# Patent

## Title
Antibodies against platelet-derived growth factor (PDGF)

## Abstract

Binding proteins that bind one or more of VEGF, PDGF and/or their receptors, including antibodies, CDR-grafted antibodies, humanized antibodies, binding fragments, fusion proteins, and bispecific or multispecific proteins thereof are disclosed. Also disclosed are methods of making and using the binding proteins.

## Background
This application claims priority to U.S. Provisional Application Ser. No. 62/175,546, filed Jun. 15, 2015, and U.S. Provisional Application Ser. No. 62/291,964, filed Feb. 5, 2016, each of which is incorporated herein by reference in its entirety.


SEQUENCE LISTING
The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 5, 2016, is named 12252_0202-00000_SL.txt and is 4,068,254 bytes in size.
FIELD
The invention relates to antibodies and antigen-binding fragments thereof, as well as multivalent and multispecific binding proteins, that bind vascular endothelial growth factor (VEGF) and/or platelet-derived growth factor (PDGF), as well as their receptors, and methods of making, and using the constructs in the diagnosis, prevention, and/or treatment of acute and chronic inflammatory diseases, cancer, and other disorders.
BACKGROUND
Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a role in the pathogenesis of many diseases, including ocular diseases such as age-related macular degeneration (AMD) or diabetic macular edema (DME). Vascular endothelial growth factor (VEGF) plays a role in the regulation of normal and abnormal angiogenesis (Ferrara et al, (1997) Endoer. Rev. 18:4-25). Several anti-VEGF agents are provided in the art, e.g., in U.S. Pat. No. 7,169,901, which discloses VEGF antibodies for inhibiting VEGF-induced cell proliferation, and U.S. Pat. No. 7,070,959, which discloses isolated nucleic acid molecules encoding fusion proteins capable of binding VEGF.
Targeting VEGF with currently available therapeutics is not effective in all patients or for all diseases associated with inflammation and/or angiogenesis. A significant population of non-responders present following anti-VEGF monotherapy, and the disease prevalence will only increase as the aging population increases globally.
A currently preferred treatment for wet AMD consists of intravitreal injections of an anti-VEGF agent. However, although anti-VEGF therapy reduces choroidal neovascularization, it does not have an effect on regression of the mature vasculature. Also, current agents do not provide an anti-fibrotic effect, so that once scarring of the retina occurs; visual acuity cannot be recovered. Other limitations of the existing treatments regimens include patient discomfort, the need for repeat injections with inherent complications including endophthalmitis, retinal tear and detachment, intraocular hemorrhage, and cataract formation. There is a substantial time burden on ophthalmologists to provide monthly intravitreal treatment and optical coherence tomography (OCT) measurements on a large volume patients. As a result, there is a significant medical and economic need for an AMD therapeutic with greater efficacy, or that can be delivered less frequently and still achieve optimal efficacy.
Platelet-derived growth factor (PDGF) is a growth factor involved in the regulation of blood vessels from pre-existing vessel tissue. PDGF binds to receptors on pericytes in newly-forming abnormal blood vessels. This may contribute to neovascularization of abnormal blood vessels by providing a protective perictye coating, for example, during ocular disorders such as wet AMD.
Engineered proteins, such as antibodies, fragments, and multispecific binding proteins capable of binding two or more antigens, are known in the art. Such multispecific binding proteins can be generated using cell fusion, chemical conjugation, or recombinant DNA techniques. There are a variety of multispecific binding protein structures known in the art and many structures and methods have distinct disadvantages.
Bispecific antibodies have been produced using quadroma technology. Bispecific antibodies can also be produced by chemical conjugation of two different mAbs. Other approaches include coupling of two parental antibodies with a hetero-bifunctional crosslinker, production of tandem single-chain Fv molecules, diabodies, bispecific diabodies, single-chain diabodies, and di-diabodies. In addition, a multivalent antibody construct comprising two Fab repeats in the heavy chain of an IgG and capable of binding four antigen molecules has been described (see PCT Publication No. WO 01/77342 and Miller et al. (2003) J. Immunol. 170(9):4854-61).
U.S. Pat. No. 7,612,181 (incorporated herein by reference in its entirety) provides a novel family of binding proteins capable of binding two or more antigens with high affinity, which are called dual variable domain binding proteins (DVD-Ig binding protein) or dual variable domain immunoglobulins (DVD-Ig). DVD-Ig molecules are binding proteins that may be used to bind two distinct epitopes on the same molecule or two different molecules simultaneously. DVD-Ig molecules are unique binding proteins comprised of two variable domains fused to N-terminal constant regions. The variable domains may be directly fused to one another or connected via synthetic peptide linkers of assorted length and amino acid composition. DVD-Ig binding proteins may be engineered with intact and functional Fc domains, or otherwise modified constant domains, allowing them to mediate appropriate effector functions and exhibit other desired properties. The DVD-Ig format, due to its flexibility of choice of variable domain pair, orientation of two antigen-binding domains, and the length of the linker that joins them, may provide novel therapeutic modalities.
Accordingly, while VEGF monotherapy has had some success in the art, there remains a need for constructs exhibiting better targeting, efficiency, and/or efficacy in binding to VEGF, as well as improved targeting of other pathways involved in inflammation (such as ocular inflammation), e.g., the PDGF pathway. Improved targeting of either of these molecules, alone or in combination, may lead to improvements in, e.g., preventing, diagnosing, and/or treating disorders such as angiogenic, inflammatory, and/or ocular disorders. Also, while a variety of structures have been provided in the art, with various advantages and disadvantages, new variable domain sequences can further improve the properties of binding proteins targeting VEGF and/or PDGF, or their cognate receptors.
SUMMARY
Disclosed herein are binding proteins capable of binding VEGF and/or PDGF, and/or their cognate receptors. In some embodiments, the binding proteins are antibodies to VEGF and/or PDGF, or antigen-binding fragments thereof. In some embodiments, the binding proteins are bispecific and capable of binding VEGF and PDGF. In some embodiments, the binding proteins comprise one or more sequences from any one of Tables A, 27-30, 38-42, 46-50, or 56-58, or the CDR amino acid residues from those sequences.
In various embodiments, the binding proteins are bispecific or multispecific binding proteins capable of binding one or more of VEGF and/or PDGF, and/or their cognate receptors. In some embodiments, the binding proteins are dual variable domain immunoglobulins (DVD-Igs or DVD-Ig binding proteins) using the binding protein framework disclosed in U.S. Pat. No. 7,612,181 (incorporated herein by reference in its entirety).
In some embodiments, the DVD-Ig binding proteins contain particular first and second polypeptide chains, each comprising first and second variable domains comprising sequences (e.g., sequences selected from those listed in Tables A, 27-30, 38-42, 46-50, or 56-58, or the CDR amino acid residues from those sequences) that form functional binding sites for binding targets such as VEGF and/or PDGF, or their cognate receptors. In some embodiments, the first and second polypeptide chains of the binding protein each independently comprise VD1-(X1)n-VD2-C-X2, wherein VD1 is a first variable domain; VD2 is a second variable domain; C is a constant domain; X1 is a linker; X2 is an Fc region that is either present or absent; n is 0 or 1, and wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site for VEGF, PDGF, or a cognate receptor, and the VD2 domains on the first and second polypeptide chains form a second functional target binding site for VEGF, PDGF, or a cognate receptor. In some embodiments, (a) the first polypeptide chain of the binding protein comprises VD1-(X1)n-VD2-C-X2, wherein VD1 is a first heavy chain variable domain; VD2 is a second heavy chain variable domain; C is a heavy chain constant domain; X1 is a linker; X2 is an Fc region; and n is 0 or 1 (i.e., X1 and X2 are either present or absent, depending on whether n is independently chosen to be 0 or 1 for each position); and (b) the second polypeptide chain of the binding protein comprises VD1-(X1)n-VD2-C-X2, wherein VD1 is a first light chain variable domain; VD2 is a second light chain variable domain; C is a light chain constant domain; X1 is a linker; X2 is an Fc region; and n is 0 or 1 for X1 and n is 0 for X2 (i.e., the Fc region is absent on the second polypeptide chain); and (c) wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site for VEGF, PDGF, or a cognate receptor, and the VD2 domains on the first and second polypeptide chains form a second functional target binding site for VEGF, PDGF, or a cognate receptor. In some embodiments, the VD1 position forms a binding site for VEGF and the VD2 position forms a binding site for PDGF. In some embodiments, the CDR and/or variable domains at the VD1 and VD2 positions are antibody variable domains and the constant domains are antibody constant domains. Any of the CDR and/or variable domain and/or first and second polypeptide chain sequences disclosed herein may be incorporated in these DVD-Ig binding protein structures to form binding domains for VEGF and/or PDGF, and/or their cognate receptors.
In some embodiments, both the first and second binding sites of a DVD-Ig construct disclosed herein target VEGF. In some embodiments, both the first and second binding sites target PDGF. In some embodiments, the first binding site targets VEGF and the second binding site targets PDGF. In some embodiments, the first binding site targets PDGF and the second binding site targets VEGF. In some embodiments, an Fc domain is present on one polypeptide chain and absent on the other, or absent on both polypeptide chains. In some embodiments, the sequences of the first and second variable domains on each polypeptide chain (i.e., the VD1 and VD2 positions) are independently selected from the sequences in Table A, 27-30, 38-42, 46-50, or 56-58 to form functional binding sites. In some embodiments, the sequences of the first and second variable domains each contain the three complementarity determining regions (i.e., CDRs 1-3) from the selected sequences listed in Tables A, 27-30, 38-42, 46-50, or 56-58, and are arranged in the same order as shown in the Tables, thereby forming functional binding sites (i.e., the binding domains are capable of binding to their target antigen, VEGF or PDGF). In some embodiments, the paired variable domain sequences on the first and second polypeptide chains (i.e., the VD1 sequence on the first chain paired with the VD1 sequence on the second chain and the VD2 sequence on the first chain paired with the VD2 sequence on the second chain) form functional binding sites for binding targets VEGF and/or PDGF using the sequences in the Tables. In some embodiments, the binding proteins are capable of binding to VEGF and/or PDGF with improved binding affinity and/or neutralization potency, improved in vivo efficacy, improved expression, and/or improved drug-like properties (e.g., thermal stability, storage stability, solubility, etc.).
Also disclosed herein are methods of making and using the claimed binding proteins, e.g., in the detection, inhibition, reduction, prevention, and/or treatment of cancers, tumors, fibrosis, renal disease, inflammation, age-related macular degeneration (AMD), wet AMD, diabetic retinopathy, other angiogenesis-dependent diseases, or angiogenesis-independent diseases characterized by aberrant VEGF and/or PDGF expression or activity.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A and FIG. 1B are schematic representations of a Dual Variable Domain (DVD) binding protein construct.
FIG. 2A and FIG. 2B show the reactivity of anti-PDGF-BB antibodies and anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules to ECM-associated PDGF-BB.
FIG. 3 illustrates the inhibition of sprouting from a HUVEC/MSC co-culture sprouting assay by anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules.
FIG. 4 is a bar graph showing the area of subretinal neovascularization in Rho/huVEGF transgenic mice.
FIG. 5 is a bar graph showing the area of choroidal neovascularization in Rho/huVEGF transgenic mice.
FIG. 6 is a bar graph comparing choroidal neovascularization in the untreated eye among the different treatment groups.
FIG. 7 is a bar graph showing number of partial, total, and undetached eyes in Tet/opsin/VEGF mice.



DETAILED DESCRIPTION
Vascular endothelial growth factor (VEGF) is a signal protein that regulates physiological angiogenesis during embryogenesis, skeletal growth, and reproductive functions. Aberrant expression of VEGF is implicated in pathological angiogenesis and is associated with tumors, intraocular neovascular disorders, and other diseases. The VEGF family members include VEGF-A, placenta growth factor (PGF), VEGF-B, VEGF-C, and VEGF-D. Multiple isoforms of VEGF-A exist that result from alternative splicing of a single, 8-exon VEGFA gene. The biological effects of VEGF are mediated by various receptors, including two receptor tyrosine kinases, VEGF receptor-1 (VEGFR1) and VEGF receptor-2 (VEGFR2), which differ in their signaling properties. When cells are deficient in oxygen, they produce hypoxia-inducible factor (HIF) which releases VEGF and other mediators triggering a tyrosine kinase pathway leading to angiogenesis (Ferrara et al. (2003) Nat. Med. 9:669-676). In various embodiments, the binding proteins disclosed herein can bind one or more of the VEGF family members, including alternate isoforms, and/or can bind one or more of the cognate VEGF receptors.
Platelet-derived growth factor (PDGF) is a protein that stimulates growth, survival, and motility of mesenchymal cells and certain other cell types. It has significant functions during embryonal development and in the control of blood vessel formation as an adult. PDGF is composed of a dimeric glycoprotein made up of two A (-AA), two B (-BB) chains, or a combination of the two (-AB). There are five different isoforms of PDGF that moderate cellular responses through two receptors, alpha (PDGFRA) and beta (PDGFRB) (Heldin (2013) Cell Commun Sig. 11:97). PDGF plays an important role in driving the proliferation of undifferentiated mesenchyme and some progenitor populations. Overactivity or inappropriate PDGF signaling is associated with the development of certain malignant diseases, as well as non-malignant diseases characterized by excessive cell proliferation and other inflammatory disorders. In various embodiments, the binding proteins disclosed herein can bind one or more of the PDGF isoforms, and/or can bind one or more of the cognate PDGF receptors.
Binding Proteins
Disclosed herein are binding proteins capable of binding one or more of VEGF, PDGF, and their cognate receptors. In some embodiments, the binding protein is an antibody or an antigen-binding fragment thereof. In an embodiment, the binding protein is an antibody, a monoclonal antibody, a murine antibody, a human antibody, a humanized antibody, a bispecific antibody, a chimeric antibody, a Fab, a Fab′, a F(ab′)2, an ScFv, an SMIP, an affibody, an avimer, a versabody, a nanobody, a fynomab, a domain antibody, or an antigen binding fragment of any of the foregoing. In an embodiment, the binding protein comprises antibody heavy chain variable domain sequences and antibody light chain variable domain sequences that are capable of binding one or more of VEGF, PDGF, and their cognate receptors. In an embodiment, the binding protein comprises the paired heavy and light chain variable domain sequences of any of the binding sites disclosed in Tables 27-30, 38-42, 46-50, or the CDR sequences from those variable domains. The CDR sequences of the variable domains in the Tables are identified in bold.
