (e.g., automated nucleic acid synthesis using, for example one of the methods described in Engels et al. (Agnew. Chem. Int. Ed. Engl., 28:716-734 1989)), 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, 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 protein of interest or of a fragment or variant of the protein. 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 GH encoding gene encodes a protein from any one of Table 1, or a fragment or variant thereof.
A gene or polynucleotide encoding the GH portion of the subject GHXTEN protein, in the case of an expressed fusion protein that comprises a single GH is then be cloned into a construct, which is 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 GH gene by cloning it into the construct adjacent and in frame with the gene(s) coding for the GH. This second step occurs 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.
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, including methods more fully described in the Examples. The methods disclosed herein can be used, for example, to ligate short sequences of polynucleotides encoding XTEN into longer XTEN genes of a desired length and sequence. In one embodiment, the method ligates two or more codon-optimized oligonucleotides encoding XTEN motif or segment sequences of about 9 to 14 amino acids, or about 12 to 20 amino acids, or about 18 to 36 amino acids, or about 48 to about 144 amino acids, or about 144 to about 288 or longer, or any combination of the foregoing ranges of motif or segment lengths.
Alternatively, the disclosed method is used to multimerize XTEN-encoding sequences into longer sequences of a desired length; e.g., a gene encoding 36 amino acids of XTEN can be dimerized into a gene encoding 72 amino acids, then 144, then 288, etc. Even with multimerization, XTEN polypeptides can be constructed such that the XTEN-encoding gene has low or virtually no repetitiveness through design of the codons selected for the motifs of the shortest unit used, which can reduce recombination and increase stability of the encoding gene in the transformed host. Genes encoding XTEN with non-repetitive sequences is 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. 4 and 5. 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. Exemplary methods to achieve the foregoing are disclosed in the Examples.
Polynucleotide Libraries
In another aspect, the invention provides libraries of polynucleotides that encode XTEN sequences that is used to assemble genes that encode XTEN of a desired length and sequence.
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, e.g., 12 amino acid motifs can be dimerized and/or ligated into a library of polynucleotides that encode 36 amino acids. Libraries encoding motifs of different lengths; e.g., 9-14 amino acid motifs leading to libraries encoding 27 to 42 amino acids are contemplated by the invention. In turn, the library of polynucleotides that encode 27 to 42 amino acids, and preferably 36 amino acids (as described in the Examples) can be serially dimerized into a library containing successively longer lengths of polynucleotides that encode XTEN sequences of a desired length for incorporation into the gene encoding the GHXTEN fusion protein, as disclosed herein. In some embodiments, libraries are assembled of polynucleotides that encode amino acids that are limited to specific sequence XTEN families; e.g., AD, AE, AF, AG, AM, or AQ sequences of Table 2. In other embodiments, libraries comprise sequences that encode two or more of the motif family sequences from Table 2. The names and sequences of representative, non-limiting polynucleotide sequences of libraries that encode 36mers are presented in Tables 8-11, and the methods used to create them are described more fully in the Examples. In other embodiments, libraries that encode XTEN are constructed from segments of polynucleotide codons linked in a randomized sequence that encode amino acids wherein 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 97%, or at least about 98%, or at least about 99% of the codons are selected from the group consisting of condons for glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) amino acids. The libraries can be used, in turn, for serial dimerization or ligation to achieve polynucleotide sequence libraries that encode XTEN sequences, for example, of 48, 72, 144, 288, 576, 864, 875, 912, 923, 1318 amino acids, or up to a total length of about 3000 amino acids, as well as intermediate lengths, in which the encoded XTEN can have one or more of the properties disclosed herein, when expressed as a component of a GHXTEN fusion protein. In some cases, the polynucleotide library sequences may also include additional bases used as “sequencing islands,” described more fully below.
FIG. 5 is a schematic flowchart of representative, non-limiting steps in the assembly of a XTEN polynucleotide construct and a GHXTEN polynucleotide construct in the embodiments of the invention. Individual oligonucleotides 501 are 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 optionally encodes 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 GH gene (encoding hGH in this example) 508, resulting in the gene encoding a GHXTEN comprising a single GH 500. A non-exhaustive list of the XTEN names for polynucleotides encoding XTEN and precursor sequences is provided in Table 7.







TABLE 7







DNA sequences of XTEN and precursor sequences









XTEN
SEQ ID 



Name
NO:
DNA Nucleotide Sequence





AE48
107
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACCCCGGGTAGCGGTA




CTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGCT




TCTCCGGGCACCAGCTCTACCGGTTCT


 


AM48
108
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTGCATCCCCGGGCACCA




GCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACCGGCTCTCCAGGTAGC




TCTACCCCGTCTGGTGCTACTGGCTCT


 


AE144
109
GGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTC




CTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCTGGCTCTGAAACCCCAGGTAGCCC




GGCAGGCTCTCCGACTTCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGGGTAGC




GCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAGGTAGCGAACCTGCTA




CCTCCGGCTCTGAAACTCCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACTCCAGG




TACCTCTACCGAACCTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCT




GAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTA




CCGAACCGTCCGAAGGTAGCGCACCA


 


AF144
110
GGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTACTTCTCCTAGCGGTGAATC




TTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACTGCTCCAGGTTCTACCA




GCTCTACCGCTGAATCTCCTGGCCCAGGTTCTACCAGCGAATCCCCGTCTGGCACCGC




ACCAGGTTCTACTAGCTCTACCGCAGAATCTCCGGGTCCAGGTACTTCCCCTAGCGGT




GAATCTTCTACTGCTCCAGGTACCTCTACTCCGGAAAGCGGCTCCGCATCTCCAGGTTC




TACTAGCTCTACTGCTGAATCTCCTGGTCCAGGTACCTCCCCTAGCGGCGAATCTTCTA




CTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTACCTCCCCTAGC




GGTGAATCTTCTACCGCACCA


 


AE288
111
GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCG




GCTCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGA




ACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCT




GGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGCTGGCT




CTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCT




GAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGG




CTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGC




ACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCT




ACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTA




GCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTC




TGAAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACT




GAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTC




CAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTAC




TCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA


 


AE576
112
GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGAAAGCGCTACTC




CTGAGTCTGGTCCAGGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCCC




AGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGC




GCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCG




CTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAGG




TAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCAGGCTCTCCGACC




TCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCTA




CCGAACCGTCTGAGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCG




CACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAACC




GTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGT




ACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGAAG




GTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACC




GGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCA




CCAGGTACTTCTACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAA




CCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTA




GCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGA




ATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCTGAA




AGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTC




CAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTC




CGAAGGCAGCGCTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACC




TCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTA




GCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGA




ACCGTCCGAGGGTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA




GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAACCC




CGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTC




TGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGC




GCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCT




CTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGG




TAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCG




GAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA


 


AF576
113
GGTTCTACTAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCCACTAGCTCTACCGCAGA




ATCTCCGGGCCCAGGTTCTACTAGCGAATCCCCTTCTGGTACCGCTCCAGGTTCTACTA




GCTCTACCGCTGAATCTCCGGGTCCAGGTTCTACCAGCTCTACTGCAGAATCTCCTGGC




CCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGTTCTACCAGCGAATCTCC




TTCTGGCACCGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTA




CTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCTTCTGGCACC




GCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTACTAGCGAATC




TCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTA




CCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTACTAGCGAATCTCCTTCTGGC




ACTGCACCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCG




AATCTCCGTCTGGCACTGCACCAGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCA




GGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAGGTACTTCTACCCCTGAAAGCGG




CTCCGCTTCTCCAGGTTCCACTAGCTCTACCGCTGAATCTCCGGGTCCAGGTTCTACTA




GCTCTACTGCAGAATCTCCTGGCCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATC




TCCAGGTACTTCTACCCCTGAAAGCGGTTCTGCATCTCCAGGTTCTACTAGCGAATCCC




CGTCTGGTACCGCACCAGGTACTTCTACCCCGGAAAGCGGCTCTGCTTCTCCAGGTAC




TTCTACCCCGGAAAGCGGCTCCGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGTA




CCGCTCCAGGTTCTACCAGCGAATCCCCGTCTGGTACTGCTCCAGGTTCTACCAGCGA




ATCTCCTTCTGGTACTGCACCAGGTTCTACTAGCTCTACTGCAGAATCTCCTGGCCCAG




GTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTACTTCTACCCCTGAAAGCGG




TTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCA




GCGAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCT




CCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCC




GTCTGGCACTGCACCAGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGTACTT




CTCCGAGCGGTGAATCTTCTACCGCACCAGGTTCTACTAGCTCTACCGCTGAATCTCCG




GGCCCAGGTACTTCTCCGAGCGGTGAATCTTCTACTGCTCCAGGTTCCACTAGCTCTAC




TGCTGAATCTCCTGGCCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGTT




CTACTAGCGAATCTCCGTCTGGCACCGCACCAGGTTCTACTAGCTCTACTGCAGAATCT




CCTGGCCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTACTTCTACCCC




TGAAAGCGGTTCTGCATCTCCA


 


AE624
114
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACCCCGGGTAGCGGTA




CTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGCT




TCTCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTAC




TGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTGAA




CCGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAG




GTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGA




ACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAA




ACTCCAGGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCG




CAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAG




GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTAC




CTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCT




ACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCG




GTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTGAAAGCGC




AACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGT




ACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGTCTGAAG




GTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCGGAATCCGGCCCAGGTACCTCTGA




AAGCGCAACCCCGGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACC




TCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTA




CCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGG




TAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTACT




GAACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTCTGAAGGTAGCGCAC




CAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCC




TACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACC




TCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTCTG




AGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGC




AACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA




GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACTC




CTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCC




GGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCTACT




GAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAA




CCGTCTGAGGGCAGCGCACCA


 


AM875
115
GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCAGGTAGCGAACCGGCTACTTCCG




GTTCTGAAACCCCAGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTAC




CAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCA




TCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACTAGCGAATC




CCCGTCTGGTACTGCTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGTA




CCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACCGGCAACCTCCGGCTC




TGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCCGGCCCAGGTAGCCCGGCA




GGTTCTCCGACTTCCACTGAGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTC




CAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTC




CGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAG




CCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGT




AGCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAA




GCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCC




AGGTACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGTCC




GAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTACTT




CTACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCGAACCTGCTACTTCTGGTTCTGA




AACCCCAGGTAGCCCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCCG




TCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGG




TAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTACCTCTACCGAACCGTCCGAGG




GTAGCGCACCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAACC




GGCAACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTGAG




GAAGGTAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGGTACTTCTACCGAACCTT




CCGAAGGTAGCGCTCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTACTT




CTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCAC




CGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCT




ACCGCTGAATCTCCTGGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAG




GTACTTCCCCTAGCGGTGAATCTTCTACTGCACCAGGTACCCCTGGCAGCGGTACCGC




TTCTTCCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCTCCAGGTTCTAGCC




CGTCTGCATCTACCGGTACCGGCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAAC




TCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGGTAGCGAACCGGCTACT




TCCGGCTCTGAAACCCCAGGTTCCACCAGCTCTACTGCAGAATCTCCGGGCCCAGGTT




CTACTAGCTCTACTGCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTCT




ACCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACTCCAGGTAGCGAACCTG




CAACCTCCGGCTCTGAAACCCCAGGTACTTCTACTGAACCTTCTGAGGGCAGCGCACC




AGGTTCTACCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGC




GGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTACTTC




TACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGC




GCTCCAGGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTAGCTCTACTCCGT




CTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAGGT




GCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTAGCGAACCTGCTACCTCCGGTTC




TGAAACCCCAGGTACCTCTGAAAGCGCAACTCCGGAGTCTGGTCCAGGTAGCCCTGCA




GGTTCTCCTACCTCCACTGAGGAAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCCCC




AGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCT




CTACTGGTTCTCCAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCT




ACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCG




CACCA


 


AE864
116
GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGAAAGCGCTACTC




CTGAGTCTGGTCCAGGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCCC




AGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGC




GCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCG




CTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAGG




TAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCAGGCTCTCCGACC




TCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCTA




CCGAACCGTCTGAGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCG




CACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAACC




GTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGT




ACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGAAG




GTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACC




GGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCA




CCAGGTACTTCTACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAA




CCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTA




GCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGA




ATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCTGAA




AGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTC




CAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTC




CGAAGGCAGCGCTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACC




TCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTA




GCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGA




ACCGTCCGAGGGTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA




GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAACCC




CGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTC




TGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGC




GCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCT




CTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGG




TAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCG




GAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTACCTCTG




AAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGAC




TCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACC




TCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTA




CTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTC




CACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACC




GGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTC




CAACTTCTACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTAC




TTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAA




TCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGG




CTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCC




AGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCC




GAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGC




GAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAAT




CTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA


 


AF864
117
GGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCTAGCGGCGAATC




TTCTACCGCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACTA




GCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCT




CCAGGTACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTTCTACCAGCGAATCTC




CTTCTGGCACCGCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTACT




TCTCCTAGCGGCGAATCTTCTACCGCACCAGGTTCTACTAGCGAATCTCCGTCTGGCAC




TGCTCCAGGTACTTCTCCTAGCGGTGAATCTTCTACCGCTCCAGGTACTTCCCCTAGCG




GCGAATCTTCTACCGCTCCAGGTTCTACTAGCTCTACTGCAGAATCTCCGGGCCCAGGT




ACCTCTCCTAGCGGTGAATCTTCTACCGCTCCAGGTACTTCTCCGAGCGGTGAATCTTC




TACCGCTCCAGGTTCTACTAGCTCTACTGCAGAATCTCCTGGCCCAGGTACCTCTACTC




CGGAAAGCGGCTCTGCATCTCCAGGTACTTCTACCCCTGAAAGCGGTTCTGCATCTCC




AGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCGT




CTGGCACTGCACCAGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGTTCTACC




AGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCAT




CTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTACTTCTCCGAGCGGT




GAATCTTCTACCGCACCAGGTTCTACTAGCTCTACCGCTGAATCTCCGGGCCCAGGTA




CTTCTCCGAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTACTCCTGAAAGCGGTTCT




GCATCTCCAGGTTCCACTAGCTCTACCGCAGAATCTCCGGGCCCAGGTTCTACTAGCTC




TACTGCTGAATCTCCTGGCCCAGGTTCTACTAGCTCTACTGCTGAATCTCCGGGTCCAG




GTTCTACCAGCTCTACTGCTGAATCTCCTGGTCCAGGTACCTCCCCGAGCGGTGAATCT




TCTACTGCACCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAG




CGAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCCCTGAAAGCGGTCCXXXXXXX




XXXXXTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAXXXXXXXXTAGCGAATCTCCT




TCTGGTACCGCTCCAGGTTCTACCAGCGAATCCCCGTCTGGTACTGCTCCAGGTTCTAC




CAGCGAATCTCCTTCTGGTACTGCACCAGGTTCTACTAGCGAATCTCCTTCTGGTACCG




CTCCAGGTTCTACCAGCGAATCCCCGTCTGGTACTGCTCCAGGTTCTACCAGCGAATCT




CCTTCTGGTACTGCACCAGGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTAC




TTCTCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTA




CTGCTCCAGGTTCTACCAGCTCTACTGCTGAATCTCCGGGTCCAGGTACTTCCCCGAGC




GGTGAATCTTCTACTGCACCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGG




TTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTTCTACTAGCGAATCCCCGTCTG




GTACCGCACCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTTCTACTAG




CGAATCCCCGTCTGGTACCGCACCAGGTACTTCTACCCCGGAAAGCGGCTCTGCTTCT




CCAGGTACTTCTACCCCGGAAAGCGGCTCCGCATCTCCAGGTTCTACTAGCGAATCTC




CTTCTGGTACCGCTCCAGGTACTTCTACCCCTGAAAGCGGCTCCGCTTCTCCAGGTTCC




ACTAGCTCTACCGCTGAATCTCCGGGTCCAGGTTCTACCAGCGAATCTCCTTCTGGCAC




CGCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTACTTCTCCTAGCG




GCGAATCTTCTACCGCACCAGGTTCTACCAGCTCTACTGCTGAATCTCCGGGTCCAGGT




ACTTCCCCGAGCGGTGAATCTTCTACTGCACCAGGTACTTCTACTCCGGAAAGCGGTT




CCGCTTCTCCAGGTACCTCCCCTAGCGGCGAATCTTCTACTGCTCCAGGTACCTCTCCT




AGCGGCGAATCTTCTACCGCTCCAGGTACCTCCCCTAGCGGTGAATCTTCTACCGCAC




CAGGTTCTACTAGCTCTACTGCTGAATCTCCGGGTCCAGGTTCTACCAGCTCTACTGCT




GAATCTCCTGGTCCAGGTACCTCCCCGAGCGGTGAATCTTCTACTGCACCAGGTTCTA




GCCCTTCTGCTTCCACCGGTACCGGCCCAGGTAGCTCTACTCCGTCTGGTGCAACTGGC




TCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCCCCA




XXXX was inserted in two areas where no sequence




information is available.


 


AG864
118
GGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTTCTAGCCCGTCTGCTTCTAC




TGGTACTGGTCCAGGTTCTAGCCCTTCTGCTTCCACTGGTACTGGTCCAGGTACCCCGG




GTAGCGGTACCGCTTCTTCTTCTCCAGGTAGCTCTACTCCGTCTGGTGCTACCGGCTCT




CCAGGTTCTAACCCTTCTGCATCCACCGGTACCGGCCCAGGTGCTTCTCCGGGCACCA




GCTCTACTGGTTCTCCAGGTACCCCGGGCAGCGGTACCGCATCTTCTTCTCCAGGTAGC




TCTACTCCTTCTGGTGCAACTGGTTCTCCAGGTACTCCTGGCAGCGGTACCGCTTCTTC




TTCTCCAGGTGCTTCTCCTGGTACTAGCTCTACTGGTTCTCCAGGTGCTTCTCCGGGCA




CTAGCTCTACTGGTTCTCCAGGTACCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGT




AGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAGCTCTAC




CGGTTCTCCAGGTACCCCGGGTAGCGGTACCGCTTCTTCTTCTCCAGGTAGCTCTACTC




CGTCTGGTGCTACCGGCTCTCCAGGTTCTAACCCTTCTGCATCCACCGGTACCGGCCCA




GGTTCTAGCCCTTCTGCTTCCACCGGTACTGGCCCAGGTAGCTCTACCCCTTCTGGTGC




TACCGGCTCCCCAGGTAGCTCTACTCCTTCTGGTGCAACTGGCTCTCCAGGTGCATCTC




CGGGCACTAGCTCTACTGGTTCTCCAGGTGCATCCCCTGGCACTAGCTCTACTGGTTCT




CCAGGTGCTTCTCCTGGTACCAGCTCTACTGGTTCTCCAGGTACTCCTGGCAGCGGTAC




CGCTTCTTCTTCTCCAGGTGCTTCTCCTGGTACTAGCTCTACTGGTTCTCCAGGTGCTTC




TCCGGGCACTAGCTCTACTGGTTCTCCAGGTGCTTCCCCGGGCACTAGCTCTACCGGTT




CTCCAGGTTCTAGCCCTTCTGCATCTACTGGTACTGGCCCAGGTACTCCGGGCAGCGGT




ACTGCTTCTTCCTCTCCAGGTGCATCTCCGGGCACTAGCTCTACTGGTTCTCCAGGTGC




ATCCCCTGGCACTAGCTCTACTGGTTCTCCAGGTGCTTCTCCTGGTACCAGCTCTACTG




GTTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGTTCCCCAGGTAGCTCTACTCCT




TCTGGTGCTACTGGCTCCCCAGGTGCATCCCCTGGCACCAGCTCTACCGGTTCTCCAGG




TACCCCGGGCAGCGGTACCGCATCTTCCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTA




CCGGTTCCCCAGGTAGCTCTACCCCGTCTGGTGCAACCGGCTCCCCAGGTAGCTCTACT




CCGTCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCC




AGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTGCATCCCCGGGTACCAGC




TCTACCGGTTCTCCAGGTACTCCTGGCAGCGGTACTGCATCTTCCTCTCCAGGTGCTTC




TCCGGGCACCAGCTCTACTGGTTCTCCAGGTGCATCTCCGGGCACTAGCTCTACTGGTT




CTCCAGGTGCATCCCCTGGCACTAGCTCTACTGGTTCTCCAGGTGCTTCTCCTGGTACC




AGCTCTACTGGTTCTCCAGGTACCCCTGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAG




CTCTACTCCGTCTGGTGCTACCGGTTCTCCAGGTACCCCGGGTAGCGGTACCGCATCTT




CTTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGC




GGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGG




TAGCTCTACCCCGTCTGGTGCTACTGGCTCCCCAGGTTCTAGCCCTTCTGCATCCACCG




GTACCGGTCCAGGTTCTAGCCCGTCTGCATCTACTGGTACTGGTCCAGGTGCATCCCCG




GGCACTAGCTCTACCGGTTCTCCAGGTACTCCTGGTAGCGGTACTGCTTCTTCTTCTCC




AGGTAGCTCTACTCCTTCTGGTGCTACTGGTTCTCCAGGTTCTAGCCCTTCTGCATCCA




CCGGTACCGGCCCAGGTTCTAGCCCGTCTGCTTCTACCGGTACTGGTCCAGGTGCTTCT




CCGGGTACTAGCTCTACTGGTTCTCCAGGTGCATCTCCTGGTACTAGCTCTACTGGTTC




TCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCTCCAGGTTCTAGCCCTTCTGCAT




CTACCGGTACTGGTCCAGGTGCATCCCCTGGTACCAGCTCTACCGGTTCTCCAGGTTCT




AGCCCTTCTGCTTCTACCGGTACCGGTCCAGGTACCCCTGGCAGCGGTACCGCATCTTC




CTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGTTCCCCAGGTAGCTCTACTCCTT




CTGGTGCTACTGGCTCCCCAGGTGCATCCCCTGGCACCAGCTCTACCGGTTCTCCA


 


AM923
119
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTGCATCCCCGGGCACCA




GCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACCGGCTCTCCAGGTAGC




TCTACCCCGTCTGGTGCTACTGGCTCTCCAGGTACTTCTACTGAACCGTCTGAAGGCAG




CGCACCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCCAGGTAGCCCAGCAGGT




TCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCAGAATCTCCTGGTCCAG




GTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCT




GGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTAC




TCCTGAAAGCGGTTCCGCTTCTCCAGGTACCTCTACTCCGGAAAGCGGTTCTGCATCTC




CAGGTAGCGAACCGGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTAC




TCCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGTACC




TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGT




CCGGTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACCGA




ACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACTTCTACCGAACCTTCCG




AGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTC




TGAAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACTGAACCTTCCGAAGGCAGC




GCTCCAGGTACCTCTACCGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCG




CAACCCCTGAATCCGGTCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTCCAGG




TAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGCCCGGCTGGCTCTCCGACC




TCCACCGAGGAAGGTAGCTCTACCCCGTCTGGTGCTACTGGTTCTCCAGGTACTCCGG




GCAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCTCT




CCAGGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCGT




CTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACTCCAGGTAG




CCCTGCTGGCTCTCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTTCTA




CTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTGCAAGCGCAA




GCGGCGCGCCAAGCACGGGAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAG




GTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAAC




TTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCTACTA




GCGAATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTAGCGGTGAATCTTCTACTGC




ACCAGGTACCCCTGGCAGCGGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCCGTCTG




GTGCTACTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCGGTACCGGCCCAGGTAG




CGAACCGGCAACCTCCGGCTCTGAAACTCCAGGTACTTCTGAAAGCGCTACTCCGGAA




TCCGGCCCAGGTAGCGAACCGGCTACTTCCGGCTCTGAAACCCCAGGTTCCACCAGCT




CTACTGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACTGCAGAATCTCCGGGTCC




AGGTACTTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTAGCGAACCGGCAACCTCT




GGCTCTGAAACTCCAGGTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGGTACTT




CTACTGAACCTTCTGAGGGCAGCGCACCAGGTTCTACCAGCTCTACCGCAGAATCTCC




TGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAA




TCTCCTTCTGGCACTGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAG




GTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTCTGA




AGGTAGCGCACCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTTCTAGC




CCGTCTGCTTCCACTGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTC




TCCAGGTAGCGAACCTGCTACCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGCA




ACTCCGGAGTCTGGTCCAGGTAGCCCTGCAGGTTCTCCTACCTCCACTGAGGAAGGTA




GCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGGT




ACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTACCTCTGAAA




GCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCC




AGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA


 


AE912
120
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACCCCGGGTAGCGGTA




CTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGCT




TCTCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTAC




TGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTGAA




CCGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAG




GTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGA




ACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAA




ACTCCAGGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCG




CAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAG




GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTAC




CTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCT




ACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCG




GTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTGAAAGCGC




AACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGT




ACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGTCTGAAG




GTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCGGAATCCGGCCCAGGTACCTCTGA




AAGCGCAACCCCGGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACC




TCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTA




CCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGG




TAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTACT




GAACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTCTGAAGGTAGCGCAC




CAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCC




TACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACC




TCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTCTG




AGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGC




AACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA




GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACTC




CTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCC




GGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCTACT




GAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAA




CCGTCTGAGGGCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAG




GTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCC




GGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCT




GAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCG




CACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGC




AACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGT




ACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTT




CCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTAC




CGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGC




CCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTA




CCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAG




CGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCC




ACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTG




AACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCC




AGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCC




GAGGGCAGCGCACCA


 


AM1318
121
GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCAGGTAGCGAACCGGCTACTTCCG




GTTCTGAAACCCCAGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTAC




CAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCA




TCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACTAGCGAATC




CCCGTCTGGTACTGCTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGTA




CCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACCGGCAACCTCCGGCTC




TGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCCGGCCCAGGTAGCCCGGCA




GGTTCTCCGACTTCCACTGAGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTC




CAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTC




CGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAG




CCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGT




AGCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAA




GCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCC




AGGTACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGTCC




GAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTACTT




CTACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCGAACCTGCTACTTCTGGTTCTGA




AACCCCAGGTAGCCCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCCG




TCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGG




TAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTACCTCTACCGAACCGTCCGAGG




GTAGCGCACCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAACC




GGCAACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTGAG




GAAGGTAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGGTACTTCTACCGAACCTT




CCGAAGGTAGCGCTCCAGGTCCAGAACCAACGGGGCCGGCCCCAAGCGGAGGTAGCG




AACCGGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATC




CGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGTACTTCTGAAAGC




GCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAG




GTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTGAAAGCGCTACTCC




TGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCG




GCTGGCTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCCTGG




CCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTAGCGGT




GAATCTTCTACTGCACCAGGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTTC




TACTAGCGAATCCCCGTCTGGTACCGCACCAGGTACTTCTCCTAGCGGCGAATCTTCTA




CCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAG




CGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCA




GGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTC




CGGAATCTGGTCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGTCCAGGTACCTC




TACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCC




GGTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACCTCCCCTAGCG




GCGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGT




ACCTCCCCTAGCGGTGAATCTTCTACCGCACCAGGTACTTCTACCGAACCGTCCGAGG




GTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTAC




CGAACCGTCCGAGGGTAGCGCACCAGGTTCTAGCCCTTCTGCTTCCACCGGTACCGGC




CCAGGTAGCTCTACTCCGTCTGGTGCAACTGGCTCTCCAGGTAGCTCTACTCCGTCTGG




TGCAACCGGCTCCCCAGGTAGCTCTACCCCGTCTGGTGCTACCGGCTCTCCAGGTAGC




TCTACCCCGTCTGGTGCAACCGGCTCCCCAGGTGCATCCCCGGGTACTAGCTCTACCG




GTTCTCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTACTTCTCCGAGCG




GTGAATCTTCTACCGCACCAGGTTCTACTAGCTCTACCGCTGAATCTCCGGGCCCAGGT




ACTTCTCCGAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTGAAAGCGCTACTCCGG




AGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTAC




TGAACCGTCCGAAGGTAGCGCACCAGGTTCTAGCCCTTCTGCATCTACTGGTACTGGC




CCAGGTAGCTCTACTCCTTCTGGTGCTACCGGCTCTCCAGGTGCTTCTCCGGGTACTAG




CTCTACCGGTTCTCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTACTT




CTCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACT




GCTCCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTA




CTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGG




TTCTACCAGCGAATCCCCTTCTGGTACTGCTCCAGGTTCTACCAGCGAATCCCCTTCTG




GCACCGCACCAGGTACTTCTACCCCTGAAAGCGGCTCCGCTTCTCCAGGTAGCCCGGC




AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGC




CCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTAGCCCTGCTGGCTCTC




CAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA




GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTAGCTCTACCCCGTCTGGTGCTAC




CGGTTCCCCAGGTGCTTCTCCTGGTACTAGCTCTACCGGTTCTCCAGGTAGCTCTACCC




CGTCTGGTGCTACTGGCTCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACTGCTCCA




GGTACTTCCCCTAGCGGTGAATCTTCTACTGCTCCAGGTTCTACCAGCTCTACCGCAGA




ATCTCCGGGTCCAGGTAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGCATCCC




CGGGTACCAGCTCTACCGGTTCTCCAGGTACTCCGGGTAGCGGTACCGCTTCTTCCTCT




CCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTC




CGACTTCTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGCTCCA


 


BC864
122
GGTACTTCCACCGAACCATCCGAACCAGGTAGCGCAGGTACTTCCACCGAACCATCCG




AACCTGGCAGCGCAGGTAGCGAACCGGCAACCTCTGGTACTGAACCATCAGGTAGCG




GCGCATCCGAGCCTACCTCTACTGAACCAGGTAGCGAACCGGCTACCTCCGGTACTGA




GCCATCAGGTAGCGAACCGGCAACTTCCGGTACTGAACCATCAGGTAGCGAACCGGC




AACTTCCGGCACTGAACCATCAGGTAGCGGTGCATCTGAGCCGACCTCTACTGAACCA




GGTACTTCTACTGAACCATCTGAGCCGGGCAGCGCAGGTAGCGAACCAGCTACTTCTG




GCACTGAACCATCAGGTACTTCTACTGAACCATCCGAACCAGGTAGCGCAGGTAGCGA




ACCTGCTACCTCTGGTACTGAGCCATCAGGTAGCGAACCGGCTACCTCTGGTACTGAA




CCATCAGGTACTTCTACCGAACCATCCGAGCCTGGTAGCGCAGGTACTTCTACCGAAC




CATCCGAGCCAGGCAGCGCAGGTAGCGAACCGGCAACCTCTGGCACTGAGCCATCAG




GTAGCGAACCAGCAACTTCTGGTACTGAACCATCAGGTACTAGCGAGCCATCTACTTC




CGAACCAGGTGCAGGTAGCGGCGCATCCGAACCTACTTCCACTGAACCAGGTACTAGC




GAGCCATCCACCTCTGAACCAGGTGCAGGTAGCGAACCGGCAACTTCCGGCACTGAA




CCATCAGGTAGCGAACCGGCTACCTCTGGTACTGAACCATCAGGTACTTCTACCGAAC




CATCCGAGCCTGGTAGCGCAGGTACTTCTACCGAACCATCCGAGCCAGGCAGCGCAG




GTAGCGGTGCATCCGAGCCGACCTCTACTGAACCAGGTAGCGAACCAGCAACTTCTGG




CACTGAGCCATCAGGTAGCGAACCAGCTACCTCTGGTACTGAACCATCAGGTAGCGAA




CCGGCTACTTCCGGCACTGAACCATCAGGTAGCGAACCAGCAACCTCCGGTACTGAAC




CATCAGGTACTTCCACTGAACCATCCGAACCGGGTAGCGCAGGTAGCGAACCGGCAA




CTTCCGGCACTGAACCATCAGGTAGCGGTGCATCTGAGCCGACCTCTACTGAACCAGG




TACTTCTACTGAACCATCTGAGCCGGGCAGCGCAGGTAGCGAACCTGCAACCTCCGGC




ACTGAGCCATCAGGTAGCGGCGCATCTGAACCAACCTCTACTGAACCAGGTACTTCCA




CCGAACCATCTGAGCCAGGCAGCGCAGGTAGCGGCGCATCTGAACCAACCTCTACTG




AACCAGGTAGCGAACCAGCAACTTCTGGTACTGAACCATCAGGTAGCGGCGCATCTG




AGCCTACTTCCACTGAACCAGGTAGCGAACCGGCAACTTCCGGCACTGAACCATCAGG




TAGCGGTGCATCTGAGCCGACCTCTACTGAACCAGGTACTTCTACTGAACCATCTGAG




CCGGGCAGCGCAGGTAGCGAACCGGCAACTTCCGGCACTGAACCATCAGGTAGCGGT




GCATCTGAGCCGACCTCTACTGAACCAGGTACTTCTACTGAACCATCTGAGCCGGGCA




GCGCAGGTAGCGAACCAGCTACTTCTGGCACTGAACCATCAGGTACTTCTACTGAACC




ATCCGAACCAGGTAGCGCAGGTAGCGAACCTGCTACCTCTGGTACTGAGCCATCAGGT




ACTTCTACTGAACCATCCGAGCCGGGTAGCGCAGGTACTTCCACTGAACCATCTGAAC




CTGGTAGCGCAGGTACTTCCACTGAACCATCCGAACCAGGTAGCGCAGGTACTTCTAC




TGAACCATCCGAGCCGGGTAGCGCAGGTACTTCCACTGAACCATCTGAACCTGGTAGC




GCAGGTACTTCCACTGAACCATCCGAACCAGGTAGCGCAGGTACTAGCGAACCATCCA




CCTCCGAACCAGGCGCAGGTAGCGGTGCATCTGAACCGACTTCTACTGAACCAGGTAC




TTCCACTGAACCATCTGAGCCAGGTAGCGCAGGTACTTCCACCGAACCATCCGAACCA




GGTAGCGCAGGTACTTCCACCGAACCATCCGAACCTGGCAGCGCAGGTAGCGAACCG




GCAACCTCTGGTACTGAACCATCAGGTAGCGGTGCATCCGAGCCGACCTCTACTGAAC




CAGGTAGCGAACCAGCAACTTCTGGCACTGAGCCATCAGGTAGCGAACCAGCTACCTC




TGGTACTGAACCATCAGGTAGCGAACCGGCAACCTCTGGCACTGAGCCATCAGGTAGC




GAACCAGCAACTTCTGGTACTGAACCATCAGGTACTAGCGAGCCATCTACTTCCGAAC




CAGGTGCAGGTAGCGAACCTGCAACCTCCGGCACTGAGCCATCAGGTAGCGGCGCAT




CTGAACCAACCTCTACTGAACCAGGTACTTCCACCGAACCATCTGAGCCAGGCAGCGC




AGGTAGCGAACCTGCAACCTCCGGCACTGAGCCATCAGGTAGCGGCGCATCTGAACC




AACCTCTACTGAACCAGGTACTTCCACCGAACCATCTGAGCCAGGCAGCGCA


 


BD864
123
GGTAGCGAAACTGCTACTTCCGGCTCTGAGACTGCAGGTACTAGTGAATCCGCAACTA




GCGAATCTGGCGCAGGTAGCACTGCAGGCTCTGAGACTTCCACTGAAGCAGGTACTAG




CGAGTCCGCAACCAGCGAATCCGGCGCAGGTAGCGAAACTGCTACCTCTGGCTCCGA




GACTGCAGGTAGCGAAACTGCAACCTCTGGCTCTGAAACTGCAGGTACTTCCACTGAA




GCAAGTGAAGGCTCCGCATCAGGTACTTCCACCGAAGCAAGCGAAGGCTCCGCATCA




GGTACTAGTGAGTCCGCAACTAGCGAATCCGGTGCAGGTAGCGAAACCGCTACCTCTG




GTTCCGAAACTGCAGGTACTTCTACCGAGGCTAGCGAAGGTTCTGCATCAGGTAGCAC




TGCTGGTTCCGAGACTTCTACTGAAGCAGGTACTAGCGAATCTGCTACTAGCGAATCC




GGCGCAGGTACTAGCGAATCCGCTACCAGCGAATCCGGCGCAGGTAGCGAAACTGCA




ACCTCTGGTTCCGAGACTGCAGGTACTAGCGAGTCCGCTACTAGCGAATCTGGCGCAG




GTACTTCCACTGAAGCTAGTGAAGGTTCTGCATCAGGTAGCGAAACTGCTACTTCTGG




TTCCGAAACTGCAGGTAGCGAAACCGCTACCTCTGGTTCCGAAACTGCAGGTACTTCT




ACCGAGGCTAGCGAAGGTTCTGCATCAGGTAGCACTGCTGGTTCCGAGACTTCTACTG




AAGCAGGTACTAGCGAGTCCGCTACTAGCGAATCTGGCGCAGGTACTTCCACTGAAGC




TAGTGAAGGTTCTGCATCAGGTAGCGAAACTGCTACTTCTGGTTCCGAAACTGCAGGT




AGCACTGCTGGCTCCGAGACTTCTACCGAAGCAGGTAGCACTGCAGGTTCCGAAACTT




CCACTGAAGCAGGTAGCGAAACTGCTACCTCTGGCTCTGAGACTGCAGGTACTAGCGA




ATCTGCTACTAGCGAATCCGGCGCAGGTACTAGCGAATCCGCTACCAGCGAATCCGGC




GCAGGTAGCGAAACTGCAACCTCTGGTTCCGAGACTGCAGGTACTAGCGAATCTGCTA




CTAGCGAATCCGGCGCAGGTACTAGCGAATCCGCTACCAGCGAATCCGGCGCAGGTA




GCGAAACTGCAACCTCTGGTTCCGAGACTGCAGGTAGCGAAACCGCTACCTCTGGTTC




CGAAACTGCAGGTACTTCTACCGAGGCTAGCGAAGGTTCTGCATCAGGTAGCACTGCT




GGTTCCGAGACTTCTACTGAAGCAGGTAGCGAAACTGCTACTTCCGGCTCTGAGACTG




CAGGTACTAGTGAATCCGCAACTAGCGAATCTGGCGCAGGTAGCACTGCAGGCTCTGA




GACTTCCACTGAAGCAGGTAGCACTGCTGGTTCCGAAACCTCTACCGAAGCAGGTAGC




ACTGCAGGTTCTGAAACCTCCACTGAAGCAGGTACTTCCACTGAGGCTAGTGAAGGCT




CTGCATCAGGTAGCACTGCTGGTTCCGAAACCTCTACCGAAGCAGGTAGCACTGCAGG




TTCTGAAACCTCCACTGAAGCAGGTACTTCCACTGAGGCTAGTGAAGGCTCTGCATCA




GGTAGCACTGCAGGTTCTGAGACTTCCACCGAAGCAGGTAGCGAAACTGCTACTTCTG




GTTCCGAAACTGCAGGTACTTCCACTGAAGCTAGTGAAGGTTCCGCATCAGGTACTAG




TGAGTCCGCAACCAGCGAATCCGGCGCAGGTAGCGAAACCGCAACCTCCGGTTCTGA




AACTGCAGGTACTAGCGAATCCGCAACCAGCGAATCTGGCGCAGGTACTAGTGAGTC




CGCAACCAGCGAATCCGGCGCAGGTAGCGAAACCGCAACCTCCGGTTCTGAAACTGC




AGGTACTAGCGAATCCGCAACCAGCGAATCTGGCGCAGGTAGCGAAACTGCTACTTCC




GGCTCTGAGACTGCAGGTACTTCCACCGAAGCAAGCGAAGGTTCCGCATCAGGTACTT




CCACCGAGGCTAGTGAAGGCTCTGCATCAGGTAGCACTGCTGGCTCCGAGACTTCTAC




CGAAGCAGGTAGCACTGCAGGTTCCGAAACTTCCACTGAAGCAGGTAGCGAAACTGC




TACCTCTGGCTCTGAGACTGCAGGTACTAGCGAATCTGCTACTAGCGAATCCGGCGCA




GGTACTAGCGAATCCGCTACCAGCGAATCCGGCGCAGGTAGCGAAACTGCAACCTCT




GGTTCCGAGACTGCAGGTAGCGAAACTGCTACTTCCGGCTCCGAGACTGCAGGTAGCG




AAACTGCTACTTCTGGCTCCGAAACTGCAGGTACTTCTACTGAGGCTAGTGAAGGTTC




CGCATCAGGTACTAGCGAGTCCGCAACCAGCGAATCCGGCGCAGGTAGCGAAACTGC




TACCTCTGGCTCCGAGACTGCAGGTAGCGAAACTGCAACCTCTGGCTCTGAAACTGCA




GGTACTAGCGAATCTGCTACTAGCGAATCCGGCGCAGGTACTAGCGAATCCGCTACCA




GCGAATCCGGCGCAGGTAGCGAAACTGCAACCTCTGGTTCCGAGACTGCA









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, luciferase, 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 very repetitive amino acid sequences. Codon optimization is 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 comprises 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: 124). In another embodiment, a sequencing island is the sequence 5′-AGGTCCAGAACCAACGGGGCCGGCCCCAAGCGGAGGT-3′ (SEQ ID NO: 125).
As an alternative, one can construct codon libraries where all members of the library encode the same amino acid sequence but where codon usage for the respective amino acids in the sequence 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 allows 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.
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 GH gene(s) by cloning it into the construct adjacent and in frame with the gene coding for GH or, optionally, adjacent to a spacer sequence. The invention provides various permutations of the foregoing, depending on the GHXTEN to be encoded. For example, a gene encoding a GHXTEN fusion protein comprising a GH and two XTEN, such as embodied by formula VI, as depicted above, the gene would have polynucleotides encoding GH, encoding two XTEN, which can be identical or different in composition and sequence length. In one non-limiting embodiment of the foregoing, the GH polynucleotides would encode human growth hormone and the polynucleotides encoding the N-terminus XTEN would encode AE912 and the polynucleotides encoding the C-terminus XTEN would encode AE144. The step of cloning the GH genes into the XTEN construct can occur through a ligation or multimerization step. As shown in FIG. 2, the constructs encoding GHXTEN fusion proteins can be designed in different configurations of the components XTEN 202, GH 203, and spacer sequences 204. In one embodiment, as illustrated in FIG. 2A, the construct comprises polynucleotide sequences complementary to, or those that encode a monomeric polypeptide of components in the following order (5′ to 3′) GH 203 and XTEN 202, or the reverse order. In another embodiment, as illustrated in FIG. 2B, the construct comprises polynucleotide sequences complementary to, or those that encode a monomeric polypeptide of components in the following order (5′ to 3′) GH 203, spacer sequence 204, and XTEN 202, or the reverse order. In another embodiment, as illustrated in FIG. 2C, the construct 201 encodes a monomeric GHXTEN comprising polynucleotide sequences complementary to, or those that encode components in the following order (5′ to 3′): two molecules of GH 203 and XTEN 202, or the reverse order.
In another embodiment, as illustrated in FIG. 2D, the construct comprises polynucleotide sequences complementary to, or those that encode a monomeric polypeptide of components in the following order (5′ to 3′): two molecules of GH 203, spacer sequence 204, and XTEN 202, or the reverse order. In another embodiment, as illustrated in FIG. 2E, the construct comprises polynucleotide sequences complementary to, or those that encode a monomeric polypeptide of components in the following order (5′ to 3′): GH 203, spacer sequence 204, a second molecule of GH 203, and XTEN 202, or the reverse order. In another embodiment, as illustrated in FIG. 2F, the construct comprises polynucleotide sequences complementary to, or those that encode a monomeric polypeptide of components in the following order (5′ to 3′): GH 203, XTEN 202, GH 203, and a second XTEN 202, or the reverse sequence. The spacer polynucleotides can optionally comprise sequences encoding cleavage sequences. As will be apparent to those of skill in the art, other permutations 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 7, 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 GHXTEN sequences under stringent conditions, such as those described herein.
The resulting polynucleotides encoding the GHXTEN chimeric fusion proteins can then be individually cloned into an expression vector. The nucleic acid sequence is 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 which 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. The invention provides for the use of plasmid vectors containing replication and control sequences that are compatible with and recognized by the host cell, and are operably linked to the GHXTEN gene for controlled expression of the GHXTEN fusion proteins. The vector ordinarily carries a replication site, as well as sequences that encode proteins that are capable of providing phenotypic selection in transformed 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. “Expression vector” refers to a DNA construct containing a DNA sequence that is operably linked to a suitable control sequence capable of effecting the expression of the DNA encoding the fusion protein in a suitable host. Such control sequences include a promoter to effect transcription, an optional operator sequence to control such transcription, a sequence encoding suitable mRNA ribosome binding sites, and sequences that control termination of transcription and translation. Other 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)], all would be operably linked to the DNA encoding GHXTEN polypeptides. Promoters for use in bacterial systems can also contain a Shine-Dalgarno (S.D.) sequence, operably linked to the DNA encoding GHXTEN polypeptides.
The invention contemplates use of other expression systems including, for example, a baculovirus expression system with both non-fusion transfer vectors, such as, but not limited to pVL941 Summers, et al., Virology 84:390-402 (1978)), pVL1393 (Invitrogen), pVL1392 (Summers, et al., Virology 84:390-402 (1978) and Invitrogen) and pBlueBacIII (Invitrogen), and fusion transfer vectors such as, but not limited to, pAc700 (Summers, et al., Virology 84:390-402 (1978)), pAc701 and pAc70-2 (same as pAc700, with different reading frames), pAc360 Invitrogen) and pBlueBacHisA, B, C (Invitrogen) can be used.
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 (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 (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 (Invitrogen), pCEP4 (Invitrogen), pMEP4 (Invitrogen), pREP8 (Invitrogen), pREP9 (Invitrogen), and pEBVHis (Invitrogen).
Selectable mammalian expression vectors for use in the invention include, but are not limited to, pRc/CMV (Invitrogen), pRc/RSV (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, pMJ601 pTKgptFlSand 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 (Invitrogen), the fusion pYESHisA, B, C (Invitrogen), pRS vectors and the like.
In addition, the expression vector containing the chimeric GHXTEN 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 GHXTEN fusion protein composition is 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 GHXTEN sequence, separated by a protease cleavage site. While any leader peptide sequence which 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: 126), 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: 127)), Factor Xa (IDGR (SEQ ID NO: 128)), thrombin (LVPRGS (SEQ ID NO: 129)), PreScissionTM (LEVLFQGP (SEQ ID NO: 130)), TEV protease (EQLYFQG (SEQ ID NO: 131)), 3C protease (ETLFQGP (SEQ ID NO: 132)), Sortase A (LPETG (SEQ ID NO: 133)), Granzyme B (D/X, N/X, M/N or SA), inteins, SUMO, DAPase (TAGZymeTM), 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 cases, the invention provides constructs and methods of making constructs comprising an polynucleotide sequence optimized for expression that encodes at least about 20 to about 60 amino acids with XTEN characteristics that can be included at the N-terminus of an XTEN carrier encoding sequence (in other words, the polynucleotides encoding the 20-60 encoded optimized amino acids are linked in frame to polynucleotides encoding an XTEN component that is N-terminal to GH) 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 AE912. In another embodiment of the foregoing, the optimized polynucleotide encodes an XTEN sequence with at least about 90% sequence identity to AM923. In another embodiment of the foregoing, the optimized polynucleotide encodes an XTEN sequence with at least about 90% sequence identity to AE48. In another embodiment of the foregoing, the optimized polynucleotide encodes an XTEN sequence with at least about 90% sequence identity to AM48. In one embodiment, the optimized polynucleotide NTS comprises a sequence that exhibits at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, sequence identity to a sequence or its complement selected from







AE 48:


(SEQ ID NO: 134)


5′-ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACCCC


 


GGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTG


 


CAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAGCTCTACCGGTTCTCC


 


A-3′


and


 


AM 48:


(SEQ ID NO: 135)


5′-ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTGCATC


 


CCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTGGTG


 


CTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCTCC


 


A-3′






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 kallikrein, plasma kallikrein, trypsin, pepsin, chymotrypsin, thrombin, and matrix metalloproteinases, or the proteases of Table 6.
In this manner, a chimeric DNA molecule coding for a monomeric GHXTEN 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 of GHXTEN.
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'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 GH polypeptide or against a synthetic peptide based on the DNA sequences provided herein or against exogenous sequence fused to GH and encoding a specific antibody 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 GHXTEN polypeptide 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 GHXTEN 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).
VIII). Pharmaceutical Compositions
The present invention provides pharmaceutical compositions comprising GHXTEN. In one embodiment, the pharmaceutical composition comprises the GHXTEN fusion protein and at least one pharmaceutically acceptable carrier. GHXTEN polypeptides 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's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980), in the form of lyophilized formulations or aqueous solutions.
The pharmaceutical compositions can be administered orally, intranasally, parenterally or by inhalation therapy, and may take the form of tablets, lozenges, granules, capsules, pills, ampoules, suppositories or aerosol form. They may also take the form of suspensions, solutions and emulsions of the active ingredient in aqueous or nonaqueous diluents, syrups, granulates or powders. In addition, the pharmaceutical compositions can also contain other pharmaceutically active compounds or a plurality of compounds of the invention.
More particularly, the present 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 one embodiment, the pharmaceutical composition is administered subcutaneously. 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.
Extended release formulations useful in the present invention may be oral formulations comprising a matrix and a coating composition. Suitable matrix materials may include waxes (e.g., camauba, bees wax, paraffin wax, ceresine, shellac wax, fatty acids, and fatty alcohols), oils, hardened oils or fats (e.g., hardened rapeseed oil, castor oil, beef tallow, palm oil, and soya bean oil), and polymers (e.g., hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, and polyethylene glycol). Other suitable matrix tabletting materials are microcrystalline cellulose, powdered cellulose, hydroxypropyl cellulose, ethyl cellulose, with other carriers, and fillers. Tablets may also contain granulates, coated powders, or pellets. Tablets may also be multi-layered. Multi-layered tablets are especially preferred when the active ingredients have markedly different pharmacokinetic profiles. Optionally, the finished tablet may be coated or uncoated.
The coating composition may comprise an insoluble matrix polymer and/or a water soluble material. Water soluble materials can be polymers such as polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, or monomeric materials such as sugars (e.g., lactose, sucrose, fructose, mannitol and the like), salts (e.g., sodium chloride, potassium chloride and the like), organic acids (e.g., fumaric acid, succinic acid, lactic acid, and tartaric acid), and mixtures thereof. Optionally, an enteric polymer may be incorporated into the coating composition. Suitable enteric polymers include hydroxypropyl methyl cellulose, acetate succinate, hydroxypropyl methyl cellulose, phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, and polymethacrylates containing carboxyl groups. The coating composition may be plasticised by adding suitable plasticisers such as, for example, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutylsebacate, and castor oil. The coating composition may also include a filler, which can be an insoluble material such as silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch, powdered cellulose, MCC, or polacrilin potassium. The coating composition may be applied as a solution or latex in organic solvents or aqueous solvents or mixtures thereof. Solvents such as water, lower alcohol, lower chlorinated hydrocarbons, ketones, or mixtures thereof may be used.
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 K100M, Premium CR Methocel K100M, 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, propionates, 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.
In another embodiment, the compositions of the present invention are encapsulated in liposomes, which have demonstrated utility in delivering beneficial active agents in a controlled manner over prolonged periods of time. Liposomes are closed bilayer membranes containing an entrapped aqueous volume. Liposomes may also be unilamellar vesicles possessing a single membrane bilayer or multilamellar vesicles with multiple membrane bilayers, each separated from the next by an aqueous layer. The structure of the resulting membrane bilayer is such that the hydrophobic (non-polar) tails of the lipid are oriented toward the center of the bilayer while the hydrophilic (polar) heads orient towards the aqueous phase. In one embodiment, the liposome may be coated with a flexible water soluble polymer that avoids uptake by the organs of the mononuclear phagocyte system, primarily the liver and spleen. Suitable hydrophilic polymers for surrounding the liposomes include, without limitation, PEG, polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxethylacrylate, hydroxymethylcellulose hydroxyethylcellulose, polyethyleneglycol, polyaspartamide and hydrophilic peptide sequences as described in U.S. Pat. Nos. 6,316,024; 6,126,966; 6,056,973; 6,043,094, the contents of which are incorporated by reference in their entirety.
Liposomes may be comprised of any lipid or lipid combination known in the art. For example, the vesicle-forming lipids may be naturally-occurring or synthetic lipids, including phospholipids, such as phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phasphatidylglycerol, phosphatidylinositol, and sphingomyelin as disclosed in U.S. Pat. Nos. 6,056,973 and 5,874,104. The vesicle-forming lipids may also be glycolipids, cerebrosides, or cationic lipids, such as 1,2-dioleyloxy-3-(trimethylamino) propane (DOTAP); N-[1-(2,3,-ditetradecyloxy)propyl-N,N-dimethyl-N-hydroxyethylammonium bromide (DMRIE); N-[1 [(2,3,-dioleyloxy)propyl]-N,N-dimethyl-N-hydroxy ethylammonium bromide (DORIE); N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA); 3 [N-(N′,N′-dimethylaminoethane) carbamoly] cholesterol (DC-Chol); or dimethyldioctadecylammonium (DDAB) also as disclosed in U.S. Pat. No. 6,056,973. Cholesterol may also be present in the proper range to impart stability to the vesicle as disclosed in U.S. Pat. Nos. 5,916,588 and 5,874,104.
Additional liposomal technologies are described in U.S. Pat. Nos. 6,759,057; 6,406,713; 6,352,716; 6,316,024; 6,294,191; 6,126,966; 6,056,973; 6,043,094; 5,965,156; 5,916,588; 5,874,104; 5,215,680; and 4,684,479, the contents of which are incorporated herein by reference. These describe liposomes and lipid-coated microbubbles, and methods for their manufacture. Thus, one skilled in the art, considering both the disclosure of this invention and the disclosures of these other patents could produce a liposome for the extended release of the polypeptides of the present invention.
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.
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.
Osmotic pumps may be used as slow release agents in the form of tablets, pills, capsules or implantable devices. Osmotic pumps are well known in the art and readily available to one of ordinary skill in the art from companies experienced in providing osmotic pumps for extended release drug delivery. Examples are ALZA's DUROSTM; ALZA's OROSTM; Osmotica Pharmaceutical's OsmodexTM system; Shire Laboratories' EnSoTrolTM system; and AlzetTM. Patents that describe osmotic pump technology are U.S. Pat. Nos. 6,890,918; 6,838,093; 6,814,979; 6,713,086; 6,534,090; 6,514,532; 6,361,796; 6,352,721; 6,294,201; 6,284,276; 6,110,498; 5,573,776; 4,200,0984; and 4,088,864, 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 an osmotic pump for the extended release of the polypeptides of the present invention.
Syringe pumps may also be used as slow release agents. 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. A.
IX). Pharmaceutical Kits
In another aspect, the invention provides a kit to facilitate the use of the GHXTEN polypeptides. The kit comprises the pharmaceutical composition provided herein, a label identifying the pharmaceutical composition, and an instruction for storage, reconstitution and/or administration of the pharmaceutical compositions to a subject. In some embodiment, the kit comprises, preferably: (a) an amount of a GHXTEN fusion protein composition sufficient to treat a disease, condition or disorder upon administration to a subject in need thereof; 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 GHXTEN drug and storage and handling conditions, and a sheet of the approved indications for the drug, instructions for the reconstitution and/or administration of the GHXTEN 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 of the foregoing, the kit can comprise a second container that can carry a suitable diluent for the GHXTEN composition, which will provide the user with the appropriate concentration of GHXTEN 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: 136), GSEGSSGPGESS (SEQ ID NO: 137), GSSESGSSEGGP (SEQ ID NO: 138), or GSGGEPSESGSS (SEQ ID NO: 139). The insert was obtained by annealing the following pairs of phosphorylated synthetic oligonucleotide pairs:









(SEQ ID NO: 140)



AD1for: AGGTGAATCTCCDGGTGGYTCYAGCGGTTCYGARTC


 



(SEQ ID NO: 141)



AD1rev: ACCTGAYTCRGAACCGCTRGARCCACCHGGAGATTC


 



(SEQ ID NO: 142)



AD2for: AGGTAGCGAAGGTTCTTCYGGTCCDGGYGARTCYTC


 



(SEQ ID NO: 143)



AD2rev: ACCTGARGAYTCRCCHGGACCRGAAGAACCTTCGCT


 



(SEQ ID NO: 144)



AD3for: AGGTTCYTCYGAAAGCGGTTCTTCYGARGGYGGTCC


 



(SEQ ID NO: 145)



AD3rev: ACCTGGACCRCCYTCRGAAGAACCGCTTTCRGARGA


 



(SEQ ID NO: 146)



AD4for: AGGTTCYGGTGGYGAACCDTCYGARTCTGGTAGCTC






We also annealed the phosphorylated oligonucleotide 3KpnIstopperFor: AGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 147) and the non-phosphorylated oligonucleotide pr_3KpnIstopperRev: CCTCGAGTGAAGACGA (SEQ ID NO: 148). 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 for these segments are listed in Table 8.







TABLE 8







DNA and Amino Acid Sequences for 36-mer motifs











File name
Amino acid sequence
SEQ ID NO:
Nucleotide sequence
SEQ ID NO:





LCW0401_001_GFP-
GSGGEPSESGSSGESPGG
149
GGTTCTGGTGGCGAACCGTCCGAGTCTGGTAGC
150


N_A01.ab1
SSGSESGESPGGSSGSES

TCAGGTGAATCTCCGGGTGGCTCTAGCGGTTCC






GAGTCAGGTGAATCTCCTGGTGGTTCCAGCGGT






TCCGAGTCA



 


LCW0401_002_GFP-
GSEGSSGPGESSGESPGG
151
GGTAGCGAAGGTTCTTCTGGTCCTGGCGAGTCT
152


N_B01.ab1
SSGSESGSSESGSSEGGP

TCAGGTGAATCTCCTGGTGGTTCCAGCGGTTCT






GAATCAGGTTCCTCCGAAAGCGGTTCTTCCGAG






GGCGGTCCA



 


LCW0401_003_GFP-
GSSESGSSEGGPGSSESG
153
GGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGT
154


N_C01.ab1
SSEGGPGESPGGSSGSES

CCAGGTTCCTCTGAAAGCGGTTCTTCTGAGGGT






GGTCCAGGTGAATCTCCGGGTGGCTCCAGCGGT






TCCGAGTCA



 


LCW0401_004_GFP-
GSGGEPSESGSSGSSESG
155
GGTTCCGGTGGCGAACCGTCTGAATCTGGTAGC
156


N_D01.ab1
SSEGGPGSGGEPSESGSS

TCAGGTTCTTCTGAAAGCGGTTCTTCCGAGGGT






GGTCCAGGTTCTGGTGGTGAACCTTCCGAGTCT






GGTAGCTCA



 


LCW0401_007_GFP-
GSSESGSSEGGPGSEGSS
157
GGTTCTTCCGAAAGCGGTTCTTCTGAGGGTGGT
158


N_F01.ab1
GPGESSGSEGSSGPGESS

CCAGGTAGCGAAGGTTCTTCCGGTCCAGGTGAG






TCTTCAGGTAGCGAAGGTTCTTCTGGTCCTGGT






GAATCTTCA



 


LCW0401_008_GFP-
GSSESGSSEGGPGESPGG
159
GGTTCCTCTGAAAGCGGTTCTTCCGAGGGTGGT
160


N_G01.ab1
SSGSESGSEGSSGPGESS

CCAGGTGAATCTCCAGGTGGTTCCAGCGGTTCT






GAGTCAGGTAGCGAAGGTTCTTCTGGTCCAGGT






GAATCCTCA



 


LCW0401_012_GFP-
GSGGEPSESGSSGSGGEP
161
GGTTCTGGTGGTGAACCGTCTGAGTCTGGTAGC
162


N_H01.ab1
SESGSSGSEGSSGPGESS

TCAGGTTCCGGTGGCGAACCATCCGAATCTGGT






AGCTCAGGTAGCGAAGGTTCTTCCGGTCCAGGT






GAGTCTTCA



 


LCW0401_015_GFP-
GSSESGSSEGGPGSEGSS
163
GGTTCTTCCGAAAGCGGTTCTTCCGAAGGCGGT
164


N_A02.ab1
GPGESSGESPGGSSGSES

CCAGGTAGCGAAGGTTCTTCTGGTCCAGGCGAA






TCTTCAGGTGAATCTCCTGGTGGCTCCAGCGGT






TCTGAGTCA



 


LCW0401_016_GFP-
GSSESGSSEGGPGSSESG
165
GGTTCCTCCGAAAGCGGTTCTTCTGAGGGCGGT
166


N_B02.ab1
SSEGGPGSSESGSSEGGP

CCAGGTTCCTCCGAAAGCGGTTCTTCCGAGGGC






GGTCCAGGTTCTTCTGAAAGCGGTTCTTCCGAG






GGCGGTCCA



 


LCW0401_020_GFP-
GSGGEPSESGSSGSEGSS
167
GGTTCCGGTGGCGAACCGTCCGAATCTGGTAGC
168


N_E02.ab1
GPGESSGSSESGSSEGGP

TCAGGTAGCGAAGGTTCTTCTGGTCCAGGCGAA






TCTTCAGGTTCCTCTGAAAGCGGTTCTTCTGAG






GGCGGTCCA



 


LCW0401_022_GFP-
GSGGEPSESGSSGSSESG
169
GGTTCTGGTGGTGAACCGTCCGAATCTGGTAGC
170


N_F02.ab1
SSEGGPGSGGEPSESGSS

TCAGGTTCTTCCGAAAGCGGTTCTTCTGAAGGT






GGTCCAGGTTCCGGTGGCGAACCTTCTGAATCT






GGTAGCTCA



 


LCW0401_024_GFP-
GSGGEPSESGSSGSSESG
171
GGTTCTGGTGGCGAACCGTCCGAATCTGGTAGC
172


N_G02.ab1
SSEGGPGESPGGSSGSES

TCAGGTTCCTCCGAAAGCGGTTCTTCTGAAGGT






GGTCCAGGTGAATCTCCAGGTGGTTCTAGCGGT






TCTGAATCA



 


LCW0401_026_GFP-
GSGGEPSESGSSGESPGG
173
GGTTCTGGTGGCGAACCGTCTGAGTCTGGTAGC
174


N_H02.ab1
SSGSESGSEGSSGPGESS

TCAGGTGAATCTCCTGGTGGCTCCAGCGGTTCT






GAATCAGGTAGCGAAGGTTCTTCTGGTCCTGGT






GAATCTTCA



 


LCW0401_027_GFP-
GSGGEPSESGSSGESPGG
175
GGTTCCGGTGGCGAACCTTCCGAATCTGGTAGC
176


N_A03.ab1
SSGSESGSGGEPSESGSS

TCAGGTGAATCTCCGGGTGGTTCTAGCGGTTCT






GAGTCAGGTTCTGGTGGTGAACCTTCCGAGTCT






GGTAGCTCA



 


LCW0401_028_GFP-
GSSESGSSEGGPGSSESG
177
GGTTCCTCTGAAAGCGGTTCTTCTGAGGGCGGT
178


N_B03.ab1
SSEGGPGSSESGSSEGGP

CCAGGTTCTTCCGAAAGCGGTTCTTCCGAGGGC






GGTCCAGGTTCTTCCGAAAGCGGTTCTTCTGAA






GGCGGTCCA



 


LCW0401_030_GFP-
GESPGGSSGSESGSEGSS
179
GGTGAATCTCCGGGTGGCTCCAGCGGTTCTGAG
180


N_C03.ab1
GPGESSGSEGSSGPGESS

TCAGGTAGCGAAGGTTCTTCCGGTCCGGGTGAG






TCCTCAGGTAGCGAAGGTTCTTCCGGTCCTGGT






GAGTCTTCA



 


LCW0401_031_GFP-
GSGGEPSESGSSGSGGEP
181
GGTTCTGGTGGCGAACCTTCCGAATCTGGTAGC
182


N_D03.ab1
SESGSSGSSESGSSEGGP

TCAGGTTCCGGTGGTGAACCTTCTGAATCTGGT






AGCTCAGGTTCTTCTGAAAGCGGTTCTTCCGAG






GGCGGTCCA



 


LCW0401_033_GFP-
GSGGEPSESGSSGSGGEP
183
GGTTCCGGTGGTGAACCTTCTGAATCTGGTAGC
184


N_E03.ab1
SESGSSGSGGEPSESGSS

TCAGGTTCCGGTGGCGAACCATCCGAGTCTGGT






AGCTCAGGTTCCGGTGGTGAACCATCCGAGTCT






GGTAGCTCA



 


LCW0401_037_GFP-
GSGGEPSESGSSGSSESG
185
GGTTCCGGTGGCGAACCTTCTGAATCTGGTAGC
186


N_F03.ab1
SSEGGPGSEGSSGPGESS

TCAGGTTCCTCCGAAAGCGGTTCTTCTGAGGGC






GGTCCAGGTAGCGAAGGTTCTTCTGGTCCGGGC






GAGTCTTCA



 


LCW0401_038_GFP-
GSGGEPSESGSSGSEGSS
187
GGTTCCGGTGGTGAACCGTCCGAGTCTGGTAGC
188


N_G03.ab1
GPGESSGSGGEPSESGSS

TCAGGTAGCGAAGGTTCTTCTGGTCCGGGTGAG






TCTTCAGGTTCTGGTGGCGAACCGTCCGAATCT






GGTAGCTCA



 


LCW0401_039_GFP-
GSGGEPSESGSSGESPGG
189
GGTTCTGGTGGCGAACCGTCCGAATCTGGTAGC
190


N_H03.ab1
SSGSESGSGGEPSESGSS

TCAGGTGAATCTCCTGGTGGTTCCAGCGGTTCC






GAGTCAGGTTCTGGTGGCGAACCTTCCGAATCT






GGTAGCTCA



 


LCW0401_040_GFP-
GSSESGSSEGGPGSGGEP
191
GGTTCTTCCGAAAGCGGTTCTTCCGAGGGCGGT
192


N_A04.ab1
SESGSSGSSESGSSEGGP

CCAGGTTCCGGTGGTGAACCATCTGAATCTGGT






AGCTCAGGTTCTTCTGAAAGCGGTTCTTCTGAA






GGTGGTCCA



 


LCW0401_042_GFP-
GSEGSSGPGESSGESPGG
193
GGTAGCGAAGGTTCTTCCGGTCCTGGTGAGTCT
194


N_C04.ab1
SSGSESGSEGSSGPGESS

TCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCC






GAGTCAGGTAGCGAAGGTTCTTCTGGTCCTGGC






GAGTCCTCA



 


LCW0401_046_GFP-
GSSESGSSEGGPGSSESG
195
GGTTCCTCTGAAAGCGGTTCTTCCGAAGGCGGT
196


N_D04.ab1
SSEGGPGSSESGSSEGGP

CCAGGTTCTTCCGAAAGCGGTTCTTCTGAGGGC






GGTCCAGGTTCCTCCGAAAGCGGTTCTTCTGAG






GGTGGTCCA



 


LCW0401_047_GFP-
GSGGEPSESGSSGESPGG
197
GGTTCTGGTGGCGAACCTTCCGAGTCTGGTAGC
198


N_E04.ab1
SSGSESGESPGGSSGSES

TCAGGTGAATCTCCGGGTGGTTCTAGCGGTTCC






GAGTCAGGTGAATCTCCGGGTGGTTCCAGCGGT






TCTGAGTCA



 


LCW0401_051_GFP-
GSGGEPSESGSSGSEGSS
199
GGTTCTGGTGGCGAACCATCTGAGTCTGGTAGC
200


N_F04.ab1
GPGESSGESPGGSSGSES

TCAGGTAGCGAAGGTTCTTCCGGTCCAGGCGAG






TCTTCAGGTGAATCTCCTGGTGGCTCCAGCGGT






TCTGAGTCA



 


LCW0401_053_GFP-
GESPGGSSGSESGESPGG
201
GGTGAATCTCCTGGTGGTTCCAGCGGTTCCGAG
202


N_H04.ab1
SSGSESGESPGGSSGSES

TCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCC






GAGTCAGGTGAATCTCCTGGTGGTTCTAGCGGT






TCTGAATCA



 


LCW0401_054_GFP-
GSEGSSGPGESSGSEGSS
203
GGTAGCGAAGGTTCTTCCGGTCCAGGTGAATCT
204


N_A05.ab1
GPGESSGSGGEPSESGSS

TCAGGTAGCGAAGGTTCTTCTGGTCCTGGTGAA






TCCTCAGGTTCCGGTGGCGAACCATCTGAATCT






GGTAGCTCA



 


LCW0401_059_GFP-
GSGGEPSESGSSGSEGSS
205
GGTTCTGGTGGCGAACCATCCGAATCTGGTAGC
206


N_D05.ab1
GPGESSGESPGGSSGSES

TCAGGTAGCGAAGGTTCTTCTGGTCCTGGCGAA






TCTTCAGGTGAATCTCCAGGTGGCTCTAGCGGT






TCCGAATCA



 


LCW0401_060_GFP-
GSGGEPSESGSSGSSESG
207
GGTTCCGGTGGTGAACCGTCCGAATCTGGTAGC
208


N_E05.ab1
SSEGGPGSGGEPSESGSS

TCAGGTTCCTCTGAAAGCGGTTCTTCCGAGGGT






GGTCCAGGTTCCGGTGGTGAACCTTCTGAGTCT






GGTAGCTCA



 


LCW0401_061_GFP-
GSSESGSSEGGPGSGGEP
209
GGTTCCTCTGAAAGCGGTTCTTCTGAGGGCGGT
210


N_F05.ab1
SESGSSGSEGSSGPGESS

CCAGGTTCTGGTGGCGAACCATCTGAATCTGGT






AGCTCAGGTAGCGAAGGTTCTTCCGGTCCGGGT






GAATCTTCA



 


LCW0401_063_GFP-
GSGGEPSESGSSGSEGSS
211
GGTTCTGGTGGTGAACCGTCCGAATCTGGTAGC
212


N_H05.ab1
GPGESSGSEGSSGPGESS

TCAGGTAGCGAAGGTTCTTCTGGTCCTGGCGAG






TCTTCAGGTAGCGAAGGTTCTTCTGGTCCTGGT






GAATCTTCA



 


LCW0401_066_GFP-
GSGGEPSESGSSGSSESG
213
GGTTCTGGTGGCGAACCATCCGAGTCTGGTAGC
214


N_B06.ab1
SSEGGPGSGGEPSESGSS

TCAGGTTCTTCCGAAAGCGGTTCTTCCGAAGGC






GGTCCAGGTTCTGGTGGTGAACCGTCCGAATCT






GGTAGCTCA



 


LCW0401_067_GFP-
GSGGEPSESGSSGESPGG
215
GGTTCCGGTGGCGAACCTTCCGAATCTGGTAGC
216


N_C06.ab1
SSGSESGESPGGSSGSES

TCAGGTGAATCTCCGGGTGGTTCTAGCGGTTCC






GAATCAGGTGAATCTCCAGGTGGTTCTAGCGGT






TCCGAATCA



 


LCW0401_069_GFP-
GSGGEPSESGSSGSGGEP
217
GGTTCCGGTGGTGAACCATCTGAGTCTGGTAGC
218


N_D06.ab1
SESGSSGESPGGSSGSES

TCAGGTTCCGGTGGCGAACCGTCCGAGTCTGGT






AGCTCAGGTGAATCTCCGGGTGGTTCCAGCGGT






TCCGAATCA



 


LCW0401_070_GFP-
GSEGSSGPGESSGSSESG
219
GGTAGCGAAGGTTCTTCTGGTCCGGGCGAATCC
220


N_E06.ab1
SSEGGPGSEGSSGPGESS

TCAGGTTCCTCCGAAAGCGGTTCTTCCGAAGGT






GGTCCAGGTAGCGAAGGTTCTTCCGGTCCTGGT






GAATCTTCA



 


LCW0401_078_GFP-
GSSESGSSEGGPGESPGG
221
GGTTCCTCTGAAAGCGGTTCTTCTGAAGGCGGT
222


N_F06.ab1
SSGSESGESPGGSSGSES

CCAGGTGAATCTCCGGGTGGCTCCAGCGGTTCT






GAATCAGGTGAATCTCCTGGTGGCTCCAGCGGT






TCCGAGTCA



 


LCW0401_079_GFP-
GSEGSSGPGESSGSEGSS
223
GGTAGCGAAGGTTCTTCTGGTCCAGGCGAGTCT
224


N_G06.ab1
GPGESSGSGGEPSESGSS

TCAGGTAGCGAAGGTTCTTCCGGTCCTGGCGAG






TCTTCAGGTTCCGGTGGCGAACCGTCCGAATCT






GGTAGCTCA









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: 225), GSEPATSGSE TP (SEQ ID NO: 226), GTSESA TPESGP (SEQ ID NO: 227), or GTSTEPSEGSAP (SEQ ID NO: 228). The insert was obtained by annealing the following pairs of phosphorylated synthetic oligonucleotide pairs:









(SEQ ID NO: 229)



AE1for: AGGTAGCCCDGCWGGYTCTCCDACYTCYACYGARGA


 



(SEQ ID NO: 230)



AE1rev: ACCTTCYTCRGTRGARGTHGGAGARCCWGCHGGGCT


 



(SEQ ID NO: 231)



AE2for: AGGTAGCGAACCKGCWACYTCYGGYTCTGARACYCC


 



(SEQ ID NO: 232)



AE2rev: ACCTGGRGTYTCAGARCCRGARGTWGCMGGTTCGCT


 



(SEQ ID NO: 233)



AE3for: AGGTACYTCTGAAAGCGCWACYCCKGARTCYGGYCC


 



(SEQ ID NO: 234)



AE3rev: ACCTGGRCCRGAYTCMGGRGTWGCGCTTTCAGARGT


 



(SEQ ID NO: 235)



AE4for: AGGTACYTCTACYGAACCKTCYGARGGYAGCGCWCC


 



(SEQ ID NO: 236)



AE4rev: ACCTGGWGCGCTRCCYTCRGAMGGTTCRGTAGARGT






We also annealed the phosphorylated oligonucleotide 3KpnIstopperFor: AGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 237) and the non-phosphorylated oligonucleotide pr_3KpnIstopperRev: CCTCGAGTGAAGACGA (SEQ ID NO: 238). 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 for these segments are listed in Table 9.







TABLE 9







DNA and Amino Acid Sequences for 36-mer motifs











File name
Amino acid sequence
SEQ ID NO:
Nucleotide sequence
SEQ ID NO:





LCW0402_002_GFP-
GSPAGSPTSTEEGTSE
239
GGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAA
240


N_A07.ab1
SATPESGPGTSTEPSE

GGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCA




GSAP

GGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA



 


LCW0402_003_GFP-
GTSTEPSEGSAPGTST
241
GGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCA
242


N_B07.ab1
EPSEGSAPGTSTEPSE

GGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCA




GSAP

GGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCA



 


LCW0402_004_GFP-
GTSTEPSEGSAPGTSE
243
GGTACCTCTACCGAACCGTCTGAAGGTAGCGCACCA
244


N_C07.ab1
SATPESGPGTSESATP

GGTACCTCTGAAAGCGCAACTCCTGAGTCCGGTCCA




ESGP

GGTACTTCTGAAAGCGCAACCCCGGAGTCTGGCCCA



 


LCW0402_005_GFP-
GTSTEPSEGSAPGTSE
245
GGTACTTCTACTGAACCGTCTGAAGGTAGCGCACCA
246


N_D07.ab1
SATPESGPGTSESATP

GGTACTTCTGAAAGCGCAACCCCGGAATCCGGCCCA




ESGP

GGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCA



 


LCW0402_006_GFP-
GSEPATSGSETPGTSE
247
GGTAGCGAACCGGCAACCTCCGGCTCTGAAACCCCA
248


N_E07.ab1
SATPESGPGSPAGSPT

GGTACCTCTGAAAGCGCTACTCCTGAATCCGGCCCA




STEE

GGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAA



 


LCW0402_008_GFP-
GTSESATPESGPGSEP
249
GGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCA
250


N_F07.ab1
ATSGSETPGTSTEPSE

GGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCA




GSAP

GGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA



 


LCW0402_009_GFP-
GSPAGSPTSTEEGSPA
251
GGTAGCCCGGCTGGCTCTCCAACCTCCACTGAGGAA
252


N_G07.ab1
GSPTSTEEGSEPATSG

GGTAGCCCGGCTGGCTCTCCAACCTCCACTGAAGAA




SETP

GGTAGCGAACCGGCTACCTCCGGCTCTGAAACTCCA



 


LCW0402_011_GFP-
GSPAGSPTSTEEGTSE
253
GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAA
254


N_A08.ab1
SATPESGPGTSTEPSE

GGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




GSAP

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCA



 


LCW0402_012_GFP-
GSPAGSPTSTEEGSPA
255
GGTAGCCCTGCTGGCTCTCCGACTTCTACTGAGGAA
256


N_B08.ab1
GSPTSTEEGTSTEPSE

GGTAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAA




GSAP

GGTACTTCTACCGAACCTTCCGAAGGTAGCGCTCCA



 


LCW0402_013_GFP-
GTSESATPESGPGTST
257
GGTACTTCTGAAAGCGCTACTCCGGAGTCCGGTCCA
258


N_C08.ab1
EPSEGSAPGTSTEPSE

GGTACCTCTACCGAACCGTCCGAAGGCAGCGCTCCA




GSAP

GGTACTTCTACTGAACCTTCTGAGGGTAGCGCTCCA



 


LCW0402_014_GFP-
GTSTEPSEGSAPGSPA
259
GGTACCTCTACCGAACCTTCCGAAGGTAGCGCTCCA
260


N_D08.ab1
GSPTSTEEGTSTEPSE

GGTAGCCCGGCAGGTTCTCCTACTTCCACTGAGGAA




GSAP

GGTACTTCTACCGAACCTTCTGAGGGTAGCGCACCA



 


LCW0402_015_GFP-
GSEPATSGSETPGSPA
261
GGTAGCGAACCGGCTACTTCCGGCTCTGAGACTCCA
262


N_E08.ab1
GSPTSTEEGTSESATP

GGTAGCCCTGCTGGCTCTCCGACCTCTACCGAAGAA




ESGP

GGTACCTCTGAAAGCGCTACCCCTGAGTCTGGCCCA



 


LCW0402_016_GFP-
GTSTEPSEGSAPGTSE
263
GGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCA
264


N_F08.ab1
SATPESGPGTSESATP

GGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCA




ESGP

GGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCA



 


LCW0402_020_GFP-
GTSTEPSEGSAPGSEP
265
GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCA
266


N_G08.ab1
ATSGSETPGSPAGSPT

GGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCCA




STEE

GGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAA



 


LCW0402_023_GFP-
GSPAGSPTSTEEGTSE
267
GGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAA
268


N_A09.ab1
SATPESGPGSEPATSG

GGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCA




SETP

GGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCA



 


LCW0402_024_GFP-
GTSESATPESGPGSPA
269
GGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCA
270


N_B09.ab1
GSPTSTEEGSPAGSPT

GGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAA




STEE

GGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAA



 


LCW0402_025_GFP-
GTSTEPSEGSAPGTSE
271
GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
272


N_C09.ab1
SATPESGPGTSTEPSE

GGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCA




GSAP

GGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA



 


LCW0402_026_GFP-
GSPAGSPTSTEEGTST
273
GGTAGCCCGGCAGGCTCTCCGACTTCCACCGAGGAA
274


N_D09.ab1
EPSEGSAPGSEPATSG

GGTACCTCTACTGAACCTTCTGAGGGTAGCGCTCCA




SETP

GGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCA



 


LCW0402_027_GFP-
GSPAGSPTSTEEGTST
275
GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAA
276


N_E09.ab1
EPSEGSAPGTSTEPSE

GGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCA




GSAP

GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA



 


LCW0402_032_GFP-
GSEPATSGSETPGTSE
277
GGTAGCGAACCTGCTACCTCCGGTTCTGAAACCCCA
278


N_H09.ab1
SATPESGPGSPAGSPT

GGTACCTCTGAAAGCGCAACTCCGGAGTCTGGTCCA




STEE

GGTAGCCCTGCAGGTTCTCCTACCTCCACTGAGGAA



 


LCW0402_034_GFP-
GTSESATPESGPGTST
279
GGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCA
280


N_A10.ab1
EPSEGSAPGTSTEPSE

GGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCA




GSAP

GGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA



 


LCW0402_036_GFP-
GSPAGSPTSTEEGTST
281
GGTAGCCCGGCTGGTTCTCCGACTTCCACCGAGGAA
282


N_C10.ab1
EPSEGSAPGTSTEPSE

GGTACCTCTACTGAACCTTCTGAGGGTAGCGCTCCA




GSAP

GGTACCTCTACTGAACCTTCCGAAGGCAGCGCTCCA



 


LCW0402_039_GFP-
GTSTEPSEGSAPGTST
283
GGTACTTCTACCGAACCGTCCGAGGGCAGCGCTCCA
284


N_E10.ab1
EPSEGSAPGTSTEPSE

GGTACTTCTACTGAACCTTCTGAAGGCAGCGCTCCA




GSAP

GGTACTTCTACTGAACCTTCCGAAGGTAGCGCACCA



 


LCW0402_040_GFP-
GSEPATSGSETPGTSE
285
GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCA
286


N_F10.ab1
SATPESGPGTSTEPSE

GGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA




GSAP

GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA



 


LCW0402_041_GFP-
GTSTEPSEGSAPGSPA
287
GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
288


N_G10.ab1
GSPTSTEEGTSTEPSE

GGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GSAP

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA



 


LCW0402_050_GFP-
GSEPATSGSETPGTSE
289
GGTAGCGAACCGGCAACCTCCGGCTCTGAAACTCCA
290


N_A11.ab1
SATPESGPGSEPATSG

GGTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCA




SETP

GGTAGCGAACCGGCTACTTCCGGCTCTGAAACCCCA



 


LCW0402_051_GFP-
GSEPATSGSETPGTSE
291
GGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCA
292


N_B11.ab1
SATPESGPGSEPATSG

GGTACTTCTGAAAGCGCTACTCCTGAGTCTGGCCCA




SETP

GGTAGCGAACCTGCTACCTCTGGCTCTGAAACCCCA



 


LCW0402_059_GFP-
GSEPATSGSETPGSEP
293
GGTAGCGAACCGGCAACCTCTGGCTCTGAAACTCCA
294


N_E11.ab1
ATSGSETPGTSTEPSE

GGTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCA




GSAP

GGTACTTCTACTGAACCTTCTGAGGGCAGCGCACCA



 


LCW0402_060_GFP-
GTSESATPESGPGSEP
295
GGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCA
296


N_F11.ab1
ATSGSETPGSEPATSG

GGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCA




SETP

GGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA



 


LCW0402_061_GFP-
GTSTEPSEGSAPGTST
297
GGTACCTCTACTGAACCTTCCGAAGGCAGCGCTCCA
298


N_G11.ab1
EPSEGSAPGTSESATP

GGTACCTCTACCGAACCGTCCGAGGGCAGCGCACCA




ESGP

GGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCA



 


LCW0402_065_GFP-
GSEPATSGSETPGTSE
299
GGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCA
300


N_A12.ab1
SATPESGPGTSESATP

GGTACCTCTGAAAGCGCTACTCCGGAATCTGGTCCA




ESGP

GGTACTTCTGAAAGCGCTACTCCGGAATCCGGTCCA



 


LCW0402_066_GFP-
GSEPATSGSETPGSEP
301
GGTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCA
302


N_B12.ab1
ATSGSETPGTSTEPSE

GGTAGCGAACCGGCTACTTCCGGTTCTGAAACTCCA




GSAP

GGTACCTCTACCGAACCTTCCGAAGGCAGCGCACCA



 


LCW0402_067_GFP-
GSEPATSGSETPGTST
303
GGTAGCGAACCTGCTACTTCTGGTTCTGAAACTCCA
304


N_C12.ab1
EPSEGSAPGSEPATSG

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCTCCA




SETP

GGTAGCGAACCTGCTACTTCTGGTTCTGAAACTCCA



 


LCW0402_069_GFP-
GTSTEPSEGSAPGTST
305
GGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCA
306


N_D12.ab1
EPSEGSAPGSEPATSG

GGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCA




SETP

GGTAGCGAACCGGCAACCTCCGGTTCTGAAACTCCA



 


LCW0402_073_GFP-
GTSTEPSEGSAPGSEP
307
GGTACTTCTACTGAACCTTCCGAAGGTAGCGCTCCA
308


N_F12.ab1
ATSGSETPGSPAGSPT

GGTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCA




STEE

GGTAGCCCGGCTGGCTCTCCGACCTCCACCGAGGAA



 


LCW0402_074_GFP-
GSEPATSGSETPGSPA
309
GGTAGCGAACCGGCTACTTCCGGCTCTGAGACTCCA
310


N_G12.ab1
GSPTSTEEGTSESATP

GGTAGCCCAGCTGGTTCTCCAACCTCTACTGAGGAA




ESGP

GGTACTTCTGAAAGCGCTACCCCTGAATCTGGTCCA



 


LCW0402_075_GFP-
GTSESATPESGPGSEP
311
GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA
312


N_H12.ab1
ATSGSETPGTSESATP

GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCA




ESGP

GGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCA









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: 313), GTSTPESGSASP (SEQ ID NO: 314), GTSPSGESSTAP (SEQ ID NO: 315), or GSTSSTAESPGP (SEQ ID NO: 316). The insert was obtained by annealing the following pairs of phosphorylated synthetic oligonucleotide pairs:









(SEQ ID NO: 317)



AF1for: AGGTTCTACYAGCGAATCYCCKTCTGGYACYGCWCC


 



(SEQ ID NO: 318)



AF1rev: ACCTGGWGCRGTRCCAGAMGGRGATTCGCTRGTAGA


 



(SEQ ID NO: 319)



AF2for: AGGTACYTCTACYCCKGAAAGCGGYTCYGCWTCTCC


 



(SEQ ID NO: 320)



AF2rev: ACCTGGAGAWGCRGARCCGCTTTCMGGRGTAGARGT


 



(SEQ ID NO: 321)



AF3for: AGGTACYTCYCCKAGCGGYGAATCTTCTACYGCWCC


 



(SEQ ID NO: 322)



AF3rev: ACCTGGWGCRGTAGAAGATTCRCCGCTMGGRGARGT


 



(SEQ ID NO: 323)



AF4for: AGGTTCYACYAGCTCTACYGCWGAATCTCCKGGYCC


 



(SEQ ID NO: 324)



AF4rev: ACCTGGRCCMGGAGATTCWGCRGTAGAGCTRGTRGA






We also annealed the phosphorylated oligonucleotide 3KpnIstopperFor: AGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 325) and the non-phosphorylated oligonucleotide pr_3KpnIstopperRev: CCTCGAGTGAAGACGA (SEQ ID NO: 326). 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 for these segments are listed in Table 10.







TABLE 10







DNA and Amino Acid Sequences for 36-mer motifs











File name
Amino acid sequence
SEQ ID NO:
Nucleotide sequence
SEQ ID NO:





LCW0403_004_GFP-
GTSTPESGSASPGTSP
327
GGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCA
328


N_A01.ab1
SGESSTAPGTSPSGES

GGTACTTCTCCTAGCGGTGAATCTTCTACTGCTCCAG




STAP

GTACCTCTCCTAGCGGCGAATCTTCTACTGCTCCA



 


LCW0403_005_GFP-
GTSPSGESSTAPGSTS
329
GGTACTTCTCCGAGCGGTGAATCTTCTACCGCACCA



N_B01.ab1
STAESPGPGTSPSGES

GGTTCTACTAGCTCTACCGCTGAATCTCCGGGCCCAG
330



STAP

GTACTTCTCCGAGCGGTGAATCTTCTACTGCTCCA



 


LCW0403_006_GFP-
GSTSSTAESPGPGTSP
331
GGTTCCACCAGCTCTACTGCTGAATCTCCTGGTCCAG
332


N_C01.ab1
SGESSTAPGTSTPESG

GTACCTCTCCTAGCGGTGAATCTTCTACTGCTCCAGG




SASP

TACTTCTACTCCTGAAAGCGGCTCTGCTTCTCCA



 


LCW0403_007_GFP-
GSTSSTAESPGPGSTS
333
GGTTCTACCAGCTCTACTGCAGAATCTCCTGGCCCAG
334


N_D01.ab1
STAESPGPGTSPSGES

GTTCCACCAGCTCTACCGCAGAATCTCCGGGTCCAG




STAP

GTACTTCCCCTAGCGGTGAATCTTCTACCGCACCA



 


LCW0403_008_GFP-
GSTSSTAESPGPGTSP
335
GGTTCTACTAGCTCTACTGCTGAATCTCCTGGCCCAG
336


N_E01.ab1
SGESSTAPGTSTPESG

GTACTTCTCCTAGCGGTGAATCTTCTACCGCTCCAGG




SASP

TACCTCTACTCCGGAAAGCGGTTCTGCATCTCCA



 


LCW0403_010_GFP-
GSTSSTAESPGPGTST
337
GGTTCTACCAGCTCTACCGCAGAATCTCCTGGTCCAG
338


N_F01.ab1
PESGSASPGSTSESPS

GTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAG




GTAP

GTTCTACTAGCGAATCTCCTTCTGGCACTGCACCA



 


LCW0403_011_GFP-
GSTSSTAESPGPGTST
339
GGTTCTACTAGCTCTACTGCAGAATCTCCTGGCCCAG
340


N_G01.ab1
PESGSASPGTSTPESG

GTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAG




SASP

GTACTTCTACCCCTGAAAGCGGTTCTGCATCTCCA



 


LCW0403_012_GFP-
GSTSESPSGTAPGTSP
341
GGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAG
342


N_H01.ab1
SGESSTAPGSTSESPS

GTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGG




GTAP

TTCTACTAGCGAATCTCCTTCTGGCACTGCACCA



 


LCW0403_013_GFP-
GSTSSTAESPGPGSTS
343
GGTTCCACCAGCTCTACTGCAGAATCTCCGGGCCCA
344


N_A02.ab1
STAESPGPGTSPSGES

GGTTCTACTAGCTCTACTGCAGAATCTCCGGGTCCAG




STAP

GTACTTCTCCTAGCGGCGAATCTTCTACCGCTCCA



 


LCW0403_014_GFP-
GSTSSTAESPGPGTST
345
GGTTCCACTAGCTCTACTGCAGAATCTCCTGGCCCAG
346


N_B02.ab1
PESGSASPGSTSESPS

GTACCTCTACCCCTGAAAGCGGCTCTGCATCTCCAG




GTAP

GTTCTACCAGCGAATCCCCGTCTGGCACCGCACCA



 


LCW0403_015_GFP-
GSTSSTAESPGPGSTS
347
GGTTCTACTAGCTCTACTGCTGAATCTCCGGGTCCAG
348


N_C02.ab1
STAESPGPGTSPSGES

GTTCTACCAGCTCTACTGCTGAATCTCCTGGTCCAGG




STAP

TACCTCCCCGAGCGGTGAATCTTCTACTGCACCA



 


LCW0403_017_GFP-
GSTSSTAESPGPGSTS
349
GGTTCTACCAGCTCTACCGCTGAATCTCCTGGCCCAG
350


N_D02.ab1
ESPSGTAPGSTSSTAE

GTTCTACCAGCGAATCCCCGTCTGGCACCGCACCAG




SPGP

GTTCTACTAGCTCTACCGCTGAATCTCCGGGTCCA



 


LCW0403_018_GFP-
GSTSSTAESPGPGSTS
351
GGTTCTACCAGCTCTACCGCAGAATCTCCTGGCCCA
352


N_E02.ab1
STAESPGPGSTSSTAE

GGTTCCACTAGCTCTACCGCTGAATCTCCTGGTCCAG




SPGP

GTTCTACTAGCTCTACCGCTGAATCTCCTGGTCCA



 


LCW0403_019_GFP-
GSTSESPSGTAPGSTS
353
GGTTCTACTAGCGAATCCCCTTCTGGTACTGCTCCAG
354


N_F02.ab1
STAESPGPGSTSSTAE

GTTCCACTAGCTCTACCGCTGAATCTCCTGGCCCAGG




SPGP

TTCCACTAGCTCTACTGCAGAATCTCCTGGTCCA



 


LCW0403_023_GFP-
GSTSESPSGTAPGSTS
355
GGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAG
356


N_H02.ab1
ESPSGTAPGSTSESPS

GTTCTACCAGCGAATCCCCGTCTGGTACTGCTCCAGG




GTAP

TTCTACCAGCGAATCTCCTTCTGGTACTGCACCA



 


LCW0403_024_GFP-
GSTSSTAESPGPGSTS
357
GGTTCCACCAGCTCTACTGCTGAATCTCCTGGCCCAG
358


N_A03.ab1
STAESPGPGSTSSTAE

GTTCTACCAGCTCTACTGCTGAATCTCCGGGCCCAGG




SPGP

TTCCACCAGCTCTACCGCTGAATCTCCGGGTCCA



 


LCW0403_025_GFP-
GSTSSTAESPGPGSTS
359
GGTTCCACTAGCTCTACCGCAGAATCTCCTGGTCCAG
360


N_B03.ab1
STAESPGPGTSPSGES

GTTCTACTAGCTCTACTGCTGAATCTCCGGGTCCAGG




STAP

TACCTCCCCTAGCGGCGAATCTTCTACCGCTCCA



 


LCW0403_028_GFP-
GSSPSASTGTGPGSST
361
GGTTCTAGCCCTTCTGCTTCCACCGGTACCGGCCCAG
362


N_D03.ab1
PSGATGSPGSSTPSGA

GTAGCTCTACTCCGTCTGGTGCAACTGGCTCTCCAGG




TGSP

TAGCTCTACTCCGTCTGGTGCAACCGGCTCCCCA



 


LCW0403_029_GFP-
GTSPSGESSTAPGTST
363
GGTACTTCCCCTAGCGGTGAATCTTCTACTGCTCCAG
364


N_E03.ab1
PESGSASPGSTSSTAE

GTACCTCTACTCCGGAAAGCGGCTCCGCATCTCCAG




SPGP

GTTCTACTAGCTCTACTGCTGAATCTCCTGGTCCA



 


LCW0403_030_GFP-
GSTSSTAESPGPGSTS
365
GGTTCTACTAGCTCTACCGCTGAATCTCCGGGTCCAG
366


N_F03.ab1
STAESPGPGTSTPESG

GTTCTACCAGCTCTACTGCAGAATCTCCTGGCCCAGG




SASP

TACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCA



 


LCW0403_031_GFP-
GTSPSGESSTAPGSTS
367
GGTACTTCTCCTAGCGGTGAATCTTCTACCGCTCCAG
368


N_G03.ab1
STAESPGPGTSTPESG

GTTCTACCAGCTCTACTGCTGAATCTCCTGGCCCAGG




SASP

TACTTCTACCCCGGAAAGCGGCTCCGCTTCTCCA



 


LCW0403_033_GFP-
GSTSESPSGTAPGSTS
369
GGTTCTACTAGCGAATCCCCTTCTGGTACTGCACCAG
370


N_H03.ab1
STAESPGPGSTSSTAE

GTTCTACCAGCTCTACTGCTGAATCTCCGGGCCCAGG




SPGP

TTCCACCAGCTCTACCGCAGAATCTCCTGGTCCA



 


LCW0403_035_GFP-
GSTSSTAESPGPGSTS
371
GGTTCCACCAGCTCTACCGCTGAATCTCCGGGCCCA
372


N_A04.ab1
ESPSGTAPGSTSSTAE

GGTTCTACCAGCGAATCCCCTTCTGGCACTGCACCA




SPGP

GGTTCTACTAGCTCTACCGCAGAATCTCCGGGCCCA



 


LCW0403_036_GFP-
GSTSSTAESPGPGTSP
373
GGTTCTACCAGCTCTACTGCTGAATCTCCGGGTCCAG
374


N_B04.ab1
SGESSTAPGTSTPESG

GTACTTCCCCGAGCGGTGAATCTTCTACTGCACCAG




SASP

GTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCA



 


LCW0403_039_GFP-
GSTSESPSGTAPGSTS
375
GGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAG
376


N_C04.ab1
ESPSGTAPGTSPSGES

GTTCTACTAGCGAATCCCCGTCTGGTACCGCACCAG




STAP

GTACTTCTCCTAGCGGCGAATCTTCTACCGCACCA



 


LCW0403_041_GFP-
GSTSESPSGTAPGSTS
377
GGTTCTACCAGCGAATCCCCTTCTGGTACTGCTCCAG
378


N_D04.ab1
ESPSGTAPGTSTPESG

GTTCTACCAGCGAATCCCCTTCTGGCACCGCACCAG




SASP

GTACTTCTACCCCTGAAAGCGGCTCCGCTTCTCCA



 


LCW0403_044_GFP-
GTSTPESGSASPGSTS
379
GGTACCTCTACTCCTGAAAGCGGTTCTGCATCTCCAG
380


N_E04.ab1
STAESPGPGSTSSTAE

GTTCCACTAGCTCTACCGCAGAATCTCCGGGCCCAG




SPGP

GTTCTACTAGCTCTACTGCTGAATCTCCTGGCCCA



 


LCW0403_046_GFP-
GSTSESPSGTAPGSTS
381
GGTTCTACCAGCGAATCCCCTTCTGGCACTGCACCA
382


N_F04.ab1
ESPSGTAPGTSPSGES

GGTTCTACTAGCGAATCCCCTTCTGGTACCGCACCAG




STAP

GTACTTCTCCGAGCGGCGAATCTTCTACTGCTCCA



 


LCW0403_047_GFP-
GSTSSTAESPGPGSTS
383
GGTTCTACTAGCTCTACCGCTGAATCTCCTGGCCCAG
384


N_G04.ab1
STAESPGPGSTSESPS

GTTCCACTAGCTCTACCGCAGAATCTCCGGGCCCAG




GTAP

GTTCTACTAGCGAATCCCCTTCTGGTACCGCTCCA



 


LCW0403_049_GFP-
GSTSSTAESPGPGSTS
385
GGTTCCACCAGCTCTACTGCAGAATCTCCTGGCCCA
386


N_H04.ab1
STAESPGPGTSTPESG

GGTTCTACTAGCTCTACCGCAGAATCTCCTGGTCCAG




SASP

GTACCTCTACTCCTGAAAGCGGTTCCGCATCTCCA



 


LCW0403_051_GFP-
GSTSSTAESPGPGSTS
387
GGTTCTACTAGCTCTACTGCTGAATCTCCGGGCCCAG
388


N_A05.ab1
STAESPGPGSTSESPS

GTTCTACTAGCTCTACCGCTGAATCTCCGGGTCCAGG




GTAP

TTCTACTAGCGAATCTCCTTCTGGTACCGCTCCA



 


LCW0403_053_GFP-
GTSPSGESSTAPGSTS
389
GGTACCTCCCCGAGCGGTGAATCTTCTACTGCACCA
390


N_B05.ab1
ESPSGTAPGSTSSTAE

GGTTCTACTAGCGAATCCCCTTCTGGTACTGCTCCAG




SPGP

GTTCCACCAGCTCTACTGCAGAATCTCCGGGTCCA



 


LCW0403_054_GFP-
GSTSESPSGTAPGTSP
391
GGTTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAG
392


N_C05.ab1
SGESSTAPGSTSSTAE

GTACTTCCCCTAGCGGTGAATCTTCTACTGCTCCAGG




SPGP

TTCTACCAGCTCTACCGCAGAATCTCCGGGTCCA



 


LCW0403_057_GFP-
GSTSSTAESPGPGSTS
393
GGTTCTACCAGCTCTACCGCTGAATCTCCTGGCCCAG
394


N_D05.ab1
ESPSGTAPGTSPSGES

GTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAG




STAP

GTACTTCCCCTAGCGGTGAATCTTCTACTGCACCA



 


LCW0403_058_GFP-
GSTSESPSGTAPGSTS
395
GGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAG
396


N_E05.ab1
ESPSGTAPGTSTPESG

GTTCTACCAGCGAATCTCCGTCTGGCACTGCACCAG




SASP

GTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCA



 


LCW0403_060_GFP-
GTSTPESGSASPGSTS
397
GGTACCTCTACTCCGGAAAGCGGTTCCGCATCTCCA
398


N_F05.ab1
ESPSGTAPGSTSSTAE

GGTTCTACCAGCGAATCCCCGTCTGGCACCGCACCA




SPGP

GGTTCTACTAGCTCTACTGCTGAATCTCCGGGCCCA



 


LCW0403_063_GFP-
GSTSSTAESPGPGTSP
399
GGTTCTACTAGCTCTACTGCAGAATCTCCGGGCCCA
400


N_G05.ab1
SGESSTAPGTSPSGES

GGTACCTCTCCTAGCGGTGAATCTTCTACCGCTCCAG




STAP

GTACTTCTCCGAGCGGTGAATCTTCTACCGCTCCA



 


LCW0403_064_GFP-
GTSPSGESSTAPGTSP
401
GGTACCTCCCCTAGCGGCGAATCTTCTACTGCTCCAG
402


N_H05.ab1
SGESSTAPGTSPSGES

GTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGG




STAP

TACCTCCCCTAGCGGTGAATCTTCTACCGCACCA



 


LCW0403_065_GFP-
GSTSSTAESPGPGTST
403
GGTTCCACTAGCTCTACTGCTGAATCTCCTGGCCCAG
404


N_A06.ab1
PESGSASPGSTSESPS

GTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGG




GTAP

TTCTACTAGCGAATCTCCGTCTGGCACCGCACCA



 


LCW0403_066_GFP-
GSTSESPSGTAPGTSP
405
GGTTCTACTAGCGAATCTCCGTCTGGCACTGCTCCAG
406


N_B06.ab1
SGESSTAPGTSPSGES

GTACTTCTCCTAGCGGTGAATCTTCTACCGCTCCAGG




STAP

TACTTCCCCTAGCGGCGAATCTTCTACCGCTCCA



 


LCW0403_067_GFP-
GSTSESPSGTAPGTST
407
GGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAG
408


N_C06.ab1
PESGSASPGSTSSTAE

GTACTTCTACCCCTGAAAGCGGCTCCGCTTCTCCAGG




SPGP

TTCCACTAGCTCTACCGCTGAATCTCCGGGTCCA



 


LCW0403_068_GFP-
GSTSSTAESPGPGSTS
409
GGTTCCACTAGCTCTACTGCTGAATCTCCTGGCCCAG
410


N_D06.ab1
STAESPGPGSTSESPS

GTTCTACCAGCTCTACCGCTGAATCTCCTGGCCCAGG




GTAP

TTCTACCAGCGAATCTCCGTCTGGCACCGCACCA



 


LCW0403_069_GFP-
GSTSESPSGTAPGTST
411
GGTTCTACTAGCGAATCCCCGTCTGGTACCGCACCA
412


N_E06.ab1
PESGSASPGTSTPESG

GGTACTTCTACCCCGGAAAGCGGCTCTGCTTCTCCAG




SASP

GTACTTCTACCCCGGAAAGCGGCTCCGCATCTCCA












414











LCW0403_070_GFP-
GSTSESPSGTAPGTST
413
GGTTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAG



N_F06.ab1
PESGSASPGTSTPESG

GTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGG




SASP

TACCTCTACTCCGGAAAGCGGTTCTGCATCTCCA









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: 415), GSSTPSGATGSP (SEQ ID NO: 416), GSSPSASTGTGP (SEQ ID NO: 417), or GASPGTSSTGSP (SEQ ID NO: 418). The insert was obtained by annealing the following pairs of phosphorylated synthetic oligonucleotide pairs:









(SEQ ID NO: 419)



AG1for: AGGTACYCCKGGYAGCGGTACYGCWTCTTCYTCTCC


 



(SEQ ID NO: 420)



AG1rev: ACCTGGAGARGAAGAWGCRGTACCGCTRCCMGGRGT


 



(SEQ ID NO: 421)



AG2for: AGGTAGCTCTACYCCKTCTGGTGCWACYGGYTCYCC


 



(SEQ ID NO: 422)



AG2rev: ACCTGGRGARCCRGTWGCACCAGAMGGRGTAGAGCT


 



(SEQ ID NO: 423)



AG3for: AGGTTCTAGCCCKTCTGCWTCYACYGGTACYGGYCC


 



(SEQ ID NO: 424)



AG3rev: ACCTGGRCCRGTACCRGTRGAWGCAGAMGGGCTAGA


 



(SEQ ID NO: 425)



AG4for: AGGTGCWTCYCCKGGYACYAGCTCTACYGGTTCTCC


 



(SEQ ID NO: 426)



AG4rev: ACCTGGAGAACCRGTAGAGCTRGTRCCMGGRGAWGC






We also annealed the phosphorylated oligonucleotide 3KpnIstopperFor: AGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 427) and the non-phosphorylated oligonucleotide pr_3KpnIstopperRev: CCTCGAGTGAAGACGA (SEQ ID NO: 428). 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 for these segments are listed in Table 11.







TABLE 11







DNA and Amino Acid Sequences for 36-mer motifs











File name
Amino acid sequence
SEQ ID NO:
Nucleotide sequence
SEQ ID NO:





LCW0404_001_GFP-
GASPGTSSTGSPGTPG
429
GGTGCATCCCCGGGCACTAGCTCTACCGGTTCTCCA
430


N_A07.ab1
SGTASSSPGSSTPSGA

GGTACTCCTGGTAGCGGTACTGCTTCTTCTTCTCCAG




TGSP

GTAGCTCTACTCCTTCTGGTGCTACTGGTTCTCCA



 


LCW0404_003_GFP-
GSSTPSGATGSPGSSP
431
GGTAGCTCTACCCCTTCTGGTGCTACCGGCTCTCCAG
432


N_B07.ab1
SASTGTGPGSSTPSGA

GTTCTAGCCCGTCTGCTTCTACCGGTACCGGTCCAGG




TGSP

TAGCTCTACCCCTTCTGGTGCTACTGGTTCTCCA



 


LCW0404_006_GFP-
GASPGTSSTGSPGSSP
433
GGTGCATCTCCGGGTACTAGCTCTACCGGTTCTCCAG
434


N_C07.ab1
SASTGTGPGSSTPSGA

GTTCTAGCCCTTCTGCTTCCACTGGTACCGGCCCAGG




TGSP

TAGCTCTACCCCGTCTGGTGCTACTGGTTCCCCA



 


LCW0404_007_GFP-
GTPGSGTASSSPGSST
435
GGTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAG
436


N_D07.ab1
PSGATGSPGASPGTSS

GTAGCTCTACCCCTTCTGGTGCAACTGGTTCCCCAGG




TGSP

TGCATCCCCTGGTACTAGCTCTACCGGTTCTCCA



 


LCW0404_009_GFP-
GTPGSGTASSSPGASP
437
GGTACCCCTGGCAGCGGTACTGCTTCTTCTTCTCCAG
438


N_E07.ab1
GTSSTGSPGSRPSAST

GTGCTTCCCCTGGTACCAGCTCTACCGGTTCTCCAGG




GTGP

TTCTAGACCTTCTGCATCCACCGGTACTGGTCCA



 


LCW0404_011_GFP-
GASPGTSSTGSPGSST
439
GGTGCATCTCCTGGTACCAGCTCTACCGGTTCTCCAG
440


N_F07.ab1
PSGATGSPGASPGTSS

GTAGCTCTACTCCTTCTGGTGCTACTGGCTCTCCAGG




TGSP

TGCTTCCCCGGGTACCAGCTCTACCGGTTCTCCA



 


LCW0404_012_GFP-
GTPGSGTASSSPGSST
441
GGTACCCCGGGCAGCGGTACCGCATCTTCCTCTCCA
442


N_G07.ab1
PSGATGSPGSSTPSGA

GGTAGCTCTACCCCGTCTGGTGCTACCGGTTCCCCAG




TGSP

GTAGCTCTACCCCGTCTGGTGCAACCGGCTCCCCA



 


LCW0404_014_GFP-
GASPGTSSTGSPGASP
443
GGTGCATCTCCGGGCACTAGCTCTACTGGTTCTCCAG
444


N_H07.ab1
GTSSTGSPGASPGTSS

GTGCATCCCCTGGCACTAGCTCTACTGGTTCTCCAGG




TGSP

TGCTTCTCCTGGTACCAGCTCTACTGGTTCTCCA



 


LCW0404_015_GFP-
GSSTPSGATGSPGSSP
445
GGTAGCTCTACTCCGTCTGGTGCAACCGGCTCCCCA
446


N_A08.ab1
SASTGTGPGASPGTSS

GGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAG




TGSP

GTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCA



 


LCW0404_016_GFP-
GSSTPSGATGSPGSST
447
GGTAGCTCTACTCCTTCTGGTGCTACCGGTTCCCCAG
448


N_B08.ab1
PSGATGSPGTPGSGT

GTAGCTCTACTCCTTCTGGTGCTACTGGTTCCCCAGG




ASSSP

TACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCA



 


LCW0404_017_GFP-
GSSTPSGATGSPGSST
449
GGTAGCTCTACTCCGTCTGGTGCAACCGGTTCCCCAG
450


N_C08.ab1
PSGATGSPGASPGTSS

GTAGCTCTACTCCTTCTGGTGCTACTGGCTCCCCAGG




TGSP

TGCATCCCCTGGCACCAGCTCTACCGGTTCTCCA



 


LCW0404_018_GFP-
GTPGSGTASSSPGSSP
451
GGTACTCCTGGTAGCGGTACCGCATCTTCCTCTCCAG
452


N_D08.ab1
SASTGTGPGSSTPSGA

GTTCTAGCCCTTCTGCATCTACCGGTACCGGTCCAGG




TGSP

TAGCTCTACTCCTTCTGGTGCTACTGGCTCTCCA



 


LCW0404_023_GFP-
GASPGTSSTGSPGSSP
453
GGTGCTTCCCCGGGCACTAGCTCTACCGGTTCTCCAG
454


N_F08.ab1
SASTGTGPGTPGSGT

GTTCTAGCCCTTCTGCATCTACTGGTACTGGCCCAGG




ASSSP

TACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCA



 


LCW0404_025_GFP-
GSSTPSGATGSPGSST
455
GGTAGCTCTACTCCGTCTGGTGCTACCGGCTCTCCAG
456


N_G08.ab1
PSGATGSPGASPGTSS

GTAGCTCTACCCCTTCTGGTGCAACCGGCTCCCCAGG




TGSP

TGCTTCTCCGGGTACCAGCTCTACTGGTTCTCCA



 


LCW0404_029_GFP-
GTPGSGTASSSPGSST
457
GGTACCCCTGGCAGCGGTACCGCTTCTTCCTCTCCAG
458


N_A09.ab1
PSGATGSPGSSPSAST

GTAGCTCTACCCCGTCTGGTGCTACTGGCTCTCCAGG




GTGP

TTCTAGCCCGTCTGCATCTACCGGTACCGGCCCA



 


LCW0404_030_GFP-
GSSTPSGATGSPGTPG
459
GGTAGCTCTACTCCTTCTGGTGCAACCGGCTCCCCAG
460


N_B09.ab1
SGTASSSPGTPGSGTA

GTACCCCGGGCAGCGGTACCGCATCTTCCTCTCCAG




SSSP

GTACTCCGGGTAGCGGTACTGCTTCTTCTTCTCCA



 


LCW0404_031_GFP-
GTPGSGTASSSPGSST
461
GGTACCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAG
462


N_C09.ab1
PSGATGSPGASPGTSS

GTAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGG




TGSP

TGCTTCTCCGGGCACCAGCTCTACCGGTTCTCCA



 


LCW0404_034_GFP-
GSSTPSGATGSPGSST
463
GGTAGCTCTACCCCGTCTGGTGCTACCGGCTCTCCAG
464


N_D09.ab1
PSGATGSPGASPGTSS

GTAGCTCTACCCCGTCTGGTGCAACCGGCTCCCCAG




TGSP

GTGCATCCCCGGGTACTAGCTCTACCGGTTCTCCA



 


LCW0404_035_GFP-
GASPGTSSTGSPGTPG
465
GGTGCTTCTCCGGGCACCAGCTCTACTGGTTCTCCAG
466


N_E09.ab1
SGTASSSPGSSTPSGA

GTACCCCGGGCAGCGGTACCGCATCTTCTTCTCCAG




TGSP

GTAGCTCTACTCCTTCTGGTGCAACTGGTTCTCCA



 


LCW0404_036_GFP-
GSSPSASTGTGPGSST
467
GGTTCTAGCCCGTCTGCTTCCACCGGTACTGGCCCAG
468


N_F09.ab1
PSGATGSPGTPGSGT

GTAGCTCTACCCCGTCTGGTGCAACTGGTTCCCCAGG




ASSSP

TACCCCTGGTAGCGGTACCGCTTCTTCTTCTCCA



 


LCW0404_037_GFP-
GASPGTSSTGSPGSSP
469
GGTGCTTCTCCGGGCACCAGCTCTACTGGTTCTCCAG
470


N_G09.ab1
SASTGTGPGSSTPSGA

GTTCTAGCCCTTCTGCATCCACCGGTACCGGTCCAGG




TGSP

TAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCA



 


LCW0404_040_GFP-
GASPGTSSTGSPGSST
471
GGTGCATCCCCGGGCACCAGCTCTACCGGTTCTCCA
472


N_H09.ab1
PSGATGSPGSSTPSGA

GGTAGCTCTACCCCGTCTGGTGCTACCGGCTCTCCAG




TGSP

GTAGCTCTACCCCGTCTGGTGCTACTGGCTCTCCA



 


LCW0404_041_GFP-
GTPGSGTASSSPGSST
473
GGTACCCCTGGTAGCGGTACTGCTTCTTCCTCTCCAG
474


N_A10.ab1
PSGATGSPGTPGSGT

GTAGCTCTACTCCGTCTGGTGCTACCGGTTCTCCAGG




ASSSP

TACCCCGGGTAGCGGTACCGCATCTTCTTCTCCA



 


LCW0404_043_GFP-
GSSPSASTGTGPGSST
475
GGTTCTAGCCCTTCTGCTTCCACCGGTACTGGCCCAG
476


N_C10.ab1
PSGATGSPGSSTPSGA

GTAGCTCTACCCCTTCTGGTGCTACCGGCTCCCCAGG




TGSP

TAGCTCTACTCCTTCTGGTGCAACTGGCTCTCCA



 


LCW0404_045_GFP-
GASPGTSSTGSPGSSP
477
GGTGCTTCTCCTGGCACCAGCTCTACTGGTTCTCCAG
478


N_D10.ab1
SASTGTGPGSSPSAST

GTTCTAGCCCTTCTGCTTCTACCGGTACTGGTCCAGG




GTGP

TTCTAGCCCTTCTGCATCCACTGGTACTGGTCCA



 


LCW0404_047_GFP-
GTPGSGTASSSPGASP
479
GGTACTCCTGGCAGCGGTACCGCTTCTTCTTCTCCAG
480


N_F10.ab1
GTSSTGSPGASPGTSS

GTGCTTCTCCTGGTACTAGCTCTACTGGTTCTCCAGG




TGSP

TGCTTCTCCGGGCACTAGCTCTACTGGTTCTCCA



 


LCW0404_048_GFP-
GSSTPSGATGSPGASP
481
GGTAGCTCTACCCCGTCTGGTGCTACCGGTTCCCCAG
482


N_G10.ab1
GTSSTGSPGSSTPSGA

GTGCTTCTCCTGGTACTAGCTCTACCGGTTCTCCAGG




TGSP

TAGCTCTACCCCGTCTGGTGCTACTGGCTCTCCA



 


LCW0404_049_GFP-
GSSTPSGATGSPGTPG
483
GGTAGCTCTACCCCGTCTGGTGCTACTGGTTCTCCAG
484


N_H10.ab1
SGTASSSPGSSTPSGA

GTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGG




TGSP

TAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCA



 


LCW0404_050_GFP-
GASPGTSSTGSPGSSP
485
GGTGCATCTCCTGGTACCAGCTCTACTGGTTCTCCAG
486


N_A11.ab1
SASTGTGPGSSTPSGA

GTTCTAGCCCTTCTGCTTCTACCGGTACCGGTCCAGG




TGSP

TAGCTCTACTCCTTCTGGTGCTACCGGTTCTCCA



 


LCW0404_051_GFP-
GSSTPSGATGSPGSST
487
GGTAGCTCTACCCCGTCTGGTGCTACTGGCTCTCCAG
488


N_B11.ab1
PSGATGSPGSSTPSGA

GTAGCTCTACTCCTTCTGGTGCTACTGGTTCCCCAGG




TGSP

TAGCTCTACCCCGTCTGGTGCAACTGGCTCTCCA



 


LCW0404_052_GFP-
GASPGTSSTGSPGTPG
489
GGTGCATCCCCGGGTACCAGCTCTACCGGTTCTCCA
490


N_C11.ab1
SGTASSSPGASPGTSS

GGTACTCCTGGCAGCGGTACTGCATCTTCCTCTCCAG




TGSP

GTGCTTCTCCGGGCACCAGCTCTACTGGTTCTCCA



 


LCW0404_053_GFP-
GSSTPSGATGSPGSSP
491
GGTAGCTCTACTCCTTCTGGTGCAACTGGTTCTCCAG
492


N_D11.ab1
SASTGTGPGASPGTSS

GTTCTAGCCCGTCTGCATCCACTGGTACCGGTCCAGG




TGSP

TGCTTCCCCTGGCACCAGCTCTACCGGTTCTCCA












494











LCW0404_057_GFP-
GASPGTSSTGSPGSST
493
GGTGCATCTCCTGGTACTAGCTCTACTGGTTCTCCAG



N_E11.ab1
PSGATGSPGSSPSAST

GTAGCTCTACTCCGTCTGGTGCAACCGGCTCTCCAGG




GTGP

TTCTAGCCCTTCTGCATCTACCGGTACTGGTCCA



 


LCW0404_060_GFP-
GTPGSGTASSSPGSST
495
GGTACTCCTGGCAGCGGTACCGCATCTTCCTCTCCAG
496


N_F11.ab1
PSGATGSPGASPGTSS

GTAGCTCTACTCCGTCTGGTGCAACTGGTTCCCCAGG




TGSP

TGCTTCTCCGGGTACCAGCTCTACCGGTTCTCCA



 


LCW0404_062_GFP-
GSSTPSGATGSPGTPG
497
GGTAGCTCTACCCCGTCTGGTGCAACCGGCTCCCCA
498


N_G11.ab1
SGTASSSPGSSTPSGA

GGTACTCCTGGTAGCGGTACCGCTTCTTCTTCTCCAG




TGSP

GTAGCTCTACTCCGTCTGGTGCTACCGGCTCCCCA



 


LCW0404_066_GFP-
GSSPSASTGTGPGSSP
499
GGTTCTAGCCCTTCTGCATCCACCGGTACCGGCCCAG
500


N_H11.ab1
SASTGTGPGASPGTSS

GTTCTAGCCCGTCTGCTTCTACCGGTACTGGTCCAGG




TGSP

TGCTTCTCCGGGTACTAGCTCTACTGGTTCTCCA



 


LCW0404_067_GFP-
GTPGSGTASSSPGSST
501
GGTACCCCGGGTAGCGGTACCGCTTCTTCTTCTCCAG
502


N_A12.ab1
PSGATGSPGSNPSAST

GTAGCTCTACTCCGTCTGGTGCTACCGGCTCTCCAGG




GTGP

TTCTAACCCTTCTGCATCCACCGGTACCGGCCCA



 


LCW0404_068_GFP-
GSSPSASTGTGPGSST
503
GGTTCTAGCCCTTCTGCATCTACTGGTACTGGCCCAG
504


N_B12.ab1
PSGATGSPGASPGTSS

GTAGCTCTACTCCTTCTGGTGCTACCGGCTCTCCAGG




TGSP

TGCTTCTCCGGGTACTAGCTCTACCGGTTCTCCA



 


LCW0404_069_GFP-
GSSTPSGATGSPGASP
505
GGTAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAG
506


N_C12.ab1
GTSSTGSPGTPGSGTA

GTGCATCCCCGGGTACCAGCTCTACCGGTTCTCCAG




SSSP

GTACTCCGGGTAGCGGTACCGCTTCTTCCTCTCCA



 


LCW0404_070_GFP-
GSSTPSGATGSPGSST
507
GGTAGCTCTACTCCGTCTGGTGCAACCGGTTCCCCAG
508


N_D12.ab1
PSGATGSPGSSTPSGA

GTAGCTCTACCCCTTCTGGTGCAACCGGCTCCCCAGG




TGSP

TAGCTCTACCCCTTCTGGTGCAACTGGCTCTCCA



 


LCW0404_073_GFP-
GASPGTSSTGSPGTPG
509
GGTGCTTCTCCTGGCACTAGCTCTACCGGTTCTCCAG
510


N_E12.ab1
SGTASSSPGSSTPSGA

GTACCCCTGGTAGCGGTACCGCATCTTCCTCTCCAGG




TGSP

TAGCTCTACTCCTTCTGGTGCTACTGGTTCCCCA



 


LCW0404_075_GFP-
GSSTPSGATGSPGSSP
511
GGTAGCTCTACCCCGTCTGGTGCTACTGGCTCCCCAG
512


N_F12.ab1
SASTGTGPGSSPSAST

GTTCTAGCCCTTCTGCATCCACCGGTACCGGTCCAGG




GTGP

TTCTAGCCCGTCTGCATCTACTGGTACTGGTCCA



 


LCW0404_080_GFP-
GASPGTSSTGSPGSSP
513
GGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAG
514


N_G12.ab1
SASTGTGPGSSPSAST

GTTCTAGCCCGTCTGCTTCTACTGGTACTGGTCCAGG




GTGP

TTCTAGCCCTTCTGCTTCCACTGGTACTGGTCCA



 


LCW0404_081_GFP-
GASPGTSSTGSPGSSP
515
GGTGCTTCCCCGGGTACCAGCTCTACCGGTTCTCCAG
516


N_H12.ab1
SASTGTGPGTPGSGT

GTTCTAGCCCTTCTGCTTCTACCGGTACCGGTCCAGG




ASSSP

TACCCCTGGCAGCGGTACCGCATCTTCCTCTCCA









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 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 for these segments are listed in Table 12.







TABLE 12







DNA and amino acid sequences for AM144 segments











Clone
Sequence Trimmed
SEQ ID NO:
Protein Sequence
SEQ ID NO:





LCW462_r1
GGTACCCCGGGCAGCGGTACCGCATCTTCCTCTCCAG
517
GTPGSGTASSSPGSST
518



GTAGCTCTACCCCGTCTGGTGCTACCGGTTCCCCAGG

PSGATGSPGSSTPSGA




TAGCTCTACCCCGTCTGGTGCAACCGGCTCCCCAGGT

TGSPGSPAGSPTSTEE




AGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTA

GTSESATPESGPGTST




CTTCTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTAC

EPSEGSAPGSSPSAST




CTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTTCT

GTGPGSSPSASTGTGP




AGCCCTTCTGCATCCACCGGTACCGGCCCAGGTTCTA

GASPGTSSTGSPGTST




GCCCGTCTGCTTCTACCGGTACTGGTCCAGGTGCTTCT

EPSEGSAPGTSTEPSE




CCGGGTACTAGCTCTACTGGTTCTCCAGGTACCTCTA

GSAPGSEPATSGSETP




CCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTAC






TGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAACC






GGCAACCTCCGGTTCTGAAACTCCA





 


LCW462_r5
GGTTCTACCAGCGAATCCCCTTCTGGCACTGCACCAG
519
GSTSESPSGTAPGSTS
520



GTTCTACTAGCGAATCCCCTTCTGGTACCGCACCAGG

ESPSGTAPGTSPSGES




TACTTCTCCGAGCGGCGAATCTTCTACTGCTCCAGGT

STAPGTSTEPSEGSAP




ACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTA

GTSTEPSEGSAPGTSE




CCTCTACCGAACCGTCCGAGGGCAGCGCACCAGGTAC

SATPESGPGASPGTSS




TTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTGCA

TGSPGSSTPSGATGSP




TCTCCTGGTACCAGCTCTACCGGTTCTCCAGGTAGCTC

GASPGTSSTGSPGSTS




TACTCCTTCTGGTGCTACTGGCTCTCCAGGTGCTTCCC

ESPSGTAPGSTSESPS




CGGGTACCAGCTCTACCGGTTCTCCAGGTTCTACTAG

GTAPGTSTPESGSASP




CGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGC






GAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCC






CTGAAAGCGGTTCCGCTTCTCCA





 


LCW462_r9
GGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAG
521
GTSTEPSEGSAPGTSE
522



GTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGG

SATPESGPGTSESATP




TACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGT

ESGPGTSTEPSEGSAP




ACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTA

GTSESATPESGPGTST




CTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTAC

EPSEGSAPGTSTEPSE




TTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACT

GSAPGSEPATSGSETP




TCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCG

GSPAGSPTSTEEGASP




AACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGCCC

GTSSTGSPGSSPSAST




GGCTGGCTCTCCGACCTCCACCGAGGAAGGTGCTTCT

GTGPGSSPSASTGTGP




CCTGGCACCAGCTCTACTGGTTCTCCAGGTTCTAGCC






CTTCTGCTTCTACCGGTACTGGTCCAGGTTCTAGCCCT






TCTGCATCCACTGGTACTGGTCCA





 


LCW462_r10
GGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAG
523
GSEPATSGSETPGTSE
524



GTACCTCTGAAAGCGCTACTCCGGAATCTGGTCCAGG

SATPESGPGTSESATP




TACTTCTGAAAGCGCTACTCCGGAATCCGGTCCAGGT

ESGPGSTSESPSGTAP




TCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTT

GSTSESPSGTAPGTSP




CTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTAC

SGESSTAPGASPGTSS




TTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTGCA

TGSPGSSPSASTGTGP




TCTCCGGGTACTAGCTCTACCGGTTCTCCAGGTTCTAG

GSSTPSGATGSPGSST




CCCTTCTGCTTCCACTGGTACCGGCCCAGGTAGCTCT

PSGATGSPGSSTPSGA




ACCCCGTCTGGTGCTACTGGTTCCCCAGGTAGCTCTA

TGSPGASPGTSSTGSP




CTCCGTCTGGTGCAACCGGTTCCCCAGGTAGCTCTAC






TCCTTCTGGTGCTACTGGCTCCCCAGGTGCATCCCCTG






GCACCAGCTCTACCGGTTCTCCA





 


LCW462_r15
GGTGCTTCTCCGGGCACCAGCTCTACTGGTTCTCCAG
525
GASPGTSSTGSPGSSP
526



GTTCTAGCCCTTCTGCATCCACCGGTACCGGTCCAGG

SASTGTGPGSSTPSGA




TAGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGT

TGSPGTSESATPESGP




ACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTA

GSEPATSGSETPGSEP




GCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAG

ATSGSETPGTSESATP




CGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTACT

ESGPGTSTEPSEGSAP




TCTGAAAGCGCTACTCCGGAGTCCGGTCCAGGTACCT

GTSTEPSEGSAPGTST




CTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACTTC

EPSEGSAPGTSTEPSE




TACTGAACCTTCTGAGGGTAGCGCTCCAGGTACCTCT

GSAPGSEPATSGSETP




ACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTA






CTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAACC






GGCAACCTCCGGTTCTGAAACTCCA





 


LCW462_r16
GGTACCTCTACCGAACCTTCCGAAGGTAGCGCTCCAG
527
GTSTEPSEGSAPGSPA
528



GTAGCCCGGCAGGTTCTCCTACTTCCACTGAGGAAGG

GSPTSTEEGTSTEPSE




TACTTCTACCGAACCTTCTGAGGGTAGCGCACCAGGT

GSAPGTSESATPESGP




ACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTA

GSEPATSGSETPGTSE




GCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTAC

SATPESGPGSPAGSPT




CTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGC

STEEGTSESATPESGP




CCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTT

GTSTEPSEGSAPGSEP




CTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCTC

ATSGSETPGTSTEPSE




TACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCGA

GSAPGSEPATSGSETP




ACCTGCTACTTCTGGTTCTGAAACTCCAGGTACTTCTA






CCGAACCGTCCGAGGGTAGCGCTCCAGGTAGCGAAC






CTGCTACTTCTGGTTCTGAAACTCCA





 


LCW462_r20
GGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAG
529
GTSTEPSEGSAPGTST
530



GTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGG

EPSEGSAPGTSTEPSE




TACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGT

GSAPGTSTEPSEGSAP




ACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTA

GTSTEPSEGSAPGTST




CCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTAC

EPSEGSAPGTSTEPSE




CTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACT

GSAPGTSESATPESGP




TCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTT

GTSESATPESGPGTST




CTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTC

EPSEGSAPGSEPATSG




TGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCT

SETPGSPAGSPTSTEE




ACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCGAAC






CTGCTACTTCTGGTTCTGAAACCCCAGGTAGCCCGGC






TGGCTCTCCGACCTCCACCGAGGAA





 


LCW462_r23
GGTACTTCTACCGAACCGTCCGAGGGCAGCGCTCCAG
531
GTSTEPSEGSAPGTST
532



GTACTTCTACTGAACCTTCTGAAGGCAGCGCTCCAGG

EPSEGSAPGTSTEPSE




TACTTCTACTGAACCTTCCGAAGGTAGCGCACCAGGT

GSAPGSTSESPSGTAP




TCTACCAGCGAATCCCCTTCTGGTACTGCTCCAGGTTC

GSTSESPSGTAPGTST




TACCAGCGAATCCCCTTCTGGCACCGCACCAGGTACT

PESGSASPGSEPATSG




TCTACCCCTGAAAGCGGCTCCGCTTCTCCAGGTAGCG

SETPGTSESATPESGP




AACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTC

GTSTEPSEGSAPGTST




TGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCT

EPSEGSAPGTSESATP




ACTGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTA

ESGPGTSESATPESGP




CTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGA






AAGCGCAACCCCGGAATCCGGCCCAGGTACCTCTGA






AAGCGCAACCCCGGAGTCCGGCCCA





 


LCW462_r24
GGTAGCTCTACCCCTTCTGGTGCTACCGGCTCTCCAG
533
GSSTPSGATGSPGSSP
534



GTTCTAGCCCGTCTGCTTCTACCGGTACCGGTCCAGG

SASTGTGPGSSTPSGA




TAGCTCTACCCCTTCTGGTGCTACTGGTTCTCCAGGTA

TGSPGSPAGSPTSTEE




GCCCTGCTGGCTCTCCGACTTCTACTGAGGAAGGTAG

GSPAGSPTSTEEGTST




CCCGGCTGGTTCTCCGACTTCTACTGAGGAAGGTACT

EPSEGSAPGASPGTSS




TCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTGCTT

TGSPGSSPSASTGTGP




CCCCGGGCACTAGCTCTACCGGTTCTCCAGGTTCTAG

GTPGSGTASSSPGSTS




CCCTTCTGCATCTACTGGTACTGGCCCAGGTACTCCG

STAESPGPGTSPSGES




GGCAGCGGTACTGCTTCTTCCTCTCCAGGTTCTACTAG

STAPGTSTPESGSASP




CTCTACTGCTGAATCTCCTGGCCCAGGTACTTCTCCTA






GCGGTGAATCTTCTACCGCTCCAGGTACCTCTACTCC






GGAAAGCGGTTCTGCATCTCCA





 


LCW462_r27
GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAG
535
GTSTEPSEGSAPGTSE
536



GTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGG

SATPESGPGTSTEPSE




TACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGT

GSAPGTSTEPSEGSAP




ACTTCTACTGAACCGTCTGAAGGTAGCGCACCAGGTA

GTSESATPESGPGTSE




CTTCTGAAAGCGCAACCCCGGAATCCGGCCCAGGTAC

SATPESGPGTPGSGTA




CTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTACT

SSSPGASPGTSSTGSP




CCTGGCAGCGGTACCGCTTCTTCTTCTCCAGGTGCTTC

GASPGTSSTGSPGSPA




TCCTGGTACTAGCTCTACTGGTTCTCCAGGTGCTTCTC

GSPTSTEEGSPAGSPT




CGGGCACTAGCTCTACTGGTTCTCCAGGTAGCCCTGC

STEEGTSTEPSEGSAP




TGGCTCTCCGACTTCTACTGAGGAAGGTAGCCCGGCT






GGTTCTCCGACTTCTACTGAGGAAGGTACTTCTACCG






AACCTTCCGAAGGTAGCGCTCCA





 


LCW462_r28
GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAG
537
GSPAGSPTSTEEGTST
538



GTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGG

EPSEGSAPGTSTEPSE




TACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGT

GSAPGTSTEPSEGSAP




ACCTCTACCGAACCGTCTGAAGGTAGCGCACCAGGTA

GTSESATPESGPGTSE




CCTCTGAAAGCGCAACTCCTGAGTCCGGTCCAGGTAC

SATPESGPGTPGSGTA




TTCTGAAAGCGCAACCCCGGAGTCTGGCCCAGGTACC

SSSPGSSTPSGATGSP




CCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCT

GASPGTSSTGSPGTST




CTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCT

EPSEGSAPGTSESATP




CCGGGCACCAGCTCTACCGGTTCTCCAGGTACCTCTA

ESGPGTSTEPSEGSAP




CTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGA






AAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACT






GAACCGTCCGAAGGTAGCGCACCA





 


LCW462_r38
GGTAGCGAACCGGCAACCTCCGGCTCTGAAACTCCAG
539
GSEPATSGSETPGTSE
540



GTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGG

SATPESGPGSEPATSG




TAGCGAACCGGCTACTTCCGGCTCTGAAACCCCAGGT

SETPGSSTPSGATGSP




AGCTCTACCCCGTCTGGTGCAACCGGCTCCCCAGGTA

GTPGSGTASSSPGSST




CTCCTGGTAGCGGTACCGCTTCTTCTTCTCCAGGTAGC

PSGATGSPGASPGTSS




TCTACTCCGTCTGGTGCTACCGGCTCCCCAGGTGCAT

TGSPGSSTPSGATGSP




CTCCTGGTACCAGCTCTACCGGTTCTCCAGGTAGCTCT

GASPGTSSTGSPGSEP




ACTCCTTCTGGTGCTACTGGCTCTCCAGGTGCTTCCCC

ATSGSETPGTSTEPSE




GGGTACCAGCTCTACCGGTTCTCCAGGTAGCGAACCT

GSAPGSEPATSGSETP




GCTACTTCTGGTTCTGAAACTCCAGGTACTTCTACCG






AACCGTCCGAGGGTAGCGCTCCAGGTAGCGAACCTG






CTACTTCTGGTTCTGAAACTCCA





 


LCW462_r39
GGTACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAG
541
GTSTEPSEGSAPGTST
542



GTACCTCTACCGAACCGTCCGAGGGCAGCGCACCAG

EPSEGSAPGTSESATP




GTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGG

ESGPGSPAGSPTSTEE




TAGCCCTGCTGGCTCTCCGACTTCTACTGAGGAAGGT

GSPAGSPTSTEEGTST




AGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGGTA

EPSEGSAPGSPAGSPT




CTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTAG

STEEGTSTEPSEGSAP




CCCGGCTGGTTCTCCGACTTCCACCGAGGAAGGTACC

GTSTEPSEGSAPGASP




TCTACTGAACCTTCTGAGGGTAGCGCTCCAGGTACCT

GTSSTGSPGSSPSAST




CTACTGAACCTTCCGAAGGCAGCGCTCCAGGTGCTTC

GTGPGSSPSASTGTGP




CCCGGGCACCAGCTCTACTGGTTCTCCAGGTTCTAGC






CCGTCTGCTTCTACTGGTACTGGTCCAGGTTCTAGCCC






TTCTGCTTCCACTGGTACTGGTCCA





 


LCW462_r41
GGTAGCTCTACCCCGTCTGGTGCTACCGGTTCCCCAG
543
GSSTPSGATGSPGASP
544



GTGCTTCTCCTGGTACTAGCTCTACCGGTTCTCCAGGT

GTSSTGSPGSSTPSGA




AGCTCTACCCCGTCTGGTGCTACTGGCTCTCCAGGTA

TGSPGSPAGSPTSTEE




GCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTAC

GTSESATPESGPGSEP




CTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGC

ATSGSETPGASPGTSS




GAACCGGCAACCTCCGGTTCTGAAACCCCAGGTGCAT

TGSPGSSTPSGATGSP




CTCCTGGTACTAGCTCTACTGGTTCTCCAGGTAGCTCT

GSSPSASTGTGPGSTS




ACTCCGTCTGGTGCAACCGGCTCTCCAGGTTCTAGCC

ESPSGTAPGSTSESPS




CTTCTGCATCTACCGGTACTGGTCCAGGTTCTACCAG

GTAPGTSTPESGSASP




CGAATCCCCTTCTGGTACTGCTCCAGGTTCTACCAGC






GAATCCCCTTCTGGCACCGCACCAGGTACTTCTACCC






CTGAAAGCGGCTCCGCTTCTCCA





 


LCW462_r42
GGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAG
545
GSTSESPSGTAPGSTS
546



GTTCTACTAGCGAATCCCCGTCTGGTACCGCACCAGG

ESPSGTAPGTSPSGES




TACTTCTCCTAGCGGCGAATCTTCTACCGCACCAGGT

STAPGTSESATPESGP




ACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTA

GTSTEPSEGSAPGTST




CCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAC

EPSEGSAPGTSTEPSE




TTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACC

GSAPGTSESATPESGP




TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTT

GTSTEPSEGSAPGTST




CTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTC

PSGATGSPGASPGTSS




TACTGAACCGTCCGAAGGTAGCGCACCAGGTAGCTCT

TGSPGSSTPSGATGSP




ACCCCGTCTGGTGCTACCGGTTCCCCAGGTGCTTCTCC






TGGTACTAGCTCTACCGGTTCTCCAGGTAGCTCTACC






CCGTCTGGTGCTACTGGCTCTCCA





 


LCW462_r43
GGTTCTACTAGCTCTACTGCAGAATCTCCGGGCCCAG
547
GSTSSTAESPGPGTSP
548



GTACCTCTCCTAGCGGTGAATCTTCTACCGCTCCAGG

SGESSTAPGTSPSGES




TACTTCTCCGAGCGGTGAATCTTCTACCGCTCCAGGTT

STAPGSTSSTAESPGP




CTACTAGCTCTACCGCTGAATCTCCGGGTCCAGGTTC

GSTSSTAESPGPGTST




TACCAGCTCTACTGCAGAATCTCCTGGCCCAGGTACT

PESGSASPGTSPSGES




TCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGTACTT

STAPGSTSSTAESPGP




CTCCTAGCGGTGAATCTTCTACCGCTCCAGGTTCTACC

GTSTPESGSASPGSTS




AGCTCTACTGCTGAATCTCCTGGCCCAGGTACTTCTA

STAESPGPGSTSESPS




CCCCGGAAAGCGGCTCCGCTTCTCCAGGTTCTACCAG

GTAPGTSPSGESSTAP




CTCTACCGCTGAATCTCCTGGCCCAGGTTCTACTAGC






GAATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTA






GCGGTGAATCTTCTACTGCACCA





 


LCW462_r45
GGTACCTCTACTCCGGAAAGCGGTTCCGCATCTCCAG
549
GTSTPESGSASPGSTS
550



GTTCTACCAGCGAATCCCCGTCTGGCACCGCACCAGG

ESPSGTAPGSTSSTAE




TTCTACTAGCTCTACTGCTGAATCTCCGGGCCCAGGT

SPGPGTSTEPSEGSAP




ACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTA

GTSTEPSEGSAPGTSE




CCTCTACCGAACCGTCCGAGGGCAGCGCACCAGGTAC

SATPESGPGTSESATP




TTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTACC

ESGPGTSTEPSEGSAP




TCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCT

GTSTEPSEGSAPGTSE




CTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTC

SATPESGPGTSTEPSE




TACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT

GSAPGTSTEPSEGSAP




GAAAGCGCTACTCCGGAGTCCGGTCCAGGTACCTCTA






CCGAACCGTCCGAAGGCAGCGCTCCAGGTACTTCTAC






TGAACCTTCTGAGGGTAGCGCTCCC





 


LCW462_r47
GGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAG
551
GTSTEPSEGSAPGTST
552



GTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGG

EPSEGSAPGSEPATSG




TAGCGAACCGGCAACCTCCGGTTCTGAAACTCCAGGT

SETPGTSTEPSEGSAP




ACTTCTACTGAACCGTCTGAAGGTAGCGCACCAGGTA

GTSESATPESGPGTSE




CTTCTGAAAGCGCAACCCCGGAATCCGGCCCAGGTAC

SATPESGPGASPGTSS




CTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTGC

TGSPGSSPSASTGTGP




ATCTCCGGGTACTAGCTCTACCGGTTCTCCAGGTTCTA

GSSTPSGATGSPGSST




GCCCTTCTGCTTCCACTGGTACCGGCCCAGGTAGCTC

PSGATGSPGSSTPSGA




TACCCCGTCTGGTGCTACTGGTTCCCCAGGTAGCTCT

TGSPGASPGTSSTGSP




ACTCCGTCTGGTGCAACCGGTTCCCCAGGTAGCTCTA






CTCCTTCTGGTGCTACTGGCTCCCCAGGTGCATCCCCT






GGCACCAGCTCTACCGGTTCTCCA





 


LCW462_r54
GGTAGCGAACCGGCAACCTCTGGCTCTGAAACTCCAG
553
GSEPATSGSETPGSEP
554



GTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGG

ATSGSETPGTSTEPSE




TACTTCTACTGAACCTTCTGAGGGCAGCGCACCAGGT

GSAPGSEPATSGSETP




AGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTA

GTSESATPESGPGTST




CCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTAC

EPSEGSAPGSSTPSGA




TTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAGC

TGSPGSSTPSGATGSP




TCTACTCCGTCTGGTGCTACCGGCTCTCCAGGTAGCTC

GASPGTSSTGSPGSST




TACCCCTTCTGGTGCAACCGGCTCCCCAGGTGCTTCTC

PSGATGSPGASPGTSS




CGGGTACCAGCTCTACTGGTTCTCCAGGTAGCTCTAC

TGSPGSSTPSGATGSP




CCCGTCTGGTGCTACCGGTTCCCCAGGTGCTTCTCCTG






GTACTAGCTCTACCGGTTCTCCAGGTAGCTCTACCCC






GTCTGGTGCTACTGGCTCTCCA





 


LCW462_r55
GGTACTTCTACCGAACCGTCCGAGGGCAGCGCTCCAG
555
GTSTEPSEGSAPGTST
556



GTACTTCTACTGAACCTTCTGAAGGCAGCGCTCCAGG

EPSEGSAPGTSTEPSE




TACTTCTACTGAACCTTCCGAAGGTAGCGCACCAGGT

GSAPGTSESATPESGP




ACTTCTGAAAGCGCTACTCCGGAGTCCGGTCCAGGTA

GTSTEPSEGSAPGTST




CCTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTAC

EPSEGSAPGSTSESPS




TTCTACTGAACCTTCTGAGGGTAGCGCTCCAGGTTCT

GTAPGTSPSGESSTAP




ACTAGCGAATCTCCGTCTGGCACTGCTCCAGGTACTT

GTSPSGESSTAPGSPA




CTCCTAGCGGTGAATCTTCTACCGCTCCAGGTACTTCC

GSPTSTEEGTSESATP




CCTAGCGGCGAATCTTCTACCGCTCCAGGTAGCCCGG

ESGPGTSTEPSEGSAP




CTGGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGA






AAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACT






GAACCGTCCGAAGGTAGCGCTCCA





 


LCW462_r57
GGTACTTCTACTGAACCTTCCGAAGGTAGCGCTCCAG
557
GTSTEPSEGSAPGSEP
558



GTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGG

ATSGSETPGSPAGSPT




TAGCCCGGCTGGCTCTCCGACCTCCACCGAGGAAGGT

STEEGSPAGSPTSTEE




AGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTA

GTSESATPESGPGTST




CTTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTAC

EPSEGSAPGTSTEPSE




CTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTACC

GSAPGTSTEPSEGSAP




TCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTACCT

GTSESATPESGPGSST




CTACCGAACCGTCCGAGGGCAGCGCACCAGGTACTTC

PSGATGSPGSSPSAST




TGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCTCT

GTGPGASPGTSSTGSP




ACTCCGTCTGGTGCAACCGGCTCCCCAGGTTCTAGCC






CGTCTGCTTCCACTGGTACTGGCCCAGGTGCTTCCCC






GGGCACCAGCTCTACTGGTTCTCCA





 


LCW462_r61
GGTAGCGAACCGGCTACTTCCGGCTCTGAGACTCCAG
559
GSEPATSGSETPGSPA
560



GTAGCCCTGCTGGCTCTCCGACCTCTACCGAAGAAGG

GSPTSTEEGTSESATP




TACCTCTGAAAGCGCTACCCCTGAGTCTGGCCCAGGT

ESGPGTSTEPSEGSAP




ACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTA

GTSTEPSEGSAPGTSE




CCTCTACCGAACCGTCCGAGGGCAGCGCACCAGGTAC

SATPESGPGTSTPESG




TTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTACC

SASPGSTSESPSGTAP




TCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTTCTA

GSTSSTAESPGPGTSE




CCAGCGAATCCCCGTCTGGCACCGCACCAGGTTCTAC

SATPESGPGTSTEPSE




TAGCTCTACTGCTGAATCTCCGGGCCCAGGTACTTCT

GSAPGTSTEPSEGSAP




GAAAGCGCTACTCCGGAGTCCGGTCCAGGTACCTCTA






CCGAACCGTCCGAAGGCAGCGCTCCAGGTACTTCTAC






TGAACCTTCTGAGGGTAGCGCTCCA





 


LCW462_r64
GGTACTTCTACCGAACCGTCCGAGGGCAGCGCTCCAG
561
GTSTEPSEGSAPGTST
562



GTACTTCTACTGAACCTTCTGAAGGCAGCGCTCCAGG

EPSEGSAPGTSTEPSE




TACTTCTACTGAACCTTCCGAAGGTAGCGCACCAGGT

GSAPGTSTEPSEGSAP




ACCTCTACCGAACCGTCTGAAGGTAGCGCACCAGGTA

GTSESATPESGPGTSE




CCTCTGAAAGCGCAACTCCTGAGTCCGGTCCAGGTAC

SATPESGPGTPGSGTA




TTCTGAAAGCGCAACCCCGGAGTCTGGCCCAGGTACT

SSSPGSSTPSGATGSP




CCTGGCAGCGGTACCGCATCTTCCTCTCCAGGTAGCT

GASPGTSSTGSPGSTS




CTACTCCGTCTGGTGCAACTGGTTCCCCAGGTGCTTCT

STAESPGPGTSPSGES




CCGGGTACCAGCTCTACCGGTTCTCCAGGTTCCACCA

STAPGTSTPESGSASP




GCTCTACTGCTGAATCTCCTGGTCCAGGTACCTCTCCT






AGCGGTGAATCTTCTACTGCTCCAGGTACTTCTACTCC






TGAAAGCGGCTCTGCTTCTCCA





 


LCW462_r67
GGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAG
563
GSPAGSPTSTEEGTSE
564



GTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGG

SATPESGPGTSTEPSE




TACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGT

GSAPGTSESATPESGP




ACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTA

GSEPATSGSETPGTST




GCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGTAC

EPSEGSAPGSPAGSPT




TTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTAGC

STEEGTSTEPSEGSAP




CCGGCTGGTTCTCCGACTTCCACCGAGGAAGGTACCT

GTSTEPSEGSAPGTST




CTACTGAACCTTCTGAGGGTAGCGCTCCAGGTACCTC

EPSEGSAPGTSTEPSE




TACTGAACCTTCCGAAGGCAGCGCTCCAGGTACTTCT

GSAPGTSTEPSEGSAP




ACCGAACCGTCCGAGGGCAGCGCTCCAGGTACTTCTA






CTGAACCTTCTGAAGGCAGCGCTCCAGGTACTTCTAC






TGAACCTTCCGAAGGTAGCGCACCA





 


LCW462_r69
GGTACTTCTCCGAGCGGTGAATCTTCTACCGCACCAG
565
GTSPSGESSTAPGSTS
566



GTTCTACTAGCTCTACCGCTGAATCTCCGGGCCCAGG

STAESPGPGTSPSGES




TACTTCTCCGAGCGGTGAATCTTCTACTGCTCCAGGT

STAPGTSESATPESGP




ACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTA

GTSTEPSEGSAPGTST




CCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAC

EPSEGSAPGSSPSAST




TTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTTCT

GTGPGSSTPSGATGSP




AGCCCTTCTGCATCTACTGGTACTGGCCCAGGTAGCT

GASPGTSSTGSPGTST




CTACTCCTTCTGGTGCTACCGGCTCTCCAGGTGCTTCT

PESGSASPGTSPSGES




CCGGGTACTAGCTCTACCGGTTCTCCAGGTACTTCTA

STAPGTSPSGESSTAP




CTCCGGAAAGCGGTTCCGCATCTCCAGGTACTTCTCC






TAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTCCTA






GCGGCGAATCTTCTACTGCTCCA





 


LCW462_r70
GGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAG
567
GTSESATPESGPGTST
568



GTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGG

EPSEGSAPGTSTEPSE




TACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGT

GSAPGSPAGSPTSTEE




AGCCCTGCTGGCTCTCCGACTTCTACTGAGGAAGGTA

GSPAGSPTSTEEGTST




GCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGGTAC

EPSEGSAPGSSPSAST




TTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTTCT

GTGPGSSTPSGATGSP




AGCCCTTCTGCTTCCACCGGTACTGGCCCAGGTAGCT

GSSTPSGATGSPGSEP




CTACCCCTTCTGGTGCTACCGGCTCCCCAGGTAGCTCT

ATSGSETPGTSESATP




ACTCCTTCTGGTGCAACTGGCTCTCCAGGTAGCGAAC

ESGPGSEPATSGSETP




CGGCAACTTCCGGCTCTGAAACCCCAGGTACTTCTGA






AAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAACCT






GCTACCTCTGGCTCTGAAACCCCA





 


LCW462_r72
GGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAG
569
GTSTEPSEGSAPGTST
570



GTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGG

EPSEGSAPGTSTEPSE




TACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGT

GSAPGSSTPSGATGSP




AGCTCTACCCCGTCTGGTGCTACCGGTTCCCCAGGTG

GASPGTSSTGSPGSST




CTTCTCCTGGTACTAGCTCTACCGGTTCTCCAGGTAGC

PSGATGSPGTSESATP




TCTACCCCGTCTGGTGCTACTGGCTCTCCAGGTACTTC

ESGPGSEPATSGSETP




TGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGA

GTSTEPSEGSAPGSTS




ACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCT

ESPSGTAPGSTSESPS




ACCGAACCGTCCGAAGGTAGCGCACCAGGTTCTACTA

GTAPGTSTPESGSASP




GCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAG






CGAATCTCCGTCTGGCACTGCACCAGGTACCTCTACC






CCTGAAAGCGGTTCCGCTTCTCCA





 


LCW462_r73
GGTACCTCTACTCCTGAAAGCGGTTCTGCATCTCCAG
571
GTSTPESGSASPGSTS
572



GTTCCACTAGCTCTACCGCAGAATCTCCGGGCCCAGG

STAESPGPGSTSSTAE




TTCTACTAGCTCTACTGCTGAATCTCCTGGCCCAGGTT

SPGPGSSPSASTGTGP




CTAGCCCTTCTGCATCTACTGGTACTGGCCCAGGTAG

GSSTPSGATGSPGASP




CTCTACTCCTTCTGGTGCTACCGGCTCTCCAGGTGCTT

GTSSTGSPGSEPATSG




CTCCGGGTACTAGCTCTACCGGTTCTCCAGGTAGCGA

SETPGTSESATPESGP




ACCGGCAACCTCCGGCTCTGAAACCCCAGGTACCTCT

GSPAGSPTSTEEGSTS




GAAAGCGCTACTCCTGAATCCGGCCCAGGTAGCCCGG

ESPSGTAPGSTSESPS




CAGGTTCTCCGACTTCCACTGAGGAAGGTTCTACTAG

GTAPGTSTPESGSASP




CGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGC






GAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCC






CTGAAAGCGGTTCCGCTTCTCCC





 


LCW462_r78
GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAG
573
GSPAGSPTSTEEGTSE
574



GTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCAGG

SATPESGPGTSTEPSE




TACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGT

GSAPGSTSESPSGTAP




TCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTT

GSTSESPSGTAPGTSP




CTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTAC

SGESSTAPGTSTEPSE




TTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTACC

GSAPGSPAGSPTSTEE




TCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTAGCC

GTSTEPSEGSAPGSEP




CGGCAGGTTCTCCTACTTCCACTGAGGAAGGTACTTC

ATSGSETPGTSESATP




TACCGAACCTTCTGAGGGTAGCGCACCAGGTAGCGA

ESGPGTSTEPSEGSAP




ACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCT






GAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTA






CTGAACCGTCCGAGGGCAGCGCACCA





 


LCW462_r79
GGTACCTCTACCGAACCTTCCGAAGGTAGCGCTCCAG
575
GTSTEPSEGSAPGSPA
576



GTAGCCCGGCAGGTTCTCCTACTTCCACTGAGGAAGG

GSPTSTEEGTSTEPSE




TACTTCTACCGAACCTTCTGAGGGTAGCGCACCAGGT

GSAPGTSPSGESSTAP




ACCTCCCCTAGCGGCGAATCTTCTACTGCTCCAGGTA

GTSPSGESSTAPGTSP




CCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTAC

SGESSTAPGSTSESPS




CTCCCCTAGCGGTGAATCTTCTACCGCACCAGGTTCT

GTAPGSTSESPSGTAP




ACCAGCGAATCCCCTTCTGGTACTGCTCCAGGTTCTA

GTSTPESGSASPGSEP




CCAGCGAATCCCCTTCTGGCACCGCACCAGGTACTTC

ATSGSETPGTSESATP




TACCCCTGAAAGCGGCTCCGCTTCTCCAGGTAGCGAA

ESGPGTSTEPSEGSAP




CCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTG






AAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTAC






TGAACCGTCCGAGGGCAGCGCACCA





 


LCW462_r87
GGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAG
577
GSEPATSGSETPGTSE
578



GTACCTCTGAAAGCGCTACTCCGGAATCTGGTCCAGG

SATPESGPGTSESATP




TACTTCTGAAAGCGCTACTCCGGAATCCGGTCCAGGT

ESGPGTSPSGESSTAP




ACTTCTCCGAGCGGTGAATCTTCTACCGCACCAGGTT

GSTSSTAESPGPGTSP




CTACTAGCTCTACCGCTGAATCTCCGGGCCCAGGTAC

SGESSTAPGSTSESPS




TTCTCCGAGCGGTGAATCTTCTACTGCTCCAGGTTCTA

GTAPGTSPSGESSTAP




CTAGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTC

GSTSSTAESPGPGSST




CCCTAGCGGTGAATCTTCTACTGCTCCAGGTTCTACC

PSGATGSPGSSTPSGA




AGCTCTACCGCAGAATCTCCGGGTCCAGGTAGCTCTA

TGSPGSSTPSGANWL




CTCCGTCTGGTGCAACCGGTTCCCCAGGTAGCTCTAC

S




CCCTTCTGGTGCAACCGGCTCCCCAGGTAGCTCTACC






CCTTCTGGTGCAAACTGGCTCTCC





 


LCW462_r88
GGTAGCCCTGCTGGCTCTCCGACTTCTACTGAGGAAG
579
GSPAGSPTSTEEGSPA
580



GTAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGG

GSPTSTEEGTSTEPSE




TACTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGT

GSAPGTSTEPSEGSAP




ACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTA

GTSTEPSEGSAPGTSE




CCTCTACCGAACCGTCCGAGGGCAGCGCACCAGGTAC

SATPESGPGASPGTSS




TTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTGCA

TGSPGSSTPSGATGSP




TCTCCTGGTACCAGCTCTACCGGTTCTCCAGGTAGCTC

GASPGTSSTGSPGSST




TACTCCTTCTGGTGCTACTGGCTCTCCAGGTGCTTCCC

PSGATGSPGTPGSGT




CGGGTACCAGCTCTACCGGTTCTCCAGGTAGCTCTAC

ASSSPGSSTPSGATGS




CCCGTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGC

P




AGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCC






TTCTGGTGCTACTGGCTCTCCA





 


LCW462_r89
GGTAGCTCTACCCCGTCTGGTGCTACTGGTTCTCCAG
581
GSSTPSGATGSPGTPG
582



GTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGG

SGTASSSPGSSTPSGA




TAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTA

TGSPGSPAGSPTSTEE




GCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTAC

GTSESATPESGPGTST




TTCTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACC

EPSEGSAPGTSESATP




TCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTACCT

ESGPGSEPATSGSETP




CTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGA

GTSESATPESGPGTST




ACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCT

EPSEGSAPGTSESATP




GAAAGCGCAACCCCGGAATCTGGTCCAGGTACTTCTA

ESGPGTSESATPESGP




CTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGA






AAGCGCAACCCCGGAATCCGGCCCAGGTACCTCTGA






AAGCGCAACCCCGGAGTCCGGCCCA









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. Plasmid was 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 of 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-KpnIforP: AGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 583) and the non-phosphorylated oligonucleotide BsaI-AscI-KpnIrev: CCTCGAGTGAAGACGAACCTCCCGTGCTTGGCGCGCCGCTTGCGCTTGC (SEQ ID NO: 584) for introducing the sequencing island A (SI-A) which encodes amino acids GASASGAPSTG (SEQ ID NO: 585) 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-KpnIforP: AGGTCCAGAACCAACGGGGCCGGCCCCAAGCGGAGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 586) and the non-phosphorylated oligonucleotide BsaI-FseI-KpnIrev: CCTCGAGTGAAGACGAACCTCCGCTTGGGGCCGGCCCCGTTGGTTCTGG (SEQ ID NO: 587) for introducing the sequencing island B (SI-B) which encodes amino acids GPEPTGPAPSG (SEQ ID NO: 588) 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 (<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 13).







TABLE 13







Theoretical Diversity and Sampling Numbers for


12mer 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
MASPAGSPTSTEE
589
572
2 plates







(168)


 


LCW547
AE12
MATSESATPESGP
590
1536
5 plates







(420)


 


LCW548
AF12
MATSPSGESSTAP
591
192
2 plates







(168)


 


LCW549
AF12
MESTSSTAESPGP
592
384
2 plates







(168)


 


LCW552
AG12
MASSTPSGATGSP
593
384
2 plates







(168)


 


LCW553
AG12
MEASPGTSSTGSP
594
384
2 plates







(168)


 


LCW554
(CBD-
MASTPESGSSG
595
32
1 plate



like)



(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. 9 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 <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 14), 4 from LCW546, 4 from LCW547 and 4 from LCW552 were selected for further optimization.