In some embodiments, the binding proteins disclosed herein is bispecific or multispecific. The bispecific or multispecific construct may be monovalent or bivalent. Various bispecific or multispecific constructs are known in the art (see e.g., Spiess et al. (2015) Mol. Immunol. 67; 95-106). Bispecific or multispecific constructs include, but are not limited to, an asymmetric bispecific antibody, an asymmetric bispecific IgG4, a CrossMab binding protein, a bispecific antibody, a bispecific binding protein, a multispecific binding protein, a DAF (dual action Fab antibody; two-in-one), a DAF (dual action Fab antibody; four-in-one), a DutaMab, a DT-IgG, a knobs-in-holes binding protein, a Charge pair binding protein, a Fab-arm exchange binding protein, a SEEDbody, a Triomab (Triomab quadroma bispecific or removab bispecific), a LUZ-Y, a Fcab, a κλ-body, an iMab (innovative multimer), and an Orthogonal Fab. In some embodiments, the bispecific or multispecific construct is a DVD-Ig binding protein, an IgG(H)-scFv, an scFv-(H)IgG, an IgG(L)-scFv, an scFv-(L)IgG, an IgG(L, H)-Fv, an IgG(H)-V, a V(H)-IgG, an IgG(L)-V, a V(L)-IgG, a KIH IgG-scFab, a 2scFv-IgG, an IgG-2scFv, an scFv4-Ig, a Zybody, or a DVI-IgG (four-in-one). In some embodiments, the bispecific or multispecific construct also can be a nanobody (or VHH), a bispecific tandem nanobody, a bispecific trivalent tandem nanobody, a nanobody-HSA, a BiTE (bispecific T-cell engager) binding protein, a Diabody, a DART (dual affinity retargeting) binding protein, a TandAb (tetravalent bispecifc tandem antibody), an scDiabody, an scDiabody-CH3, a Diabody-CH3, a Triple Body, a Miniantibody, a Minibody, a TriBi minibody, an scFv-CH3 KIH, a Fab-scFv, an scFv-CH-CL-scFv, a F(ab′)2, a F(ab′)2 scFv2, an scFv-KIH, a Fab-scFv-Fc, a Tetravalent HCAb, an scDiabody-Fc, a Diabody-Fc, a Tandem scFv-Fc, a Fabsc, a bsFc-1/2, a CODV-Ig (cross-over dual variable immunoglobulin), a biclonics antibody or an Intrabody. Bispecific or multispecific constructs also include, for example, a Dock and Lock binding protein, an ImmTAC, an HSAbody, an scDiabody-HSA, a Tandem scFv-Toxin, an IgG-IgG binding protein, a Cov-X-Body, and an scFv1-PEG-scFv2. In some embodiments, the bispecific or multispecific construct is a DVD-Ig binding protein, a CrossMab binding protein, a diabody, a tandem single-chain Fv molecule, a bispecific diabody, a single-chain diabody molecule, or a di-diabody. In some embodiments, the binding protein is a DVD-Ig binding protein. See, e.g., U.S. Pat. No. 7,612,181 (incorporated herein by reference in its entirety). The bispecific or multispecific construct may comprise one or more binding sites for VEGF, PDGF, and/or their receptors. The bispecific or multispecific construct may comprise binding sites only for VEGF, PDGF, and/or their receptors, or may comprise additional binding sites for other antigen targets. The bispecific or multispecific construct may comprise binding sites for more than one epitope on VEGF, PDGF, and/or their receptors, e.g., using different CDR sets or variable domains from those disclosed herein to form binding sites targeting different epitopes.
In various embodiments, the binding protein is capable of binding VEGF, and comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs 1-3 from SEQ ID NO: 18, CDRs 1-3 from SEQ ID NO: 19 and CDRs 1-3 from SEQ ID NO: 20, CDRs 1-3 from SEQ ID NO: 21 and CDRs 1-3 from SEQ ID NO: 22, CDRs 1-3 from SEQ ID NO: 23 and CDRs 1-3 from SEQ ID NO: 24, CDRs 1-3 from SEQ ID NO: 25 and CDRs 1-3 from SEQ ID NO: 26, CDRs 1-3 from SEQ ID NO: 27 and CDRs 1-3 from SEQ ID NO: 28, CDRs 1-3 from SEQ ID NO: 29 and CDRs 1-3 from SEQ ID NO: 30, CDRs 1-3 from SEQ ID NO: 31 and CDRs 1-3 from SEQ ID NO: 32, CDRs 1-3 from SEQ ID NO: 33 and CDRs 1-3 from SEQ ID NO: 34, CDRs 1-3 from SEQ ID NO: 35 and CDRs 1-3 from SEQ ID NO: 36, CDRs 1-3 from SEQ ID NO: 37 and CDRs 1-3 from SEQ ID NO: 38, CDRs 1-3 from SEQ ID NO: 39 and CDRs 1-3 from SEQ ID NO: 40, CDRs 1-3 from SEQ ID NO: 41 and CDRs 1-3 from SEQ ID NO: 42, or CDRs 1-3 from SEQ ID NO: 43 and CDRs 1-3 from SEQ ID NO: 44. In an embodiment, the binding protein is capable of binding VEGF, and comprises SEQ ID NO: 17 and SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, or SEQ ID NO: 43 and SEQ ID NO: 44. Any of said binding proteins capable of binding VEGF may also be capable of binding PDGF, and may comprise any of the PDGF binding sequences as described herein.
In various embodiments, the binding protein is capable of binding PDGF, and comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs 1-3 from SEQ ID NO: 2, CDRs 1-3 from SEQ ID NO: 3 and CDRs 1-3 from SEQ ID NO: 4, CDRs 1-3 from SEQ ID NO: 5 and CDRs 1-3 from SEQ ID NO: 6, CDRs 1-3 from SEQ ID NO: 7 and CDRs 1-3 from SEQ ID NO: 8, CDRs 1-3 from SEQ ID NO: 9 and CDRs 1-3 from SEQ ID NO: 10, CDRs 1-3 from SEQ ID NO: 11 and CDRs 1-3 from SEQ ID NO: 12, CDRs 1-3 from SEQ ID NO: 13 and CDRs 1-3 from SEQ ID NO: 14, CDRs 1-3 from SEQ ID NO: 15 and CDRs 1-3 from SEQ ID NO: 16, or CDRs 1-3 from SEQ ID NO: 211 and CDRs 1-3 from SEQ ID NO: 212. In an embodiment, the binding protein is capable of binding PDGF, and comprises SEQ ID NO: 1 and SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, or SEQ ID NO: 211 and SEQ ID NO: 212. Any of said binding proteins capable of binding PDGF may also be capable of binding VEGF, and may comprise any of the VEGF binding sequences as described herein.
In an embodiment, the binding protein is a bispecific or multispecific antibody capable of binding one or more of VEGF, PDGF, and their cognate receptors, or another multispecific construct capable of binding the targets. In certain embodiments, the treatment is with bispecific antibodies that have been produced by quadroma technology (Milstein and Cuello (1983) Nature 305(5934): 537-40), by chemical conjugation of two different monoclonal antibodies (Staerz et al. (1985) Nature 314(6012): 628-31), or by knob-into-hole or similar approaches which introduces mutations in the Fc region (Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90(14): 6444-6448). In some embodiments, the multispecific binding protein is a dual variable domain immunoglobulin (DVD-Ig), e.g., as disclosed in U.S. Pat. No. 7,612,181 (incorporated herein by reference in their entirety). In an embodiment, the DVD-Ig binding protein comprises one or more binding sites comprising the paired heavy and light chain variable domain sequences of any of the binding sites disclosed in Tables 27-30, 38-42, 46-50, or 56-58, or the CDR sequences from those variable domains. For instance, a binding site for VEGF can comprise a paired set of heavy and light chain variable domain sequences from any one of Tables 27 or 38-42, or the CDR regions from those sequences, while the PDGF can comprise the paired heavy and light chain variable domain sequences in Tables 28 or 46-50, or the CDR regions from those sequences. The CDR regions of some of these sequences are shown in Table A and in Table 57.
In some embodiments, a multispecific binding protein disclosed herein is capable of binding VEGF and PDGF, and allows for fewer injections or a lower concentration of active agent, as compared to combination antibody therapy.
In some embodiments, the DVD-Ig binding protein comprises first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-X2, wherein: VD1 is a first variable domain; VD2 is a second variable domain; C is a constant domain; X1 is a linker; X2 is an Fc region that is either present or absent; n is independently 0 or 1 on the first and second chains, and wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site and the VD2 domains on the first and second polypeptide chains form a second functional target binding site. In some embodiments, the binding protein is capable of binding one or more of VEGF, PDGF, and their cognate receptors, e.g., using a paired set of sequences from any one of Tables 27-30, 38-42, 46-50, or 56-58. In some embodiments, the binding protein comprises VD1 sequences on the first and second polypeptide chains (i.e., a VD1 sequence on the first chain paired with a VD1 sequence on the second chain) that together form a binding domain capable of binding a target selected from VEGF, PDGF, and their cognate receptors. In some embodiments, the binding protein is capable of binding VEGF at both the VD1 and VD2 positions. In some embodiments, the binding protein is capable of binding PDGF at both the VD1 and VD2 positions. In some embodiments, the binding protein is capable of binding VEGF at the VD1 position and PDGF at the VD2 position. In some embodiments, the binding protein is capable of binding PDGF at the VD1 position and VEGF at the VD2 position.
When a binding protein comprises the CDRs from a sequence selected from any one of Tables 27-30, 38-42, 46-50, or 56-58, the CDRs are arranged in the order specified by the sequence in the Table and separated by suitable framework sequences to form a functional binding site. The paired sequences selected from the Tables that form a functional binding site for a target (e.g., a binding site for VEGF and/or PDGF), or the CDRs from those sequences, may be placed in either the VD1 or VD2 positions on the first and second polypeptide chains to form a binding site at either the VD1 or VD2 domain.
The binding proteins disclosed herein comprise VD1 and VD2 binding domains that are capable of binding to first and second target antigens. As used herein, a VD1 domain or a VD2 domain, or a VD1 position or VD2 position, may refer to either the variable domain sequence on one polypeptide chain (e.g., a VD1 heavy chain sequence) or to the variable domain sequences on both the first and second polypeptide chain (e.g., a VD1 heavy chain sequence and a VD1 light chain sequence) that together form the functional binding site, as indicated by the context in which it is discussed.
In some embodiments, a DVD-Ig binding protein can comprise two first and two second polypeptide chains forming four functional binding sites on two arms of the construct. An example of a four chain structure having two arms, each arm comprising a first and second polypeptide chain and two functional binding sites, is shown in FIG. 1.
In an embodiment, the DVD-Ig binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs 1-3 from SEQ ID NO: 18, CDRs 1-3 from SEQ ID NO: 19 and CDRs 1-3 from SEQ ID NO: 20, CDRs 1-3 from SEQ ID NO: 21 and CDRs 1-3 from SEQ ID NO: 22, CDRs 1-3 from SEQ ID NO: 23 and CDRs 1-3 from SEQ ID NO: 24, CDRs 1-3 from SEQ ID NO: 25 and CDRs 1-3 from SEQ ID NO: 26, CDRs 1-3 from SEQ ID NO: 27 and CDRs 1-3 from SEQ ID NO: 28, CDRs 1-3 from SEQ ID NO: 29 and CDRs 1-3 from SEQ ID NO: 30, CDRs 1-3 from SEQ ID NO: 31 and CDRs 1-3 from SEQ ID NO: 32, CDRs 1-3 from SEQ ID NO: 33 and CDRs 1-3 from SEQ ID NO: 34, CDRs 1-3 from SEQ ID NO: 35 and CDRs 1-3 from SEQ ID NO: 36, CDRs 1-3 from SEQ ID NO: 37 and CDRs 1-3 from SEQ ID NO: 38, CDRs 1-3 from SEQ ID NO: 39 and CDRs 1-3 from SEQ ID NO: 40, CDRs 1-3 from SEQ ID NO: 41 and CDRs 1-3 from SEQ ID NO: 42, or CDRs 1-3 from SEQ ID NO: 43 and CDRs 1-3 from SEQ ID NO: 44. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, or SEQ ID NO: 43 and SEQ ID NO: 44.
In an embodiment, a DVD-Ig binding protein is disclosed that is capable of binding VEGF and PDGF, wherein the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs 1-3 from SEQ ID NO: 2, CDRs 1-3 from SEQ ID NO: 3 and CDRs 1-3 from SEQ ID NO: 4, CDRs 1-3 from SEQ ID NO: 5 and CDRs 1-3 from SEQ ID NO: 6, CDRs 1-3 from SEQ ID NO: 7 and CDRs 1-3 from SEQ ID NO: 8, CDRs 1-3 from SEQ ID NO: 9 and CDRs 1-3 from SEQ ID NO: 10, CDRs 1-3 from SEQ ID NO: 11 and CDRs 1-3 from SEQ ID NO: 12, CDRs 1-3 from SEQ ID NO: 13 and CDRs 1-3 from SEQ ID NO: 14, CDRs 1-3 from SEQ ID NO: 15 and CDRs 1-3 from SEQ ID NO: 16, or CDRs 1-3 from SEQ ID NO: 211 and CDRs 1-3 from SEQ ID NO: 212. In an embodiment, the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, or SEQ ID NO: 211 and SEQ ID NO: 212.
In an embodiment, the DVD-Ig binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs 1-3 from SEQ ID NO: 18, CDRs 1-3 from SEQ ID NO: 19 and CDRs 1-3 from SEQ ID NO: 20, CDRs 1-3 from SEQ ID NO: 21 and CDRs 1-3 from SEQ ID NO: 22, CDRs 1-3 from SEQ ID NO: 23 and CDRs 1-3 from SEQ ID NO: 24, CDRs 1-3 from SEQ ID NO: 25 and CDRs 1-3 from SEQ ID NO: 26, CDRs 1-3 from SEQ ID NO: 27 and CDRs 1-3 from SEQ ID NO: 28, CDRs 1-3 from SEQ ID NO: 29 and CDRs 1-3 from SEQ ID NO: 30, CDRs 1-3 from SEQ ID NO: 31 and CDRs 1-3 from SEQ ID NO: 32, CDRs 1-3 from SEQ ID NO: 33 and CDRs 1-3 from SEQ ID NO: 34, CDRs 1-3 from SEQ ID NO: 35 and CDRs 1-3 from SEQ ID NO: 36, CDRs 1-3 from SEQ ID NO: 37 and CDRs 1-3 from SEQ ID NO: 38, CDRs 1-3 from SEQ ID NO: 39 and CDRs 1-3 from SEQ ID NO: 40, CDRs 1-3 from SEQ ID NO: 41 and CDRs 1-3 from SEQ ID NO: 42, or CDRs 1-3 from SEQ ID NO: 43 and CDRs 1-3 from SEQ ID NO: 44; and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs 1-3 from SEQ ID NO: 2, CDRs 1-3 from SEQ ID NO: 3 and CDRs 1-3 from SEQ ID NO: 4, CDRs 1-3 from SEQ ID NO: 5 and CDRs 1-3 from SEQ ID NO: 6, CDRs 1-3 from SEQ ID NO: 7 and CDRs 1-3 from SEQ ID NO: 8, CDRs 1-3 from SEQ ID NO: 9 and CDRs 1-3 from SEQ ID NO: 10, CDRs 1-3 from SEQ ID NO: 11 and CDRs 1-3 from SEQ ID NO: 12, CDRs 1-3 from SEQ ID NO: 13 and CDRs 1-3 from SEQ ID NO: 14, CDRs 1-3 from SEQ ID NO: 15 and CDRs 1-3 from SEQ ID NO: 16, or CDRs 1-3 from SEQ ID NO: 211 and CDRs 1-3 from SEQ ID NO: 212. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, or SEQ ID NO: 43 and SEQ ID NO: 44; and the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, or SEQ ID NO: 211 and SEQ ID NO: 212.
In various embodiments, the DVD-Ig binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 35 and CDRs-1-3 from SEQ ID NO: 36, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 35 and SEQ ID NO: 36, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. In any of these embodiments, the binding site for VEGF may be the outer binding domain or VD1 position as described herein, and the binding site for PDGF may be the inner domain or VD2 position as described herein. In various embodiments, any of the DVD-Ig binding proteins disclosed herein can comprise one or more of the X1 linkers shown in Table 55. In an embodiment, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10(dR) linker. In an embodiment, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10 linker. In an embodiment, the X1 linker on the heavy chain is an HG-short linker and the X1 linker on the light chain is an LK-long linker.
In various embodiments, any of the antibodies, binding proteins, or DVD-Ig binding proteins disclosed herein can comprise a human IgG (e.g., an IgG1) heavy chain constant region on the first polypeptide chain comprising substitutions of leucines at positions 234 and 235 with alanines, and optionally also (or alternatively) a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering. In various embodiments, the antibody, binding protein, or DVD-Ig binding protein can also comprise a human kappa or lambda light chain constant region on the second polypeptide chain. In an embodiment, the light chain comprises a wild-type human kappa light chain constant region sequence.
In an embodiment, the DVD-Ig binding protein is capable of binding VEGF and PDGF, and comprises PR-1610561 (comprising SEQ ID NOs: 131 and 132). In an embodiment, the binding protein comprises a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, and optionally also comprising a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence. In an embodiment, the binding protein comprises an IgG1 constant region with substitution of leucines at positions 234 and 235 with alanines, and a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence. In some embodiments, the L234A, L235A, and H435 mutations are present in a DVD-Ig binding protein comprising PR-1610561 (comprising SEQ ID NOs: 131 and 132). In some embodiments, the binding protein carrying the constant region mutations has increased ocular duration over an antibody, but is rapidly cleared from systemic circulation (e.g., by altering FcRn recognition), as compared to an antibody or as compared to the same binding protein lacking the constant region mutations. In some embodiments, the high ocular duration allows for less frequent administration and/or fewer overall injections while achieving a comparable or improved efficacy as compared to administration of a combination of anti-VEGF and anti-PDGF antibodies or as compared to administration of the binding protein lacking the constant region mutations. In some embodiments, the binding protein carrying the constant region mutations has decreased ADCC and CDC effector functions mediated by binding to extracellular matrix-associated VEGF-A and/or PDGF-BB, as compared to administration of the binding protein lacking the constant region mutations. In some embodiments, the binding protein carrying the constant region mutations does not bind to one or more Fc-gamma receptors. In some embodiments, systemic levels of the binding protein in a patient drops below detectable levels after less than 20, 25, 30, 35, or 40 hours following administration at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg/kg, or more (or any concentration in between) in an intravenous bolus dose.
In an embodiment, the DVD-Ig binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs-1-3 from SEQ ID NO: 18, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs-1-3 from SEQ ID NO: 2. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, and the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2. In an embodiment, the DVD-Ig binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 39 and CDRs-1-3 from SEQ ID NO: 40, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 39 and SEQ ID NO: 40, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. In any of these embodiments, the binding site for VEGF may be the outer binding domain or VD1 sequence as described herein, and the binding site for PDGF may be the inner domain or VD2 sequence as described herein. In various embodiments, the binding proteins can comprise one or more of the X1 linkers shown in Table 55. In an embodiment, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10(dR) linker. In an embodiment, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10 linker. In an embodiment, the X1 linker on the heavy chain is an HG-short linker and the X1 linker on the light chain is an LK-long linker. In an embodiment, the binding protein is capable of binding VEGF and PDGF, and comprises PR-1572102 (comprising SEQ ID NOs: 88 and 89) or PR-1572105 (comprising SEQ ID NOs: 94 and 95) or PR1611292 (comprising SEQ ID NOs: 141 and 142). In an embodiment, the binding protein comprises a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, and optionally also comprising a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence.
In an embodiment, the DVD-Ig binding protein comprises the first and second polypeptide chains of any of the DVD-Ig binding proteins disclosed in Tables 56-58. The CDR sequences of the variable domains in Tables 56-58 are in bold and the linker sequences are italicized.
In an embodiment, the DVD-Ig binding protein comprises the first and second polypeptide chains of PR-1563988 (comprising SEQ ID NOs: 45 and 46), PR-1563990 (comprising SEQ ID NOs: 47 and 48), PR-1563998 (comprising SEQ ID NOs: 49 and 50), PR-1564009 (comprising SEQ ID NOs: 51 and 52), PR-1564010 (comprising SEQ ID NOs: 53 and 54), PR-1564011 (comprising SEQ ID NOs: 55 and 56), PR-1564012 (comprising SEQ ID NOs: 57 and 58), PR-1564013 (comprising SEQ ID NOs: 59 and 60), PR-1565031 (comprising SEQ ID NOs: 76 and 77), PR-1565032 (comprising SEQ ID NOs: 78 and 79), PR-1565035 (comprising SEQ ID NOs: 80 and 81), PR-1572102 (comprising SEQ ID NOs: 88 and 89), PR-1572103 (comprising SEQ ID NOs: 90 and 91), PR-1572104 (comprising SEQ ID NOs: 92 and 93), PR-1572105 (comprising SEQ ID NOs: 94 and 95), PR-1572106 (comprising SEQ ID NOs: 96 and 97), PR-1575832 (comprising SEQ ID NOs: 99 and 100), PR-1575834 (comprising SEQ ID NOs: 101 and 102), PR-1575835 (comprising SEQ ID NOs: 103 and 104), PR-1577165 (comprising SEQ ID NOs: 105 and 106), PR-1577166 (comprising SEQ ID NOs: 107 and 108), PR-1577547 (comprising SEQ ID NOs: 109 and 110), PR-1577548 (comprising SEQ ID NOs: 111 and 112), PR-1577550 (comprising SEQ ID NOs: 113 and 114), PR-1578137 (comprising SEQ ID NOs: 116 and 117), PR-1610560 (comprising SEQ ID NOs: 129 and 130), PR-1610561 (comprising SEQ ID NOs: 131 and 132), PR-1610562 (comprising SEQ ID NOs: 133 and 134), PR-1610563 (comprising SEQ ID NOs: 135 and 136), PR-1611291 (comprising SEQ ID NOs: 139 and 140), PR-1611292 (comprising SEQ ID NOs: 141 and 142), PR-1612489 (comprising SEQ ID NOs: 161 and 162), PR-1612491 (comprising SEQ ID NOs: 163 and 164), PR-1612492 (comprising SEQ ID NOs: 165 and 166), PR-1612495 (comprising SEQ ID NOs: 171 and 172), PR-1612496 (comprising SEQ ID NOs: 173 and 174), PR-1612499 (comprising SEQ ID NOs: 177 and 178), PR-1612500 (comprising SEQ ID NOs: 179 and 180), PR-1612501 (comprising SEQ ID NOs: 181 and 182), PR-1612502 (comprising SEQ ID NOs: 183 and 184), PR-1613183 (comprising SEQ ID NOs: 185 and 186), PR-1613184 (comprising SEQ ID NOs: 187 and 188), PR-1613185 (comprising SEQ ID NOs: 189 and 190), PR-1613190 (comprising SEQ ID NOs: 199 and 200), PR-1565040 (comprising SEQ ID NOs: 3844 and 3845), PR-1565042 (comprising SEQ ID NOs: 3837 and 3838), PR-1565044 (comprising SEQ ID NOs: 213 and 214), PR-1565051 (comprising SEQ ID NOs: 215 and 216), PR-1565083 (comprising SEQ ID NOs: 217 and 218), PR-1565084 (comprising SEQ ID NOs: 219 and 220), PR-1565085 (comprising SEQ ID NOs: 221 and 222), PR-1565086 (comprising SEQ ID NOs: 223 and 224), PR-1571821 (comprising SEQ ID NOs: 225 and 226), PR-1571823 (comprising SEQ ID NOs: 227 and 228), PR-1575521 (comprising SEQ ID NOs: 229 and 230), PR-1571824 (comprising SEQ ID NOs: 231 and 232), PR-1571825 (comprising SEQ ID NOs: 233 and 234), PR-1571826 (comprising SEQ ID NOs: 235 and 236), PR-1571827 (comprising SEQ ID NOs: 237 and 238), PR-1571828 (comprising SEQ ID NOs: 239 and 240), PR-1571830 (comprising SEQ ID NOs: 241 and 242), PR-1571831 (comprising SEQ ID NOs: 243 and 244), PR-1571832 (comprising SEQ ID NOs: 245 and 246), PR-1571836 (comprising SEQ ID NOs: 247 and 248), PR-1577053 (comprising SEQ ID NOs: 249 and 250), or PR-1577056 (comprising SEQ ID NOs: 251 and 252.
In some embodiments, a binding protein, including a DVD-Ig binding protein, antibody, or fragment thereof, is capable of binding VEGF and/or PDGF and has at least about 80%, 90%, 95%, or 99% homology to CDRs 1-3 or to the full variable domains of any of the sequences in Tables 27, 28, 38-42, or 46-50. As used herein, the term percent (%) homology defines the percentage of residues in the amino acid sequence variant that are identical after aligning the sequences and introducing gaps and other spacing, e.g., using the BLAST alignment software.
In an embodiment, the binding protein has an on rate constant (Kon) to one or more targets of at least about 102M−1s−1; at least about 103M−1s−1; at least about 104M−1s−1; at least about 105M−1s−1; or at least about 106M−1s−1, as measured by surface plasmon resonance. In an embodiment, the binding protein has an on rate constant (Kon) to one or more targets from about 102M−1s−1 to about 103M−1s−1; from about 103M−1s−1 to about 104M−1s−1; from about 104M−1s−1 to about 105M−1s−1; or from about 105M−1s−1 to about 106M−1s−1, as measured by surface plasmon resonance.
In an embodiment, the binding protein has an off rate constant (Koff) for one or more targets of at most about 10−3s−1; at most about 10−4s−1; at most about 10−5s−1; or at most about 10−6s−1, as measured by surface plasmon resonance. In an embodiment, the binding protein has an off rate constant (Koff) to one or more targets of about 10−3s−1 to about 10−4s−1; of about 10−4s−1 to about 10−5s−1; or of about 10−5s−1 to about 10−6s−1, as measured by surface plasmon resonance.
In an embodiment, the binding protein has a dissociation constant (Kd) to one or more targets of at most about 10−7M; at most about 10−8M; at most about 10−9M; at most about 10−10 M; at most about 10−11M; at most about 10−12M; or at most 10−13M. In an embodiment, the binding protein has a dissociation constant (Kd) to its targets of about 10−7M to about 10−8M; of about 10−8M to about 10−9M; of about 10−9M to about 10−10 M; of about 10−10 M to about 10−11M; of about 10−11M to about 10−12M; or of about 10−12 to M about 10−13M.
In an embodiment, the binding protein is a conjugate further comprising an agent. In an embodiment, the agent is an immunoadhesion molecule, an imaging agent, a therapeutic agent, or a cytotoxic agent. In an embodiment, the imaging agent is a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, or biotin. In another embodiment, the radiolabel is 3H, 14C, 35S, 90Y, 99Tc, 111In, 125I, 131I, 177Lu, 166Ho, or 153Sm. In yet another embodiment, the therapeutic or cytotoxic agent is an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, toxin, or an apoptotic agent, or an immunosuppressive agent.
In an embodiment, the binding protein is a crystallized binding protein and exists as a crystal. In an embodiment, the crystal is a carrier-free pharmaceutical controlled release crystal. In another embodiment, the crystallized binding protein has a greater half-life in vivo than the soluble counterpart of the binding protein. In yet another embodiment, the crystallized binding protein retains biological activity.
In certain embodiments, a binding protein disclosed herein can compete for binding to VEGF, PDGF, and/or a cognate receptor with any of the antibodies, binding proteins, or bispecific antibodies disclosed herein. In certain embodiments, a binding protein disclosed herein can compete for binding with an antibody, binding protein, or bispecific antibody comprising CDRs and/or variable domains selected from those identified in Tables 27, 28, 38-42, or 46-50. In certain embodiments, a binding protein disclosed herein can compete for binding with PR-1610561 (comprising SEQ ID NOs: 131 and 132) or a binding protein comprising the CDRs and/or variable domains of PR-1610561. In certain embodiments, a binding protein disclosed herein can compete for binding with PR-1572102 (comprising SEQ ID NOs: 88 and 89) or PR-1572105 (comprising SEQ ID NOs: 94 and 95) or PR1611292 (comprising SEQ ID NOs: 141 and 142).
According to certain embodiments, a binding protein disclosed herein can bind to the same epitope of VEGF, PDGF, and/or a cognate receptor as any of the antibodies, binding proteins, or bispecific antibodies disclosed herein. In certain embodiments, a binding protein disclosed herein can bind to the same epitope of VEGF, PDGF, and/or a cognate receptor bound by an antibody, binding protein, or bispecific antibody comprising CDRs and/or variable domains selected from those identified in Tables 27, 28, 38-42, or 46-50. In certain embodiments, a binding protein disclosed herein can bind to the same epitope as PR-1610561 (comprising SEQ ID NOs: 131 and 132) or a binding protein comprising the CDRs and/or variable domains of PR-1610561. In certain embodiments, a binding protein disclosed herein binds to the same epitope as PR-1572102 (comprising SEQ ID NOs: 88 and 89) or PR-1572105 (comprising SEQ ID NOs: 94 and 95) or PR1611292 (comprising SEQ ID NOs: 141 and 142).
In certain embodiments, competitive binding can be evaluated using a cross-blocking assay, such as the assay described in ANTIBODIES, A LABORATORY MANUAL, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1st edition 1988, 2nd edition 2014). In some embodiments, competitive binding is identified when a test antibody or binding protein reduces binding of a reference antibody or binding protein (e.g., a binding protein comprising CDRs and/or variable domains selected from those identified in Tables 27, 28, 38-42, or 46-50) to VEGF, PDGF, and/or a cognate receptor by at least about 50% in the cross-blocking assay (e.g., 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, or more, or any percentage in between), and/or vice versa. In some embodiments, competitive binding can be due to shared or similar (e.g., partially overlapping) epitopes, or due to steric hindrance where antibodies or binding proteins bind at nearby epitopes. See, e.g., Tzartos, Methods in Molecular Biology, vol. 66, Epitope Mapping Protocols, pages 55-66, Humana Press Inc. (1998). In some embodiments, competitive binding can be used to sort groups of binding proteins that share similar epitopes, e.g., those that compete for binding can be “binned” as a group of binding proteins that have overlapping or nearby epitopes, while those that do not compete are placed in a separate group of binding proteins that do not have overlapping or nearby epitopes
In an embodiment, the binding protein described herein is glycosylated. For example, the glycosylation pattern may be a human glycosylation pattern.
In various embodiments, a pharmaceutical composition comprising a binding protein disclosed herein and a pharmaceutically acceptable carrier is provided. In a further embodiment, the pharmaceutical composition comprises at least one additional agent such as a therapeutic agent for treating a disorder or a diagnostic agent. For example, the additional agent may be a therapeutic agent, an imaging agent, a cytotoxic agent, an angiogenesis inhibitor (including but not limited to an anti-VEGF antibody or a VEGF-trap), a kinase inhibitor (including but not limited to a KDR and a TIE-2 inhibitor), a co-stimulation molecule blocker (including but not limited to anti-B7.1, anti-B7.2, CTLA4-Ig, anti-CD20), an adhesion molecule blocker (including but not limited to an anti-LFA-1 antibody, an anti-E/L selectin antibody, a small molecule inhibitor), an anti-cytokine antibody or functional fragment thereof (including but not limited to an anti-IL-18, an anti-TNF, and an anti-IL-6/cytokine receptor antibody), methotrexate, cyclosporin, rapamycin, FK506, a detectable label or reporter, a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an erythropoietin, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an epinephrine or analog, a cytokine, or a cytokine antagonist.
In various embodiments, a binding protein disclosed herein binds to VEGF and comprises CDRs and/or variable domains selected from those identified in Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding protein comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of the CDR sets listed in Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding protein comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding protein is a bispecific or multispecific binding protein, comprising CDRs and/or variable domains selected from Tables A, 2.4.1-2.4.9, 27, and 38-42. The binding protein may further comprise heavy and light chain constant domains selected from Table 3. In some embodiments, the binding protein is also capable of binding to PDGF.
In some embodiments, a binding protein disclosed herein binds to PDGF and comprises CDRs and/or variable domains selected from those identified in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding protein comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of the CDR sets listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding protein comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding protein is a bispecific or multispecific binding protein, comprising CDRs and/or variable domains selected from Tables A, 1.4.1-1.4.7, 28, and 46-50. The binding protein may further comprise heavy and light chain constant domains selected from Table 3. In some embodiments, the binding protein is also capable of binding to VEGF.
In some embodiments, a binding protein disclosed herein binds to VEGF and PDGF, wherein the binding site for VEGF comprises CDRs and/or variable domains selected from those identified in Tables A, 2.4.1-2.4.9, 27, and 38-42 and the binding site for PDGF comprises CDRs and/or variable domains selected from those identified in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding sites for VEGF and PDGF comprises CDRs and/or variable domains selected from any of the variable domains listed in Tables 56-59, 95, and 96. In some embodiments, binding proteins disclosed herein comprise binding sites for VEGF and PDGF comprising the paired CDRs and/or variable domains from any one of the bispecific binding proteins selected from Tables 56-59, 95, and 96. In some embodiments, the binding proteins are DVD-Ig binding proteins, or any of the other bispecific or multispecific formats disclosed herein. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.
In some embodiments, a binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs-1-3 from SEQ ID NO: 18, and the binding site for PDGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 35 and CDRs-1-3 from SEQ ID NO: 36, and the binding site for PDGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 39 and CDRs-1-3 from SEQ ID NO: 40, and the binding site for PDGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, and the binding site for PDGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 35 and SEQ ID NO: 36, and the binding site for PDGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 39 and SEQ ID NO: 40, and the binding site for PDGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.