TABLE 14







Advanced 12mer DNA Nucleotide Sequences









Clone
DNA Nucleotide Sequence
SEQ ID NO:





LCW546_02
ATGGCTAGTCCGGCTGGCTCTCCGACCTCCACTGAGGAAGGTACTTCTACT
596


 


LCW546_06
ATGGCTAGTCCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACTTCTACT
597


 


LCW546_07
ATGGCTAGTCCAGCAGGCTCTCCTACCTCCACCGAGGAAGGTACTTCTACT
598


 


LCW546_09
ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTACT
599


 


LCW547_03
ATGGCTACATCCGAAAGCGCAACCCCTGAGTCCGGTCCAGGTACTTCTACT
600


 


LCW547_06
ATGGCTACATCCGAAAGCGCAACCCCTGAATCTGGTCCAGGTACTTCTACT
601


 


LCW547_10
ATGGCTACGTCTGAAAGCGCTACTCCGGAATCTGGTCCAGGTACTTCTACT
602


 


LCW547_17
ATGGCTACGTCCGAAAGCGCTACCCCTGAATCCGGTCCAGGTACTTCTACT
603


 


LCW552_03
ATGGCTAGTTCTACCCCGTCTGGTGCAACCGGTTCCCCAGGTACTTCTACT
604


 


LCW552_05
ATGGCTAGCTCCACTCCGTCTGGTGCTACCGGTTCCCCAGGTACTTCTACT
605


 


LCW552_10
ATGGCTAGCTCTACTCCGTCTGGTGCTACTGGTTCCCCAGGTACTTCTACT
606


 


LCW552_11
ATGGCTAGTTCTACCCCTTCTGGTGCTACTGGTTCTCCAGGTACTTCTACT
607









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. 10). 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. 11). 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 15. 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 15







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 16.







TABLE 16







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. 12). 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 17).







TABLE 17







Relative Performance of Clones Starting


with LCW546_06 and LCW459_09













All

All



LCW546_06
Others
LCW546_09
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 18. 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 18







Combinatorial 12mer and 36mer Clones Superior to Benchmark Clone











Clone Name
First 60 codons
SEQ ID NO:
12mer Name
36mer Name





LCW580_51
ATGGCTAGTCCTGCTGGCTCTCCAACCTCCACT
608
LCW546_06
LCW0404_040



GAGGAAGGTGCATCCCCGGGCACCAGCTCTACC






GGTTCTCCAGGTAGCTCTACCCCGTCTGGTGCT






ACCGGCTCTCCAGGTAGCTCTACCCCGTCTGGT






GCTACTGGCTCTCCAGGTACTTCTACTGAACCG






TCTGAAGGCAGCGCA





 


LCW580_81
ATGGCTAGTCCTGCTGGCTCTCCAACCTCCACT
609
LCW546_06
LCW0404_040



GAGGAAGGTGCATCCCCGGGCACCAGCTCTACC






GGTTCTCCAGGTAGCTCTACCCCGTCTGGTGCT






ACCGGCTCTCCAGGTAGCTCTACCCCGTCTGGT






GCTACTGGCTCTCCAGGTACTTCTACTGAACCG






TCTGAAGGCAGCGCA





 


LCW580_38
ATGGCTAGTCCTGCTGGCTCTCCAACCTCCACT
610
LCW546_06
LCW0402_041



GAGGAAGGTACTTCTACCGAACCGTCCGAGGGT






AGCGCACCAGGTAGCCCAGCAGGTTCTCCTACC






TCCACCGAGGAAGGTACTTCTACCGAACCGTCC






GAGGGTAGCGCACCAGGTACTTCTACTGAACCG






TCTGAAGGCAGCGCA





 


LCW580_63
ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACT
611
LCW546_09
LCW0402_020



GAGGAAGGTACTTCTACTGAACCGTCTGAAGGC






AGCGCACCAGGTAGCGAACCGGCTACTTCCGGT






TCTGAAACCCCAGGTAGCCCAGCAGGTTCTCCA






ACTTCTACTGAAGAAGGTACTTCTACTGAACCG






TCTGAAGGCAGCGCA





 


LCW580_06
ATGGCTAGTCCTGCTGGCTCTCCAACCTCCACT
612
LCW546_06
LCW0404_031



GAGGAAGGTACCCCGGGTAGCGGTACTGCTTCT






TCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCAA






CCGGCTCTCCAGGTGCTTCTCCGGGCACCAGCT






CTACCGGTTCTCCAGGTACTTCTACTGAACCGT






CTGAAGGCAGCGCA





 


LCW580_35
ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACT
613
LCW546_09
LCW0402_020



GAGGAAGGTACTTCTACTGAACCGTCTGAAGGC






AGCGCACCAGGTAGCGAACCGGCTACTTCCGGT






TCTGAAACCCCAGGTAGCCCAGCAGGTTCTCCA






ACTTCTACTGAAGAAGGTACTTCTACTGAACCG






TCTGAAGGCAGCGCA





 


LCW580_67
ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACT
614
LCW546_09
LCW0403_064



GAGGAAGGTACCTCCCCTAGCGGCGAATCTTCT






ACTGCTCCAGGTACCTCTCCTAGCGGCGAATCT






TCTACCGCTCCAGGTACCTCCCCTAGCGGTGAA






TCTTCTACCGCACCAGGTACTTCTACTGAACCG






TCTGAAGGCAGCGCA





 


LCW580_13
ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACT
615
LCW546_09
LCW0403_060



GAGGAAGGTACCTCTACTCCGGAAAGCGGTTCC






GCATCTCCAGGTTCTACCAGCGAATCCCCGTCT






GGCACCGCACCAGGTTCTACTAGCTCTACTGCT






GAATCTCCGGGCCCAGGTACTTCTACTGAACCG






TCTGAAGGCAGCGCA





 


LCW580_88
ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACT
616
LCW546_09
LCW0403_064



GAGGAAGGTACCTCCCCTAGCGGCGAATCTTCT






ACTGCTCCAGGTACCTCTCCTAGCGGCGAATCT






TCTACCGCTCCAGGTACCTCCCCTAGCGGTGAA






TCTTCTACCGCACCAGGTACTTCTACTGAACCG






TCTGAAGGCAGCGCA





 


LCW580_11
ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACT
617
LCW546_09
LCW0403_060



GAGGAAGGTACCTCTACTCCGGAAAGCGGTTCC






GCATCTCCAGGTTCTACCAGCGAATCCCCGTCT






GGCACCGCACCAGGTTCTACTAGCTCTACTGCT






GAATCTCCGGGCCCAGGTACTTCTACTGAACCG






TCTGAAGGCAGCGCA









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 19 and 20). 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 19







Preferred N-terminal Combinations for XTEN-AM875














Number of







Clone Name
Replicates
12mer
36mer
Mean
SD
CV





CBD-AM875
NA
NA
NA
1715
418
16%


LCW587_08
7
LCW546_06_3 = GAA
LCW404_40
2333
572
18%


LCW587_17
5
LCW546_09_3 = GAA
LCW403_64
2172
293
10%
















TABLE 20







Preferred N-terminal Combinations for XTEN-AE864














Number of







Clone 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 19 and 20), 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 21 and the preferred clones were analyzed by SDS-PAGE to independently confirm expression (see FIG. 13). The complete sequences of XTEN_AM923 and XTEN_AE912 were selected for further analysis.








TABLE 21







Preferred DNA Nucleotide Sequences for first 48 Amino Acid Residues



of N-terminal XTEN-AM875 and XTEN-AE864












XTEN

SEQ ID


Clone Name
Modified
DNA Nucleotide Sequence
NO:





LCW587_08
AM875
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTGCATC
618




CCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTG





GTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGC





TCTCCAGGTACTTCTACTGAACCGTCTGAAGGCAGCGCA



 


LCW587_17
AM875
ATGGCTGAACCTGCTGGCTCTCCGACCTCTACTGAGGAAGGTACCTC
619




CCCTAGCGGCGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCG





AATCTTCTACCGCTCCAGGTACCTCCCCTAGCGGTGAATCTTCTACC





GCACCAGGTACTTCTACTGAACCGTCTGAAGGCAGCGCA



 


LCW588_14
AE864
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACCCC
620




GGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGG





TGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAGCTCTACCGGTT





CTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTACTGAG



 


LCW588_27
AE864
ATGGCTGAAACTGCTGGCTCTCCAACCTCCACTGAGGAAGGTGCATC
621




CCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTG





GTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGC





TCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTACTGAG









Example 18: Methods of Producing and Evaluating GHXTEN; XTEN-hGH as Example
A general schema for producing and evaluating GHXTEN compositions is presented in FIG. 6, and forms the basis for the general description of this Example. Using the disclosed methods and those known to one of ordinary skill in the art, together with guidance provided in the illustrative examples, a skilled artesian can create and evaluate a range of GHXTEN fusion proteins comprising, XTENs, GH and variants of GH known in the art. The Example is, therefore, to be construed as merely illustrative, and not limitative of the methods in any way whatsoever; numerous variations will be apparent to the ordinarily skilled artisan. In this Example, a GHXTEN of human growth hormone linked to an XTEN of the AE family of motifs would be created.
The general scheme for producing polynucleotides encoding XTEN is presented in FIGS. 4 and 5. FIG. 5 is a schematic flowchart of representative steps in the assembly of a XTEN polynucleotide construct in one of the embodiments of the invention. Individual oligonucleotides 501 are 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. The motif libraries can be limited to specific sequence XTEN families; e.g., AD, AE, AF, AG, AM, or AQ sequences of Table 1. In this case, the motifs of the AE family would be used as the motif library, which are annealed to the 12-mer to create a “building block” length; e.g., a segment that encodes 36 amino acids. The gene encoding the XTEN sequence can be assembled by ligation and multimerization of the “building blocks” until the desired length of the XTEN gene 504 is achieved. As illustrated in FIG. 5, the XTEN length in this case is 48 amino acid residues, but longer lengths can be achieved by this process. For example, multimerization can be performed by ligation, overlap extension, PCR assembly or similar cloning techniques known in the art. The XTEN gene can be cloned into a stuffer vector. In the example illustrated in FIG. 5, the vector can encode a Flag sequence 506 followed by a stuffer sequence that is flanked by BsaI, BbsI, and KpnI sites 507 and a GH gene (e.g., hGH) 508, resulting in the gene encoding the GHXTEN 500, which, in this case encodes the fusion protein in the configuration, N- to C-terminus, XTEN-hGH.
DNA sequences encoding GH can be conveniently obtained by standard procedures known in the art from a cDNA library prepared from an appropriate cellular source, from a genomic library, or may be created synthetically (e.g., automated nucleic acid synthesis) using DNA sequences obtained from publicly available databases, patents, or literature references. A gene or polynucleotide encoding the GH portion of the protein can be then be cloned into a construct, such as those described herein, 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. A second gene or polynucleotide coding for the XTEN portion (in the case of FIG. 5 illustrated as an AE with 48 amino acid residues) can be genetically fused to the nucleotides encoding the N-terminus of the hGH gene by cloning it into the construct adjacent and in frame with the gene coding for the hGH, through a ligation or multimerization step. In this manner, a chimeric DNA molecule coding for (or complementary to) the XTEN-hGH GHXTEN fusion protein would be generated within the construct. Optionally, a gene encoding for a second XTEN could be inserted and ligated in-frame to the nucleotides encoding the C-terminus of the XTEN-hGH gene, resulting in a construct encoding an XTEN-hGH-XTEN fusion protein. The construct can be designed in different configurations to encode the various permutations of the fusion partners as a monomeric polypeptide. For example, the gene can be created to encode the fusion protein in the order (N- to C-terminus): hGH-XTEN; XTEN-hGH; hGH-XTEN-hGH; XTEN-hGH-XTEN; as well as multimers of the foregoing. 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 would be transformed with the chimeric DNA molecule. The vectors containing the DNA segments of interest can be transferred into an appropriate host cell by well-known methods, depending on the type of cellular host, as described supra.
Host cells containing the XTEN-GH expression vector would be cultured in conventional nutrient media modified as appropriate for activating the promoter. 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. After expression of the fusion protein, cells would be harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for purification of the fusion protein, as described below. For GHXTEN compositions secreted by the host cells, supernatant from centrifugation would be separated and retained for further purification.
Gene expression would 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, gene expression would be measured by immunological of fluorescent methods, such as immunohistochemical staining of cells 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 the hGH sequence polypeptide using a synthetic peptide based on the sequences provided herein or against exogenous sequence fused to hGH and encoding a specific antibody 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).
The XTEN-hGH polypeptide product would be purified via methods known in the art. Procedures such as gel filtration, affinity purification, salt fractionation, ion exchange chromatography, size exclusion chromatography, hydroxyapatite adsorption chromatography, hydrophobic interaction chromatography or gel electrophoresis are all techniques that may be used in the purification. Specific 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).
As illustrated in FIG. 6, the isolated XTEN-hGH fusion proteins would then be characterized for their chemical and activity properties. Isolated fusion protein would be characterized, e.g., for sequence, purity, apparent molecular weight, solubility and stability using standard methods known in the art. The fusion protein meeting expected standards would then be evaluated for activity, which can be measured in vitro or in vivo by measuring one of the growth hormone-associated parameters described herein, using one or more assays disclosed herein, or using the assays of the Examples or Table 34.
In addition, the XTEN-hGH fusion protein would be administered to one or more animal species to determine standard pharmacokinetic parameters, as described in Examples 30-32.
By the iterative process of producing, expressing, and recovering XTEN-hGH constructs, followed by their characterization using methods disclosed herein or others known in the art, the GHXTEN compositions comprising hGH and an XTEN can be produced and evaluated by one of ordinary skill in the art to confirm the expected properties such as enhanced solubility, enhanced stability, improved pharmacokinetics and reduced immunogenicity, leading to an overall enhanced therapeutic activity compared to the corresponding unfused hGH. For those fusion proteins not possessing the desired properties, a different sequence can be constructed, expressed, isolated and evaluated by these methods in order to obtain a composition with such properties.
Example 19: Construction of Genes and Vectors of hGH Linked to K and Y XTEN Sequences
K Series GHXTEN Constructs
A pET-series vector was constructed with T7 promoter, which expresses a protein containing cellulose binding domain (CBD) at the N-terminus, followed by a Tomato Etch Virus (TEV) protease cleavage site, followed by the hGH coding sequence, and by the K288 coding sequence: CBD-K288-hGH. The K288 has the repetitive sequence (GEGGGEGGE)32 (SEQ ID NO: 622). The CBD sequence used is shown in Swissprot file Q06851 and the purification of CBD fusion proteins is described in Ofir, K. et al. (2005) Proteomics 5:1806. The sequence of the TEV cleavage site is ENLYFQ/X (SEQ ID NO: 623); G was used in the X position. This construct was transformed into BL21(DE3)-star E. coli strain and grown under conditions promoting expression. Cells were collected and disrupted. The cellular supernatant was applied on beaded cellulose resin (Perloza 100), washed with buffer A (25 mM Tris pH=8.0) and eluted from the column with 20 mM NaOH. pH was adjusted by titrating the sample with 1M Tris buffer pH=8.0. Protein purity was estimated to be above 90%. The eluted protein was digested with purified TEV protease overnight at 4° C., and the digested sample was applied to a beaded cellulose resin (Perloza 100). The CBD was retained on the column, and the K288-hGH was found in the column flow-through. The pooled flow-through was loaded on the anion-exchange (Q-sepharose, Pharmacia), washed with buffer A (25 mM Tris pH=8.0) and eluted from the column using a shallow linear gradient of same buffer with 1M NaCl. The eluted fusion protein was pooled, dialyzed against buffer A, concentrated, and purified by size-exclusion chromatography (SEC) as the final purification. Protein purity was estimated to be above 98%. The final protein is K288-hGH. SDS PAGE analyses of samples throughout the purification process are shown in FIG. 20.
Y Series GHXTEN Constructs
The gene encoding hGH was amplified by polymerase chain reaction (PCR), which introduced BbsI and HindIII restriction sites that are compatible with the BbsI and HindIII sites that flank the stuffer in the XTEN destination vector. The pCBD-XTEN plasmid is a pET30 derivative from Novagen in the format of Cellulose Binding Domain (CBD)-XTEN-Stuffer, where Stuffer is green fluorescent protein (GFP) and XTEN can be any length from 36 to 576 or greater. Constructs were generated by replacing a stuffer sequence in pCBD-XTEN with the hGH-encoding fragment (FIG. 7B). The pCBD-XTEN features a T7 promoter upstream of CBD followed by an XTEN sequence fused in-frame upstream of the stuffer sequence. The XTEN sequences employed belong to family XTEN_Y and encode lengths that include 36, 72, 144, 288, and 576 amino acids. The stuffer fragment was removed by restriction digest using BbsI and HindIII endonucleases. Restriction digested hGH DNA fragment was ligated into the cleaved pCBD-XTEN vector using T4 DNA ligase and electroporated into BL21(DE3) Gold (Stratagene). Transformants were screened by DNA miniprep and the desired construct was confirmed by DNA sequencing. The final vector yields the CBD_XTEN_hGH gene under the control of a T7 promoter. The resulting DNA sequences encoded for GH linked to XTEN of lengths of 36, 72, 144, and 288 amino acids, respectively.
Example 20: Construction of hGH-XTEN Genes and Vectors Using AE and AM XTEN Sequences
The gene encoding hGH was amplified by polymerase chain reaction (PCR), which introduced NdeI and BbsI restriction sites that are compatible with the NdeI and BsaI sites that flank the stuffer in the XTEN destination vector. The pXTEN plasmid is a pET30 derivative from Novagen in the format of Stuffer-XTEN, where Stuffer can be either green fluorescent protein (GFP) or CBD and XTEN can be any length from 36 to 1318 amino acids or greater (FIG. 7). Constructs were generated by replacing a stuffer sequence in pXTEN with the hGH-encoding fragment. The pXTEN features a T7 promoter upstream of the stuffer sequence, and an XTEN sequence fused in-frame downstream of the stuffer sequence. The XTEN sequences employed belong to the AE or AM family of XTEN and encode lengths that include 36, 72, 144, 288, 576, 864, 875 and 1318 amino acids. The stuffer fragment was removed by restriction digest using NdeI and BsaI endonucleases. Restriction digested hGH DNA fragment was ligated into the cleaved pXTEN vector using T4 DNA ligase and electroporated into BL21(DE3) Gold (Stratagene). Transformants were screened by DNA miniprep and the desired constructs were confirmed by DNA sequencing. The final vector yields the hGH-XTEN gene under the control of a T7 promoter, and would be used to express a fusion protein with hGH at the N-terminus.
Example 21: Construction of XTEN-hGH and XTEN-hGH Genes and Vectors Using AE and AM XTEN Sequences
The gene encoding hGH was amplified by polymerase chain reaction (PCR), which introduced BbsI and HindIII restriction sites that are compatible with the BbsI and HindIII sites that flank the stuffer in the XTEN destination vector. The pCBD-XTEN plasmid is a pET30 derivative from Novagen in the format of Cellulose Binding Domain (CBD)-XTEN-Stuffer, where Stuffer is green fluorescent protein (GFP) and XTEN can be any length from 36 to 1318 or greater (FIG. 7). Constructs were generated by replacing a stuffer sequence in pCBD-XTEN with the hGH-encoding fragment. The pCBD-XTEN features a T7 promoter upstream of CBD followed by an XTEN sequence fused in-frame upstream of the stuffer sequence. The XTEN sequences employed belong to family XTEN_AE and XTEN_AM and encode lengths that include 36, 72, 144, 288, 576, 864, 875 and 1318 amino acids. The stuffer fragment was removed by restriction digest using BbsI and HindIII endonucleases. Restriction digested hGH DNA fragment was ligated into the cleaved pCBD-XTEN vector using T4 DNA ligase and electroporated into BL21(DE3) Gold (Stratagene). Transformants were screened by DNA miniprep and the desired construct was confirmed by DNA sequencing. The final vector yields the CBD_XTEN_hGH gene under the control of a T7 promoter, and would be used to express a fusion protein with hGH at the C-terminus.
Example 22: Construction of XTEN-AE_hGH_XTEN-AE Genes and Vectors
The gene encoding hGH was amplified by polymerase chain reaction (PCR), which introduced BsaI and HindIII restriction sites that are compatible with the BbsI and HindIII sites that flank the stuffer in the pNTS-XTEN destination vector. The pNTS-XTEN_AE plasmid is a pET30 derivative from Novagen in the format of N-terminal XTEN expression sequence of 48 amino acids-XTEN-Stuffer, where Stuffer is green fluorescent protein (GFP) and XTEN can be any length from 36 to 576 or greater. Constructs were generated by replacing a stuffer sequence in pNTS-XTEN with the hGH-encoding fragment. The pNTS-XTEN features a T7 promoter upstream of NTS followed by an XTEN sequence fused in-frame upstream of the stuffer sequence. The XTEN sequences employed belong to family XTEN_AE and encode lengths that can include 36, 72, 144, 288, 576, 864, and 1296 amino acids. The stuffer fragment was removed by restriction digest using BbsI and HindIII endonucleases. Restriction digested hGH DNA fragment was ligated into the cleaved pNTS-XTEN vector using T4 DNA ligase and electroporated into BL21(DE3) Gold (Stratagene). In some cases, a second XTEN_AE sequence of 144 or 288 amino acids was ligated to the C-terminus of the hGH encoding gene, the steps of which are illustrated in FIG. 8. The gene encoding hGH was amplified by polymerase chain reaction (PCR), which introduced BsaI and HindIII (with additional BbsI in front of HindIII) restriction sites that are compatible with the BbsI and HindIII sites that flank the stuffer in the pNTS-XTEN destination vector. After restriction enzyme digestions, ligation and transformation, the resulting intermediate plasmid has the format of pNTS-XTEN-hGH with the BbsI/HindIII restriction sites at the C-terminus of hGH. The intermediate plasmid was further digested with BbsI and HindIII, ligated with the second XTEN_AE sequence of 144 or 288 amino acids flanked by BsaI and HindIII, placing the AE144 or the AE288 encoding sequences at the C-terminus of the XTEN-hGH gene, and transformed into BL21(DE3)Gold. Transformants were screened by DNA miniprep and the desired construct was confirmed by DNA sequencing. The final vectors, described above, yield the genes in configurations of either NTS_XTEN_hGH or NTS_XTEN_hGH_XTEN, under the control of a T7 promoter, as shown in FIGS. 7C and 7D.
Example 23: Purification of GHXTEN_AE Constructs
Protein Expression
The plasmids described above were transformed into BL21(DE3)-Gold E. coli strain (Novagen) and plated on an LB-agar plate with the appropriate antibiotics and grown overnight at 37° C. A single colony was inoculated into 5 ml of TB125 medium and grown overnight at 37° C. The next day the inoculum was transformed into a 2 L vessel with 500 ml of TB125, and grown until an OD=0.6 was reached, followed by continued growth at 26° C. for 16 hr with 0.1 mM IPTG.
Cells were collected by centrifugation and the cell pellet was resuspended in 50 ml Buffer containing 5 mM Tris pH 8.0, 100 mM NaCl. Cells were disrupted using an APV-2000 homogenizer. The pH of the lysate was then adjusted to pH 4.5 with acetic acid to precipitate contaminating host cell proteins and was subsequently clarified by centrifugation. The clarified, acid-treated lysate was then applied to a DE52 Anion exchange chromatography column and eluted with NaCl. The eluted fraction was then further acidified to pH 4.2 and applied to a MacroCapSP cation exchange chromatography column Product was eluted using sequential elution with NaCl. An additional chromatography step employing Macrocap Q was implemented to remove product-related aggregates and residual host cell impurities (e.g. endotoxin, DNA, host cell protein).
Protein purity was estimated to be above 98%. The quantity of eluted fusion protein was determined by SDS-PAGE analysis and by measurement of total protein concentration. The high quantity of eluted GHXTEN fusion protein reflects the higher degree of solubility of the fusion protein relative to hGH not linked to XTEN (see, e.g., Singh, S. M., et al. (2005) J Biosci Bioeng, 99: 303; Patra, A. K., et al. (2000) Protein Expr Purif, 18: 182), as well as the ability to remain soluble at acidified conditions that result in the precipitation of host cell protein.
Final Formulation and Storage
The buffer exchanged proteins were then concentrated using 10K MWCO Vivacell 100 centrifugal ultrafiltration unit to not less than 15 mg/ml. The concentrate was sterile filtered using a 0.22 um syringe filter. The final solution was aliquoted and stored at −80° C.
Example 24: Characterization of GHXTEN Constructs
SDS-PAGE Analysis
5 μg of final purified GHXTEN proteins of GH linked to Y576 (either N- or C-terminus of Y576) was subjected to both non-reducing and reducing SDS-PAGE using NuPAGE 4-12% Bis-Tris gel from Invitrogen according to manufacturer's specifications. The resulting gel is shown in FIG. 20.
Analytical Size Exclusion Chromatography
Size exclusion chromatography analysis was performed using a TSKGel-G4000 SWXL (7.8 mm×30 cm) column. 20 ug of the purified protein at a concentration of 1 mg/ml was separated at a flowrate 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 was 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). The chromatographic profiles of Y576-GH were generated and demonstrate that the apparent molecular weight of each construct is significantly larger than that expected for a globular protein, in comparison to the standard proteins run in the same assay (data not shown).
Analytical RP-HPLC
Analytical RP-HPLC chromatography analysis was performed using a C4 (7.8 mm×20 cm) column. The column was equilibrated with 100% AcetonNitrile plus 0.1% TFA in the mobile phase at a flowrate of 1 ml/min. Twenty micro gram of the purified protein, with and without denaturing, at a concentration of 0.2 mg/ml was injected separately. The protein was separated and eluted by liner gradient within 15 min from 5% to 60% of buffer containing HPLC grade H20 plus 0.1% TFA. Chromatogram profiles were monitored using OD214 nm and OD280 nm. The chromatographic profiles of native and denatured Y576-GH are shown as an overlay in FIG. 21.
Example 25: ELISA-Based Binding Assays
XTEN fusions to GH were tested in a standard ELISA-based assay to evaluate their ability to bind to GH Receptor. Assays were performed using a sandwich ELISA format in which a recombinant hGH receptor (hGHR-Fc) is coated onto wells of an ELISA plate. The wells were then blocked, washed, and GHXTEN samples are then incubated in the wells at varying dilutions to allow capture of the GHXTEN. Wells were washed extensively, and bound protein was detected using a biotinylated preparation of a polyclonal or monoclonal anti-GH or anti-XTEN antibody and streptavidin HRP. The fraction of bound protein can be calculated by comparing the colorimetric response at each serum dilution to a standard curve of unmodified GH. In a first assay comparing hGH bound to K288 compared to recombinant hGH, the results, show in FIG. 15, demonstrate the ability of GHXTEN to bind to the hGH receptor. In a second assay, two configurations of GHXTEN; AM864-hGH and hGH-AM864; compared to recombinant hGH. The results, shown in FIG. 16, indicate apparent EC50 values for native hGH of 0.0701 nM, AM864-hGH of 0.3905, and hGH-AM864 of 2.733. In a third assay, recombinant hGH was compared to AE912-hGH-AE144 in order to show the ability to reduce binding affinity by the addition of a C-terminal XTEN to the hGH component of an GHXTEN fusion protein, and the results (FIG. 18) demonstrate a decrease in binding affinity of approximately 17-fold compared to hGH.
Example 26: Effect of Heat Treatment on the Stability of hGH and GHXTEN
The ability of XTEN to confer structural stability on the attached therapeutic molecule was investigated. Samples of hGH and AM864-hGH were incubated at 25° C. and 80° C., and then analyzed by gel electrophoresis and Coomassie staining FIG. 17A is an SDS-PAGE gel of the two preparations treated at 25° C. and 80° C. for 15 minutes, while FIG. 17B shows the corresponding percentage of receptor binding activity of the 80° C. sample relative to the 25° C. treatment. The results indicate that hGH denatures under the treatment conditions while the GHXTEN construct remains largely stable under the experimental conditions, retaining nearly 80% of its receptor binding activity.
Conclusions:
The XTEN component of the GHXTEN fusion protein confers enhanced solubility and stability properties to the fusion protein in comparison to hGH not linked to XTEN.
Example 27: Comparative Effects of hGH and AM864-hGH on Secretion of IGF-1
The ability of a GHXTEN to retain pharmacologic potency was assessed using the measured parameter of circulating IGF-1 in response to administered compound. FIG. 24 shows the effects of daily administration of hGH (0.071 mg/kg daily) or a single dose of AM864-hGH (5 mg/kg; equivalent to 1.1 mg/kg) on circulating IGF-1 levels in cynomolgus monkeys (n=4/group), depicted as percentage change compared to baseline. The results show enhanced activity by the GHXTEN construct, despite being dosed only once at the beginning of the experiment.
Example 28: Comparative Effects of hGH and AM864-hGH on Body Weight Gain
The ability of a GHXTEN to retain pharmacologic potency was assessed using the measured parameter of body weight gain in a hypox rat in response to administered compound. FIG. 25 shows the effects of administration of hGH or AM864-hGH at the indicated doses and dose frequency on body weight in hypox rats. The results show retention of biologic activity by the GHXTEN constructs that is equivalent in potency to comparable dosage of hGH, yet with less frequent dosing. Increased dosage of AM864-hGH led to increases in body weight gains showing enhancement of the pharmacodynamic properties of the GHXTEN compared to hGH under these conditions.
Example 29: Comparative Effects of hGH and AM864-hGH on Bone Cartilage
The ability of a GHXTEN to retain pharmacologic potency was assessed using the measured parameter of increase in tibial epiphyseal plate width in hypox rats. FIG. 26 shows the comparative effects of administration of placebo, hGH, and AM864-hGH, shown in histologic cross-sections of the tibia from rats after 9 days of treatment, with the margins denoted with dotted lines. Groups are the same as shown in FIG. 26. FIG. 26A shows that the placebo group had an average cross-section width of 344±38.6 μm of the plate after 9 days. FIG. 26B shows that the hGH group (10 μg daily) had an average cross-section width of 598±8.5 μm after 9 days. FIG. 26C shows that the AM864-hGH (15 mg/kg q3d) had an average cross-section width of 944±8.5 μm after 9 days. The results show enhanced activity by the GHXTEN construct compared to hGH, despite being dosed at less frequent intervals.
Example 30: PK Analysis of GHXTEN Protein Fusions
GH-Y576 and Y576 h-GH (in this case indicating the N- to C-terminus order of GH and XTEN) were injected into cynomolgus monkeys in order to determine in vivo pharmacokinetic parameters. The compositions were provided in an aqueous buffer and were administered by intravenous routes into separate animals at 0.15 mg/kg dosing. Serum samples were collected at various time points following administration and analyzed for serum concentrations of the accessory proteins. Analysis was performed using a sandwich ELISA format. Rabbit polyclonal anti-XTEN (to Y-type XTEN) antibodies were coated onto wells of an ELISA plate. Serum samples were then incubated in the wells at varying dilutions to allow capture of the compound by the coated antibodies. Wells were washed extensively, and bound protein was detected using a biotinylated preparation of the polyclonal anti-XTEN antibody and streptavidin HRP. Serum protein concentrations were calculated at each time point by comparing the colorimetric response at each serum dilution to a standard curve. Pharmacokinetic parameters were calculated using the WinNonLin software package.
FIG. 22 shows the concentration profile of the two GH constructs following intravenous administration to cynomolgus monkeys. Following IV administration, the half-life was calculated to be 7 hours for hGH-Y576 and 10.5 hours for Y576-hGH. For reference, the published half-life of unmodified GH is well described in the literature as 10-15 minutes in adult humans (see, e.g., Hindmarch, P. C., et al., Clinical Endocrinology (2008) 30(4): 443-450). The results show that the orientation (N- versus C-terminal) of hGH relative to the XTEN did not affect the clearance of the fusion proteins, and that addition of the Y576 greatly extended the terminal half-life of the fusion protein.
Another pharmacokinetic study in cynomolgus monkeys was performed using the AM864-hGH construct. FIG. 23 shows the pharmacokinetic profile after a single dose of 5 mg/kg AM864-hGH administered subcutaneously to cynomolgus monkeys, with the derived equivalent hGH concentration shown (dashed line).
Conclusions:
The XTEN component of the GHXTEN fusion protein confers enhanced pharmacokinetic properties to the fusion protein in comparison to hGH not linked to XTEN, under these conditions.
Example 31: PK Analysis of hGH XTEN Fusion Polypeptides in Rats
The GHXTEN fusion proteins AE912-hGH, AM864-hGH (synonym to AM875-hGH for this and following Examples), AE912-hGH-AE144 and AE912-hGH-AE288 were evaluated in rats in order to determine in vivo pharmacokinetic parameters of the hGHXTEN polypeptides. All compositions were provided in an aqueous buffer and were administered by subcutaneous (SC) route into separate animals using 1.5 mg/kg single doses. Plasma samples were collected at various time points following administration and analyzed for concentrations of the test articles. Analysis was performed using a sandwich ELISA format. Recombinant hGHR-Fc was coated onto wells of an ELISA plate. The wells were blocked, washed and plasma samples were then incubated in the wells at varying dilutions to allow capture of the compound by the coated antibodies. Wells were washed extensively, and bound protein was detected using a biotinylated preparation of the polyclonal anti hGH antibody and streptavidin HRP. Concentrations of test article were calculated at each time point by comparing the colorimetric response at each serum dilution to a standard curve. Pharmacokinetic parameters were calculated using the WinNonLin software package.
FIG. 27 shows the concentration profiles of the four hGH XTEN constructs after subcutaneous administration. The calculated terminal half-life for AE912-hGH was 7.5 h, 6.8 h for AM864-hGH (synonym for AM875-hGH), 12.4 h for AE912-hGH-AE144 and 13.1 h for AE912-hGH-AE288. For comparison, unmodified hGH was run in parallel in the same experiment and showed a dramatically shorter plasma half-life.
Conclusions:
The incorporation of different XTEN sequences into fusion proteins comprising hGH results in significant enhancement of pharmacokinetic parameters for all four compositions compared to unmodified hGH, as demonstrated in the rodent model under these conditions. The addition of a second XTEN protein to the C-terminus of the AE-hGH constructs results in a further enhancement of the terminal half-life compared to the constructs with a single XTEN; likely due to reduced receptor mediated clearance.
Example 32: PK Analysis of hGH XTEN Fusion Polypeptides in Cynomolgus Monkeys
GHXTEN fusion proteins containing one or two XTEN molecules (AE912-hGH, AM864-hGH, and AE912-hGH-AE144) were evaluated in cynomolgus monkeys in order to determine the effect of the inclusion of a second XTEN on in vivo pharmacokinetic parameters of the hGHXTEN polypeptides. All compositions were provided in an aqueous buffer and were administered by subcutaneous (SC) route into separate animals using 1.5 mg/kg single doses. Plasma samples were collected at various time points following administration and analyzed for concentrations of the test articles. Analysis was performed using a sandwich ELISA format. Recombinant hGHR-Fc was coated onto wells of an ELISA plate. The wells were blocked, washed and plasma samples were then incubated in the wells at varying dilutions to allow capture of the compound by the coated antibodies. Wells were washed extensively, and bound protein was detected using a biotinylated preparation of the polyclonal anti hGH antibody and streptavidin HRP. Concentrations of test article were calculated at each time point by comparing the colorimetric response at each serum dilution to a standard curve. Pharmacokinetic parameters were calculated using the WinNonLin software package, and FIG. 28 shows the concentration profiles of the three hGH XTEN constructs after subcutaneous administration over the 336 h period. The average terminal half-life for the fusion proteins were 33 h for AM864-hGH, 44 h for AE912-hGH, and 110 h for the AE912-hGH-AE144 (containing two XTEN linked to the N- and C-termini of hGH).
Conclusions:
The incorporation of different XTEN sequences into fusion proteins comprising hGH resulted in significant enhancement of pharmacokinetic parameters for all three compositions, as demonstrated in the cyno model under these conditions, with the construct containing a second XTEN linked to the C-terminus of the hGH showing a greater than about two-fold enhancement of the terminal half-life compared to the GHXTEN with a single XTEN at the N-terminus.
Example 33: Assessment of Pharmacodynamic Effects of AE912-hGH-AE144 GHXTEN by Measurement of IGF-1 Response in Cynomolgus Monkeys
AE912-hGH-AE144 was administered to male and female cynos SC at 0.3, 1.5, and 7.5 mg/kg and dose volumes ranging from 0.80 to 1.13 ml. 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 timepoints (16), and processed into plasma. PK was measured by ELISA assay using the anti-XTEN capture antibody and the biotinylated anti-hGH detection antibody. IGF-1 samples were sent to and analyzed by Millipore. PK parameters were calculated by analysis using the WinNonLin software package and are shown in the table below. Plasma concentration profiles of the three doses of GHXTEN and IGF-1 levels are shown in FIG. 29 and FIG. 30, respectively (open circles=0.3 mg/kg; squares=1.5 mg/kg; triangles=7.5 mg/kg). The results show that administration of AE912-hGH-AE144 results in a sustained increase in IGF-1 levels, consistent with both the biological mode of action of growth hormone and the long plasma half-life of AE912-hGH-AE144.







TABLE 22







PK parameters in cynomolgus monkeys











0.3 mg/kg
1.5 mg/kg
7.5 mg/kg















Route
SC
SC
SC



T1⁄2 (hrs)
84.4
97.5
101.1



Cmax (nM)
41
910
340



AUC (nM * hr)
5,170
162,000
64,100









Example 34: Comparative Bioavailability of AE912-hGH-AE144 Via Subcutaneous and Intramuscular Administration to Cynomolgus Monkeys
AE912-hGH-AE144 was administered to male and female cynos SC at 1.5 mg/kg via intravenous, subcutaneous, and intramuscular routes. 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 timepoints (16), and processed into plasma. Plasma levels at each time point were measured by ELISA assay using the anti-XTEN capture antibody and the biotinylated anti-hGH detection antibody. PK and bioavailability parameters were calculated by analysis using the WinNonLin software package and are shown in the table below. Plasma concentration profiles are shown in FIG. 31 (open circles=subcutaneous; triangle=IV; squares=intramuscular). For bioavailability calculations, the AUC for intravenous administration was defined to be 100%. The results show that AE912-hGH-AE144 shows a high bioavailability and distributes rapidly from the injection site to the blood compartment following injection.







TABLE 23







PK parameters in cynomolgus monkeys











1.5 mg/kg
1.5 mg/kg
1.5 mg/kg















Route
SC
IV
IM



T1⁄2 (hrs)
97.5
107.7
102.2



Cmax (nM)
910
462
245



AUC (nM * hr)
162,000
60,300
43,200



Bioavailability
~100%
100%
72%









Example 35: Determination of the Therapeutic Window for AE912-hGH-AE144
The specific activity of the GHXTEN AE912-hGH-AE144 was assessed using the measured parameter of body weight gain in a hypophysectomized (hypox) rat in response to administered compound. FIG. 32 shows the effects of administration of vehicle (open circles), recombinant hGH dosed at 5 nmol/kg/day (closed circles), the GHXTEN AE912-hGH-AE144 at varying doses and dose frequency (closed triangles=0.5 nmol/kg/day; open triangles=1.5 nmol/day; squares=3 nmol/kg/Q2D) on body weight in hypox rats. The results show that a dose of the GHXTEN AE912-hGH-AE144 as low as 1.5 nmol/kg/day yields comparable growth to hGH alone. However, a lower dose of 0.5 nmol/kg/day does not promote growth in these animals. Based on the pharmacokinetic profiles determined in the rats, a model for plasma levels following repeat dosing was constructed as shown in FIG. 33 (same groups as per FIG. 32). The model clearly differentiates the efficacious doses from the non-efficacious lower dose. The results show that plasma concentration of AE912-hGH-AE144 generally should remain above about 1 nmol/L concentration in order to maintain optimal growth in the hypophysectomized rat model.
Example 36: Human Clinical Trial Designs for Evaluating GHXTEN
Clinical trials can be designed such that the efficacy and advantages of the GHXTEN compositions, relative to the corresponding growth hormone biologics, can be verified in humans. For example, the GHXTEN fusion constructs comprising growth, as described in the Examples above, can be used in clinical trials for characterizing the efficacy of the compositions. The trials can be conducted in one or more growth hormone-related diseases, disorders, or conditions that are improved, ameliorated, or inhibited by the administration of growth hormone. Such studies in adult patients comprise three phases. First, a Phase I safety and pharmacokinetics study in adult patients is conducted to determine the maximum tolerated dose and pharmacokinetics and pharmacodynamics in humans (either normal subjects or patients with a growth disease or condition), as well as to define potential toxicities and adverse events to be tracked in future studies. The study is conducted in which single rising doses of compositions of fusion proteins of GHXTEN is administered and biochemical, PK, and clinical parameters is measured. This permits the determination of the maximum tolerated dose and establishes the threshold and maximum concentrations in dosage and circulating drug that constitute the therapeutic window for the respective components. Thereafter, clinical trials are conducted in patients with the disease, disorder or condition.
Phase II and III Clinical Trials
A phase II dosing study is conducted in patients where blood growth hormone pharmacodynamics and other physiologic, PK, safety and clinical parameters (such as listed below) appropriate for trials, such as for reversal of short stature due to GH deficiency in pediatric patients, treatment of Turner syndrome, chronic renal failure, Prader-Willi syndrome, intrauterine growth retardation, or improvements in body mass composition (increase in lean body mass, decrease in fat mass) in adult patients (such as HIV+ or acquired pituitary tumor patients). Parameters and clinical endpoints are measured as a function of the dosing of the fusion proteins compositions, yielding dose-ranging information on doses that would be appropriate for a subsequent Phase III trial, in addition to collecting safety data related to adverse events. The PK parameters are correlated to the physiologic, clinical and safety parameter data to establish the therapeutic window and the therapeutic dose regimen for the GHXTEN composition, permitting the clinician to establish the appropriate dose ranges for a GHXTEN composition. Finally, a phase III efficacy study is conducted wherein patients would be administered the GHXTEN composition at the dose regimen, and a positive control (such as a commercially-available, approved growth hormone), or a placebo is administered daily or using other dosing schedule deemed appropriate given the pharmacokinetic and pharmacodynamic properties of the control composition, with all agents administered for an appropriately extended period of time to achieve the study endpoints. Parameters that are monitored include GH, IGF-1 and IGFBP3 concentrations, changes in height velocity, lean body mass, total body fat, trunk fat, parameters associated with insulin resistance syndrome, measurement of division and multiplication rates of chondrocytes, and/or changes in bone density and/or bone growth; parameters that would be tracked relative to the placebo or positive control groups. Efficacy outcomes would be determined using standard statistical methods. Toxicity and adverse event markers are also be followed in this study to verify that the compound is safe when used in the manner described.
Example 37: 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. 34. 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, including a GHXTEN composition, 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 24. 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 24







SEC analysis of various polypeptides














XTEN



Apparent



Con-
or
Thera-
Actual
Apparent
Molecular


struct
fusion
peutic
MW
MW
Weight
RH


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


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 38: Pharmacokinetics of Extended Polypeptides Fused to GFP in Cynomolgus Monkeys
The pharmacokinetics of GFP-L288, GFP-L576, GFP-XTEN_AF576, GFP-XTEN_Y576 and XTEN_AD836-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. 35. 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 39: 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. 14. 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 GHXTEN to degradation due to serum proteases; a factor in the enhancement of pharmacokinetic properties of the GHXTEN fusion proteins.
Example 40: PK Analysis of Ex4-XTEN Fusion Protein in Multiple Species and Predicted Human Half-Life
To determine the predicted pharmacokinetic profile in humans of a therapeutic protein fused to XTEN, studies were performed using exendin-4 fused to the AE864 XTEN as a single fusion polypeptide. The Ex4-XTEN construct was administered to four different animal species at 0.5-1.0 mg/kg, subcutaneously and intravenously. Serum samples were collected at intervals following administration, with serum concentrations determined using standard methods. The half-life for each species was determined, and is tabulated in Table 25. The results were used to predict the human half-life using allometric scaling of terminal half-life, volume of distribution, and clearance rates based on average body mass. FIG. 36A shows a plot of measured terminal half-life versus body mass in the animal species, with a predicted T1/2 in a 75 kg human of 140 h, compared to the reported half-life of exenatide of 2.4 h (Bond, A. Proc (Bayl Univ Med Cent) 19(3): 281-284. (2006)). FIG. 36B shows measured drug clearance versus body mass, with a predicted clearance rate value of 30 ml/h in a 75 kg human FIG. 36C shows measured volume of distribution versus body mass, with a predicted value of 5970 ml in a 75 kg human.
Conclusions:
It can be concluded from the results that addition of an XTEN to a glucose-regulating peptide, such as exendin-4, can greatly increase the terminal half-life compared to the peptide not linked to XTEN.







TABLE 25







Half-life of Ex4-XTEN










Species
Half-Life (hr)






Mouse
13.5



Rat
31.7



Monkey
60.7



Dog
72.8



Human
140*  





*Predicted value based on allometric scaling






Example 41: Increasing Solubility and Stability of a Peptide Payload by Linking to XTEN
In order to evaluate the ability of XTEN to enhance the physical/chemical 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 26. 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 GHXTEN 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).
Conclusions:
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 26







Solubility of Glucagon-XTEN constructs










Test Article
Solubility














Glucagon
60
μM



Glucagon-Y36
>370
μM



Glucagon-Y72
>293
μM



Glucagon-AF108
>145
μM



Glucagon-AF120
>160
μM



Glucagon-Y144
>497
μM



Glucagon-AE144
>467
μM



Glucagon-AF144
>3600
μM



Glucagon-Y288
>163
μM









Example 42: Characterization of XTEN Fusion Protein Secondary Structure
The fusion protein Ex4-AE864 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. 37 shows no evidence of stable secondary structure and is consistent with an unstructured polypeptide.
Example 43: 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=misc1 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-pbil.ibcp.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 27.
The results indicate that, by the Chou-Fasman calculations, the four motifs of the AE family (Table 1) have no alpha-helices or beta sheets. The sequence up to 288 residues was similarly found to have no alpha-helices or beta sheets. The 432 residue sequence is predicted to have a small amount of secondary structure, with only 2 amino acids contributing to an alpha-helix for an overall percentage of 0.5%. The full-length AF864 polypeptide has the same two amino acids contributing to an alpha-helix, for an overall percentage of 0.2%. Calculations for random coil formation revealed that with increasing length, the percentage of random coil formation increased. The first 24 amino acids of the sequence had 91% random coil formation, which increased with increasing length up to the 99.77% value for the full-length sequence.
Numerous XTEN sequences of 500 amino acids or longer from the other motif families were also analyzed and revealed that the majority had greater than 95% random coil formation. The exceptions 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.
In contrast, a polypeptide sequence of 84 residues limited to A, S, and P amino acids was assessed by the Chou-Fasman algorithm, which predicted a high degree of predicted alpha-helices. The sequence, which had multiple repeat “AA” and “AAA” sequences, had an overall predicted percentage of alpha-helix structure of 69%. The GOR algorithm predicted 78.57% random coil formation; far less than any sequence consisting of 12 amino acid sequence motifs consisting of the amino acids G, S, T, E, P, analyzed in the present Example.
Conclusions:
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. In contrast, polypeptides created from amino acids limited to A, S and P that have a higher degree of internal repetitiveness are predicted to have a high percentage of alpha-helices, as determined by the Chou-Fasman algorithm, as well as 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) greater than about 400 amino acid residues in length 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 1 can be used to create an XTEN polypeptide of a length greater than about 400 residues that will result in an XTEN sequence that is substantially devoid of secondary structure. Such sequences are expected to have the characteristics described in the GHXTEN embodiments of the invention disclosed herein.







TABLE 27







CHOU-FASMAN and GOR prediction calculations of polypeptide sequences












SEQ

SEQ ID
No.
Chou-Fasman
GOR


NAME
Sequence
NO:
Residues
Calculation
Calculation
















GSTSESPSGTAP
624
12
Residue totals*: H: 0 E: 0
Not






percent: H: 0.0 E: 0.0
Determined


 



GTS TPESGSASP
625
12
Residue totals: H: 0 E: 0
Not






percent: H: 0.0 E: 0.0
Determined


 



GTSPSGESSTAP
626
12
Residue totals: H: 0 E: 0
Not






percent: H: 0.0 E: 0.0
Determined


 



GSTSSTAESPGP
627
12
Residue totals: H: 0 E: 0
Not






percent: H: 0.0 E: 0.0
Determined


 



GSPAGSPTSTEEGTSESATPESGP
628
24
Residue totals: H: 0 E: 0
91.67%






percent: H: 0.0 E: 0.0



 



GSPAGSPTSTEEGTSESATPESGPG
629
36
Residue totals: H: 0 E: 0
94.44%



TSTEPSEGSAP


percent: H: 0.0 E: 0.0



 



GSPAGSPTSTEEGTSESATPESGPG
630
48
Residue totals: H: 0 E: 0
93.75%



TSTEPSEGSAPGSPAGSPTSTEE


percent: H: 0.0 E: 0.0



 



GSPAGSPTSTEEGTSESATPESGPG
631
60
Residue totals: H: 0 E: 0
96.67%



TSTEPSEGSAPGSPAGSPTSTEEGTS


percent: H: 0.0 E: 0.0




TEPSEGSAP






 



GSPAGSPTSTEEGTSESATPESGPG
632
108
Residue totals: H: 0 E: 0
97.22%



TSTEPSEGSAPGSPAGSPTSTEEGTS


percent: H: 0.0 E: 0.0




TEPSEGSAPGTSTEPSEGSAPGTSES







ATPESGPGSEPATSGSE







TPGSEPATSGSETP






 



GSPAGSPTSTEEGTSESATPESGPG
633
216
Residue totals: H: 0 E: 0
99.07%



TSTEPSEGSAPGSPAGSPTSTEEGTS


percent: H: 0.0 E: 0.0




TEPSEGSAPGTSTEPSEGSAPGTSES







ATPESGPGSEPATSGSETPGSEPAT







SGSETPGSPAGSPTSTEEGTSESATP







ESGPGTSTEPSEGSAPGTSTEPSEGS







APGSPAGSPTSTEEGTSTEPSEGSA







PGTSTEPSEGSAPGTSESATPESGP







GTSTEPSEGSAP






 



GSPAGSPTSTEEGTSESATPESGPG
634
432
Residue totals: H: 2 E: 3
99.54%



TSTEPSEGSAPGSPAGSPTSTEEGTS


percent: H: 0.5 E: 0.7




TEPSEGSAPGTSTEPSEGSAPGTSES







ATPESGPGSEPATSGSETPGSEPAT







SGSETPGSPAGSPTSTEEGTSESATP







ESGPGTSTEPSEGSAPGTSTEPSEGS







APGSPAGSPTSTEEGTSTEPSEGSA







PGTSTEPSEGSAPGTSESATPESGP







GTSTEPSEGSAPGTSESATPESGPG







SEPATSGSETPGTSTEPSEGSAPGTS







TEPSEGSAPGTSESATPESGPGTSES







ATPESGPGSPAGSPTSTEEGTSESA







TPESGPGSEPATSGSETPGTSESATP







ESGPGTSTEPSEGSAPGTSTEPSEGS







APGTSTEPSEGSAPGTSTEPSEGSA







PGTSTEPSEGSAPGTSTEPSEGSAP







GSPAGSPTSTEEGTSTEPSEGSAP






 


AE864
GSPAGSPTSTEEGTSESATPESGPG
635
864
Residue totals: H: 2 E: 3
99.77%



TSTEPSEGSAPGSPAGSPTSTEEGTS


percent: H: 0.2 E: 0.3




TEPSEGSAPGTSTEPSEGSAPGTSES







ATPESGPGSEPATSGSETPGSEPAT







SGSETPGSPAGSPTSTEEGTSESATP







ESGPGTSTEPSEGSAPGTSTEPSEGS







APGSPAGSPTSTEEGTSTEPSEGSA







PGTSTEPSEGSAPGTSESATPESGP







GTSTEPSEGSAPGTSESATPESGPG







SEPATSGSETPGTSTEPSEGSAPGTS







TEPSEGSAPGTSESATPESGPGTSES







ATPESGPGSPAGSPTSTEEGTSESA







TPESGPGSEPATSGSETPGTSESATP







ESGPGTSTEPSEGSAPGTSTEPSEGS







APGTSTEPSEGSAPGTSTEPSEGSA







PGTSTEPSEGSAPGTSTEPSEGSAP







GSPAGSPTSTEEGTSTEPSEGSAPG







TSESATPESGPGSEPATSGSETPGTS







ESATPESGPGSEPATSGSETPGTSES







ATPESGPGTSTEPSEGSAPGTSESA







TPESGPGSPAGSPTSTEEGSPAGSPT







STEEGSPAGSPTSTEEGTSESATPES







GPGTSTEPSEGSAPGTSESATPESG







PGSEPATSGSETPGTSESATPESGP







GSEPATSGSETPGTSESATPESGPG







TSTEPSEGSAPGSPAGSPTSTEEGTS







ESATPESGPGSEPATSGSETPGTSES







ATPESGPGSPAGSPTSTEEGSPAGS







PTSTEEGTSTEPSEGSAPGTSESATP







ESGPGTSESATPESGPGTSESATPES







GPGSEPATSGSETPGSEPATSGSET







PGSPAGSPTSTEEGTSTEPSEGSAP







GTSTEPSEGSAPGSEPATSGSETPG







TSESATPESGPGTSTEPSEGSAP






 


AD 576
GSSESGSSEGGPGSGGEPSESGSSG
636
576
Residue totals: H: 7 E: 0
99.65%



SSESGSSEGGPGSSESGSSEGGPGSS


percent: H: 1.2 E: 0.0




ESGSSEGGPGSSESGSSEGGPGSSE







SGSSEGGPGESPGGSSGSESGSEGS







SGPGESSGSSESGSSEGGPGSSESGS







SEGGPGSSESGSSEGGPGSGGEPSE







SGSSGESPGGSSGSESGESPGGSSG







SESGSGGEPSESGSSGSSESGSSEG







GPGSGGEPSESGSSGSGGEPSESGS







SGSEGSSGPGESSGESPGGSSGSES







GSGGEPSESGSSGSGGEPSESGSSG







SGGEPSESGSSGSSESGSSEGGPGE







SPGGSSGSESGESPGGSSGSESGESP







GGSSGSESGESPGGSSGSESGESPG







GSSGSESGSSESGSSEGGPGSGGEP







SESGSSGSEGSSGPGESSGSSESGSS







EGGPGSGGEPSESGSSGSSESGSSE







GGPGSGGEPSESGSSGESPGGSSGS







ESGESPGGSSGSESGSSESGSSEGG







PGSGGEPSESGSSGSSESGSSEGGP







GSGGEPSESGSSGSGGEPSESGSSG







ESPGGSSGSESGSEGSSGPGESSGSS







ESGSSEGGPGSEGSSGPGESS






 


AE576
GSPAGSPTSTEEGTSESATPESGPG
637
576
Residue totals: H: 2 E: 0
99.65%



TSTEPSEGSAPGSPAGSPTSTEEGTS


percent: H: 0.4 E: 0.0




TEPSEGSAPGTSTEPSEGSAPGTSES







ATPESGPGSEPATSGSETPGSEPAT







SGSETPGSPAGSPTSTEEGTSESATP







ESGPGTSTEPSEGSAPGTSTEPSEGS







APGSPAGSPTSTEEGTSTEPSEGSA







PGTSTEPSEGSAPGTSESATPESGP







GTSTEPSEGSAPGTSESATPESGPG







SEPATSGSETPGTSTEPSEGSAPGTS







TEPSEGSAPGTSESATPESGPGTSES







ATPESGPGSPAGSPTSTEEGTSESA







TPESGPGSEPATSGSETPGTSESATP







ESGPGTSTEPSEGSAPGTSTEPSEGS







APGTSTEPSEGSAPGTSTEPSEGSA







PGTSTEPSEGSAPGTSTEPSEGSAP







GSPAGSPTSTEEGTSTEPSEGSAPG







TSESATPESGPGSEPATSGSETPGTS







ESATPESGPGSEPATSGSETPGTSES







ATPESGPGTSTEPSEGSAPGTSESA







TPESGPGSPAGSPTSTEEGSPAGSPT







STEEGSPAGSPTSTEEGTSESATPES







GPGTSTEPSEGSAP






 


AF540
GSTSSTAESPGPGSTSSTAESPGPGS
638
540
Residue totals: H: 2 E: 0
99.65



TSESPSGTAPGSTSSTAESPGPGSTS


percent: H: 0.4 E: 0.0




STAESPGPGTSTPESGSASPGSTSES







PSGTAPGTSPSGESSTAPGSTSESPS







GTAPGSTSESPSGTAPGTSPSGESST







APGSTSESPSGTAPGSTSESPSGTAP







GTSPSGESSTAPGSTSESPSGTAPGS







TSESPSGTAPGSTSESPSGTAPGTST







PESGSASPGSTSESPSGTAPGTSTPE







SGSASPGSTSSTAESPGPGSTSSTAE







SPGPGTSTPESGSASPGTSTPESGSA







SPGSTSESPSGTAPGTSTPESGSASP







GTSTPESGSASPGSTSESPSGTAPGS







TSESPSGTAPGSTSESPSGTAPGSTS







STAESPGPGTSTPESGSASPGTSTPE







SGSASPGSTSESPSGTAPGSTSESPS







GTAPGTSTPESGSASPGSTSESPSGT







APGSTSESPSGTAPGTSTPESGSASP







GTSPSGESSTAPGSTSSTAESPGPGT







SPSGESSTAPGSTSSTAESPGPGTST







PESGSASPGSTSESPSGTAP






 


AF504
GASPGTSSTGSPGSSPSASTGTGPG
639
504
Residue totals: H: 0 E: 0
94.44%



SSPSASTGTGPGTPGSGTASSSPGSS


percent: H: 0.0 E: 0.0




TPSGATGSPGSNPSASTGTGPGASP







GTSSTGSPGTPGSGTASSSPGSSTPS







GATGSPGTPGSGTASSSPGASPGTS







STGSPGASPGTSSTGSPGTPGSGTA







SSSPGSSTPSGATGSPGASPGTSSTG







SPGTPGSGTASSSPGSSTPSGATGSP







GSNPSASTGTGPGSSPSASTGTGPG







SSTPSGATGSPGSSTPSGATGSPGA







SPGTSSTGSPGASPGTSSTGSPGASP







GTSSTGSPGTPGSGTASSSPGASPG







TSSTGSPGASPGTSSTGSPGASPGT







SSTGSPGSSPSASTGTGPGTPGSGT







ASSSPGASPGTSSTGSPGASPGTSST







GSPGASPGTSSTGSPGSSTPSGATG







SPGSSTPSGATGSPGASPGTSSTGSP







GTPGSGTASSSPGSSTPSGATGSPG







SSTPSGATGSPGSSTPSGATGSPGSS







PSASTGTGPGASPGTSSTGSP






 


AE864
GSPAGSPTSTEEGTSESATPESGPG
640
864
Residue totals: H: 2 E: 3
99.77%



TSTEPSEGSAPGSPAGSPTSTEEGTS


percent: H: 0.2 E: 0.4




TEPSEGSAPGTSTEPSEGSAPGTSES







ATPESGPGSEPATSGSETPGSEPAT







SGSETPGSPAGSPTSTEEGTSESATP







ESGPGTSTEPSEGSAPGTSTEPSEGS







APGSPAGSPTSTEEGTSTEPSEGSA







PGTSTEPSEGSAPGTSESATPESGP







GTSTEPSEGSAPGTSESATPESGPG







SEPATSGSETPGTSTEPSEGSAPGTS







TEPSEGSAPGTSESATPESGPGTSES







ATPESGPGSPAGSPTSTEEGTSESA







TPESGPGSEPATSGSETPGTSESATP







ESGPGTSTEPSEGSAPGTSTEPSEGS







APGTSTEPSEGSAPGTSTEPSEGSA







PGTSTEPSEGSAPGTSTEPSEGSAP







GSPAGSPTSTEEGTSTEPSEGSAPG







TSESATPESGPGSEPATSGSETPGTS







ESATPESGPGSEPATSGSETPGTSES







ATPESGPGTSTEPSEGSAPGTSESA







TPESGPGSPAGSPTSTEEGSPAGSPT







STEEGSPAGSPTSTEEGTSESATPES







GPGTSTEPSEGSAPGTSESATPESG







PGSEPATSGSETPGTSESATPESGP







GSEPATSGSETPGTSESATPESGPG







TSTEPSEGSAPGSPAGSPTSTEEGTS







ESATPESGPGSEPATSGSETPGTSES







ATPESGPGSPAGSPTSTEEGSPAGS







PTSTEEGTSTEPSEGSAPGTSESATP







ESGPGTSESATPESGPGTSESATPES







GPGSEPATSGSETPGSEPATSGSET







PGSPAGSPTSTEEGTSTEPSEGSAP







GTSTEPSEGSAPGSEPATSGSETPG







TSESATPESGPGTSTEPSEGSAP






 


AF864
GSTSESPSGTAPGTSPSGESSTAPGS
641
875
Residue totals: H: 2 E: 0
95.20%



TSESPSGTAPGSTSESPSGTAPGTST


percent: H: 0.2 E: 0.0




PESGSASPGTSTPESGSASPGSTSES







PSGTAPGSTSESPSGTAPGTSPSGES







STAPGSTSESPSGTAPGTSPSGESST







APGTSPSGESSTAPGSTSSTAESPGP







GTSPSGESSTAPGTSPSGESSTAPGS







TSSTAESPGPGTSTPESGSASPGTST







PESGSASPGSTSESPSGTAPGSTSES







PSGTAPGTSTPESGSASPGSTSSTAE







SPGPGTSTPESGSASPGSTSESPSGT







APGTSPSGESSTAPGSTSSTAESPGP







GTSPSGESSTAPGTSTPESGSASPGS







TSSTAESPGPGSTSSTAESPGPGSTS







STAESPGPGSTSSTAESPGPGTSPSG







ESSTAPGSTSESPSGTAPGSTSESPS







GTAPGTSTPESGPXXXGASASGAP







STXXXXSESPSGTAPGSTSESPSGT







APGSTSESPSGTAPGSTSESPSGTAP







GSTSESPSGTAPGSTSESPSGTAPGT







STPESGSASPGTSPSGESSTAPGTSP







SGESSTAPGSTSSTAESPGPGTSPSG







ESSTAPGTSTPESGSASPGSTSESPS







GTAPGSTSESPSGTAPGTSPSGESST







APGSTSESPSGTAPGTSTPESGSASP







GTSTPESGSASPGSTSESPSGTAPGT







STPESGSASPGSTSSTAESPGPGSTS







ESPSGTAPGSTSESPSGTAPGTSPSG







ESSTAPGSTSSTAESPGPGTSPSGES







STAPGTSTPESGSASPGTSPSGESST







APGTSPSGESSTAPGTSPSGESSTAP







GSTSSTAESPGPGSTSSTAESPGPGT







SPSGESSTAPGSSPSASTGTGPGSST







PSGATGSPGSSTPSGATGSP






 


AG864
GGSPGASPGTSSTGSPGSSPSASTG
642
868
Residue totals: H: 0 E: 0
94.70%



TGPGSSPSASTGTGPGTPGSGTASS


percent: H: 0.0 E: 0.0




SPGSSTPSGATGSPGSNPSASTGTG







PGASPGTSSTGSPGTPGSGTASSSP







GSSTPSGATGSPGTPGSGTASSSPG







ASPGTSSTGSPGASPGTSSTGSPGT







PGSGTASSSPGSSTPSGATGSPGAS







PGTSSTGSPGTPGSGTASSSPGSSTP







SGATGSPGSNPSASTGTGPGSSPSA







STGTGPGSSTPSGATGSPGSSTPSG







ATGSPGASPGTSSTGSPGASPGTSS







TGSPGASPGTSSTGSPGTPGSGTAS







SSPGASPGTSSTGSPGASPGTSSTGS







PGASPGTSSTGSPGSSPSASTGTGP







GTPGSGTASSSPGASPGTSSTGSPG







ASPGTSSTGSPGASPGTSSTGSPGSS







TPSGATGSPGSSTPSGATGSPGASP







GTSSTGSPGTPGSGTASSSPGSSTPS







GATGSPGSSTPSGATGSPGSSTPSG







ATGSPGSSPSASTGTGPGASPGTSS







TGSPGASPGTSSTGSPGTPGSGTAS







SSPGASPGTSSTGSPGASPGTSSTGS







PGASPGTSSTGSPGASPGTSSTGSP







GTPGSGTASSSPGSSTPSGATGSPG







TPGSGTASSSPGSSTPSGATGSPGT







PGSGTASSSPGSSTPSGATGSPGSST







PSGATGSPGSSPSASTGTGPGSSPS







ASTGTGPGASPGTSSTGSPGTPGSG







TASSSPGSSTPSGATGSPGSSPSAST







GTGPGSSPSASTGTGPGASPGTSST







GSPGASPGTSSTGSPGSSTPSGATG







SPGSSPSASTGTGPGASPGTSSTGSP







GSSPSASTGTGPGTPGSGTASSSPG







SSTPSGATGSPGSSTPSGATGSPGA







SPGTSSTGSP






 


AM875
GTSTEPSEGSAPGSEPATSGSETPG
643
875
Residue totals: H: 7 E: 3
98.63%



SPAGSPTSTEEGSTSSTAESPGPGTS


percent: H: 0.8 E: 0.3




TPESGSASPGSTSESPSGTAPGSTSE







SPSGTAPGTSTPESGSASPGTSTPES







GSASPGSEPATSGSETPGTSESATP







ESGPGSPAGSPTSTEEGTSTEPSEGS







APGTSESATPESGPGTSTEPSEGSA







PGTSTEPSEGSAPGSPAGSPTSTEE







GTSTEPSEGSAPGTSTEPSEGSAPG







TSESATPESGPGTSESATPESGPGTS







TEPSEGSAPGTSTEPSEGSAPGTSES







ATPESGPGTSTEPSEGSAPGSEPAT







SGSETPGSPAGSPTSTEEGSSTPSGA







TGSPGTPGSGTASSSPGSSTPSGAT







GSPGTSTEPSEGSAPGTSTEPSEGS







APGSEPATSGSETPGSPAGSPTSTE







EGSPAGSPTSTEEGTSTEPSEGSAP







GASASGAPSTGGTSESATPESGPGS







PAGSPTSTEEGSPAGSPTSTEEGSTS







STAESPGPGSTSESPSGTAPGTSPSG







ESSTAPGTPGSGTASSSPGSSTPSG







ATGSPGSSPSASTGTGPGSEPATSG







SETPGTSESATPESGPGSEPATSGSE







TPGSTSSTAESPGPGSTSSTAESPGP







GTSPSGESSTAPGSEPATSGSETPGS







EPATSGSETPGTSTEPSEGSAPGSTS







STAESPGPGTSTPESGSASPGSTSES







PSGTAPGTSTEPSEGSAPGTSTEPSE







GSAPGTSTEPSEGSAPGSSTPSGAT







GSPGSSPSASTGTGPGASPGTSSTG







SPGSEPATSGSETPGTSESATPESGP







GSPAGSPTSTEEGSSTPSGATGSPG







SSPSASTGTGPGASPGTSSTGSPGT







SESATPESGPGTSTEPSEGSAPGTST







EPSEGSAP






 


AM1318
GTSTEPSEGSAPGSEPATSGSETPG
644
1318
Residue totals: H: 7 E: 0
99.17%



SPAGSPTSTEEGSTSSTAESPGPGTS


percent: H: 0.7 E: 0.0




TPESGSASPGSTSESPSGTAPGSTSE







SPSGTAPGTSTPESGSASPGTSTPES







GSASPGSEPATSGSETPGTSESATP







ESGPGSPAGSPTSTEEGTSTEPSEGS







APGTSESATPESGPGTSTEPSEGSA







PGTSTEPSEGSAPGSPAGSPTSTEE







GTSTEPSEGSAPGTSTEPSEGSAPG







TSESATPESGPGTSESATPESGPGTS







TEPSEGSAPGTSTEPSEGSAPGTSES







ATPESGPGTSTEPSEGSAPGSEPAT







SGSETPGSPAGSPTSTEEGSSTPSGA







TGSPGTPGSGTASSSPGSSTPSGAT







GSPGTSTEPSEGSAPGTSTEPSEGS







APGSEPATSGSETPGSPAGSPTSTE







EGSPAGSPTSTEEGTSTEPSEGSAP







GPEPTGPAPSGGSEPATSGSETPGT







SESATPESGPGSPAGSPTSTEEGTSE







SATPESGPGSPAGSPTSTEEGSPAG







SPTSTEEGTSESATPESGPGSPAGSP







TSTEEGSPAGSPTSTEEGSTSSTAES







PGPGSTSESPSGTAPGTSPSGESSTA







PGSTSESPSGTAPGSTSESPSGTAPG







TSPSGESSTAPGTSTEPSEGSAPGTS







ESATPESGPGTSESATPESGPGSEP







ATSGSETPGTSESATPESGPGTSES







ATPESGPGTSTEPSEGSAPGTSESA







TPESGPGTSTEPSEGSAPGTSPSGES







STAPGTSPSGESSTAPGTSPSGESST







APGTSTEPSEGSAPGSPAGSPTSTE







EGTSTEPSEGSAPGSSPSASTGTGP







GSSTPSGATGSPGSSTPSGATGSPG







SSTPSGATGSPGSSTPSGATGSPGA







SPGTSSTGSPGASASGAPSTGGTSP







SGESSTAPGSTSSTAESPGPGTSPSG







ESSTAPGTSESATPESGPGTSTEPSE







GSAPGTSTEPSEGSAPGSSPSASTG







TGPGSSTPSGATGSPGASPGTSSTG







SPGTSTPESGSASPGTSPSGESSTAP







GTSPSGESSTAPGTSESATPESGPGS







EPATSGSETPGTSTEPSEGSAPGSTS







ESPSGTAPGSTSESPSGTAPGTSTPE







SGSASPGSPAGSPTSTEEGTSESATP







ESGPGTSTEPSEGSAPGSPAGSPTST







EEGTSESATPESGPGSEPATSGSETP







GSSTPSGATGSPGASPGTSSTGSPG







SSTPSGATGSPGSTSESPSGTAPGTS







PSGESSTAPGSTSSTAESPGPGSSTP







SGATGSPGASPGTSSTGSPGTPGSG







TASSSPGSPAGSPTSTEEGSPAGSPT







STEEGTSTEPSEGSAP






 


AM923
MAEPAGSPTSTEEGASPGTSSTGSP
645
924
Residue totals: H: 4 E: 3
98.70%



GSSTPSGATGSPGSSTPSGATGSPG


percent: H: 0.4 E: 0.3




TSTEPSEGSAPGSEPATSGSETPGSP







AGSPTSTEEGSTSSTAESPGPGTSTP







ESGSASPGSTSESPSGTAPGSTSESP







SGTAPGTSTPESGSASPGTSTPESGS







ASPGSEPATSGSETPGTSESATPES







GPGSPAGSPTSTEEGTSTEPSEGSA







PGTSESATPESGPGTSTEPSEGSAP







GTSTEPSEGSAPGSPAGSPTSTEEG







TSTEPSEGSAPGTSTEPSEGSAPGTS







ESATPESGPGTSESATPESGPGTSTE







PSEGSAPGTSTEPSEGSAPGTSESA







TPESGPGTSTEPSEGSAPGSEPATS







GSETPGSPAGSPTSTEEGSSTPSGA







TGSPGTPGSGTASSSPGSSTPSGAT







GSPGTSTEPSEGSAPGTSTEPSEGS







APGSEPATSGSETPGSPAGSPTSTE







EGSPAGSPTSTEEGTSTEPSEGSAP







GASASGAPSTGGTSESATPESGPGS







PAGSPTSTEEGSPAGSPTSTEEGSTS







STAESPGPGSTSESPSGTAPGTSPSG







ESSTAPGTPGSGTASSSPGSSTPSG







ATGSPGSSPSASTGTGPGSEPATSG







SETPGTSESATPESGPGSEPATSGSE







TPGSTSSTAESPGPGSTSSTAESPGP







GTSPSGESSTAPGSEPATSGSETPGS







EPATSGSETPGTSTEPSEGSAPGSTS







STAESPGPGTSTPESGSASPGSTSES







PSGTAPGTSTEPSEGSAPGTSTEPSE







GSAPGTSTEPSEGSAPGSSTPSGAT







GSPGSSPSASTGTGPGASPGTSSTG







SPGSEPATSGSETPGTSESATPESGP







GSPAGSPTSTEEGSSTPSGATGSPG







SSPSASTGTGPGASPGTSSTGSPGT







SESATPESGPGTSTEPSEGSAPGTST







EPSEGSAP






 


AE912
MAEPAGSPTSTEEGTPGSGTASSSP
646
913
Residue totals: H: 8 E: 3
99.45%



GSSTPSGATGSPGASPGTSSTGSPG


percent: H: 0.9 E: 0.3




SPAGSPTSTEEGTSESATPESGPGTS







TEPSEGSAPGSPAGSPTSTEEGTSTE







PSEGSAPGTSTEPSEGSAPGTSESA







TPESGPGSEPATSGSETPGSEPATS







GSETPGSPAGSPTSTEEGTSESATPE







SGPGTSTEPSEGSAPGTSTEPSEGS







APGSPAGSPTSTEEGTSTEPSEGSA







PGTSTEPSEGSAPGTSESATPESGP







GTSTEPSEGSAPGTSESATPESGPG







SEPATSGSETPGTSTEPSEGSAPGTS







TEPSEGSAPGTSESATPESGPGTSES







ATPESGPGSPAGSPTSTEEGTSESA







TPESGPGSEPATSGSETPGTSESATP







ESGPGTSTEPSEGSAPGTSTEPSEGS







APGTSTEPSEGSAPGTSTEPSEGSA







PGTSTEPSEGSAPGTSTEPSEGSAP







GSPAGSPTSTEEGTSTEPSEGSAPG







TSESATPESGPGSEPATSGSETPGTS







ESATPESGPGSEPATSGSETPGTSES







ATPESGPGTSTEPSEGSAPGTSESA







TPESGPGSPAGSPTSTEEGSPAGSPT







STEEGSPAGSPTSTEEGTSESATPES







GPGTSTEPSEGSAPGTSESATPESG







PGSEPATSGSETPGTSESATPESGP







GSEPATSGSETPGTSESATPESGPG







TSTEPSEGSAPGSPAGSPTSTEEGTS







ESATPESGPGSEPATSGSETPGTSES







ATPESGPGSPAGSPTSTEEGSPAGS







PTSTEEGTSTEPSEGSAPGTSESATP







ESGPGTSESATPESGPGTSESATPES







GPGSEPATSGSETPGSEPATSGSET







PGSPAGSPTSTEEGTSTEPSEGSAP







GTSTEPSEGSAPGSEPATSGSETPG







TSESATPESGPGTSTEPSEGSAP






 


BC 864
GTSTEPSEPGSAGTSTEPSEPGSAG
647

Residue totals: H: 0 E: 0
99.77%



SEPATSGTEPSGSGASEPTSTEPGSE


percent: H: 0 E: 0




PATSGTEPSGSEPATSGTEPSGSEP







ATSGTEPSGSGASEPTSTEPGTSTEP







SEPGSAGSEPATSGTEPSGTSTEPSE







PGSAGSEPATSGTEPSGSEPATSGT







EPSGTSTEPSEPGSAGTSTEPSEPGS







AGSEPATSGTEPSGSEPATSGTEPS







GTSEPSTSEPGAGSGASEPTSTEPG







TSEPSTSEPGAGSEPATSGTEPSGSE







PATSGTEPSGTSTEPSEPGSAGTSTE







PSEPGSAGSGASEPTSTEPGSEPATS







GTEPSGSEPATSGTEPSGSEPATSG







TEPSGSEPATSGTEPSGTSTEPSEPG







SAGSEPATSGTEPSGSGASEPTSTE







PGTSTEPSEPGSAGSEPATSGTEPS







GSGASEPTSTEPGTSTEPSEPGSAG







SGASEPTSTEPGSEPATSGTEPSGS







GASEPTSTEPGSEPATSGTEPSGSG







ASEPTSTEPGTSTEPSEPGSAGSEPA







TSGTEPSGSGASEPTSTEPGTSTEPS







EPGSAGSEPATSGTEPSGTSTEPSEP







GSAGSEPATSGTEPSGTSTEPSEPG







SAGTSTEPSEPGSAGTSTEPSEPGS







AGTSTEPSEPGSAGTSTEPSEPGSA







GTSTEPSEPGSAGTSEPSTSEPGAG







SGASEPTSTEPGTSTEPSEPGSAGTS







TEPSEPGSAGTSTEPSEPGSAGSEP







ATSGTEPSGSGASEPTSTEPGSEPA







TSGTEPSGSEPATSGTEPSGSEPATS







GTEPSGSEPATSGTEPSGTSEPSTSE







PGAGSEPATSGTEPSGSGASEPTST







EPGTSTEPSEPGSAGSEPATSGTEPS







GSGASEPTSTEPGTSTEPSEPGSA






 



ASPAAPAPASPAAPAPSAPAAAPA
648
84
Residue totals: H: 58 E: 0
78.57%



SPAPAAPSAPAPAAPSAASPAAPSA


percent: H: 69.0 E: 0.0




PPAAASPAAPSAPPAASAAAPAAA







SAAASAPSAAA





*H: alpha-helix E: beta-sheet






Example 44: 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 results, shown in Table 28, 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: 649), 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'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 28







Subsequence score calculations of polypeptide sequences










Seq

SEQ ID



Name
Amino Acid Sequence
NO:
Score













J288
GSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGE
650
33.3



GGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSG





GEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGS





GGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEG





GSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGE





GGSGGEGGSGGEGGSGGEGGSGGEG




 


K288
GEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGG
651
46.9



EGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEG





GGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEG





EGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGG





EGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGE





GGEGEGGGEGGEGEGGGEGGEGEGGGEG




 


L288
SSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSS
652
50.0



ESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSES





SESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSE





SSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESS





SSESSSESSESSSSESSSESSESSSSESSSESSESSSSES




 


Y288
GEGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEGGSEGSEGEGGSEGSEG
653
26.8



EGSGEGSEGEGGSEGSEGEGSGEGSEGEGSEGGSEGEGGSEGSEGEGSGEGSEGE





GGEGGSEGEGSEGSGEGEGSGEGSEGEGSEGSGEGEGSGEGSEGEGSEGSGEGE





GSEGSGEGEGGSEGSEGEGSEGSGEGEGGEGSGEGEGSGEGSEGEGGGEGSEGE





GSGEGGEGEGSEGGSEGEGGSEGGEGEGSEGSGEGEGSEGGSEGEGSEGGSEGE





GSEGSGEGEGSEGSGE




 


Q576
GGKPGEGGKPEGGGGKPGGKPEGEGEGKPGGKPEGGGKPGGGEGGKPEGGKPE
654
18.5



GEGKPGGGEGKPGGKPEGGGGKPEGEGKPGGGGGKPGGKPEGEGKPGGGEGG





KPEGKPGEGGEGKPGGKPEGGGEGKPGGGKPGEGGKPGEGKPGGGEGGKPEGG





KPEGEGKPGGGEGKPGGKPGEGGKPEGGGEGKPGGKPGEGGEGKPGGGKPEGE





GKPGGGKPGGGEGGKPEGEGKPGGKPEGGGEGKPGGKPEGGGKPEGGGEGKP





GGGKPGEGGKPGEGEGKPGGKPEGEGKPGGEGGGKPEGKPGGGEGGKPEGGKP





GEGGKPEGGKPGEGGEGKPGGGKPGEGGKPEGGGKPEGEGKPGGGGKPGEGG





KPEGGKPEGGGEGKPGGGKPEGEGKPGGGEGKPGGKPEGGGGKPGEGGKPEGG





KPGGEGGGKPEGEGKPGGKPGEGGGGKPGGKPEGEGKPGEGGEGKPGGKPEGG





GEGKPGGKPEGGGEGKPGGGKPGEGGKPEGGGKPGEGGKPGEGGKPEGEGKPG





GGEGKPGGKPGEGGKPEGGGEGKPGGKPGGEGGGKPEGGKPGEGGKPEG




 


U576
GEGKPGGKPGSGGGKPGEGGKPGSGEGKPGGKPGSGGSGKPGGKPGEGGKPEG
655
18.1



GSGGKPGGGGKPGGKPGGEGSGKPGGKPEGGGKPEGGSGGKPGGKPEGGSGG





KPGGKPGSGEGGKPGGGKPGGEGKPGSGKPGGEGSGKPGGKPEGGSGGKPGGK





PEGGSGGKPGGSGKPGGKPGEGGKPEGGSGGKPGGSGKPGGKPEGGGSGKPGG





KPGEGGKPGSGEGGKPGGGKPGGEGKPGSGKPGGEGSGKPGGKPGSGGEGKPG





GKPEGGSGGKPGGGKPGGEGKPGSGGKPGEGGKPGSGGGKPGGKPGGEGEGKP





GGKPGEGGKPGGEGSGKPGGGGKPGGKPGGEGGKPEGSGKPGGGSGKPGGKPE





GGGGKPEGSGKPGGGGKPEGSGKPGGGKPEGGSGGKPGGSGKPGGKPGEGGG





KPEGSGKPGGGSGKPGGKPEGGGKPEGGSGGKPGGKPEGGSGGKPGGKPGGEG





SGKPGGKPGSGEGGKPGGKPGEGSGGKPGGKPEGGSGGKPGGSGKPGGKPEGG





GSGKPGGKPGEGGKPGGEGSGKPGGSGKPG




 


W576
GGSGKPGKPGGSGSGKPGSGKPGGGSGKPGSGKPGGGSGKPGSGKPGGGSGKP
656
23.4



GSGKPGGGGKPGSGSGKPGGGKPGGSGGKPGGGSGKPGKPGSGGSGKPGSGKP





GGGSGGKPGKPGSGGSGGKPGKPGSGGGSGKPGKPGSGGSGGKPGKPGSGGSG





GKPGKPGSGGSGKPGSGKPGGGSGKPGSGKPGSGGSGKPGKPGSGGSGKPGSG





KPGSGSGKPGSGKPGGGSGKPGSGKPGSGGSGKPGKPGSGGGKPGSGSGKPGG





GKPGSGSGKPGGGKPGGSGGKPGGSGGKPGKPGSGGGSGKPGKPGSGGGSGKP





GKPGGSGSGKPGSGKPGGGSGKPGSGKPGSGGSGKPGKPGSGGSGGKPGKPGS





GGGKPGSGSGKPGGGKPGSGSGKPGGGKPGSGSGKPGGGKPGSGSGKPGGSGK





PGSGKPGGGSGGKPGKPGSGGSGKPGSGKPGSGGSGKPGKPGGSGSGKPGSGKP





GGGSGKPGSGKPGGGSGKPGSGKPGGGSGKPGSGKPGGGGKPGSGSGKPGGSG





GKPGKPGSGGSGGKPGKPGSGGSGKPGSGKPGGGSGGKPGKPGSGG




 


Y576
GEGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEGSEGSGEGEGGEGSGE
657
15.7



GEGSGEGSEGEGGGEGSEGEGSGEGGEGEGSEGGSEGEGGSEGGEGEGSEGSGE





GEGSEGGSEGEGSEGGSEGEGSEGSGEGEGSEGSGEGEGSEGSGEGEGSEGSGEG





EGSEGGSEGEGGSEGSEGEGSGEGSEGEGGSEGSEGEGGGEGSEGEGSGEGSEGE





GGSEGSEGEGGSEGSEGEGGEGSGEGEGSEGSGEGEGSGEGSEGEGSEGSGEGE





GSEGSGEGEGGSEGSEGEGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEG





GSEGSEGEGGSEGSEGEGGEGSGEGEGSEGSGEGEGSGEGSEGEGSEGSGEGEGS





EGSGEGEGGSEGSEGEGSEGSGEGEGGEGSGEGEGSGEGSEGEGGGEGSEGEGS





EGSGEGEGSEGSGEGEGSEGGSEGEGGSEGSEGEGSEGGSEGEGSEGGSEGEGSE





GSGEGEGSEGSGEGEGSGEGSEGEGGSEGGEGEGSEGGSEGEGSEGGSEGEGGE





GSGEGEGGGEGSEGEGSEGSGEGEGSGEGSE




 


AD576
GSSESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSSESGSSEGGPGSSESGSSE
658
13.6



GGPGSSESGSSEGGPGSSESGSSEGGPGESPGGSSGSESGSEGSSGPGESSGSSESG





SSEGGPGSSESGSSEGGPGSSESGSSEGGPGSGGEPSESGSSGESPGGSSGSESGES





PGGSSGSESGSGGEPSESGSSGSSESGSSEGGPGSGGEPSESGSSGSGGEPSESGSS





GSEGSSGPGESSGESPGGSSGSESGSGGEPSESGSSGSGGEPSESGSSGSGGEPSES





GSSGSSESGSSEGGPGESPGGSSGSESGESPGGSSGSESGESPGGSSGSESGESPGG





SSGSESGESPGGSSGSESGSSESGSSEGGPGSGGEPSESGSSGSEGSSGPGESSGSSE





SGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSGGEPSESGSSGESPGGSSGSESG





ESPGGSSGSESGSSESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSGGEPSESG





SSGSGGEPSESGSSGESPGGSSGSESGSEGSSGPGESSGSSESGSSEGGPGSEGSSG





PGESS




 


AE576
AGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSE
659
6.1



GSAPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAG





SPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTS





TEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPG





SEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESG





PGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEG





SAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPS





EGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSES





ATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSP





AGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAP




 


AF540
GSTSSTAESPGPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGSTSSTAESP
660
8.8



GPGTSTPESGSASPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPS





GTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSES





PSGTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSTSESPSGTAPGTST





PESGSASPGSTSSTAESPGPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSASPGS





TSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAP





GSTSESPSGTAPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSASPGSTSESPSGT





APGSTSESPSGTAPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESG





SASPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGSTSSTAESPGPGTSTPE





SGSASPGSTSESPSGTAP




 


AF504
GASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGAT
661
7.0



GSPGSNPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSG





TASSSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGAS





PGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSNPSASTGTGPGSSPSASTGTGP





GSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSST





GSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSPSA





STGTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSS





TPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSP





GSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSP




 


AE864
GSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS
662
6.1



APGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSP





TSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTE





PSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSE





PATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPG





SPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSA





PGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEG





SAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESAT





PESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPA





GSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGT





SESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGP





GTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPES





GPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATP





ESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEP





SEGSAP




 


AF864
GSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSA
663
7.5



SPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSESPS





GTAPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSPSG





ESSTAPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGSTS





ESPSGTAPGTSTPESGSASPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGT





SPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASPGSTSSTAESPGP





GSTSSTAESPGPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSTSESPSGT





APGSTSESPSGTAPGTSTPESGPXXXGASASGAPSTXXXXSESPSGTAPGSTSESPS





GTAPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPE





SGSASPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTST





PESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGT





STPESGSASPGTSTPESGSASPGSTSESPSGTAPGTSTPESGSASPGSTSSTAESPGP





GSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESST





APGTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAE





SPGPGSTSSTAESPGPGTSPSGESSTAPGSSPSASTGTGPGSSTPSGATGSPGSSTPS





GATGSP




 


AG868
GGSPGASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTP
664
7.5



SGATGSPGSNPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGT





PGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGS





PGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSNPSASTGTGPGSSPSAST





GTGPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPG





TSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSS





PSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSP





GSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGAT





GSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGT





SSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGAS





PGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSP





GTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTG





TGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSA





STGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGPGAS





PGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSP





GASPGTSSTGSP




 


AM875
GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSA
665
4.5



SPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSG





SETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEP





SEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSE





SATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGT





STEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSP





GSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTST





EEGSPAGSPTSTEEGTSTEPSEGSAPGASASGAPSTGGTSESATPESGPGSPAGSPT





STEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESSTAPGTPGSG





TASSSPGSSTPSGATGSPGSSPSASTGTGPGSEPATSGSETPGTSESATPESGPGSEP





ATSGSETPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSEPATSGSETPGS





EPATSGSETPGTSTEPSEGSAPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAP





GTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSSTPSGATGSPGSSPSASTGT





GPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSSTPSG





ATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPGTSTEPSEGSAPGTST





EPSEGSAP




 


AM1318
GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSA
666
4.5



SPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSG





SETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEP





SEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSE





SATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGT





STEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSP





GSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTST





EEGSPAGSPTSTEEGTSTEPSEGSAPGPEPTGPAPSGGSEPATSGSETPGTSESATP





ESGPGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSESA





TPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSP





SGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGTSTEPSEGSAPGT





SESATPESGPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSESATPESGP





GTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSPSGESSTAPGTSPSGESST





APGTSPSGESSTAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGSSPSAST





GTGPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGASPG





TSSTGSPGASASGAPSTGGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTS





ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSSPSASTGTGPGSSTPSGATGSP





GASPGTSSTGSPGTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGTSESATPES





GPGSEPATSGSETPGTSTEPSEGSAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESG





SASPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESA





TPESGPGSEPATSGSETPGSSTPSGATGSPGASPGTSSTGSPGSSTPSGATGSPGSTS





ESPSGTAPGTSPSGESSTAPGSTSSTAESPGPGSSTPSGATGSPGASPGTSSTGSPGT





PGSGTASSSPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAP









Example 45: 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 29 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 29 were added. The HLA*0101B score of a 9mer peptide with the sequence FDKLPRTSG (SEQ ID NO: 667) 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 30-33 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: 668)) 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 29







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 30







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 31







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 32







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 33







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
















TABLE 34







Exemplary Biological Activity, Exemplary Assays and Preferred Indications










Biologically Active

Exemplary Activity



Protein
Biological Activity
Assay
Preferred Indication:





Insulin-like
IGF-1 is a pleiotropic
IGF-1 activity may be
Diabetes mellitus; Growth


growth
polypeptide with a
assayed in vitro using
disorders; Frailty;


factor-1
wide range of actions
an serum withdrawal
Amyotrophic lateral


(Mecasermin;
in both
apoptosis-protection
sclerosis; Osteoarthritis;


Somazon; IGF-1;
central and
assay. (J Endocrinol
Kidney disease &


IGF-1
peripheral
2000 October; 167(1):
neuropathy; Dwarfism; HIV-


complex; CEP
nervous sytems. It is
165-74). Proliferation
1 infections; Myocardial


151;
involved in growth
assay using breast
ischaemia; Osteoporosis;


CGP 35126; FK
and
carcinoma cell
Multiple sclerosis; Nerve


780;
development and
line MCF-7 (Karey
disorders; Burns; diabetes;


Mecar; RHIGF-1;
protects neurons
1988
peripheral


Somatomedin-1;
against cell death via
Cancer Res. 48:



Somatomedin-C;
the activation of
4083)



SOMATOKINE;
intracellular




MYOTROPHIN;
pathways




IGEF;
implicating




DepoIGF-1)
phosphatidylinositide





3/Akt kinase.