In some embodiments, a binding protein is capable of binding VEGF and PDGF, wherein the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs-1-3 from SEQ ID NO: 2, and the binding site for VEGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16, and the binding site for VEGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2, and the binding site for VEGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16, and the binding site for VEGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 2.4.1-2.4.9, 27, and 38-42. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.
In some embodiments, a binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs-1-3 from SEQ ID NO: 18, and the binding site PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs-1-3 from SEQ ID NO: 2. In some embodiments, the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 35 and CDRs-1-3 from SEQ ID NO: 36, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. In some embodiments, the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 39 and CDRs-1-3 from SEQ ID NO: 40, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.
In some embodiments, a binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, and the binding site PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 35 and SEQ ID NO: 36, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 39 and SEQ ID NO: 40, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.
In some embodiments, the binding protein is a DVD-Ig binding protein, capable of binding VEGF and PDGF. In some embodiment, the heavy chain of the binding protein comprises a DVD-Ig heavy chain variable domain and paired DVD-Ig light chain variable domain selected from Tables 56-59, 95, and 96. In some embodiments, the binding protein comprises DVD-Ig heavy and light chain variable domains of SEQ ID NO: 131 and SEQ ID NO: 132. In some embodiments, the binding protein comprises DVD-Ig heavy and light chain variable domains of SEQ ID NO: 88 and SEQ ID NO: 89. In some embodiments, the binding protein comprises DVD-Ig heavy and light chain variable domains of SEQ ID NO: 94 and SEQ ID NO: 95. In some embodiments, the binding protein comprises DVD-Ig heavy and light chain variable domains of SEQ ID NO: 141 and SEQ ID NO: 142. The DVD-Ig binding protein described herein may further comprise heavy and light chain constant domains selected from Table 3.
In certain embodiments, a binding protein disclosed herein is a DVD-Ig binding protein, comprising first and second polypeptide chains of SEQ ID NO: 131 and SEQ ID NO: 132. In some embodiments, the DVD-Ig binding protein comprises first and second polypeptide chains of SEQ ID NO: 88 and SEQ ID NO: 89. In some embodiments, the DVD-Ig binding protein comprises first and second polypeptide chains of SEQ ID NO: 94 and SEQ ID NO: 95. In some embodiments, the DVD-Ig binding protein comprises first and second polypeptide chains of SEQ ID NO: 141 and SEQ ID NO: 142.
Binding Protein Properties
The development and production of a binding protein for use as a human therapeutic agent, e.g., as an anti-inflammatory agent or oncologic agent, may require more than the identification of a binding protein capable of binding to a desired target or targets. The binding proteins disclosed herein exhibit favorable properties in one or more of the following categories (a) the binding kinetics (on-rate, off-rate and affinity) for both the inner and outer antigen-binding domains, (b) potencies in various biochemical and cellular bioassays, (c) in vivo efficacies in relevant tumor models, (d) pharmacokinetic and pharmacodynamics properties, (e) manufacturability, including protein expression level in selected cell lines, scalability, post-translational modification, physicochemical properties such as monomer percentage, solubility, and stability (intrinsic, freeze/thaw, storage stability, etc.), (f) formulation properties, (g) potential immunogenicity risk, (h) toxicological properties, and (i) binding mode and valency. Binding mode and valency may affect binding properties and cellular potencies of a molecule.
The binding proteins disclosed herein exhibit favorable properties in some or each of the categories listed above, including surprisingly high binding affinity at both the VD1 and VD2 positions.
In some embodiments a binding protein or binding proteins disclosed herein targeting VEGF and PDGF serve to both reduce choroidal neovascularization and increase regression of mature vasculature, e.g., in ocular conditions such as AMD. In some embodiments a binding protein or binding proteins disclosed herein targeting VEGF and PDGF neutralize VEGF and PDGF simultaneously. In some embodiments, the binding protein exhibits one or more of high potency to VEGF and/or PDGF, extended ocular duration, and rapid clearance from systemic circulation. In some embodiments, the binding protein is a bispecific and allows for a single injection of an agent to both targets (VEGF and PDGDF), reducing injection volume/frequency while still retaining the drug-like products of a traditional antibody.
In some embodiments, the disclosed binding protein exhibits superior in vivo efficacy (e.g., in a preclinical model of choroidal neovascularization or AMD) as compared to existing treatments for AMD (e.g., ElyeaTM and/or LucentisTM). In some embodiments, the disclosed binding protein is a DVD-Ig binding protein and exhibits a high ocular duration. In some embodiments, the DVD-Ig binding protein may be, e.g., 150-200 kDa in weight or greater, and may provide for a longer ocular duration as compared to lower weight agents such as monoclonal antibodies. In some embodiments, the binding protein disclosed herein is a DVD-Ig binding protein and has an ocular half life of at least about 4 days, or at least about 4. 6 days, or at least about 5 days, or at least about 6 days, or at least about 6.5 days, or more. In some embodiments, the DVD-Ig ocular half life is greater than the half-life of an antibody or other construct having a smaller size, while retaining a more rapid systemic clearance similar to that of the antibody. In some embodiments, the DVD-Ig binding protein has an ocular half life of at least about 4 (or at least about 4.6) days after intravitreoius administration at 0.25 mg.
In some embodiments, the disclosed binding proteins are DVD-Ig binding proteins and exhibit improved drug-like properties, including one or more of high thermostability (e.g., a Tonset of greater than 50°, 55°, 60°, 61°, 62°, 63°, 64°, or 65° C.), a solubility of at least about 70, 72, 74, 76, 78, or 80 mg/ml, a viscosity at room temperature and at a concentration of 100 mg/ml of about 7.2 centipoise, an effective storage stability in a universal buffer, and/or high freeze-thaw stability. In some embodiments, the DVD-Ig binding protein does not exhibit a significant change in monomer percentage at low concentration after storage at 5° C. or 40° C. for 10, 15, 20, 21, 22, 23, 24, 25, or more days, and/or does not exhibit a significant increase in aggregation at 50-150 mg/ml (or 100+/−10 mg/ml) after 1, 2, 3, 4, 5, or more freeze/thaw cycles.
In certain embodiments, a binding protein exhibiting particularly favorable properties in some or each of the categories listed above is a DVD-Ig binding protein capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 35 and CDRs-1-3 from SEQ ID NO: 36, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 35 and SEQ ID NO: 36, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. In an embodiment, the binding protein is capable of binding VEGF and PDGF, and comprises PR-1610561 (comprising SEQ ID NOs: 131 and 132). In an embodiment, the binding protein comprises a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, and optionally also comprising a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence
In certain embodiments, a binding protein exhibiting particularly favorable properties in some or each of the categories listed above is a DVD-Ig binding protein capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs-1-3 from SEQ ID NO: 18, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs-1-3 from SEQ ID NO: 2. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, and the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2. In an embodiment, the binding protein is capable of binding VEGF and PDGF, and comprises PR-1572102 (comprising SEQ ID NOs: 88 and 89) or PR-1572105 (comprising SEQ ID NOs: 94 and 95) or PR1611292 (comprising SEQ ID NOs: 141 and 142). In an embodiment, the binding protein comprises a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, and optionally also comprising a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence.
For instance, in some embodiments, the binding protein disclosed herein (e.g., PR-1610561, PR-1572102, PR-1572105, or PR1611292) may exhibit one or more of the following features: enhanced in vivo efficacy in human VEGF transgenic mice, enhanced potency (as measured, e.g., via BIACORE, ELISA, or co-culture sprouting assay), improved expression (e.g., in HEK293 or CHO cells), and improved drug-like properties (e.g., thermal stability, storage stability, solubility, physicochemical properties, and/or pharmacokinetics) as compared to another binding protein or combination of binding proteins targeting VEGF and PDGF.
Preparation of Binding Proteins
In another aspect, the disclosure provides a method of making a binding protein that binds PDGF, VEGF, and/or either or both cognate receptors. In an embodiment, the method of making a binding protein comprises the steps of a) obtaining a first parent antibody, or antigen binding portion thereof, that binds PDGF, VEGF, or a cognate receptor; b) obtaining a second parent antibody, or antigen binding portion thereof, that binds PDGF, VEGF, or a cognate receptor; c) determining the sequences of the variable domains of the parent antibodies or antigen binding portions thereof; d) preparing construct(s) encoding any of the binding proteins described herein using those variable domain sequences; and e) expressing the polypeptide chains, such that a binding protein that binds PDGF, VEGF, and/or either or both cognate receptors is generated.
In any of the embodiments herein, the VD1 heavy chain variable domain, if present, and light chain variable domain, if present, can be from a first parent antibody or antigen binding portion thereof; the VD2 heavy chain variable domain, if present, and light chain variable domain, if present, can be from a second parent antibody or antigen binding portion thereof. The first and second parent antibodies can be the same or different.
In one embodiment, the first parent antibody or antigen binding portion thereof, binds a first antigen, and the second parent antibody or antigen binding portion thereof, binds a second antigen. In an embodiment, the first and second antigens are the same antigen. In another embodiment, the parent antibodies bind different epitopes on the same antigen. In another embodiment, the first and second antigens are different antigens. In another embodiment, the first parent antibody or antigen binding portion thereof, binds the first antigen with a potency different from the potency with which the second parent antibody or antigen binding portion thereof, binds the second antigen. In yet another embodiment, the first parent antibody or antigen binding portion thereof, binds the first antigen with an affinity different from the affinity with which the second parent antibody or antigen binding portion thereof, binds the second antigen.
In another embodiment, the first parent antibody or antigen binding portion thereof, and the second parent antibody or antigen binding portion thereof, are a human antibody, CDR grafted antibody, humanized antibody, and/or affinity matured antibody. The “parent antibody”, which provides at least one antigen binding specificity of the multivalent and or multispecific binding protein, may be one that is internalized (and/or catabolized) by a cell expressing an antigen to which the antibody binds; and/or may be an agonist, cell death-inducing, and/or apoptosis-inducing antibody, and the multivalent and or multispecific binding protein as described herein may display improvement(s) in one or more of these properties. Moreover, the parent antibody may lack any one or more of these properties, but may acquire one or more of them when constructed as a multivalent binding protein as described herein. For example, different Fc mutants may prevent FcR, FcR-gamma, complement, or C′ binding, or extend half-life.
In various embodiments, an isolated nucleic acid encoding any one of the binding proteins disclosed herein is also provided. Also provided is a composition comprising one or more nucleic acids wherein said one or more nucleic acids encode a nucleic acid encoding any one of the binding proteins disclosed herein. For example, the composition may comprise a nucleic acid that encodes a first polypeptide and a nucleic acid that encodes a second polypeptide, wherein said first and second polypeptide together form a binding protein as described herein. A further embodiment provides a vector (e.g., an expression vector) comprising the isolated nucleic acid disclosed herein. Also provided is a vector (e.g. an expression vector) that comprises one or more nucleic acids that encode a binding protein as described herein. Also provided is a composition comprising one or more vectors that encode a binding protein as described herein. For example, the composition may comprise a vector that encodes a first polypeptide and a vector that encodes a second polypeptide, wherein said first and second polypeptide together form a binding protein as described herein. In some embodiments, the vector is pcDNA; pTT (Durocher et al. (2002) Nucleic Acids Res. 30(2):e9; pTT3 (pTT with additional multiple cloning site; pEFBOS (Mizushima and Nagata (1990) Nucleic Acids Res. 18:17); pBV; pJV; pcDNA3.1 TOPO; pEF6 TOPO; pBOS; pHybE; or pBJ. In an embodiment, the vector is a vector disclosed in U.S. Pat. No. 8,187,836.
In another aspect, a host cell is transformed with the vector disclosed herein. In an embodiment, the host cell is a prokaryotic cell, for example, E. coli. In another embodiment, the host cell is a eukaryotic cell, for example, a protist cell, an animal cell, a plant cell, or a fungal cell. In an embodiment, the host cell is a mammalian cell including, but not limited to, CHO, COS, NSO, SP2, PER.C6, or a fungal cell, such as Saccharomyces cerevisiae, or an insect cell, such as Sf9. In an embodiment, two or more binding proteins, e.g., with different specificities, are produced in a single recombinant host cell. For example, the expression of a mixture of antibodies has been called OligoclonicsTM (Merus B.V., The Netherlands) disclosed in U.S. Pat. Nos. 7,262,028 and 7,429,486.
In various embodiments, a binding proteins disclosed herein can be prepared by culturing any one of the host cells disclosed herein in a culture medium under conditions sufficient to produce the binding protein.
One embodiment provides a composition for the release of a binding protein wherein the composition comprises a crystallized binding protein, an ingredient, and at least one polymeric carrier. In an embodiment, the polymeric carrier is poly (acrylic acid), a poly (cyanoacrylate), a poly (amino acid), a poly (anhydride), a poly (depsipeptide), a poly (ester), poly (lactic acid), poly (lactic-co-glycolic acid) or PLGA, poly (b-hydroxybutyrate), poly (caprolactone), poly (dioxanone), poly (ethylene glycol), poly ((hydroxypropyl) methacrylamide, poly [(organo)phosphazene], a poly (ortho ester), poly (vinyl alcohol), poly (vinylpyrrolidone), a maleic anhydride-alkyl vinyl ether copolymer, a pluronic polyol, albumin, alginate, cellulose, a cellulose derivative, collagen, fibrin, gelatin, hyaluronic acid, an oligosaccharide, a glycaminoglycan, a sulfated polysaccharide, or blends and copolymers thereof. In an embodiment, the ingredient is albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-β-cyclodextrin, methoxypolyethylene glycol, or polyethylene glycol.
The binding proteins provided herein, such as DVD-Ig binding proteins, may be produced by any of a number of techniques known in the art. For example, expression from host cells, wherein expression vector(s) encoding the DVD-Ig heavy and DVD-Ig light chains is (are) transfected into a host cell by standard techniques. Although it is possible to express the DVD-Ig binding proteins provided herein in either prokaryotic or eukaryotic host cells, DVD-Ig binding proteins are preferably expressed in eukaryotic cells, for example, mammalian host cells.
In an exemplary system for recombinant expression of DVD-Ig proteins, a recombinant expression vector encoding both the DVD-Ig heavy chain and the DVD-Ig light chain is introduced into dhfr-CHO cells by calcium phosphate-mediated transfection. Within the recombinant expression vector, the DVD-Ig heavy and light chain sequences are each operatively linked to CMV enhancer/AdMLP promoter regulatory elements to drive high levels of transcription of the genes. The recombinant expression vector also carries a DHFR gene, which allows for selection of CHO cells that have been transfected with the vector using methotrexate selection/amplification. The selected transformant host cells are cultured to allow for expression of the DVD-Ig heavy and light chains and intact DVD-Ig protein is recovered from the culture medium. Standard molecular biology techniques may be used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells and recover the DVD-Ig protein from the culture medium. In some embodiments, a method of synthesizing a DVD-Ig binding protein by culturing a host cell provided herein in a suitable culture medium until a DVD-Ig binding protein is synthesized is also provided. The method may further comprise isolating the DVD-Ig protein from the culture medium.
A feature of a DVD-Ig binding protein is that it can be produced and purified in a similar way to a conventional antibody. The design of the full length DVD-Ig binding protein heavy and light chains provided herein leads to assemble primarily to the desired dual-specific multivalent full length binding proteins. In an embodiment, 50%-75% of the binding protein produced by this method is a dual specific tetravalent binding protein (e.g., a DVD-Ig binding protein). In another embodiment, 75%-90% of the binding protein produced by this method is a dual specific tetravalent binding protein. In another embodiment, 90%-95% of the binding protein produced is a dual specific tetravalent binding protein. In some embodiments, at least 50%, at least 75% and at least 90% of the assembled, and expressed dual variable domain immunoglobulin molecules are the desired dual-specific tetravalent protein.
In various embodiments, the disclosure provides methods of expressing a dual variable domain light chain and a dual variable domain heavy chain in a single cell leading to a primary product of a dual-specific tetravalent full length binding protein, where the primary product is more than 50%, such as more than 75% and more than 90%, of all assembled protein, comprising a dual variable domain light chain and a dual variable domain heavy chain.
Therapeutic and Diagnostic Uses
Also disclosed herein, in various embodiments, are methods for diagnosing and treating a mammal (e.g., a human) comprising the step of administering to the mammal, or a sample taken from the mammal, an effective amount of a composition disclosed herein. A binding protein as described herein may be used in a method for therapy or diagnosis.
Given their ability to bind VEGF, PLGF, and/or their cognate receptors, in some embodiments, the binding proteins provided herein can be used to detect one or more of those antigens (e.g., in a biological sample, such as serum or plasma), using a conventional immunoassay, such as an enzyme linked immunosorbent assays (ELISA), a radioimmunoassay (RIA), or tissue immunohistochemistry. The binding protein is directly or indirectly labeled with a detectable substance to facilitate detection of the bound or unbound antibody. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin. An example of a luminescent material is luminol and examples of suitable radioactive materials include 3H, 14C, 35S, 90Y, 99Tc, 111In, 125I, 131I, 177Lu, 166Ho, and 153Sm.
In some embodiments, a method is disclosed for treating a human subject suffering from a disorder in which the target, or targets, capable of being bound by the binding proteins disclosed herein is/are detrimental, comprising administering to the human subject a binding protein disclosed herein such that the activity of the target, or targets, in the human subject is inhibited and one or more symptoms is alleviated or treatment is achieved is provided. In various embodiments, treatment comprises reducing, improving, or ameliorating one or more symptom of a disorder. Treatment includes but does not necessarily require curing (i.e., completely eliminating) a disorder or a symptom of a disorder.
The binding proteins provided herein can be used to treat humans suffering from diseases such as, for example, those associated with increased angiogenesis and/or inflammation (e.g., ocular inflammation). In an embodiment, the binding proteins provided herein or antigen-binding portions thereof, are used to treat an autoimmune disorder, asthma, ocular inflammation, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), insulin dependent diabetes mellitus, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus (SLE), multiple sclerosis, sepsis, a neurodegenerative disease, or an oncological disorder. In an embodiment, a binding protein disclosed herein is used to treat an eye disorder (e.g., an angiogenic eye disorder). In an embodiment, the eye disorder is a macular degeneration, such as wet macular degeneration, dry macular degeneration, age related macular degeneration (AMD), exudative AMD, dry eye, glaucoma, diabetic retinopathy, diabetic macular edema, central retinal vein occlusion, corneal neovascularization, iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), choroidal neovascularization, optic disc neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, macular edema, diabetic macular edema (DME), vascular retinopathy, retinal degeneration, uveitis, keratoconjunctivitis sicca, blepharitis, keratitis or another inflammatory disease of the eye.
In an embodiment, the binding proteins provided herein are capable of neutralizing the activity of their antigen targets both in vitro and in vivo. Accordingly, such binding proteins can be used to inhibit antigen activity, e.g., in a cell culture containing the antigens, in human subjects or in other mammalian subjects having the antigens with which a binding protein provided herein cross-reacts. In another embodiment, a method for reducing antigen activity in a subject suffering from a disease or disorder in which the antigen activity is detrimental is provided. A binding protein provided herein may be administered to a human subject for therapeutic purposes. In some embodiments, the binding protein (e.g., the DVD-Ig binding protein) is administered to a patient, e.g., a patient suffering from wet AMD, and can have one or more effects selected from regressing mature vasculature (e.g., via VEGF binding), reducing choroidal neovascularization (e.g., via VEGF binding), allowing access to blood vessels by stripping off pericytes (e.g., via PDGF binding), and/or providing anti-fibrotic effects to reduce visual loss from scarring (e.g., via PDGF binding). In some embodiments, the binding protein is multispecific for VEGF and PDGF, and is administered at a reduced number of injections and/or a reduced injection frequency, as compared to a combination antibody therapy.
The term “a disorder in which antigen activity is detrimental” encompasses diseases and other disorders in which the presence of the antigen in a subject suffering from the disorder has been shown to be or is suspected of being either responsible for the pathophysiology of the disorder or a factor that contributes to a worsening of the disorder. Accordingly, a disorder in which antigen activity is detrimental is a disorder in which reduction of antigen activity is expected to alleviate the symptoms and/or progression of the disorder. Such disorders may be evidenced, for example, by an increase in the concentration of the antigen in a biological fluid of a subject suffering from the disorder (e.g., an increase in the concentration of antigen in serum, plasma, synovial fluid, etc., of the subject). Non-limiting examples of disorders that can be treated with the binding proteins provided herein include those disorders discussed below and in the section pertaining to pharmaceutical compositions comprising the binding proteins.
Binding proteins disclosed herein, such as the DVD-Ig binding proteins, can be employed in some embodiments for tissue-specific delivery (target a tissue marker and a disease mediator for enhanced local PK thus higher efficacy and/or lower toxicity), including intracellular delivery (targeting an internalizing receptor and an intracellular molecule), delivering through a biological barrier, such as to the inside of the eye or brain (e.g., targeting transferrin receptor and a CNS disease mediator for crossing the blood-brain barrier). The binding proteins may also serve as carrier proteins to deliver an antigen to a specific location via binding to a non-neutralizing epitope of that antigen and also to increase the half-life of the antigen. Furthermore, the binding protein may be designed to either be physically linked to medical devices implanted into patients or target these medical devices (see Burke et al. (2006) Advanced Drug Deliv. Rev. 58(3): 437-446; Hildebrand et al. (2006) Surface and Coatings Technol. 200(22-23): 6318-6324; Drug/device combinations for local drug therapies and infection prophylaxis, Wu (2006) Biomaterials 27(11):2450-2467; Mediation of the cytokine network in the implantation of orthopedic devices, Marques (2005) Biodegradable Systems in Tissue Engineer. Regen. Med. 377-397).
In an embodiment, diseases that can be treated or diagnosed with the compositions and methods disclosed herein include, but are not limited to, primary and metastatic cancers, including carcinomas of breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gallbladder and bile ducts, small intestine, urinary tract (including kidney, bladder and urothelium), female genital tract (including cervix, uterus, and ovaries as well as choriocarcinoma and gestational trophoblastic disease), male genital tract (including prostate, seminal vesicles, testes and germ cell tumors), endocrine glands (including the thyroid, adrenal, and pituitary glands), and skin, as well as hemangiomas, melanomas, sarcomas (including those arising from bone and soft tissues as well as Kaposi's sarcoma), tumors of the brain, nerves, eyes, and meninges (including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, Schwannomas, and meningiomas), solid tumors arising from hematopoietic malignancies such as leukemias, and lymphomas (both Hodgkin's and non-Hodgkin's lymphomas).
Another embodiment provides for the use of the binding protein in the treatment of a disease or disorder, wherein the disorder is arthritis, osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft versus host disease, organ transplant rejection, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, heart failure, myocardial infarction, Addison's disease, sporadic poly glandular deficiency type I and polyglandular deficiency type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthopathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitic arthropathy, enteropathic synovitis, chlamydia, yersinia and salmonella associated arthropathy, spondyloarthopathy, atheromatous disease/arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, myalgic encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired Immunodeficiency Syndrome, Acquired Immunodeficiency Related Diseases, Hepatitis B, Hepatitis C, common varied immunodeficiency (common variable hypogammaglobulinaemia), dilated cardiomyopathy, female infertility, ovarian failure, premature ovarian failure, fibrotic lung disease, cryptogenic fibrosing alveolitis, post-inflammatory interstitial lung disease, interstitial pneumonitis, connective tissue disease associated interstitial lung disease, mixed connective tissue disease associated lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease, dermatomyositis/polymyositis associated lung disease, Sjögren's disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, fibrosis, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasulitis of the kidneys, lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjörgren's syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, idiopathic thrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo acute liver disease, chronic liver diseases, alcoholic cirrhosis, alcohol-induced liver injury, cholestasis, idiosyncratic liver disease, Drug-Induced hepatitis, Non-alcoholic Steatohepatitis, allergy and asthma, group B streptococci (GBS) infection, mental disorders (e.g., depression and schizophrenia), Th2 Type and Th1 Type mediated diseases, acute and chronic pain (different forms of pain), and cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma) abetalipoproteinemia, Acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial ectopic beats, AIDS dementia complex, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha-1-antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti cd3 therapy, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, aordic and peripheral aneuryisms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bundle branch block, Burkitt's lymphoma, burns, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chronic myelocytic leukemia (CML), chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, colorectal carcinoma, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture negative sepsis, cystic fibrosis, cytokine therapy associated disorders, Dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatologic conditions, diabetes, diabetes mellitus, diabetic ateriosclerotic disease, Diffuse Lewy body disease, dilated congestive cardiomyopathy, disorders of the basal ganglia, Down's Syndrome in middle age, drug-induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, epstein-barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, graft rejection of any organ or tissue, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallerrorden-Spatz disease, hashimoto's thyroiditis, hay fever, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, hepatitis A, His bundle arryhthmias, HIV infection/HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorders, hypersensitity reactions, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody mediated cytotoxicity, Asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza a, ionizing radiation exposure, iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, kidney transplant rejection, legionella, leishmaniasis, leprosy, lesions of the corticospinal system, lipedema, liver transplant rejection, lymphederma, malaria, malignamt Lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic/idiopathic, migraine headache, mitochondrial multi.system disorder, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Mencel Dejerine-Thomas Shy-Drager and Machado-Joseph), myasthenia gravis, mycobacterium avium intracellulare, mycobacterium tuberculosis, myelodyplastic syndrome, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic I muscular atrophies, neutropenic fever, non-hodgkins lymphoma, occlusion of the abdominal aorta and its branches, occlusive arterial disorders, okt3 therapy, orchitis/epidydimitis, orchitis/vasectomy reversal procedures, organomegaly, osteoporosis, pancreas transplant rejection, pancreatic carcinoma, paraneoplastic syndrome/hypercalcemia of malignancy, parathyroid transplant rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherlosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia, pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), post perfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, Progressive supranucleo Palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and disease, Raynoud's disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcomas, scleroderma, senile chorea, Senile Dementia of Lewy body type, seronegative arthropathies, shock, sickle cell anemia, skin allograft rejection, skin changes syndrome, small bowel transplant rejection, solid tumors, specific arrythmias, spinal ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, Subacute sclerosing panencephalitis, Syncope, syphilis of the cardiovascular system, systemic anaphalaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans, thrombocytopenia, toxicity, transplants, trauma/hemorrhage, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart diseases, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular fibrillation, viral and fungal infections, vital encephalitis/aseptic meningitis, vital-associated hemaphagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, acute coronary syndromes, acute idiopathic polyneuritis, acute inflammatory demyelinating polyradiculoneuropathy, acute ischemia, adult Still's disease, anaphylaxis, anti-phospholipid antibody syndrome, aplastic anemia, atopic eczema, atopic dermatitis, autoimmune dermatitis, autoimmune disorder associated with streptococcus infection, autoimmune enteropathy, autoimmune hearing loss, autoimmune lymphoproliferative syndrome (ALPS), autoimmune myocarditis, autoimmune premature ovarian failure, blepharitis, bronchiectasis, bullous pemphigoid, cardiovascular disease, catastrophic antiphospholipid syndrome, celiac disease, cervical spondylosis, chronic ischemia, cicatricial pemphigoid, clinically isolated syndrome (cis) with risk for multiple sclerosis, childhood onset psychiatric disorder, dacryocystitis, dermatomyositis, diabetic retinopathy, disk herniation, disk prolaps, drug induced immune hemolytic anemia, endometriosis, endophthalmitis, episcleritis, erythema multiforme, erythema multiforme major, gestational pemphigoid, Guillain-Barré syndrome (GBS), hay fever, Hughes syndrome, idiopathic Parkinson's disease, idiopathic interstitial pneumonia, IgE-mediated allergy, immune hemolytic anemia, inclusion body myositis, infectious ocular inflammatory disease, inflammatory demyelinating disease, inflammatory heart disease, inflammatory kidney disease, IPF/UIP, iritis, keratitis, keratoconjunctivitis sicca, Kussmaul disease or Kussmaul-Meier disease, Landry's paralysis, Langerhan's cell histiocytosis, livedo reticularis, macular degeneration, microscopic polyangiitis, morbus bechterev, motor neuron disorders, mucous membrane pemphigoid, multiple organ failure, myelodysplastic syndrome, myocarditis, nerve root disorders, neuropathy, non-A non-B hepatitis, optic neuritis, osteolysis, ovarian cancer, pauciarticular JRA, peripheral artery occlusive disease (PAOD), peripheral vascular disease (PVD), peripheral artery, disease (PAD), phlebitis, polyarteritis nodosa (or periarteritis nodosa), polychondritis, polymyalgia rheumatica, poliosis, polyarticular JRA, polyendocrine deficiency syndrome, polymyositis, post-pump syndrome, primary Parkinsonism, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), prostatitis, pure red cell aplasia, primary adrenal insufficiency, recurrent neuromyelitis optica, restenosis, rheumatic heart disease, sapho (synovitis, acne, pustulosis, hyperostosis, and osteitis), scleroderma, secondary amyloidosis, shock lung, scleritis, sciatica, secondary adrenal insufficiency, silicone associated connective tissue disease, sneddon-wilkinson dermatosis, spondilitis ankylosans, Stevens-Johnson syndrome (SJS), systemic inflammatory response syndrome, temporal arteritis, toxoplasmic retinitis, toxic epidermal necrolysis, transverse myelitis, TRAPS (tumor necrosis factor receptor, type 1 allergic reaction, type II diabetes, usual interstitial pneumonia (UIP), vernal conjunctivitis, viral retinitis, Vogt-Koyanagi-Harada syndrome (VKH syndrome), wet macular degeneration, wound healing, fibrosis, renal disease, wet macular degeneration, wound healing, age related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, central retinal vein occlusion, corneal neovascularization, exudative AMD, iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), choroidal neovascularization, optic disc neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, macular edema, diabetic macular edema (DME), vascular retinopathy, retinal degeneration, uveitis, or an inflammatory disease of the eye.
In some embodiments, any one of the binding proteins disclosed herein can be used to treat a disorder listed above. In certain embodiments, the binding protein used to treat any of the disorders discussed herein is one or more of the binding proteins listed in Tables 27-30, 38-42, 46-50, or 55-58. In certain embodiments, the binding protein used to treat any of the disorders discussed herein is one or more of the binding proteins listed in Tables 56-58. In certain embodiments, the binding protein is PR-1572102, PR-1572105, PR-1610561, or PR1611292.
In some embodiments, a binding protein (e.g., PR-1572102, PR-1572105, PR1611292, or PR-1610561) may be used to treat wet AMD that is non-responsive to anti-VEGF monotherapy. For instance, a binding protein targeting VEGF and PDGF (e.g., PR-1572102, PR-1572105, or PR-1610561) may lead to better regression of angiogenesis, thereby providing for a more effective treatment (this does not necessarily mean, however, that such a binding protein would have a reduced administration frequency; whether that is the case is presently unknown). The dual inhibition of both VEGF and PDGF may provide for certain improved treatment outcomes, as compared to anti-VEGF monotherapy.
In another aspect, methods of treating a patient suffering from a disorder are disclosed, comprising the step of administering any one of the binding proteins disclosed herein before, concurrently, or after the administration of a second agent, are provided. In an embodiment, the second agent is an imaging agent, cytotoxic agent, angiogenesis inhibitor, kinase inhibitor, co-stimulation molecule blocker, adhesion molecule blocker, anti-cytokine antibody or functional fragment thereof, methotrexate, cyclosporin, rapamycin, FK506, detectable label or reporter, TNF antagonist, antirheumatic, muscle relaxant, narcotic, non-steroid anti-inflammatory drug (NSAID), analgesic, anesthetic, sedative, local anesthetic, neuromuscular blocker, antimicrobial, antipsoriatic, corticosteriod, anabolic steroid, erythropoietin, immunization, immunoglobulin, immunosuppressive, growth hormone, hormone replacement drug, radiopharmaceutical, antidepressant, antipsychotic, stimulant, asthma medication, beta agonist, inhaled steroid, epinephrine or analog, cytokine, or cytokine antagonist.