Human growth
Binds to two GHR
1) Ba/F3-hGHR
Acromegaly; Growth failure;


hormone
molecules and
proliferation assay, a
Growth hormone


(Pegvisamont;
Induces signal
novel specific
replacement; Growth


Somatrem;
transduction through
bioassay for serum
hormone deficiency;


Somatropin;
receptor dimerization
human growth
Pediatric Growth Hormone


TROVERT;

hormone. J Clin
Deficiency; Adult Growth


PROTROPIN;

Endocrinol Metab
Hormone Deficiency;


BIO-TROPIN;

2000 November; 85(11):
Idiopathic Growth Hormone


HUMATROPE;

4274-9 Plasma
Deficiency; Growth


NUTROPIN;

growth hormone (GH)
retardation; Prader-


NUTROPINAQ;

immunoassay and
Willi Syndrome; Prader-Willi


NUTROPHIN;

tibial bioassay, Appl
Syndrome in children 2


NORDITROPIN;

Physiol (2000) 89(6):
years or older; Growth


GENOTROPIN;

2174-8.
deficiencies; Growth failure


SAIZEN;

Growth hormone
associated with chronic


SEROSTIM)

(hGH) receptor
renal insufficiency;




mediated cell
Osteoporosis;




mediated
Postmenopausal




proliferation, Growth
osteoporosis; Osteopenia,




Horm IGF Res 2000
Osteoclastogenesis; burns;




October; 10(5): 248-55
Cachexia; Cancer




International standard
Cachexia; Dwarfism;




for growth hormone,
Metabolic Disorders;




Horm Res 1999; 51
Obesity; Renal failure;




Suppl 1: 7-12
Turner's Syndrome;




2) Detection of human
Fibromyalgia; Fracture




growth hormone
treatment; Frailty, AIDS




detected by direct
wasting; Muscle Wasting;




radioimmunoassay
Short Stature; Diagnostic




performed on serial
Agents; Female Infertility;




dilutions of lysed cell
lipodystrophy.




supernatants using





the Phadebas HGH





PRIST kit (Farmacia).





U.S. Pat. No.





4,898,830

















TABLE 35







Exemplary GHXTEN comprising growth hormones and single XTEN












GHXTEN

SEQ ID

SEQ ID


Name*
Amino Acid Sequence
NO:
DNA Nucleotide Sequence
NO:





AE48-
MAEPAGSPTSTEEGT
669
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
670


hGH
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC




GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG




GSPGFPTIPLSRLFDN

CTCTACCGGTTCTCCAGGTTTTCCGACTATTCCGCTGTCTCGTCT




AMLRAHRLHQLAFD

GTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGG




TYQEFEEAYIPKEQK

CCTTTGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAA




YSFLQNPQTSLCFSE

GAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTG




SIPTPSNREETQQKS

CTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTC




NLELLRISLLLIQSWL

AGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTG




EPVQFLRSVFANSLV

ATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTT




YGASDSNVYDLLKD

CGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATAC




LEEGIQTLMGRLEDG

GATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGG




SPRTGQIFKQTYSKF

GTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAG




DTNSHNDDALLKNY

CAGACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGC




GLLYCFRKDMDKVE

GCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATA




TFLRIVQCRSVEGSC

TGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCC




GF

GTTGAGGGCAGCTGTGGTTTCTAA



 


AM48-
MAEPAGSPTSTEEGA
671
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTG
672


hGH
SPGTSSTGSPGSSTPS

CATCCCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACC




GATGSPGSSTPSGAT

CCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGG




GSPGFPTIPLSRLFDN

TGCTACTGGCTCTCCAGGTTTTCCGACTATTCCGCTGTCTCGTCT




AMLRAHRLHQLAFD

GTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGG




TYQEFEEAYIPKEQK

CCTTTGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAA




YSFLQNPQTSLCFSE

GAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTG




SIPTPSNREETQQKS

CTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTC




NLELLRISLLLIQSWL

AGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTG




EPVQFLRSVFANSLV

ATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTT




YGASDSNVYDLLKD

CGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATAC




LEEGIQTLMGRLEDG

GATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGG




SPRTGQIFKQTYSKF

GTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAG




DTNSHNDDALLKNY

CAGACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGC




GLLYCFRKDMDKVE

GCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATA




TFLRIVQCRSVEGSC

TGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCC




GF

GTTGAGGGCAGCTGTGGTTTCTAA



 


AE144-
GSEPATSGSETPGTS
673
GGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACTT
674


hGH
ESATPESGPGSEPAT

CTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAACCTGC




SGSETPGSPAGSPTST

TACCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCTCCGA




EEGTSTEPSEGSAPG

CTTCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGGGTAGC




SEPATSGSETPGSEP

GCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAG




ATSGSETPGSEPATS

GTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGTAGCGA




GSETPGTSTEPSEGS

ACCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTACCGAAC




APGTSESATPESGPG

CTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCC




SEPATSGSETPGTSTE

TGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAG




PSEGSAPGFPTIPLSR

ACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAG




LFDNAMLRAHRLHQ

GTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGC




LAFDTYQEFEEAYIP

TGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAG




KEQKYSFLQNPQTSL

GAATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTT




CFSESIPTPSNREETQ

CCTGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTC




QKSNLELLRISLLLIQ

CGACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCT




SWLEPVQFLRSVFA

GGAACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAG




NSLVYGASDSNVYD

AACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTT




LLKDLEEGIQTLMGR

TATGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATC




LEDGSPRTGQIFKQT

TCGAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGG




YSKFDTNSHNDDAL

CTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAAT




LKNYGLLYCFRKDM

TTGATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTA




DKVETFLRIVQCRSV

TGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAA




EGSCGF

CCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGT






GGTTTCTAA



 


AE288-
GTSESATPESGPGSE
675
GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCG
676


hGH
PATSGSETPGTSESA

AACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGC




TPESGPGSEPATSGS

GCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTG




ETPGTSESATPESGP

GCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCT




GTSTEPSEGSAPGSP

GGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAG




AGSPTSTEEGTSESA

GTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT




TPESGPGSEPATSGS

GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAA




ETPGTSESATPESGP

CCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCT




GSPAGSPTSTEEGSP

GAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCG




AGSPTSTEEGTSTEPS

AGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGG




EGSAPGTSESATPES

TACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTG




GPGTSESATPESGPG

AAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGC




TSESATPESGPGSEP

TACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGG




ATSGSETPGSEPATS

AATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACC




GSETPGSPAGSPTST

CCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTA




EEGTSTEPSEGSAPG

GCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACT




TSTEPSEGSAPGSEP

GAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTT




ATSGSETPGTSESAT

CTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTC




PESGPGTSTEPSEGS

TGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCC




APGFPTIPLSRLFDNA

CAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTTTT




MLRAHRLHQLAFDT

CCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGT




YQEFEEAYIPKEQKY

GCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATT




SFLQNPQTSLCFSESI

TGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGC




PTPSNREETQQKSNL

AAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACG




ELLRISLLLIQSWLEP

CCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAAC




VQFLRSVFANSLVY

TACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCA




GASDSNVYDLLKDL

GTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGG




EEGIQTLMGRLEDGS

CGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTCGAG




PRTGQIFKQTYSKFD

GAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTC




TNSHNDDALLKNYG

CGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGAT




LLYCFRKDMDKVET

ACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATGGTC




FLRIVQCRSVEGSCGF

TGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTTC






CTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTT






CTAA



 


AF144-
GTSTPESGSASPGTSP
677
GGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTACTTC
678


hGH
SGESSTAPGTSPSGES

TCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCG




STAPGSTSSTAESPGP

GCGAATCTTCTACTGCTCCAGGTTCTACCAGCTCTACCGCTGAA




GSTSESPSGTAPGSTS

TCTCCTGGCCCAGGTTCTACCAGCGAATCCCCGTCTGGCACCGC




STAESPGPGTSPSGES

ACCAGGTTCTACTAGCTCTACCGCAGAATCTCCGGGTCCAGGTA




STAPGTSTPESGSASP

CTTCCCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTACT




GSTSSTAESPGPGTSP

CCGGAAAGCGGCTCCGCATCTCCAGGTTCTACTAGCTCTACTGC




SGESSTAPGTSPSGES

TGAATCTCCTGGTCCAGGTACCTCCCCTAGCGGCGAATCTTCTA




STAPGTSPSGESSTAP

CTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCA




GFPTIPLSRLFDNAM

GGTACCTCCCCTAGCGGTGAATCTTCTACCGCACCAGGTTTTCC




LRAHRLHQLAFDTY

GACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGTG




QEFEEAYTPKEQKYS

CGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATTT




FLQNPQTSLCFSESIP

GAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCA




TPSNREETQQKSNLE

AAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACGC




LLRISLLLIQSWLEPV

CTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAACT




QFLRSVFANSLVYG

ACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAG




ASDSNVYDLLKDLE

TGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGC




EGIQTLMGRLEDGSP

GCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTCGAGG




RTGQIFKQTYSKFDT

AAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCC




NSHNDDALLKNYGL

GCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGATA




LYCFRKDMDKVETF

CTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATGGTCT




LRIVQCRSVEGSCGF

GCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTTCC






TGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTC






TAA



 


AD576-
GSSESGSSEGGPGSG
679
GGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCAGGTTCCTC
680


hGH
GEPSESGSSGSSESGS

TGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAATCTCCGGGT




SEGGPGSSESGSSEG

GGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCTTCCGA




GPGSSESGSSEGGPG

GTCTGGTAGCTCAGGTGAATCTCCGGGTGGTTCTAGCGGTTCCG




SSESGSSEGGPGSSES

AGTCAGGTGAATCTCCGGGTGGTTCCAGCGGTTCTGAGTCAGGT




GSSEGGPGESPGGSS

TCCTCCGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTCCGA




GSESGSEGSSGPGES

AAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTGAAAGCGGTT




SGSSESGSSEGGPGS

CTTCCGAGGGCGGTCCAGGTGAATCTCCTGGTGGTTCCAGCGGT




SESGSSEGGPGSSES

TCCGAGTCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAGTC




GSSEGGPGSGGEPSE

AGGTGAATCTCCTGGTGGTTCTAGCGGTTCTGAATCAGGTTCCT




SGSSGESPGGSSGSE

CCGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTCCGAAAG




SGESPGGSSGSESGS

CGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTGAAAGCGGTTCTT




GGEPSESGSSGSSES

CCGAGGGCGGTCCAGGTTCCTCTGAAAGCGGTTCTTCTGAGGG




GSSEGGPGSGGEPSE

CGGTCCAGGTTCTTCCGAAAGCGGTTCTTCCGAGGGCGGTCCAG




SGSSGSGGEPSESGS

GTTCTTCCGAAAGCGGTTCTTCTGAAGGCGGTCCAGGTTCTGGT




SGSEGSSGPGESSGE

GGCGAACCGTCCGAGTCTGGTAGCTCAGGTGAATCTCCGGGTG




SPGGSSGSESGSGGE

GCTCTAGCGGTTCCGAGTCAGGTGAATCTCCTGGTGGTTCCAGC




PSESGSSGSGGEPSES

GGTTCCGAGTCAGGTTCCGGTGGCGAACCGTCCGAATCTGGTA




GSSGSGGEPSESGSS

GCTCAGGTAGCGAAGGTTCTTCTGGTCCAGGCGAATCTTCAGGT




GSSESGSSEGGPGES

TCCTCTGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCGGTGG




PGGSSGSESGESPGG

CGAACCGTCCGAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTG




SSGSESGESPGGSSG

GTCCAGGCGAATCTTCAGGTTCCTCTGAAAGCGGTTCTTCTGAG




SESGESPGGSSGSES

GGCGGTCCAGGTTCCGGTGGCGAACCTTCCGAATCTGGTAGCTC




GESPGGSSGSESGSS

AGGTGAATCTCCGGGTGGTTCTAGCGGTTCTGAGTCAGGTTCTG




ESGSSEGGPGSGGEP

GTGGTGAACCTTCCGAGTCTGGTAGCTCAGGTTCTGGTGGCGAA




SESGSSGSEGSSGPG

CCATCCGAGTCTGGTAGCTCAGGTTCTTCCGAAAGCGGTTCTTC




ESSGSSESGSSEGGP

CGAAGGCGGTCCAGGTTCTGGTGGTGAACCGTCCGAATCTGGT




GSGGEPSESGSSGSS

AGCTCAGGTTCTGGTGGCGAACCATCCGAATCTGGTAGCTCAG




ESGSSEGGPGSGGEP

GTAGCGAAGGTTCTTCTGGTCCTGGCGAATCTTCAGGTGAATCT




SESGSSGESPGGSSG

CCAGGTGGCTCTAGCGGTTCCGAATCAGGTAGCGAAGGTTCTTC




SESGESPGGSSGSES

CGGTCCAGGTGAATCTTCAGGTAGCGAAGGTTCTTCTGGTCCTG




GSSESGSSEGGPGSG

GTGAATCCTCAGGTTCCGGTGGCGAACCATCTGAATCTGGTAGC




GEPSESGSSGSSESGS

TCAGGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCAGGTTC




SEGGPGSGGEPSESG

CTCTGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAATCTCCGG




SSGSGGEPSESGSSG

GTGGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCATCC




ESPGGSSGSESGSEG

GAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTGGTCCTGGCGA




SSGPGESSGSSESGSS

ATCTTCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAATCAG




EGGPGSEGSSGPGES

GTAGCGAAGGTTCTTCCGGTCCTGGTGAGTCTTCAGGTGAATCT




SGFPTIPLSRLFDNA

CCAGGTGGCTCTAGCGGTTCCGAGTCAGGTAGCGAAGGTTCTTC




MLRAHRLHQLAFDT

TGGTCCTGGCGAGTCCTCAGGTTTTCCGACTATTCCGCTGTCTC




YQEFEEAYIPKEQKY

GTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCACCAG




SFLQNPQTSLCFSESI

CTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACATTCC




PTPSNREETQQKSNL

TAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTC




ELLRISLLLIQSWLEP

TCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAA




VQFLRSVFANSLVY

ACTCAGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCT




GASDSNVYDLLKDL

TCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCG




EEGIQTLMGRLEDGS

TCTTCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA




PRTGQIFKQTYSKFD

TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGA




TNSHNDDALLKNYG

TGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTC




LLYCFRKDMDKVET

AAGCAGACTTACTCTAAATTTGATACTAACAGCCACAATGACG




FLRIVQCRSVEGSCGF

ATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAA






GATATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCG






TTCCGTTGAGGGCAGCTGTGGTTTCTAA



 


AE576-
GSPAGSPTSTEEGTS
681
GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTC
682


hGH
ESATPESGPGTSTEPS

TGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTGAAC




EGSAPGSPAGSPTST

CGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTCTCCGAC




EEGTSTEPSEGSAPG

TTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGC




TSTEPSEGSAPGTSES

GCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAG




ATPESGPGSEPATSG

GTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGA




SETPGSEPATSGSETP

ACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCT




GSPAGSPTSTEEGTS

ACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCAGGCTCTCCGAC




ESATPESGPGTSTEPS

CTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCC




EGSAPGTSTEPSEGS

GGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAG




APGSPAGSPTSTEEG

GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCC




TSTEPSEGSAPGTSTE

AGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAAC




PSEGSAPGTSESATP

CGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCTTCTGA




ESGPGTSTEPSEGSA

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCC




PGTSESATPESGPGS

GGTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAG




EPATSGSETPGTSTEP

GTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGA




SEGSAPGTSTEPSEG

ACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAAC




SAPGTSESATPESGP

CGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGTCTGA




GTSESATPESGPGSP

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCGGAATCC




AGSPTSTEEGTSESA

GGCCCAGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCAG




TPESGPGSEPATSGS

GTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT




ETPGTSESATPESGP

GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAA




GTSTEPSEGSAPGTS

CCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCG




TEPSEGSAPGTSTEPS

GAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCG




EGSAPGTSTEPSEGS

CTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGG




APGTSTEPSEGSAPG

TACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTA




TSTEPSEGSAPGSPA

CTGAACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCT




GSPTSTEEGTSTEPSE

TCTGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGG




GSAPGTSESATPESG

GTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGA




PGSEPATSGSETPGT

GGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT




SESATPESGPGSEPA

ACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAAC




TSGSETPGTSESATPE

CTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCA




SGPGTSTEPSEGSAP

ACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCT




GTSESATPESGPGSP

CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGC




AGSPTSTEEGSPAGS

CCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTA




PTSTEEGSPAGSPTST

CTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCT




EEGTSESATPESGPG

GGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCC




TSTEPSEGSAPGFPTI

AACTTCTACTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCT




PLSRLFDNAMLRAH

ACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCC




RLHQLAFDTYQEFEE

CAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTTT




AYIPKEQKYSFLQNP

TCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCG




QTSLCFSESIPTPSNR

TGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAAT




EETQQKSNLELLRIS

TTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTG




LLLIQSWLEPVQFLR

CAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGAC




SVFANSLVYGASDS

GCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAA




NVYDLLKDLEEGIQT

CTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACC




LMGRLEDGSPRTGQI

AGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATG




FKQTYSKFDTNSHN

GCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTCGA




DDALLKNYGLLYCF

GGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCT




RKDMDKVETFLRIV

CCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGA




QCRSVEGSCGF

TACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATGGT






CTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTT






CCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTT






TCTAA



 


AF576-
GSTSSTAESPGPGSTS
683
GGTTCTACTAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCCAC
684


hGH
STAESPGPGSTSESPS

TAGCTCTACCGCAGAATCTCCGGGCCCAGGTTCTACTAGCGAAT




GTAPGSTSSTAESPG

CCCCTTCTGGTACCGCTCCAGGTTCTACTAGCTCTACCGCTGAA




PGSTSSTAESPGPGTS

TCTCCGGGTCCAGGTTCTACCAGCTCTACTGCAGAATCTCCTGG




TPESGSASPGSTSESP

CCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGTT




SGTAPGTSPSGESST

CTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCT




APGSTSESPSGTAPG

AGCGGCGAATCTTCTACCGCTCCAGGTTCTACTAGCGAATCTCC




STSESPSGTAPGTSPS

TTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCTTCTGGCA




GESSTAPGSTSESPSG

CCGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCA




TAPGSTSESPSGTAP

GGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTAC




GTSPSGESSTAPGSTS

CAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCTAGCG




ESPSGTAPGSTSESPS

GCGAATCTTCTACCGCTCCAGGTTCTACTAGCGAATCTCCTTCT




GTAPGSTSESPSGTA

GGCACTGCACCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGC




PGTSTPESGSASPGST

ACCAGGTTCTACCAGCGAATCTCCGTCTGGCACTGCACCAGGTA




SESPSGTAPGTSTPES

CCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGTTCTACTAGC




GSASPGSTSSTAESP

GAATCTCCTTCTGGTACCGCTCCAGGTACTTCTACCCCTGAAAG




GPGSTSSTAESPGPG

CGGCTCCGCTTCTCCAGGTTCCACTAGCTCTACCGCTGAATCTC




TSTPESGSASPGTSTP

CGGGTCCAGGTTCTACTAGCTCTACTGCAGAATCTCCTGGCCCA




ESGSASPGSTSESPSG

GGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTACTTC




TAPGTSTPESGSASP

TACCCCTGAAAGCGGTTCTGCATCTCCAGGTTCTACTAGCGAAT




GTSTPESGSASPGSTS

CCCCGTCTGGTACCGCACCAGGTACTTCTACCCCGGAAAGCGG




ESPSGTAPGSTSESPS

CTCTGCTTCTCCAGGTACTTCTACCCCGGAAAGCGGCTCCGCAT




GTAPGSTSESPSGTA

CTCCAGGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAGGT




PGSTSSTAESPGPGTS

TCTACCAGCGAATCCCCGTCTGGTACTGCTCCAGGTTCTACCAG




TPESGSASPGTSTPES

CGAATCTCCTTCTGGTACTGCACCAGGTTCTACTAGCTCTACTG




GSASPGSTSESPSGT

CAGAATCTCCTGGCCCAGGTACCTCTACTCCGGAAAGCGGCTCT




APGSTSESPSGTAPG

GCATCTCCAGGTACTTCTACCCCTGAAAGCGGTTCTGCATCTCC




TSTPESGSASPGSTSE

AGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTA




SPSGTAPGSTSESPSG

CCAGCGAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCCCT




TAPGTSTPESGSASP

GAAAGCGGTTCCGCTTCTCCAGGTTCTACTAGCGAATCTCCTTC




GTSPSGESSTAPGSTS

TGGCACTGCACCAGGTTCTACCAGCGAATCTCCGTCTGGCACTG




STAESPGPGTSPSGES

CACCAGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGT




STAPGSTSSTAESPGP

ACTTCTCCGAGCGGTGAATCTTCTACCGCACCAGGTTCTACTAG




GTSTPESGSASPGSTS

CTCTACCGCTGAATCTCCGGGCCCAGGTACTTCTCCGAGCGGTG




ESPSGTAPGSTSSTA

AATCTTCTACTGCTCCAGGTTCCACTAGCTCTACTGCTGAATCT




ESPGPGTSTPESGSAS

CCTGGCCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCC




PGTSTPESGSASPGFP

AGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAGGTTCTA




TIPLSRLFDNAMLRA

CTAGCTCTACTGCAGAATCTCCTGGCCCAGGTACCTCTACTCCG




HRLHQLAFDTYQEF

GAAAGCGGCTCTGCATCTCCAGGTACTTCTACCCCTGAAAGCG




EEAYIPKEQKYSFLQ

GTTCTGCATCTCCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGT




NPQTSLCFSESIPTPS

TTGATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCC




NREETQQKSNLELLR

TTTGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGA




ISLLLIQSWLEPVQFL

GCAGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCT




RSVFANSLVYGASD

TCAGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCA




SNVYDLLKDLEEGIQ

GCAAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGA




TLMGRLEDGSPRTG

TTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTC




QIFKQTYSKFDTNSH

GCCAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACG




NDDALLKNYGLLYC

ATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGG




FRKDMDKVETFLRI

TCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGC




VQCRSVEGSCGF

AGACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGC






GCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATA






TGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCC






GTTGAGGGCAGCTGTGGTTTCTAA



 


AE624-
MAEPAGSPTSTEEGT
685
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
686


hGH
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC




GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG




GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




FPTIPLSRLFDNAML

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




RAHRLHQLAFDTYQ

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




EFEEAYIPKEQKYSF

GCAGCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTT




LQNPQTSLCFSESIPT

GATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT




PSNREETQQKSNLEL

TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGC




LRISLLLIQSWLEPVQ

AGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTC




FLRSVFANSLVYGAS

AGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC




DSNVYDLLKDLEEGI

AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATT




QTLMGRLEDGSPRT

CAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGC




GQIFKQTYSKFDTNS

CAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGAT




HNDDALLKNYGLLY

CTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC




CFRKDMDKVETFLRI

GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG




VQCRSVEGSCGF

ACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCT






TCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGG






ACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTT






GAGGGCAGCTGTGGTTTCTAA



 


AD836-
GSSESGSSEGGPGSS
687
GGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCAGGTTCCTC
688


hGH
ESGSSEGGPGESPGG

TGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAATCTCCGGGT




SSGSESGSGGEPSES

GGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCTTCCGA




GSSGESPGGSSGSES

GTCTGGTAGCTCAGGTGAATCTCCGGGTGGTTCTAGCGGTTCCG




GESPGGSSGSESGES

AGTCAGGTGAATCTCCGGGTGGTTCCAGCGGTTCTGAGTCAGGT




ESGSSEGGPGSSESG

TCCTCCGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTCCGA




SSEGGPGSSESGSSE

AAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTGAAAGCGGTT




GGPGESPGGSSGSES

CTTCCGAGGGCGGTCCAGGTGAATCTCCTGGTGGTTCCAGCGGT




GESPGGSSGSESGES

TCCGAGTCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAGTC




PGGSSGSESGSSESG

AGGTGAATCTCCTGGTGGTTCTAGCGGTTCTGAATCAGGTTCCT




SSEGGPGSSESGSSE

CCGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTCCGAAAG




GGPGSSESGSSEGGP

CGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTGAAAGCGGTTCTT




GSSESGSSEGGPGSS

CCGAGGGCGGTCCAGGTTCCTCTGAAAGCGGTTCTTCTGAGGG




ESGSSEGGPGSSESG

CGGTCCAGGTTCTTCCGAAAGCGGTTCTTCCGAGGGCGGTCCAG




SSEGGPGSGGEPSES

GTTCTTCCGAAAGCGGTTCTTCTGAAGGCGGTCCAGGTTCTGGT




GSSGESPGGSSGSES

GGCGAACCGTCCGAGTCTGGTAGCTCAGGTGAATCTCCGGGTG




GESPGGSSGSESGSG

GCTCTAGCGGTTCCGAGTCAGGTGAATCTCCTGGTGGTTCCAGC




GEPSESGSSGSEGSS

GGTTCCGAGTCAGGTTCCGGTGGCGAACCGTCCGAATCTGGTA




GPGESSGSSESGSSE

GCTCAGGTAGCGAAGGTTCTTCTGGTCCAGGCGAATCTTCAGGT




GGPGSGGEPSESGSS

TCCTCTGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCGGTGG




GSEGSSGPGESSGSS

CGAACCGTCCGAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTG




ESGSSEGGPGSGGEP

GTCCAGGCGAATCTTCAGGTTCCTCTGAAAGCGGTTCTTCTGAG




SESGSSGESPGGSSG

GGCGGTCCAGGTTCCGGTGGCGAACCTTCCGAATCTGGTAGCTC




SESGSGGEPSESGSS

AGGTGAATCTCCGGGTGGTTCTAGCGGTTCTGAGTCAGGTTCTG




GSGGEPSESGSSGSS

GTGGTGAACCTTCCGAGTCTGGTAGCTCAGGTTCTGGTGGCGAA




ESGSSEGGPGSGGEP

CCATCCGAGTCTGGTAGCTCAGGTTCTTCCGAAAGCGGTTCTTC




SESGSSGSGGEPSES

CGAAGGCGGTCCAGGTTCTGGTGGTGAACCGTCCGAATCTGGT




GSSGSEGSSGPGESS

AGCTCAGGTTCTGGTGGCGAACCATCCGAATCTGGTAGCTCAG




GESPGGSSGSESGSE

GTAGCGAAGGTTCTTCTGGTCCTGGCGAATCTTCAGGTGAATCT




GSSGPGESSGSEGSS

CCAGGTGGCTCTAGCGGTTCCGAATCAGGTAGCGAAGGTTCTTC




GPGESSGSGGEPSES

CGGTCCAGGTGAATCTTCAGGTAGCGAAGGTTCTTCTGGTCCTG




GSSGSSESGSSEGGP

GTGAATCCTCAGGTTCCGGTGGCGAACCATCTGAATCTGGTAGC




GSSESGSSEGGPGES

TCAGGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCAGGTTC




PGGSSGSESGSGGEP

CTCTGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAATCTCCGG




SESGSSGSEGSSGPG

GTGGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCATCC




ESSGESPGGSSGSES

GAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTGGTCCTGGCGA




GSEGSSGPGSSESGS

ATCTTCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAATCAG




SEGGPGSGGEPSESG

GTAGCGAAGGTTCTTCCGGTCCaGGTTCCTCTGAAAGCGGTTCT




SSGSEGSSGPGESSG

TCTGAGGGCGGTCCAGGTTCTGGTGGCGAACCATCTGAATCTG




SEGSSGPGESSGSEG

GTAGCTCAGGTAGCGAAGGTTCTTCCGGTCCGGGTGAATCTTCA




SSGPGESSGSGGEPS

GGTAGCGAAGGTTCTTCCGGTCCAGGTGAATCTTCAGGTAGCG




ESGSSGSGGEPSESG

AAGGTTCTTCTGGTCCTGGTGAATCCTCAGGTTCCGGTGGCGAA




SSGESPGGSSGSESG

CCATCTGAATCTGGTAGCTCAGGTTCTGGTGGCGAACCATCCGA




ESPGGSSGSESGSGG

ATCTGGTAGCTCAGGTGAATCTCCGGGTGGCTCCAGCGGTTCTG




EPSESGSSGSEGSSGP

AATCAGGTGAATCTCCTGGTGGCTCCAGCGGTTCTGAGTCAGGT




GESSGESPGGSSGSE

TCTGGTGGCGAACCATCCGAATCTGGTAGCTCAGGTAGCGAAG




SGSSESGSSEGGPGS

GTTCTTCTGGTCCTGGCGAATCTTCAGGTGAATCTCCAGGTGGC




SESGSSEGGPGSSES

TCTAGCGGTTCCGAATCAGGTTCCTCTGAAAGCGGTTCTTCTGA




GSSEGGPGSGGEPSE

GGGCGGTCCAGGTTCTTCCGAAAGCGGTTCTTCCGAGGGCGGT




SGSSGSSESGSSEGG

CCAGGTTCTTCCGAAAGCGGTTCTTCTGAAGGCGGTCCAGGTTC




PGESPGGSSGSESGS

TGGTGGCGAACCGTCCGAATCTGGTAGCTCAGGTTCCTCCGAA




GGEPSESGSSGSSES

AGCGGTTCTTCTGAAGGTGGTCCAGGTGAATCTCCAGGTGGTTC




GSSEGGPGESPGGSS

TAGCGGTTCTGAATCAGGTTCTGGTGGCGAACCGTCCGAATCTG




GSESGSGGEPSESGS

GTAGCTCAGGTTCCTCCGAAAGCGGTTCTTCTGAAGGTGGTCCA




SGESPGGSSGSESGS

GGTGAATCTCCAGGTGGTTCTAGCGGTTCTGAATCAGGTTCTGG




GGEPSESGSSGFPTIP

TGGCGAACCGTCCGAATCTGGTAGCTCAGGTGAATCTCCTGGTG




LSRLFDNAMLRAHR

GTTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCTTCCGAA




LHQLAFDTYQEFEE

TCTGGTAGCTCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTT




AYIPKEQKYSFLQNP

GATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT




QTSLCFSESIPTPSNR

TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGC




EETQQKSNLELLRIS

AGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTC




LLLIQSWLEPVQFLR

AGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC




SVFANSLVYGASDS

AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATT




NVYDLLKDLEEGIQT

CAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGC




LMGRLEDGSPRTGQI

CAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGAT




FKQTYSKFDTNSHN

CTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC




DDALLKNYGLLYCF

GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG




RKDMDKVETFLRIV

ACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCT




QCRSVEGSCGF

TCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGG






ACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTT






GAGGGCAGCTGTGGTTTCTAA



 


AE864-
GSPAGSPTSTEEGTS
689
GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTC
690


hGH
ESATPESGPGTSTEPS

TGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTGAAC




EGSAPGSPAGSPTST

CGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTCTCCGAC




EEGTSTEPSEGSAPG

TTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGC




TSTEPSEGSAPGTSES

GCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAG




ATPESGPGSEPATSG

GTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGA




SETPGSEPATSGSETP

ACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCT




GSPAGSPTSTEEGTS

ACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCAGGCTCTCCGAC




ESATPESGPGTSTEPS

CTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCC




EGSAPGTSTEPSEGS

GGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAG




APGSPAGSPTSTEEG

GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCC




TSTEPSEGSAPGTSTE

AGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAAC




PSEGSAPGTSESATP

CGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCTTCTGA




ESGPGTSTEPSEGSA

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCC




PGTSESATPESGPGS

GGTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAG




EPATSGSETPGTSTEP

GTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGA




SEGSAPGTSTEPSEG

ACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAAC




SAPGTSESATPESGP

CGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGTCTGA




GTSESATPESGPGSP

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCGGAATCC




AGSPTSTEEGTSESA

GGCCCAGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCAG




TPESGPGSEPATSGS

GTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT




ETPGTSESATPESGP

GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAA




GTSTEPSEGSAPGTS

CCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCG




TEPSEGSAPGTSTEPS

GAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCG




EGSAPGTSTEPSEGS

CTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGG




APGTSTEPSEGSAPG

TACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTA




TSTEPSEGSAPGSPA

CTGAACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCT




GSPTSTEEGTSTEPSE

TCTGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGG




GSAPGTSESATPESG

GTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGA




PGSEPATSGSETPGT

GGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT




SESATPESGPGSEPA

ACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAAC




TSGSETPGTSESATPE

CTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCA




SGPGTSTEPSEGSAP

ACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCT




GTSESATPESGPGSP

CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGC




AGSPTSTEEGSPAGS

CCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTA




PTSTEEGSPAGSPTST

CTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCT




EEGTSESATPESGPG

GGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCC




TSTEPSEGSAPGTSES

AACTTCTACTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCT




ATPESGPGSEPATSG

ACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCC




SETPGTSESATPESGP

CAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTAC




GSEPATSGSETPGTS

CTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCT




ESATPESGPGTSTEPS

GCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAA




EGSAPGSPAGSPTST

CCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCTCT




EEGTSESATPESGPG

GAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCC




SEPATSGSETPGTSES

CAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAG




ATPESGPGSPAGSPT

CCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAA




STEEGSPAGSPTSTEE

GCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACCTC




GTSTEPSEGSAPGTS

CGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGT




ESATPESGPGTSESA

CCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGA




TPESGPGTSESATPES

AGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTT




GPGSEPATSGSETPG

CTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAG




SEPATSGSETPGSPA

CGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTC




GSPTSTEEGTSTEPSE

CTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




GSAPGTSTEPSEGSA

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




PGSEPATSGSETPGT

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




SESATPESGPGTSTEP

AGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAAC




SEGSAPGFPTIPLSRL

CTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAG




FDNAMLRAHRLHQL

GGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAA




AFDTYQEFEEAYIPK

CCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGT




EQKYSFLQNPQTSLC

ACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTTTTCCGAC




FSESIPTPSNREETQQ

TATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGTGCGC




KSNLELLRISLLLIQS

ACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATTTGAA




WLEPVQFLRSVFAN

GAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAA




SLVYGASDSNVYDL

CCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT




LKDLEEGIQTLMGRL

CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAACTACT




EDGSPRTGQIFKQTY

CCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAGTGC




SKFDTNSHNDDALL

AATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCA




KNYGLLYCFRKDMD

TCCGACAGCAACGTATACGATCTCCTGAAAGATCTCGAGGAAG




KVETFLRIVQCRSVE

GCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT




GSCGF

ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGATACTAA






CAGCCACAATGACGATGCGCTTCTAAAAAACTATGGTCTGCTGT






ATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGCGT






ATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAA



 


AF864-
GSTSESPSGTAPGTSP
691
GGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTC
692


hGH
SGESSTAPGSTSESPS

TCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTACTAGCGAAT




GTAPGSTSESPSGTA

CTCCTTCTGGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCT




PGTSTPESGSASPGTS

GGTACTGCTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTC




TPESGSASPGSTSESP

TCCAGGTACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTT




SGTAPGSTSESPSGT

CTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTTCTACTAGC




APGTSPSGESSTAPG

GAATCCCCGTCTGGTACCGCACCAGGTACTTCTCCTAGCGGCGA




STSESPSGTAPGTSPS

ATCTTCTACCGCACCAGGTTCTACTAGCGAATCTCCGTCTGGCA




GESSTAPGTSPSGESS

CTGCTCCAGGTACTTCTCCTAGCGGTGAATCTTCTACCGCTCCA




TAPGSTSSTAESPGP

GGTACTTCCCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTAC




GTSPSGESSTAPGTSP

TAGCTCTACTGCAGAATCTCCGGGCCCAGGTACCTCTCCTAGCG




SGESSTAPGSTSSTA

GTGAATCTTCTACCGCTCCAGGTACTTCTCCGAGCGGTGAATCT




ESPGPGTSTPESGSAS

TCTACCGCTCCAGGTTCTACTAGCTCTACTGCAGAATCTCCTGG




PGTSTPESGSASPGST

CCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTA




SESPSGTAPGSTSESP

CTTCTACCCCTGAAAGCGGTTCTGCATCTCCAGGTTCTACTAGC




SGTAPGTSTPESGSA

GAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCC




SPGSTSSTAESPGPGT

GTCTGGCACTGCACCAGGTACCTCTACCCCTGAAAGCGGTTCCG




STPESGSASPGSTSES

CTTCTCCAGGTTCTACCAGCTCTACCGCAGAATCTCCTGGTCCA




PSGTAPGTSPSGESST

GGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTTCTAC




APGSTSSTAESPGPG

TAGCGAATCTCCTTCTGGCACTGCACCAGGTACTTCTCCGAGCG




TSPSGESSTAPGTSTP

GTGAATCTTCTACCGCACCAGGTTCTACTAGCTCTACCGCTGAA




ESGSASPGSTSSTAES

TCTCCGGGCCCAGGTACTTCTCCGAGCGGTGAATCTTCTACTGC




PGPGSTSSTAESPGP

TCCAGGTACCTCTACTCCTGAAAGCGGTTCTGCATCTCCAGGTT




GSTSSTAESPGPGSTS

CCACTAGCTCTACCGCAGAATCTCCGGGCCCAGGTTCTACTAGC




STAESPGPGTSPSGES

TCTACTGCTGAATCTCCTGGCCCAGGTTCTACTAGCTCTACTGC




STAPGSTSESPSGTAP

TGAATCTCCGGGTCCAGGTTCTACCAGCTCTACTGCTGAATCTC




GSTSESPSGTAPGTS

CTGGTCCAGGTACCTCCCCGAGCGGTGAATCTTCTACTGCACCA




TPESGPXXXGASASG

GGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTAC




APSTXXXXSESPSGT

CAGCGAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCCCTG




APGSTSESPSGTAPG

AAAGCGGTCCXXXXXXXXXXXXTGCAAGCGCAAGCGGCGCGC




STSESPSGTAPGSTSE

CAAGCACGGGAXXXXXXXXTAGCGAATCTCCTTCTGGTACCGC




SPSGTAPGSTSESPSG

TCCAGGTTCTACCAGCGAATCCCCGTCTGGTACTGCTCCAGGTT




TAPGSTSESPSGTAP

CTACCAGCGAATCTCCTTCTGGTACTGCACCAGGTTCTACTAGC




GTSTPESGSASPGTSP

GAATCTCCTTCTGGTACCGCTCCAGGTTCTACCAGCGAATCCCC




SGESSTAPGTSPSGES

GTCTGGTACTGCTCCAGGTTCTACCAGCGAATCTCCTTCTGGTA




STAPGSTSSTAESPGP

CTGCACCAGGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCA




GTSPSGESSTAPGTS

GGTACTTCTCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTC




TPESGSASPGSTSESP

TCCTAGCGGCGAATCTTCTACTGCTCCAGGTTCTACCAGCTCTA




SGTAPGSTSESPSGT

CTGCTGAATCTCCGGGTCCAGGTACTTCCCCGAGCGGTGAATCT




APGTSPSGESSTAPG

TCTACTGCACCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTC




STSESPSGTAPGTSTP

TCCAGGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTT




ESGSASPGTSTPESGS

CTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTACTTCTCCT




ASPGSTSESPSGTAP

AGCGGCGAATCTTCTACCGCACCAGGTTCTACTAGCGAATCCCC




GTSTPESGSASPGSTS

GTCTGGTACCGCACCAGGTACTTCTACCCCGGAAAGCGGCTCTG




STAESPGPGSTSESPS

CTTCTCCAGGTACTTCTACCCCGGAAAGCGGCTCCGCATCTCCA




GTAPGSTSESPSGTA

GGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAGGTACTTC




PGTSPSGESSTAPGST

TACCCCTGAAAGCGGCTCCGCTTCTCCAGGTTCCACTAGCTCTA




SSTAESPGPGTSPSGE

CCGCTGAATCTCCGGGTCCAGGTTCTACCAGCGAATCTCCTTCT




SSTAPGTSTPESGSAS

GGCACCGCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACCGC




PGTSPSGESSTAPGTS

ACCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTT




PSGESSTAPGTSPSGE

CTACCAGCTCTACTGCTGAATCTCCGGGTCCAGGTACTTCCCCG




SSTAPGSTSSTAESPG

AGCGGTGAATCTTCTACTGCACCAGGTACTTCTACTCCGGAAAG




PGSTSSTAESPGPGTS

CGGTTCCGCTTCTCCAGGTACCTCCCCTAGCGGCGAATCTTCTA




PSGESSTAPGSSPSAS

CTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCA




TGTGPGSSTPSGATG

GGTACCTCCCCTAGCGGTGAATCTTCTACCGCACCAGGTTCTAC




SPGSSTPSGATGSPG

TAGCTCTACTGCTGAATCTCCGGGTCCAGGTTCTACCAGCTCTA




FPTIPLSRLFDNAML

CTGCTGAATCTCCTGGTCCAGGTACCTCCCCGAGCGGTGAATCT




RAHRLHQLAFDTYQ

TCTACTGCACCAGGTTCTAGCCCTTCTGCTTCCACCGGTACCGG




EFEEAYIPKEQKYSF

CCCAGGTAGCTCTACTCCGTCTGGTGCAACTGGCTCTCCAGGTA




LQNPQTSLCFSESIPT

GCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTTTTCCGACT




PSNREETQQKSNLEL

ATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCA




LRISLLLIQSWLEPVQ

CCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATTTGAAG




FLRSVFANSLVYGAS

AAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAAC




DSNVYDLLKDLEEGI

CCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTC




QTLMGRLEDGSPRT

CAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAACTACTC




GQIFKQTYSKFDTNS

CGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCA




HNDDALLKNYGLLY

ATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCAT




CFRKDMDKVETFLRI

CCGACAGCAACGTATACGATCTCCTGAAAGATCTCGAGGAAGG




VQCRSVEGSCGF

CATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTA






CTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGATACTAAC






AGCCACAATGACGATGCGCTTCTAAAAAACTATGGTCTGCTGT






ATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGCGT






ATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAA



 


AG864-
GASPGTSSTGSPGSS
693
GGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTTCTAG
694


hGH
PSASTGTGPGSSPSA

CCCGTCTGCTTCTACTGGTACTGGTCCAGGTTCTAGCCCTTCTGC




STGTGPGTPGSGTAS

TTCCACTGGTACTGGTCCAGGTACCCCGGGTAGCGGTACCGCTT




SSPGSSTPSGATGSP

CTTCTTCTCCAGGTAGCTCTACTCCGTCTGGTGCTACCGGCTCTC




GSNPSASTGTGPGAS

CAGGTTCTAACCCTTCTGCATCCACCGGTACCGGCCCAGGTGCT




PGTSSTGSPGTPGSG

TCTCCGGGCACCAGCTCTACTGGTTCTCCAGGTACCCCGGGCAG




TASSSPGSSTPSGAT

CGGTACCGCATCTTCTTCTCCAGGTAGCTCTACTCCTTCTGGTGC




GSPGTPGSGTASSSP

AACTGGTTCTCCAGGTACTCCTGGCAGCGGTACCGCTTCTTCTT




GASPGTSSTGSPGAS

CTCCAGGTGCTTCTCCTGGTACTAGCTCTACTGGTTCTCCAGGT




PGTSSTGSPGTPGSG

GCTTCTCCGGGCACTAGCTCTACTGGTTCTCCAGGTACCCCGGG




TASSSPGSSTPSGAT

TAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGG




GSPGASPGTSSTGSP

TGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAGCTCTACCG




GTPGSGTASSSPGSS

GTTCTCCAGGTACCCCGGGTAGCGGTACCGCTTCTTCTTCTCCA




TPSGATGSPGSNPSA

GGTAGCTCTACTCCGTCTGGTGCTACCGGCTCTCCAGGTTCTAA




STGTGPGSSPSASTG

CCCTTCTGCATCCACCGGTACCGGCCCAGGTTCTAGCCCTTCTG




TGPGSSTPSGATGSP

CTTCCACCGGTACTGGCCCAGGTAGCTCTACCCCTTCTGGTGCT




GSSTPSGATGSPGAS

ACCGGCTCCCCAGGTAGCTCTACTCCTTCTGGTGCAACTGGCTC




PGTSSTGSPGASPGT

TCCAGGTGCATCTCCGGGCACTAGCTCTACTGGTTCTCCAGGTG




SSTGSPGASPGTSST

CATCCCCTGGCACTAGCTCTACTGGTTCTCCAGGTGCTTCTCCT




GSPGTPGSGTASSSP

GGTACCAGCTCTACTGGTTCTCCAGGTACTCCTGGCAGCGGTAC




GASPGTSSTGSPGAS

CGCTTCTTCTTCTCCAGGTGCTTCTCCTGGTACTAGCTCTACTGG




PGTSSTGSPGASPGT

TTCTCCAGGTGCTTCTCCGGGCACTAGCTCTACTGGTTCTCCAG




SSTGSPGSSPSASTGT

GTGCTTCCCCGGGCACTAGCTCTACCGGTTCTCCAGGTTCTAGC




GPGTPGSGTASSSPG

CCTTCTGCATCTACTGGTACTGGCCCAGGTACTCCGGGCAGCGG




ASPGTSSTGSPGASP

TACTGCTTCTTCCTCTCCAGGTGCATCTCCGGGCACTAGCTCTA




GTSSTGSPGASPGTS

CTGGTTCTCCAGGTGCATCCCCTGGCACTAGCTCTACTGGTTCT




STGSPGSSTPSGATG

CCAGGTGCTTCTCCTGGTACCAGCTCTACTGGTTCTCCAGGTAG




SPGSSTPSGATGSPG

CTCTACTCCGTCTGGTGCAACCGGTTCCCCAGGTAGCTCTACTC




ASPGTSSTGSPGTPG

CTTCTGGTGCTACTGGCTCCCCAGGTGCATCCCCTGGCACCAGC




SGTASSSPGSSTPSG

TCTACCGGTTCTCCAGGTACCCCGGGCAGCGGTACCGCATCTTC




ATGSPGSSTPSGATG

CTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACCGGTTCCCCAG




SPGSSTPSGATGSPG

GTAGCTCTACCCCGTCTGGTGCAACCGGCTCCCCAGGTAGCTCT




SSPSASTGTGPGASP

ACTCCGTCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGC




GTSSTGSPGASPGTS

TTCCACTGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTA




STGSPGTPGSGTASS

CTGGTTCTCCAGGTGCATCCCCGGGTACCAGCTCTACCGGTTCT




SPGASPGTSSTGSPG

CCAGGTACTCCTGGCAGCGGTACTGCATCTTCCTCTCCAGGTGC




ASPGTSSTGSPGASP

TTCTCCGGGCACCAGCTCTACTGGTTCTCCAGGTGCATCTCCGG




GTSSTGSPGASPGTS

GCACTAGCTCTACTGGTTCTCCAGGTGCATCCCCTGGCACTAGC




STGSPGTPGSGTASS

TCTACTGGTTCTCCAGGTGCTTCTCCTGGTACCAGCTCTACTGGT




SPGSSTPSGATGSPG

TCTCCAGGTACCCCTGGTAGCGGTACTGCTTCTTCCTCTCCAGG




TPGSGTASSSPGSSTP

TAGCTCTACTCCGTCTGGTGCTACCGGTTCTCCAGGTACCCCGG




SGATGSPGTPGSGTA

GTAGCGGTACCGCATCTTCTTCTCCAGGTAGCTCTACCCCGTCT




SSSPGSSTPSGATGSP

GGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTGCTTC




GSSTPSGATGSPGSS

TTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCC




PSASTGTGPGSSPSA

AGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCCCCAGGTTCTA




STGTGPGASPGTSST

GCCCTTCTGCATCCACCGGTACCGGTCCAGGTTCTAGCCCGTCT




GSPGTPGSGTASSSP

GCATCTACTGGTACTGGTCCAGGTGCATCCCCGGGCACTAGCTC




GSSTPSGATGSPGSS

TACCGGTTCTCCAGGTACTCCTGGTAGCGGTACTGCTTCTTCTTC




PSASTGTGPGSSPSA

TCCAGGTAGCTCTACTCCTTCTGGTGCTACTGGTTCTCCAGGTTC




STGTGPGASPGTSST

TAGCCCTTCTGCATCCACCGGTACCGGCCCAGGTTCTAGCCCGT




GSPGASPGTSSTGSP

CTGCTTCTACCGGTACTGGTCCAGGTGCTTCTCCGGGTACTAGC




GSSTPSGATGSPGSS

TCTACTGGTTCTCCAGGTGCATCTCCTGGTACTAGCTCTACTGG




PSASTGTGPGASPGT

TTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCTCCAG




SSTGSPGSSPSASTGT

GTTCTAGCCCTTCTGCATCTACCGGTACTGGTCCAGGTGCATCC




GPGTPGSGTASSSPG

CCTGGTACCAGCTCTACCGGTTCTCCAGGTTCTAGCCCTTCTGC




SSTPSGATGSPGSSTP

TTCTACCGGTACCGGTCCAGGTACCCCTGGCAGCGGTACCGCAT




SGATGSPGASPGTSS

CTTCCTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGTTCC




TGSPGFPTIPLSRLFD

CCAGGTAGCTCTACTCCTTCTGGTGCTACTGGCTCCCCAGGTGC




NAMLRAHRLHQLAF

ATCCCCTGGCACCAGCTCTACCGGTTCTCCAGGTTTTCCGACTA




DTYQEFEEAYIPKEQ

TTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCAC




KYSFLQNPQTSLCFS

CGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGA




ESIPTPSNREETQQKS

AGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACC




NLELLRISLLLIQSWL

CACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCC




EPVQFLRSVFANSLV

AATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAACTACTCC




YGASDSNVYDLLKD

GCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAA




LEEGIQTLMGRLEDG

TTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCC




SPRTGQIFKQTYSKF

GACAGCAACGTATACGATCTCCTGAAAGATCTCGAGGAAGGCA




DTNSHNDDALLKNY

TTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACT




GLLYCFRKDMDKVE

GGTCAGATCTTCAAGCAGACTTACTCTAAATTTGATACTAACAG




TFLRIVQCRSVEGSC

CCACAATGACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATT




GF

GTTTTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGCGTATT






GTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAA



 


AM875-
GTSTEPSEGSAPGSE
695
GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCAGGTAGCG
696


hGH
PATSGSETPGSPAGS

AACCGGCTACTTCCGGTTCTGAAACCCCAGGTAGCCCAGCAGG




PTSTEEGSTSSTAESP

TTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCAG




GPGTSTPESGSASPG

AATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCA




STSESPSGTAPGSTSE

TCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGG




SPSGTAPGTSTPESGS

TTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTA




ASPGTSTPESGSASP

CTCCTGAAAGCGGTTCCGCTTCTCCAGGTACCTCTACTCCGGAA




GSEPATSGSETPGTS

AGCGGTTCTGCATCTCCAGGTAGCGAACCGGCAACCTCCGGCT




ESATPESGPGSPAGS

CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCCGG




PTSTEEGTSTEPSEGS

CCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGT




APGTSESATPESGPG

ACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGA




TSTEPSEGSAPGTSTE

AAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGT




PSEGSAPGSPAGSPT

CCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGG




STEEGTSTEPSEGSAP

TAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAG




GTSTEPSEGSAPGTS

GAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTA




ESATPESGPGTSESA

CTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAA




TPESGPGTSTEPSEGS

AGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTA




APGTSTEPSEGSAPG

CTCCTGAATCCGGTCCAGGTACCTCTACTGAACCTTCCGAAGGC




TSESATPESGPGTSTE

AGCGCTCCAGGTACCTCTACCGAACCGTCCGAGGGCAGCGCAC




PSEGSAPGSEPATSG

CAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAC




SETPGSPAGSPTSTEE

TTCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCGAACCTG




GSSTPSGATGSPGTP

CTACTTCTGGTTCTGAAACCCCAGGTAGCCCGGCTGGCTCTCCG




GSGTASSSPGSSTPS

ACCTCCACCGAGGAAGGTAGCTCTACCCCGTCTGGTGCTACTGG




GATGSPGTSTEPSEG

TTCTCCAGGTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAG




SAPGTSTEPSEGSAP

GTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTACCTCT




GSEPATSGSETPGSP

ACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAAC




AGSPTSTEEGSPAGS

CGTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCCGG




PTSTEEGTSTEPSEGS

TTCTGAAACTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTG




APGASASGAPSTGGT

AGGAAGGTAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGG




SESATPESGPGSPAG

TACTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTGCAAGC




SPTSTEEGSPAGSPTS

GCAAGCGGCGCGCCAAGCACGGGAGGTACTTCTGAAAGCGCTA




TEEGSTSSTAESPGP

CTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCC




GSTSESPSGTAPGTSP

ACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAG




SGESSTAPGTPGSGT

AAGGTTCTACCAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCT




ASSSPGSSTPSGATG

ACTAGCGAATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTAG




SPGSSPSASTGTGPG

CGGTGAATCTTCTACTGCACCAGGTACCCCTGGCAGCGGTACCG




SEPATSGSETPGTSES

CTTCTTCCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGCT




ATPESGPGSEPATSG

CTCCAGGTTCTAGCCCGTCTGCATCTACCGGTACCGGCCCAGGT




SETPGSTSSTAESPGP

AGCGAACCGGCAACCTCCGGCTCTGAAACTCCAGGTACTTCTG




GSTSSTAESPGPGTSP

AAAGCGCTACTCCGGAATCCGGCCCAGGTAGCGAACCGGCTAC




SGESSTAPGSEPATS

TTCCGGCTCTGAAACCCCAGGTTCCACCAGCTCTACTGCAGAAT




GSETPGSEPATSGSE

CTCCGGGCCCAGGTTCTACTAGCTCTACTGCAGAATCTCCGGGT




TPGTSTEPSEGSAPG

CCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTAG




STSSTAESPGPGTSTP

CGAACCGGCAACCTCTGGCTCTGAAACTCCAGGTAGCGAACCT




ESGSASPGSTSESPSG

GCAACCTCCGGCTCTGAAACCCCAGGTACTTCTACTGAACCTTC




TAPGTSTEPSEGSAP

TGAGGGCAGCGCACCAGGTTCTACCAGCTCTACCGCAGAATCT




GTSTEPSEGSAPGTS

CCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCC




TEPSEGSAPGSSTPSG

AGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTACTT




ATGSPGSSPSASTGT

CTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTACTGA




GPGASPGTSSTGSPG

ACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTCTG




SEPATSGSETPGTSES

AAGGTAGCGCACCAGGTAGCTCTACTCCGTCTGGTGCAACCGG




ATPESGPGSPAGSPT

CTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAG




STEEGSSTPSGATGS

GTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTAGCGAA




PGSSPSASTGTGPGA

CCTGCTACCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGC




SPGTSSTGSPGTSESA

AACTCCGGAGTCTGGTCCAGGTAGCCCTGCAGGTTCTCCTACCT




TPESGPGTSTEPSEGS

CCACTGAGGAAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCC




APGTSTEPSEGSAPG

CCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAGGTGC




FPTIPLSRLFDNAML

TTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTACCTCTGAAA




RAHRLHQLAFDTYQ

GCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGTCT




EFEEAYIPKEQKYSF

GAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTA




LQNPQTSLCFSESIPT

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




PSNREETQQKSNLEL

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




LRISLLLIQSWLEPVQ

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




FLRSVFANSLVYGAS

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




DSNVYDLLKDLEEGI

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




QTLMGRLEDGSPRT

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




GQIFKQTYSKFDTNS

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAA




HNDDALLKNYGLLY

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




CFRKDMDKVETFLRI

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




VQCRSVEGSCGF

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT






ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA






AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA






AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG






GCAGCTGTGGTTTCTAA



 


AE912-
MAEPAGSPTSTEEGT
697
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
698


hGH
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC




GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG




GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




TSESATPESGPGSEP

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




ATSGSETPGTSESAT

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




PESGPGSEPATSGSE

GCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




TPGTSESATPESGPG

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




TSTEPSEGSAPGSPA

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSPTSTEEGTSESATP

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




ESGPGSEPATSGSET

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




PGTSESATPESGPGSP

CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




AGSPTSTEEGSPAGS

GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA




PTSTEEGTSTEPSEGS

GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGA




APGTSESATPESGPG

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




TSESATPESGPGTSES

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




ATPESGPGSEPATSG

ACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCAC




SETPGSEPATSGSETP

CAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT




GSPAGSPTSTEEGTS

TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAG




TEPSEGSAPGTSTEPS

CGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCT




EGSAPGSEPATSGSE

GGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTG




TPGTSESATPESGPG

AAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA




TSTEPSEGSAPGFPTI

AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACC




PLSRLFDNAMLRAH

TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTG




RLHQLAFDTYQEFEE

CAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT




AYIPKEQKYSFLQNP

CCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCA




QTSLCFSESIPTPSNR

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




EETQQKSNLELLRIS

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




LLLIQSWLEPVQFLR

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




SVFANSLVYGASDS

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




NVYDLLKDLEEGIQT

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




LMGRLEDGSPRTGQI

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




FKQTYSKFDTNSHN

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAA




DDALLKNYGLLYCF

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




RKDMDKVETFLRIV

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




QCRSVEGSCGF

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT






ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA






AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA






AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG






GCAGCTGTGGTTTCTAA



 


AM923-
MAEPAGSPTSTEEGA
699
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTG
700


hGH
SPGTSSTGSPGSSTPS

CATCCCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACC




GATGSPGSSTPSGAT

CCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGG




GSPGTSTEPSEGSAP

TGCTACTGGCTCTCCAGGTACTTCTACTGAACCGTCTGAAGGCA




GSEPATSGSETPGSP

GCGCACCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCC




AGSPTSTEEGSTSST

AGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTA




AESPGPGTSTPESGS

CCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCG




ASPGSTSESPSGTAP

GAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTC




GSTSESPSGTAPGTS

TGGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACTG




TPESGSASPGTSTPES

CTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGT




GSASPGSEPATSGSE

ACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACC




TPGTSESATPESGPG

GGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




SPAGSPTSTEEGTSTE

ACTCCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTC




PSEGSAPGTSESATP

CACTGAGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCT




ESGPGTSTEPSEGSA

CCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTA




PGTSTEPSEGSAPGSP

CTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACC




AGSPTSTEEGTSTEPS

GAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTC




EGSAPGTSTEPSEGS

CTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGG




APGTSESATPESGPG

TAGCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCA




TSESATPESGPGTSTE

CCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTA




PSEGSAPGTSTEPSE

CTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACT




GSAPGTSESATPESG

GAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGT




PGTSTEPSEGSAPGS

CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGA




EPATSGSETPGSPAG

ATCCGGTCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTC




SPTSTEEGSSTPSGAT

CAGGTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGC




GSPGTPGSGTASSSP

CCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCC




GSSTPSGATGSPGTS

GTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTG




TEPSEGSAPGTSTEPS

CTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCT




EGSAPGSEPATSGSE

CTCCAGGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGG




TPGSPAGSPTSTEEG

TACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAA




SPAGSPTSTEEGTSTE

CCGGCAACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTC




PSEGSAPGASASGAP

TCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTT




STGGTSESATPESGP

CTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGC




GSPAGSPTSTEEGSP

TCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTACT




AGSPTSTEEGSTSST

TCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTG




AESPGPGSTSESPSGT

GCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCA




APGTSPSGESSTAPG

ACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCC




TPGSGTASSSPGSSTP

TGGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAG




SGATGSPGSSPSAST

GTACTTCCCCTAGCGGTGAATCTTCTACTGCACCAGGTACCCCT




GTGPGSEPATSGSET

GGCAGCGGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCCGTC




PGTSESATPESGPGS

TGGTGCTACTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCG




EPATSGSETPGSTSST

GTACCGGCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAAC




AESPGPGSTSSTAESP

TCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGGT




GPGTSPSGESSTAPG

AGCGAACCGGCTACTTCCGGCTCTGAAACCCCAGGTTCCACCA




SEPATSGSETPGSEP

GCTCTACTGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACT




ATSGSETPGTSTEPSE

GCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTC




GSAPGSTSSTAESPG

TACCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACT




PGTSTPESGSASPGST

CCAGGTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGGTA




SESPSGTAPGTSTEPS

CTTCTACTGAACCTTCTGAGGGCAGCGCACCAGGTTCTACCAGC




EGSAPGTSTEPSEGS

TCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAG




APGTSTEPSEGSAPG

CGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCA




SSTPSGATGSPGSSPS

CTGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCC




ASTGTGPGASPGTSS

AGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCT




TGSPGSEPATSGSET

CTACCGAACCTTCTGAAGGTAGCGCACCAGGTAGCTCTACTCCG




PGTSESATPESGPGSP

TCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCAC




AGSPTSTEEGSSTPS

TGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTT




GATGSPGSSPSASTG

CTCCAGGTAGCGAACCTGCTACCTCCGGTTCTGAAACCCCAGGT




TGPGASPGTSSTGSP

ACCTCTGAAAGCGCAACTCCGGAGTCTGGTCCAGGTAGCCCTG




GTSESATPESGPGTS

CAGGTTCTCCTACCTCCACTGAGGAAGGTAGCTCTACTCCGTCT




TEPSEGSAPGTSTEPS

GGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGG




EGSAPGFPTIPLSRLF

TACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTC




DNAMLRAHRLHQL

CAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTAC




AFDTYQEFEEAYIPK

CTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTG




EQKYSFLQNPQTSLC

AACCGTCCGAAGGTAGCGCACCAGGTTTTCCGACTATTCCGCTG




FSESIPTPSNREETQQ

TCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCA




KSNLELLRISLLLIQS

CCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACA




WLEPVQFLRSVFAN

TTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACT




SLVYGASDSNVYDL

TCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGA




LKDLEEGIQTLMGRL

GGAAACTCAGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTC




EDGSPRTGQIFKQTY

TGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGT




SKFDTNSHNDDALL

TCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA




KNYGLLYCFRKDMD

CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACC




KVETFLRIVQCRSVE

CTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGAT




GSCGF

CTTCAAGCAGACTTACTCTAAATTTGATACTAACAGCCACAATG






ACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGT






AAAGATATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTG






TCGTTCCGTTGAGGGCAGCTGTGGTTTCTAA



 


AM1318-
GTSTEPSEGSAPGSE
701
GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCAGGTAGCG
702


hGH
PATSGSETPGSPAGS

AACCGGCTACTTCCGGTTCTGAAACCCCAGGTAGCCCAGCAGG




PTSTEEGSTSSTAESP

TTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCAG




GPGTSTPESGSASPG

AATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCA




STSESPSGTAPGSTSE

TCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGG




SPSGTAPGTSTPESGS

TTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTA




ASPGTSTPESGSASP

CTCCTGAAAGCGGTTCCGCTTCTCCAGGTACCTCTACTCCGGAA




GSEPATSGSETPGTS

AGCGGTTCTGCATCTCCAGGTAGCGAACCGGCAACCTCCGGCT




ESATPESGPGSPAGS

CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCCGG




PTSTEEGTSTEPSEGS

CCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGT




APGTSESATPESGPG

ACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGA




TSTEPSEGSAPGTSTE

AAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGT




PSEGSAPGSPAGSPT

CCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGG




STEEGTSTEPSEGSAP

TAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAG




GTSTEPSEGSAPGTS

GAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTA




ESATPESGPGTSESA

CTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAA




TPESGPGTSTEPSEGS

AGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTA




APGTSTEPSEGSAPG

CTCCTGAATCCGGTCCAGGTACCTCTACTGAACCTTCCGAAGGC




TSESATPESGPGTSTE

AGCGCTCCAGGTACCTCTACCGAACCGTCCGAGGGCAGCGCAC




PSEGSAPGSEPATSG

CAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAC




SETPGSPAGSPTSTEE

TTCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCGAACCTG




GSSTPSGATGSPGTP

CTACTTCTGGTTCTGAAACCCCAGGTAGCCCGGCTGGCTCTCCG




GSGTASSSPGSSTPS

ACCTCCACCGAGGAAGGTAGCTCTACCCCGTCTGGTGCTACTGG




GATGSPGTSTEPSEG

TTCTCCAGGTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAG




SAPGTSTEPSEGSAP

GTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTACCTCT




GSEPATSGSETPGSP

ACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAAC




AGSPTSTEEGSPAGS

CGTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCCGG




PTSTEEGTSTEPSEGS

TTCTGAAACTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTG




APGPEPTGPAPSGGS

AGGAAGGTAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGG




EPATSGSETPGTSES

TACTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTCCAGAAC




ATPESGPGSPAGSPT

CAACGGGGCCGGCCCCAAGCGGAGGTAGCGAACCGGCAACCTC




STEEGTSESATPESGP

CGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAAT




GSPAGSPTSTEEGSP

CCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGA




AGSPTSTEEGTSESA

AGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGC




TPESGPGSPAGSPTST

CCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTG




EEGSPAGSPTSTEEG

GCTCTCCAACTTCTACTGAAGAAGGTACTTCTGAAAGCGCTACT




STSSTAESPGPGSTSE

CCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCAC




SPSGTAPGTSPSGESS

CGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAA




TAPGSTSESPSGTAP

GGTTCTACCAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCTAC




GSTSESPSGTAPGTSP

TAGCGAATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTAGCG




SGESSTAPGTSTEPSE

GTGAATCTTCTACTGCACCAGGTTCTACCAGCGAATCTCCTTCT




GSAPGTSESATPESG

GGCACCGCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACCGC




PGTSESATPESGPGS

ACCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTA




EPATSGSETPGTSES

CTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAA




ATPESGPGTSESATP

AGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTA




ESGPGTSTEPSEGSA

CTCCTGAATCCGGTCCAGGTAGCGAACCGGCAACCTCTGGCTCT




PGTSESATPESGPGT

GAAACCCCAGGTACCTCTGAAAGCGCTACTCCGGAATCTGGTC




STEPSEGSAPGTSPSG

CAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGTCCAGGTAC




ESSTAPGTSPSGESST

CTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAA




APGTSPSGESSTAPG

GCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCC




TSTEPSEGSAPGSPA

GAAGGTAGCGCACCAGGTACCTCCCCTAGCGGCGAATCTTCTA




GSPTSTEEGTSTEPSE

CTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCA




GSAPGSSPSASTGTG

GGTACCTCCCCTAGCGGTGAATCTTCTACCGCACCAGGTACTTC




PGSSTPSGATGSPGS

TACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGT




STPSGATGSPGSSTPS

TCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGA




GATGSPGSSTPSGAT

GGGTAGCGCACCAGGTTCTAGCCCTTCTGCTTCCACCGGTACCG




GSPGASPGTSSTGSP

GCCCAGGTAGCTCTACTCCGTCTGGTGCAACTGGCTCTCCAGGT




GASASGAPSTGGTSP

AGCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTAGCTCTAC




SGESSTAPGSTSSTA

CCCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTG




ESPGPGTSPSGESSTA

GTGCAACCGGCTCCCCAGGTGCATCCCCGGGTACTAGCTCTACC




PGTSESATPESGPGT

GGTTCTCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAG




STEPSEGSAPGTSTEP

GTACTTCTCCGAGCGGTGAATCTTCTACCGCACCAGGTTCTACT




SEGSAPGSSPSASTG

AGCTCTACCGCTGAATCTCCGGGCCCAGGTACTTCTCCGAGCGG




TGPGSSTPSGATGSP

TGAATCTTCTACTGCTCCAGGTACCTCTGAAAGCGCTACTCCGG




GASPGTSSTGSPGTS

AGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCT




TPESGSASPGTSPSGE

CCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTT




SSTAPGTSPSGESSTA

CTAGCCCTTCTGCATCTACTGGTACTGGCCCAGGTAGCTCTACT




PGTSESATPESGPGS

CCTTCTGGTGCTACCGGCTCTCCAGGTGCTTCTCCGGGTACTAG




EPATSGSETPGTSTEP

CTCTACCGGTTCTCCAGGTACTTCTACTCCGGAAAGCGGTTCCG




SEGSAPGSTSESPSGT

CATCTCCAGGTACTTCTCCTAGCGGTGAATCTTCTACTGCTCCA




APGSTSESPSGTAPG

GGTACCTCTCCTAGCGGCGAATCTTCTACTGCTCCAGGTACTTC




TSTPESGSASPGSPA

TGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCT




GSPTSTEEGTSESATP

ACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGA




ESGPGTSTEPSEGSA

AGGTAGCGCACCAGGTTCTACCAGCGAATCCCCTTCTGGTACTG




PGSPAGSPTSTEEGT

CTCCAGGTTCTACCAGCGAATCCCCTTCTGGCACCGCACCAGGT




SESATPESGPGSEPA

ACTTCTACCCCTGAAAGCGGCTCCGCTTCTCCAGGTAGCCCGGC




TSGSETPGSSTPSGA

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




TGSPGASPGTSSTGS

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




PGSSTPSGATGSPGS

GCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGA




TSESPSGTAPGTSPSG

AGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGT




ESSTAPGSTSSTAESP

AGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTAGCTCTA




GPGSSTPSGATGSPG

CCCCGTCTGGTGCTACCGGTTCCCCAGGTGCTTCTCCTGGTACT




ASPGTSSTGSPGTPG

AGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTGGTGCTAC




SGTASSSPGSPAGSP

TGGCTCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACTGCTC




TSTEEGSPAGSPTSTE

CAGGTACTTCCCCTAGCGGTGAATCTTCTACTGCTCCAGGTTCT




EGTSTEPSEGSAPGF

ACCAGCTCTACCGCAGAATCTCCGGGTCCAGGTAGCTCTACCCC




PTIPLSRLFDNAMLR

TTCTGGTGCAACCGGCTCTCCAGGTGCATCCCCGGGTACCAGCT




AHRLHQLAFDTYQE

CTACCGGTTCTCCAGGTACTCCGGGTAGCGGTACCGCTTCTTCC




FEEAYIPKEQKYSFL

TCTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTGAGGAAGG




QNPQTSLCFSESIPTP

TAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGGTACTTCTA




SNREETQQKSNLELL

CCGAACCTTCCGAAGGTAGCGCTCCAGGTTTTCCGACTATTCCG




RISLLLIQSWLEPVQF

CTGTCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCT




LRSVFANSLVYGAS

GCACCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcT




DSNVYDLLKDLEEGI

ACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACA




QTLMGRLEDGSPRT

GACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATC




GQIFKQTYSKFDTNS

GCGAGGAAACTCAGCAAAAGTCCAATCTGGAACTACTCCGCAT




HNDDALLKNYGLLY

TTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTC




CFRKDMDKVETFLRI

TGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCCGAC




VQCRSVEGSCGF

AGCAACGTATACGATCTCCTGAAAGATCTCGAGGAAGGCATTC






AGACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGT






CAGATCTTCAAGCAGACTTACTCTAAATTTGATACTAACAGCCA






CAATGACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTT






TTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGCGTATTGTT






CAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAA



 


hGH-
FPTIPLSRLFDNAML
703
TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTG
704