Also disclosed, in various embodiments, are anti-idiotype antibodies to the binding proteins disclosed herein. An anti-idiotype antibody includes any protein or peptide-containing molecule that comprises at least a portion of an immunoglobulin molecule such as, but not limited to, at least one complementarily determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework region, or any portion thereof, that can be incorporated into a binding protein provided herein.
Also disclosed herein, in various embodiments, are methods of determining the presence, amount or concentration of VEGF and/or PDGF, or fragment thereof, in a test sample. In some embodiments, the methods comprise assaying the test sample for the antigen, or fragment thereof, by an immunoassay. The immunoassay (i) employs at least one binding protein and at least one detectable label and (ii) comprises comparing a signal generated by the detectable label as a direct or indirect indication of the presence, amount or concentration of the antigen, or fragment thereof, in the test sample to a signal generated as a direct or indirect indication of the presence, amount or concentration of the antigen, or fragment thereof, in a control or a calibrator. The calibrator is optionally part of a series of calibrators in which each of the calibrators differs from the other calibrators in the series by the concentration of the antigen, or fragment thereof. The method can comprise (i) contacting the test sample with at least one capture agent, which binds to an epitope on the antigen, or fragment thereof, so as to form a capture agent/antigen, or fragment thereof, complex, (ii) contacting the capture agent/antigen, or fragment thereof, complex with at least one detection agent, which comprises a detectable label and binds to an epitope on the antigen, or fragment thereof, that is not bound by the capture agent, to form a capture agent/antigen, or fragment thereof/detection agent complex, and (iii) determining the presence, amount or concentration of the antigen, or fragment thereof, in the test sample based on the signal generated by the detectable label in the capture agent/antigen, or fragment thereof/detection agent complex formed in (ii), wherein at least one capture agent and/or at least one detection agent is the at least one binding protein.
Alternatively, the method may comprise (i) contacting the test sample with at least one capture agent, which binds to an epitope on the antigen, or fragment thereof, so as to form a capture agent/antigen, or fragment thereof, complex, and simultaneously or sequentially, in either order, contacting the test sample with detectably labeled antigen, or fragment thereof, which can compete with any antigen, or fragment thereof, in the test sample for binding to the at least one capture agent, wherein any antigen, or fragment thereof, present in the test sample and the detectably labeled antigen compete with each other to form a capture agent/antigen, or fragment thereof, complex and a capture agent/detectably labeled antigen, or fragment thereof, complex, respectively, and (ii) determining the presence, amount or concentration of the antigen, or fragment thereof, in the test sample based on the signal generated by the detectable label in the capture agent/detectably labeled antigen, or fragment thereof, complex formed in (ii), wherein at least one capture agent is the at least one binding protein and wherein the signal generated by the detectable label in the capture agent/detectably labeled antigen, or fragment thereof, complex is inversely proportional to the amount or concentration of antigen, or fragment thereof, in the test sample.
In some embodiments, the test sample is from a patient, in which case the method can further comprise diagnosing, prognosticating, or assessing the efficacy of therapeutic/prophylactic treatment of the patient. If the method further comprises assessing the efficacy of therapeutic/prophylactic treatment of the patient, the method optionally further comprises modifying the therapeutic/prophylactic treatment of the patient as needed to improve efficacy. The method can be adapted for use in an automated system or a semi-automated system. Accordingly, the methods described herein also can be used to determine whether or not a subject has or is at risk of developing a given disease, disorder or condition. Specifically, such a method can comprise the steps of: (a) determining the concentration or amount in a test sample from a subject of analyte, or fragment thereof, (e.g., using the methods described herein, or methods known in the art); and (b) comparing the concentration or amount of analyte, or fragment thereof, determined in step (a) with a predetermined level, wherein, if the concentration or amount of analyte determined in step (a) is favorable with respect to a predetermined level, then the subject is determined not to have or be at risk for a given disease, disorder or condition. However, if the concentration or amount of analyte determined in step (a) is unfavorable with respect to the predetermined level, then the subject is determined to have or be at risk for a given disease, disorder or condition.
Additionally, in various embodiments, provided herein are methods of monitoring the progression of disease in a subject. In some embodiments, the method can comprise the steps of: (a) determining the concentration or amount in a test sample from a subject of analyte; (b) determining the concentration or amount in a later test sample from the subject of analyte; and (c) comparing the concentration or amount of analyte as determined in step (b) with the concentration or amount of analyte determined in step (a), wherein if the concentration or amount determined in step (b) is unchanged or is unfavorable when compared to the concentration or amount of analyte determined in step (a), then the disease in the subject is determined to have continued, progressed or worsened. By comparison, if the concentration or amount of analyte as determined in step (b) is favorable when compared to the concentration or amount of analyte as determined in step (a), then the disease in the subject is determined to have discontinued, regressed or improved.
Optionally, the method further comprises comparing the concentration or amount of analyte as determined in step (b), for example, with a predetermined level. Further, optionally the method comprises treating the subject with one or more pharmaceutical compositions for a period of time if the comparison shows that the concentration or amount of analyte as determined in step (b), for example, is unfavorably altered with respect to the predetermined level.
Also provided, in various embodiments, are kits for assaying a test sample for VEGF and/or PDGF, or fragment thereof. The kit may comprise at least one component for assaying the test sample for an antigen, or fragment thereof, and instructions for assaying the test sample for an antigen, or fragment thereof, wherein the at least one component includes at least one composition comprising the binding protein disclosed herein, wherein the binding protein is optionally detectably labeled.
Unless otherwise defined herein, scientific and technical terms used herein have the meanings that are commonly understood by those of ordinary skill in the art. In the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The use of “or” means “and/or” unless stated otherwise. The use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting. Any range disclosed herein is intended to encompass the endpoints of that range unless stated otherwise.
Generally, nomenclatures used in connection with cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those known and commonly used in the art. The methods and techniques provided herein are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The nomenclatures used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.
That the disclosure may be more readily understood, select terms are defined below.
The term “antibody” refers to an immunoglobulin (Ig) molecule, which is may comprise four polypeptide chains, two heavy (H) chains and two light (L) chains, or it may comprise a functional fragment, mutant, variant, or derivative thereof, that retains the epitope binding features of an Ig molecule. Such fragment, mutant, variant, or derivative antibody formats are known in the art. In an embodiment of a full-length antibody, each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (CH). In the case of an IgG molecule, the CH comprises three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The CL is comprised of a single CL domain. The VH and VL can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Generally, each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. CDR regions may be determined by standard methods, e.g., those of Kabat et al. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), or subclass.
The term “bispecific antibody” refers to an antibody that binds one antigen (or epitope) on one of its two binding arms (one pair of HC/LC), and binds a different antigen (or epitope) on its second binding arm (a different pair of HC/LC). A bispecific antibody is a type of bispecific binding protein. A bispecific antibody may have two distinct antigen binding arms (in both specificity and CDR sequences), and may be monovalent for each antigen to which it binds. Bispecific antibodies include those generated by quadroma technology (Milstein and Cuello (1983) Nature 305(5934): 537-40), by chemical conjugation of two different monoclonal antibodies (Staerz et al. (1985) Nature 314(6012): 628-31), or by knob-into-hole or similar approaches which introduces mutations in the Fc region (Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90(14): 6444-6448).
The term “affinity matured” refers to an antibody or binding protein with one or more alterations in one or more CDR or framework (FR) regions thereof, which may result in an improvement in the affinity for an antigen, compared to a parent antibody or binding protein which does not possess those alteration(s). Exemplary affinity matured antibodies or binding protein will have nanomolar or even picomolar affinities for the target antigen. Affinity matured antibodies or binding protein may be produced by procedures known in the art, e.g., Marks et al. (1992) BioTechnology 10:779-783 describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of CDR and/or framework residues is described by Barbas et al. (1994) Proc. Nat. Acad. Sci. USA 91:3809-3813; Schier et al. (1995) Gene 169:147-155; Yelton et al. (1995) J. Immunol. 155:1994-2004; Jackson et al. (1995) J. Immunol. 154(7):3310-9; Hawkins et al. (1992) J. Mol. Biol. 226:889-896 and mutation at selective mutagenesis positions, contact or hypermutation positions with an activity enhancing amino acid residue as described in U.S. Pat. No. 6,914,128.
The term “CDR-grafted” refers to an antibody or binding protein that comprises heavy and light chain variable region sequences in which the sequences of one or more of the CDR regions of VH and/or VL are replaced with CDR sequences of another antibody or binding protein. For example, the two antibodies or binding protein can be from different species, such as antibodies or binding protein having murine heavy and light chain variable regions in which one or more of the murine CDRs has been replaced with human CDR sequences.
The term “humanized” refers to an antibody or binding protein from a non-human species that has been altered to be more “human-like”, i.e., more similar to human germline sequences. One type of humanized antibody or binding protein is a CDR-grafted antibody or binding protein, in which non-human CDR sequences are introduced into human VH and VL sequences to replace the corresponding human CDR sequences. A humanized antibody or binding protein also encompasses a variant, derivative, analog or fragment of an antibody or binding protein that comprises framework region (FR) sequences having substantially (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% identity to) the amino acid sequence of a human antibody and at least one CDR having substantially the amino acid sequence of a non-human antibody. A humanized antibody or binding protein may comprise substantially all of at least one variable domain (Fab, Fab′, F(ab′) 2, FabC, Fv) in which the sequence of all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin (i.e., donor antibody) and the sequence of all or substantially all of the FR regions are those of a human immunoglobulin. The humanized antibody or binding protein also may include the CH1, hinge, CH2, CH3, and/or CH4 regions of the heavy chain. In an embodiment, a humanized antibody or binding protein may also comprise at least a portion of a human immunoglobulin Fc region. In some embodiments, a humanized antibody or binding protein only contains a humanized light chain. In some embodiments, a humanized antibody or binding protein only contains a humanized heavy chain. In some embodiments, a humanized antibody or binding protein only contains a humanized variable domain of a light chain and/or humanized variable domain of a heavy chain. In some embodiments, a humanized antibody or binding protein contains a humanized light chain as well as at least a variable domain of a heavy chain. In some embodiments, a humanized antibody or binding protein contains a humanized heavy chain as well as at least a variable domain of a light chain.
The term “anti-idiotypic antibody” refers to an antibody raised against the amino acid sequence of the antigen combining site of another antibody. Anti-idiotypic antibodies may be administered to enhance an immune response against an antigen.
The term “biological activity” refers to any one or more biological properties of a molecule (whether present naturally as found in vivo, or provided or enabled by recombinant means). Biological properties include, but are not limited to, binding a receptor, inducing cell proliferation, inhibiting cell growth, inducing other cytokines, inducing apoptosis, and enzymatic activity.
The term “neutralizing” refers to counteracting the biological activity of an antigen when a binding protein specifically binds to the antigen. In an embodiment, a neutralizing binding protein binds to an antigen (e.g., VEGF and/or PDGF or their receptors) and reduces the antigen's biological activity by at least about 20%, about 40%, about 60%, about 80%, about 85%, about 90%, about 95%, or about 100% (or any percentage in between).
The term “specificity” refers to the ability of a binding protein to selectively bind an antigen.
The term “affinity” refers to the strength of the interaction between a binding protein and an antigen, and is determined by the sequence of the CDRs of the binding protein as well as by the nature of the antigen, such as its size, shape, and/or charge. Binding proteins may be selected for affinities that provide desired therapeutic end-points while minimizing negative side-effects. Affinity may be measured using methods known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
The term “potency” refers to the ability of a binding protein to achieve a desired effect, and is a measurement of its therapeutic efficacy. Potency may be assessed using methods known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
The term “cross-reactivity” refers to the ability of a binding protein to bind a target other than that against which it was raised. Generally, a binding protein will bind its target tissue(s)/antigen(s) with an appropriately high affinity, but will display an appropriately low affinity for non-target normal tissues. Methods of assessing cross-reactivity are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
The term “biological function” refers the specific in vitro or in vivo actions of a binding protein. Binding proteins may target several classes of antigens and achieve desired therapeutic outcomes through multiple mechanisms of action. Binding proteins may target soluble proteins, cell surface antigens, as well as extracellular protein deposits. Binding proteins may agonize, antagonize, or neutralize the activity of their targets. Binding proteins may assist in the clearance of the targets to which they bind, or may result in cytotoxicity when bound to cells. Portions of two or more antibodies may be incorporated into a multivalent format to achieve distinct functions in a single binding protein molecule. The in vitro assays and in vivo models used to assess biological function are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
A “stable” binding protein refers to one in which the binding protein retains some level of its physical stability, chemical stability and/or biological activity upon storage. Methods of stabilizing binding proteins and assessing their stability at various temperatures are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
The term “solubility” refers to the ability of a protein to remain dispersed within an aqueous solution. The solubility of a protein in an aqueous formulation depends upon the proper distribution of hydrophobic and hydrophilic amino acid residues, and therefore, solubility can correlate with the production of correctly folded proteins. A person skilled in the art will be able to detect an increase or decrease in solubility of a binding protein using routine HPLC techniques and methods known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
Binding proteins may be produced using a variety of host cells or may be produced in vitro, and the relative yield per effort determines the “production efficiency.” Factors influencing production efficiency include, but are not limited to, host cell type (prokaryotic or eukaryotic), choice of expression vector, choice of nucleotide sequence, and methods employed. The materials and methods used in binding protein production, as well as the measurement of production efficiency, are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
The term “immunogenicity” means the ability of a substance to induce an immune response. Administration of a therapeutic binding protein may result in a certain incidence of an immune response. Potential elements that might induce immunogenicity in a multivalent format may be analyzed during selection of the parental antibodies, and steps to reduce such risk can be taken to optimize the parental antibodies prior to incorporating their sequences into a multivalent binding protein format. Methods of reducing the immunogenicity of antibodies and binding proteins are known to one skilled in the art (U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
The terms “label” and “detectable label” refer to a moiety attached to a member of a specific binding pair, such as an antibody/binding protein or its analyte to render a reaction (e.g., binding) between the members of the specific binding pair, detectable. The labeled member of the specific binding pair is referred to as “detectably labeled.” Thus, the term “labeled binding protein” refers to a protein with a label incorporated that provides for the identification of the binding protein. In an embodiment, the label is a detectable marker that can produce a signal that is detectable by visual or instrumental means, e.g., incorporation of a radiolabeled amino acid or attachment to a polypeptide of biotinyl moieties that can be detected by marked avidin (e.g., streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or colorimetric methods). Examples of labels for polypeptides include, but are not limited to, the following: radioisotopes or radionuclides (e.g., 3H, 14C, 35S, 90Y, 99Tc, 111In, 125I, 131I, 177Lu, 166Ho, or 153Sm); chromogens, fluorescent labels (e.g., FITC, rhodamine, lanthanide phosphors), enzymatic labels (e.g., horseradish peroxidase, luciferase, alkaline phosphatase); chemiluminescent markers; biotinyl groups; predetermined polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags); and magnetic agents, such as gadolinium chelates. Representative examples of labels commonly employed for immunoassays include moieties that produce light, e.g., acridinium compounds, and moieties that produce fluorescence, e.g., fluorescein. In this regard, the moiety itself may not be detectably labeled but may become detectable upon reaction with yet another moiety.
The term “conjugate” refers to a binding protein that is chemically linked to a second chemical moiety, such as a therapeutic or cytotoxic agent. The term “agent” includes a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials. In an embodiment, the therapeutic or cytotoxic agents include, but are not limited to, pertussis toxin, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. When employed in the context of an immunoassay, the conjugate antibody may be a detectably labeled antibody used as the detection antibody.
The terms “crystal” and “crystallized” refer to a binding protein (e.g., an antibody), or antigen binding portion thereof, that exists in the form of a crystal. Crystals are one form of the solid state of matter, which is distinct from other forms such as the amorphous solid state or the liquid crystalline state. Crystals are composed of regular, repeating, three-dimensional arrays of atoms, ions, molecules (e.g., proteins such as antibodies), or molecular assemblies (e.g., antigen/antibody complexes). These three-dimensional arrays are arranged according to specific mathematical relationships that are well-understood in the field. The fundamental unit, or building block, that is repeated in a crystal is called the asymmetric unit. Repetition of the asymmetric unit in an arrangement that conforms to a given, well-defined crystallographic symmetry provides the “unit cell” of the crystal. Repetition of the unit cell by regular translations in all three dimensions provides the crystal. (See Giege and Ducruix (1999) CRYSTALLIZATION OF NUCLEIC ACIDS AND PROTEINS, A PRACTICAL APPROACH, 2nd ed., pp. 20 1-16, Oxford University Press, NY, N.Y.).
The term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked One type of vector is a “plasmid,” which refers to a circular double stranded DNA loop into which additional DNA segments may be ligated. Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. Other vectors include RNA vectors. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Certain vectors are capable of directing the expression of genes to which they are operatively linked Such vectors are referred to herein as “recombinant expression vectors” (or simply, “expression vectors”). In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, “plasmid” and “vector” may be used interchangeably as the plasmid is the most commonly used form of vector. However, other forms of expression vectors are also included, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions. A group of pHybE vectors (e.g., U.S. Pat. No. 8,187,836) may be used for parental antibody and DVD-binding protein cloning. V1, derived from pJP183; pHybE-hCg1,z,non-a V2; and pJP184, may be used for cloning of antibody and DVD heavy chains with a wild type constant region or modified constant region (e.g., a L234, L235, H435A modified IgG1 constant region). V2, derived from pJP191 (with or without modifications to the Kozak site); pHybE-hCk V3, may be used for cloning of antibody and DVD light chains with a kappa constant region. V3, derived from pJP192; pHybE-hCl V2, may be used for cloning of antibody and DVD light chains with a lambda constant region. V4, built with a lambda signal peptide and a kappa constant region, may be used for cloning of DVD light chains with a lambda-kappa hybrid V domain. V5, built with a kappa signal peptide and a lambda constant region, may be used for cloning of DVD light chains with a kappa-lambda hybrid V domain. V7, derived from pJP183; pHybE-hCg1,z,non-a V2, may be used for cloning of antibody and DVD heavy chains with a (234,235 AA) mutant constant region.
The terms “recombinant host cell” or “host cell” refer to a cell into which exogenous, e.g., recombinant, DNA has been introduced. Such terms refer not only to the particular subject cell, but to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” as used herein. In an embodiment, host cells include prokaryotic and eukaryotic cells. In an embodiment, eukaryotic cells include protist, fungal, plant and animal cells. In another embodiment, host cells include but are not limited to the prokaryotic cell line E. coli; mammalian cell lines CHO, HEK 293, COS, NSO, SP2 and PER.C6; the insect cell line Sf9; and the fungal cell Saccharomyces cerevisiae. 
The term “transfection” encompasses a variety of techniques commonly used for the introduction of exogenous nucleic acid (e.g., DNA) into a host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like.
The term “cytokine” refers to a protein released by one cell population that acts on another cell population as an intercellular mediator. The term “cytokine” includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the native sequence cytokines.
The term “biological sample” refers to a quantity of a substance from a living thing or formerly living thing Such substances include, but are not limited to, blood, plasma, serum, urine, amniotic fluid, synovial fluid, endothelial cells, leukocytes, monocytes, other cells, organs, tissues, bone marrow, lymph nodes and spleen.
The term “component” refers to an element of a composition. In relation to a diagnostic kit, for example, a component may be a capture antibody, a detection or conjugate antibody, a control, a calibrator, a series of calibrators, a sensitivity panel, a container, a buffer, a diluent, a salt, an enzyme, a co-factor for an enzyme, a detection reagent, a pretreatment reagent/solution, a substrate (e.g., as a solution), a stop solution, and the like that can be included in a kit for assay of a test sample. Thus, a “component” can include a polypeptide or other analyte as above, that is immobilized on a solid support, such as by binding to an anti-analyte (e.g., anti-polypeptide) antibody. Some components can be in solution or lyophilized for reconstitution for use in an assay.
“Control” refers to a composition known to not analyte (“negative control”) or to contain analyte (“positive control”). A positive control can comprise a known concentration of analyte. A “positive control” can be used to establish assay performance characteristics and is a useful indicator of the integrity of reagents (e.g., analytes).
“Predetermined cutoff” and “predetermined level” refer generally to an assay cutoff value that is used to assess diagnostic/prognostic/therapeutic efficacy results by comparing the assay results against the predetermined cutoff/level, where the predetermined cutoff/level already has been linked or associated with various clinical parameters (e.g., severity of disease, progression/nonprogression/improvement, etc.). While the present disclosure may provide exemplary predetermined levels, it is well-known that cutoff values may vary depending on the nature of the immunoassay (e.g., antibodies employed, etc.). It further is well within the ordinary skill of one in the art to adapt the disclosure herein for other immunoassays to obtain immunoassay-specific cutoff values for those other immunoassays based on this disclosure. Whereas the precise value of the predetermined cutoff/level may vary between assays, correlations as described herein (if any) may be generally applicable.
“Pretreatment reagent,” e.g., lysis, precipitation and/or solubilization reagent, as used in a diagnostic assay as described herein refers to one that lyses any cells and/or solubilizes any analyte that is/are present in a test sample. Pretreatment is not necessary for all samples, as described further herein. Among other things, solubilizing the analyte (e.g., polypeptide of interest) may entail release of the analyte from any endogenous binding proteins present in the sample. A pretreatment reagent may be homogeneous (not requiring a separation step) or heterogeneous (requiring a separation step). With use of a heterogeneous pretreatment reagent there is removal of any precipitated analyte binding proteins from the test sample prior to proceeding to the next step of the assay.
“Quality control reagents” in the context of immunoassays and kits described herein, include, but are not limited to, calibrators, controls, and sensitivity panels. A “calibrator” or “standard” typically is used (e.g., one or more, such as a plurality) in order to establish calibration (standard) curves for interpolation of the concentration of an analyte, such as an antibody or an analyte. Alternatively, a single calibrator, which is near a predetermined positive/negative cutoff, can be used. Multiple calibrators (i.e., more than one calibrator or a varying amount of calibrator(s)) can be used in conjunction so as to comprise a “sensitivity panel.”
The term “specific binding partner” refers to a member of a specific binding pair. A specific binding pair comprises two different molecules that specifically bind to each other through chemical or physical means. Therefore, in addition to antigen and antibody specific binding, other specific binding pairs can include biotin and avidin (or streptavidin), carbohydrates and lectins, complementary nucleotide sequences, effector and receptor molecules, cofactors and enzymes, enzyme inhibitors and enzymes, and the like. Furthermore, specific binding pairs can include members that are analogs of the original specific binding members, for example, an analyte-analog. Immunoreactive specific binding members include antigens, antigen fragments, and antibodies, including monoclonal and polyclonal antibodies as well as complexes, fragments, and variants (including fragments of variants) thereof, whether isolated or recombinantly produced.
The term “Fc region” refers to the C-terminal region of an immunoglobulin heavy chain, which may be generated by papain digestion of an intact antibody or binding protein. The Fc region may be a native sequence Fc region or a variant Fc region. The Fc region of an immunoglobulin generally comprises two constant domains, a CH2 domain and a CH3 domain, and optionally comprises a CH4 domain. Replacements of amino acid residues in the Fc portion to alter effector function are known in the art (e.g., U.S. Pat. Nos. 5,648,260 and 5,624,821). The Fc region mediates several important effector functions, e.g., cytokine induction, antibody dependent cell mediated cytotoxicity (ADCC), phagocytosis, complement dependent cytotoxicity (CDC), and half-life/clearance rate of antibody or binding protein and antigen-antibody or antigen-binding protein complexes. In some cases these effector functions are desirable for a therapeutic immunoglobulin but in other cases might be unnecessary or even deleterious, depending on the therapeutic objectives.
The term “antigen-binding portion” of a binding protein refers to one or more fragments of a binding protein that retain the ability to specifically bind to an antigen. The antigen-binding function of a binding protein may be performed by fragments of a full-length binding protein, including bispecific, dual specific, or multi-specific formats; for instance, binding to two or more different antigens. Examples of binding fragments encompassed within the term “antigen-binding portion” of an binding protein include (i) an Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) an F(ab′)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody or binding protein, (v) a dAb fragment, which comprises a single variable domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they may be joined, e.g., using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv). Such single chain antibodies or binding proteins are also intended to be encompassed within the term “antigen-binding portion” of an antibody or binding protein. Other forms of single chain antibodies, such as diabodies are also encompassed. In addition, single chain antibodies or binding protein also include “linear” antibodies or binding protein comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen binding regions.
The term “multivalent binding protein” refers to a binding protein comprising two or more antigen binding sites. In an embodiment, the multivalent binding protein is engineered to have three or more antigen binding sites, and may not be a naturally occurring antibody. The term “multispecific binding protein” refers to a binding protein capable of binding two or more related or unrelated targets. In an embodiment, the dual variable domain (DVD) binding proteins provided herein comprise two or more antigen binding sites and are tetravalent or multivalent binding proteins.
The term “linker” refers to an amino acid residue or a polypeptide comprising two or more amino acid residues joined by peptide bonds that are used to link two polypeptides (e.g., two VH or two VL domains) Such linker polypeptides are well known in the art (see, e.g., Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al. (1994) Structure 2:1121-1123). A number of suitable linkers for use in the binding proteins described herein are set out in Table 55. In some embodiments, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10(dR) linker. In some embodiments, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10 linker. In some embodiments, the X1 linker on the heavy chain is an HG-short linker and the X1 linker on the light chain is an LK-long linker.
The terms “Kabat numbering”, “Kabat definitions” and “Kabat labeling” are used interchangeably herein. These terms, which are recognized in the art, refer to a system of numbering amino acid residues which are more variable (i.e., hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody or binding protein, or an antigen binding portion thereof (Kabat et al. (1971) Ann. NY Acad. Sci. 190:382-391 and, Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3. For the light chain variable region, the hypervariable region ranges from amino acid positions 24 to 34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3. In some embodiments, the CDR sequences, framework sequences, and or constant region sequences are identified using Kabat numbering.
The term “CDR” refers to a complementarity determining region within an immunoglobulin variable region sequence. There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the heavy and light chain variable regions. The term “CDR set” refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody or binding protein, but also provides precise residue boundaries defining the three CDRs in each heavy or light chain sequence. These CDRs may be referred to as Kabat CDRs. Chothia and coworkers (Chothia and Lesk (1987) J. Mol. Biol. 196:901-917; Chothia et al. (1989) Nature 342:877-883) found that certain sub-portions within Kabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub-portions were designated as L1, L2 and L3 or H1, H2 and H3 where the “L” and the “H” designates the light chain and the heavy chain regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan (1995) FASEB J. 9:133-139 and MacCallum (1996) J. Mol. Biol. 262(5):732-45). Still other CDR boundary definitions may not strictly follow one of the herein systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, although certain embodiments use Kabat or Chothia defined CDRs.
The term “epitope” refers to a region of an antigen that is specifically bound by a binding protein disclosed herein. In certain embodiments, epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl, and, in certain embodiments, may have specific three dimensional structural characteristics, and/or specific charge characteristics. An antigen or fragment can contain more than one epitope. An epitope may be determined by obtaining an X-ray crystal structure of an antibody:antigen complex and determining which residues on the antigen (e.g., VEGF or PDGF or a receptor) are within a specified distance of residues on the antibody of interest, wherein the specified distance is, 5 Å or less, e.g., 5 Å, 4 Å, 3 Å, 2 Å, 1 Å or less, or any distance in between. In some embodiments, the epitope is defined as a stretch of 8 or more contiguous amino acid residues along the antigen sequence in which at least 50%, 70% or 85% of the residues are within the specified distance of the antibody or binding protein in the X-ray crystal structure.
In certain embodiments, a binding protein specifically binds an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macromolecules. Binding proteins that bind to the same or similar epitopes will likely cross-compete (one prevents the binding or modulating effect of the other). Cross-competition, however, can occur even without partial or complete epitope overlap, e.g., if epitopes are adjacent in three-dimensional space and/or due to steric hindrance.
The term “pharmacokinetic(s)” refers to the process by which a drug is absorbed, distributed, metabolized, and excreted by an organism. To generate a multivalent binding protein molecule with a desired pharmacokinetic profile, parent monoclonal antibodies with similarly desired pharmacokinetic profiles are selected. The PK profiles of the selected parental monoclonal antibodies can be easily determined in rodents using methods known to one skilled in the art (see, e.g., U.S. Pat. No. 7,612,181).
The term “bioavailability” refers to the degree and rate at which a drug is absorbed into a living system or is made available at the site of physiological activity. Bioavailability can be a function of several of the previously described properties, including stability, solubility, immunogenicity and pharmacokinetics, and can be assessed using methods known to one skilled in the art (see, e.g., U.S. Pat. No. 7,612,181).
The term “surface plasmon resonance” refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIAcore® system (BIAcore International AB, a GE Healthcare company, Uppsala, Sweden and Piscataway, N.J.). For further descriptions, see Jönsson et al. (1993) Ann. Biol. Clin. 51:19-26. The term “Kon” refers to the on rate constant for association of a binding protein (e.g., an antibody or DVD-Ig) to the antigen to form the, e.g., DVD-Ig/antigen complex. The term “Kon” also refers to “association rate constant”, or “ka”, as is used interchangeably herein. This value indicating the binding rate of a binding protein to its target antigen or the rate of complex formation between a binding protein, e.g., an antibody, and antigen also is shown by the equation below:

Antibody (“Ab”)+Antigen (“Ag”)→Ab-Ag

The term “Koff” refers to the off rate constant for dissociation, or “dissociation rate constant”, of a binding protein (e.g., an antibody or DVD-Ig) from the, e.g., DVD-Ig/antigen complex as is known in the art. This value indicates the dissociation rate of a binding protein, e.g., an antibody, from its target antigen or separation of Ab-Ag complex over time into free antibody and antigen as shown by the equation below:

Ab+Ag←Ab-Ag

The terms “Kd” and “equilibrium dissociation constant” may refer to the value obtained in a titration measurement at equilibrium, or by dividing the dissociation rate constant (Koff) by the association rate constant (Kon). The association rate constant, the dissociation rate constant and the equilibrium dissociation constant, are used to represent the binding affinity of a binding protein (e.g., an antibody or DVD-Ig) to an antigen. Methods for determining association and dissociation rate constants are well known in the art. Using fluorescence-based techniques offers high sensitivity and the ability to examine samples in physiological buffers at equilibrium. Other experimental approaches and instruments such as a BIAcore® (biomolecular interaction analysis) assay, can be used (e.g., instrument available from BIAcore International AB, a GE Healthcare company, Uppsala, Sweden). Additionally, a KinExA® (Kinetic Exclusion Assay) assay, available from Sapidyne Instruments (Boise, Id.), can also be used.
The term “variant” refers to a polypeptide that differs from a given polypeptide in amino acid sequence by the addition (e.g., insertion), deletion, or conservative substitution of amino acids, but that retains the biological activity of the given polypeptide (e.g., a variant VEGF antibody can compete with anti-VEGF antibody for binding to VEGF). A conservative substitution of an amino acid, i.e., replacing an amino acid with a different amino acid of similar properties (e.g., hydrophilicity and degree and distribution of charged regions) is recognized in the art as typically involving a minor change. These minor changes can be identified, in part, by considering the hydropathic index of amino acids, as understood in the art (see, e.g., Kyte et al. (1982) J. Mol. Biol. 157: 105-132). The hydropathic index of an amino acid is based on a consideration of its hydrophobicity and charge. It is known in the art that amino acids of similar hydropathic indexes in a protein can be substituted and the protein still retains protein function. In one aspect, amino acids having hydropathic indexes of ±2 are substituted. The hydrophilicity of amino acids also can be used to reveal substitutions that would result in proteins retaining biological function. A consideration of the hydrophilicity of amino acids in the context of a peptide permits calculation of the greatest local average hydrophilicity of that peptide, a useful measure that has been reported to correlate well with antigenicity and immunogenicity (see, e.g., U.S. Pat. No. 4,554,101). Substitution of amino acids having similar hydrophilicity values can result in peptides retaining biological activity, for example immunogenicity, as is understood in the art. In one aspect, substitutions are performed with amino acids having hydrophilicity values within ±2 of each other. Both the hydrophobicity index and the hydrophilicity value of amino acids are influenced by the particular side chain of that amino acid. Consistent with that observation, amino acid substitutions that are compatible with biological function are understood to depend on the relative similarity of the amino acids, and particularly the side chains of those amino acids, as revealed by the hydrophobicity, hydrophilicity, charge, size, and other properties. The term “variant” also includes polypeptide or fragment thereof that has been differentially processed, such as by proteolysis, phosphorylation, or other post-translational modification, yet retains its biological activity or antigen reactivity, e.g., the ability to bind to VEGF. The term “variant” encompasses fragments of a variant unless otherwise defined. A variant may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, or 75% identical to the wild type sequence.