AE144
RAHRLHQLAFDTYQ

CGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGA




EFEEAYIPKEQKYSF

ATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCC




LQNPQTSLCFSESIPT

TGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCG




PSNREETQQKSNLEL

ACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG




LRISLLLIQSWLEPVQ

AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAA




FLRSVFANSLVYGAS

CCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTA




DSNVYDLLKDLEEGI

TGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTC




QTLMGRLEDGSPRT

GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCT




GQIFKQTYSKFDTNS

CTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTT




HNDDALLKNYGLLY

GATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATG




CFRKDMDKVETFLRI

GTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACC




VQCRSVEGSCGFGG

TTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG




SEPATSGSETPGTSES

TTTCTAAGGTGGTAGCGAACCGGCAACTTCCGGCTCTGAAACCC




ATPESGPGSEPATSG

CAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGC




SETPGSPAGSPTSTEE

GAACCTGCTACCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAG




GTSTEPSEGSAPGSE

GCTCTCCGACTTCCACCGAGGAAGGTACCTCTACTGAACCTTCT




PATSGSETPGSEPAT

GAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTG




SGSETPGSEPATSGS

AAACCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAAACTCC




ETPGTSTEPSEGSAP

AGGTAGCGAACCGGCTACTTCCGGTTCTGAAACTCCAGGTACCT




GTSESATPESGPGSE

CTACCGAACCTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAG




PATSGSETPGTSTEPS

CGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCT




EGSAP

GGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTA






GCGCACCA



 


hGH-
FPTIPLSRLFDNAML
705
TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTG
706


AE288
RAHRLHQLAFDTYQ

CGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGA




EFEEAYIPKEQKYSF

ATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCC




LQNPQTSLCFSESIPT

TGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCG




PSNREETQQKSNLEL

ACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG




LRISLLLIQSWLEPVQ

AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAA




FLRSVFANSLVYGAS

CCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTA




DSNVYDLLKDLEEGI

TGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTC




QTLMGRLEDGSPRT

GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCT




GQIFKQTYSKFDTNS

CTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTT




HNDDALLKNYGLLY

GATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATG




CFRKDMDKVETFLRI

GTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACC




VQCRSVEGSCGFGG

TTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG




TSESATPESGPGSEP

TTTCTAAGGTGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCC




ATSGSETPGTSESAT

CAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTAC




PESGPGSEPATSGSE

CTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCT




TPGTSESATPESGPG

GCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTA




TSTEPSEGSAPGSPA

CTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGC




GSPTSTEEGTSESATP

AGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAG




ESGPGSEPATSGSET

AAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAG




PGTSESATPESGPGSP

CGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAA




AGSPTSTEEGSPAGS

AGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCC




PTSTEEGTSTEPSEGS

GACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTA




APGTSESATPESGPG

CTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACC




TSESATPESGPGTSES

AGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTT




ATPESGPGSEPATSG

CTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGC




SETPGSEPATSGSETP

GCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTG




GSPAGSPTSTEEGTS

GTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGA




TEPSEGSAPGTSTEPS

AACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAA




EGSAPGSEPATSGSE

GGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTC




TPGTSESATPESGPG

TACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCA




TSTEPSEGSAP

ACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCC






TGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGC






GCACCA



 


hGH-
FPTIPLSRLFDNAML
707
TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTG
708


AF144
RAHRLHQLAFDTYQ

CGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGA




EFEEAYIPKEQKYSF

ATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCC




LQNPQTSLCFSESIPT

TGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCG




PSNREETQQKSNLEL

ACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG




LRISLLLIQSWLEPVQ

AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAA




FLRSVFANSLVYGAS

CCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTA




DSNVYDLLKDLEEGI

TGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTC




QTLMGRLEDGSPRT

GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCT




GQIFKQTYSKFDTNS

CTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTT




HNDDALLKNYGLLY

GATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATG




CFRKDMDKVETFLRI

GTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACC




VQCRSVEGSCGFGG

TTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG




TSTPESGSASPGTSPS

TTTCTAAGGTGGTACTTCTACTCCGGAAAGCGGTTCCGCATCTC




GESSTAPGTSPSGESS

CAGGTACTTCTCCTAGCGGTGAATCTTCTACTGCTCCAGGTACC




TAPGSTSSTAESPGP

TCTCCTAGCGGCGAATCTTCTACTGCTCCAGGTTCTACCAGCTC




GSTSESPSGTAPGSTS

TACCGCTGAATCTCCTGGCCCAGGTTCTACCAGCGAATCCCCGT




STAESPGPGTSPSGES

CTGGCACCGCACCAGGTTCTACTAGCTCTACCGCAGAATCTCCG




STAPGTSTPESGSASP

GGTCCAGGTACTTCCCCTAGCGGTGAATCTTCTACTGCTCCAGG




GSTSSTAESPGPGTSP

TACCTCTACTCCGGAAAGCGGCTCCGCATCTCCAGGTTCTACTA




SGESSTAPGTSPSGES

GCTCTACTGCTGAATCTCCTGGTCCAGGTACCTCCCCTAGCGGC




STAPGTSPSGESSTAP

GAATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTC






TACCGCTCCAGGTACCTCCCCTAGCGGTGAATCTTCTACCGCAC






CA



 


hGH-
FPTIPLSRLFDNAML
709
TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTG
710


AD576
RAHRLHQLAFDTYQ

CGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGA




EFEEAYIPKEQKYSF

ATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCC




LQNPQTSLCFSESIPT

TGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCG




PSNREETQQKSNLEL

ACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG




LRISLLLIQSWLEPVQ

AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAA




FLRSVFANSLVYGAS

CCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTA




DSNVYDLLKDLEEGI

TGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTC




QTLMGRLEDGSPRT

GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCT




GQIFKQTYSKFDTNS

CTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTT




HNDDALLKNYGLLY

GATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATG




CFRKDMDKVETFLRI

GTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACC




VQCRSVEGSCGFGG

TTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG




SSESGSSEGGPGSGG

TTTCTAAGGTGGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTC




EPSESGSSGSSESGSS

CAGGTTCCTCTGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAA




EGGPGSSESGSSEGG

TCTCCGGGTGGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGA




PGSSESGSSEGGPGS

ACCTTCCGAGTCTGGTAGCTCAGGTGAATCTCCGGGTGGTTCTA




SESGSSEGGPGSSES

GCGGTTCCGAGTCAGGTGAATCTCCGGGTGGTTCCAGCGGTTCT




GSSEGGPGESPGGSS

GAGTCAGGTTCCTCCGAAAGCGGTTCTTCTGAGGGCGGTCCAG




GSESGSEGSSGPGES

GTTCCTCCGAAAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTCT




SGSSESGSSEGGPGS

GAAAGCGGTTCTTCCGAGGGCGGTCCAGGTGAATCTCCTGGTG




SESGSSEGGPGSSES

GTTCCAGCGGTTCCGAGTCAGGTGAATCTCCAGGTGGCTCTAGC




GSSEGGPGSGGEPSE

GGTTCCGAGTCAGGTGAATCTCCTGGTGGTTCTAGCGGTTCTGA




SGSSGESPGGSSGSE

ATCAGGTTCCTCCGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTT




SGESPGGSSGSESGS

CCTCCGAAAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTGAA




GGEPSESGSSGSSES

AGCGGTTCTTCCGAGGGCGGTCCAGGTTCCTCTGAAAGCGGTTC




GSSEGGPGSGGEPSE

TTCTGAGGGCGGTCCAGGTTCTTCCGAAAGCGGTTCTTCCGAGG




SGSSGSGGEPSESGS

GCGGTCCAGGTTCTTCCGAAAGCGGTTCTTCTGAAGGCGGTCCA




SGSEGSSGPGESSGE

GGTTCTGGTGGCGAACCGTCCGAGTCTGGTAGCTCAGGTGAAT




SPGGSSGSESGSGGE

CTCCGGGTGGCTCTAGCGGTTCCGAGTCAGGTGAATCTCCTGGT




PSESGSSGSGGEPSES

GGTTCCAGCGGTTCCGAGTCAGGTTCCGGTGGCGAACCGTCCG




GSSGSGGEPSESGSS

AATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTGGTCCAGGCGA




GSSESGSSEGGPGES

ATCTTCAGGTTCCTCTGAAAGCGGTTCTTCTGAGGGCGGTCCAG




PGGSSGSESGESPGG

GTTCCGGTGGCGAACCGTCCGAATCTGGTAGCTCAGGTAGCGA




SSGSESGESPGGSSG

AGGTTCTTCTGGTCCAGGCGAATCTTCAGGTTCCTCTGAAAGCG




SESGESPGGSSGSES

GTTCTTCTGAGGGCGGTCCAGGTTCCGGTGGCGAACCTTCCGAA




GESPGGSSGSESGSS

TCTGGTAGCTCAGGTGAATCTCCGGGTGGTTCTAGCGGTTCTGA




ESGSSEGGPGSGGEP

GTCAGGTTCTGGTGGTGAACCTTCCGAGTCTGGTAGCTCAGGTT




SESGSSGSEGSSGPG

CTGGTGGCGAACCATCCGAGTCTGGTAGCTCAGGTTCTTCCGAA




ESSGSSESGSSEGGP

AGCGGTTCTTCCGAAGGCGGTCCAGGTTCTGGTGGTGAACCGTC




GSGGEPSESGSSGSS

CGAATCTGGTAGCTCAGGTTCTGGTGGCGAACCATCCGAATCTG




ESGSSEGGPGSGGEP

GTAGCTCAGGTAGCGAAGGTTCTTCTGGTCCTGGCGAATCTTCA




SESGSSGESPGGSSG

GGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAATCAGGTAGCG




SESGESPGGSSGSES

AAGGTTCTTCCGGTCCAGGTGAATCTTCAGGTAGCGAAGGTTCT




GSSESGSSEGGPGSG

TCTGGTCCTGGTGAATCCTCAGGTTCCGGTGGCGAACCATCTGA




GEPSESGSSGSSESGS

ATCTGGTAGCTCAGGTTCCTCTGAAAGCGGTTCTTCCGAAGGTG




SEGGPGSGGEPSESG

GTCCAGGTTCCTCTGAAAGCGGTTCTTCTGAGGGTGGTCCAGGT




SSGSGGEPSESGSSG

GAATCTCCGGGTGGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGG




ESPGGSSGSESGSEG

CGAACCATCCGAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTG




SSGPGESSGSSESGSS

GTCCTGGCGAATCTTCAGGTGAATCTCCAGGTGGCTCTAGCGGT




EGGPGSEGSSGPGESS

TCCGAATCAGGTAGCGAAGGTTCTTCCGGTCCTGGTGAGTCTTC






AGGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAGTCAGGTAGC






GAAGGTTCTTCTGGTCCTGGCGAGTCCTCA



 


hGH-
FPTIPLSRLFDNAML
711
TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTG
712


AE576
RAHRLHQLAFDTYQ

CGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGA




EFEEAYIPKEQKYSF

ATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCC




LQNPQTSLCFSESIPT

TGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCG




PSNREETQQKSNLEL

ACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG




LRISLLLIQSWLEPVQ

AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAA




FLRSVFANSLVYGAS

CCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTA




DSNVYDLLKDLEEGI

TGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTC




QTLMGRLEDGSPRT

GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCT




GQIFKQTYSKFDTNS

CTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTT




HNDDALLKNYGLLY

GATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATG




CFRKDMDKVETFLRI

GTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACC




VQCRSVEGSCGFGG

TTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG




SPAGSPTSTEEGTSES

TTTCTAAGGTGGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGG




ATPESGPGTSTEPSE

AAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACC




GSAPGSPAGSPTSTE

TCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAG




EGTSTEPSEGSAPGT

GCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCC




STEPSEGSAPGTSES

GAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCA




ATPESGPGSEPATSG

GCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCC




SETPGSEPATSGSETP

AGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGC




GSPAGSPTSTEEGTS

GAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCAG




ESATPESGPGTSTEPS

GCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAAC




EGSAPGTSTEPSEGS

CCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGC




APGSPAGSPTSTEEG

AGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCAC




TSTEPSEGSAPGTSTE

CAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTAC




PSEGSAPGTSESATP

TTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTG




ESGPGTSTEPSEGSA

AACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTAC




PGTSESATPESGPGS

CCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGAAGGT




EPATSGSETPGTSTEP

AGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTC




SEGSAPGTSTEPSEG

CAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGTACT




SAPGTSESATPESGP

TCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACTG




GTSESATPESGPGSP

AACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAAC




AGSPTSTEEGTSESA

CCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCCGGAG




TPESGPGSEPATSGS

TCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGA




ETPGTSESATPESGP

AGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGC




GTSTEPSEGSAPGTS

GAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCTGAAA




TEPSEGSAPGTSTEPS

GCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGTCT




EGSAPGTSTEPSEGS

GAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTA




APGTSTEPSEGSAPG

GCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCC




TSTEPSEGSAPGSPA

AGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCT




GSPTSTEEGTSTEPSE

CTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTACCGA




GSAPGTSESATPESG

ACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCT




PGSEPATSGSETPGT

ACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTA




SESATPESGPGSEPA

GCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCC




TSGSETPGTSESATPE

AGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCT




SGPGTSTEPSEGSAP

CTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGC




GTSESATPESGPGSP

AACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTC




AGSPTSTEEGSPAGS

CTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAG




PTSTEEGSPAGSPTST

CGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCA




EEGTSESATPESGPG

GGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCC




TSTEPSEGSAP

CGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGCAGG






CTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCC






CGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAG






CGCACCA



 


hGH-
FPTIPLSRLFDNAML
713
TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTG
714


AF576
RAHRLHQLAFDTYQ

CGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGA




EFEEAYIPKEQKYSF

ATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCC




LQNPQTSLCFSESIPT

TGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCG




PSNREETQQKSNLEL

ACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG




LRISLLLIQSWLEPVQ

AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAA




FLRSVFANSLVYGAS

CCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTA




DSNVYDLLKDLEEGI

TGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTC




QTLMGRLEDGSPRT

GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCT




GQIFKQTYSKFDTNS

CTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTT




HNDDALLKNYGLLY

GATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATG




CFRKDMDKVETFLRI

GTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACC




VQCRSVEGSCGFGG

TTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG




STSSTAESPGPGSTSS

TTTCTAAGGTGGTTCTACTAGCTCTACCGCTGAATCTCCTGGCC




TAESPGPGSTSESPSG

CAGGTTCCACTAGCTCTACCGCAGAATCTCCGGGCCCAGGTTCT




TAPGSTSSTAESPGP

ACTAGCGAATCCCCTTCTGGTACCGCTCCAGGTTCTACTAGCTC




GSTSSTAESPGPGTS

TACCGCTGAATCTCCGGGTCCAGGTTCTACCAGCTCTACTGCAG




TPESGSASPGSTSESP

AATCTCCTGGCCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCT




SGTAPGTSPSGESST

TCTCCAGGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGG




APGSTSESPSGTAPG

TACCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTACTA




STSESPSGTAPGTSPS

GCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCT




GESSTAPGSTSESPSG

CCTTCTGGCACCGCTCCAGGTACCTCTCCTAGCGGCGAATCTTC




TAPGSTSESPSGTAP

TACCGCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCAC




GTSPSGESSTAPGSTS

CAGGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACC




ESPSGTAPGSTSESPS

TCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTACTAGCGA




GTAPGSTSESPSGTA

ATCTCCTTCTGGCACTGCACCAGGTTCTACTAGCGAATCTCCTT




PGTSTPESGSASPGST

CTGGCACTGCACCAGGTTCTACCAGCGAATCTCCGTCTGGCACT




SESPSGTAPGTSTPES

GCACCAGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGG




GSASPGSTSSTAESP

TTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAGGTACTTCTA




GPGSTSSTAESPGPG

CCCCTGAAAGCGGCTCCGCTTCTCCAGGTTCCACTAGCTCTACC




TSTPESGSASPGTSTP

GCTGAATCTCCGGGTCCAGGTTCTACTAGCTCTACTGCAGAATC




ESGSASPGSTSESPSG

TCCTGGCCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTC




TAPGTSTPESGSASP

CAGGTACTTCTACCCCTGAAAGCGGTTCTGCATCTCCAGGTTCT




GTSTPESGSASPGSTS

ACTAGCGAATCCCCGTCTGGTACCGCACCAGGTACTTCTACCCC




ESPSGTAPGSTSESPS

GGAAAGCGGCTCTGCTTCTCCAGGTACTTCTACCCCGGAAAGC




GTAPGSTSESPSGTA

GGCTCCGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGTAC




PGSTSSTAESPGPGTS

CGCTCCAGGTTCTACCAGCGAATCCCCGTCTGGTACTGCTCCAG




TPESGSASPGTSTPES

GTTCTACCAGCGAATCTCCTTCTGGTACTGCACCAGGTTCTACT




GSASPGSTSESPSGT

AGCTCTACTGCAGAATCTCCTGGCCCAGGTACCTCTACTCCGGA




APGSTSESPSGTAPG

AAGCGGCTCTGCATCTCCAGGTACTTCTACCCCTGAAAGCGGTT




TSTPESGSASPGSTSE

CTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCA




SPSGTAPGSTSESPSG

CCAGGTTCTACCAGCGAATCTCCGTCTGGCACTGCACCAGGTAC




TAPGTSTPESGSASP

CTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGTTCTACTAGCG




GTSPSGESSTAPGSTS

AATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCG




STAESPGPGTSPSGES

TCTGGCACTGCACCAGGTACCTCTACCCCTGAAAGCGGTTCCGC




STAPGSTSSTAESPGP

TTCTCCAGGTACTTCTCCGAGCGGTGAATCTTCTACCGCACCAG




GTSTPESGSASPGSTS

GTTCTACTAGCTCTACCGCTGAATCTCCGGGCCCAGGTACTTCT




ESPSGTAPGSTSSTA

CCGAGCGGTGAATCTTCTACTGCTCCAGGTTCCACTAGCTCTAC




ESPGPGTSTPESGSAS

TGCTGAATCTCCTGGCCCAGGTACTTCTACTCCGGAAAGCGGTT




PGTSTPESGSASP

CCGCTTCTCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCA






CCAGGTTCTACTAGCTCTACTGCAGAATCTCCTGGCCCAGGTAC






CTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTACTTCTACCC






CTGAAAGCGGTTCTGCATCTCCA



 


hGH-
FPTIPLSRLFDNAML
715
TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTG
716


AE624
RAHRLHQLAFDTYQ

CGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGA




EFEEAYIPKEQKYSF

ATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCC




LQNPQTSLCFSESIPT

TGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCG




PSNREETQQKSNLEL

ACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG




LRISLLLIQSWLEPVQ

AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAA




FLRSVFANSLVYGAS

CCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTA




DSNVYDLLKDLEEGI

TGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTC




QTLMGRLEDGSPRT

GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCT




GQIFKQTYSKFDTNS

CTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTT




HNDDALLKNYGLLY

GATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATG




CFRKDMDKVETFLRI

GTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACC




VQCRSVEGSCGFGM

TTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG




AEPAGSPTSTEEGTP

TTTCTAAGGTATGGCTGAACCTGCTGGCTCTCCAACCTCCACTG




GSGTASSSPGSSTPS

AGGAAGGTACCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGT




GATGSPGASPGTSST

AGCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCC




GSPGSPAGSPTSTEE

GGGCACCAGCTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTC




GTSESATPESGPGTS

CTACCTCTACTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAG




TEPSEGSAPGSPAGS

TCTGGTCCAGGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCC




PTSTEEGTSTEPSEGS

AGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACT




APGTSTEPSEGSAPG

TCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGA




TSESATPESGPGSEP

ACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCC




ATSGSETPGSEPATS

CGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGA




GSETPGSPAGSPTST

AACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA




EEGTSESATPESGPG

GGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTT




TSTEPSEGSAPGTSTE

CTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGA




PSEGSAPGSPAGSPT

ACCGTCTGAGGGCAGCGCACCAGGTACTTCTACCGAACCGTCC




STEEGTSTEPSEGSAP

GAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCA




GTSTEPSEGSAPGTS

CCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACC




ESATPESGPGTSTEPS

AGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTT




EGSAPGTSESATPES

CTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGA




GPGSEPATSGSETPG

ACCGTCCGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAACC




TSTEPSEGSAPGTSTE

CCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGA




PSEGSAPGTSESATP

GACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA




ESGPGTSESATPESG

GGTACTTCTACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTC




PGSPAGSPTSTEEGT

TGAAAGCGCAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGC




SESATPESGPGSEPA

GCAACCCCGGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAA




TSGSETPGTSESATPE

CCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATC




SGPGTSTEPSEGSAP

CGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCA




GTSTEPSEGSAPGTS

GGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTC




TEPSEGSAPGTSTEPS

TACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAAC




EGSAPGTSTEPSEGS

CGTCCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGA




APGTSTEPSEGSAPG

AGGCAGCGCTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGC




SPAGSPTSTEEGTSTE

GCTCCAGGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCC




ESGPGSEPATSGSET

AGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAAC




PGTSESATPESGPGS

CGTCCGAGGGTAGCGCACCAGGTACCTCTGAAAGCGCAACTCC




EPATSGSETPGTSES

TGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAG




ATPESGPGTSTEPSE

ACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAG




GSAPGTSESATPESG

GTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCT




PGSPAGSPTSTEEGSP

GAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACC




AGSPTSTEEGSPAGS

GTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACTCCT




PTSTEEGTSESATPES

GAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCG




GPGTSTEPSEGSAP

AGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGG






TAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTG






AAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACC






GTCTGAGGGCAGCGCACCA



 


hGH-
FPTIPLSRLFDNAML
717
TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTG
718


AD836
RAHRLHQLAFDTYQ

CGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGA




EFEEAYIPKEQKYSF

ATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCC




LQNPQTSLCFSESIPT

TGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCG




PSNREETQQKSNLEL

ACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG




LRISLLLIQSWLEPVQ

AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAA




FLRSVFANSLVYGAS

CCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTA




DSNVYDLLKDLEEGI

TGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTC




QTLMGRLEDGSPRT

GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCT




GQIFKQTYSKFDTNS

CTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTT




HNDDALLKNYGLLY

GATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATG




CFRKDMDKVETFLRI

GTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACC




VQCRSVEGSCGFGG

TTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG




SSESGSSEGGPGSSES

TTTCTAAGGTGGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTC




GSSEGGPGESPGGSS

CAGGTTCCTCTGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAA




GSESGSGGEPSESGS

TCTCCGGGTGGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGA




SGESPGGSSGSESGE

ACCTTCCGAGTCTGGTAGCTCAGGTGAATCTCCGGGTGGTTCTA




SPGGSSGSESGSSES

GCGGTTCCGAGTCAGGTGAATCTCCGGGTGGTTCCAGCGGTTCT




GSSEGGPGSSESGSS

GAGTCAGGTTCCTCCGAAAGCGGTTCTTCTGAGGGCGGTCCAG




EGGPGSSESGSSEGG

GTTCCTCCGAAAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTCT




PGESPGGSSGSESGE

GAAAGCGGTTCTTCCGAGGGCGGTCCAGGTGAATCTCCTGGTG




SPGGSSGSESGESPG

GTTCCAGCGGTTCCGAGTCAGGTGAATCTCCAGGTGGCTCTAGC




GSSGSESGSSESGSSE

GGTTCCGAGTCAGGTGAATCTCCTGGTGGTTCTAGCGGTTCTGA




GGPGSSESGSSEGGP

ATCAGGTTCCTCCGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTT




GSSESGSSEGGPGSS

CCTCCGAAAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTGAA




ESGSSEGGPGSSESG

AGCGGTTCTTCCGAGGGCGGTCCAGGTTCCTCTGAAAGCGGTTC




SSEGGPGSSESGSSE

TTCTGAGGGCGGTCCAGGTTCTTCCGAAAGCGGTTCTTCCGAGG




GGPGSGGEPSESGSS

GCGGTCCAGGTTCTTCCGAAAGCGGTTCTTCTGAAGGCGGTCCA




GESPGGSSGSESGES

GGTTCTGGTGGCGAACCGTCCGAGTCTGGTAGCTCAGGTGAAT




PGGSSGSESGSGGEP

CTCCGGGTGGCTCTAGCGGTTCCGAGTCAGGTGAATCTCCTGGT




SESGSSGSEGSSGPG

GGTTCCAGCGGTTCCGAGTCAGGTTCCGGTGGCGAACCGTCCG




ESSGSSESGSSEGGP

AATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTGGTCCAGGCGA




GSGGEPSESGSSGSE

ATCTTCAGGTTCCTCTGAAAGCGGTTCTTCTGAGGGCGGTCCAG




GSSGPGESSGSSESG

GTTCCGGTGGCGAACCGTCCGAATCTGGTAGCTCAGGTAGCGA




SSEGGPGSGGEPSES

AGGTTCTTCTGGTCCAGGCGAATCTTCAGGTTCCTCTGAAAGCG




GSSGESPGGSSGSES

GTTCTTCTGAGGGCGGTCCAGGTTCCGGTGGCGAACCTTCCGAA




GSGGEPSESGSSGSG

TCTGGTAGCTCAGGTGAATCTCCGGGTGGTTCTAGCGGTTCTGA




GEPSESGSSGSSESGS

GTCAGGTTCTGGTGGTGAACCTTCCGAGTCTGGTAGCTCAGGTT




SEGGPGSGGEPSESG

CTGGTGGCGAACCATCCGAGTCTGGTAGCTCAGGTTCTTCCGAA




SSGSGGEPSESGSSG

AGCGGTTCTTCCGAAGGCGGTCCAGGTTCTGGTGGTGAACCGTC




SEGSSGPGESSGESP

CGAATCTGGTAGCTCAGGTTCTGGTGGCGAACCATCCGAATCTG




GGSSGSESGSEGSSG

GTAGCTCAGGTAGCGAAGGTTCTTCTGGTCCTGGCGAATCTTCA




PGESSGSEGSSGPGE

GGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAATCAGGTAGCG




SSGSGGEPSESGSSG

AAGGTTCTTCCGGTCCAGGTGAATCTTCAGGTAGCGAAGGTTCT




SSESGSSEGGPGSSES

TCTGGTCCTGGTGAATCCTCAGGTTCCGGTGGCGAACCATCTGA




GSSEGGPGESPGGSS

ATCTGGTAGCTCAGGTTCCTCTGAAAGCGGTTCTTCCGAAGGTG




GSESGSGGEPSESGS

GTCCAGGTTCCTCTGAAAGCGGTTCTTCTGAGGGTGGTCCAGGT




SGSEGSSGPGESSGE

GAATCTCCGGGTGGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGG




SPGGSSGSESGSEGS

CGAACCATCCGAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTG




SGPGSSESGSSEGGP

GTCCTGGCGAATCTTCAGGTGAATCTCCAGGTGGCTCTAGCGGT




GSGGEPSESGSSGSE

TCCGAATCAGGTAGCGAAGGTTCTTCCGGTCCaGGTTCCTCTGA




GSSGPGESSGSEGSS

AAGCGGTTCTTCTGAGGGCGGTCCAGGTTCTGGTGGCGAACCA




GPGESSGSEGSSGPG

TCTGAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCCGGTCCGGG




ESSGSGGEPSESGSS

TGAATCTTCAGGTAGCGAAGGTTCTTCCGGTCCAGGTGAATCTT




GSGGEPSESGSSGES

CAGGTAGCGAAGGTTCTTCTGGTCCTGGTGAATCCTCAGGTTCC




PGGSSGSESGESPGG

GGTGGCGAACCATCTGAATCTGGTAGCTCAGGTTCTGGTGGCG




SSGSESGSGGEPSES

AACCATCCGAATCTGGTAGCTCAGGTGAATCTCCGGGTGGCTCC




GSSGSEGSSGPGESS

AGCGGTTCTGAATCAGGTGAATCTCCTGGTGGCTCCAGCGGTTC




GESPGGSSGSESGES

TGAGTCAGGTTCTGGTGGCGAACCATCCGAATCTGGTAGCTCA




ESGSSEGGPGSSESG

GGTAGCGAAGGTTCTTCTGGTCCTGGCGAATCTTCAGGTGAATC




SSEGGPGSSESGSSE

TCCAGGTGGCTCTAGCGGTTCCGAATCAGGTTCCTCTGAAAGCG




GGPGSGGEPSESGSS

GTTCTTCTGAGGGCGGTCCAGGTTCTTCCGAAAGCGGTTCTTCC




GSSESGSSEGGPGES

GAGGGCGGTCCAGGTTCTTCCGAAAGCGGTTCTTCTGAAGGCG




PGGSSGSESGSGGEP

GTCCAGGTTCTGGTGGCGAACCGTCCGAATCTGGTAGCTCAGGT




SESGSSGSSESGSSEG

TCCTCCGAAAGCGGTTCTTCTGAAGGTGGTCCAGGTGAATCTCC




GPGESPGGSSGSESG

AGGTGGTTCTAGCGGTTCTGAATCAGGTTCTGGTGGCGAACCGT




SGGEPSESGSSGESP

CCGAATCTGGTAGCTCAGGTTCCTCCGAAAGCGGTTCTTCTGAA




GGSSGSESGSGGEPS

GGTGGTCCAGGTGAATCTCCAGGTGGTTCTAGCGGTTCTGAATC




ESGSS

AGGTTCTGGTGGCGAACCGTCCGAATCTGGTAGCTCAGGTGAA






TCTCCTGGTGGTTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGA






ACCTTCCGAATCTGGTAGCTCA



 


hGH-
FPTIPLSRLFDNAML
719
TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTG
720


AE864
RAHRLHQLAFDTYQ

CGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGA




EFEEAYIPKEQKYSF

ATTTGAAGAAGCCTACATTCCTAAAGAGCAGAAGTACTCTTTCC




LQNPQTSLCFSESIPT

TGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCG




PSNREETQQKSNLEL

ACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG




LRISLLLIQSWLEPVQ

AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAA




FLRSVFANSLVYGAS

CCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTA




DSNVYDLLKDLEEGI

TGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTC




QTLMGRLEDGSPRT

GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCT




GQIFKQTYSKFDTNS

CTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTT




HNDDALLKNYGLLY

GATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATG




CFRKDMDKVETFLRI

GTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACC




VQCRSVEGSCGFGG

TTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG




SPAGSPTSTEEGTSES

TTTCTAAGGTGGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGG




ATPESGPGTSTEPSE

AAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACC




GSAPGSPAGSPTSTE

TCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAG




EGTSTEPSEGSAPGT

GCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCC




STEPSEGSAPGTSES

GAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCA




ATPESGPGSEPATSG

GCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCC




SETPGSEPATSGSETP

AGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGC




GSPAGSPTSTEEGTS

GAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCAG




ESATPESGPGTSTEPS

GCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAAC




EGSAPGTSTEPSEGS

CCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGC




APGSPAGSPTSTEEG

AGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCAC




TSTEPSEGSAPGTSTE

CAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTAC




PSEGSAPGTSESATP

TTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTG




ESGPGTSTEPSEGSA

AACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTAC




PGTSESATPESGPGS

CCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGAAGGT




EPATSGSETPGTSTEP

AGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTC




SEGSAPGTSTEPSEG

CAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGTACT




SAPGTSESATPESGP

TCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACTG




GTSESATPESGPGSP

AACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAAC




AGSPTSTEEGTSESA

CCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCCGGAG




TPESGPGSEPATSGS

TCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGA




ETPGTSESATPESGP

AGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGC




GTSTEPSEGSAPGTS

GAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCTGAAA




TEPSEGSAPGTSTEPS

GCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGTCT




EGSAPGTSTEPSEGS

GAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTA




APGTSTEPSEGSAPG

GCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCC




TSTEPSEGSAPGSPA

AGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCT




GSPTSTEEGTSTEPSE

CTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTACCGA




GSAPGTSESATPESG

ACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCT




PGSEPATSGSETPGT

ACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTA




SESATPESGPGSEPA

GCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCC




TSGSETPGTSESATPE

AGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCT




SGPGTSTEPSEGSAP

CTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGC




GTSESATPESGPGSP

AACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTC




AGSPTSTEEGSPAGS

CTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAG




PTSTEEGSPAGSPTST

CGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCA




EEGTSESATPESGPG

GGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCC




TSTEPSEGSAPGTSES

CGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGCAGG




ATPESGPGSEPATSG

CTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCC




SETPGTSESATPESGP

CGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAG




GSEPATSGSETPGTS

CGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA




ESATPESGPGTSTEPS

GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTC




EGSAPGSPAGSPTST

TGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCA




EEGTSESATPESGPG

ACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCC




SEPATSGSETPGTSES

TGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGC




ATPESGPGSPAGSPT

GCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAG




STEEGSPAGSPTSTEE

GTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGA




GTSTEPSEGSAPGTS

ACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGC




ESATPESGPGTSESA

GCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGAC




TPESGPGTSESATPES

TTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTG




GPGSEPATSGSETPG

AAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGG




SEPATSGSETPGSPA

TACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTG




GSPTSTEEGTSTEPSE

AAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCT




GSAPGTSTEPSEGSA

ACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTC




PGSEPATSGSETPGT

TGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACT




SESATPESGPGTSTEP

CCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTA




SEGSAP

CTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACT






GAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCT






CTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAA






TCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCAC






CA



 


hGH-
FPTIPLSRLFDNAML
721
TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTG
722


AF864
RAHRLHQLAFDTYQ

CGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGA




EFEEAYIPKEQKYSF

ATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCC




LQNPQTSLCFSESIPT

TGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCG




PSNREETQQKSNLEL

ACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG




LRISLLLIQSWLEPVQ

AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAA




FLRSVFANSLVYGAS

CCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTA




DSNVYDLLKDLEEGI

TGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTC




QTLMGRLEDGSPRT

GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCT




GQIFKQTYSKFDTNS

CTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTT




HNDDALLKNYGLLY

GATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATG




CFRKDMDKVETFLRI

GTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACC




VQCRSVEGSCGFGG

TTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG




STSESPSGTAPGTSPS

TTTCTAAGGTGGTTCTACCAGCGAATCTCCTTCTGGCACCGCTC




GESSTAPGSTSESPSG

CAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCT




TAPGSTSESPSGTAP

ACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACTAGCGA




GTSTPESGSASPGTS

ATCCCCGTCTGGTACTGCTCCAGGTACTTCTACTCCTGAAAGCG




TPESGSASPGSTSESP

GTTCCGCTTCTCCAGGTACCTCTACTCCGGAAAGCGGTTCTGCA




SGTAPGSTSESPSGT

TCTCCAGGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGG




APGTSPSGESSTAPG

TTCTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTACTTCTC




STSESPSGTAPGTSPS

CTAGCGGCGAATCTTCTACCGCACCAGGTTCTACTAGCGAATCT




GESSTAPGTSPSGESS

CCGTCTGGCACTGCTCCAGGTACTTCTCCTAGCGGTGAATCTTC




TAPGSTSSTAESPGP

TACCGCTCCAGGTACTTCCCCTAGCGGCGAATCTTCTACCGCTC




GTSPSGESSTAPGTSP

CAGGTTCTACTAGCTCTACTGCAGAATCTCCGGGCCCAGGTACC




SGESSTAPGSTSSTA

TCTCCTAGCGGTGAATCTTCTACCGCTCCAGGTACTTCTCCGAG




ESPGPGTSTPESGSAS

CGGTGAATCTTCTACCGCTCCAGGTTCTACTAGCTCTACTGCAG




PGTSTPESGSASPGST

AATCTCCTGGCCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCA




SESPSGTAPGSTSESP

TCTCCAGGTACTTCTACCCCTGAAAGCGGTTCTGCATCTCCAGG




SGTAPGTSTPESGSA

TTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCA




SPGSTSSTAESPGPGT

GCGAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCCCTGAA




STPESGSASPGSTSES

AGCGGTTCCGCTTCTCCAGGTTCTACCAGCTCTACCGCAGAATC




PSGTAPGTSPSGESST

TCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTC




APGSTSSTAESPGPG

CAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTACT




TSPSGESSTAPGTSTP

TCTCCGAGCGGTGAATCTTCTACCGCACCAGGTTCTACTAGCTC




ESGSASPGSTSSTAES

TACCGCTGAATCTCCGGGCCCAGGTACTTCTCCGAGCGGTGAAT




PGPGSTSSTAESPGP

CTTCTACTGCTCCAGGTACCTCTACTCCTGAAAGCGGTTCTGCA




GSTSSTAESPGPGSTS

TCTCCAGGTTCCACTAGCTCTACCGCAGAATCTCCGGGCCCAGG




STAESPGPGTSPSGES

TTCTACTAGCTCTACTGCTGAATCTCCTGGCCCAGGTTCTACTA




STAPGSTSESPSGTAP

GCTCTACTGCTGAATCTCCGGGTCCAGGTTCTACCAGCTCTACT




GSTSESPSGTAPGTS

GCTGAATCTCCTGGTCCAGGTACCTCCCCGAGCGGTGAATCTTC




TPESGPXXXGASASG

TACTGCACCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCAC




APSTXXXXSESPSGT

CAGGTTCTACCAGCGAATCTCCGTCTGGCACTGCACCAGGTACC




APGSTSESPSGTAPG

TCTACCCCTGAAAGCGGTCCXXXXXXXXXXXXTGCAAGCGCAA




STSESPSGTAPGSTSE

GCGGCGCGCCAAGCACGGGAXXXXXXXXTAGCGAATCTCCTTC




SPSGTAPGSTSESPSG

TGGTACCGCTCCAGGTTCTACCAGCGAATCCCCGTCTGGTACTG




TAPGSTSESPSGTAP

CTCCAGGTTCTACCAGCGAATCTCCTTCTGGTACTGCACCAGGT




GTSTPESGSASPGTSP

TCTACTAGCGAATCTCCTTCTGGTACCGCTCCAGGTTCTACCAG




SGESSTAPGTSPSGES

CGAATCCCCGTCTGGTACTGCTCCAGGTTCTACCAGCGAATCTC




STAPGSTSSTAESPGP

CTTCTGGTACTGCACCAGGTACTTCTACTCCGGAAAGCGGTTCC




GTSPSGESSTAPGTS

GCATCTCCAGGTACTTCTCCTAGCGGTGAATCTTCTACTGCTCC




TPESGSASPGSTSESP

AGGTACCTCTCCTAGCGGCGAATCTTCTACTGCTCCAGGTTCTA




SGTAPGSTSESPSGT

CCAGCTCTACTGCTGAATCTCCGGGTCCAGGTACTTCCCCGAGC




APGTSPSGESSTAPG

GGTGAATCTTCTACTGCACCAGGTACTTCTACTCCGGAAAGCGG




STSESPSGTAPGTSTP

TTCCGCTTCTCCAGGTTCTACCAGCGAATCTCCTTCTGGCACCG




ESGSASPGTSTPESGS

CTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACCGCACCAGGT




ASPGSTSESPSGTAP

ACTTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTTCTACTAG




GTSTPESGSASPGSTS

CGAATCCCCGTCTGGTACCGCACCAGGTACTTCTACCCCGGAAA




STAESPGPGSTSESPS

GCGGCTCTGCTTCTCCAGGTACTTCTACCCCGGAAAGCGGCTCC




GTAPGSTSESPSGTA

GCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCC




PGTSPSGESSTAPGST

AGGTACTTCTACCCCTGAAAGCGGCTCCGCTTCTCCAGGTTCCA




SSTAESPGPGTSPSGE

CTAGCTCTACCGCTGAATCTCCGGGTCCAGGTTCTACCAGCGAA




SSTAPGTSTPESGSAS

TCTCCTTCTGGCACCGCTCCAGGTTCTACTAGCGAATCCCCGTC




PGTSPSGESSTAPGTS

TGGTACCGCACCAGGTACTTCTCCTAGCGGCGAATCTTCTACCG




PSGESSTAPGTSPSGE

CACCAGGTTCTACCAGCTCTACTGCTGAATCTCCGGGTCCAGGT




SSTAPGSTSSTAESPG

ACTTCCCCGAGCGGTGAATCTTCTACTGCACCAGGTACTTCTAC




PGSTSSTAESPGPGTS

TCCGGAAAGCGGTTCCGCTTCTCCAGGTACCTCCCCTAGCGGCG




PSGESSTAPGSSPSAS

AATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCT




TGTGPGSSTPSGATG

ACCGCTCCAGGTACCTCCCCTAGCGGTGAATCTTCTACCGCACC




SPGSSTPSGATGSP

AGGTTCTACTAGCTCTACTGCTGAATCTCCGGGTCCAGGTTCTA






CCAGCTCTACTGCTGAATCTCCTGGTCCAGGTACCTCCCCGAGC






GGTGAATCTTCTACTGCACCAGGTTCTAGCCCTTCTGCTTCCAC






CGGTACCGGCCCAGGTAGCTCTACTCCGTCTGGTGCAACTGGCT






CTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCCCCA



 


hGH-
FPTIPLSRLFDNAML
723
TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTG
724


AG864
RAHRLHQLAFDTYQ

CGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGA




EFEEAYIPKEQKYSF

ATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCC




LQNPQTSLCFSESIPT

TGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCG




PSNREETQQKSNLEL

ACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG




LRISLLLIQSWLEPVQ

AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAA




FLRSVFANSLVYGAS

CCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTA




DSNVYDLLKDLEEGI

TGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTC




QTLMGRLEDGSPRT

GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCT




GQIFKQTYSKFDTNS

CTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTT




HNDDALLKNYGLLY

GATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATG




CFRKDMDKVETFLRI

GTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACC




VQCRSVEGSCGFGG

TTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG




ASPGTSSTGSPGSSPS

TTTCTAAGGTGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTC




ASTGTGPGSSPSAST

CAGGTTCTAGCCCGTCTGCTTCTACTGGTACTGGTCCAGGTTCT




GTGPGTPGSGTASSS

AGCCCTTCTGCTTCCACTGGTACTGGTCCAGGTACCCCGGGTAG




PGSSTPSGATGSPGS

CGGTACCGCTTCTTCTTCTCCAGGTAGCTCTACTCCGTCTGGTGC




NPSASTGTGPGASPG

TACCGGCTCTCCAGGTTCTAACCCTTCTGCATCCACCGGTACCG




TSSTGSPGTPGSGTA

GCCCAGGTGCTTCTCCGGGCACCAGCTCTACTGGTTCTCCAGGT




SSSPGSSTPSGATGSP

ACCCCGGGCAGCGGTACCGCATCTTCTTCTCCAGGTAGCTCTAC




GTPGSGTASSSPGAS

TCCTTCTGGTGCAACTGGTTCTCCAGGTACTCCTGGCAGCGGTA




PGTSSTGSPGASPGT

CCGCTTCTTCTTCTCCAGGTGCTTCTCCTGGTACTAGCTCTACTG




SSTGSPGTPGSGTAS

GTTCTCCAGGTGCTTCTCCGGGCACTAGCTCTACTGGTTCTCCA




SSPGSSTPSGATGSP

GGTACCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTC




GASPGTSSTGSPGTP

TACCCCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCA




GSGTASSSPGSSTPS

CCAGCTCTACCGGTTCTCCAGGTACCCCGGGTAGCGGTACCGCT




GATGSPGSNPSASTG

TCTTCTTCTCCAGGTAGCTCTACTCCGTCTGGTGCTACCGGCTCT




TGPGSSPSASTGTGP

CCAGGTTCTAACCCTTCTGCATCCACCGGTACCGGCCCAGGTTC




GSSTPSGATGSPGSS

TAGCCCTTCTGCTTCCACCGGTACTGGCCCAGGTAGCTCTACCC




TPSGATGSPGASPGT

CTTCTGGTGCTACCGGCTCCCCAGGTAGCTCTACTCCTTCTGGT




SSTGSPGASPGTSST

GCAACTGGCTCTCCAGGTGCATCTCCGGGCACTAGCTCTACTGG




GSPGASPGTSSTGSP

TTCTCCAGGTGCATCCCCTGGCACTAGCTCTACTGGTTCTCCAG




GTPGSGTASSSPGAS

GTGCTTCTCCTGGTACCAGCTCTACTGGTTCTCCAGGTACTCCT




PGTSSTGSPGASPGT

GGCAGCGGTACCGCTTCTTCTTCTCCAGGTGCTTCTCCTGGTAC




SSTGSPGASPGTSST

TAGCTCTACTGGTTCTCCAGGTGCTTCTCCGGGCACTAGCTCTA




GSPGSSPSASTGTGP

CTGGTTCTCCAGGTGCTTCCCCGGGCACTAGCTCTACCGGTTCT




GTPGSGTASSSPGAS

CCAGGTTCTAGCCCTTCTGCATCTACTGGTACTGGCCCAGGTAC




PGTSSTGSPGASPGT

TCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGGTGCATCTCCGG




SSTGSPGASPGTSST

GCACTAGCTCTACTGGTTCTCCAGGTGCATCCCCTGGCACTAGC




GSPGSSTPSGATGSP

TCTACTGGTTCTCCAGGTGCTTCTCCTGGTACCAGCTCTACTGGT




GSSTPSGATGSPGAS

TCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGTTCCCCAGG




PGTSSTGSPGTPGSG

TAGCTCTACTCCTTCTGGTGCTACTGGCTCCCCAGGTGCATCCC




TASSSPGSSTPSGAT

CTGGCACCAGCTCTACCGGTTCTCCAGGTACCCCGGGCAGCGGT




GSPGSSTPSGATGSP

ACCGCATCTTCCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTAC




GSSTPSGATGSPGSS

CGGTTCCCCAGGTAGCTCTACCCCGTCTGGTGCAACCGGCTCCC




PSASTGTGPGASPGT

CAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTTCT




SSTGSPGASPGTSST

AGCCCGTCTGCTTCCACTGGTACTGGCCCAGGTGCTTCCCCGGG




GSPGTPGSGTASSSP

CACCAGCTCTACTGGTTCTCCAGGTGCATCCCCGGGTACCAGCT




GASPGTSSTGSPGAS

CTACCGGTTCTCCAGGTACTCCTGGCAGCGGTACTGCATCTTCC




PGTSSTGSPGASPGT

TCTCCAGGTGCTTCTCCGGGCACCAGCTCTACTGGTTCTCCAGG




SSTGSPGASPGTSST

TGCATCTCCGGGCACTAGCTCTACTGGTTCTCCAGGTGCATCCC




GSPGTPGSGTASSSP

CTGGCACTAGCTCTACTGGTTCTCCAGGTGCTTCTCCTGGTACC




GSSTPSGATGSPGTP

AGCTCTACTGGTTCTCCAGGTACCCCTGGTAGCGGTACTGCTTC




GSGTASSSPGSSTPS

TTCCTCTCCAGGTAGCTCTACTCCGTCTGGTGCTACCGGTTCTCC




GATGSPGTPGSGTAS

AGGTACCCCGGGTAGCGGTACCGCATCTTCTTCTCCAGGTAGCT




SSPGSSTPSGATGSP

CTACCCCGTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGC




GSSTPSGATGSPGSS

GGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCT




PSASTGTGPGSSPSA

ACTGGCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGCTC




STGTGPGASPGTSST

CCCAGGTTCTAGCCCTTCTGCATCCACCGGTACCGGTCCAGGTT




GSPGTPGSGTASSSP

CTAGCCCGTCTGCATCTACTGGTACTGGTCCAGGTGCATCCCCG




GSSTPSGATGSPGSS

GGCACTAGCTCTACCGGTTCTCCAGGTACTCCTGGTAGCGGTAC




PSASTGTGPGSSPSA

TGCTTCTTCTTCTCCAGGTAGCTCTACTCCTTCTGGTGCTACTGG




STGTGPGASPGTSST

TTCTCCAGGTTCTAGCCCTTCTGCATCCACCGGTACCGGCCCAG




GSPGASPGTSSTGSP

GTTCTAGCCCGTCTGCTTCTACCGGTACTGGTCCAGGTGCTTCT




GSSTPSGATGSPGSS

CCGGGTACTAGCTCTACTGGTTCTCCAGGTGCATCTCCTGGTAC




PSASTGTGPGASPGT

TAGCTCTACTGGTTCTCCAGGTAGCTCTACTCCGTCTGGTGCAA




SSTGSPGSSPSASTGT

CCGGCTCTCCAGGTTCTAGCCCTTCTGCATCTACCGGTACTGGT




GPGTPGSGTASSSPG

CCAGGTGCATCCCCTGGTACCAGCTCTACCGGTTCTCCAGGTTC




SSTPSGATGSPGSSTP

TAGCCCTTCTGCTTCTACCGGTACCGGTCCAGGTACCCCTGGCA




SGATGSPGASPGTSS

GCGGTACCGCATCTTCCTCTCCAGGTAGCTCTACTCCGTCTGGT




TGSP

GCAACCGGTTCCCCAGGTAGCTCTACTCCTTCTGGTGCTACTGG






CTCCCCAGGTGCATCCCCTGGCACCAGCTCTACCGGTTCTCCA



 


hGH-
FPTIPLSRLFDNAML
725
TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTG
726


AM875
RAHRLHQLAFDTYQ

CGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGA




EFEEAYIPKEQKYSF

ATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCC




LQNPQTSLCFSESIPT

TGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCG




PSNREETQQKSNLEL

ACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG




LRISLLLIQSWLEPVQ

AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAA




FLRSVFANSLVYGAS

CCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTA




DSNVYDLLKDLEEGI

TGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTC




QTLMGRLEDGSPRT

GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCT




GQIFKQTYSKFDTNS

CTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTT




HNDDALLKNYGLLY

GATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATG




CFRKDMDKVETFLRI

GTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACC




VQCRSVEGSCGFGG

TTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG




TSTEPSEGSAPGSEP

TTTCTAAGGTGGTACTTCTACTGAACCGTCTGAAGGCAGCGCAC




ATSGSETPGSPAGSP

CAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCCAGGTAG




TSTEEGSTSSTAESPG

CCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCT




PGTSTPESGSASPGST

CTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGC




SESPSGTAPGSTSESP

GGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCAC




SGTAPGTSTPESGSA

TGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAG




SPGTSTPESGSASPGS

GTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGTACCTCT




EPATSGSETPGTSES

ACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACCGGCAA




ATPESGPGSPAGSPT

CCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCT




STEEGTSTEPSEGSAP

GAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTG




GTSESATPESGPGTS

AGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGG




TEPSEGSAPGTSTEPS

TACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTA




EGSAPGSPAGSPTST

CTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACCGAACC




EEGTSTEPSEGSAPG

GTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACC




TSTEPSEGSAPGTSES

TCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCG




ATPESGPGTSESATP

CACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGG




ESGPGTSTEPSEGSA

TACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTG




PGTSTEPSEGSAPGT

AAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACTGAACCT




SESATPESGPGTSTEP

TCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGTCCGAGG




SEGSAPGSEPATSGS

GCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGG




ETPGSPAGSPTSTEE

TCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTA




GSSTPSGATGSPGTP

GCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGCCCGGCT




GSGTASSSPGSSTPS

GGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCCGTCTGG




GATGSPGTSTEPSEG

TGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTGCTTCTT




SAPGTSTEPSEGSAP

CCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCA




GSEPATSGSETPGSP

GGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




AGSPTSTEEGSPAGS

CTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGC




PTSTEEGTSTEPSEGS

AACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTCTCCGA




APGASASGAPSTGGT

CTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTTCTACT




SESATPESGPGSPAG

GAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGCTCCAG




SPTSTEEGSPAGSPTS

GTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTACTTCTGA




TEEGSTSSTAESPGP

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




GSTSESPSGTAPGTSP

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




SGESSTAPGTPGSGT

ACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCCTGGCCC




ASSSPGSSTPSGATG

AGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAGGTACTT




SPGSSPSASTGTGPG

CCCCTAGCGGTGAATCTTCTACTGCACCAGGTACCCCTGGCAGC




SEPATSGSETPGTSES

GGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCCGTCTGGTGC




ATPESGPGSEPATSG

TACTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCGGTACCG




SETPGSTSSTAESPGP

GCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAACTCCAGG




GSTSSTAESPGPGTSP

TACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGGTAGCGAA




SGESSTAPGSEPATS

CCGGCTACTTCCGGCTCTGAAACCCCAGGTTCCACCAGCTCTAC




GSETPGSEPATSGSE

TGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACTGCAGAAT




TPGTSTEPSEGSAPG

CTCCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCT




STSSTAESPGPGTSTP

CCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACTCCAGGTA




ESGSASPGSTSESPSG

GCGAACCTGCAACCTCCGGCTCTGAAACCCCAGGTACTTCTACT




TAPGTSTEPSEGSAP

GAACCTTCTGAGGGCAGCGCACCAGGTTCTACCAGCTCTACCG




GTSTEPSEGSAPGTS

CAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCT




TEPSEGSAPGSSTPSG

GCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACC




ATGSPGSSPSASTGT

AGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACC




GPGASPGTSSTGSPG

TCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGA




SEPATSGSETPGTSES

ACCTTCTGAAGGTAGCGCACCAGGTAGCTCTACTCCGTCTGGTG




ATPESGPGSPAGSPT

CAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGGTACT




STEEGSSTPSGATGS

GGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGG




PGSSPSASTGTGPGA

TAGCGAACCTGCTACCTCCGGTTCTGAAACCCCAGGTACCTCTG




SPGTSSTGSPGTSESA

AAAGCGCAACTCCGGAGTCTGGTCCAGGTAGCCCTGCAGGTTC




TPESGPGTSTEPSEGS

TCCTACCTCCACTGAGGAAGGTAGCTCTACTCCGTCTGGTGCAA




APGTSTEPSEGSAP

CCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGC






CCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTAC






CTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTG






AACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCC






GAAGGTAGCGCACCA



 


hGH-
FPTIPLSRLFDNAML
727
TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTG
728


AM1318
RAHRLHQLAFDTYQ

CGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGA




EFEEAYIPKEQKYSF

ATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCC




LQNPQTSLCFSESIPT

TGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCG




PSNREETQQKSNLEL

ACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG




LRISLLLIQSWLEPVQ

AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAA




FLRSVFANSLVYGAS

CCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTA




DSNVYDLLKDLEEGI

TGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTC




QTLMGRLEDGSPRT

GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCT




GQIFKQTYSKFDTNS

CTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTT




HNDDALLKNYGLLY

GATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATG




CFRKDMDKVETFLRI

GTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACC




VQCRSVEGSCGFGG

TTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG




TSTEPSEGSAPGSEP

TTTCTAAGGTGGTACTTCTACTGAACCGTCTGAAGGCAGCGCAC




ATSGSETPGSPAGSP

CAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCCAGGTAG




TSTEEGSTSSTAESPG

CCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCT




PGTSTPESGSASPGST

CTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGC




SESPSGTAPGSTSESP

GGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCAC




SGTAPGTSTPESGSA

TGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAG




SPGTSTPESGSASPGS

GTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGTACCTCT




EPATSGSETPGTSES

ACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACCGGCAA




ATPESGPGSPAGSPT

CCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCT




STEEGTSTEPSEGSAP

GAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTG




GTSESATPESGPGTS

AGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGG




TEPSEGSAPGTSTEPS

TACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTA




EGSAPGSPAGSPTST

CTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACCGAACC




EEGTSTEPSEGSAPG

GTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACC




TSTEPSEGSAPGTSES

TCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCG




ATPESGPGTSESATP

CACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGG




ESGPGTSTEPSEGSA

TACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTG




PGTSTEPSEGSAPGT

AAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACTGAACCT




SESATPESGPGTSTEP

TCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGTCCGAGG




SEGSAPGSEPATSGS

GCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGG




ETPGSPAGSPTSTEE

TCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTA




GSSTPSGATGSPGTP

GCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGCCCGGCT




GSGTASSSPGSSTPS

GGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCCGTCTGG




GATGSPGTSTEPSEG

TGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTGCTTCTT




SAPGTSTEPSEGSAP

CCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCA




GSEPATSGSETPGSP

GGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




AGSPTSTEEGSPAGS

CTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGC




PTSTEEGTSTEPSEGS

AACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTCTCCGA




APGPEPTGPAPSGGS

CTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTTCTACT




EPATSGSETPGTSES

GAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGCTCCAG




ATPESGPGSPAGSPT

GTCCAGAACCAACGGGGCCGGCCCCAAGCGGAGGTAGCGAAC




STEEGTSESATPESGP

CGGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGC




GSPAGSPTSTEEGSP

TACTCCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTT




AGSPTSTEEGTSESA

CCACTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGG




TPESGPGSPAGSPTST

CCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGT




EEGSPAGSPTSTEEG

AGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTGA




STSSTAESPGPGSTSE

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




SPSGTAPGTSPSGESS

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




TAPGSTSESPSGTAP

ACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCCTGGCCC




GSTSESPSGTAPGTSP

AGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAGGTACTT




SGESSTAPGTSTEPSE

CCCCTAGCGGTGAATCTTCTACTGCACCAGGTTCTACCAGCGAA




GSAPGTSESATPESG

TCTCCTTCTGGCACCGCTCCAGGTTCTACTAGCGAATCCCCGTC




PGTSESATPESGPGS

TGGTACCGCACCAGGTACTTCTCCTAGCGGCGAATCTTCTACCG




EPATSGSETPGTSES

CACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGG




ATPESGPGTSESATP

TACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTG




ESGPGTSTEPSEGSA

AAAGCGCTACTCCTGAATCCGGTCCAGGTAGCGAACCGGCAAC




PGTSESATPESGPGT

CTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCGG




STEPSEGSAPGTSPSG

AATCTGGTCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGT




ESSTAPGTSPSGESST

CCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAC




APGTSPSGESSTAPG

TTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTG




TSTEPSEGSAPGSPA

AACCGTCCGAAGGTAGCGCACCAGGTACCTCCCCTAGCGGCGA




GSPTSTEEGTSTEPSE

ATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTA




GSAPGSSPSASTGTG

CCGCTCCAGGTACCTCCCCTAGCGGTGAATCTTCTACCGCACCA




PGSSTPSGATGSPGS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCC




STPSGATGSPGSSTPS

CAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAA




GATGSPGSSTPSGAT

CCGTCCGAGGGTAGCGCACCAGGTTCTAGCCCTTCTGCTTCCAC




GSPGASPGTSSTGSP

CGGTACCGGCCCAGGTAGCTCTACTCCGTCTGGTGCAACTGGCT




GASASGAPSTGGTSP

CTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGT




SGESSTAPGSTSSTA

AGCTCTACCCCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTAC




ESPGPGTSPSGESSTA

CCCGTCTGGTGCAACCGGCTCCCCAGGTGCATCCCCGGGTACTA




PGTSESATPESGPGT

GCTCTACCGGTTCTCCAGGTGCAAGCGCAAGCGGCGCGCCAAG




STEPSEGSAPGTSTEP

CACGGGAGGTACTTCTCCGAGCGGTGAATCTTCTACCGCACCA




SEGSAPGSSPSASTG

GGTTCTACTAGCTCTACCGCTGAATCTCCGGGCCCAGGTACTTC




TGPGSSTPSGATGSP

TCCGAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTGAAAGCG




GASPGTSSTGSPGTS

CTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAG




TPESGSASPGTSPSGE

GGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCG




SSTAPGTSPSGESSTA

CACCAGGTTCTAGCCCTTCTGCATCTACTGGTACTGGCCCAGGT




PGTSESATPESGPGS

AGCTCTACTCCTTCTGGTGCTACCGGCTCTCCAGGTGCTTCTCC




EPATSGSETPGTSTEP

GGGTACTAGCTCTACCGGTTCTCCAGGTACTTCTACTCCGGAAA




SEGSAPGSTSESPSGT

GCGGTTCCGCATCTCCAGGTACTTCTCCTAGCGGTGAATCTTCT




APGSTSESPSGTAPG

ACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACTGCTCC




TSTPESGSASPGSPA

AGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGC




GSPTSTEEGTSESATP

GAACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGA




ESGPGTSTEPSEGSA

ACCGTCCGAAGGTAGCGCACCAGGTTCTACCAGCGAATCCCCT




PGSPAGSPTSTEEGT

TCTGGTACTGCTCCAGGTTCTACCAGCGAATCCCCTTCTGGCAC




SESATPESGPGSEPA

CGCACCAGGTACTTCTACCCCTGAAAGCGGCTCCGCTTCTCCAG




TSGSETPGSSTPSGA

GTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCT




TGSPGASPGTSSTGS

GAAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAAC




PGSSTPSGATGSPGS

CGTCTGAGGGCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAAC




TSESPSGTAPGTSPSG

CTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCC




ESSTAPGSTSSTAESP

GGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAG




GPGSSTPSGATGSPG

GTAGCTCTACCCCGTCTGGTGCTACCGGTTCCCCAGGTGCTTCT




ASPGTSSTGSPGTPG

CCTGGTACTAGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTC




SGTASSSPGSPAGSP

TGGTGCTACTGGCTCTCCAGGTTCTACTAGCGAATCCCCGTCTG




TSTEEGSPAGSPTSTE

GTACTGCTCCAGGTACTTCCCCTAGCGGTGAATCTTCTACTGCT




EGTSTEPSEGSAP

CCAGGTTCTACCAGCTCTACCGCAGAATCTCCGGGTCCAGGTAG






CTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGCATCCCCGG






GTACCAGCTCTACCGGTTCTCCAGGTACTCCGGGTAGCGGTACC






GCTTCTTCCTCTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACT






GAGGAAGGTAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAG






GTACTTCTACCGAACCTTCCGAAGGTAGCGCTCCA





*Sequence name reflects N- to C-terminus configuration of the growth factor and XTEN components













TABLE 36







Exemplary GHXTEN comprising growth hormones and


two XTEN sequences











GHXTEN

SEQ ID

SEQ ID


Name*
Amino Acid Sequence
NO:
DNA Nucleotide Sequence
NO:





AE48-
MAEPAGSPTSTEEGT
729
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
730


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



AE144
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG




GSPGFPTIPLSRLFDN

CTCTACCGGTTCTCCAGGTTTTCCGACTATTCCGCTGTCTCGTCT




AMLRAHRLHQLAFD

GTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGG




TYQEFEEAYIPKEQK

CCTTTGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAA




YSFLQNPQTSLCFSE

GAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTG




SIPTPSNREETQQKS

CTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTC




NLELLRISLLLIQSWL

AGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTG




EPVQFLRSVFANSLV

ATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTT




YGASDSNVYDLLKD

CGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATAC




LEEGIQTLMGRLEDG

GATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGG




SPRTGQIFKQTYSKF

GTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAG




DTNSHNDDALLKNY

CAGACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGC




GLLYCFRKDMDKVE

GCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATA




TFLRIVQCRSVEGSC

TGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCC




GFGGSEPATSGSETP

GTTGAGGGCAGCTGTGGTTTCTAAGGTGGTAGCGAACCGGCAA




GTSESATPESGPGSE

CTTCCGGCTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCT




PATSGSETPGSPAGS

GAGTCTGGCCCAGGTAGCGAACCTGCTACCTCTGGCTCTGAAA




PTSTEEGTSTEPSEGS

CCCCAGGTAGCCCGGCAGGCTCTCCGACTTCCACCGAGGAAGG




APGSEPATSGSETPG

TACCTCTACTGAACCTTCTGAGGGTAGCGCTCCAGGTAGCGAAC




SEPATSGSETPGSEP

CGGCAACCTCTGGCTCTGAAACCCCAGGTAGCGAACCTGCTAC




ATSGSETPGTSTEPSE

CTCCGGCTCTGAAACTCCAGGTAGCGAACCGGCTACTTCCGGTT




GSAPGTSESATPESG

CTGAAACTCCAGGTACCTCTACCGAACCTTCCGAAGGCAGCGC




PGSEPATSGSETPGT

ACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGT




STEPSEGSAP

AGCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTAC






CGAACCGTCCGAAGGTAGCGCACCA



 


AM48-
MAEPAGSPTSTEEGA
731
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTG
732


hGH-
SPGTSSTGSPGSSTPS

CATCCCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACC



AE144
GATGSPGSSTPSGAT

CCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGG




GSPGFPTIPLSRLFDN

TGCTACTGGCTCTCCAGGTTTTCCGACTATTCCGCTGTCTCGTCT




AMLRAHRLHQLAFD

GTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGG




TYQEFEEAYIPKEQK

CCTTTGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAA




YSFLQNPQTSLCFSE

GAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTG




SIPTPSNREETQQKS

CTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTC




NLELLRISLLLIQSWL

AGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTG




EPVQFLRSVFANSLV

ATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTT




YGASDSNVYDLLKD

CGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATAC




LEEGIQTLMGRLEDG

GATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGG




SPRTGQIFKQTYSKF

GTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAG




DTNSHNDDALLKNY

CAGACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGC




GLLYCFRKDMDKVE

GCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATA




TFLRIVQCRSVEGSC

TGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCC




GFGGSEPATSGSETP

GTTGAGGGCAGCTGTGGTTTCTAAGGTGGTAGCGAACCGGCAA




GTSESATPESGPGSE

CTTCCGGCTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCT




PATSGSETPGSPAGS

GAGTCTGGCCCAGGTAGCGAACCTGCTACCTCTGGCTCTGAAA




PTSTEEGTSTEPSEGS

CCCCAGGTAGCCCGGCAGGCTCTCCGACTTCCACCGAGGAAGG




APGSEPATSGSETPG

TACCTCTACTGAACCTTCTGAGGGTAGCGCTCCAGGTAGCGAAC




SEPATSGSETPGSEP

CGGCAACCTCTGGCTCTGAAACCCCAGGTAGCGAACCTGCTAC




ATSGSETPGTSTEPSE

CTCCGGCTCTGAAACTCCAGGTAGCGAACCGGCTACTTCCGGTT




GSAPGTSESATPESG

CTGAAACTCCAGGTACCTCTACCGAACCTTCCGAAGGCAGCGC




PGSEPATSGSETPGT

ACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGT




STEPSEGSAP

AGCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTAC






CGAACCGTCCGAAGGTAGCGCACCA



 


AE144-
GSEPATSGSETPGTS
733
GGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACTT
734


hGH-
ESATPESGPGSEPAT

CTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAACCTGC



AE144
SGSETPGSPAGSPTST

TACCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCTCCGA




EEGTSTEPSEGSAPG

CTTCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGGGTAGC




SEPATSGSETPGSEP

GCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAG




ATSGSETPGSEPATS

GTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGTAGCGA




GSETPGTSTEPSEGS

ACCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTACCGAAC




APGTSESATPESGPG

CTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCC




SEPATSGSETPGTSTE

TGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAG




PSEGSAPGFPTIPLSR

ACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAG




LFDNAMLRAHRLHQ

GTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGC




LAFDTYQEFLEAYIP

TGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAG




KEQKYSFLQNPQTSL

GAATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTT




CFSESIPTPSNREETQ

CCTGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTC




QKSNLELLRISLLLIQ

CGACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCT




SWLEPVQFLRSVFA

GGAACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAG




NSLVYGASDSNVYD

AACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTT




LLKDLEEGIQTLMGR

TATGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATC




LEDGSPRTGQIFKQT

TCGAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGG




YSKFDTNSHNDDAL

CTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAAT




LKNYGLLYCFRKDM

TTGATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTA




DKVETFLRIVQCRSV

TGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAA




EGSCGFGGSEPATSG

CCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGT




SETPGTSESATPESGP

GGTTTCTAAGGTGGTAGCGAACCGGCAACTTCCGGCTCTGAAA




GSEPATSGSETPGSP

CCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGCCCAGGT




AGSPTSTEEGTSTEPS

AGCGAACCTGCTACCTCTGGCTCTGAAACCCCAGGTAGCCCGG




EGSAPGSEPATSGSE

CAGGCTCTCCGACTTCCACCGAGGAAGGTACCTCTACTGAACCT




TPGSEPATSGSETPG

TCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCTGGCT




SEPATSGSETPGTSTE

CTGAAACCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAAAC




PSEGSAPGTSESATP

TCCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACTCCAGGTA




ESGPGSEPATSGSET

CCTCTACCGAACCTTCCGAAGGCAGCGCACCAGGTACTTCTGA




PGTSTEPSEGSAP

AAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACT






TCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGG






TAGCGCACCA



 


AE288-
GTSESATPESGPGSE
735
GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCG
736


hGH-
PATSGSETPGTSESA

AACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGC



AE144
TPESGPGSEPATSGS

GCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTG




ETPGTSESATPESGP

GCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCT




GTSTEPSEGSAPGSP

GGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAG




AGSPTSTEEGTSESA

GTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT




TPESGPGSEPATSGS

GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAA




ETPGTSESATPESGP

CCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCT




GSPAGSPTSTEEGSP

GAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCG




AGSPTSTEEGTSTEPS

AGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGG




EGSAPGTSESATPES

TACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTG




GPGTSESATPESGPG

AAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGC




TSESATPESGPGSEP

TACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGG




ATSGSETPGSEPATS

AATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACC




GSETPGSPAGSPTST

CCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTA




EEGTSTEPSEGSAPG

GCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACT




TSTEPSEGSAPGSEP

GAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTT




ATSGSETPGTSESAT

CTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTC




PESGPGTSTEPSEGS

TGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCC




APGFPTIPLSRLFDNA

CAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTTTT




MLRAHRLHQLAFDT

CCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGT




YQEFEEAYIPKEQKY

GCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATT




SFLQNPQTSLCFSESI

TGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGC




PTPSNREETQQKSNL

AAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACG




ELLRISLLLIQSWLEP

CCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAAC




VQFLRSVFANSLVY

TACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCA




GASDSNVYDLLKDL

GTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGG




EEGIQTLMGRLEDGS

CGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTCGAG




PRTGQIFKQTYSKFD

GAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTC




TNSHNDDALLKNYG

CGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGAT




LLYCFRKDMDKVET

ACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATGGTC




FLRIVQCRSVEGSCG

TGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTTC




FGGSEPATSGSETPG

CTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTT




TSESATPESGPGSEP

CTAAGGTGGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCA




ATSGSETPGSPAGSP

GGTACTTCTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCG




TSTEEGTSTEPSEGS

AACCTGCTACCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGG




APGSEPATSGSETPG

CTCTCCGACTTCCACCGAGGAAGGTACCTCTACTGAACCTTCTG




SEPATSGSETPGSEP

AGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGA




ATSGSETPGTSTEPSE

AACCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCA




GSAPGTSESATPESG

GGTAGCGAACCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTC




PGSEPATSGSETPGT

TACCGAACCTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGC




STEPSEGSAP

GCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTG






GCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAG






CGCACCA



 


AF144-
GTSTPESGSASPGTSP
737
GGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTACTTC
738


hGH-
SGESSTAPGTSPSGES

TCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCG



AE144
STAPGSTSSTAESPGP

GCGAATCTTCTACTGCTCCAGGTTCTACCAGCTCTACCGCTGAA




GSTSESPSGTAPGSTS

TCTCCTGGCCCAGGTTCTACCAGCGAATCCCCGTCTGGCACCGC




STAESPGPGTSPSGES

ACCAGGTTCTACTAGCTCTACCGCAGAATCTCCGGGTCCAGGTA




STAPGTSTPESGSASP

CTTCCCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTACT




GSTSSTAESPGPGTSP

CCGGAAAGCGGCTCCGCATCTCCAGGTTCTACTAGCTCTACTGC




SGESSTAPGTSPSGES

TGAATCTCCTGGTCCAGGTACCTCCCCTAGCGGCGAATCTTCTA




STAPGTSPSGESSTAP

CTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCA




GFPTIPLSRLFDNAM

GGTACCTCCCCTAGCGGTGAATCTTCTACCGCACCAGGTTTTCC




LRAHRLHQLAFDTY

GACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGTG




QEFEEAYIPKEQKYS

CGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATTT




FLQNPQTSLCFSESIP

GAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCA




TPSNREETQQKSNLE

AAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACGC




LLRISLLLIQSWLEPV

CTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAACT




QFLRSVFANSLVYG

ACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAG




ASDSNVYDLLKDLE

TGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGC




EGIQTLMGRLEDGSP

GCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTCGAGG




RTGQIFKQTYSKFDT

AAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCC




NSHNDDALLKNYGL

GCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGATA




LYCFRKDMDKVETF

CTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATGGTCT




LRIVQCRSVEGSCGF

GCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTTCC




GGSEPATSGSETPGT

TGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTC




SESATPESGPGSEPA

TAAGGTGGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAG




TSGSETPGSPAGSPTS

GTACTTCTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGA




TEEGTSTEPSEGSAP

ACCTGCTACCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCT




GSEPATSGSETPGSE

CTCCGACTTCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAG




PATSGSETPGSEPAT

GGTAGCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAA




SGSETPGTSTEPSEGS

CCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGT




APGTSESATPESGPG

AGCGAACCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTAC




SEPATSGSETPGTSTE

CGAACCTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCA




PSEGSAP

ACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTC






TGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCA






CCA



 


AD576-
GSSESGSSEGGPGSG
739
GGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCAGGTTCCTC
740


hGH-
GEPSESGSSGSSESGS

TGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAATCTCCGGGT



AE144
SEGGPGSSESGSSEG

GGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCTTCCGA




GPGSSESGSSEGGPG

GTCTGGTAGCTCAGGTGAATCTCCGGGTGGTTCTAGCGGTTCCG




SSESGSSEGGPGSSES

AGTCAGGTGAATCTCCGGGTGGTTCCAGCGGTTCTGAGTCAGGT




GSSEGGPGESPGGSS

TCCTCCGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTCCGA




GSESGSEGSSGPGES

AAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTGAAAGCGGTT




SGSSESGSSEGGPGS

CTTCCGAGGGCGGTCCAGGTGAATCTCCTGGTGGTTCCAGCGGT




SESGSSEGGPGSSES

TCCGAGTCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAGTC




GSSEGGPGSGGEPSE

AGGTGAATCTCCTGGTGGTTCTAGCGGTTCTGAATCAGGTTCCT




SGSSGESPGGSSGSE

CCGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTCCGAAAG




SGESPGGSSGSESGS

CGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTGAAAGCGGTTCTT




GGEPSESGSSGSSES

CCGAGGGCGGTCCAGGTTCCTCTGAAAGCGGTTCTTCTGAGGG




GSSEGGPGSGGEPSE

CGGTCCAGGTTCTTCCGAAAGCGGTTCTTCCGAGGGCGGTCCAG




SGSSGSGGEPSESGS

GTTCTTCCGAAAGCGGTTCTTCTGAAGGCGGTCCAGGTTCTGGT




SGSEGSSGPGESSGE

GGCGAACCGTCCGAGTCTGGTAGCTCAGGTGAATCTCCGGGTG




SPGGSSGSESGSGGE

GCTCTAGCGGTTCCGAGTCAGGTGAATCTCCTGGTGGTTCCAGC




PSESGSSGSGGEPSES

GGTTCCGAGTCAGGTTCCGGTGGCGAACCGTCCGAATCTGGTA




GSSGSGGEPSESGSS

GCTCAGGTAGCGAAGGTTCTTCTGGTCCAGGCGAATCTTCAGGT




GSSESGSSEGGPGES

TCCTCTGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCGGTGG




PGGSSGSESGESPGG

CGAACCGTCCGAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTG




SSGSESGESPGGSSG

GTCCAGGCGAATCTTCAGGTTCCTCTGAAAGCGGTTCTTCTGAG




SESGESPGGSSGSES

GGCGGTCCAGGTTCCGGTGGCGAACCTTCCGAATCTGGTAGCTC




GESPGGSSGSESGSS

AGGTGAATCTCCGGGTGGTTCTAGCGGTTCTGAGTCAGGTTCTG




ESGSSEGGPGSGGEP

GTGGTGAACCTTCCGAGTCTGGTAGCTCAGGTTCTGGTGGCGAA




SESGSSGSEGSSGPG

CCATCCGAGTCTGGTAGCTCAGGTTCTTCCGAAAGCGGTTCTTC




ESSGSSESGSSEGGP

CGAAGGCGGTCCAGGTTCTGGTGGTGAACCGTCCGAATCTGGT




GSGGEPSESGSSGSS

AGCTCAGGTTCTGGTGGCGAACCATCCGAATCTGGTAGCTCAG




ESGSSEGGPGSGGEP

GTAGCGAAGGTTCTTCTGGTCCTGGCGAATCTTCAGGTGAATCT




SESGSSGESPGGSSG

CCAGGTGGCTCTAGCGGTTCCGAATCAGGTAGCGAAGGTTCTTC




SESGESPGGSSGSES

CGGTCCAGGTGAATCTTCAGGTAGCGAAGGTTCTTCTGGTCCTG




GSSESGSSEGGPGSG

GTGAATCCTCAGGTTCCGGTGGCGAACCATCTGAATCTGGTAGC




GEPSESGSSGSSESGS

TCAGGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCAGGTTC




SEGGPGSGGEPSESG

CTCTGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAATCTCCGG




SSGSGGEPSESGSSG

GTGGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCATCC




ESPGGSSGSESGSEG

GAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTGGTCCTGGCGA




SSGPGESSGSSESGSS

ATCTTCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAATCAG




EGGPGSEGSSGPGES

GTAGCGAAGGTTCTTCCGGTCCTGGTGAGTCTTCAGGTGAATCT




SGFPTIPLSRLFDNA

CCAGGTGGCTCTAGCGGTTCCGAGTCAGGTAGCGAAGGTTCTTC




MLRAHRLHQLAFDT

TGGTCCTGGCGAGTCCTCAGGTTTTCCGACTATTCCGCTGTCTC




YQEFEEAYIPKEQKY

GTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCACCAG




SFLQNPQTSLCFSESI

CTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACATTCC




PTPSNREETQQKSNL

TAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTC




ELLRISLLLIQSWLEP

TCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAA




VQFLRSVFANSLVY

ACTCAGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCT




GASDSNVYDLLKDL

TCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCG




EEGIQTLMGRLEDGS

TCTTCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA




PRTGQIFKQTYSKFD

TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGA




TNSHNDDALLKNYG

TGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTC




LLYCFRKDMDKVET

AAGCAGACTTACTCTAAATTTGATACTAACAGCCACAATGACG




FLRIVQCRSVEGSCG

ATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAA




FGGSEPATSGSETPG

GATATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCG




TSESATPESGPGSEP

TTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTAGCGAACCG




ATSGSETPGSPAGSP

GCAACTTCCGGCTCTGAAACCCCAGGTACTTCTGAAAGCGCTAC




TSTEEGTSTEPSEGS

TCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCTGGCTCTG




APGSEPATSGSETPG

AAACCCCAGGTAGCCCGGCAGGCTCTCCGACTTCCACCGAGGA




SEPATSGSETPGSEP

AGGTACCTCTACTGAACCTTCTGAGGGTAGCGCTCCAGGTAGC




ATSGSETPGTSTEPSE

GAACCGGCAACCTCTGGCTCTGAAACCCCAGGTAGCGAACCTG




GSAPGTSESATPESG

CTACCTCCGGCTCTGAAACTCCAGGTAGCGAACCGGCTACTTCC




PGSEPATSGSETPGT

GGTTCTGAAACTCCAGGTACCTCTACCGAACCTTCCGAAGGCA




STEPSEGSAP

GCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCC






AGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTT






CTACCGAACCGTCCGAAGGTAGCGCACCA



 


AE576-
GSPAGSPTSTEEGTS
741
GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTC
742


hGH-
ESATPESGPGTSTEPS

TGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTGAAC



AE144
EGSAPGSPAGSPTST

CGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTCTCCGAC




EEGTSTEPSEGSAPG

TTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGC




TSTEPSEGSAPGTSES

GCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAG




ATPESGPGSEPATSG

GTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGA




SETPGSEPATSGSETP

ACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCT




GSPAGSPTSTEEGTS

ACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCAGGCTCTCCGAC




ESATPESGPGTSTEPS

CTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCC




EGSAPGTSTEPSEGS

GGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAG




APGSPAGSPTSTEEG

GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCC




TSTEPSEGSAPGTSTE

AGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAAC




PSEGSAPGTSESATP

CGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCTTCTGA




ESGPGTSTEPSEGSA

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCC




PGTSESATPESGPGS

GGTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAG




EPATSGSETPGTSTEP

GTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGA




SEGSAPGTSTEPSEG

ACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAAC




SAPGTSESATPESGP

CGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGTCTGA




GTSESATPESGPGSP

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCGGAATCC




AGSPTSTEEGTSESA

GGCCCAGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCAG




TPESGPGSEPATSGS

GTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT




ETPGTSESATPESGP

GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAA




GTSTEPSEGSAPGTS

CCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCG




TEPSEGSAPGTSTEPS

GAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCG




EGSAPGTSTEPSEGS

CTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGG




APGTSTEPSEGSAPG

TACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTA




TSTEPSEGSAPGSPA

CTGAACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCT




GSPTSTEEGTSTEPSE

TCTGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGG




GSAPGTSESATPESG

GTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGA




PGSEPATSGSETPGT

GGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT




SESATPESGPGSEPA

ACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAAC




TSGSETPGTSESATPE

CTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCA




SGPGTSTEPSEGSAP

ACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCT




GTSESATPESGPGSP

CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGC




AGSPTSTEEGSPAGS

CCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTA




PTSTEEGSPAGSPTST

CTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCT




EEGTSESATPESGPG

GGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCC




TSTEPSEGSAPGFPTI

AACTTCTACTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCT




PLSRLFDNAMLRAH

ACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCC




RLHQLAFDTYQEFEE

CAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTTT




AYIPKEQKYSFLQNP

TCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCG




QTSLCFSESIPTPSNR

TGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAAT




EETQQKSNLELLRIS

TTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTG




LLLIQSWLEPVQFLR

CAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGAC




SVFANSLVYGASDS

GCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAA




NVYDLLKDLEEGIQT

CTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACC




LMGRLEDGSPRTGQI

AGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATG




FKQTYSKFDTNSHN

GCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTCGA




DDALLKNYGLLYCF

GGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCT




RKDMDKVETFLRIV

CCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGA




QCRSVEGSCGFGGSE

TACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATGGT




PATSGSETPGTSESA

CTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTT




TPESGPGSEPATSGS

CCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTT




ETPGSPAGSPTSTEE

TCTAAGGTGGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCC




GTSTEPSEGSAPGSE

AGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGC




PATSGSETPGSEPAT

GAACCTGCTACCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAG




SGSETPGSEPATSGS

GCTCTCCGACTTCCACCGAGGAAGGTACCTCTACTGAACCTTCT




ETPGTSTEPSEGSAP

GAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTG




GTSESATPESGPGSE

AAACCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAAACTCC




PATSGSETPGTSTEPS

AGGTAGCGAACCGGCTACTTCCGGTTCTGAAACTCCAGGTACCT




EGSAP

CTACCGAACCTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAG






CGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCT






GGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTA






GCGCACCA



 


AF576-
GSTSSTAESPGPGSTS
743
GGTTCTACTAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCCAC
744


hGH-
STAESPGPGSTSESPS

TAGCTCTACCGCAGAATCTCCGGGCCCAGGTTCTACTAGCGAAT



AE144
GTAPGSTSSTAESPG

CCCCTTCTGGTACCGCTCCAGGTTCTACTAGCTCTACCGCTGAA




PGSTSSTAESPGPGTS

TCTCCGGGTCCAGGTTCTACCAGCTCTACTGCAGAATCTCCTGG




TPESGSASPGSTSESP

CCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGTT




SGTAPGTSPSGESST

CTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCT




APGSTSESPSGTAPG

AGCGGCGAATCTTCTACCGCTCCAGGTTCTACTAGCGAATCTCC




STSESPSGTAPGTSPS

TTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCTTCTGGCA




GESSTAPGSTSESPSG

CCGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCA




TAPGSTSESPSGTAP

GGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTAC




GTSPSGESSTAPGSTS

CAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCTAGCG




ESPSGTAPGSTSESPS

GCGAATCTTCTACCGCTCCAGGTTCTACTAGCGAATCTCCTTCT




GTAPGSTSESPSGTA

GGCACTGCACCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGC




PGTSTPESGSASPGST

ACCAGGTTCTACCAGCGAATCTCCGTCTGGCACTGCACCAGGTA




SESPSGTAPGTSTPES

CCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGTTCTACTAGC




GSASPGSTSSTAESP

GAATCTCCTTCTGGTACCGCTCCAGGTACTTCTACCCCTGAAAG




GPGSTSSTAESPGPG

CGGCTCCGCTTCTCCAGGTTCCACTAGCTCTACCGCTGAATCTC




TSTPESGSASPGTSTP

CGGGTCCAGGTTCTACTAGCTCTACTGCAGAATCTCCTGGCCCA




ESGSASPGSTSESPSG

GGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTACTTC




TAPGTSTPESGSASP

TACCCCTGAAAGCGGTTCTGCATCTCCAGGTTCTACTAGCGAAT




GTSTPESGSASPGSTS

CCCCGTCTGGTACCGCACCAGGTACTTCTACCCCGGAAAGCGG




ESPSGTAPGSTSESPS

CTCTGCTTCTCCAGGTACTTCTACCCCGGAAAGCGGCTCCGCAT




GTAPGSTSESPSGTA

CTCCAGGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAGGT




PGSTSSTAESPGPGTS

TCTACCAGCGAATCCCCGTCTGGTACTGCTCCAGGTTCTACCAG




TPESGSASPGTSTPES

CGAATCTCCTTCTGGTACTGCACCAGGTTCTACTAGCTCTACTG




GSASPGSTSESPSGT

CAGAATCTCCTGGCCCAGGTACCTCTACTCCGGAAAGCGGCTCT




APGSTSESPSGTAPG

GCATCTCCAGGTACTTCTACCCCTGAAAGCGGTTCTGCATCTCC




TSTPESGSASPGSTSE

AGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTA




SPSGTAPGSTSESPSG

CCAGCGAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCCCT




TAPGTSTPESGSASP

GAAAGCGGTTCCGCTTCTCCAGGTTCTACTAGCGAATCTCCTTC




GTSPSGESSTAPGSTS

TGGCACTGCACCAGGTTCTACCAGCGAATCTCCGTCTGGCACTG




STAESPGPGTSPSGES

CACCAGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGT




STAPGSTSSTAESPGP

ACTTCTCCGAGCGGTGAATCTTCTACCGCACCAGGTTCTACTAG




GTSTPESGSASPGSTS

CTCTACCGCTGAATCTCCGGGCCCAGGTACTTCTCCGAGCGGTG




ESPSGTAPGSTSSTA

AATCTTCTACTGCTCCAGGTTCCACTAGCTCTACTGCTGAATCT




ESPGPGTSTPESGSAS

CCTGGCCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCC




PGTSTPESGSASPGFP

AGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAGGTTCTA




TIPLSRLFDNAMLRA

CTAGCTCTACTGCAGAATCTCCTGGCCCAGGTACCTCTACTCCG




HRLHQLAFDTYQEF

GAAAGCGGCTCTGCATCTCCAGGTACTTCTACCCCTGAAAGCG




EEAYIPKEQKYSFLQ

GTTCTGCATCTCCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGT




NPQTSLCFSESIPTPS

TTGATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCC




NREETQQKSNLELLR

TTTGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGA




ISLLLIQSWLEPVQFL

GCAGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCT




RSVFANSLVYGASD

TCAGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCA




SNVYDLLKDLEEGIQ

GCAAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGA




TLMGRLEDGSPRTG

TTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTC




QIFKQTYSKFDTNSH

GCCAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACG




NDDALLKNYGLLYC

ATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGG




FRKDMDKVETFLRI

TCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGC




VQCRSVEGSCGFGG

AGACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGC




SEPATSGSETPGTSES

GCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATA




ATPESGPGSEPATSG

TGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCC




SETPGSPAGSPTSTEE

GTTGAGGGCAGCTGTGGTTTCTAAGGTGGTAGCGAACCGGCAA




GTSTEPSEGSAPGSE

CTTCCGGCTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCT




PATSGSETPGSEPAT

GAGTCTGGCCCAGGTAGCGAACCTGCTACCTCTGGCTCTGAAA




SGSETPGSEPATSGS

CCCCAGGTAGCCCGGCAGGCTCTCCGACTTCCACCGAGGAAGG




ETPGTSTEPSEGSAP

TACCTCTACTGAACCTTCTGAGGGTAGCGCTCCAGGTAGCGAAC




GTSESATPESGPGSE

CGGCAACCTCTGGCTCTGAAACCCCAGGTAGCGAACCTGCTAC




PATSGSETPGTSTEPS

CTCCGGCTCTGAAACTCCAGGTAGCGAACCGGCTACTTCCGGTT




EGSAP

CTGAAACTCCAGGTACCTCTACCGAACCTTCCGAAGGCAGCGC






ACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGT






AGCGAACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTAC






CGAACCGTCCGAAGGTAGCGCACCA



 


AE624-
MAEPAGSPTSTEEGT
745
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
746


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



AE144
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG




GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




FPTIPLSRLFDNAML

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




RAHRLHQLAFDTYQ

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




EFEEAYIPKEQKYSF

GCAGCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTT




LQNPQTSLCFSESIPT

GATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT




PSNREETQQKSNLEL

TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGC




LRISLLLIQSWLEPVQ

AGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTC




FLRSVFANSLVYGAS

AGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC




DSNVYDLLKDLEEGI

AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATT




QTLMGRLEDGSPRT

CAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGC




GQIFKQTYSKFDTNS

CAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGAT




HNDDALLKNYGLLY

CTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC




CFRKDMDKVETFLRI

GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG




VQCRSVEGSCGFGG

ACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCT




SEPATSGSETPGTSES

TCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGG




ATPESGPGSEPATSG

ACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTT




SETPGSPAGSPTSTEE

GAGGGCAGCTGTGGTTTCTAAGGTGGTAGCGAACCGGCAACTT




GTSTEPSEGSAPGSE

CCGGCTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTGAG




PATSGSETPGSEPAT

TCTGGCCCAGGTAGCGAACCTGCTACCTCTGGCTCTGAAACCCC




SGSETPGSEPATSGS

AGGTAGCCCGGCAGGCTCTCCGACTTCCACCGAGGAAGGTACC




ETPGTSTEPSEGSAP

TCTACTGAACCTTCTGAGGGTAGCGCTCCAGGTAGCGAACCGG




GTSESATPESGPGSE

CAACCTCTGGCTCTGAAACCCCAGGTAGCGAACCTGCTACCTCC




PATSGSETPGTSTEPS

GGCTCTGAAACTCCAGGTAGCGAACCGGCTACTTCCGGTTCTGA




EGSAP

AACTCCAGGTACCTCTACCGAACCTTCCGAAGGCAGCGCACCA






GGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCG






AACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAA






CCGTCCGAAGGTAGCGCACCA



 


AD836-
GSSESGSSEGGPGSS
747
GGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCAGGTTCCTC
748


hGH-
ESGSSEGGPGESPGG

TGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAATCTCCGGGT



AE144
SSGSESGSGGEPSES

GGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCTTCCGA




GSSGESPGGSSGSES

GTCTGGTAGCTCAGGTGAATCTCCGGGTGGTTCTAGCGGTTCCG




GESPGGSSGSESGES

AGTCAGGTGAATCTCCGGGTGGTTCCAGCGGTTCTGAGTCAGGT




ESGSSEGGPGSSESG

TCCTCCGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTCCGA




SSEGGPGSSESGSSE

AAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTGAAAGCGGTT




GGPGESPGGSSGSES

CTTCCGAGGGCGGTCCAGGTGAATCTCCTGGTGGTTCCAGCGGT




GESPGGSSGSESGES

TCCGAGTCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAGTC




PGGSSGSESGSSESG

AGGTGAATCTCCTGGTGGTTCTAGCGGTTCTGAATCAGGTTCCT




SSEGGPGSSESGSSE

CCGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTCCGAAAG




GGPGSSESGSSEGGP

CGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTGAAAGCGGTTCTT




GSSESGSSEGGPGSS

CCGAGGGCGGTCCAGGTTCCTCTGAAAGCGGTTCTTCTGAGGG




ESGSSEGGPGSSESG

CGGTCCAGGTTCTTCCGAAAGCGGTTCTTCCGAGGGCGGTCCAG




SSEGGPGSGGEPSES

GTTCTTCCGAAAGCGGTTCTTCTGAAGGCGGTCCAGGTTCTGGT




GSSGESPGGSSGSES

GGCGAACCGTCCGAGTCTGGTAGCTCAGGTGAATCTCCGGGTG




GESPGGSSGSESGSG

GCTCTAGCGGTTCCGAGTCAGGTGAATCTCCTGGTGGTTCCAGC




GEPSESGSSGSEGSS

GGTTCCGAGTCAGGTTCCGGTGGCGAACCGTCCGAATCTGGTA




GPGESSGSSESGSSE

GCTCAGGTAGCGAAGGTTCTTCTGGTCCAGGCGAATCTTCAGGT




GGPGSGGEPSESGSS

TCCTCTGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCGGTGG




GSEGSSGPGESSGSS

CGAACCGTCCGAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTG




ESGSSEGGPGSGGEP

GTCCAGGCGAATCTTCAGGTTCCTCTGAAAGCGGTTCTTCTGAG




SESGSSGESPGGSSG

GGCGGTCCAGGTTCCGGTGGCGAACCTTCCGAATCTGGTAGCTC




SESGSGGEPSESGSS

AGGTGAATCTCCGGGTGGTTCTAGCGGTTCTGAGTCAGGTTCTG




GSGGEPSESGSSGSS

GTGGTGAACCTTCCGAGTCTGGTAGCTCAGGTTCTGGTGGCGAA




ESGSSEGGPGSGGEP

CCATCCGAGTCTGGTAGCTCAGGTTCTTCCGAAAGCGGTTCTTC




SESGSSGSGGEPSES

CGAAGGCGGTCCAGGTTCTGGTGGTGAACCGTCCGAATCTGGT




GSSGSEGSSGPGESS

AGCTCAGGTTCTGGTGGCGAACCATCCGAATCTGGTAGCTCAG




GESPGGSSGSESGSE

GTAGCGAAGGTTCTTCTGGTCCTGGCGAATCTTCAGGTGAATCT




GSSGPGESSGSEGSS

CCAGGTGGCTCTAGCGGTTCCGAATCAGGTAGCGAAGGTTCTTC




GPGESSGSGGEPSES

CGGTCCAGGTGAATCTTCAGGTAGCGAAGGTTCTTCTGGTCCTG




GSSGSSESGSSEGGP

GTGAATCCTCAGGTTCCGGTGGCGAACCATCTGAATCTGGTAGC




GSSESGSSEGGPGES

TCAGGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCAGGTTC




PGGSSGSESGSGGEP

CTCTGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAATCTCCGG




SESGSSGSEGSSGPG

GTGGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCATCC




ESSGESPGGSSGSES

GAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTGGTCCTGGCGA




GSEGSSGPGSSESGS

ATCTTCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAATCAG




SEGGPGSGGEPSESG

GTAGCGAAGGTTCTTCCGGTCCaGGTTCCTCTGAAAGCGGTTCT




SSGSEGSSGPGESSG

TCTGAGGGCGGTCCAGGTTCTGGTGGCGAACCATCTGAATCTG




SEGSSGPGESSGSEG

GTAGCTCAGGTAGCGAAGGTTCTTCCGGTCCGGGTGAATCTTCA




SSGPGESSGSGGEPS

GGTAGCGAAGGTTCTTCCGGTCCAGGTGAATCTTCAGGTAGCG




ESGSSGSGGEPSESG

AAGGTTCTTCTGGTCCTGGTGAATCCTCAGGTTCCGGTGGCGAA




SSGESPGGSSGSESG

CCATCTGAATCTGGTAGCTCAGGTTCTGGTGGCGAACCATCCGA




ESPGGSSGSESGSGG

ATCTGGTAGCTCAGGTGAATCTCCGGGTGGCTCCAGCGGTTCTG




EPSESGSSGSEGSSGP

AATCAGGTGAATCTCCTGGTGGCTCCAGCGGTTCTGAGTCAGGT




GESSGESPGGSSGSE

TCTGGTGGCGAACCATCCGAATCTGGTAGCTCAGGTAGCGAAG




SGSSESGSSEGGPGS

GTTCTTCTGGTCCTGGCGAATCTTCAGGTGAATCTCCAGGTGGC




SESGSSEGGPGSSES

TCTAGCGGTTCCGAATCAGGTTCCTCTGAAAGCGGTTCTTCTGA




GSSEGGPGSGGEPSE

GGGCGGTCCAGGTTCTTCCGAAAGCGGTTCTTCCGAGGGCGGT




SGSSGSSESGSSEGG

CCAGGTTCTTCCGAAAGCGGTTCTTCTGAAGGCGGTCCAGGTTC




PGESPGGSSGSESGS

TGGTGGCGAACCGTCCGAATCTGGTAGCTCAGGTTCCTCCGAA




GGEPSESGSSGSSES

AGCGGTTCTTCTGAAGGTGGTCCAGGTGAATCTCCAGGTGGTTC




GSSEGGPGESPGGSS

TAGCGGTTCTGAATCAGGTTCTGGTGGCGAACCGTCCGAATCTG




GSESGSGGEPSESGS

GTAGCTCAGGTTCCTCCGAAAGCGGTTCTTCTGAAGGTGGTCCA




SGESPGGSSGSESGS

GGTGAATCTCCAGGTGGTTCTAGCGGTTCTGAATCAGGTTCTGG




GGEPSESGSSGFPTIP

TGGCGAACCGTCCGAATCTGGTAGCTCAGGTGAATCTCCTGGTG




LSRLFDNAMLRAHR

GTTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCTTCCGAA




LHQLAFDTYQEFEE

TCTGGTAGCTCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTT




AYIPKEQKYSFLQNP

GATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT




QTSLCFSESIPTPSNR

TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGC




EETQQKSNLELLRIS

AGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTC




LLLIQSWLEPVQFLR

AGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC




SVFANSLVYGASDS

AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATT




NVYDLLKDLEEGIQT

CAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGC




LMGRLEDGSPRTGQI

CAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGAT




FKQTYSKFDTNSHN

CTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC




DDALLKNYGLLYCF

GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG




RKDMDKVETFLRIV

ACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCT




QCRSVEGSCGFGGSE

TCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGG




PATSGSETPGTSESA

ACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTT




TPESGPGSEPATSGS

GAGGGCAGCTGTGGTTTCTAAGGTGGTAGCGAACCGGCAACTT




ETPGSPAGSPTSTEE

CCGGCTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTGAG




GTSTEPSEGSAPGSE

TCTGGCCCAGGTAGCGAACCTGCTACCTCTGGCTCTGAAACCCC




PATSGSETPGSEPAT

AGGTAGCCCGGCAGGCTCTCCGACTTCCACCGAGGAAGGTACC




SGSETPGSEPATSGS

TCTACTGAACCTTCTGAGGGTAGCGCTCCAGGTAGCGAACCGG




ETPGTSTEPSEGSAP

CAACCTCTGGCTCTGAAACCCCAGGTAGCGAACCTGCTACCTCC




GTSESATPESGPGSE

GGCTCTGAAACTCCAGGTAGCGAACCGGCTACTTCCGGTTCTGA




PATSGSETPGTSTEPS

AACTCCAGGTACCTCTACCGAACCTTCCGAAGGCAGCGCACCA




EGSAP

GGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCG






AACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAA






CCGTCCGAAGGTAGCGCACCA



 


AE864-
GSPAGSPTSTEEGTS
749
GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTC
750


hGH-
ESATPESGPGTSTEPS

TGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTGAAC



AE144
EGSAPGSPAGSPTST

CGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTCTCCGAC




EEGTSTEPSEGSAPG

TTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGC




TSTEPSEGSAPGTSES

GCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAG




ATPESGPGSEPATSG

GTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGA




SETPGSEPATSGSETP

ACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCT




GSPAGSPTSTEEGTS

ACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCAGGCTCTCCGAC




ESATPESGPGTSTEPS

CTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCC




EGSAPGTSTEPSEGS

GGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAG




APGSPAGSPTSTEEG

GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCC




TSTEPSEGSAPGTSTE

AGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAAC




PSEGSAPGTSESATP

CGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCTTCTGA




ESGPGTSTEPSEGSA

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCC




PGTSESATPESGPGS

GGTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAG




EPATSGSETPGTSTEP

GTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGA




SEGSAPGTSTEPSEG

ACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAAC




SAPGTSESATPESGP

CGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGTCTGA




GTSESATPESGPGSP

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCGGAATCC




AGSPTSTEEGTSESA

GGCCCAGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCAG




TPESGPGSEPATSGS

GTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT




ETPGTSESATPESGP

GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAA




GTSTEPSEGSAPGTS

CCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCG




TEPSEGSAPGTSTEPS

GAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCG




EGSAPGTSTEPSEGS

CTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGG




APGTSTEPSEGSAPG

TACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTA




TSTEPSEGSAPGSPA

CTGAACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCT




GSPTSTEEGTSTEPSE

TCTGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGG




GSAPGTSESATPESG

GTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGA




PGSEPATSGSETPGT

GGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT




SESATPESGPGSEPA

ACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAAC




TSGSETPGTSESATPE

CTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCA




SGPGTSTEPSEGSAP

ACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCT




GTSESATPESGPGSP

CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGC




AGSPTSTEEGSPAGS

CCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTA




PTSTEEGSPAGSPTST

CTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCT




EEGTSESATPESGPG

GGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCC




TSTEPSEGSAPGTSES

AACTTCTACTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCT




ATPESGPGSEPATSG

ACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCC




SETPGTSESATPESGP

CAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTAC




GSEPATSGSETPGTS

CTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCT




ESATPESGPGTSTEPS

GCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAA




EGSAPGSPAGSPTST

CCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCTCT




EEGTSESATPESGPG

GAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCC




SEPATSGSETPGTSES

CAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAG




ATPESGPGSPAGSPT

CCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAA




STEEGSPAGSPTSTEE

GCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACCTC




GTSTEPSEGSAPGTS

CGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGT




ESATPESGPGTSESA

CCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGA




TPESGPGTSESATPES

AGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTT




GPGSEPATSGSETPG

CTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAG




SEPATSGSETPGSPA

CGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTC




GSPTSTEEGTSTEPSE

CTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




GSAPGTSTEPSEGSA

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




PGSEPATSGSETPGT

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




SESATPESGPGTSTEP

AGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAAC




SEGSAPGFPTIPLSRL

CTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAG




FDNAMLRAHRLHQL

GGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAA




AFDTYQEFEEAYIPK

CCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGT




EQKYSFLQNPQTSLC

ACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTTTTCCGAC




FSESIPTPSNREETQQ

TATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGTGCGC




KSNLELLRISLLLIQS

ACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATTTGAA




WLEPVQFLRSVFAN

GAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAA




SLVYGASDSNVYDL

CCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT




LKDLEEGIQTLMGRL

CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAACTACT




EDGSPRTGQIFKQTY

CCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAGTGC




SKFDTNSHNDDALL

AATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCA




KNYGLLYCFRKDMD

TCCGACAGCAACGTATACGATCTCCTGAAAGATCTCGAGGAAG




KVETFLRIVQCRSVE

GCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT




GSCGFGGSEPATSGS

ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGATACTAA




ETPGTSESATPESGP

CAGCCACAATGACGATGCGCTTCTAAAAAACTATGGTCTGCTGT




GSEPATSGSETPGSP

ATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGCGT




AGSPTSTEEGTSTEPS

ATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGG




EGSAPGSEPATSGSE

TGGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACT




TPGSEPATSGSETPG

TCTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAACCTG




SEPATSGSETPGTSTE

CTACCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCTCCG




PSEGSAPGTSESATP

ACTTCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGGGTA




ESGPGSEPATSGSET

GCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCC




PGTSTEPSEGSAP

AGGTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGTAGC






GAACCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTACCGA






ACCTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCAACC






CCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGA






GACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA



 


AF864-
GSTSESPSGTAPGTSP
751
GGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTC
752


hGH-
SGESSTAPGSTSESPS

TCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTACTAGCGAAT



AE144
GTAPGSTSESPSGTA

CTCCTTCTGGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCT




PGTSTPESGSASPGTS

GGTACTGCTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTC




TPESGSASPGSTSESP

TCCAGGTACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTT




SGTAPGSTSESPSGT

CTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTTCTACTAGC




APGTSPSGESSTAPG

GAATCCCCGTCTGGTACCGCACCAGGTACTTCTCCTAGCGGCGA




STSESPSGTAPGTSPS

ATCTTCTACCGCACCAGGTTCTACTAGCGAATCTCCGTCTGGCA




GESSTAPGTSPSGESS

CTGCTCCAGGTACTTCTCCTAGCGGTGAATCTTCTACCGCTCCA




TAPGSTSSTAESPGP

GGTACTTCCCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTAC




GTSPSGESSTAPGTSP

TAGCTCTACTGCAGAATCTCCGGGCCCAGGTACCTCTCCTAGCG




SGESSTAPGSTSSTA

GTGAATCTTCTACCGCTCCAGGTACTTCTCCGAGCGGTGAATCT




ESPGPGTSTPESGSAS

TCTACCGCTCCAGGTTCTACTAGCTCTACTGCAGAATCTCCTGG




PGTSTPESGSASPGST

CCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTA




SESPSGTAPGSTSESP

CTTCTACCCCTGAAAGCGGTTCTGCATCTCCAGGTTCTACTAGC




SGTAPGTSTPESGSA

GAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCC




SPGSTSSTAESPGPGT

GTCTGGCACTGCACCAGGTACCTCTACCCCTGAAAGCGGTTCCG




STPESGSASPGSTSES

CTTCTCCAGGTTCTACCAGCTCTACCGCAGAATCTCCTGGTCCA




PSGTAPGTSPSGESST

GGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTTCTAC




APGSTSSTAESPGPG

TAGCGAATCTCCTTCTGGCACTGCACCAGGTACTTCTCCGAGCG




TSPSGESSTAPGTSTP

GTGAATCTTCTACCGCACCAGGTTCTACTAGCTCTACCGCTGAA




ESGSASPGSTSSTAES

TCTCCGGGCCCAGGTACTTCTCCGAGCGGTGAATCTTCTACTGC




PGPGSTSSTAESPGP

TCCAGGTACCTCTACTCCTGAAAGCGGTTCTGCATCTCCAGGTT




GSTSSTAESPGPGSTS

CCACTAGCTCTACCGCAGAATCTCCGGGCCCAGGTTCTACTAGC




STAESPGPGTSPSGES

TCTACTGCTGAATCTCCTGGCCCAGGTTCTACTAGCTCTACTGC




STAPGSTSESPSGTAP

TGAATCTCCGGGTCCAGGTTCTACCAGCTCTACTGCTGAATCTC




GSTSESPSGTAPGTS

CTGGTCCAGGTACCTCCCCGAGCGGTGAATCTTCTACTGCACCA




TPESGPXXXGASASG

GGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTAC




APSTXXXXSESPSGT

CAGCGAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCCCTG




APGSTSESPSGTAPG

AAAGCGGTCCXXXXXXXXXXXXTGCAAGCGCAAGCGGCGCGC




STSESPSGTAPGSTSE

CAAGCACGGGAXXXXXXXXTAGCGAATCTCCTTCTGGTACCGC




SPSGTAPGSTSESPSG

TCCAGGTTCTACCAGCGAATCCCCGTCTGGTACTGCTCCAGGTT




TAPGSTSESPSGTAP

CTACCAGCGAATCTCCTTCTGGTACTGCACCAGGTTCTACTAGC




GTSTPESGSASPGTSP

GAATCTCCTTCTGGTACCGCTCCAGGTTCTACCAGCGAATCCCC




SGESSTAPGTSPSGES

GTCTGGTACTGCTCCAGGTTCTACCAGCGAATCTCCTTCTGGTA




STAPGSTSSTAESPGP

CTGCACCAGGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCA




GTSPSGESSTAPGTS

GGTACTTCTCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTC




TPESGSASPGSTSESP

TCCTAGCGGCGAATCTTCTACTGCTCCAGGTTCTACCAGCTCTA




SGTAPGSTSESPSGT

CTGCTGAATCTCCGGGTCCAGGTACTTCCCCGAGCGGTGAATCT




APGTSPSGESSTAPG

TCTACTGCACCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTC




STSESPSGTAPGTSTP

TCCAGGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTT




ESGSASPGTSTPESGS

CTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTACTTCTCCT




ASPGSTSESPSGTAP

AGCGGCGAATCTTCTACCGCACCAGGTTCTACTAGCGAATCCCC




GTSTPESGSASPGSTS

GTCTGGTACCGCACCAGGTACTTCTACCCCGGAAAGCGGCTCTG




STAESPGPGSTSESPS

CTTCTCCAGGTACTTCTACCCCGGAAAGCGGCTCCGCATCTCCA




GTAPGSTSESPSGTA

GGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAGGTACTTC




PGTSPSGESSTAPGST

TACCCCTGAAAGCGGCTCCGCTTCTCCAGGTTCCACTAGCTCTA




SSTAESPGPGTSPSGE

CCGCTGAATCTCCGGGTCCAGGTTCTACCAGCGAATCTCCTTCT




SSTAPGTSTPESGSAS

GGCACCGCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACCGC




PGTSPSGESSTAPGTS

ACCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTT




PSGESSTAPGTSPSGE

CTACCAGCTCTACTGCTGAATCTCCGGGTCCAGGTACTTCCCCG




SSTAPGSTSSTAESPG

AGCGGTGAATCTTCTACTGCACCAGGTACTTCTACTCCGGAAAG




PGSTSSTAESPGPGTS

CGGTTCCGCTTCTCCAGGTACCTCCCCTAGCGGCGAATCTTCTA




PSGESSTAPGSSPSAS

CTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCA




TGTGPGSSTPSGATG

GGTACCTCCCCTAGCGGTGAATCTTCTACCGCACCAGGTTCTAC




SPGSSTPSGATGSPG

TAGCTCTACTGCTGAATCTCCGGGTCCAGGTTCTACCAGCTCTA




FPTIPLSRLFDNAML

CTGCTGAATCTCCTGGTCCAGGTACCTCCCCGAGCGGTGAATCT




RAHRLHQLAFDTYQ

TCTACTGCACCAGGTTCTAGCCCTTCTGCTTCCACCGGTACCGG




EFEEAYIPKEQKYSF

CCCAGGTAGCTCTACTCCGTCTGGTGCAACTGGCTCTCCAGGTA




LQNPQTSLCFSESIPT

GCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTTTTCCGACT




PSNREETQQKSNLEL

ATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCA




LRISLLLIQSWLEPVQ

CCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATTTGAAG




FLRSVFANSLVYGAS

AAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAAC




DSNVYDLLKDLEEGI

CCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTC




QTLMGRLEDGSPRT

CAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAACTACTC




GQIFKQTYSKFDTNS

CGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCA




HNDDALLKNYGLLY

ATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCAT




CFRKDMDKVETFLRI

CCGACAGCAACGTATACGATCTCCTGAAAGATCTCGAGGAAGG




VQCRSVEGSCGFGG

CATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTA




SEPATSGSETPGTSES

CTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGATACTAAC




ATPESGPGSEPATSG

AGCCACAATGACGATGCGCTTCTAAAAAACTATGGTCTGCTGT




SETPGSPAGSPTSTEE

ATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGCGT




GTSTEPSEGSAPGSE

ATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGG




PATSGSETPGSEPAT

TGGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACT




SGSETPGSEPATSGS

TCTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAACCTG




ETPGTSTEPSEGSAP

CTACCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCTCCG




GTSESATPESGPGSE

ACTTCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGGGTA




PATSGSETPGTSTEPS

GCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCC




EGSAP

AGGTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGTAGC






GAACCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTACCGA






ACCTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCAACC






CCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGA






GACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA



 


AG864-
GASPGTSSTGSPGSS
753
GGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTTCTAG
754


hGH-
PSASTGTGPGSSPSA

CCCGTCTGCTTCTACTGGTACTGGTCCAGGTTCTAGCCCTTCTGC



AE144
STGTGPGTPGSGTAS

TTCCACTGGTACTGGTCCAGGTACCCCGGGTAGCGGTACCGCTT




SSPGSSTPSGATGSP

CTTCTTCTCCAGGTAGCTCTACTCCGTCTGGTGCTACCGGCTCTC




GSNPSASTGTGPGAS

CAGGTTCTAACCCTTCTGCATCCACCGGTACCGGCCCAGGTGCT




PGTSSTGSPGTPGSG

TCTCCGGGCACCAGCTCTACTGGTTCTCCAGGTACCCCGGGCAG




TASSSPGSSTPSGAT

CGGTACCGCATCTTCTTCTCCAGGTAGCTCTACTCCTTCTGGTGC




GSPGTPGSGTASSSP

AACTGGTTCTCCAGGTACTCCTGGCAGCGGTACCGCTTCTTCTT




GASPGTSSTGSPGAS

CTCCAGGTGCTTCTCCTGGTACTAGCTCTACTGGTTCTCCAGGT




PGTSSTGSPGTPGSG

GCTTCTCCGGGCACTAGCTCTACTGGTTCTCCAGGTACCCCGGG




TASSSPGSSTPSGAT

TAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGG




GSPGASPGTSSTGSP

TGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAGCTCTACCG




GTPGSGTASSSPGSS

GTTCTCCAGGTACCCCGGGTAGCGGTACCGCTTCTTCTTCTCCA




TPSGATGSPGSNPSA

GGTAGCTCTACTCCGTCTGGTGCTACCGGCTCTCCAGGTTCTAA




STGTGPGSSPSASTG

CCCTTCTGCATCCACCGGTACCGGCCCAGGTTCTAGCCCTTCTG




TGPGSSTPSGATGSP

CTTCCACCGGTACTGGCCCAGGTAGCTCTACCCCTTCTGGTGCT




GSSTPSGATGSPGAS

ACCGGCTCCCCAGGTAGCTCTACTCCTTCTGGTGCAACTGGCTC




PGTSSTGSPGASPGT

TCCAGGTGCATCTCCGGGCACTAGCTCTACTGGTTCTCCAGGTG




SSTGSPGASPGTSST

CATCCCCTGGCACTAGCTCTACTGGTTCTCCAGGTGCTTCTCCT




GSPGTPGSGTASSSP

GGTACCAGCTCTACTGGTTCTCCAGGTACTCCTGGCAGCGGTAC




GASPGTSSTGSPGAS

CGCTTCTTCTTCTCCAGGTGCTTCTCCTGGTACTAGCTCTACTGG




PGTSSTGSPGASPGT

TTCTCCAGGTGCTTCTCCGGGCACTAGCTCTACTGGTTCTCCAG




SSTGSPGSSPSASTGT

GTGCTTCCCCGGGCACTAGCTCTACCGGTTCTCCAGGTTCTAGC




GPGTPGSGTASSSPG

CCTTCTGCATCTACTGGTACTGGCCCAGGTACTCCGGGCAGCGG




ASPGTSSTGSPGASP

TACTGCTTCTTCCTCTCCAGGTGCATCTCCGGGCACTAGCTCTA




GTSSTGSPGASPGTS

CTGGTTCTCCAGGTGCATCCCCTGGCACTAGCTCTACTGGTTCT




STGSPGSSTPSGATG

CCAGGTGCTTCTCCTGGTACCAGCTCTACTGGTTCTCCAGGTAG




SPGSSTPSGATGSPG

CTCTACTCCGTCTGGTGCAACCGGTTCCCCAGGTAGCTCTACTC




ASPGTSSTGSPGTPG

CTTCTGGTGCTACTGGCTCCCCAGGTGCATCCCCTGGCACCAGC




SGTASSSPGSSTPSG

TCTACCGGTTCTCCAGGTACCCCGGGCAGCGGTACCGCATCTTC




ATGSPGSSTPSGATG

CTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACCGGTTCCCCAG




SPGSSTPSGATGSPG

GTAGCTCTACCCCGTCTGGTGCAACCGGCTCCCCAGGTAGCTCT




SSPSASTGTGPGASP

ACTCCGTCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGC




GTSSTGSPGASPGTS

TTCCACTGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTA




STGSPGTPGSGTASS

CTGGTTCTCCAGGTGCATCCCCGGGTACCAGCTCTACCGGTTCT




SPGASPGTSSTGSPG

CCAGGTACTCCTGGCAGCGGTACTGCATCTTCCTCTCCAGGTGC




ASPGTSSTGSPGASP

TTCTCCGGGCACCAGCTCTACTGGTTCTCCAGGTGCATCTCCGG




GTSSTGSPGASPGTS

GCACTAGCTCTACTGGTTCTCCAGGTGCATCCCCTGGCACTAGC




STGSPGTPGSGTASS

TCTACTGGTTCTCCAGGTGCTTCTCCTGGTACCAGCTCTACTGGT




SPGSSTPSGATGSPG

TCTCCAGGTACCCCTGGTAGCGGTACTGCTTCTTCCTCTCCAGG




TPGSGTASSSPGSSTP

TAGCTCTACTCCGTCTGGTGCTACCGGTTCTCCAGGTACCCCGG




SGATGSPGTPGSGTA

GTAGCGGTACCGCATCTTCTTCTCCAGGTAGCTCTACCCCGTCT




SSSPGSSTPSGATGSP

GGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTGCTTC




GSSTPSGATGSPGSS

TTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCC




PSASTGTGPGSSPSA

AGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCCCCAGGTTCTA




STGTGPGASPGTSST

GCCCTTCTGCATCCACCGGTACCGGTCCAGGTTCTAGCCCGTCT




GSPGTPGSGTASSSP

GCATCTACTGGTACTGGTCCAGGTGCATCCCCGGGCACTAGCTC




GSSTPSGATGSPGSS

TACCGGTTCTCCAGGTACTCCTGGTAGCGGTACTGCTTCTTCTTC




PSASTGTGPGSSPSA

TCCAGGTAGCTCTACTCCTTCTGGTGCTACTGGTTCTCCAGGTTC




STGTGPGASPGTSST

TAGCCCTTCTGCATCCACCGGTACCGGCCCAGGTTCTAGCCCGT




GSPGASPGTSSTGSP

CTGCTTCTACCGGTACTGGTCCAGGTGCTTCTCCGGGTACTAGC




GSSTPSGATGSPGSS

TCTACTGGTTCTCCAGGTGCATCTCCTGGTACTAGCTCTACTGG




PSASTGTGPGASPGT

TTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCTCCAG




SSTGSPGSSPSASTGT

GTTCTAGCCCTTCTGCATCTACCGGTACTGGTCCAGGTGCATCC




GPGTPGSGTASSSPG

CCTGGTACCAGCTCTACCGGTTCTCCAGGTTCTAGCCCTTCTGC




SSTPSGATGSPGSSTP

TTCTACCGGTACCGGTCCAGGTACCCCTGGCAGCGGTACCGCAT




SGATGSPGASPGTSS

CTTCCTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGTTCC




TGSPGFPTIPLSRLFD

CCAGGTAGCTCTACTCCTTCTGGTGCTACTGGCTCCCCAGGTGC




NAMLRAHRLHQLAF

ATCCCCTGGCACCAGCTCTACCGGTTCTCCAGGTTTTCCGACTA




DTYQEFEEAYIPKEQ

TTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCAC




KYSFLQNPQTSLCFS

CGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGA




ESIPTPSNREETQQKS

AGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACC




NLELLRISLLLIQSWL

CACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCC




EPVQFLRSVFANSLV

AATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAACTACTCC




YGASDSNVYDLLKD

GCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAA




LEEGIQTLMGRLEDG

TTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCC




SPRTGQIFKQTYSKF

GACAGCAACGTATACGATCTCCTGAAAGATCTCGAGGAAGGCA




DTNSHNDDALLKNY

TTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACT




GLLYCFRKDMDKVE

GGTCAGATCTTCAAGCAGACTTACTCTAAATTTGATACTAACAG




TFLRIVQCRSVEGSC

CCACAATGACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATT




GFGGSEPATSGSETP

GTTTTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGCGTATT




GTSESATPESGPGSE

GTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGG




PATSGSETPGSPAGS

TAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACTTCTG




PTSTEEGTSTEPSEGS

AAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTAC




APGSEPATSGSETPG

CTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCTCCGACTT




SEPATSGSETPGSEP

CCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGGGTAGCGC




ATSGSETPGTSTEPSE

TCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAGGT




GSAPGTSESATPESG

AGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGTAGCGAAC




PGSEPATSGSETPGT

CGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTACCGAACCT




STEPSEGSAP

TCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTG






AATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACT






CCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA



 


AM875-
GTSTEPSEGSAPGSE
755
GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCAGGTAGCG
756


hGH-
PATSGSETPGSPAGS

AACCGGCTACTTCCGGTTCTGAAACCCCAGGTAGCCCAGCAGG



AE144
PTSTEEGSTSSTAESP

TTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCAG




GPGTSTPESGSASPG

AATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCA




STSESPSGTAPGSTSE

TCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGG




SPSGTAPGTSTPESGS

TTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTA




ASPGTSTPESGSASP

CTCCTGAAAGCGGTTCCGCTTCTCCAGGTACCTCTACTCCGGAA




GSEPATSGSETPGTS

AGCGGTTCTGCATCTCCAGGTAGCGAACCGGCAACCTCCGGCT




ESATPESGPGSPAGS

CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCCGG




PTSTEEGTSTEPSEGS

CCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGT




APGTSESATPESGPG

ACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGA




TSTEPSEGSAPGTSTE

AAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGT




PSEGSAPGSPAGSPT

CCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGG




STEEGTSTEPSEGSAP

TAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAG




GTSTEPSEGSAPGTS

GAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTA




ESATPESGPGTSESA

CTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAA




TPESGPGTSTEPSEGS

AGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTA




APGTSTEPSEGSAPG

CTCCTGAATCCGGTCCAGGTACCTCTACTGAACCTTCCGAAGGC




TSESATPESGPGTSTE

AGCGCTCCAGGTACCTCTACCGAACCGTCCGAGGGCAGCGCAC




PSEGSAPGSEPATSG

CAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAC




SETPGSPAGSPTSTEE

TTCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCGAACCTG




GSSTPSGATGSPGTP

CTACTTCTGGTTCTGAAACCCCAGGTAGCCCGGCTGGCTCTCCG




GSGTASSSPGSSTPS

ACCTCCACCGAGGAAGGTAGCTCTACCCCGTCTGGTGCTACTGG




GATGSPGTSTEPSEG

TTCTCCAGGTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAG




SAPGTSTEPSEGSAP

GTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTACCTCT




GSEPATSGSETPGSP

ACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAAC




AGSPTSTEEGSPAGS

CGTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCCGG




PTSTEEGTSTEPSEGS

TTCTGAAACTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTG




APGASASGAPSTGGT

AGGAAGGTAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGG




SESATPESGPGSPAG

TACTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTGCAAGC




SPTSTEEGSPAGSPTS

GCAAGCGGCGCGCCAAGCACGGGAGGTACTTCTGAAAGCGCTA




TEEGSTSSTAESPGP

CTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCC




GSTSESPSGTAPGTSP

ACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAG




SGESSTAPGTPGSGT

AAGGTTCTACCAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCT




ASSSPGSSTPSGATG

ACTAGCGAATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTAG




SPGSSPSASTGTGPG

CGGTGAATCTTCTACTGCACCAGGTACCCCTGGCAGCGGTACCG




SEPATSGSETPGTSES

CTTCTTCCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGCT




ATPESGPGSEPATSG

CTCCAGGTTCTAGCCCGTCTGCATCTACCGGTACCGGCCCAGGT




SETPGSTSSTAESPGP

AGCGAACCGGCAACCTCCGGCTCTGAAACTCCAGGTACTTCTG




GSTSSTAESPGPGTSP

AAAGCGCTACTCCGGAATCCGGCCCAGGTAGCGAACCGGCTAC




SGESSTAPGSEPATS

TTCCGGCTCTGAAACCCCAGGTTCCACCAGCTCTACTGCAGAAT




GSETPGSEPATSGSE

CTCCGGGCCCAGGTTCTACTAGCTCTACTGCAGAATCTCCGGGT




TPGTSTEPSEGSAPG

CCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTAG




STSSTAESPGPGTSTP

CGAACCGGCAACCTCTGGCTCTGAAACTCCAGGTAGCGAACCT




ESGSASPGSTSESPSG

GCAACCTCCGGCTCTGAAACCCCAGGTACTTCTACTGAACCTTC




TAPGTSTEPSEGSAP

TGAGGGCAGCGCACCAGGTTCTACCAGCTCTACCGCAGAATCT




GTSTEPSEGSAPGTS

CCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCC




TEPSEGSAPGSSTPSG

AGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTACTT




ATGSPGSSPSASTGT

CTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTACTGA




GPGASPGTSSTGSPG

ACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTCTG




SEPATSGSETPGTSES

AAGGTAGCGCACCAGGTAGCTCTACTCCGTCTGGTGCAACCGG




ATPESGPGSPAGSPT

CTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAG




STEEGSSTPSGATGS

GTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTAGCGAA




PGSSPSASTGTGPGA

CCTGCTACCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGC




SPGTSSTGSPGTSESA

AACTCCGGAGTCTGGTCCAGGTAGCCCTGCAGGTTCTCCTACCT




TPESGPGTSTEPSEGS

CCACTGAGGAAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCC




APGTSTEPSEGSAPG

CCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAGGTGC




FPTIPLSRLFDNAML

TTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTACCTCTGAAA




RAHRLHQLAFDTYQ

GCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGTCT




EFEEAYIPKEQKYSF

GAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTA




LQNPQTSLCFSESIPT

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




PSNREETQQKSNLEL

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




LRISLLLIQSWLEPVQ

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




FLRSVFANSLVYGAS

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




DSNVYDLLKDLEEGI

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




QTLMGRLEDGSPRT

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




GQIFKQTYSKFDTNS

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAA




HNDDALLKNYGLLY

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




CFRKDMDKVETFLRI

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




VQCRSVEGSCGFGG

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT




SEPATSGSETPGTSES

ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA




ATPESGPGSEPATSG

AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA




SETPGSPAGSPTSTEE

AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG




GTSTEPSEGSAPGSE

GCAGCTGTGGTTTCTAAGGTGGTAGCGAACCGGCAACTTCCGG




PATSGSETPGSEPAT

CTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCTG




SGSETPGSEPATSGS

GCCCAGGTAGCGAACCTGCTACCTCTGGCTCTGAAACCCCAGG




ETPGTSTEPSEGSAP

TAGCCCGGCAGGCTCTCCGACTTCCACCGAGGAAGGTACCTCT




GTSESATPESGPGSE

ACTGAACCTTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAA




PATSGSETPGTSTEPS

CCTCTGGCTCTGAAACCCCAGGTAGCGAACCTGCTACCTCCGGC




EGSAP

TCTGAAACTCCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAAC






TCCAGGTACCTCTACCGAACCTTCCGAAGGCAGCGCACCAGGT






ACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAAC






CGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCG






TCCGAAGGTAGCGCACCA



 


AE912-
MAEPAGSPTSTEEGT
757
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
758


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



AE144
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG




GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




TSESATPESGPGSEP

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




ATSGSETPGTSESAT

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




PESGPGSEPATSGSE

GCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




TPGTSESATPESGPG

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




TSTEPSEGSAPGSPA

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSPTSTEEGTSESATP

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




ESGPGSEPATSGSET

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




PGTSESATPESGPGSP

CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




AGSPTSTEEGSPAGS

GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA




PTSTEEGTSTEPSEGS

GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGA




APGTSESATPESGPG

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




TSESATPESGPGTSES

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




ATPESGPGSEPATSG

ACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCAC




SETPGSEPATSGSETP

CAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT




GSPAGSPTSTEEGTS

TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAG




TEPSEGSAPGTSTEPS

CGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCT




EGSAPGSEPATSGSE

GGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTG




TPGTSESATPESGPG

AAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA




TSTEPSEGSAPGFPTI

AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACC




PLSRLFDNAMLRAH

TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTG




RLHQLAFDTYQEFEE

CAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT




AYIPKEQKYSFLQNP

CCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCA




QTSLCFSESIPTPSNR

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




EETQQKSNLELLRIS

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




LLLIQSWLEPVQFLR

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




SVFANSLVYGASDS

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




NVYDLLKDLEEGIQT

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




LMGRLEDGSPRTGQI

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




FKQTYSKFDTNSHN

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAA




DDALLKNYGLLYCF

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




RKDMDKVETFLRIV

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




QCRSVEGSCGFGGTS

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT




ESATPESGPGTSTEPS

ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA




EGSAPGTSTEPSEGS

AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA




APGTSESATPESGPG

AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG




TSTEPSEGSAPGTSTE

GCAGCTGTGGTTTCTAAGGTGGTAGCGAACCGGCAACTTCCGG




PSEGSAPGTSESATP

CTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCTG




ESGPGTSTEPSEGSA

GCCCAGGTAGCGAACCTGCTACCTCTGGCTCTGAAACCCCAGG




PGTSTEPSEGSAPGT

TAGCCCGGCAGGCTCTCCGACTTCCACCGAGGAAGGTACCTCT




STEPSEGSAPGSPAG

ACTGAACCTTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAA




SPTSTEEGTSTEPSEG

CCTCTGGCTCTGAAACCCCAGGTAGCGAACCTGCTACCTCCGGC




SAPG

TCTGAAACTCCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAAC






TCCAGGTACCTCTACCGAACCTTCCGAAGGCAGCGCACCAGGT






ACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAAC






CGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCG






TCCGAAGGTAGCGCACCA



 


AM923-
MAEPAGSPTSTEEGA
759
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
760


hGH-
SPGTSSTGSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



AE144
GATGSPGSSTPSGAT

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG




GSPGTSTEPSEGSAP

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GSEPATSGSETPGSP

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




AGSPTSTEEGSTSST

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




AESPGPGTSTPESGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




ASPGSTSESPSGTAP

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




GSTSESPSGTAPGTS

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




TPESGSASPGTSTPES

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSASPGSEPATSGSE

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




TPGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




SPAGSPTSTEEGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGTSESATP

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




ESGPGTSTEPSEGSA

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




PGTSTEPSEGSAPGSP

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




AGSPTSTEEGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSTEPSEGS

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




APGTSESATPESGPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSESATPESGPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSTEPSE

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




GSAPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGTSTEPSEGSAPGS

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




EPATSGSETPGSPAG

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




SPTSTEEGSSTPSGAT

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




GSPGTPGSGTASSSP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GSSTPSGATGSPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGSEPATSGSE

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




TPGSPAGSPTSTEEG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGASASGAP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




STGGTSESATPESGP

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




GSPAGSPTSTEEGSP

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




AGSPTSTEEGSTSST

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




AESPGPGSTSESPSGT

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




APGTSPSGESSTAPG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




TPGSGTASSSPGSSTP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




SGATGSPGSSPSAST

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




GTGPGSEPATSGSET

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




PGTSESATPESGPGS

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




EPATSGSETPGSTSST

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




AESPGPGSTSSTAESP

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




GPGTSPSGESSTAPG

GCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




SEPATSGSETPGSEP

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATSGSETPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGSTSSTAESPG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGTSTPESGSASPGST

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




SESPSGTAPGTSTEPS

CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




EGSAPGTSTEPSEGS

GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA




APGTSTEPSEGSAPG

GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGA




SSTPSGATGSPGSSPS

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




ASTGTGPGASPGTSS

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




TGSPGSEPATSGSET

ACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCAC




PGTSESATPESGPGSP

CAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT




AGSPTSTEEGSSTPS

TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAG




GATGSPGSSPSASTG

CGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCT




TGPGASPGTSSTGSP

GGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTG




GTSESATPESGPGTS

AAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA




TEPSEGSAPGTSTEPS

AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACC




EGSAPGFPTIPLSRLF

TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTG




DNAMLRAHRLHQL

CAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT




AFDTYQEFEEAYIPK

CCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCA




EQKYSFLQNPQTSLC

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




FSESIPTPSNREETQQ

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




KSNLELLRISLLLIQS

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




WLEPVQFLRSVFAN

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




SLVYGASDSNVYDL

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




LKDLEEGIQTLMGRL

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




EDGSPRTGQIFKQTY

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTgTTCGCCAA




SKFDTNSHNDDALL

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




KNYGLLYCFRKDMD

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




KVETFLRIVQCRSVE

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT




GSCGFGGSEPATSGS

ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA




ETPGTSESATPESGP

AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA




GSEPATSGSETPGSP

AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG




AGSPTSTEEGTSTEPS

GCAGCTGTGGTTTCGGAGGTACTTCTGAAAGCGCTACTCCGGA




EGSAPGSEPATSGSE

GTCCGGTCCAGGTACCTCTACCGAACCGTCCGAAGGCAGCGCT




TPGSEPATSGSETPG

CCAGGTACTTCTACTGAACCTTCTGAGGGTAGCGCTCCAGGTAC




SEPATSGSETPGTSTE

TTCTGAAAGCGCTACTCCGGAGTCCGGTCCAGGTACCTCTACCG




PSEGSAPGTSESATP

AACCGTCCGAAGGCAGCGCTCCAGGTACTTCTACTGAACCTTCT




ESGPGSEPATSGSET

GAGGGTAGCGCTCCAGGTACCTCTGAAAGCGCTACTCCGGAGT




PGTSTEPSEGSAP

CTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCA






GGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTC






TACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGT






TCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGA






GGGTAGCGCACCAGGTTAA



 


AM1318-
GTSTEPSEGSAPGSE
761
GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCAGGTAGCG
762


hGH-
PATSGSETPGSPAGS

AACCGGCTACTTCCGGTTCTGAAACCCCAGGTAGCCCAGCAGG



AE144
PTSTEEGSTSSTAESP

TTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCAG




GPGTSTPESGSASPG

AATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCA




STSESPSGTAPGSTSE

TCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGG




SPSGTAPGTSTPESGS

TTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTA




ASPGTSTPESGSASP

CTCCTGAAAGCGGTTCCGCTTCTCCAGGTACCTCTACTCCGGAA




GSEPATSGSETPGTS

AGCGGTTCTGCATCTCCAGGTAGCGAACCGGCAACCTCCGGCT




ESATPESGPGSPAGS

CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCCGG




PTSTEEGTSTEPSEGS

CCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGT




APGTSESATPESGPG

ACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGA




TSTEPSEGSAPGTSTE

AAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGT




PSEGSAPGSPAGSPT

CCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGG




STEEGTSTEPSEGSAP

TAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAG




GTSTEPSEGSAPGTS

GAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTA




ESATPESGPGTSESA

CTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAA




TPESGPGTSTEPSEGS

AGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTA




APGTSTEPSEGSAPG

CTCCTGAATCCGGTCCAGGTACCTCTACTGAACCTTCCGAAGGC




TSESATPESGPGTSTE

AGCGCTCCAGGTACCTCTACCGAACCGTCCGAGGGCAGCGCAC




PSEGSAPGSEPATSG

CAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAC




SETPGSPAGSPTSTEE

TTCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCGAACCTG




GSSTPSGATGSPGTP

CTACTTCTGGTTCTGAAACCCCAGGTAGCCCGGCTGGCTCTCCG




GSGTASSSPGSSTPS

ACCTCCACCGAGGAAGGTAGCTCTACCCCGTCTGGTGCTACTGG




GATGSPGTSTEPSEG

TTCTCCAGGTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAG




SAPGTSTEPSEGSAP

GTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTACCTCT




GSEPATSGSETPGSP

ACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAAC




AGSPTSTEEGSPAGS

CGTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCCGG




PTSTEEGTSTEPSEGS

TTCTGAAACTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTG




APGPEPTGPAPSGGS

AGGAAGGTAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGG




EPATSGSETPGTSES

TACTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTCCAGAAC




ATPESGPGSPAGSPT

CAACGGGGCCGGCCCCAAGCGGAGGTAGCGAACCGGCAACCTC




STEEGTSESATPESGP

CGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAAT




GSPAGSPTSTEEGSP

CCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGA




AGSPTSTEEGTSESA

AGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGC




TPESGPGSPAGSPTST

CCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTG




EEGSPAGSPTSTEEG

GCTCTCCAACTTCTACTGAAGAAGGTACTTCTGAAAGCGCTACT




STSSTAESPGPGSTSE

CCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCAC




SPSGTAPGTSPSGESS

CGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAA




TAPGSTSESPSGTAP

GGTTCTACCAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCTAC




GSTSESPSGTAPGTSP

TAGCGAATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTAGCG




SGESSTAPGTSTEPSE

GTGAATCTTCTACTGCACCAGGTTCTACCAGCGAATCTCCTTCT




GSAPGTSESATPESG

GGCACCGCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACCGC




PGTSESATPESGPGS

ACCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTA




EPATSGSETPGTSES

CTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAA




ATPESGPGTSESATP

AGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTA




ESGPGTSTEPSEGSA

CTCCTGAATCCGGTCCAGGTAGCGAACCGGCAACCTCTGGCTCT




PGTSESATPESGPGT

GAAACCCCAGGTACCTCTGAAAGCGCTACTCCGGAATCTGGTC




STEPSEGSAPGTSPSG

CAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGTCCAGGTAC




ESSTAPGTSPSGESST

CTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAA




APGTSPSGESSTAPG

GCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCC




TSTEPSEGSAPGSPA

GAAGGTAGCGCACCAGGTACCTCCCCTAGCGGCGAATCTTCTA




GSPTSTEEGTSTEPSE

CTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCA




GSAPGSSPSASTGTG

GGTACCTCCCCTAGCGGTGAATCTTCTACCGCACCAGGTACTTC




PGSSTPSGATGSPGS

TACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGT




STPSGATGSPGSSTPS

TCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGA




GATGSPGSSTPSGAT

GGGTAGCGCACCAGGTTCTAGCCCTTCTGCTTCCACCGGTACCG




GSPGASPGTSSTGSP

GCCCAGGTAGCTCTACTCCGTCTGGTGCAACTGGCTCTCCAGGT




GASASGAPSTGGTSP

AGCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTAGCTCTAC




SGESSTAPGSTSSTA

CCCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTG




ESPGPGTSPSGESSTA

GTGCAACCGGCTCCCCAGGTGCATCCCCGGGTACTAGCTCTACC




PGTSESATPESGPGT

GGTTCTCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAG




STEPSEGSAPGTSTEP

GTACTTCTCCGAGCGGTGAATCTTCTACCGCACCAGGTTCTACT




SEGSAPGSSPSASTG

AGCTCTACCGCTGAATCTCCGGGCCCAGGTACTTCTCCGAGCGG




TGPGSSTPSGATGSP

TGAATCTTCTACTGCTCCAGGTACCTCTGAAAGCGCTACTCCGG




GASPGTSSTGSPGTS

AGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCT




TPESGSASPGTSPSGE

CCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTT




SSTAPGTSPSGESSTA

CTAGCCCTTCTGCATCTACTGGTACTGGCCCAGGTAGCTCTACT




PGTSESATPESGPGS

CCTTCTGGTGCTACCGGCTCTCCAGGTGCTTCTCCGGGTACTAG




EPATSGSETPGTSTEP

CTCTACCGGTTCTCCAGGTACTTCTACTCCGGAAAGCGGTTCCG




SEGSAPGSTSESPSGT

CATCTCCAGGTACTTCTCCTAGCGGTGAATCTTCTACTGCTCCA




APGSTSESPSGTAPG

GGTACCTCTCCTAGCGGCGAATCTTCTACTGCTCCAGGTACTTC




TSTPESGSASPGSPA

TGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCT




GSPTSTEEGTSESATP

ACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGA




ESGPGTSTEPSEGSA

AGGTAGCGCACCAGGTTCTACCAGCGAATCCCCTTCTGGTACTG




PGSPAGSPTSTEEGT

CTCCAGGTTCTACCAGCGAATCCCCTTCTGGCACCGCACCAGGT




SESATPESGPGSEPA

ACTTCTACCCCTGAAAGCGGCTCCGCTTCTCCAGGTAGCCCGGC




TSGSETPGSSTPSGA

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




TGSPGASPGTSSTGS

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




PGSSTPSGATGSPGS

GCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGA




TSESPSGTAPGTSPSG

AGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGT




ESSTAPGSTSSTAESP

AGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTAGCTCTA




GPGSSTPSGATGSPG

CCCCGTCTGGTGCTACCGGTTCCCCAGGTGCTTCTCCTGGTACT




ASPGTSSTGSPGTPG

AGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTGGTGCTAC




SGTASSSPGSPAGSP

TGGCTCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACTGCTC




TSTEEGSPAGSPTSTE

CAGGTACTTCCCCTAGCGGTGAATCTTCTACTGCTCCAGGTTCT




EGTSTEPSEGSAPGF

ACCAGCTCTACCGCAGAATCTCCGGGTCCAGGTAGCTCTACCCC




PTIPLSRLFDNAMLR

TTCTGGTGCAACCGGCTCTCCAGGTGCATCCCCGGGTACCAGCT




AHRLHQLAFDTYQE

CTACCGGTTCTCCAGGTACTCCGGGTAGCGGTACCGCTTCTTCC




FEEAYIPKEQKYSFL

TCTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTGAGGAAGG




QNPQTSLCFSESIPTP

TAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGGTACTTCTA




SNREETQQKSNLELL

CCGAACCTTCCGAAGGTAGCGCTCCAGGTTTTCCGACTATTCCG




RISLLLIQSWLEPVQF

CTGTCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCT




LRSVFANSLVYGAS

GCACCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcT




DSNVYDLLKDLEEGI

ACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACA




QTLMGRLEDGSPRT

GACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATC




GQIFKQTYSKFDTNS

GCGAGGAAACTCAGCAAAAGTCCAATCTGGAACTACTCCGCAT




HNDDALLKNYGLLY

TTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTC




CFRKDMDKVETFLRI

TGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCCGAC




VQCRSVEGSCGFGG

AGCAACGTATACGATCTCCTGAAAGATCTCGAGGAAGGCATTC




SEPATSGSETPGTSES

AGACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGT




ATPESGPGSEPATSG

CAGATCTTCAAGCAGACTTACTCTAAATTTGATACTAACAGCCA




SETPGSPAGSPTSTEE

CAATGACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTT




GTSTEPSEGSAPGSE

TTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGCGTATTGTT




PATSGSETPGSEPAT

CAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTAG




SGSETPGSEPATSGS

CGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACTTCTGAA




ETPGTSTEPSEGSAP

AGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTC




GTSESATPESGPGSE

TGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCTCCGACTTCCA




PATSGSETPGTSTEPS

CCGAGGAAGGTACCTCTACTGAACCTTCTGAGGGTAGCGCTCC




EGSAP

AGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAGGTAGC






GAACCTGCTACCTCCGGCTCTGAAACTCCAGGTAGCGAACCGG






CTACTTCCGGTTCTGAAACTCCAGGTACCTCTACCGAACCTTCC






GAAGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAAT






CCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCA






GGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA



 


AE48-
MAEPAGSPTSTEEGT
763
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
764


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



AE288
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG




GSPGFPTIPLSRLFDN

CTCTACCGGTTCTCCAGGTTTTCCGACTATTCCGCTGTCTCGTCT




AMLRAHRLHQLAFD

GTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGG




TYQEFEEAYIPKEQK

CCTTTGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAA




YSFLQNPQTSLCFSE

GAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTG




SIPTPSNREETQQKS

CTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTC




NLELLRISLLLIQSWL

AGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTG




EPVQFLRSVFANSLV

ATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTT




YGASDSNVYDLLKD

CGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATAC




LEEGIQTLMGRLEDG

GATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGG




SPRTGQIFKQTYSKF

GTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAG




DTNSHNDDALLKNY

CAGACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGC




GLLYCFRKDMDKVE

GCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATA




TFLRIVQCRSVEGSC

TGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCC




GFGGTSESATPESGP

GTTGAGGGCAGCTGTGGTTTCTAAGGTGGTACCTCTGAAAGCG




GSEPATSGSETPGTS

CAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGC




ESATPESGPGSEPAT

TCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTG




SGSETPGTSESATPES

GTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGG




GPGTSTEPSEGSAPG

TACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTA




SPAGSPTSTEEGTSES

CTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGCTGGCTC




ATPESGPGSEPATSG

TCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCT




SETPGTSESATPESGP

GAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAA




GSPAGSPTSTEEGSP

CCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGT




AGSPTSTEEGTSTEPS

AGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGG




EGSAPGTSESATPES

CTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTACCGAACCT




GPGTSESATPESGPG

TCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTG




TSESATPESGPGSEP

AGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGT




ATSGSETPGSEPATS

CCAGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTA




GSETPGSPAGSPTST

GCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACC




EEGTSTEPSEGSAPG

GGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCAGCAGGCTCTC




TSTEPSEGSAPGSEP

CGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGC




ATSGSETPGTSESAT

AGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTC




PESGPGTSTEPSEGS

CAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTAC




AP

CTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTG






AACCGTCCGAGGGCAGCGCACCA



 


AM48-
MAEPAGSPTSTEEGA
765
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTG
766


hGH-
SPGTSSTGSPGSSTPS

CATCCCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACC



AE288
GATGSPGSSTPSGAT

CCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGG




GSPGFPTIPLSRLFDN

TGCTACTGGCTCTCCAGGTTTTCCGACTATTCCGCTGTCTCGTCT




AMLRAHRLHQLAFD

GTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGG




TYQEFEEAYIPKEQK

CCTTTGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAA




YSFLQNPQTSLCFSE

GAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTG




SIPTPSNREETQQKS

CTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTC




NLELLRISLLLIQSWL

AGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTG




EPVQFLRSVFANSLV

ATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTT




YGASDSNVYDLLKD

CGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATAC




LEEGIQTLMGRLEDG

GATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGG




SPRTGQIFKQTYSKF

GTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAG




DTNSHNDDALLKNY

CAGACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGC




GLLYCFRKDMDKVE

GCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATA




TFLRIVQCRSVEGSC

TGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCC




GFGGTSESATPESGP

GTTGAGGGCAGCTGTGGTTTCTAAGGTGGTACCTCTGAAAGCG




GSEPATSGSETPGTS

CAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGC




ESATPESGPGSEPAT

TCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTG




SGSETPGTSESATPES

GTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGG




GPGTSTEPSEGSAPG

TACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTA




SPAGSPTSTEEGTSES

CTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGCTGGCTC




ATPESGPGSEPATSG

TCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCT




SETPGTSESATPESGP

GAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAA




GSPAGSPTSTEEGSP

CCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGT




AGSPTSTEEGTSTEPS

AGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGG




EGSAPGTSESATPES

CTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTACCGAACCT




GPGTSESATPESGPG

TCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTG




TSESATPESGPGSEP

AGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGT




ATSGSETPGSEPATS

CCAGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTA




GSETPGSPAGSPTST

GCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACC




EEGTSTEPSEGSAPG

GGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCAGCAGGCTCTC




TSTEPSEGSAPGSEP

CGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGC




ATSGSETPGTSESAT

AGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTC




PESGPGTSTEPSEGS

CAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTAC




AP

CTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTG






AACCGTCCGAGGGCAGCGCACCA



 


AE144-
GSEPATSGSETPGTS
767
GGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACTT
768


hGH-
ESATPESGPGSEPAT

CTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAACCTGC



AE288
SGSETPGSPAGSPTST

TACCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCTCCGA




EEGTSTEPSEGSAPG

CTTCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGGGTAGC




SEPATSGSETPGSEP

GCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAG




ATSGSETPGSEPATS

GTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGTAGCGA




GSETPGTSTEPSEGS

ACCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTACCGAAC




APGTSESATPESGPG

CTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCC




SEPATSGSETPGTSTE

TGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAG




PSEGSAPGFPTIPLSR

ACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAG




LFDNAMLRAHRLHQ

GTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGC




LAFDTYQEFEEAYIP

TGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAG




KEQKYSFLQNPQTSL

GAATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTT




CFSESIPTPSNREETQ

CCTGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTC




QKSNLELLRISLLLIQ

CGACGCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCT




SWLEPVQFLRSVFA

GGAACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAG




NSLVYGASDSNVYD

AACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTT




LLKDLEEGIQTLMGR

TATGGCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATC




LEDGSPRTGQIFKQT

TCGAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGG




YSKFDTNSHNDDAL

CTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAAT




LKNYGLLYCFRKDM

TTGATACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTA




DKVETFLRIVQCRSV

TGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAA




EGSCGFGGTSESATP

CCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGT




ESGPGSEPATSGSET

GGTTTCTAAGGTGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




PGTSESATPESGPGS

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




EPATSGSETPGTSES

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




ATPESGPGTSTEPSE

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




GSAPGSPAGSPTSTE

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




EGTSESATPESGPGS

CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




EPATSGSETPGTSES

GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA




ATPESGPGSPAGSPT

GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGA




STEEGSPAGSPTSTEE

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




GTSTEPSEGSAPGTS

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




ESATPESGPGTSESA

ACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCAC




TPESGPGTSESATPES

CAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT




GPGSEPATSGSETPG

TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAG




SEPATSGSETPGSPA

CGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCT




GSPTSTEEGTSTEPSE

GGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTG




GSAPGTSTEPSEGSA

AAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA




PGSEPATSGSETPGT

AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACC




SESATPESGPGTSTEP

TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTG




SEGSAP

CAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT






CCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCA






GCGCACCA



 


AE288-
GTSESATPESGPGSE
769
GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCG
770


hGH-
PATSGSETPGTSESA

AACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGC



AE288
TPESGPGSEPATSGS

GCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTG




ETPGTSESATPESGP

GCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCT




GTSTEPSEGSAPGSP

GGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAG




AGSPTSTEEGTSESA

GTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT




TPESGPGSEPATSGS

GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAA




ETPGTSESATPESGP

CCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCT




GSPAGSPTSTEEGSP

GAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCG




AGSPTSTEEGTSTEPS

AGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGG




EGSAPGTSESATPES

TACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTG




GPGTSESATPESGPG

AAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGC




TSESATPESGPGSEP

TACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGG




ATSGSETPGSEPATS

AATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACC




GSETPGSPAGSPTST

CCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTA




EEGTSTEPSEGSAPG

GCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACT




TSTEPSEGSAPGSEP

GAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTT




ATSGSETPGTSESAT

CTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTC




PESGPGTSTEPSEGS

TGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCC




APGFPTIPLSRLFDNA

CAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTTTT




MLRAHRLHQLAFDT

CCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGT




YQEFEEAYIPKEQKY

GCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATT




SFLQNPQTSLCFSESI

TGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGC




PTPSNREETQQKSNL

AAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACG




ELLRISLLLIQSWLEP

CCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAAC




VQFLRSVFANSLVY

TACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCA




GASDSNVYDLLKDL

GTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGG




EEGIQTLMGRLEDGS

CGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTCGAG




PRTGQIFKQTYSKFD

GAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTC




TNSHNDDALLKNYG

CGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGAT




LLYCFRKDMDKVET

ACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATGGTC




FLRIVQCRSVEGSCG

TGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTTC




FGGTSESATPESGPG

CTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTT




SEPATSGSETPGTSES

CTAAGGTGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA




ATPESGPGSEPATSG

GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTC




SETPGTSESATPESGP

TGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCA




GTSTEPSEGSAPGSP

ACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCC




AGSPTSTEEGTSESA

TGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGC




TPESGPGSEPATSGS

GCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAG




ETPGTSESATPESGP

GTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGA




GSPAGSPTSTEEGSP

ACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGC




AGSPTSTEEGTSTEPS

GCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGAC




EGSAPGTSESATPES

TTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTG




GPGTSESATPESGPG

AAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGG




TSESATPESGPGSEP

TACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTG




ATSGSETPGSEPATS

AAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCT




GSETPGSPAGSPTST

ACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTC




EEGTSTEPSEGSAPG

TGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACT




TSTEPSEGSAPGSEP

CCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTA




ATSGSETPGTSESAT

CTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACT




PESGPGTSTEPSEGS

GAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCT




AP

CTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAA






TCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCAC






CA



 


AF144-
GTSTPESGSASPGTSP
771
GGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTACTTC
772


hGH-
SGESSTAPGTSPSGES

TCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCG



AE288
STAPGSTSSTAESPGP

GCGAATCTTCTACTGCTCCAGGTTCTACCAGCTCTACCGCTGAA




GSTSESPSGTAPGSTS

TCTCCTGGCCCAGGTTCTACCAGCGAATCCCCGTCTGGCACCGC




STAESPGPGTSPSGES

ACCAGGTTCTACTAGCTCTACCGCAGAATCTCCGGGTCCAGGTA




STAPGTSTPESGSASP

CTTCCCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTACT




GSTSSTAESPGPGTSP

CCGGAAAGCGGCTCCGCATCTCCAGGTTCTACTAGCTCTACTGC




SGESSTAPGTSPSGES

TGAATCTCCTGGTCCAGGTACCTCCCCTAGCGGCGAATCTTCTA




STAPGTSPSGESSTAP

CTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCA




GFPTIPLSRLFDNAM

GGTACCTCCCCTAGCGGTGAATCTTCTACCGCACCAGGTTTTCC




LRAHRLHQLAFDTY

GACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGTG




QEFEEAYIPKEQKYS

CGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATTT




FLQNPQTSLCFSESIP

GAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCA




TPSNREETQQKSNLE

AAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACGC




LLRISLLLIQSWLEPV

CTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAACT




QFLRSVFANSLVYG

ACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAG




ASDSNVYDLLKDLE

TGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGC




EGIQTLMGRLEDGSP

GCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTCGAGG




RTGQIFKQTYSKFDT

AAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCC




NSHNDDALLKNYGL

GCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGATA




LYCFRKDMDKVETF

CTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATGGTCT




LRIVQCRSVEGSCGF

GCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTTCC




GGTSESATPESGPGS

TGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTC




EPATSGSETPGTSES

TAAGGTGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAG




ATPESGPGSEPATSG

GTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCT




SETPGTSESATPESGP

GAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAA




GTSTEPSEGSAPGSP

CCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCT




AGSPTSTEEGTSESA

GAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCG




TPESGPGSEPATSGS

CACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGG




ETPGTSESATPESGP

TACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAA




GSPAGSPTSTEEGSP

CCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCG




AGSPTSTEEGTSTEPS

CTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACT




EGSAPGTSESATPES

TCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGA




GPGTSESATPESGPG

AGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGT




TSESATPESGPGSEP

ACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGA




ATSGSETPGSEPATS

AAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTA




GSETPGSPAGSPTST

CCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCT




EEGTSTEPSEGSAPG

GAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTC




TSTEPSEGSAPGSEP

CAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTAC




ATSGSETPGTSESAT

TTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTG




PESGPGTSTEPSEGS

AACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTC




AP

TGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAAT






CTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA



 


AD576-
GSSESGSSEGGPGSG
773
GGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCAGGTTCCTC
774


hGH-
GEPSESGSSGSSESGS

TGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAATCTCCGGGT



AE288
SEGGPGSSESGSSEG

GGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCTTCCGA




GPGSSESGSSEGGPG

GTCTGGTAGCTCAGGTGAATCTCCGGGTGGTTCTAGCGGTTCCG




SSESGSSEGGPGSSES

AGTCAGGTGAATCTCCGGGTGGTTCCAGCGGTTCTGAGTCAGGT




GSSEGGPGESPGGSS

TCCTCCGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTCCGA




GSESGSEGSSGPGES

AAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTGAAAGCGGTT




SGSSESGSSEGGPGS

CTTCCGAGGGCGGTCCAGGTGAATCTCCTGGTGGTTCCAGCGGT




SESGSSEGGPGSSES

TCCGAGTCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAGTC




GSSEGGPGSGGEPSE

AGGTGAATCTCCTGGTGGTTCTAGCGGTTCTGAATCAGGTTCCT




SGSSGESPGGSSGSE

CCGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTCCGAAAG




SGESPGGSSGSESGS

CGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTGAAAGCGGTTCTT




GGEPSESGSSGSSES

CCGAGGGCGGTCCAGGTTCCTCTGAAAGCGGTTCTTCTGAGGG




GSSEGGPGSGGEPSE

CGGTCCAGGTTCTTCCGAAAGCGGTTCTTCCGAGGGCGGTCCAG




SGSSGSGGEPSESGS

GTTCTTCCGAAAGCGGTTCTTCTGAAGGCGGTCCAGGTTCTGGT




SGSEGSSGPGESSGE

GGCGAACCGTCCGAGTCTGGTAGCTCAGGTGAATCTCCGGGTG




SPGGSSGSESGSGGE

GCTCTAGCGGTTCCGAGTCAGGTGAATCTCCTGGTGGTTCCAGC




PSESGSSGSGGEPSES

GGTTCCGAGTCAGGTTCCGGTGGCGAACCGTCCGAATCTGGTA




GSSGSGGEPSESGSS

GCTCAGGTAGCGAAGGTTCTTCTGGTCCAGGCGAATCTTCAGGT




GSSESGSSEGGPGES

TCCTCTGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCGGTGG




PGGSSGSESGESPGG

CGAACCGTCCGAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTG




SSGSESGESPGGSSG

GTCCAGGCGAATCTTCAGGTTCCTCTGAAAGCGGTTCTTCTGAG




SESGESPGGSSGSES

GGCGGTCCAGGTTCCGGTGGCGAACCTTCCGAATCTGGTAGCTC




GESPGGSSGSESGSS

AGGTGAATCTCCGGGTGGTTCTAGCGGTTCTGAGTCAGGTTCTG




ESGSSEGGPGSGGEP

GTGGTGAACCTTCCGAGTCTGGTAGCTCAGGTTCTGGTGGCGAA




SESGSSGSEGSSGPG

CCATCCGAGTCTGGTAGCTCAGGTTCTTCCGAAAGCGGTTCTTC




ESSGSSESGSSEGGP

CGAAGGCGGTCCAGGTTCTGGTGGTGAACCGTCCGAATCTGGT




GSGGEPSESGSSGSS

AGCTCAGGTTCTGGTGGCGAACCATCCGAATCTGGTAGCTCAG




ESGSSEGGPGSGGEP

GTAGCGAAGGTTCTTCTGGTCCTGGCGAATCTTCAGGTGAATCT




SESGSSGESPGGSSG

CCAGGTGGCTCTAGCGGTTCCGAATCAGGTAGCGAAGGTTCTTC




SESGESPGGSSGSES

CGGTCCAGGTGAATCTTCAGGTAGCGAAGGTTCTTCTGGTCCTG




GSSESGSSEGGPGSG

GTGAATCCTCAGGTTCCGGTGGCGAACCATCTGAATCTGGTAGC




GEPSESGSSGSSESGS

TCAGGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCAGGTTC




SEGGPGSGGEPSESG

CTCTGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAATCTCCGG




SSGSGGEPSESGSSG

GTGGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCATCC




ESPGGSSGSESGSEG

GAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTGGTCCTGGCGA




SSGPGESSGSSESGSS

ATCTTCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAATCAG




EGGPGSEGSSGPGES

GTAGCGAAGGTTCTTCCGGTCCTGGTGAGTCTTCAGGTGAATCT




SGFPTIPLSRLFDNA

CCAGGTGGCTCTAGCGGTTCCGAGTCAGGTAGCGAAGGTTCTTC




MLRAHRLHQLAFDT

TGGTCCTGGCGAGTCCTCAGGTTTTCCGACTATTCCGCTGTCTC




YQEFEEAYIPKEQKY

GTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCACCAG




SFLQNPQTSLCFSESI

CTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACATTCC




PTPSNREETQQKSNL

TAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTC




ELLRISLLLIQSWLEP

TCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAA




VQFLRSVFANSLVY

ACTCAGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCT




GASDSNVYDLLKDL

TCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCG




EEGIQTLMGRLEDGS

TCTTCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA




PRTGQIFKQTYSKFD

TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGA




TNSHNDDALLKNYG

TGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTC




LLYCFRKDMDKVET

AAGCAGACTTACTCTAAATTTGATACTAACAGCCACAATGACG




FLRIVQCRSVEGSCG

ATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAA




FGGTSESATPESGPG

GATATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCG




SEPATSGSETPGTSES

TTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTACCTCTGAAA




ATPESGPGSEPATSG

GCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCC




SETPGTSESATPESGP

GGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAAT




GTSTEPSEGSAPGSP

CTGGTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCC




AGSPTSTEEGTSESA

AGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTT




TPESGPGSEPATSGS

CTACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGCTGG




ETPGTSESATPESGP

CTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACC




GSPAGSPTSTEEGSP

CCTGAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTG




AGSPTSTEEGTSTEPS

AAACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCC




EGSAPGTSESATPES

AGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGC




GPGTSESATPESGPG

CCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTACCGA




TSESATPESGPGSEP

ACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACC




ATSGSETPGSEPATS

CCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAATC




GSETPGSPAGSPTST

CGGTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCA




EEGTSTEPSEGSAPG

GGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCG




TSTEPSEGSAPGSEP

AACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCAGCAGG




ATSGSETPGTSESAT

CTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCG




PESGPGTSTEPSEGS

AAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAG




AP

CGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCA






GGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTC






TACTGAACCGTCCGAGGGCAGCGCACCA



 


AE576-
GSPAGSPTSTEEGTS
775
GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTC
776


hGH-
ESATPESGPGTSTEPS

TGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTGAAC



AE288
EGSAPGSPAGSPTST

CGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTCTCCGAC




EEGTSTEPSEGSAPG

TTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGC




TSTEPSEGSAPGTSES

GCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAG




ATPESGPGSEPATSG

GTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGA




SETPGSEPATSGSETP

ACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCT




GSPAGSPTSTEEGTS

ACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCAGGCTCTCCGAC




ESATPESGPGTSTEPS

CTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCC




EGSAPGTSTEPSEGS

GGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAG




APGSPAGSPTSTEEG

GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCC




TSTEPSEGSAPGTSTE

AGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAAC




PSEGSAPGTSESATP

CGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCTTCTGA




ESGPGTSTEPSEGSA

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCC




PGTSESATPESGPGS

GGTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAG




EPATSGSETPGTSTEP

GTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGA




SEGSAPGTSTEPSEG

ACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAAC




SAPGTSESATPESGP

CGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGTCTGA




GTSESATPESGPGSP

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCGGAATCC




AGSPTSTEEGTSESA

GGCCCAGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCAG




TPESGPGSEPATSGS

GTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT




ETPGTSESATPESGP

GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAA




GTSTEPSEGSAPGTS

CCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCG




TEPSEGSAPGTSTEPS

GAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCG




EGSAPGTSTEPSEGS

CTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGG




APGTSTEPSEGSAPG

TACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTA




TSTEPSEGSAPGSPA

CTGAACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCT




GSPTSTEEGTSTEPSE

TCTGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGG




GSAPGTSESATPESG

GTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGA




PGSEPATSGSETPGT

GGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT




SESATPESGPGSEPA

ACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAAC




TSGSETPGTSESATPE

CTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCA




SGPGTSTEPSEGSAP

ACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCT




GTSESATPESGPGSP

CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGC




AGSPTSTEEGSPAGS

CCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTA




PTSTEEGSPAGSPTST

CTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCT




EEGTSESATPESGPG

GGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCC




TSTEPSEGSAPGFPTI

AACTTCTACTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCT




PLSRLFDNAMLRAH

ACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCC




RLHQLAFDTYQEFEE

CAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTTT




AYIPKEQKYSFLQNP

TCCGACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCG




QTSLCFSESIPTPSNR

TGCGCACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAAT




EETQQKSNLELLRIS

TTGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTG




LLLIQSWLEPVQFLR

CAAAACCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGAC




SVFANSLVYGASDS

GCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAA




NVYDLLKDLEEGIQT

CTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACC




LMGRLEDGSPRTGQI

AGTGCAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATG




FKQTYSKFDTNSHN

GCGCATCCGACAGCAACGTATACGATCTCCTGAAAGATCTCGA




DDALLKNYGLLYCF

GGAAGGCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCT




RKDMDKVETFLRIV

CCGCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGA




QCRSVEGSCGFGGTS

TACTAACAGCCACAATGACGATGCGCTTCTAAAAAACTATGGT




ESATPESGPGSEPAT

CTGCTGTATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTT




SGSETPGTSESATPES

CCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTT




GPGSEPATSGSETPG

TCTAAGGTGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA




TSESATPESGPGTSTE

GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTC




PSEGSAPGSPAGSPT

TGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCA




STEEGTSESATPESGP

ACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCC




GSEPATSGSETPGTS

TGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGC




ESATPESGPGSPAGS

GCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAG




PTSTEEGSPAGSPTST

GTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGA




EEGTSTEPSEGSAPG

ACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGC




TSESATPESGPGTSES

GCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGAC




ATPESGPGTSESATP

TTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTG




ESGPGSEPATSGSET

AAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGG




PGSEPATSGSETPGSP

TACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTG




AGSPTSTEEGTSTEPS

AAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCT




EGSAPGTSTEPSEGS

ACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTC




APGSEPATSGSETPG

TGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACT




TSESATPESGPGTSTE

CCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTA




PSEGSAP

CTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACT






GAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCT






CTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAA






TCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCAC






CA



 


AF576-
GSTSSTAESPGPGSTS
777
GGTTCTACTAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCCAC
778


hGH-
STAESPGPGSTSESPS

TAGCTCTACCGCAGAATCTCCGGGCCCAGGTTCTACTAGCGAAT



AE288
GTAPGSTSSTAESPG

CCCCTTCTGGTACCGCTCCAGGTTCTACTAGCTCTACCGCTGAA




PGSTSSTAESPGPGTS

TCTCCGGGTCCAGGTTCTACCAGCTCTACTGCAGAATCTCCTGG




TPESGSASPGSTSESP

CCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGTT




SGTAPGTSPSGESST

CTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCT




APGSTSESPSGTAPG

AGCGGCGAATCTTCTACCGCTCCAGGTTCTACTAGCGAATCTCC




STSESPSGTAPGTSPS

TTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCTTCTGGCA




GESSTAPGSTSESPSG

CCGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCA




TAPGSTSESPSGTAP

GGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTAC




GTSPSGESSTAPGSTS

CAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCTAGCG




ESPSGTAPGSTSESPS

GCGAATCTTCTACCGCTCCAGGTTCTACTAGCGAATCTCCTTCT




GTAPGSTSESPSGTA

GGCACTGCACCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGC




PGTSTPESGSASPGST

ACCAGGTTCTACCAGCGAATCTCCGTCTGGCACTGCACCAGGTA




SESPSGTAPGTSTPES

CCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGTTCTACTAGC




GSASPGSTSSTAESP

GAATCTCCTTCTGGTACCGCTCCAGGTACTTCTACCCCTGAAAG




GPGSTSSTAESPGPG

CGGCTCCGCTTCTCCAGGTTCCACTAGCTCTACCGCTGAATCTC




TSTPESGSASPGTSTP

CGGGTCCAGGTTCTACTAGCTCTACTGCAGAATCTCCTGGCCCA




ESGSASPGSTSESPSG

GGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTACTTC




TAPGTSTPESGSASP

TACCCCTGAAAGCGGTTCTGCATCTCCAGGTTCTACTAGCGAAT




GTSTPESGSASPGSTS

CCCCGTCTGGTACCGCACCAGGTACTTCTACCCCGGAAAGCGG




ESPSGTAPGSTSESPS

CTCTGCTTCTCCAGGTACTTCTACCCCGGAAAGCGGCTCCGCAT




GTAPGSTSESPSGTA

CTCCAGGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAGGT




PGSTSSTAESPGPGTS

TCTACCAGCGAATCCCCGTCTGGTACTGCTCCAGGTTCTACCAG




TPESGSASPGTSTPES

CGAATCTCCTTCTGGTACTGCACCAGGTTCTACTAGCTCTACTG




GSASPGSTSESPSGT

CAGAATCTCCTGGCCCAGGTACCTCTACTCCGGAAAGCGGCTCT




APGSTSESPSGTAPG

GCATCTCCAGGTACTTCTACCCCTGAAAGCGGTTCTGCATCTCC




TSTPESGSASPGSTSE

AGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTA




SPSGTAPGSTSESPSG

CCAGCGAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCCCT




TAPGTSTPESGSASP

GAAAGCGGTTCCGCTTCTCCAGGTTCTACTAGCGAATCTCCTTC




GTSPSGESSTAPGSTS

TGGCACTGCACCAGGTTCTACCAGCGAATCTCCGTCTGGCACTG




STAESPGPGTSPSGES

CACCAGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGT




STAPGSTSSTAESPGP

ACTTCTCCGAGCGGTGAATCTTCTACCGCACCAGGTTCTACTAG




GTSTPESGSASPGSTS

CTCTACCGCTGAATCTCCGGGCCCAGGTACTTCTCCGAGCGGTG




ESPSGTAPGSTSSTA

AATCTTCTACTGCTCCAGGTTCCACTAGCTCTACTGCTGAATCT




ESPGPGTSTPESGSAS

CCTGGCCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCC




PGTSTPESGSASPGFP

AGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAGGTTCTA




TIPLSRLFDNAMLRA

CTAGCTCTACTGCAGAATCTCCTGGCCCAGGTACCTCTACTCCG




HRLHQLAFDTYQEF

GAAAGCGGCTCTGCATCTCCAGGTACTTCTACCCCTGAAAGCG




EEAYIPKEQKYSFLQ

GTTCTGCATCTCCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGT




NPQTSLCFSESIPTPS

TTGATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCC




NREETQQKSNLELLR

TTTGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGA




ISLLLIQSWLEPVQFL

GCAGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCT




RSVFANSLVYGASD

TCAGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCA




SNVYDLLKDLEEGIQ

GCAAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGA




TLMGRLEDGSPRTG

TTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTC




QIFKQTYSKFDTNSH

GCCAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACG




NDDALLKNYGLLYC

ATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGG




FRKDMDKVETFLRI

TCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGC




VQCRSVEGSCGFGG

AGACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGC




TSESATPESGPGSEP

GCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATA




ATSGSETPGTSESAT

TGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCC




PESGPGSEPATSGSE

GTTGAGGGCAGCTGTGGTTTCTAAGGTGGTACCTCTGAAAGCG




TPGTSESATPESGPG

CAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGC




TSTEPSEGSAPGSPA

TCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTG




GSPTSTEEGTSESATP

GTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGG




ESGPGSEPATSGSET

TACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTA




PGTSESATPESGPGSP

CTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGCTGGCTC




AGSPTSTEEGSPAGS

TCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCT




PTSTEEGTSTEPSEGS

GAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAA




APGTSESATPESGPG

CCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGT




TSESATPESGPGTSES

AGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGG




ATPESGPGSEPATSG

CTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTACCGAACCT




SETPGSEPATSGSETP

TCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTG




GSPAGSPTSTEEGTS

AGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGT




TEPSEGSAPGTSTEPS

CCAGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTA




EGSAPGSEPATSGSE

GCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACC




TPGTSESATPESGPG

GGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCAGCAGGCTCTC




TSTEPSEGSAP

CGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGC






AGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTC






CAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTAC






CTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTG






AACCGTCCGAGGGCAGCGCACCA



 


AE624-
MAEPAGSPTSTEEGT
779
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
780


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



AE288
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG




GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




FPTIPLSRLFDNAML

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




RAHRLHQLAFDTYQ

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




EFEEAYIPKEQKYSF

GCAGCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTT




LQNPQTSLCFSESIPT

GATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT




PSNREETQQKSNLEL

TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGC




LRISLLLIQSWLEPVQ

AGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTC




FLRSVFANSLVYGAS

AGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC




DSNVYDLLKDLEEGI

AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATT




QTLMGRLEDGSPRT

CAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGC




GQIFKQTYSKFDTNS

CAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGAT




HNDDALLKNYGLLY

CTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC




CFRKDMDKVETFLRI

GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG




VQCRSVEGSCGFGG

ACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCT




TSESATPESGPGSEP

TCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGG




ATSGSETPGTSESAT

ACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTT




PESGPGSEPATSGSE

GAGGGCAGCTGTGGTTTCTAAGGTGGTACCTCTGAAAGCGCAA




TPGTSESATPESGPG

CTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTCT




TSTEPSEGSAPGSPA

GAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTC




GSPTSTEEGTSESATP

CAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTAC




ESGPGSEPATSGSET

CTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTG




PGTSESATPESGPGSP

AACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGCTGGCTCTCC




AGSPTSTEEGSPAGS

AACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAA




PTSTEEGTSTEPSEGS

TCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCC




APGTSESATPESGPG

CAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAG




TSESATPESGPGTSES

CCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCT




ATPESGPGSEPATSG

GGCTCTCCAACTTCTACTGAAGAAGGTACTTCTACCGAACCTTC




SETPGSEPATSGSETP

CGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTGAG




GSPAGSPTSTEEGTS

TCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCC




TEPSEGSAPGTSTEPS

AGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGC




EGSAPGSEPATSGSE

GAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGG




TPGTSESATPESGPG

CTACCTCCGGTTCTGAAACTCCAGGTAGCCCAGCAGGCTCTCCG




TSTEPSEGSAP

ACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCA






GCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCC






AGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACC






TCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGA






ACCGTCCGAGGGCAGCGCACCA



 


AD836-
GSSESGSSEGGPGSS
781
GGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCAGGTTCCTC
782


hGH-
ESGSSEGGPGESPGG

TGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAATCTCCGGGT



AE288
SSGSESGSGGEPSES

GGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCTTCCGA




GSSGESPGGSSGSES

GTCTGGTAGCTCAGGTGAATCTCCGGGTGGTTCTAGCGGTTCCG




GESPGGSSGSESGES

AGTCAGGTGAATCTCCGGGTGGTTCCAGCGGTTCTGAGTCAGGT




ESGSSEGGPGSSESG

TCCTCCGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTCCGA




SSEGGPGSSESGSSE

AAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTGAAAGCGGTT




GGPGESPGGSSGSES

CTTCCGAGGGCGGTCCAGGTGAATCTCCTGGTGGTTCCAGCGGT




GESPGGSSGSESGES

TCCGAGTCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAGTC




PGGSSGSESGSSESG

AGGTGAATCTCCTGGTGGTTCTAGCGGTTCTGAATCAGGTTCCT




SSEGGPGSSESGSSE

CCGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTCCGAAAG




GGPGSSESGSSEGGP

CGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTGAAAGCGGTTCTT




GSSESGSSEGGPGSS

CCGAGGGCGGTCCAGGTTCCTCTGAAAGCGGTTCTTCTGAGGG




ESGSSEGGPGSSESG

CGGTCCAGGTTCTTCCGAAAGCGGTTCTTCCGAGGGCGGTCCAG




SSEGGPGSGGEPSES

GTTCTTCCGAAAGCGGTTCTTCTGAAGGCGGTCCAGGTTCTGGT




GSSGESPGGSSGSES

GGCGAACCGTCCGAGTCTGGTAGCTCAGGTGAATCTCCGGGTG




GESPGGSSGSESGSG

GCTCTAGCGGTTCCGAGTCAGGTGAATCTCCTGGTGGTTCCAGC




GEPSESGSSGSEGSS

GGTTCCGAGTCAGGTTCCGGTGGCGAACCGTCCGAATCTGGTA




GPGESSGSSESGSSE

GCTCAGGTAGCGAAGGTTCTTCTGGTCCAGGCGAATCTTCAGGT




GGPGSGGEPSESGSS

TCCTCTGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCGGTGG




GSEGSSGPGESSGSS

CGAACCGTCCGAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTG




ESGSSEGGPGSGGEP

GTCCAGGCGAATCTTCAGGTTCCTCTGAAAGCGGTTCTTCTGAG




SESGSSGESPGGSSG

GGCGGTCCAGGTTCCGGTGGCGAACCTTCCGAATCTGGTAGCTC




SESGSGGEPSESGSS

AGGTGAATCTCCGGGTGGTTCTAGCGGTTCTGAGTCAGGTTCTG




GSGGEPSESGSSGSS

GTGGTGAACCTTCCGAGTCTGGTAGCTCAGGTTCTGGTGGCGAA




ESGSSEGGPGSGGEP

CCATCCGAGTCTGGTAGCTCAGGTTCTTCCGAAAGCGGTTCTTC




SESGSSGSGGEPSES

CGAAGGCGGTCCAGGTTCTGGTGGTGAACCGTCCGAATCTGGT




GSSGSEGSSGPGESS

AGCTCAGGTTCTGGTGGCGAACCATCCGAATCTGGTAGCTCAG




GESPGGSSGSESGSE

GTAGCGAAGGTTCTTCTGGTCCTGGCGAATCTTCAGGTGAATCT




GSSGPGESSGSEGSS

CCAGGTGGCTCTAGCGGTTCCGAATCAGGTAGCGAAGGTTCTTC




GPGESSGSGGEPSES

CGGTCCAGGTGAATCTTCAGGTAGCGAAGGTTCTTCTGGTCCTG




GSSGSSESGSSEGGP

GTGAATCCTCAGGTTCCGGTGGCGAACCATCTGAATCTGGTAGC




GSSESGSSEGGPGES

TCAGGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCAGGTTC




PGGSSGSESGSGGEP

CTCTGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAATCTCCGG




SESGSSGSEGSSGPG

GTGGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCATCC




ESSGESPGGSSGSES

GAATCTGGTAGCTCAGGTAGCGAAGGTTCTTCTGGTCCTGGCGA




GSEGSSGPGSSESGS

ATCTTCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAATCAG




SEGGPGSGGEPSESG

GTAGCGAAGGTTCTTCCGGTCCaGGTTCCTCTGAAAGCGGTTCT




SSGSEGSSGPGESSG

TCTGAGGGCGGTCCAGGTTCTGGTGGCGAACCATCTGAATCTG




SEGSSGPGESSGSEG

GTAGCTCAGGTAGCGAAGGTTCTTCCGGTCCGGGTGAATCTTCA




SSGPGESSGSGGEPS

GGTAGCGAAGGTTCTTCCGGTCCAGGTGAATCTTCAGGTAGCG




ESGSSGSGGEPSESG

AAGGTTCTTCTGGTCCTGGTGAATCCTCAGGTTCCGGTGGCGAA




SSGESPGGSSGSESG

CCATCTGAATCTGGTAGCTCAGGTTCTGGTGGCGAACCATCCGA




ESPGGSSGSESGSGG

ATCTGGTAGCTCAGGTGAATCTCCGGGTGGCTCCAGCGGTTCTG




EPSESGSSGSEGSSGP

AATCAGGTGAATCTCCTGGTGGCTCCAGCGGTTCTGAGTCAGGT




GESSGESPGGSSGSE

TCTGGTGGCGAACCATCCGAATCTGGTAGCTCAGGTAGCGAAG




SGSSESGSSEGGPGS

GTTCTTCTGGTCCTGGCGAATCTTCAGGTGAATCTCCAGGTGGC




SESGSSEGGPGSSES

TCTAGCGGTTCCGAATCAGGTTCCTCTGAAAGCGGTTCTTCTGA




GSSEGGPGSGGEPSE

GGGCGGTCCAGGTTCTTCCGAAAGCGGTTCTTCCGAGGGCGGT




SGSSGSSESGSSEGG

CCAGGTTCTTCCGAAAGCGGTTCTTCTGAAGGCGGTCCAGGTTC




PGESPGGSSGSESGS

TGGTGGCGAACCGTCCGAATCTGGTAGCTCAGGTTCCTCCGAA




GGEPSESGSSGSSES

AGCGGTTCTTCTGAAGGTGGTCCAGGTGAATCTCCAGGTGGTTC




GSSEGGPGESPGGSS

TAGCGGTTCTGAATCAGGTTCTGGTGGCGAACCGTCCGAATCTG




GSESGSGGEPSESGS

GTAGCTCAGGTTCCTCCGAAAGCGGTTCTTCTGAAGGTGGTCCA




SGESPGGSSGSESGS

GGTGAATCTCCAGGTGGTTCTAGCGGTTCTGAATCAGGTTCTGG




GGEPSESGSSGFPTIP

TGGCGAACCGTCCGAATCTGGTAGCTCAGGTGAATCTCCTGGTG




LSRLFDNAMLRAHR

GTTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAACCTTCCGAA




LHQLAFDTYQEFEE

TCTGGTAGCTCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTT




AYIPKEQKYSFLQNP

GATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT




QTSLCFSESIPTPSNR

TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGC




EETQQKSNLELLRIS

AGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTC




LLLIQSWLEPVQFLR

AGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC




SVFANSLVYGASDS

AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATT




NVYDLLKDLEEGIQT

CAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGC




LMGRLEDGSPRTGQI

CAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGAT




FKQTYSKFDTNSHN

CTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC




DDALLKNYGLLYCF

GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG




RKDMDKVETFLRIV

ACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCT




QCRSVEGSCGFGGTS

TCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGG




ESATPESGPGSEPAT

ACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTT




SGSETPGTSESATPES

GAGGGCAGCTGTGGTTTCTAAGGTGGTACCTCTGAAAGCGCAA




GPGSEPATSGSETPG

CTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTCT




TSESATPESGPGTSTE

GAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTC




PSEGSAPGSPAGSPT

CAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTAC




STEEGTSESATPESGP

CTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTG




GSEPATSGSETPGTS

AACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGCTGGCTCTCC




ESATPESGPGSPAGS

AACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAA




PTSTEEGSPAGSPTST

TCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCC




EEGTSTEPSEGSAPG

CAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAG




TSESATPESGPGTSES

CCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCT




ATPESGPGTSESATP

GGCTCTCCAACTTCTACTGAAGAAGGTACTTCTACCGAACCTTC




ESGPGSEPATSGSET

CGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTGAG




PGSEPATSGSETPGSP

TCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCC




AGSPTSTEEGTSTEPS

AGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGC




EGSAPGTSTEPSEGS

GAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGG




APGSEPATSGSETPG

CTACCTCCGGTTCTGAAACTCCAGGTAGCCCAGCAGGCTCTCCG




TSESATPESGPGTSTE

ACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCA




PSEGSAP

GCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCC






AGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACC






TCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGA






ACCGTCCGAGGGCAGCGCACCA



 


AE864-
GSPAGSPTSTEEGTS
783
GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTC
784


hGH-
ESATPESGPGTSTEPS

TGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCTCTACTGAAC



AE288
EGSAPGSPAGSPTST

CGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTCTCCGAC




EEGTSTEPSEGSAPG

TTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGC




TSTEPSEGSAPGTSES

GCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAG




ATPESGPGSEPATSG

GTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGA




SETPGSEPATSGSETP

ACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCT




GSPAGSPTSTEEGTS

ACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCAGGCTCTCCGAC




ESATPESGPGTSTEPS

CTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCC




EGSAPGTSTEPSEGS

GGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAG




APGSPAGSPTSTEEG

GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCC




TSTEPSEGSAPGTSTE

AGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAAC




PSEGSAPGTSESATP

CGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCTTCTGA




ESGPGTSTEPSEGSA

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCC




PGTSESATPESGPGS

GGTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAG




EPATSGSETPGTSTEP

GTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGA




SEGSAPGTSTEPSEG

ACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAAC




SAPGTSESATPESGP

CGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACCGTCTGA




GTSESATPESGPGSP

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCGGAATCC




AGSPTSTEEGTSESA

GGCCCAGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCAG




TPESGPGSEPATSGS

GTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT




ETPGTSESATPESGP

GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAA




GTSTEPSEGSAPGTS

CCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCG




TEPSEGSAPGTSTEPS

GAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCG




EGSAPGTSTEPSEGS

CTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGG




APGTSTEPSEGSAPG

TACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTA




TSTEPSEGSAPGSPA

CTGAACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCT




GSPTSTEEGTSTEPSE

TCTGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGG




GSAPGTSESATPESG

GTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGA




PGSEPATSGSETPGT

GGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT




SESATPESGPGSEPA

ACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAAC




TSGSETPGTSESATPE

CTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCA




SGPGTSTEPSEGSAP

ACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCT




GTSESATPESGPGSP

CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGC




AGSPTSTEEGSPAGS

CCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTA




PTSTEEGSPAGSPTST

CTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCT




EEGTSESATPESGPG

GGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCC




TSTEPSEGSAPGTSES

AACTTCTACTGAAGAAGGTAGCCCGGCAGGCTCTCCGACCTCT




ATPESGPGSEPATSG

ACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCC




SETPGTSESATPESGP

CAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTAC




GSEPATSGSETPGTS

CTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCT




ESATPESGPGTSTEPS

GCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAA




EGSAPGSPAGSPTST

CCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCTCT




EEGTSESATPESGPG

GAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCC




SEPATSGSETPGTSES

CAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAG




ATPESGPGSPAGSPT

CCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAA




STEEGSPAGSPTSTEE

GCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACCTC




GTSTEPSEGSAPGTS

CGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGT




ESATPESGPGTSESA

CCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGA




TPESGPGTSESATPES

AGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTT




GPGSEPATSGSETPG

CTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAG




SEPATSGSETPGSPA

CGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTC




GSPTSTEEGTSTEPSE

CTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




GSAPGTSTEPSEGSA

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




PGSEPATSGSETPGT

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




SESATPESGPGTSTEP

AGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAAC




SEGSAPGFPTIPLSRL

CTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAG




FDNAMLRAHRLHQL

GGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAA




AFDTYQEFEEAYIPK

CCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGT




EQKYSFLQNPQTSLC

ACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTTTTCCGAC




FSESIPTPSNREETQQ

TATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGTGCGC




KSNLELLRISLLLIQS

ACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATTTGAA




WLEPVQFLRSVFAN

GAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAA




SLVYGASDSNVYDL

CCCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT




LKDLEEGIQTLMGRL

CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAACTACT




EDGSPRTGQIFKQTY

CCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAGTGC




SKFDTNSHNDDALL

AATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCA




KNYGLLYCFRKDMD

TCCGACAGCAACGTATACGATCTCCTGAAAGATCTCGAGGAAG




KVETFLRIVQCRSVE

GCATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT




GSCGFGGTSESATPE

ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGATACTAA




SGPGSEPATSGSETP

CAGCCACAATGACGATGCGCTTCTAAAAAACTATGGTCTGCTGT




GTSESATPESGPGSE

ATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGCGT




PATSGSETPGTSESA

ATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGG




TPESGPGTSTEPSEGS

TGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGC




APGSPAGSPTSTEEG

GAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAG




TSESATPESGPGSEP

CGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCT




ATSGSETPGTSESAT

GGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATC




PESGPGSPAGSPTSTE

TGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA




EGSPAGSPTSTEEGT

GGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTC




STEPSEGSAPGTSES

TGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCA




ATPESGPGTSESATP

ACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCC




ESGPGTSESATPESG

TGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCG




PGSEPATSGSETPGS

AGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGG




EPATSGSETPGSPAG

TACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTG




SPTSTEEGTSTEPSEG

AAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGC




SAPGTSTEPSEGSAP

TACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGG




GSEPATSGSETPGTS

AATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACC




ESATPESGPGTSTEPS

CCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTA




EGSAP

GCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACT






GAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTT






CTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTC






TGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCC






CAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA



 


AF864-
GSTSESPSGTAPGTSP
785
GGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTC
786


hGH-
SGESSTAPGSTSESPS

TCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTACTAGCGAAT



AE288
GTAPGSTSESPSGTA

CTCCTTCTGGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCT




PGTSTPESGSASPGTS

GGTACTGCTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTC




TPESGSASPGSTSESP

TCCAGGTACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTT




SGTAPGSTSESPSGT

CTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTTCTACTAGC




APGTSPSGESSTAPG

GAATCCCCGTCTGGTACCGCACCAGGTACTTCTCCTAGCGGCGA




STSESPSGTAPGTSPS

ATCTTCTACCGCACCAGGTTCTACTAGCGAATCTCCGTCTGGCA




GESSTAPGTSPSGESS

CTGCTCCAGGTACTTCTCCTAGCGGTGAATCTTCTACCGCTCCA




TAPGSTSSTAESPGP

GGTACTTCCCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTAC




GTSPSGESSTAPGTSP

TAGCTCTACTGCAGAATCTCCGGGCCCAGGTACCTCTCCTAGCG




SGESSTAPGSTSSTA

GTGAATCTTCTACCGCTCCAGGTACTTCTCCGAGCGGTGAATCT




ESPGPGTSTPESGSAS

TCTACCGCTCCAGGTTCTACTAGCTCTACTGCAGAATCTCCTGG




PGTSTPESGSASPGST

CCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTA




SESPSGTAPGSTSESP

CTTCTACCCCTGAAAGCGGTTCTGCATCTCCAGGTTCTACTAGC




SGTAPGTSTPESGSA

GAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCC




SPGSTSSTAESPGPGT

GTCTGGCACTGCACCAGGTACCTCTACCCCTGAAAGCGGTTCCG




STPESGSASPGSTSES

CTTCTCCAGGTTCTACCAGCTCTACCGCAGAATCTCCTGGTCCA




PSGTAPGTSPSGESST

GGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTTCTAC




APGSTSSTAESPGPG

TAGCGAATCTCCTTCTGGCACTGCACCAGGTACTTCTCCGAGCG




TSPSGESSTAPGTSTP

GTGAATCTTCTACCGCACCAGGTTCTACTAGCTCTACCGCTGAA




ESGSASPGSTSSTAES

TCTCCGGGCCCAGGTACTTCTCCGAGCGGTGAATCTTCTACTGC




PGPGSTSSTAESPGP

TCCAGGTACCTCTACTCCTGAAAGCGGTTCTGCATCTCCAGGTT




GSTSSTAESPGPGSTS

CCACTAGCTCTACCGCAGAATCTCCGGGCCCAGGTTCTACTAGC




STAESPGPGTSPSGES

TCTACTGCTGAATCTCCTGGCCCAGGTTCTACTAGCTCTACTGC




STAPGSTSESPSGTAP

TGAATCTCCGGGTCCAGGTTCTACCAGCTCTACTGCTGAATCTC




GSTSESPSGTAPGTS

CTGGTCCAGGTACCTCCCCGAGCGGTGAATCTTCTACTGCACCA




TPESGPXXXGASASG

GGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTAC




APSTXXXXSESPSGT

CAGCGAATCTCCGTCTGGCACTGCACCAGGTACCTCTACCCCTG




APGSTSESPSGTAPG

AAAGCGGTCCXXXXXXXXXXXXTGCAAGCGCAAGCGGCGCGC




STSESPSGTAPGSTSE

CAAGCACGGGAXXXXXXXXTAGCGAATCTCCTTCTGGTACCGC




SPSGTAPGSTSESPSG

TCCAGGTTCTACCAGCGAATCCCCGTCTGGTACTGCTCCAGGTT




TAPGSTSESPSGTAP

CTACCAGCGAATCTCCTTCTGGTACTGCACCAGGTTCTACTAGC




GTSTPESGSASPGTSP

GAATCTCCTTCTGGTACCGCTCCAGGTTCTACCAGCGAATCCCC




SGESSTAPGTSPSGES

GTCTGGTACTGCTCCAGGTTCTACCAGCGAATCTCCTTCTGGTA




STAPGSTSSTAESPGP

CTGCACCAGGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCA




GTSPSGESSTAPGTS

GGTACTTCTCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTC




TPESGSASPGSTSESP

TCCTAGCGGCGAATCTTCTACTGCTCCAGGTTCTACCAGCTCTA




SGTAPGSTSESPSGT

CTGCTGAATCTCCGGGTCCAGGTACTTCCCCGAGCGGTGAATCT




APGTSPSGESSTAPG

TCTACTGCACCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTC




STSESPSGTAPGTSTP

TCCAGGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTT




ESGSASPGTSTPESGS

CTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTACTTCTCCT




ASPGSTSESPSGTAP

AGCGGCGAATCTTCTACCGCACCAGGTTCTACTAGCGAATCCCC




GTSTPESGSASPGSTS

GTCTGGTACCGCACCAGGTACTTCTACCCCGGAAAGCGGCTCTG




STAESPGPGSTSESPS

CTTCTCCAGGTACTTCTACCCCGGAAAGCGGCTCCGCATCTCCA




GTAPGSTSESPSGTA

GGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAGGTACTTC




PGTSPSGESSTAPGST

TACCCCTGAAAGCGGCTCCGCTTCTCCAGGTTCCACTAGCTCTA




SSTAESPGPGTSPSGE

CCGCTGAATCTCCGGGTCCAGGTTCTACCAGCGAATCTCCTTCT




SSTAPGTSTPESGSAS

GGCACCGCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACCGC




PGTSPSGESSTAPGTS

ACCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTT




PSGESSTAPGTSPSGE

CTACCAGCTCTACTGCTGAATCTCCGGGTCCAGGTACTTCCCCG




SSTAPGSTSSTAESPG

AGCGGTGAATCTTCTACTGCACCAGGTACTTCTACTCCGGAAAG




PGSTSSTAESPGPGTS

CGGTTCCGCTTCTCCAGGTACCTCCCCTAGCGGCGAATCTTCTA




PSGESSTAPGSSPSAS

CTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCA




TGTGPGSSTPSGATG

GGTACCTCCCCTAGCGGTGAATCTTCTACCGCACCAGGTTCTAC




SPGSSTPSGATGSPG

TAGCTCTACTGCTGAATCTCCGGGTCCAGGTTCTACCAGCTCTA




FPTIPLSRLFDNAML

CTGCTGAATCTCCTGGTCCAGGTACCTCCCCGAGCGGTGAATCT




RAHRLHQLAFDTYQ

TCTACTGCACCAGGTTCTAGCCCTTCTGCTTCCACCGGTACCGG




EFEEAYIPKEQKYSF

CCCAGGTAGCTCTACTCCGTCTGGTGCAACTGGCTCTCCAGGTA




LQNPQTSLCFSESIPT

GCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTTTTCCGACT




PSNREETQQKSNLEL

ATTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCA




LRISLLLIQSWLEPVQ

CCGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATTTGAAG




FLRSVFANSLVYGAS

AAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAAC




DSNVYDLLKDLEEGI

CCACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTC




QTLMGRLEDGSPRT

CAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAACTACTC




GQIFKQTYSKFDTNS

CGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCA




HNDDALLKNYGLLY

ATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCAT




CFRKDMDKVETFLRI

CCGACAGCAACGTATACGATCTCCTGAAAGATCTCGAGGAAGG




VQCRSVEGSCGFGG

CATTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTA




TSESATPESGPGSEP

CTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTGATACTAAC




ATSGSETPGTSESAT

AGCCACAATGACGATGCGCTTCTAAAAAACTATGGTCTGCTGT




PESGPGSEPATSGSE

ATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGCGT




TPGTSESATPESGPG

ATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGG




TSTEPSEGSAPGSPA

TGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGC




GSPTSTEEGTSESATP

GAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAG




ESGPGSEPATSGSET

CGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCT




PGTSESATPESGPGSP

GGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATC




AGSPTSTEEGSPAGS

TGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA




PTSTEEGTSTEPSEGS

GGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTC




APGTSESATPESGPG

TGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCA




TSESATPESGPGTSES

ACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCC




ATPESGPGSEPATSG

TGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCG




SETPGSEPATSGSETP

AGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGG




GSPAGSPTSTEEGTS

TACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTG




TEPSEGSAPGTSTEPS

AAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGC




EGSAPGSEPATSGSE

TACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGG




TPGTSESATPESGPG

AATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACC




TSTEPSEGSAP

CCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTA






GCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACT






GAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTT






CTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTC






TGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCC






CAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA



 


AG864-
GASPGTSSTGSPGSS
787
GGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTTCTAG
788


hGH-
PSASTGTGPGSSPSA

CCCGTCTGCTTCTACTGGTACTGGTCCAGGTTCTAGCCCTTCTGC



AE288
STGTGPGTPGSGTAS

TTCCACTGGTACTGGTCCAGGTACCCCGGGTAGCGGTACCGCTT




SSPGSSTPSGATGSP

CTTCTTCTCCAGGTAGCTCTACTCCGTCTGGTGCTACCGGCTCTC




GSNPSASTGTGPGAS

CAGGTTCTAACCCTTCTGCATCCACCGGTACCGGCCCAGGTGCT




PGTSSTGSPGTPGSG

TCTCCGGGCACCAGCTCTACTGGTTCTCCAGGTACCCCGGGCAG




TASSSPGSSTPSGAT

CGGTACCGCATCTTCTTCTCCAGGTAGCTCTACTCCTTCTGGTGC




GSPGTPGSGTASSSP

AACTGGTTCTCCAGGTACTCCTGGCAGCGGTACCGCTTCTTCTT




GASPGTSSTGSPGAS

CTCCAGGTGCTTCTCCTGGTACTAGCTCTACTGGTTCTCCAGGT




PGTSSTGSPGTPGSG

GCTTCTCCGGGCACTAGCTCTACTGGTTCTCCAGGTACCCCGGG




TASSSPGSSTPSGAT

TAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGG




GSPGASPGTSSTGSP

TGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAGCTCTACCG




GTPGSGTASSSPGSS

GTTCTCCAGGTACCCCGGGTAGCGGTACCGCTTCTTCTTCTCCA




TPSGATGSPGSNPSA

GGTAGCTCTACTCCGTCTGGTGCTACCGGCTCTCCAGGTTCTAA




STGTGPGSSPSASTG

CCCTTCTGCATCCACCGGTACCGGCCCAGGTTCTAGCCCTTCTG




TGPGSSTPSGATGSP

CTTCCACCGGTACTGGCCCAGGTAGCTCTACCCCTTCTGGTGCT




GSSTPSGATGSPGAS

ACCGGCTCCCCAGGTAGCTCTACTCCTTCTGGTGCAACTGGCTC




PGTSSTGSPGASPGT

TCCAGGTGCATCTCCGGGCACTAGCTCTACTGGTTCTCCAGGTG




SSTGSPGASPGTSST

CATCCCCTGGCACTAGCTCTACTGGTTCTCCAGGTGCTTCTCCT




GSPGTPGSGTASSSP

GGTACCAGCTCTACTGGTTCTCCAGGTACTCCTGGCAGCGGTAC




GASPGTSSTGSPGAS

CGCTTCTTCTTCTCCAGGTGCTTCTCCTGGTACTAGCTCTACTGG




PGTSSTGSPGASPGT

TTCTCCAGGTGCTTCTCCGGGCACTAGCTCTACTGGTTCTCCAG




SSTGSPGSSPSASTGT

GTGCTTCCCCGGGCACTAGCTCTACCGGTTCTCCAGGTTCTAGC




GPGTPGSGTASSSPG

CCTTCTGCATCTACTGGTACTGGCCCAGGTACTCCGGGCAGCGG




ASPGTSSTGSPGASP

TACTGCTTCTTCCTCTCCAGGTGCATCTCCGGGCACTAGCTCTA




GTSSTGSPGASPGTS

CTGGTTCTCCAGGTGCATCCCCTGGCACTAGCTCTACTGGTTCT




STGSPGSSTPSGATG

CCAGGTGCTTCTCCTGGTACCAGCTCTACTGGTTCTCCAGGTAG




SPGSSTPSGATGSPG

CTCTACTCCGTCTGGTGCAACCGGTTCCCCAGGTAGCTCTACTC




ASPGTSSTGSPGTPG

CTTCTGGTGCTACTGGCTCCCCAGGTGCATCCCCTGGCACCAGC




SGTASSSPGSSTPSG

TCTACCGGTTCTCCAGGTACCCCGGGCAGCGGTACCGCATCTTC




ATGSPGSSTPSGATG

CTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACCGGTTCCCCAG




SPGSSTPSGATGSPG

GTAGCTCTACCCCGTCTGGTGCAACCGGCTCCCCAGGTAGCTCT




SSPSASTGTGPGASP

ACTCCGTCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGC




GTSSTGSPGASPGTS

TTCCACTGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTA




STGSPGTPGSGTASS

CTGGTTCTCCAGGTGCATCCCCGGGTACCAGCTCTACCGGTTCT




SPGASPGTSSTGSPG

CCAGGTACTCCTGGCAGCGGTACTGCATCTTCCTCTCCAGGTGC




ASPGTSSTGSPGASP

TTCTCCGGGCACCAGCTCTACTGGTTCTCCAGGTGCATCTCCGG




GTSSTGSPGASPGTS

GCACTAGCTCTACTGGTTCTCCAGGTGCATCCCCTGGCACTAGC




STGSPGTPGSGTASS

TCTACTGGTTCTCCAGGTGCTTCTCCTGGTACCAGCTCTACTGGT




SPGSSTPSGATGSPG

TCTCCAGGTACCCCTGGTAGCGGTACTGCTTCTTCCTCTCCAGG




TPGSGTASSSPGSSTP

TAGCTCTACTCCGTCTGGTGCTACCGGTTCTCCAGGTACCCCGG




SGATGSPGTPGSGTA

GTAGCGGTACCGCATCTTCTTCTCCAGGTAGCTCTACCCCGTCT




SSSPGSSTPSGATGSP

GGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTGCTTC




GSSTPSGATGSPGSS

TTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCC




PSASTGTGPGSSPSA

AGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCCCCAGGTTCTA




STGTGPGASPGTSST

GCCCTTCTGCATCCACCGGTACCGGTCCAGGTTCTAGCCCGTCT




GSPGTPGSGTASSSP

GCATCTACTGGTACTGGTCCAGGTGCATCCCCGGGCACTAGCTC




GSSTPSGATGSPGSS

TACCGGTTCTCCAGGTACTCCTGGTAGCGGTACTGCTTCTTCTTC




PSASTGTGPGSSPSA

TCCAGGTAGCTCTACTCCTTCTGGTGCTACTGGTTCTCCAGGTTC




STGTGPGASPGTSST

TAGCCCTTCTGCATCCACCGGTACCGGCCCAGGTTCTAGCCCGT




GSPGASPGTSSTGSP

CTGCTTCTACCGGTACTGGTCCAGGTGCTTCTCCGGGTACTAGC




GSSTPSGATGSPGSS

TCTACTGGTTCTCCAGGTGCATCTCCTGGTACTAGCTCTACTGG




PSASTGTGPGASPGT

TTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCTCCAG




SSTGSPGSSPSASTGT

GTTCTAGCCCTTCTGCATCTACCGGTACTGGTCCAGGTGCATCC




GPGTPGSGTASSSPG

CCTGGTACCAGCTCTACCGGTTCTCCAGGTTCTAGCCCTTCTGC




SSTPSGATGSPGSSTP

TTCTACCGGTACCGGTCCAGGTACCCCTGGCAGCGGTACCGCAT




SGATGSPGASPGTSS

CTTCCTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGTTCC




TGSPGFPTIPLSRLFD

CCAGGTAGCTCTACTCCTTCTGGTGCTACTGGCTCCCCAGGTGC




NAMLRAHRLHQLAF

ATCCCCTGGCACCAGCTCTACCGGTTCTCCAGGTTTTCCGACTA




DTYQEFEEAYIPKEQ

TTCCGCTGTCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCAC




KYSFLQNPQTSLCFS

CGTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGA




ESIPTPSNREETQQKS

AGCcTACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACC




NLELLRISLLLIQSWL

CACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCC




EPVQFLRSVFANSLV

AATCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAACTACTCC




YGASDSNVYDLLKD

GCATTTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAA




LEEGIQTLMGRLEDG

TTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCC




SPRTGQIFKQTYSKF

GACAGCAACGTATACGATCTCCTGAAAGATCTCGAGGAAGGCA




DTNSHNDDALLKNY

TTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACT




GLLYCFRKDMDKVE

GGTCAGATCTTCAAGCAGACTTACTCTAAATTTGATACTAACAG




TFLRIVQCRSVEGSC

CCACAATGACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATT




GFGGTSESATPESGP

GTTTTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGCGTATT




GSEPATSGSETPGTS

GTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGG




ESATPESGPGSEPAT

TACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAA




SGSETPGTSESATPES

CCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGC




GPGTSTEPSEGSAPG

AACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGC




SPAGSPTSTEEGTSES

TCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGG




ATPESGPGSEPATSG

CCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGT




SETPGTSESATPESGP

AGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGA




GSPAGSPTSTEEGSP

AAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACC




AGSPTSTEEGTSTEPS

TCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTGA




EGSAPGTSESATPES

GTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAG




GPGTSESATPESGPG

GAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTA




TSESATPESGPGSEP

CTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAA




ATSGSETPGSEPATS

AGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTA




GSETPGSPAGSPTST

CTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGAA




EEGTSTEPSEGSAPG

TCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCC




TSTEPSEGSAPGSEP

AGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGC




ATSGSETPGTSESAT

CCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGA




PESGPGTSTEPSEGS

ACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTG




AP

AGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGA






AACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA






GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA



 


AM875-
GTSTEPSEGSAPGSE
789
GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCAGGTAGCG
790


hGH-
PATSGSETPGSPAGS

AACCGGCTACTTCCGGTTCTGAAACCCCAGGTAGCCCAGCAGG



AE288
PTSTEEGSTSSTAESP

TTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCAG




GPGTSTPESGSASPG

AATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCA




STSESPSGTAPGSTSE

TCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGG




SPSGTAPGTSTPESGS

TTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTA




ASPGTSTPESGSASP

CTCCTGAAAGCGGTTCCGCTTCTCCAGGTACCTCTACTCCGGAA




GSEPATSGSETPGTS

AGCGGTTCTGCATCTCCAGGTAGCGAACCGGCAACCTCCGGCT




ESATPESGPGSPAGS

CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCCGG




PTSTEEGTSTEPSEGS

CCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGT




APGTSESATPESGPG

ACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGA




TSTEPSEGSAPGTSTE

AAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGT




PSEGSAPGSPAGSPT

CCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGG




STEEGTSTEPSEGSAP

TAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAG




GTSTEPSEGSAPGTS

GAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTA




ESATPESGPGTSESA

CTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAA




TPESGPGTSTEPSEGS

AGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTA




APGTSTEPSEGSAPG

CTCCTGAATCCGGTCCAGGTACCTCTACTGAACCTTCCGAAGGC




TSESATPESGPGTSTE

AGCGCTCCAGGTACCTCTACCGAACCGTCCGAGGGCAGCGCAC




PSEGSAPGSEPATSG

CAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAC




SETPGSPAGSPTSTEE

TTCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCGAACCTG




GSSTPSGATGSPGTP

CTACTTCTGGTTCTGAAACCCCAGGTAGCCCGGCTGGCTCTCCG




GSGTASSSPGSSTPS

ACCTCCACCGAGGAAGGTAGCTCTACCCCGTCTGGTGCTACTGG




GATGSPGTSTEPSEG

TTCTCCAGGTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAG




SAPGTSTEPSEGSAP

GTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTACCTCT




GSEPATSGSETPGSP

ACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAAC




AGSPTSTEEGSPAGS

CGTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCCGG




PTSTEEGTSTEPSEGS

TTCTGAAACTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTG




APGASASGAPSTGGT

AGGAAGGTAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGG




SESATPESGPGSPAG

TACTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTGCAAGC




SPTSTEEGSPAGSPTS

GCAAGCGGCGCGCCAAGCACGGGAGGTACTTCTGAAAGCGCTA




TEEGSTSSTAESPGP

CTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCC




GSTSESPSGTAPGTSP

ACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAG




SGESSTAPGTPGSGT

AAGGTTCTACCAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCT




ASSSPGSSTPSGATG

ACTAGCGAATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTAG




SPGSSPSASTGTGPG

CGGTGAATCTTCTACTGCACCAGGTACCCCTGGCAGCGGTACCG




SEPATSGSETPGTSES

CTTCTTCCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGCT




ATPESGPGSEPATSG

CTCCAGGTTCTAGCCCGTCTGCATCTACCGGTACCGGCCCAGGT




SETPGSTSSTAESPGP

AGCGAACCGGCAACCTCCGGCTCTGAAACTCCAGGTACTTCTG




GSTSSTAESPGPGTSP

AAAGCGCTACTCCGGAATCCGGCCCAGGTAGCGAACCGGCTAC




SGESSTAPGSEPATS

TTCCGGCTCTGAAACCCCAGGTTCCACCAGCTCTACTGCAGAAT




GSETPGSEPATSGSE

CTCCGGGCCCAGGTTCTACTAGCTCTACTGCAGAATCTCCGGGT




TPGTSTEPSEGSAPG

CCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTAG




STSSTAESPGPGTSTP

CGAACCGGCAACCTCTGGCTCTGAAACTCCAGGTAGCGAACCT




ESGSASPGSTSESPSG

GCAACCTCCGGCTCTGAAACCCCAGGTACTTCTACTGAACCTTC




TAPGTSTEPSEGSAP

TGAGGGCAGCGCACCAGGTTCTACCAGCTCTACCGCAGAATCT




GTSTEPSEGSAPGTS

CCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCC




TEPSEGSAPGSSTPSG

AGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTACTT




ATGSPGSSPSASTGT

CTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTACTGA




GPGASPGTSSTGSPG

ACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTCTG




SEPATSGSETPGTSES

AAGGTAGCGCACCAGGTAGCTCTACTCCGTCTGGTGCAACCGG




ATPESGPGSPAGSPT

CTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAG




STEEGSSTPSGATGS

GTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTAGCGAA




PGSSPSASTGTGPGA

CCTGCTACCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGC




SPGTSSTGSPGTSESA

AACTCCGGAGTCTGGTCCAGGTAGCCCTGCAGGTTCTCCTACCT




TPESGPGTSTEPSEGS

CCACTGAGGAAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCC




APGTSTEPSEGSAPG

CCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAGGTGC




FPTIPLSRLFDNAML

TTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTACCTCTGAAA




RAHRLHQLAFDTYQ

GCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGTCT




EFEEAYIPKEQKYSF

GAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTA




LQNPQTSLCFSESIPT

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




PSNREETQQKSNLEL

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




LRISLLLIQSWLEPVQ

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




FLRSVFANSLVYGAS

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




DSNVYDLLKDLEEGI

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




QTLMGRLEDGSPRT

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




GQIFKQTYSKFDTNS

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAA




HNDDALLKNYGLLY

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




CFRKDMDKVETFLRI

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




VQCRSVEGSCGFGG

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT




TSESATPESGPGSEP

ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA




ATSGSETPGTSESAT

AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA




PESGPGSEPATSGSE

AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG




TPGTSESATPESGPG

GCAGCTGTGGTTTCTAAGGTGGTACCTCTGAAAGCGCAACTCCT




TSTEPSEGSAPGSPA

GAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGA




GSPTSTEEGTSESATP

CTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGG




ESGPGSEPATSGSET

TAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTG




PGTSESATPESGPGSP

AAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCG




AGSPTSTEEGSPAGS

TCCGAGGGCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCT




PTSTEEGTSTEPSEGS

CCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGG




APGTSESATPESGPG

CCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGT




TSESATPESGPGTSES

ACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGG




ATPESGPGSEPATSG

CTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCT




SETPGSEPATSGSETP

CCAACTTCTACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGG




GSPAGSPTSTEEGTS

CAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGC




TEPSEGSAPGTSTEPS

CCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTAC




EGSAPGSEPATSGSE

TTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCG




TPGTSESATPESGPG

GCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTC




TSTEPSEGSAP

CGGTTCTGAAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCA






CTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACC






AGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGC






GAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAA






GCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCC






GAGGGCAGCGCACCA



 


AE912-
MAEPAGSPTSTEEGT
791
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
792


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



AE288
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG




GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




TSESATPESGPGSEP

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




ATSGSETPGTSESAT

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




PESGPGSEPATSGSE

GCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




TPGTSESATPESGPG

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




TSTEPSEGSAPGSPA

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSPTSTEEGTSESATP

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




ESGPGSEPATSGSET

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




PGTSESATPESGPGSP

CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




AGSPTSTEEGSPAGS

GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA




PTSTEEGTSTEPSEGS

GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGA




APGTSESATPESGPG

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




TSESATPESGPGTSES

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




ATPESGPGSEPATSG

ACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCAC




SETPGSEPATSGSETP

CAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT




GSPAGSPTSTEEGTS

TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAG




TEPSEGSAPGTSTEPS

CGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCT




EGSAPGSEPATSGSE

GGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTG




TPGTSESATPESGPG

AAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA




TSTEPSEGSAPGFPTI

AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACC




PLSRLFDNAMLRAH

TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTG




RLHQLAFDTYQEFEE

CAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT




AYIPKEQKYSFLQNP

CCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCA




QTSLCFSESIPTPSNR

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




EETQQKSNLELLRIS

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




LLLIQSWLEPVQFLR

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




SVFANSLVYGASDS

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




NVYDLLKDLEEGIQT

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




LMGRLEDGSPRTGQI

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




FKQTYSKFDTNSHN

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAA




DDALLKNYGLLYCF

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




RKDMDKVETFLRIV

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




QCRSVEGSCGFGGTS

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT




ESATPESGPGSEPAT

ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA




SGSETPGTSESATPES

AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA




GPGSEPATSGSETPG

AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG




TSESATPESGPGTSTE

GCAGCTGTGGTTTCTAAGGTGGTACCTCTGAAAGCGCAACTCCT




PSEGSAPGSPAGSPT

GAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGA




STEEGTSESATPESGP

CTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGG




GSEPATSGSETPGTS

TAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTG




ESATPESGPGSPAGS

AAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCG




PTSTEEGSPAGSPTST

TCCGAGGGCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCT




EEGTSTEPSEGSAPG

CCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGG




TSESATPESGPGTSES

CCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGT




ATPESGPGTSESATP

ACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGG




ESGPGSEPATSGSET

CTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCT




PGSEPATSGSETPGSP

CCAACTTCTACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGG




AGSPTSTEEGTSTEPS

CAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGC




EGSAPGTSTEPSEGS

CCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTAC




APGSEPATSGSETPG

TTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCG




TSESATPESGPGTSTE

GCTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTC




PSEGSAP

CGGTTCTGAAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCA






CTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACC






AGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGC






GAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAA






GCGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCC






GAGGGCAGCGCACCA



 


AM923-
MAEPAGSPTSTEEGA
793
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTG
794


hGH-
SPGTSSTGSPGSSTPS

CATCCCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACC



AE288
GATGSPGSSTPSGAT

CCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGG




GSPGTSTEPSEGSAP

TGCTACTGGCTCTCCAGGTACTTCTACTGAACCGTCTGAAGGCA




GSEPATSGSETPGSP

GCGCACCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCC




AGSPTSTEEGSTSST

AGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTA




AESPGPGTSTPESGS

CCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCG




ASPGSTSESPSGTAP

GAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTC




GSTSESPSGTAPGTS

TGGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACTG




TPESGSASPGTSTPES

CTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGT




GSASPGSEPATSGSE

ACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACC




TPGTSESATPESGPG

GGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




SPAGSPTSTEEGTSTE

ACTCCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTC




PSEGSAPGTSESATP

CACTGAGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCT




ESGPGTSTEPSEGSA

CCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTA




PGTSTEPSEGSAPGSP

CTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACC




AGSPTSTEEGTSTEPS

GAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTC




EGSAPGTSTEPSEGS

CTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGG




APGTSESATPESGPG

TAGCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCA




TSESATPESGPGTSTE

CCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTA




PSEGSAPGTSTEPSE

CTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACT




GSAPGTSESATPESG

GAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGT




PGTSTEPSEGSAPGS

CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGA




EPATSGSETPGSPAG

ATCCGGTCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTC




SPTSTEEGSSTPSGAT

CAGGTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGC




GSPGTPGSGTASSSP

CCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCC




GSSTPSGATGSPGTS

GTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTG




TEPSEGSAPGTSTEPS

CTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCT




EGSAPGSEPATSGSE

CTCCAGGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGG




TPGSPAGSPTSTEEG

TACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAA




SPAGSPTSTEEGTSTE

CCGGCAACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTC




PSEGSAPGASASGAP

TCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTT




STGGTSESATPESGP

CTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGC




GSPAGSPTSTEEGSP

TCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTACT




AGSPTSTEEGSTSST

TCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTG




AESPGPGSTSESPSGT

GCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCA




APGTSPSGESSTAPG

ACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCC




TPGSGTASSSPGSSTP

TGGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAG




SGATGSPGSSPSAST

GTACTTCCCCTAGCGGTGAATCTTCTACTGCACCAGGTACCCCT




GTGPGSEPATSGSET

GGCAGCGGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCCGTC




PGTSESATPESGPGS

TGGTGCTACTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCG




EPATSGSETPGSTSST

GTACCGGCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAAC




AESPGPGSTSSTAESP

TCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGGT




GPGTSPSGESSTAPG

AGCGAACCGGCTACTTCCGGCTCTGAAACCCCAGGTTCCACCA




SEPATSGSETPGSEP

GCTCTACTGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACT




ATSGSETPGTSTEPSE

GCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTC




GSAPGSTSSTAESPG

TACCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACT




PGTSTPESGSASPGST

CCAGGTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGGTA




SESPSGTAPGTSTEPS

CTTCTACTGAACCTTCTGAGGGCAGCGCACCAGGTTCTACCAGC




EGSAPGTSTEPSEGS

TCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAG




APGTSTEPSEGSAPG

CGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCA




SSTPSGATGSPGSSPS

CTGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCC




ASTGTGPGASPGTSS

AGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCT




TGSPGSEPATSGSET

CTACCGAACCTTCTGAAGGTAGCGCACCAGGTAGCTCTACTCCG




PGTSESATPESGPGSP

TCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCAC




AGSPTSTEEGSSTPS

TGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTT




GATGSPGSSPSASTG

CTCCAGGTAGCGAACCTGCTACCTCCGGTTCTGAAACCCCAGGT




TGPGASPGTSSTGSP

ACCTCTGAAAGCGCAACTCCGGAGTCTGGTCCAGGTAGCCCTG




GTSESATPESGPGTS

CAGGTTCTCCTACCTCCACTGAGGAAGGTAGCTCTACTCCGTCT




TEPSEGSAPGTSTEPS

GGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGG




EGSAPGFPTIPLSRLF

TACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTC




DNAMLRAHRLHQL

CAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTAC




AFDTYQEFEEAYIPK

CTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTG




EQKYSFLQNPQTSLC

AACCGTCCGAAGGTAGCGCACCAGGTTTTCCGACTATTCCGCTG




FSESIPTPSNREETQQ

TCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCA




KSNLELLRISLLLIQS

CCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACA




WLEPVQFLRSVFAN

TTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACT




SLVYGASDSNVYDL

TCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGA




LKDLEEGIQTLMGRL

GGAAACTCAGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTC




EDGSPRTGQIFKQTY

TGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGT




SKFDTNSHNDDALL

TCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA




KNYGLLYCFRKDMD

CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACC




KVETFLRIVQCRSVE

CTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGAT




GSCGFGGTSESATPE

CTTCAAGCAGACTTACTCTAAATTTGATACTAACAGCCACAATG




SGPGSEPATSGSETP

ACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGT




GTSESATPESGPGSE

AAAGATATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTG




PATSGSETPGTSESA

TCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTACCTCTG




TPESGPGTSTEPSEGS

AAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTAC




APGSPAGSPTSTEEG

CTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCCG




TSESATPESGPGSEP

GAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAA




ATSGSETPGTSESAT

CCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGT




PESGPGSPAGSPTSTE

ACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCCTG




EGSPAGSPTSTEEGT

CTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGC




STEPSEGSAPGTSES

AACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGT




ATPESGPGTSESATP

TCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGG




ESGPGTSESATPESG

CCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGT




PGSEPATSGSETPGS

AGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTAC




EPATSGSETPGSPAG

CGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCT




SPTSTEEGTSTEPSEG

ACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGA




SAPGTSTEPSEGSAP

ATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCC




GSEPATSGSETPGTS

CAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAGGTAG




ESATPESGPGTSTEPS

CGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCAGCA




EGSAP

GGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTC






CGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGC






AGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCC






CAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGTACT






TCTACTGAACCGTCCGAGGGCAGCGCACCA



 


AM1318-
GTSTEPSEGSAPGSE
795
GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCAGGTAGCG
796


hGH-
PATSGSETPGSPAGS

AACCGGCTACTTCCGGTTCTGAAACCCCAGGTAGCCCAGCAGG



AE288
PTSTEEGSTSSTAESP

TTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCAG




GPGTSTPESGSASPG

AATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCA




STSESPSGTAPGSTSE

TCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGG




SPSGTAPGTSTPESGS

TTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTA




ASPGTSTPESGSASP

CTCCTGAAAGCGGTTCCGCTTCTCCAGGTACCTCTACTCCGGAA




GSEPATSGSETPGTS

AGCGGTTCTGCATCTCCAGGTAGCGAACCGGCAACCTCCGGCT




ESATPESGPGSPAGS

CTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCCGG




PTSTEEGTSTEPSEGS

CCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGT




APGTSESATPESGPG

ACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGA




TSTEPSEGSAPGTSTE

AAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGT




PSEGSAPGSPAGSPT

CCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGG




STEEGTSTEPSEGSAP

TAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAG




GTSTEPSEGSAPGTS

GAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTA




ESATPESGPGTSESA

CTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAA




TPESGPGTSTEPSEGS

AGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTA




APGTSTEPSEGSAPG

CTCCTGAATCCGGTCCAGGTACCTCTACTGAACCTTCCGAAGGC




TSESATPESGPGTSTE

AGCGCTCCAGGTACCTCTACCGAACCGTCCGAGGGCAGCGCAC




PSEGSAPGSEPATSG

CAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAC




SETPGSPAGSPTSTEE

TTCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCGAACCTG




GSSTPSGATGSPGTP

CTACTTCTGGTTCTGAAACCCCAGGTAGCCCGGCTGGCTCTCCG




GSGTASSSPGSSTPS

ACCTCCACCGAGGAAGGTAGCTCTACCCCGTCTGGTGCTACTGG




GATGSPGTSTEPSEG

TTCTCCAGGTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAG




SAPGTSTEPSEGSAP

GTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTACCTCT




GSEPATSGSETPGSP

ACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAAC




AGSPTSTEEGSPAGS

CGTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCCGG




PTSTEEGTSTEPSEGS

TTCTGAAACTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTG




APGPEPTGPAPSGGS

AGGAAGGTAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGG




EPATSGSETPGTSES

TACTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTCCAGAAC




ATPESGPGSPAGSPT

CAACGGGGCCGGCCCCAAGCGGAGGTAGCGAACCGGCAACCTC




STEEGTSESATPESGP

CGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAAT




GSPAGSPTSTEEGSP

CCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGA




AGSPTSTEEGTSESA

AGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGC




TPESGPGSPAGSPTST

CCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTG




EEGSPAGSPTSTEEG

GCTCTCCAACTTCTACTGAAGAAGGTACTTCTGAAAGCGCTACT




STSSTAESPGPGSTSE

CCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCAC




SPSGTAPGTSPSGESS

CGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAA




TAPGSTSESPSGTAP

GGTTCTACCAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCTAC




GSTSESPSGTAPGTSP

TAGCGAATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTAGCG




SGESSTAPGTSTEPSE

GTGAATCTTCTACTGCACCAGGTTCTACCAGCGAATCTCCTTCT




GSAPGTSESATPESG

GGCACCGCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACCGC




PGTSESATPESGPGS

ACCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTA




EPATSGSETPGTSES

CTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAA




ATPESGPGTSESATP

AGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTA




ESGPGTSTEPSEGSA

CTCCTGAATCCGGTCCAGGTAGCGAACCGGCAACCTCTGGCTCT




PGTSESATPESGPGT

GAAACCCCAGGTACCTCTGAAAGCGCTACTCCGGAATCTGGTC




STEPSEGSAPGTSPSG

CAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGTCCAGGTAC




ESSTAPGTSPSGESST

CTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAA




APGTSPSGESSTAPG

GCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCC




TSTEPSEGSAPGSPA

GAAGGTAGCGCACCAGGTACCTCCCCTAGCGGCGAATCTTCTA




GSPTSTEEGTSTEPSE

CTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCA




GSAPGSSPSASTGTG

GGTACCTCCCCTAGCGGTGAATCTTCTACCGCACCAGGTACTTC




PGSSTPSGATGSPGS

TACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGT




STPSGATGSPGSSTPS

TCTCCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGA




GATGSPGSSTPSGAT

GGGTAGCGCACCAGGTTCTAGCCCTTCTGCTTCCACCGGTACCG




GSPGASPGTSSTGSP

GCCCAGGTAGCTCTACTCCGTCTGGTGCAACTGGCTCTCCAGGT




GASASGAPSTGGTSP

AGCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTAGCTCTAC




SGESSTAPGSTSSTA

CCCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTG




ESPGPGTSPSGESSTA

GTGCAACCGGCTCCCCAGGTGCATCCCCGGGTACTAGCTCTACC




PGTSESATPESGPGT

GGTTCTCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAG




STEPSEGSAPGTSTEP

GTACTTCTCCGAGCGGTGAATCTTCTACCGCACCAGGTTCTACT




SEGSAPGSSPSASTG

AGCTCTACCGCTGAATCTCCGGGCCCAGGTACTTCTCCGAGCGG




TGPGSSTPSGATGSP

TGAATCTTCTACTGCTCCAGGTACCTCTGAAAGCGCTACTCCGG




GASPGTSSTGSPGTS

AGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCT




TPESGSASPGTSPSGE

CCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTT




SSTAPGTSPSGESSTA

CTAGCCCTTCTGCATCTACTGGTACTGGCCCAGGTAGCTCTACT




PGTSESATPESGPGS

CCTTCTGGTGCTACCGGCTCTCCAGGTGCTTCTCCGGGTACTAG




EPATSGSETPGTSTEP

CTCTACCGGTTCTCCAGGTACTTCTACTCCGGAAAGCGGTTCCG




SEGSAPGSTSESPSGT

CATCTCCAGGTACTTCTCCTAGCGGTGAATCTTCTACTGCTCCA




APGSTSESPSGTAPG

GGTACCTCTCCTAGCGGCGAATCTTCTACTGCTCCAGGTACTTC




TSTPESGSASPGSPA

TGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCT




GSPTSTEEGTSESATP

ACTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGA




ESGPGTSTEPSEGSA

AGGTAGCGCACCAGGTTCTACCAGCGAATCCCCTTCTGGTACTG




PGSPAGSPTSTEEGT

CTCCAGGTTCTACCAGCGAATCCCCTTCTGGCACCGCACCAGGT




SESATPESGPGSEPA

ACTTCTACCCCTGAAAGCGGCTCCGCTTCTCCAGGTAGCCCGGC




TSGSETPGSSTPSGA

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




TGSPGASPGTSSTGS

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




PGSSTPSGATGSPGS

GCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGA




TSESPSGTAPGTSPSG

AGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGT




ESSTAPGSTSSTAESP

AGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTAGCTCTA




GPGSSTPSGATGSPG

CCCCGTCTGGTGCTACCGGTTCCCCAGGTGCTTCTCCTGGTACT




ASPGTSSTGSPGTPG

AGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTGGTGCTAC




SGTASSSPGSPAGSP

TGGCTCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACTGCTC




TSTEEGSPAGSPTSTE

CAGGTACTTCCCCTAGCGGTGAATCTTCTACTGCTCCAGGTTCT




EGTSTEPSEGSAPGF

ACCAGCTCTACCGCAGAATCTCCGGGTCCAGGTAGCTCTACCCC




PTIPLSRLFDNAMLR

TTCTGGTGCAACCGGCTCTCCAGGTGCATCCCCGGGTACCAGCT




AHRLHQLAFDTYQE

CTACCGGTTCTCCAGGTACTCCGGGTAGCGGTACCGCTTCTTCC




FEEAYIPKEQKYSFL

TCTCCAGGTAGCCCTGCTGGCTCTCCGACTTCTACTGAGGAAGG




QNPQTSLCFSESIPTP

TAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGGTACTTCTA




SNREETQQKSNLELL

CCGAACCTTCCGAAGGTAGCGCTCCAGGTTTTCCGACTATTCCG




RISLLLIQSWLEPVQF

CTGTCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCT




LRSVFANSLVYGAS

GCACCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcT




DSNVYDLLKDLEEGI

ACATTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACA




QTLMGRLEDGSPRT

GACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATC




GQIFKQTYSKFDTNS

GCGAGGAAACTCAGCAAAAGTCCAATCTGGAACTACTCCGCAT




HNDDALLKNYGLLY

TTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTC




CFRKDMDKVETFLRI

TGCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCCGAC




VQCRSVEGSCGFGG

AGCAACGTATACGATCTCCTGAAAGATCTCGAGGAAGGCATTC




TSESATPESGPGSEP

AGACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGT




ATSGSETPGTSESAT

CAGATCTTCAAGCAGACTTACTCTAAATTTGATACTAACAGCCA




PESGPGSEPATSGSE

CAATGACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTT




TPGTSESATPESGPG

TTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGCGTATTGTT




TSTEPSEGSAPGSPA

CAGTGTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTAC




GSPTSTEEGTSESATP

CTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCT




ESGPGSEPATSGSET

GCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAA




PGTSESATPESGPGSP

CCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGGCTCT




AGSPTSTEEGSPAGS

GAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCC




PTSTEEGTSTEPSEGS

CAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAG




APGTSESATPESGPG

CCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAA




TSESATPESGPGTSES

GCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACCTC




ATPESGPGSEPATSG

CGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGT




SETPGSEPATSGSETP

CCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGA




GSPAGSPTSTEEGTS

AGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTT




TEPSEGSAPGTSTEPS

CTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAG




EGSAPGSEPATSGSE

CGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTC




TPGTSESATPESGPG

CTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




TSTEPSEGSAP

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG






GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC






AGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAAC






CTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAG






GGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCTGAAA






CCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCAGGT






ACTTCTACTGAACCGTCCGAGGGCAGCGCACCA





*Sequence name reflects N- to C-terminus configuration of the growth factor and XTEN components













TABLE 37







Exemplary GHXTEN comprising growth hormones, XTEN and cleavage sequences











GHXTEN

SEQ ID

SEQ ID


Name*
Amino Acid Sequence
NO:
DNA Nucleotide Sequence
NO:





AE912-
MAEPAGSPTSTEEGT
797
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
798


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



Thrombin-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE144
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




TSESATPESGPGSEP

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




ATSGSETPGTSESAT

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




PESGPGSEPATSGSE

GCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




TPGTSESATPESGPG

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




TSTEPSEGSAPGSPA

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSPTSTEEGTSESATP

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




ESGPGSEPATSGSET

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




PGTSESATPESGPGSP

CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




AGSPTSTEEGSPAGS

GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA




PTSTEEGTSTEPSEGS

GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGA




APGTSESATPESGPG

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




TSESATPESGPGTSES

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




ATPESGPGSEPATSG

ACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCAC




SETPGSEPATSGSETP

CAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT




GSPAGSPTSTEEGTS

TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAG




TEPSEGSAPGTSTEPS

CGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCT




EGSAPGSEPATSGSE

GGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTG




TPGTSESATPESGPG

AAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA




TSTEPSEGSAPGFPTI

AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACC




PLSRLFDNAMLRAH

TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTG




RLHQLAFDTYQEFEE

CAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT




AYIPKEQKYSFLQNP

CCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCA




QTSLCFSESIPTPSNR

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




EETQQKSNLELLRIS

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




LLLIQSWLEPVQFLR

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




SVFANSLVYGASDS

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




NVYDLLKDLEEGIQT

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




LMGRLEDGSPRTGQI

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




FKQTYSKFDTNSHN

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAA




DDALLKNYGLLYCF

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




RKDMDKVETFLRIV

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




QCRSVEGSCGFGLTP

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT




RSLLVGGGGSEPATS

ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA




GSETPGTSESATPES

AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA




GPGSEPATSGSETPG

AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG




SPAGSPTSTEEGTSTE

GCAGCTGTGGTTTCTAAGGTctgaccccgcgcagcctgctggtgggcggcGGTG




PSEGSAPGSEPATSG

GTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACTTCT




SETPGSEPATSGSETP

GAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTA




GSEPATSGSETPGTS

CCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCTCCGACT




TEPSEGSAPGTSESA

TCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGGGTAGCG




TPESGPGSEPATSGS

CTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAGG




ETPGTSTEPSEGSAP

TAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGTAGCGAA






CCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTACCGAACC






TTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCT






GAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGA






CTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA



 


AE912-
MAEPAGSPTSTEEGT
799
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
800


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



FXIa-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE144
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




TSESATPESGPGSEP

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




ATSGSETPGTSESAT

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




PESGPGSEPATSGSE

GCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




TPGTSESATPESGPG

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




TSTEPSEGSAPGSPA

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSPTSTEEGTSESATP

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




ESGPGSEPATSGSET

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




PGTSESATPESGPGSP

CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




AGSPTSTEEGSPAGS

GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA




PTSTEEGTSTEPSEGS

GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGA




APGTSESATPESGPG

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




TSESATPESGPGTSES

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




ATPESGPGSEPATSG

ACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCAC




SETPGSEPATSGSETP

CAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT




GSPAGSPTSTEEGTS

TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAG




TEPSEGSAPGTSTEPS

CGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCT




EGSAPGSEPATSGSE

GGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTG




TPGTSESATPESGPG

AAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA




TSTEPSEGSAPGFPTI

AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACC




PLSRLFDNAMLRAH

TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTG




RLHQLAFDTYQEFEE

CAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT




AYIPKEQKYSFLQNP

CCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCA




QTSLCFSESIPTPSNR

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




EETQQKSNLELLRIS

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




LLLIQSWLEPVQFLR

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




SVFANSLVYGASDS

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




NVYDLLKDLEEGIQT

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




LMGRLEDGSPRTGQI

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




FKQTYSKFDTNSHN

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAA




DDALLKNYGLLYCF

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




RKDMDKVETFLRIV

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




QCRSVEGSCGFGGG

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT




KLTRVVGGGGSEPA

ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA




TSGSETPGTSESATPE

AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA




SGPGSEPATSGSETP

AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG




GSPAGSPTSTEEGTS

GCAGCTGTGGTTTCTAAGGTggcggcaaactgacccgcgtggtgggcggcGGTG




TEPSEGSAPGSEPAT

GTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACTTCT




SGSETPGSEPATSGS

GAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTA




ETPGSEPATSGSETP

CCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCTCCGACT




GTSTEPSEGSAPGTS

TCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGGGTAGCG




ESATPESGPGSEPAT

CTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAGG




SGSETPGTSTEPSEGS

TAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGTAGCGAA




AP

CCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTACCGAACC






TTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCT






GAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGA






CTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA



 


AE912-
MAEPAGSPTSTEEGT
801
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
802


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



Elastase-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE144
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




TSESATPESGPGSEP

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




ATSGSETPGTSESAT

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




PESGPGSEPATSGSE

GCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




TPGTSESATPESGPG

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




TSTEPSEGSAPGSPA

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSPTSTEEGTSESATP

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




ESGPGSEPATSGSET

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




PGTSESATPESGPGSP

CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




AGSPTSTEEGSPAGS

GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA




PTSTEEGTSTEPSEGS

GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGA




APGTSESATPESGPG

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




TSESATPESGPGTSES

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




ATPESGPGSEPATSG

ACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCAC




SETPGSEPATSGSETP

CAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT




GSPAGSPTSTEEGTS

TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAG




TEPSEGSAPGTSTEPS

CGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCT




EGSAPGSEPATSGSE

GGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTG




TPGTSESATPESGPG

AAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA




TSTEPSEGSAPGFPTI

AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACC




PLSRLFDNAMLRAH

TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTG




RLHQLAFDTYQEFEE

CAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT




AYIPKEQKYSFLQNP

CCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCA




QTSLCFSESIPTPSNR

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




EETQQKSNLELLRIS

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




LLLIQSWLEPVQFLR

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




SVFANSLVYGASDS

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




NVYDLLKDLEEGIQT

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




LMGRLEDGSPRTGQI

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




FKQTYSKFDTNSHN

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAA




DDALLKNYGLLYCF

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




RKDMDKVETFLRIV

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




QCRSVEGSCGFGGG

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT




LGPVSGVPGGSEPAT

ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA




SGSETPGTSESATPES

AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA




GPGSEPATSGSETPG

AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG




SPAGSPTSTEEGTSTE

GCAGCTGTGGTTTCTAAGGTggcggcctgggcccggtgagcggcgtgccgGGT




PSEGSAPGSEPATSG

GGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACTT




SETPGSEPATSGSETP

CTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAACCTGC




GSEPATSGSETPGTS

TACCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCTCCGA




TEPSEGSAPGTSESA

CTTCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGGGTAGC




TPESGPGSEPATSGS

GCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAG




ETPGTSTEPSEGSAP

GTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGTAGCGA






ACCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTACCGAAC






CTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCC






TGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAG






ACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA



 


AE912-
MAEPAGSPTSTEEGT
803
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
804


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



MMP-17-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE144
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATTPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




TSESATPESGPGSEP

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




ATSGSETPGTSESAT

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




PESGPGSEPATSGSE

GCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




TPGTSESATPESGPG

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




TSTEPSEGSAPGSPA

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSPTSTEEGTSESATP

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




ESGPGSEPATSGSET

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




PGTSESATPESGPGSP

CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




AGSPTSTEEGSPAGS

GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA




PTSTEEGTSTEPSEGS

GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGA




APGTSESATPESGPG

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




TSESATPESGPGTSES

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




ATPESGPGSEPATSG

ACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCAC




SETPGSEPATSGSETP

CAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT




GSPAGSPTSTEEGTS

TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAG




TEPSEGSAPGTSTEPS

CGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCT




EGSAPGSEPATSGSE

GGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTG




TPGTSESATPESGPG

AAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA




TSTEPSEGSAPGFPTI

AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACC




PLSRLFDNAMLRAH

TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTG




RLHQLAFDTYQEFEE

CAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT




AYIPKEQKYSFLQNP

CCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCA




QTSLCFSESIPTPSNR

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




EETQQKSNLELLRIS

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




LLLIQSWLEPVQFLR

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




SVFANSLVYGASDS

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




NVYDLLKDLEEGIQT

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




LMGRLEDGSPRTGQI

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




FKQTYSKFDTNSHN

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAA




DDALLKNYGLLYCF

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




RKDMDKVETFLRIV

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




QCRSVEGSCGFGAPL

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT




GLRLRGGGGSEPATS

ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA




GSETPGTSESATPES

AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA




GPGSEPATSGSETPG

AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG




SPAGSPTSTEEGTSTE

GCAGCTGTGGTTTCTAAGGTgcgccgctgggcctgcgcctgcgcggcggcGGTG




PSEGSAPGSEPATSG

GTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACTTCT




SETPGSEPATSGSETP

GAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTA




GSEPATSGSETPGTS

CCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCTCCGACT




TEPSEGSAPGTSESA

TCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGGGTAGCG




TPESGPGSEPATSGS

CTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCAGG




ETPGTSTEPSEGSAP

TAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGTAGCGAA






CCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTACCGAACC






TTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCT






GAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGA






CTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA



 


AE912-
MAEPAGSPTSTEEGT
805
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
806


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



Thrombin-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE288
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




TSESATPESGPGSEP

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




ATSGSETPGTSESAT

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




PESGPGSEPATSGSE

GCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




TPGTSESATPESGPG

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




TSTEPSEGSAPGSPA

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSPTSTEEGTSESATP

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




ESGPGSEPATSGSET

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




PGTSESATPESGPGSP

CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




AGSPTSTEEGSPAGS

GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA




PTSTEEGTSTEPSEGS

GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGA




APGTSESATPESGPG

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




TSESATPESGPGTSES

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




ATPESGPGSEPATSG

ACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCAC




SETPGSEPATSGSETP

CAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT




GSPAGSPTSTEEGTS

TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAG




TEPSEGSAPGTSTEPS

CGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCT




EGSAPGSEPATSGSE

GGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTG




TPGTSESATPESGPG

AAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA




TSTEPSEGSAPGFPTI

AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACC




PLSRLFDNAMLRAH

TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTG




RLHQLAFDTYQEFEE

CAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT




AYIPKEQKYSFLQNP

CCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCA




QTSLCFSESIPTPSNR

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




EETQQKSNLELLRIS

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




LLLIQSWLEPVQFLR

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




SVFANSLVYGASDS

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




NVYDLLKDLEEGIQT

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




LMGRLEDGSPRTGQI

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




FKQTYSKFDTNSHN

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAA




DDALLKNYGLLYCF

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




RKDMDKVETFLRIV

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




QCRSVEGSCGFGLTP

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT




RSLLVGGGGTSESAT

ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA




PESGPGSEPATSGSE

AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA




TPGTSESATPESGPG

AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG




SEPATSGSETPGTSES

GCAGCTGTGGTTTCTAAGGTctgaccccgcgcagcctgctggtgggcggcGGTG




ATPESGPGTSTEPSE

GTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGA




GSAPGSPAGSPTSTE

ACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCG




EGTSESATPESGPGS

CAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGG




EPATSGSETPGTSES

CTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTG




ATPESGPGSPAGSPT

GCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGG




STEEGSPAGSPTSTEE

TAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTG




GTSTEPSEGSAPGTS

AAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAAC




ESATPESGPGTSESA

CTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTG




TPESGPGTSESATPES

AGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGA




GPGSEPATSGSETPG

GGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGT




SEPATSGSETPGSPA

ACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGA




GSPTSTEEGTSTEPSE

AAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCT




GSAPGTSTEPSEGSA

ACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGA




PGSEPATSGSETPGT

ATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCC




SESATPESGPGTSTEP

CAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAG




SEGSAP

CCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTG






AACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCT






GAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCTG






AAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCC






AGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA



 


AE912-
MAEPAGSPTSTEEGT
807
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
808


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



FXIa-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE288
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




TSESATPESGPGSEP

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




ATSGSETPGTSESAT

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




PESGPGSEPATSGSE

GCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




TPGTSESATPESGPG

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




TSTEPSEGSAPGSPA

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSPTSTEEGTSESATP

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




ESGPGSEPATSGSET

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




PGTSESATPESGPGSP

CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




AGSPTSTEEGSPAGS

GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA




PTSTEEGTSTEPSEGS

GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGA




APGTSESATPESGPG

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




TSESATPESGPGTSES

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




ATPESGPGSEPATSG

ACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCAC




SETPGSEPATSGSETP

CAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT




GSPAGSPTSTEEGTS

TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAG




TEPSEGSAPGTSTEPS

CGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCT




EGSAPGSEPATSGSE

GGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTG




TPGTSESATPESGPG

AAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA




TSTEPSEGSAPGFPTI

AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACC




PLSRLFDNAMLRAH

TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTG




RLHQLAFDTYQEFEE

CAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT




AYIPKEQKYSFLQNP

CCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCA




QTSLCFSESIPTPSNR

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




EETQQKSNLELLRIS

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




LLLIQSWLEPVQFLR

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




SVFANSLVYGASDS

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




NVYDLLKDLEEGIQT

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




LMGRLEDGSPRTGQI

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




FKQTYSKFDTNSHN

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAA




DDALLKNYGLLYCF

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




RKDMDKVETFLRIV

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




QCRSVEGSCGFGGG

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT




KLTRVVGGGGTSES

ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA




ATPESGPGSEPATSG

AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA




SETPGTSESATPESGP

AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG




GSEPATSGSETPGTS

GCAGCTGTGGTTTCTAAGGTggcggcaaactgacccgcgtggtgggcggcGGTG




ESATPESGPGTSTEPS

GTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGA




EGSAPGSPAGSPTST

ACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCG




EEGTSESATPESGPG

CAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGG




SEPATSGSETPGTSES

CTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTG




ATPESGPGSPAGSPT

GCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGG




STEEGSPAGSPTSTEE

TAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTG




GTSTEPSEGSAPGTS

AAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAAC




ESATPESGPGTSESA

CTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTG




TPESGPGTSESATPES

AGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGA




GPGSEPATSGSETPG

GGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGT




SEPATSGSETPGSPA

ACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGA




GSPTSTEEGTSTEPSE

AAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCT




GSAPGTSTEPSEGSA

ACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGA




PGSEPATSGSETPGT

ATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCC




SESATPESGPGTSTEP

CAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAG




SEGSAP

CCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTG






AACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCT






GAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCTG






AAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCC






AGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA



 


AE912-
MAEPAGSPTSTEEGT
809
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
810


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



Elastase-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE288
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




TSESATPESGPGSEP

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




ATSGSETPGTSESAT

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




PESGPGSEPATSGSE

GCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




TPGTSESATPESGPG

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




TSTEPSEGSAPGSPA

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSPTSTEEGTSESATP

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




ESGPGSEPATSGSET

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




PGTSESATPESGPGSP

CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




AGSPTSTEEGSPAGS

GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA




PTSTEEGTSTEPSEGS

GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGA




APGTSESATPESGPG

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




TSESATPESGPGTSES

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




ATPESGPGSEPATSG

ACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCAC




SETPGSEPATSGSETP

CAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT




GSPAGSPTSTEEGTS

TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAG




TEPSEGSAPGTSTEPS

CGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCT




EGSAPGSEPATSGSE

GGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTG




TPGTSESATPESGPG

AAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA




TSTEPSEGSAPGFPTI

AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACC




PLSRLFDNAMLRAH

TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTG




RLHQLAFDTYQEFEE

CAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT




AYIPKEQKYSFLQNP

CCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCA




QTSLCFSESIPTPSNR

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




EETQQKSNLELLRIS

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




LLLIQSWLEPVQFLR

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




SVFANSLVYGASDS

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




NVYDLLKDLEEGIQT

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




LMGRLEDGSPRTGQI

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




FKQTYSKFDTNSHN

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAA




DDALLKNYGLLYCF

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




RKDMDKVETFLRIV

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




QCRSVEGSCGFGGG

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT




LGPVSGVPGGTSESA

ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA




TPESGPGSEPATSGS

AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA




ETPGTSESATPESGP

AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG




GSEPATSGSETPGTS

GCAGCTGTGGTTTCTAAGGTggcggcctgggcccggtgagcggcgtgccgGGT




ESATPESGPGTSTEPS

GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCG




EGSAPGSPAGSPTST

AACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGC




EEGTSESATPESGPG

GCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTG




SEPATSGSETPGTSES

GCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCT




ATPESGPGSPAGSPT

GGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAG




STEEGSPAGSPTSTEE

GTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAA




ESATPESGPGTSESA

CCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCT




TPESGPGTSESATPES

GAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCG




GPGSEPATSGSETPG

AGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGG




SEPATSGSETPGSPA

TACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTG




GSPTSTEEGTSTEPSE

AAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGC




GSAPGTSTEPSEGSA

TACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGG




PGSEPATSGSETPGT

AATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACC




SESATPESGPGTSTEP

CCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTA




SEGSAP

GCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACT






GAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTT






CTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTC






TGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCC






CAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA



 


AE912-
MAEPAGSPTSTEEGT
811
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
812


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



MMP-17-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE288
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




TSESATPESGPGSEP

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




ATSGSETPGTSESAT

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




PESGPGSEPATSGSE

GCAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




TPGTSESATPESGPG

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




TSTEPSEGSAPGSPA

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSPTSTEEGTSESATP

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




ESGPGSEPATSGSET

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




PGTSESATPESGPGSP

CAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAA




AGSPTSTEEGSPAGS

GAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTA




PTSTEEGTSTEPSEGS

GCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGA




APGTSESATPESGPG

AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTC




TSESATPESGPGTSES

CGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCT




ATPESGPGSEPATSG

ACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCAC




SETPGSEPATSGSETP

CAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACT




GSPAGSPTSTEEGTS

TCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAG




TEPSEGSAPGTSTEPS

CGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCT




EGSAPGSEPATSGSE

GGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTG




TPGTSESATPESGPG

AAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGA




TSTEPSEGSAPGFPTI

AGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTACC




PLSRLFDNAMLRAH

TCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTG




RLHQLAFDTYQEFEE

CAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT




AYIPKEQKYSFLQNP

CCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCA




QTSLCFSESIPTPSNR

GCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT




EETQQKSNLELLRIS

AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGA




LLLIQSWLEPVQFLR

TACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGCAGA




SVFANSLVYGASDS

AGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC




NVYDLLKDLEEGIQT

GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGCAAA




LMGRLEDGSPRTGQI

AGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG




FKQTYSKFDTNSHN

AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAA




DDALLKNYGLLYCF

TAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGATCTCC




RKDMDKVETFLRIV

TGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTCT




QCRSVEGSCGFGAPL

CGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAGACTT




GLRLRGGGGTSESA

ACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCTTCTA




TPESGPGSEPATSGS

AAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAA




ETPGTSESATPESGP

AGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGG




GSEPATSGSETPGTS

GCAGCTGTGGTTTCTAAGGTgcgccgctgggcctgcgcctgcgcggcggcGGTG




ESATPESGPGTSTEPS

GTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGA




EGSAPGSPAGSPTST

ACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCG




EEGTSESATPESGPG

CAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCTCTGG




SEPATSGSETPGTSES

CTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTG




ATPESGPGSPAGSPT

GCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGG




STEEGSPAGSPTSTEE

TAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTG




GTSTEPSEGSAPGTS

AAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAAC




ESATPESGPGTSESA

CTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTACTCCTG




TPESGPGTSESATPES

AGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGA




GPGSEPATSGSETPG

GGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGT




SEPATSGSETPGSPA

ACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGA




GSPTSTEEGTSTEPSE

AAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCT




GSAPGTSTEPSEGSA

ACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACCCCGGA




PGSEPATSGSETPGT

ATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCC




SESATPESGPGTSTEP

CAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAG




SEGSAP

CCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTG






AACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCT






GAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCTGGCTCTG






AAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCC






AGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA



 


AM923-
MAEPAGSPTSTEEGA
813
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTG
814


hGH-
SPGTSSTGSPGSSTPS

CATCCCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACC



Thrombin-
GATGSPGSSTPSGAT

CCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGG



AE144
GSPGTSTEPSEGSAP

TGCTACTGGCTCTCCAGGTACTTCTACTGAACCGTCTGAAGGCA




GSEPATSGSETPGSP

GCGCACCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCC




AGSPTSTEEGSTSST

AGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTA




AESPGPGTSTPESGS

CCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCG




ASPGSTSESPSGTAP

GAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTC




GSTSESPSGTAPGTS

TGGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACTG




TPESGSASPGTSTPES

CTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGT




GSASPGSEPATSGSE

ACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACC




TPGTSESATPESGPG

GGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




SPAGSPTSTEEGTSTE

ACTCCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTC




PSEGSAPGTSESATP

CACTGAGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCT




ESGPGTSTEPSEGSA

CCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTA




PGTSTEPSEGSAPGSP

CTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACC




AGSPTSTEEGTSTEPS

GAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTC




EGSAPGTSTEPSEGS

CTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGG




APGTSESATPESGPG

TAGCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCA




TSESATPESGPGTSTE

CCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTA




PSEGSAPGTSTEPSE

CTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACT




GSAPGTSESATPESG

GAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGT




PGTSTEPSEGSAPGS

CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGA




EPATSGSETPGSPAG

ATCCGGTCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTC




SPTSTEEGSSTPSGAT

CAGGTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGC




GSPGTPGSGTASSSP

CCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCC




GSSTPSGATGSPGTS

GTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTG




TEPSEGSAPGTSTEPS

CTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCT




EGSAPGSEPATSGSE

CTCCAGGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGG




TPGSPAGSPTSTEEG

TACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAA




SPAGSPTSTEEGTSTE

CCGGCAACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTC




PSEGSAPGASASGAP

TCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTT




STGGTSESATPESGP

CTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGC




GSPAGSPTSTEEGSP

TCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTACT




AGSPTSTEEGSTSST

TCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTG




AESPGPGSTSESPSGT

GCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCA




APGTSPSGESSTAPG

ACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCC




TPGSGTASSSPGSSTP

TGGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAG




SGATGSPGSSPSAST

GTACTTCCCCTAGCGGTGAATCTTCTACTGCACCAGGTACCCCT




GTGPGSEPATSGSET

GGCAGCGGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCCGTC




PGTSESATPESGPGS

TGGTGCTACTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCG




EPATSGSETPGSTSST

GTACCGGCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAAC




AESPGPGSTSSTAESP

TCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGGT




GPGTSPSGESSTAPG

AGCGAACCGGCTACTTCCGGCTCTGAAACCCCAGGTTCCACCA




SEPATSGSETPGSEP

GCTCTACTGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACT




ATSGSETPGTSTEPSE

GCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTC




GSAPGSTSSTAESPG

TACCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACT




PGTSTPESGSASPGST

CCAGGTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGGTA




SESPSGTAPGTSTEPS

CTTCTACTGAACCTTCTGAGGGCAGCGCACCAGGTTCTACCAGC




EGSAPGTSTEPSEGS

TCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAG




APGTSTEPSEGSAPG

CGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCA




SSTPSGATGSPGSSPS

CTGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCC




ASTGTGPGASPGTSS

AGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCT




TGSPGSEPATSGSET

CTACCGAACCTTCTGAAGGTAGCGCACCAGGTAGCTCTACTCCG




PGTSESATPESGPGSP

TCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCAC




AGSPTSTEEGSSTPS

TGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTT




GATGSPGSSPSASTG

CTCCAGGTAGCGAACCTGCTACCTCCGGTTCTGAAACCCCAGGT




TGPGASPGTSSTGSP

ACCTCTGAAAGCGCAACTCCGGAGTCTGGTCCAGGTAGCCCTG




GTSESATPESGPGTS

CAGGTTCTCCTACCTCCACTGAGGAAGGTAGCTCTACTCCGTCT




TEPSEGSAPGTSTEPS

GGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGG




EGSAPGFPTIPLSRLF

TACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTC




DNAMLRAHRLHQL

CAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTAC




AFDTYQEFEEAYIPK

CTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTG




EQKYSFLQNPQTSLC

AACCGTCCGAAGGTAGCGCACCAGGTTTTCCGACTATTCCGCTG




FSESIPTPSNREETQQ

TCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCA




KSNLELLRISLLLIQS

CCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACA




WLEPVQFLRSVFAN

TTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACT




SLVYGASDSNVYDL

TCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGA




LKDLEEGIQTLMGRL

GGAAACTCAGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTC




EDGSPRTGQIFKQTY

TGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGT




SKFDTNSHNDDALL

TCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA




KNYGLLYCFRKDMD

CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACC




KVETFLRIVQCRSVE

CTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGAT




GSCGFGLTPRSLLVG

CTTCAAGCAGACTTACTCTAAATTTGATACTAACAGCCACAATG




GGGSEPATSGSETPG

ACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGT




TSESATPESGPGSEP

AAAGATATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTG




ATSGSETPGSPAGSP

TCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTctgaccccgcgcagc




TSTEEGTSTEPSEGS

ctgctggtgggcggcGGTGGTAGCGAACCGGCAACTTCCGGCTCTGAA




APGSEPATSGSETPG

ACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGCCCAGG




SEPATSGSETPGSEP

TAGCGAACCTGCTACCTCTGGCTCTGAAACCCCAGGTAGCCCG




ATSGSETPGTSTEPSE

GCAGGCTCTCCGACTTCCACCGAGGAAGGTACCTCTACTGAAC




GSAPGTSESATPESG

CTTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCTGG




PGSEPATSGSETPGT

CTCTGAAACCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAA




STEPSEGSAP

ACTCCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACTCCAG






GTACCTCTACCGAACCTTCCGAAGGCAGCGCACCAGGTACTTCT






GAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTA






CTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAA






GGTAGCGCACCA



 


AM923-
MAEPAGSPTSTEEGA
815
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTG
816


hGH-
SPGTSSTGSPGSSTPS

CATCCCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACC



FXIa-
GATGSPGSSTPSGAT

CCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGG



AE144
GSPGTSTEPSEGSAP

TGCTACTGGCTCTCCAGGTACTTCTACTGAACCGTCTGAAGGCA




GSEPATSGSETPGSP

GCGCACCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCC




AGSPTSTEEGSTSST

AGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTA




AESPGPGTSTPESGS

CCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCG




ASPGSTSESPSGTAP

GAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTC




GSTSESPSGTAPGTS

TGGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACTG




TPESGSASPGTSTPES

CTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGT




GSASPGSEPATSGSE

ACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACC




TPGTSESATPESGPG

GGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




SPAGSPTSTEEGTSTE

ACTCCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTC




PSEGSAPGTSESATP

CACTGAGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCT




ESGPGTSTEPSEGSA

CCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTA




PGTSTEPSEGSAPGSP

CTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACC




AGSPTSTEEGTSTEPS

GAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTC




EGSAPGTSTEPSEGS

CTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGG




APGTSESATPESGPG

TAGCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCA




TSESATPESGPGTSTE

CCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTA




PSEGSAPGTSTEPSE

CTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACT




GSAPGTSESATPESG

GAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGT




PGTSTEPSEGSAPGS

CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGA




EPATSGSETPGSPAG

ATCCGGTCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTC




SPTSTEEGSSTPSGAT

CAGGTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGC




GSPGTPGSGTASSSP

CCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCC




GSSTPSGATGSPGTS

GTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTG




TEPSEGSAPGTSTEPS

CTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCT




EGSAPGSEPATSGSE

CTCCAGGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGG




TPGSPAGSPTSTEEG

TACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAA




SPAGSPTSTEEGTSTE

CCGGCAACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTC




PSEGSAPGASASGAP

TCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTT




STGGTSESATPESGP

CTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGC




GSPAGSPTSTEEGSP

TCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTACT




AGSPTSTEEGSTSST

TCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTG




AESPGPGSTSESPSGT

GCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCA




APGTSPSGESSTAPG

ACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCC




TPGSGTASSSPGSSTP

TGGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAG




SGATGSPGSSPSAST

GTACTTCCCCTAGCGGTGAATCTTCTACTGCACCAGGTACCCCT




GTGPGSEPATSGSET

GGCAGCGGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCCGTC




PGTSESATPESGPGS

TGGTGCTACTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCG




EPATSGSETPGSTSST

GTACCGGCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAAC




AESPGPGSTSSTAESP

TCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGGT




GPGTSPSGESSTAPG

AGCGAACCGGCTACTTCCGGCTCTGAAACCCCAGGTTCCACCA




SEPATSGSETPGSEP

GCTCTACTGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACT




ATSGSETPGTSTEPSE

GCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTC




GSAPGSTSSTAESPG

TACCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACT




PGTSTPESGSASPGST

CCAGGTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGGTA




SESPSGTAPGTSTEPS

CTTCTACTGAACCTTCTGAGGGCAGCGCACCAGGTTCTACCAGC




EGSAPGTSTEPSEGS

TCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAG




APGTSTEPSEGSAPG

CGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCA




SSTPSGATGSPGSSPS

CTGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCC




ASTGTGPGASPGTSS

AGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCT




TGSPGSEPATSGSET

CTACCGAACCTTCTGAAGGTAGCGCACCAGGTAGCTCTACTCCG




PGTSESATPESGPGSP

TCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCAC




AGSPTSTEEGSSTPS

TGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTT




GATGSPGSSPSASTG

CTCCAGGTAGCGAACCTGCTACCTCCGGTTCTGAAACCCCAGGT




TGPGASPGTSSTGSP

ACCTCTGAAAGCGCAACTCCGGAGTCTGGTCCAGGTAGCCCTG




GTSESATPESGPGTS

CAGGTTCTCCTACCTCCACTGAGGAAGGTAGCTCTACTCCGTCT




TEPSEGSAPGTSTEPS

GGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGG




EGSAPGFPTTPLSRLF

TACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTC




DNAMLRAHRLHQL

CAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTAC




AFDTYQEFEEAYIPK

CTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTG




EQKYSFLQNPQTSLC

AACCGTCCGAAGGTAGCGCACCAGGTTTTCCGACTATTCCGCTG




FSESIPTPSNREETQQ

TCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCA




KSNLELLRISLLLIQS

CCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACA




WLEPVQFLRSVFAN

TTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACT




SLVYGASDSNVYDL

TCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGA




LKDLEEGIQTLMGRL

GGAAACTCAGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTC




EDGSPRTGQIFKQTY

TGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGT




SKFDTNSHNDDALL

TCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA




KNYGLLYCFRKDMD

CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACC




KVETFLRIVQCRSVE

CTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGAT




GSCGFGGGKLTRVV

CTTCAAGCAGACTTACTCTAAATTTGATACTAACAGCCACAATG




GGGGSEPATSGSETP

ACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGT




GTSESATPESGPGSE

AAAGATATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTG




PATSGSETPGSPAGS

TCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTggcggcaaactgacc




PTSTEEGTSTEPSEGS

cgcgtggtgggcggcGGTGGTAGCGAACCGGCAACTTCCGGCTCTGAA




APGSEPATSGSETPG

ACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGCCCAGG




SEPATSGSETPGSEP

TAGCGAACCTGCTACCTCTGGCTCTGAAACCCCAGGTAGCCCG




ATSGSETPGTSTEPSE

GCAGGCTCTCCGACTTCCACCGAGGAAGGTACCTCTACTGAAC




GSAPGTSESATPESG

CTTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCTGG




PGSEPATSGSETPGT

CTCTGAAACCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAA




STEPSEGSAP

ACTCCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACTCCAG






GTACCTCTACCGAACCTTCCGAAGGCAGCGCACCAGGTACTTCT






GAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTA






CTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAA






GGTAGCGCACCA



 


AM923-
MAEPAGSPTSTEEGA
817
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTG
818


hGH-
SPGTSSTGSPGSSTPS

CATCCCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACC



Elastase-
GATGSPGSSTPSGAT

CCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGG



AE144
GSPGTSTEPSEGSAP

TGCTACTGGCTCTCCAGGTACTTCTACTGAACCGTCTGAAGGCA




GSEPATSGSETPGSP

GCGCACCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCC




AGSPTSTEEGSTSST

AGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTA




AESPGPGTSTPESGS

CCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCG




ASPGSTSESPSGTAP

GAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTC




GSTSESPSGTAPGTS

TGGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACTG




TPESGSASPGTSTPES

CTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGT




GSASPGSEPATSGSE

ACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACC




TPGTSESATPESGPG

GGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




SPAGSPTSTEEGTSTE

ACTCCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTC




PSEGSAPGTSESATP

CACTGAGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCT




ESGPGTSTEPSEGSA

CCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTA




PGTSTEPSEGSAPGSP

CTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACC




AGSPTSTEEGTSTEPS

GAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTC




EGSAPGTSTEPSEGS

CTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGG




APGTSESATPESGPG

TAGCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCA




TSESATPESGPGTSTE

CCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTA




PSEGSAPGTSTEPSE

CTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACT




GSAPGTSESATPESG

GAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGT




PGTSTEPSEGSAPGS

CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGA




EPATSGSETPGSPAG

ATCCGGTCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTC




SPTSTEEGSSTPSGAT

CAGGTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGC




GSPGTPGSGTASSSP

CCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCC




GSSTPSGATGSPGTS

GTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTG




TEPSEGSAPGTSTEPS

CTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCT




EGSAPGSEPATSGSE

CTCCAGGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGG




TPGSPAGSPTSTEEG

TACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAA




SPAGSPTSTEEGTSTE

CCGGCAACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTC




PSEGSAPGASASGAP

TCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTT




STGGTSESATPESGP

CTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGC




GSPAGSPTSTEEGSP

TCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTACT




AGSPTSTEEGSTSST

TCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTG




AESPGPGSTSESPSGT

GCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCA




APGTSPSGESSTAPG

ACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCC




TPGSGTASSSPGSSTP

TGGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAG




SGATGSPGSSPSAST

GTACTTCCCCTAGCGGTGAATCTTCTACTGCACCAGGTACCCCT




GTGPGSEPATSGSET

GGCAGCGGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCCGTC




PGTSESATPESGPGS

TGGTGCTACTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCG




EPATSGSETPGSTSST

GTACCGGCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAAC




AESPGPGSTSSTAESP

TCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGGT




GPGTSPSGESSTAPG

AGCGAACCGGCTACTTCCGGCTCTGAAACCCCAGGTTCCACCA




SEPATSGSETPGSEP

GCTCTACTGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACT




ATSGSETPGTSTEPSE

GCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTC




GSAPGSTSSTAESPG

TACCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACT




PGTSTPESGSASPGST

CCAGGTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGGTA




SESPSGTAPGTSTEPS

CTTCTACTGAACCTTCTGAGGGCAGCGCACCAGGTTCTACCAGC




EGSAPGTSTEPSEGS

TCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAG




APGTSTEPSEGSAPG

CGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCA




SSTPSGATGSPGSSPS

CTGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCC




ASTGTGPGASPGTSS

AGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCT




TGSPGSEPATSGSET

CTACCGAACCTTCTGAAGGTAGCGCACCAGGTAGCTCTACTCCG




PGTSESATPESGPGSP

TCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCAC




AGSPTSTEEGSSTPS

TGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTT




GATGSPGSSPSASTG

CTCCAGGTAGCGAACCTGCTACCTCCGGTTCTGAAACCCCAGGT




TGPGASPGTSSTGSP

ACCTCTGAAAGCGCAACTCCGGAGTCTGGTCCAGGTAGCCCTG




GTSESATPESGPGTS

CAGGTTCTCCTACCTCCACTGAGGAAGGTAGCTCTACTCCGTCT




TEPSEGSAPGTSTEPS

GGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGG




EGSAPGFPTIPLSRLF

TACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTC




DNAMLRAHRLHQL

CAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTAC




AFDTYQEFEEAYIPK

CTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTG




EQKYSFLQNPQTSLC

AACCGTCCGAAGGTAGCGCACCAGGTTTTCCGACTATTCCGCTG




FSESIPTPSNREETQQ

TCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCA




KSNLELLRISLLLIQS

CCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACA




WLEPVQFLRSVFAN

TTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACT




SLVYGASDSNVYDL

TCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGA




LKDLEEGIQTLMGRL

GGAAACTCAGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTC




EDGSPRTGQIFKQTY

TGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGT




SKFDTNSHNDDALL

TCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA




KNYGLLYCFRKDMD

CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACC




KVETFLRIVQCRSVE

CTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGAT




GSCGFGGGLGPVSG

CTTCAAGCAGACTTACTCTAAATTTGATACTAACAGCCACAATG




VPGGSEPATSGSETP

ACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGT




GTSESATPESGPGSE

AAAGATATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTG




PATSGSETPGSPAGS

TCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTggcggcctgggcccg




PTSTEEGTSTEPSEGS

gtgagcggcgtgccgGGTGGTAGCGAACCGGCAACTTCCGGCTCTGAA




APGSEPATSGSETPG

ACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGCCCAGG




SEPATSGSETPGSEP

TAGCGAACCTGCTACCTCTGGCTCTGAAACCCCAGGTAGCCCG




ATSGSETPGTSTEPSE

GCAGGCTCTCCGACTTCCACCGAGGAAGGTACCTCTACTGAAC




GSAPGTSESATPESG

CTTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCTGG




PGSEPATSGSETPGT

CTCTGAAACCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAA




STEPSEGSAP

ACTCCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACTCCAG






GTACCTCTACCGAACCTTCCGAAGGCAGCGCACCAGGTACTTCT






GAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTA






CTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAA






GGTAGCGCACCA



 


AM923-
MAEPAGSPTSTEEGA
819
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTG
820


hGH-
SPGTSSTGSPGSSTPS

CATCCCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACC



MMP-17-
GATGSPGSSTPSGAT

CCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGG



AE144
GSPGTSTEPSEGSAP

TGCTACTGGCTCTCCAGGTACTTCTACTGAACCGTCTGAAGGCA




GSEPATSGSETPGSP

GCGCACCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCC




AGSPTSTEEGSTSST

AGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTA




AESPGPGTSTPESGS

CCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCG




ASPGSTSESPSGTAP

GAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTC




GSTSESPSGTAPGTS

TGGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACTG




TPESGSASPGTSTPES

CTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGT




GSASPGSEPATSGSE

ACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACC




TPGTSESATPESGPG

GGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




SPAGSPTSTEEGTSTE

ACTCCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTC




PSEGSAPGTSESATP

CACTGAGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCT




ESGPGTSTEPSEGSA

CCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTA




PGTSTEPSEGSAPGSP

CTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACC




AGSPTSTEEGTSTEPS

GAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTC




EGSAPGTSTEPSEGS

CTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGG




APGTSESATPESGPG

TAGCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCA




TSESATPESGPGTSTE

CCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTA




PSEGSAPGTSTEPSE

CTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACT




GSAPGTSESATPESG

GAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGT




PGTSTEPSEGSAPGS

CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGA




EPATSGSETPGSPAG

ATCCGGTCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTC




SPTSTEEGSSTPSGAT

CAGGTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGC




GSPGTPGSGTASSSP

CCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCC




GSSTPSGATGSPGTS

GTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTG




TEPSEGSAPGTSTEPS

CTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCT




EGSAPGSEPATSGSE

CTCCAGGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGG




TPGSPAGSPTSTEEG

TACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAA




SPAGSPTSTEEGTSTE

CCGGCAACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTC




PSEGSAPGASASGAP

TCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTT




STGGTSESATPESGP

CTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGC




GSPAGSPTSTEEGSP

TCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTACT




AGSPTSTEEGSTSST

TCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTG




AESPGPGSTSESPSGT

GCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCA




APGTSPSGESSTAPG

ACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCC




TPGSGTASSSPGSSTP

TGGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAG




SGATGSPGSSPSAST

GTACTTCCCCTAGCGGTGAATCTTCTACTGCACCAGGTACCCCT




GTGPGSEPATSGSET

GGCAGCGGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCCGTC




PGTSESATPESGPGS

TGGTGCTACTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCG




EPATSGSETPGSTSST

GTACCGGCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAAC




AESPGPGSTSSTAESP

TCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGGT




GPGTSPSGESSTAPG

AGCGAACCGGCTACTTCCGGCTCTGAAACCCCAGGTTCCACCA




SEPATSGSETPGSEP

GCTCTACTGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACT




ATSGSETPGTSTEPSE

GCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTC




GSAPGSTSSTAESPG

TACCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACT




PGTSTPESGSASPGST

CCAGGTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGGTA




SESPSGTAPGTSTEPS

CTTCTACTGAACCTTCTGAGGGCAGCGCACCAGGTTCTACCAGC




EGSAPGTSTEPSEGS

TCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAG




APGTSTEPSEGSAPG

CGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCA




SSTPSGATGSPGSSPS

CTGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCC




ASTGTGPGASPGTSS

AGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCT




TGSPGSEPATSGSET

CTACCGAACCTTCTGAAGGTAGCGCACCAGGTAGCTCTACTCCG




PGTSESATPESGPGSP

TCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCAC




AGSPTSTEEGSSTPS

TGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTT




GATGSPGSSPSASTG

CTCCAGGTAGCGAACCTGCTACCTCCGGTTCTGAAACCCCAGGT




TGPGASPGTSSTGSP

ACCTCTGAAAGCGCAACTCCGGAGTCTGGTCCAGGTAGCCCTG




GTSESATPESGPGTS

CAGGTTCTCCTACCTCCACTGAGGAAGGTAGCTCTACTCCGTCT




TEPSEGSAPGTSTEPS

GGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGG




EGSAPGFPTIPLSRLF

TACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTC




DNAMLRAHRLHQL

CAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTAC




AFDTYQEFEEAYIPK

CTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTG




EQKYSFLQNPQTSLC

AACCGTCCGAAGGTAGCGCACCAGGTTTTCCGACTATTCCGCTG




FSESIPTPSNREETQQ

TCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCA




KSNLELLRISLLLIQS

CCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACA




WLEPVQFLRSVFAN

TTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACT




SLVYGASDSNVYDL

TCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGA




LKDLEEGIQTLMGRL

GGAAACTCAGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTC




EDGSPRTGQIFKQTY

TGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGT




SKFDTNSHNDDALL

TCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA




KNYGLLYCFRKDMD

CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACC




KVETFLRIVQCRSVE

CTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGAT




GSCGFGAPLGLRLR

CTTCAAGCAGACTTACTCTAAATTTGATACTAACAGCCACAATG




GGGGSEPATSGSETP

ACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGT




GTSESATPESGPGSE

AAAGATATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTG




PATSGSETPGSPAGS

TCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTgcgccgctgggcctg




PTSTEEGTSTEPSEGS

cgcctgcgcggcggcGGTGGTAGCGAACCGGCAACTTCCGGCTCTGAA




APGSEPATSGSETPG

ACCCCAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGCCCAGG




SEPATSGSETPGSEP

TAGCGAACCTGCTACCTCTGGCTCTGAAACCCCAGGTAGCCCG




ATSGSETPGTSTEPSE

GCAGGCTCTCCGACTTCCACCGAGGAAGGTACCTCTACTGAAC




GSAPGTSESATPESG

CTTCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCTGG




PGSEPATSGSETPGT

CTCTGAAACCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAA




STEPSEGSAP

ACTCCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACTCCAG






GTACCTCTACCGAACCTTCCGAAGGCAGCGCACCAGGTACTTCT






GAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTA






CTTCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAA






GGTAGCGCACCA



 


AM923-
MAEPAGSPTSTEEGA
821
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTG
822


hGH-
SPGTSSTGSPGSSTPS

CATCCCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACC



Thrombin-
GATGSPGSSTPSGAT

CCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGG



AE288
GSPGTSTEPSEGSAP

TGCTACTGGCTCTCCAGGTACTTCTACTGAACCGTCTGAAGGCA




GSEPATSGSETPGSP

GCGCACCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCC




AGSPTSTEEGSTSST

AGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTA




AESPGPGTSTPESGS

CCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCG




ASPGSTSESPSGTAP

GAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTC




GSTSESPSGTAPGTS

TGGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACTG




TPESGSASPGTSTPES

CTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGT




GSASPGSEPATSGSE

ACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACC




TPGTSESATPESGPG

GGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




SPAGSPTSTEEGTSTE

ACTCCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTC




PSEGSAPGTSESATP

CACTGAGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCT




ESGPGTSTEPSEGSA

CCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTA




PGTSTEPSEGSAPGSP

CTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACC




AGSPTSTEEGTSTEPS

GAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTC




EGSAPGTSTEPSEGS

CTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGG




APGTSESATPESGPG

TAGCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCA




TSESATPESGPGTSTE

CCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTA




PSEGSAPGTSTEPSE

CTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACT




GSAPGTSESATPESG

GAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGT




PGTSTEPSEGSAPGS

CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGA




EPATSGSETPGSPAG

ATCCGGTCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTC




SPTSTEEGSSTPSGAT

CAGGTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGC




GSPGTPGSGTASSSP

CCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCC




GSSTPSGATGSPGTS

GTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTG




TEPSEGSAPGTSTEPS

CTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCT




EGSAPGSEPATSGSE

CTCCAGGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGG




TPGSPAGSPTSTEEG

TACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAA




SPAGSPTSTEEGTSTE

CCGGCAACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTC




PSEGSAPGASASGAP

TCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTT




STGGTSESATPESGP

CTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGC




GSPAGSPTSTEEGSP

TCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTACT




AGSPTSTEEGSTSST

TCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTG




AESPGPGSTSESPSGT

GCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCA




APGTSPSGESSTAPG

ACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCC




TPGSGTASSSPGSSTP

TGGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAG




SGATGSPGSSPSAST

GTACTTCCCCTAGCGGTGAATCTTCTACTGCACCAGGTACCCCT




GTGPGSEPATSGSET

GGCAGCGGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCCGTC




PGTSESATPESGPGS

TGGTGCTACTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCG




EPATSGSETPGSTSST

GTACCGGCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAAC




AESPGPGSTSSTAESP

TCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGGT




GPGTSPSGESSTAPG

AGCGAACCGGCTACTTCCGGCTCTGAAACCCCAGGTTCCACCA




SEPATSGSETPGSEP

GCTCTACTGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACT




ATSGSETPGTSTEPSE

GCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTC




GSAPGSTSSTAESPG

TACCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACT




PGTSTPESGSASPGST

CCAGGTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGGTA




SESPSGTAPGTSTEPS

CTTCTACTGAACCTTCTGAGGGCAGCGCACCAGGTTCTACCAGC




EGSAPGTSTEPSEGS

TCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAG




APGTSTEPSEGSAPG

CGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCA




SSTPSGATGSPGSSPS

CTGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCC




ASTGTGPGASPGTSS

AGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCT




TGSPGSEPATSGSET

CTACCGAACCTTCTGAAGGTAGCGCACCAGGTAGCTCTACTCCG




PGTSESATPESGPGSP

TCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCAC




AGSPTSTEEGSSTPS

TGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTT




GATGSPGSSPSASTG

CTCCAGGTAGCGAACCTGCTACCTCCGGTTCTGAAACCCCAGGT




TGPGASPGTSSTGSP

ACCTCTGAAAGCGCAACTCCGGAGTCTGGTCCAGGTAGCCCTG




GTSESATPESGPGTS

CAGGTTCTCCTACCTCCACTGAGGAAGGTAGCTCTACTCCGTCT




TEPSEGSAPGTSTEPS

GGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGG




EGSAPGFPTIPLSRLF

TACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTC




DNAMLRAHRLHQL

CAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTAC




AFDTYQEFEEAYIPK

CTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTG




EQKYSFLQNPQTSLC

AACCGTCCGAAGGTAGCGCACCAGGTTTTCCGACTATTCCGCTG




FSESIPTPSNREETQQ

TCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCA




KSNLELLRISLLLIQS

CCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACA




WLEPVQFLRSVFAN

TTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACT




SLVYGASDSNVYDL

TCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGA




LKDLEEGIQTLMGRL

GGAAACTCAGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTC




EDGSPRTGQIFKQTY

TGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGT




SKFDTNSHNDDALL

TCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA




KNYGLLYCFRKDMD

CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACC




KVETFLRIVQCRSVE

CTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGAT




GSCGFGLTPRSLLVG

CTTCAAGCAGACTTACTCTAAATTTGATACTAACAGCCACAATG




GGGTSESATPESGPG

ACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGT




SEPATSGSETPGTSES

AAAGATATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTG




ATPESGPGSEPATSG

TCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTctgaccccgcgcagc




SETPGTSESATPESGP

ctgctggtgggcggcGGTGGTACCTCTGAAAGCGCAACTCCTGAGTCTG




GTSTEPSEGSAPGSP

GCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGG




AGSPTSTEEGTSESA

TACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAA




TPESGPGSEPATSGS

CCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGC




ETPGTSESATPESGP

TACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGG




GSPAGSPTSTEEGSP

GCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGA




AGSPTSTEEGTSTEPS

AGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGT




EGSAPGTSESATPES

AGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTG




GPGTSESATPESGPG

AAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTC




TSESATPESGPGSEP

TCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTT




ATSGSETPGSEPATS

CTACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGC




GSETPGSPAGSPTST

ACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGT




EEGTSTEPSEGSAPG

ACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGA




TSTEPSEGSAPGSEP

AAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACT




ATSGSETPGTSESAT

TCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTC




PESGPGTSTEPSEGS

TGAAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAG




AP

GAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTA






CCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCT






GCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTA






CTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGC






AGCGCACCA



 


AM923-
MAEPAGSPTSTEEGA
823
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTG
824


hGH-
SPGTSSTGSPGSSTPS

CATCCCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACC



FXIa-
GATGSPGSSTPSGAT

CCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGG



AE288
GSPGTSTEPSEGSAP

TGCTACTGGCTCTCCAGGTACTTCTACTGAACCGTCTGAAGGCA




GSEPATSGSETPGSP

GCGCACCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCC




AGSPTSTEEGSTSST

AGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTA




AESPGPGTSTPESGS

CCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCG




ASPGSTSESPSGTAP

GAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTC




GSTSESPSGTAPGTS

TGGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACTG




TPESGSASPGTSTPES

CTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGT




GSASPGSEPATSGSE

ACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACC




TPGTSESATPESGPG

GGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




SPAGSPTSTEEGTSTE

ACTCCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTC




PSEGSAPGTSESATP

CACTGAGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCT




ESGPGTSTEPSEGSA

CCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTA




PGTSTEPSEGSAPGSP

CTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACC




AGSPTSTEEGTSTEPS

GAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTC




EGSAPGTSTEPSEGS

CTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGG




APGTSESATPESGPG

TAGCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCA




TSESATPESGPGTSTE

CCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTA




PSEGSAPGTSTEPSE

CTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACT




GSAPGTSESATPESG

GAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGT




PGTSTEPSEGSAPGS

CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGA




EPATSGSETPGSPAG

ATCCGGTCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTC




SPTSTEEGSSTPSGAT

CAGGTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGC




GSPGTPGSGTASSSP

CCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCC




GSSTPSGATGSPGTS

GTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTG




TEPSEGSAPGTSTEPS

CTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCT




EGSAPGSEPATSGSE

CTCCAGGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGG




TPGSPAGSPTSTEEG

TACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAA




SPAGSPTSTEEGTSTE

CCGGCAACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTC




PSEGSAPGASASGAP

TCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTT




STGGTSESATPESGP

CTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGC




GSPAGSPTSTEEGSP

TCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTACT




AGSPTSTEEGSTSST

TCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTG




AESPGPGSTSESPSGT

GCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCA




APGTSPSGESSTAPG

ACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCC




TPGSGTASSSPGSSTP

TGGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAG




SGATGSPGSSPSAST

GTACTTCCCCTAGCGGTGAATCTTCTACTGCACCAGGTACCCCT




GTGPGSEPATSGSET

GGCAGCGGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCCGTC




PGTSESATPESGPGS

TGGTGCTACTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCG




EPATSGSETPGSTSST

GTACCGGCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAAC




AESPGPGSTSSTAESP

TCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGGT




GPGTSPSGESSTAPG

AGCGAACCGGCTACTTCCGGCTCTGAAACCCCAGGTTCCACCA




SEPATSGSETPGSEP

GCTCTACTGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACT




ATSGSETPGTSTEPSE

GCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTC




GSAPGSTSSTAESPG

TACCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACT




PGTSTPESGSASPGST

CCAGGTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGGTA




SESPSGTAPGTSTEPS

CTTCTACTGAACCTTCTGAGGGCAGCGCACCAGGTTCTACCAGC




EGSAPGTSTEPSEGS

TCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAG




APGTSTEPSEGSAPG

CGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCA




SSTPSGATGSPGSSPS

CTGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCC




ASTGTGPGASPGTSS

AGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCT




TGSPGSEPATSGSET

CTACCGAACCTTCTGAAGGTAGCGCACCAGGTAGCTCTACTCCG




PGTSESATPESGPGSP

TCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCAC




AGSPTSTEEGSSTPS

TGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTT




GATGSPGSSPSASTG

CTCCAGGTAGCGAACCTGCTACCTCCGGTTCTGAAACCCCAGGT




TGPGASPGTSSTGSP

ACCTCTGAAAGCGCAACTCCGGAGTCTGGTCCAGGTAGCCCTG




GTSESATPESGPGTS

CAGGTTCTCCTACCTCCACTGAGGAAGGTAGCTCTACTCCGTCT




TEPSEGSAPGTSTEPS

GGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGG




EGSAPGFPTTPLSRLF

TACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTC




DNAMLRAHRLHQL

CAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTAC




AFDTYQEFEEAYIPK

CTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTG




EQKYSFLQNPQTSLC

AACCGTCCGAAGGTAGCGCACCAGGTTTTCCGACTATTCCGCTG




FSESIPTPSNREETQQ

TCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCA




KSNLELLRISLLLIQS

CCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACA




WLEPVQFLRSVFAN

TTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACT




SLVYGASDSNVYDL

TCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGA




LKDLEEGIQTLMGRL

GGAAACTCAGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTC




EDGSPRTGQIFKQTY

TGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGT




SKFDTNSHNDDALL

TCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA




KNYGLLYCFRKDMD

CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACC




KVETFLRIVQCRSVE

CTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGAT




GSCGFGGGKLTRVV

CTTCAAGCAGACTTACTCTAAATTTGATACTAACAGCCACAATG




GGGGTSESATPESGP

ACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGT




GSEPATSGSETPGTS

AAAGATATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTG




ESATPESGPGSEPAT

TCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTggcggcaaactgacc




SGSETPGTSESATPES

cgcgtggtgggcggcGGTGGTACCTCTGAAAGCGCAACTCCTGAGTCT




GPGTSTEPSEGSAPG

GGCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAG




SPAGSPTSTEEGTSES

GTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGA




ATPESGPGSEPATSG

ACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGC




SETPGTSESATPESGP

GCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGA




GSPAGSPTSTEEGSP

GGGCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACC




AGSPTSTEEGTSTEPS

GAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAG




EGSAPGTSESATPES

GTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCT




GPGTSESATPESGPG

GAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCT




TSESATPESGPGSEP

CTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACT




ATSGSETPGSEPATS

TCTACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCG




GSETPGSPAGSPTST

CACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGG




EEGTSTEPSEGSAPG

TACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTG




TSTEPSEGSAPGSEP

AAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTAC




ATSGSETPGTSESAT

TTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTT




PESGPGTSTEPSEGS

CTGAAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGA




AP

GGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGT






ACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAAC






CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT






ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG






CAGCGCACCA



 


AM923-
MAEPAGSPTSTEEGA
825
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTG
826


hGH-
SPGTSSTGSPGSSTPS

CATCCCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACC



Elastase-
GATGSPGSSTPSGAT

CCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGG



AE288
GSPGTSTEPSEGSAP

TGCTACTGGCTCTCCAGGTACTTCTACTGAACCGTCTGAAGGCA




GSEPATSGSETPGSP

GCGCACCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCC




AGSPTSTEEGSTSST

AGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTA




AESPGPGTSTPESGS

CCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCG




ASPGSTSESPSGTAP

GAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTC




GSTSESPSGTAPGTS

TGGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACTG




TPESGSASPGTSTPES

CTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGT




GSASPGSEPATSGSE

ACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACC




TPGTSESATPESGPG

GGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




SPAGSPTSTEEGTSTE

ACTCCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTC




PSEGSAPGTSESATP

CACTGAGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCT




ESGPGTSTEPSEGSA

CCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTA




PGTSTEPSEGSAPGSP

CTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACC




AGSPTSTEEGTSTEPS

GAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTC




EGSAPGTSTEPSEGS

CTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGG




APGTSESATPESGPG

TAGCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCA




TSESATPESGPGTSTE

CCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTA




PSEGSAPGTSTEPSE

CTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACT




GSAPGTSESATPESG

GAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGT




PGTSTEPSEGSAPGS

CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGA




EPATSGSETPGSPAG

ATCCGGTCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTC




SPTSTEEGSSTPSGAT

CAGGTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGC




GSPGTPGSGTASSSP

CCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCC




GSSTPSGATGSPGTS

GTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTG




TEPSEGSAPGTSTEPS

CTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCT




EGSAPGSEPATSGSE

CTCCAGGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGG




TPGSPAGSPTSTEEG

TACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAA




SPAGSPTSTEEGTSTE

CCGGCAACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTC




PSEGSAPGASASGAP

TCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTT




STGGTSESATPESGP

CTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGC




GSPAGSPTSTEEGSP

TCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTACT




AGSPTSTEEGSTSST

TCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTG




AESPGPGSTSESPSGT

GCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCA




APGTSPSGESSTAPG

ACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCC




TPGSGTASSSPGSSTP

TGGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAG




SGATGSPGSSPSAST

GTACTTCCCCTAGCGGTGAATCTTCTACTGCACCAGGTACCCCT




GTGPGSEPATSGSET

GGCAGCGGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCCGTC




PGTSESATPESGPGS

TGGTGCTACTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCG




EPATSGSETPGSTSST

GTACCGGCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAAC




AESPGPGSTSSTAESP

TCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGGT




GPGTSPSGESSTAPG

AGCGAACCGGCTACTTCCGGCTCTGAAACCCCAGGTTCCACCA




SEPATSGSETPGSEP

GCTCTACTGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACT




ATSGSETPGTSTEPSE

GCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTC




GSAPGSTSSTAESPG

TACCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACT




PGTSTPESGSASPGST

CCAGGTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGGTA




SESPSGTAPGTSTEPS

CTTCTACTGAACCTTCTGAGGGCAGCGCACCAGGTTCTACCAGC




EGSAPGTSTEPSEGS

TCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAG




APGTSTEPSEGSAPG

CGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCA




SSTPSGATGSPGSSPS

CTGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCC




ASTGTGPGASPGTSS

AGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCT




TGSPGSEPATSGSET

CTACCGAACCTTCTGAAGGTAGCGCACCAGGTAGCTCTACTCCG




PGTSESATPESGPGSP

TCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCAC




AGSPTSTEEGSSTPS

TGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTT




GATGSPGSSPSASTG

CTCCAGGTAGCGAACCTGCTACCTCCGGTTCTGAAACCCCAGGT




TGPGASPGTSSTGSP

ACCTCTGAAAGCGCAACTCCGGAGTCTGGTCCAGGTAGCCCTG




GTSESATPESGPGTS

CAGGTTCTCCTACCTCCACTGAGGAAGGTAGCTCTACTCCGTCT




TEPSEGSAPGTSTEPS

GGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGG




EGSAPGFPTIPLSRLF

TACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTC




DNAMLRAHRLHQL

CAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTAC




AFDTYQEFEEAYIPK

CTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTG




EQKYSFLQNPQTSLC

AACCGTCCGAAGGTAGCGCACCAGGTTTTCCGACTATTCCGCTG




FSESIPTPSNREETQQ

TCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCA




KSNLELLRISLLLIQS

CCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACA




WLEPVQFLRSVFAN

TTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACT




SLVYGASDSNVYDL

TCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGA




LKDLEEGIQTLMGRL

GGAAACTCAGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTC




EDGSPRTGQIFKQTY

TGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGT




SKFDTNSHNDDALL

TCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA




KNYGLLYCFRKDMD

CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACC




KVETFLRIVQCRSVE

CTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGAT




GSCGFGGGLGPVSG

CTTCAAGCAGACTTACTCTAAATTTGATACTAACAGCCACAATG




VPGGTSESATPESGP

ACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGT




GSEPATSGSETPGTS

AAAGATATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTG




ESATPESGPGSEPAT

TCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTggcggcctgggcccg




SGSETPGTSESATPES

gtgagcggcgtgccgGGTGGTACCTCTGAAAGCGCAACTCCTGAGTCTG




GPGTSTEPSEGSAPG

GCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGG




SPAGSPTSTEEGTSES

TACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAA




ATPESGPGSEPATSG

CCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGC




SETPGTSESATPESGP

TACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGG




GSPAGSPTSTEEGSP

GCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGA




AGSPTSTEEGTSTEPS

AGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGT




EGSAPGTSESATPES

AGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTG




GPGTSESATPESGPG

AAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTC




TSESATPESGPGSEP

TCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTT




ATSGSETPGSEPATS

CTACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCGC




GSETPGSPAGSPTST

ACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGT




EEGTSTEPSEGSAPG

ACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGA




TSTEPSEGSAPGSEP

AAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACT




ATSGSETPGTSESAT

TCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTC




PESGPGTSTEPSEGS

TGAAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAG




AP

GAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGTA






CCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCT






GCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTA






CTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGC






AGCGCACCA



 


AM923-
MAEPAGSPTSTEEGA
827
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTG
828


hGH-
SPGTSSTGSPGSSTPS

CATCCCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACC



MMP-17-
GATGSPGSSTPSGAT

CCGTCTGGTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGG



AE288
GSPGTSTEPSEGSAP

TGCTACTGGCTCTCCAGGTACTTCTACTGAACCGTCTGAAGGCA




GSEPATSGSETPGSP

GCGCACCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCC




AGSPTSTEEGSTSST

AGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTA




AESPGPGTSTPESGS

CCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCG




ASPGSTSESPSGTAP

GAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTC




GSTSESPSGTAPGTS

TGGCACTGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACTG




TPESGSASPGTSTPES

CTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGT




GSASPGSEPATSGSE

ACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACC




TPGTSESATPESGPG

GGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




SPAGSPTSTEEGTSTE

ACTCCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTC




PSEGSAPGTSESATP

CACTGAGGAAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCT




ESGPGTSTEPSEGSA

CCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTA




PGTSTEPSEGSAPGSP

CTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACC




AGSPTSTEEGTSTEPS

GAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTC




EGSAPGTSTEPSEGS

CTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGG




APGTSESATPESGPG

TAGCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGCGCA




TSESATPESGPGTSTE

CCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTA




PSEGSAPGTSTEPSE

CTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACT




GSAPGTSESATPESG

GAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGT




PGTSTEPSEGSAPGS

CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGA




EPATSGSETPGSPAG

ATCCGGTCCAGGTACTTCTACTGAACCTTCCGAAGGTAGCGCTC




SPTSTEEGSSTPSGAT

CAGGTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTAGC




GSPGTPGSGTASSSP

CCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCC




GSSTPSGATGSPGTS

GTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTG




TEPSEGSAPGTSTEPS

CTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCT




EGSAPGSEPATSGSE

CTCCAGGTACCTCTACCGAACCGTCCGAGGGTAGCGCACCAGG




TPGSPAGSPTSTEEG

TACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCGAA




SPAGSPTSTEEGTSTE

CCGGCAACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTC




PSEGSAPGASASGAP

TCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTT




STGGTSESATPESGP

CTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGC




GSPAGSPTSTEEGSP

TCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTACT




AGSPTSTEEGSTSST

TCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTG




AESPGPGSTSESPSGT

GCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCA




APGTSPSGESSTAPG

ACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCC




TPGSGTASSSPGSSTP

TGGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAG




SGATGSPGSSPSAST

GTACTTCCCCTAGCGGTGAATCTTCTACTGCACCAGGTACCCCT




GTGPGSEPATSGSET

GGCAGCGGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCCGTC




PGTSESATPESGPGS

TGGTGCTACTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCG




EPATSGSETPGSTSST

GTACCGGCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAAC




AESPGPGSTSSTAESP

TCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGGT




GPGTSPSGESSTAPG

AGCGAACCGGCTACTTCCGGCTCTGAAACCCCAGGTTCCACCA




SEPATSGSETPGSEP

GCTCTACTGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACT




ATSGSETPGTSTEPSE

GCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTC




GSAPGSTSSTAESPG

TACCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACT




PGTSTPESGSASPGST

CCAGGTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGGTA




SESPSGTAPGTSTEPS

CTTCTACTGAACCTTCTGAGGGCAGCGCACCAGGTTCTACCAGC




EGSAPGTSTEPSEGS

TCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAG




APGTSTEPSEGSAPG

CGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCA




SSTPSGATGSPGSSPS

CTGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCC




ASTGTGPGASPGTSS

AGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCT




TGSPGSEPATSGSET

CTACCGAACCTTCTGAAGGTAGCGCACCAGGTAGCTCTACTCCG




PGTSESATPESGPGSP

TCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCAC




AGSPTSTEEGSSTPS

TGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTT




GATGSPGSSPSASTG

CTCCAGGTAGCGAACCTGCTACCTCCGGTTCTGAAACCCCAGGT




TGPGASPGTSSTGSP

ACCTCTGAAAGCGCAACTCCGGAGTCTGGTCCAGGTAGCCCTG




GTSESATPESGPGTS

CAGGTTCTCCTACCTCCACTGAGGAAGGTAGCTCTACTCCGTCT




TEPSEGSAPGTSTEPS

GGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGG




EGSAPGFPTIPLSRLF

TACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTC




DNAMLRAHRLHQL

CAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTAC




AFDTYQEFEEAYIPK

CTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTG




EQKYSFLQNPQTSLC

AACCGTCCGAAGGTAGCGCACCAGGTTTTCCGACTATTCCGCTG




FSESIPTPSNREETQQ

TCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCTGCA




KSNLELLRISLLLIQS

CCAGCTGGCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACA




WLEPVQFLRSVFAN

TTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAGACT




SLVYGASDSNVYDL

TCTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAATCGCGA




LKDLEEGIQTLMGRL

GGAAACTCAGCAAAAGTCCAATCTGGAACTACTCCGCATTTCTC




EDGSPRTGQIFKQTY

TGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCTGCGT




SKFDTNSHNDDALL

TCCGTCTTCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA




KNYGLLYCFRKDMD

CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACC




KVETFLRIVQCRSVE

CTGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGGTCAGAT




GSCGFGAPLGLRLR

CTTCAAGCAGACTTACTCTAAATTTGATACTAACAGCCACAATG




GGGGTSESATPESGP

ACGATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTTTTCGT




GSEPATSGSETPGTS

AAAGATATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTG




ESATPESGPGSEPAT

TCGTTCCGTTGAGGGCAGCTGTGGTTTCTAAGGTgcgccgctgggcctg




SGSETPGTSESATPES

cgcctgcgcggcggcGGTGGTACCTCTGAAAGCGCAACTCCTGAGTCT




GPGTSTEPSEGSAPG

GGCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAG




SPAGSPTSTEEGTSES

GTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGA




ATPESGPGSEPATSG

ACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGC




SETPGTSESATPESGP

GCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGA




GSPAGSPTSTEEGSP

GGGCAGCGCACCAGGTAGCCCTGCTGGCTCTCCAACCTCCACC




AGSPTSTEEGTSTEPS

GAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAG




EGSAPGTSESATPES

GTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCT




GPGTSESATPESGPG

GAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCT




TSESATPESGPGSEP

CTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACT




ATSGSETPGSEPATS

TCTACTGAAGAAGGTACTTCTACCGAACCTTCCGAGGGCAGCG




GSETPGSPAGSPTST

CACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGG




EEGTSTEPSEGSAPG

TACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTG




TSTEPSEGSAPGSEP

AAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTAC




ATSGSETPGTSESAT

TTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTT




PESGPGTSTEPSEGS

CTGAAACTCCAGGTAGCCCAGCAGGCTCTCCGACTTCCACTGA




AP

GGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCAGGT






ACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAAC






CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT






ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG






CAGCGCACCA



 


AE624-
MAEPAGSPTSTEEGT
829
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
830


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



Thrombin-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE144
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




FPTIPLSRLFDNAML

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




RAHRLHQLAFDTYQ

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




EFEEAYIPKEQKYSF

GCAGCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTT




LQNPQTSLCFSESIPT

GATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT




PSNREETQQKSNLEL

TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGC




LRISLLLIQSWLEPVQ

AGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTC




FLRSVFANSLVYGAS

AGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC




DSNVYDLLKDLEEGI

AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATT




QTLMGRLEDGSPRT

CAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGC




GQIFKQTYSKFDTNS

CAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGAT




HNDDALLKNYGLLY

CTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC




CFRKDMDKVETFLRI

GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG




VQCRSVEGSCGFGL

ACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCT




TPRSLLVGGGGSEPA

TCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGG




TSGSETPGTSESATPE

ACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTT




SGPGSEPATSGSETP

GAGGGCAGCTGTGGTTTCTAAGGTctgaccccgcgcagcctgctggtgggcggc




GSPAGSPTSTEEGTS

GGTGGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTA




TEPSEGSAPGSEPAT

CTTCTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAACCT




SGSETPGSEPATSGS

GCTACCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCTCC




ETPGSEPATSGSETP

GACTTCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGGGT




GTSTEPSEGSAPGTS

AGCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCC




ESATPESGPGSEPAT

CAGGTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGTAG




SGSETPGTSTEPSEGS

CGAACCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTACCG




AP

AACCTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCAAC






CCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTG






AGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACC






A



 


AE624-
MAEPAGSPTSTEEGT
831
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
832


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



FXIa-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE144
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




FPTIPLSRLFDNAML

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




RAHRLHQLAFDTYQ

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




EFEEAYIPKEQKYSF

GCAGCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTT




LQNPQTSLCFSESIPT

GATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT




PSNREETQQKSNLEL

TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGC




LRISLLLIQSWLEPVQ

AGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTC




FLRSVFANSLVYGAS

AGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC




DSNVYDLLKDLEEGI

AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATT




QTLMGRLEDGSPRT

CAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGC




GQIFKQTYSKFDTNS

CAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGAT




HNDDALLKNYGLLY

CTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC




CFRKDMDKVETFLRI

GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG




VQCRSVEGSCGFGG

ACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCT




GKLTRVVGGGGSEP

TCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGG




ATSGSETPGTSESAT

ACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTT




PESGPGSEPATSGSE

GAGGGCAGCTGTGGTTTCTAAGGTggcggcaaactgacccgcgtggtgggcgg




TPGSPAGSPTSTEEG

cGGTGGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGT




TSTEPSEGSAPGSEP

ACTTCTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAAC




ATSGSETPGSEPATS

CTGCTACCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCT




GSETPGSEPATSGSE

CCGACTTCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGG




TPGTSTEPSEGSAPG

GTAGCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAAC




TSESATPESGPGSEP

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGT




ATSGSETPGTSTEPSE

AGCGAACCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTAC




GSAP

CGAACCTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCA






ACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTC






TGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCA






CCA



 


AE624-
MAEPAGSPTSTEEGT
833
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
834


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



Elastase-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE144
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




FPTIPLSRLFDNAML

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




RAHRLHQLAFDTYQ

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




EFEEAYIPKEQKYSF

GCAGCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTT




LQNPQTSLCFSESIPT

GATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT




PSNREETQQKSNLEL

TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGC




LRISLLLIQSWLEPVQ

AGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTC




FLRSVFANSLVYGAS

AGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC




DSNVYDLLKDLEEGI

AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATT




QTLMGRLEDGSPRT

CAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGC




GQIFKQTYSKFDTNS

CAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGAT




HNDDALLKNYGLLY

CTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC




CFRKDMDKVETFLRI

GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG




VQCRSVEGSCGFGG

ACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCT




GLGPVSGVPGGSEPA

TCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGG




TSGSETPGTSESATPE

ACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTT




SGPGSEPATSGSETP

GAGGGCAGCTGTGGTTTCTAAGGTggcggcctgggcccggtgagcggcgtgcc




GSPAGSPTSTEEGTS

gGGTGGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGT




TEPSEGSAPGSEPAT

ACTTCTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAAC




SGSETPGSEPATSGS

CTGCTACCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCT




ETPGSEPATSGSETP

CCGACTTCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGG




GTSTEPSEGSAPGTS

GTAGCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAAC




ESATPESGPGSEPAT

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGT




SGSETPGTSTEPSEGS

AGCGAACCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTAC




AP

CGAACCTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCA






ACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTC






TGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCA






CCA



 


AE624-
MAEPAGSPTSTEEGT
835
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
836


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



MMP-17-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE144
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




FPTIPLSRLFDNAML

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




RAHRLHQLAFDTYQ

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




EFEEAYIPKEQKYSF

GCAGCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTT




LQNPQTSLCFSESIPT

GATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT




PSNREETQQKSNLEL

TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGC




LRISLLLIQSWLEPVQ

AGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTC




FLRSVFANSLVYGAS

AGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC




DSNVYDLLKDLEEGI

AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATT




QTLMGRLEDGSPRT

CAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGC




GQIFKQTYSKFDTNS

CAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGAT




HNDDALLKNYGLLY

CTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC




CFRKDMDKVETFLRI

GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG




VQCRSVEGSCGFGA

ACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCT




PLGLRLRGGGGSEPA

TCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGG




TSGSETPGTSESATPE

ACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTT




SGPGSEPATSGSETP

GAGGGCAGCTGTGGTTTCTAAGGTgcgccgctgggcctgcgcctgcgcggcgg




GSPAGSPTSTEEGTS

cGGTGGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGT




TEPSEGSAPGSEPAT

ACTTCTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGCGAAC




SGSETPGSEPATSGS

CTGCTACCTCTGGCTCTGAAACCCCAGGTAGCCCGGCAGGCTCT




ETPGSEPATSGSETP

CCGACTTCCACCGAGGAAGGTACCTCTACTGAACCTTCTGAGG




GTSTEPSEGSAPGTS

GTAGCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAAC




ESATPESGPGSEPAT

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGT




SGSETPGTSTEPSEGS

AGCGAACCGGCTACTTCCGGTTCTGAAACTCCAGGTACCTCTAC




AP

CGAACCTTCCGAAGGCAGCGCACCAGGTACTTCTGAAAGCGCA






ACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTC






TGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCA






CCA



 


AE624-
MAEPAGSPTSTEEGT
837
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
838


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



Thrombin-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE288
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




FPTIPLSRLFDNAML

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




RAHRLHQLAFDTYQ

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




EFEEAYIPKEQKYSF

GCAGCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTT




LQNPQTSLCFSESIPT

GATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT




PSNREETQQKSNLEL

TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGC




LRISLLLIQSWLEPVQ

AGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTC




FLRSVFANSLVYGAS

AGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC




DSNVYDLLKDLEEGI

AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATT




QTLMGRLEDGSPRT

CAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGC




GQIFKQTYSKFDTNS

CAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGAT




HNDDALLKNYGLLY

CTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC




CFRKDMDKVETFLRI

GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG




VQCRSVEGSCGFGL

ACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCT




TPRSLLVGGGGTSES

TCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGG




ATPESGPGSEPATSG

ACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTT




SETPGTSESATPESGP

GAGGGCAGCTGTGGTTTCTAAGGTctgaccccgcgcagcctgctggtgggcggc




GSEPATSGSETPGTS

GGTGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTA




ESATPESGPGTSTEPS

GCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAA




EGSAPGSPAGSPTST

AGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCT




EEGTSESATPESGPG

CTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAA




SEPATSGSETPGTSES

TCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCAC




ATPESGPGSPAGSPT

CAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTAC




STEEGSPAGSPTSTEE

CTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCG




GTSTEPSEGSAPGTS

GCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTAC




ESATPESGPGTSESA

TCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCA




TPESGPGTSESATPES

CCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGA




GPGSEPATSGSETPG

AGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACT




SEPATSGSETPGSPA

TCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAA




GSPTSTEEGTSTEPSE

GCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACC




GSAPGTSTEPSEGSA

CCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGA




PGSEPATSGSETPGT

AACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA




SESATPESGPGTSTEP

GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTT




SEGSAP

CTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGA






ACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCT






GGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATC






TGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA



 


AE624-
MAEPAGSPTSTEEGT
839
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
840


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



FXIa-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE288
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




FPTIPLSRLFDNAML

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




RAHRLHQLAFDTYQ

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




EFEEAYIPKEQKYSF

GCAGCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTT




LQNPQTSLCFSESIPT

GATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT




PSNREETQQKSNLEL

TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGC




LRISLLLIQSWLEPVQ

AGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTC




FLRSVFANSLVYGAS

AGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC




DSNVYDLLKDLEEGI

AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATT




QTLMGRLEDGSPRT

CAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGC




GQIFKQTYSKFDTNS

CAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGAT




HNDDALLKNYGLLY

CTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC




CFRKDMDKVETFLRI

GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG




VQCRSVEGSCGFGG

ACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCT




GKLTRVVGGGGTSE

TCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGG




SATPESGPGSEPATS

ACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTT




GSETPGTSESATPES

GAGGGCAGCTGTGGTTTCTAAGGTggcggcaaactgacccgcgtggtgggcgg




GPGSEPATSGSETPG

cGGTGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTA




TSESATPESGPGTSTE

GCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAA




PSEGSAPGSPAGSPT

AGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCT




STEEGTSESATPESGP

CTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAA




GSEPATSGSETPGTS

TCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCAC




ESATPESGPGSPAGS

CAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTAC




PTSTEEGSPAGSPTST

CTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCG




EEGTSTEPSEGSAPG

GCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTAC




TSESATPESGPGTSES

TCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCA




ATPESGPGTSESATP

CCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGA




ESGPGSEPATSGSET

AGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACT




PGSEPATSGSETPGSP

TCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAA




AGSPTSTEEGTSTEPS

GCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACC




EGSAPGTSTEPSEGS

CCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGA




APGSEPATSGSETPG

AACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA




TSESATPESGPGTSTE

GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTT




PSEGSAP

CTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGA






ACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCT






GGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATC






TGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA



 


AE624-
MAEPAGSPTSTEEGT
841
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
842


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



Elastase-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE288
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




FPTIPLSRLFDNAML

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




RAHRLHQLAFDTYQ

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




EFEEAYIPKEQKYSF

GCAGCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTT




LQNPQTSLCFSESIPT

GATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT




PSNREETQQKSNLEL

TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGC




LRISLLLIQSWLEPVQ

AGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTC




FLRSVFANSLVYGAS

AGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC




DSNVYDLLKDLEEGI

AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATT




QTLMGRLEDGSPRT

CAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGC




GQIFKQTYSKFDTNS

CAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGAT




HNDDALLKNYGLLY

CTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC




CFRKDMDKVETFLRI

GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG




VQCRSVEGSCGFGG

ACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCT




GLGPVSGVPGGTSES

TCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGG




ATPESGPGSEPATSG

ACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTT




SETPGTSESATPESGP

GAGGGCAGCTGTGGTTTCTAAGGTggcggcctgggcccggtgagcggcgtgcc




GSEPATSGSETPGTS

gGGTGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTA




ESATPESGPGTSTEPS

GCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAA




EGSAPGSPAGSPTST

AGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCT




EEGTSESATPESGPG

CTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAA




SEPATSGSETPGTSES

TCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCAC




ATPESGPGSPAGSPT

CAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTAC




STEEGSPAGSPTSTEE

CTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCG




GTSTEPSEGSAPGTS

GCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTAC




ESATPESGPGTSESA

TCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCA




TPESGPGTSESATPES

CCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGA




GPGSEPATSGSETPG

AGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACT




SEPATSGSETPGSPA

TCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAA




GSPTSTEEGTSTEPSE

GCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACC




GSAPGTSTEPSEGSA

CCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGA




PGSEPATSGSETPGT

AACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA




SESATPESGPGTSTEP

GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTT




SEGSAP

CTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGA






ACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCT






GGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATC






TGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA



 


AE624-
MAEPAGSPTSTEEGT
843
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTA
844


hGH-
PGSGTASSSPGSSTPS

CCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC



MMP-17-
GATGSPGASPGTSST

CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAG



AE288
GSPGSPAGSPTSTEE

CTCTACCGGTTCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTA




GTSESATPESGPGTS

CTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA




TEPSEGSAPGSPAGS

GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC




PTSTEEGTSTEPSEGS

CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAA




APGTSTEPSEGSAPG

CCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGA




TSESATPESGPGSEP

GGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAATCT




ATSGSETPGSEPATS

GGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCAG




GSETPGSPAGSPTST

GTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCC




EEGTSESATPESGPG

GGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGC




TSTEPSEGSAPGTSTE

GCAACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTG




PSEGSAPGSPAGSPT

AGGGCAGCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAG




STEEGTSTEPSEGSAP

CGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA




GTSTEPSEGSAPGTS

GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT




ESATPESGPGTSTEPS

CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGC




EGSAPGTSESATPES

GCTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGA




GPGSEPATSGSETPG

AGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCC




TSTEPSEGSAPGTSTE

GGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCAG




PSEGSAPGTSESATP

GTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCT




ESGPGTSESATPESG

ACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCG




PGSPAGSPTSTEEGT

CAACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCC




SESATPESGPGSEPA

GGAGTCCGGCCCAGGTAGCCCTGCTGGCTCTCCAACCTCCACCG




TSGSETPGTSESATPE

AAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCAGG




SGPGTSTEPSEGSAP

TAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCT




GTSTEPSEGSAPGTS

GAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAAC




TEPSEGSAPGTSTEPS

CGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA




EGSAPGTSTEPSEGS

GGTAGCGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG




APGTSTEPSEGSAPG

CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGT




SPAGSPTSTEEGTSTE

ACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTAC




PSEGSAPGTSESATP

CGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT




ESGPGSEPATSGSET

CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGG




PGTSESATPESGPGS

GTAGCGCACCAGGTACCTCTGAAAGCGCAACTCCTGAGTCTGG




EPATSGSETPGTSES

CCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGT




ATPESGPGTSTEPSE

ACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAAC




GSAPGTSESATPESG

CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT




PGSPAGSPTSTEEGSP

ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGG




AGSPTSTEEGSPAGS

CAGCGCACCAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGC




PTSTEEGTSESATPES

CCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTA




GPGTSTEPSEGSAPG

GCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGC




FPTIPLSRLFDNAML

AGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA




RAHRLHQLAFDTYQ

ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGG




EFEEAYIPKEQKYSF

GCAGCGCACCAGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTT




LQNPQTSLCFSESIPT

GATAATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT




PSNREETQQKSNLEL

TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGAGC




LRISLLLIQSWLEPVQ

AGAAGTACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTTC




FLRSVFANSLVYGAS

AGCGAATCTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC




DSNVYDLLKDLEEGI

AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCTTCTGATT




QTLMGRLEDGSPRT

CAGAGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGC




GQIFKQTYSKFDTNS

CAATAGCCTAGTTTATGGCGCATCCGACAGCAACGTATACGAT




HNDDALLKNYGLLY

CTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC




CFRKDMDKVETFLRI

GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG




VQCRSVEGSCGFGA

ACTTACTCTAAATTTGATACTAACAGCCACAATGACGATGCGCT




PLGLRLRGGGGTSES

TCTAAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGG




ATPESGPGSEPATSG

ACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCGTT




SETPGTSESATPESGP

GAGGGCAGCTGTGGTTTCTAAGGTgcgccgctgggcctgcgcctgcgcggcgg




GSEPATSGSETPGTS

cGGTGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTA




ESATPESGPGTSTEPS

GCGAACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGAA




EGSAPGSPAGSPTST

AGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAACCT




EEGTSESATPESGPG

CTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAA




SEPATSGSETPGTSES

TCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCAC




ATPESGPGSPAGSPT

CAGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTAC




STEEGSPAGSPTSTEE

CTCTGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCG




GTSTEPSEGSAPGTS

GCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGCTAC




ESATPESGPGTSESA

TCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCA




TPESGPGTSESATPES

CCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGA




GPGSEPATSGSETPG

AGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACT




SEPATSGSETPGSPA

TCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAA




GSPTSTEEGTSTEPSE

GCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGCTACC




GSAPGTSTEPSEGSA

CCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGA




PGSEPATSGSETPGT

AACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA




SESATPESGPGTSTEP

GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTT




SEGSAP

CTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGA






ACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAACCTCT






GGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATC






TGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA





*Sequence name reflects N- to C-terminus configuration of the growth factor, cleavage sequence and XTEN components

## Claims

1. An isolated fusion protein, comprising a growth hormone (GH) that is at least 90% identical to the amino acid sequence of SEQ ID NO:1, wherein said growth hormone is linked to an extended recombinant polypeptide (XTEN) of at least 100 to about 3000 amino acids residues, wherein the XTEN is characterized in that:
(a) at least 80% the XTEN sequence consist of non-overlapping sequence motifs, wherein:
(i) each sequence motif has 12 to 36 amino acid residues, and
(ii) each motif 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

(b) the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues constitutes more than 90% of the total amino acid residues of the XTEN sequence; and
wherein the XTEN comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 29-58.

2. The isolated fusion protein of claim 1, wherein the growth hormone is a human growth hormone.

3. The isolated fusion protein of claim 1, wherein each motif has 12 to 14 amino acid residues.

4. The isolated fusion protein of claim 1, wherein the sequence of any two contiguous amino acid residues in any one sequence motif does not occur more than twice in the sequence motif.

5. The isolated fusion protein of claim 1, wherein the content of any one amino acid type in the full-length XTEN does not exceed 30%.

6. The isolated fusion protein of claim 1, wherein the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues constitutes at least 95% of the total amino acid residues of the XTEN sequence.

7. The isolated fusion protein of claim 1, wherein the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues at least 99% of the total amino acid residues of the XTEN sequence.

8. The isolated fusion protein of claim 1, wherein the XTEN sequence comprises at least 400 to about 1000 amino acids residues.

9. The isolated fusion protein of claim 1, wherein the XTEN sequence comprises at least 100 to about 200 amino acids residues.

10. The isolated fusion protein of claim 1, wherein the XTEN sequence contains no three contiguous amino acids that are identical unless the amino acids are serine residues.

11. The isolated fusion protein as in any one of claims 1, 8, and 9, further comprising a second XTEN sequence.

12. The fusion protein of claim 1, wherein the fusion protein has a longer terminal half-life when administered to a subject compared to the corresponding GH that lacks the XTEN when administered to a subject at a comparable molar dose.

13. The fusion protein of claim 1, wherein the fusion protein stimulates production of IGF-1 in a subject.

14. The isolated fusion protein of claim 1, wherein the growth hormone peptide and the XTEN is linked via a spacer, wherein the spacer sequence comprises between 1 to about 50 amino acid residues.

15. A pharmaceutical composition comprising the isolated fusion protein of claim 1, and a pharmaceutically acceptable carrier.

16. The isolated protein of claim 1 that is configured according to formula I:


(XTEN)x-GH-(XTEN)y,  (I)

wherein independently for each occurrence:
(a) x is either 0 or 1; and
(b) y is either 0 or 1, wherein x+y≧1.

17. The isolated fusion protein of claim 1, wherein the XTEN is fused to the growth hormone on an N- or C-terminus of the growth hormone.

18. The isolated fusion protein as in any one of claims 1, 8, 9, and 17, wherein the XTEN sequence is at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs:63, 66-67, 69-77, and 851.

19. The isolated fusion protein as in claim 11, wherein the XTEN sequence is at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs:63, 66-67, 69-77, and 851.

20. The pharmaceutical composition of claim 15 formulated for subcutaneous administration.

21. A method of treating a growth-hormone related condition in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 15 or 20, wherein the growth-hormone related condition is selected from growth-hormone deficiency, Turner's Syndrome, Prader-Willi Syndrome, idiopathic short stature, AIDS wasting, multiple sclerosis, Crohn's disease, ulcerative colitis, and muscular dystrophy.

22. The method of claim 21, wherein the pharmaceutical composition is administered subcutaneously.

23. The method of claim 21, wherein the pharmaceutical composition is administered less frequently in comparison to the corresponding growth hormone that lacks said XTEN or said first and second polypeptide.

24. The method of claim 21, wherein a therapeutic effect is a measured parameter selected from IGF-1 concentrations, IGFBP3 concentration, height velocity, lean body mass, total body fat, trunk fat, response to insulin challenge, rate of division of chondrocytes, chondrocyte numbers, bone density, bone growth, and increase in epiphyseal plate width.