Use of Disclosed Binding Proteins in Treating Various Diseases
The binding protein molecules provided herein are useful as therapeutic molecules to treat various diseases, e.g., wherein the targets that are recognized by the binding proteins are detrimental. Such binding proteins may bind one or more targets involved in a specific disease.
Without limiting the disclosure, further information on certain disease conditions is provided.
1. Age-Related Macular Degeneration (AMD)
In various embodiments, one or more of the binding proteins disclosed herein that are capable of binding to VEGF and PDGF and/or their cognate receptors (e.g., a combination of an anti-VEGF and an anti-PDGF binding protein, or a multispecific binding protein capable of targeting both VEGF and PDGF) can be used to treat AMD. In some embodiments, any of the binding proteins disclosed herein can be used to treat AMD, or a binding protein comprising the CDR and/or variable domain sequences from any of the binding disclosed herein. In certain embodiments, the binding protein used to treat AMD is one or more of the binding proteins listed in Tables 27-30, 38-42, 46-50, or 55-58. In certain embodiments, the binding protein used to treat AMD is one or more of the binding proteins listed in Tables 56-58. In certain embodiments, the binding protein is PR-1572102, PR-1572105, or PR-1610561.
Age-Related Macular Degeneration (AMD) is the leading cause of irreversible vision loss in individuals over the age of 50 in the United States and a major cause of blindness worldwide. Globally more than 160 million people suffer from AMD. AMD is an age-related ocular disease that results in blindness due to damage to the macula; the region of the retina responsible for sharp central vision. It is associated with the degeneration of the macula and in particular the retinal pigmented epithelium (RPE).
The disease occurs in two forms, the dry or non-exudative AMD form and the wet or exudative form. The most common form of macular degeneration, dry AMD (non-neovascular), is an early stage of the disease and may result from aging and thinning of macular tissues, deposition of pigment in the macula, or a combination of both processes. Dry AMD is diagnosed when yellowish spots known as drusen accumulate in and around the macula. Drusen are thought to be deposits or debris from nearby deteriorating tissue. The onset of dry AMD is usually associated with age-related changes in Bruch's membrane, a highly specialized matrix for adhesion of retinal pigment epithelial (RPE) cells. These alterations in Bruch's membrane can result in death of RPE cells in the macula, accumulation of drusen, and damage to photoreceptor cells. Gradual central loss of vision may occur with dry AMD, but the symptoms are typically not nearly as severe as with the wet form of the disease. Dry AMD can slowly progress to late-stage geographic atrophy (GA) resulting in a gradual deterioration of retinal cells that can cause severe vision loss. Dry AMD (both early and late stage) is the most common form of AMD representing more than 85% of all diagnosed cases.
The wet or exudative form of the disease usually results in more severe vision loss. Wet macular degeneration mainly affects central vision, causing “blind spots” in the central line of vision. Approximately 10-15% of dry AMD cases progress to wet AMD. Wet AMD is characterized by new blood vessel growth beneath the retina. Clinically, this is referred to as choroidal neovascularization (CNV). Wet AMD accounts for about 10-15% of all cases of AMD. Progression of dry AMD to wet AMD is marked by the development of neovascularization within Bruch's membrane, as well as in the subretinal space. Wet AMD occurs when abnormal blood vessels behind the retina grow under the macula. These new blood vessels tend to be fragile and often leak blood and fluid. The blood and fluid result in macula inflammation and thickening and disrupts the connection between the photoreceptors and the RPE, leading to vision loss. In wet AMD, neovascularization is stimulated by many angiogenic factors; including vascular endothelial growth factor (VEGF), which appears to be the primary angiogenic factor in patients with wet AMD (Miller et al. (1994) Am. J. Pathol. 145(3):574-584). Additionally, VEGF can act as a powerful endothelial cell mitogen, increasing vascular permeability. The primary goals of current AMD treatment are to block or inhibit choroidal neovascularization (CNV) and macular edema following retinal vein occlusion (RVO), stabilize or improve vision, and to reduce the occurrence of adverse effects.
Anti-VEGF agents may reduce choroidal neovascularization (CNV) and leakage, but do not lead to regression of CNV itself. Emerging evidence indicates the important role of pericytes on the maturation of new blood vessels. Anti-PDGF agents can directly block pericyte recruitment and prevent the maturation and stabilization of choroidal neovascularization. If pericytes can be stripped away from new blood vessels, vascular endothelial cells may become more susceptible to VEGF blockade, ultimately leading to a regression of angiogenesis.
Among other functions, VEGF stimulates endothelial cell proliferation/growth, increases vascular permeability, and promotes leukocyte activity capable of damaging retinal endothelial cells (Leung et al. (1989) Science 246(4935):1306-9). In wet AMD, retinal tissues produce and release angiogenic growth factors such as VEGF that bind to specific receptors located on the endothelial cells of nearby preexisting blood vessels. Activation of endothelial cells can result in the release of enzymes targeting tight junctions. These enzymes act on the basement membrane surrounding all existing blood vessels and lead to the formation of holes in the membrane. The endothelial cells proliferate and migrate out through these holes toward the diseased tissue. Specialized adhesion molecules such as integrins promote formation of new blood vessel sprouts, and matrix metalloproteinases (MMPs) dissolve the tissue in front of the sprouting vessel tip in order to accommodate it. Finally, smooth muscle cells (pericytes) provide structural support to these newly formed blood vessel loops and blood flow begins in these new immature vessels. Thus, VEGF may serve as a rate-limiting step in angiogenesis. VEGF also increases vascular permeability by leukocyte-mediated endothelial cell injury, formation of fenestrations, and the dissolution of tight junctions. This leads to intra-retinal fluid accumulation and a detrimental effect on visual acuity. Moreover, VEGF can also cause the release of inflammatory cytokines that further reinforce the cycle of inflammation and angiogenesis.
In some embodiments, treatments inhibiting VEGF, PDGF, and/or the receptors (in a combination therapy or in one molecule) using the binding proteins disclosed herein may offer improved options for patients with wet AMD, while reducing the number of injections, reducing the safety concerns associated with multiple injections, and reducing cost.
2. Diabetic Retinopathy
Diabetic retinopathy is the most common diabetic eye disease and a leading cause of blindness in American adults. It is caused by changes in the blood vessels of the retina. In some people with diabetic retinopathy, blood vessels may swell and leak fluid. In other people, abnormal new blood vessels grow on the surface of the retina. The retina is the light-sensitive tissue at the back of the eye. A healthy retina is necessary for good vision.
Diabetic retinopathy has four stages: (1) Mild Nonproliferative Retinopathy. At this earliest stage, microaneurysms occur. They are small areas of balloon-like swelling in the retina's tiny blood vessels. (2) Moderate Nonproliferative Retinopathy. As the disease progresses, some blood vessels that nourish the retina are blocked. (3) Severe Nonproliferative Retinopathy. Many more blood vessels are blocked, depriving several areas of the retina with their blood supply. These areas of the retina send signals to the body to grow new blood vessels for nourishment. (4) Proliferative Retinopathy. At this advanced stage, the signals sent by the retina for nourishment trigger the growth of new blood vessels. This condition is called proliferative retinopathy. These new blood vessels are abnormal and fragile. They grow along the retina and along the surface of the clear, vitreous gel that fills the inside of the eye. By themselves, these blood vessels do not cause symptoms or vision loss. However, they have thin, fragile walls. If they leak blood, severe vision loss and even blindness can result.
Blood vessels damaged from diabetic retinopathy can cause vision loss in two ways: (1) Fragile, abnormal blood vessels can develop and leak blood into the center of the eye, blurring vision. This is proliferative retinopathy and is the fourth and most advanced stage of the disease. (2) Fluid can leak into the center of the macula, the part of the eye where sharp, straight-ahead vision occurs. The fluid makes the macula swell, blurring vision. This condition is called macular edema. It can occur at any stage of diabetic retinopathy, although it is more likely to occur as the disease progresses. About half of the people with proliferative retinopathy also have macular edema.
In some embodiments, the binding proteins disclosed herein may be used to inhibit VEGF, PDGF, and/or the receptors (in a combination therapy or in one molecule) to treat diabetic retinopathy.
In various embodiments, other diseases may be treated using the binding proteins disclosed herein, including but not limited to other eye disorders, cancers, fibrosis, renal disease, pathologic angiogenesis, wound healing, bone formation, or other diseases associated with aberrant (e.g., elevated) PDGF and/or VEGF expression.
Pharmaceutical Compositions
In various embodiments, pharmaceutical compositions comprising one or more of the binding proteins disclosed herein, either alone or in combination with other prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers, are provided. The pharmaceutical compositions comprising binding proteins provided herein are for use in, but not limited to, diagnosing, detecting, or monitoring a disorder, in preventing, treating, managing, or ameliorating a disorder or one or more symptoms thereof, and/or in research. The formulation of pharmaceutical compositions, either alone or in combination with prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers, are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
Methods of administering a pharmaceutical composition or a prophylactic or therapeutic agent provided herein include, but are not limited to, parenteral administration (e.g., intradermal, intramuscular, intraperitoneal, intravitreous, intravenous and subcutaneous), epidural administration, intratumoral administration, mucosal administration (e.g., intranasal and oral routes) and pulmonary administration (e.g., aerosolized compounds administered with an inhaler or nebulizer). In an embodiment, the methods of administering a pharmaceutical composition or a prophylactic or therapeutic agent provided herein include topical eye drops, gels, or creams. The formulation of pharmaceutical compositions for specific routes of administration, and the materials and techniques necessary for the various methods of administration are available and known to one skilled in the art (U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. The term “dosage unit form” refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms provided herein are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of a binding protein provided herein is 0.1-20 mg/kg, for example, 1-10 mg/kg. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
Combination Therapy
In various embodiments, a binding protein provided herein may also be administered with one or more additional therapeutic agents useful in the treatment of various diseases, the additional agent being selected by the skilled artisan for its intended purpose. For example, the additional agent can be a therapeutic agent art-recognized as being useful to treat the disease or condition being treated by the antibody provided herein, such as AMD. The combination can also include more than one additional agent, e.g., two or three additional agents.
Combination therapy agents include, but are not limited to imaging agents, cytotoxic agents, angiogenesis inhibitors, kinase inhibitors, tyrosine kinase inhibitors, tyrosine kinase receptor inhibitors, co-stimulation molecule blockers, adhesion molecule blockers, anti-cytokine antibodies or functional fragments thereof, methotrexate, cyclosporin, rapamycin, FK506, detectable labels or reporters, TNF antagonists, antirheumatics, muscle relaxants, narcotics, non-steroid anti-inflammatory drugs (NSAIDs), analgesics, anesthetics, local anesthetics, sedatives, a hyaluronidase enzyme, neuromuscular blockers, antimicrobials, antipsoriatics, corticosteriods, anabolic steroids, erythropoietin, immunizations, immunoglobulins, immunosuppressives, growth hormones, hormone replacement drugs, radiopharmaceuticals, antidepressants, antipsychotics, stimulants, asthma medications, beta agonists, inhaled steroids, epinephrine or analogs, cytokines, or cytokine antagonists.
Diagnostics
The disclosure herein also provides, in various embodiments, diagnostic applications including, but not limited to, diagnostic assay methods, diagnostic kits containing one or more binding proteins, and adaptation of the methods and kits for use in automated and/or semi-automated systems. The methods, kits, and adaptations provided may be employed in the detection, monitoring, and/or treatment of a disease or disorder in an individual. This is further elucidated below.
The present disclosure also provides a method for determining the presence, amount or concentration of an analyte, or fragment thereof, in a test sample using at least one binding protein as described herein. Any suitable assay as is known in the art can be used in the method. Examples include, but are not limited to, immunoassays and/or methods employing mass spectrometry.
Immunoassays provided by the present disclosure may include sandwich immunoassays, radioimmunoassay (RIA), enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), competitive-inhibition immunoassays, fluorescence polarization immunoassay (FPIA), enzyme multiplied immunoassay technique (EMIT), bioluminescence resonance energy transfer (BRET), and homogenous chemiluminescent assays, among others.
A chemiluminescent microparticle immunoassay, in particular one employing the ARCHITECT® automated analyzer (Abbott Laboratories, Abbott Park, Ill.), is an example of an immunoassay.
Methods employing mass spectrometry are provided by the present disclosure and include, but are not limited to MALDI (matrix-assisted laser desorption/ionization) or by SELDI (surface-enhanced laser desorption/ionization).
Methods for collecting, handling, processing, and analyzing biological test samples using immunoassays and mass spectrometry would be well-known to one skilled in the art, are provided for in the practice of the present disclosure (see, e.g., U.S. Pat. No. 7,612,181).
Kits
In various embodiments, a kit for assaying a test sample for the presence, amount or concentration of an analyte, or fragment thereof, in a test sample is also provided. The kit comprises at least one component for assaying the test sample for the analyte, or fragment thereof, and instructions for assaying the test sample for the analyte, or fragment thereof. The at least one component for assaying the test sample for the analyte, or fragment thereof, can include a composition comprising a binding protein, as disclosed herein, and/or an anti-analyte binding protein (or a fragment, a variant, or a fragment of a variant thereof), which is optionally immobilized on a solid phase.
Optionally, the kit may comprise a calibrator or control, which may comprise isolated or purified analyte. The kit can comprise at least one component for assaying the test sample for an analyte by immunoassay and/or mass spectrometry. The kit components, including the analyte, binding protein, and/or anti-analyte binding protein, or fragments thereof, may be optionally labeled using any art-known detectable label. The materials and methods for the creation provided for in the practice of the present disclosure would be known to one skilled in the art (see, e.g., U.S. Pat. No. 7,612,181).
The kit (or components thereof), as well as the method of determining the presence, amount or concentration of an analyte in a test sample by an assay, such as an immunoassay as described herein, can be adapted for use in a variety of automated and semi-automated systems (including those wherein the solid phase comprises a microparticle), as described, for example, in U.S. Pat. Nos. 5,089,424 and 5,006,309, and as commercially marketed, for example, by Abbott Laboratories (Abbott Park, Ill.) as ARCHITECT®.
Other platforms available from Abbott Laboratories include, but are not limited to, AxSYM®, IMx® (see, for example, U.S. Pat. No. 5,294,404, PRISM®, EIA (bead), and QuantumTM II, as well as other platforms. Additionally, the assays, kits and kit components can be employed in other formats, for example, on electrochemical or other hand-held or point-of-care assay systems. The present disclosure is, for example, applicable to the commercial Abbott Point of Care (i-STATED, Abbott Laboratories) electrochemical immunoassay system that performs sandwich immunoassays Immunosensors and their methods of manufacture and operation in single-use test devices are described, for example in, U.S. Pat. Nos. 5,063,081, 7,419,821, 7,682,833, 7,723,099, and 9,035,027; and U.S. Publication No. 20040018577.
Sequences
Table 1 discloses amino acid and nucleotide sequences encoding VEGF-A from different human isoforms and different species. Table 2 discloses amino acid and nucleotide sequences encoding PDGF-BB from different human isoforms and different species. Table 3 discloses human IgG heavy chain and light chain constant domains, including sequences with the indicated amino acid modifications relative to the wild-type sequence. In various embodiments, the constant domains listed in Table 3 can be used with any of the binding proteins disclosed herein. The variable domains of the binding proteins disclosed herein may be attached to constant regions of any immunoglobulin species, isotypes, or mutants. Exemplary modifications in constant domain mutants include those with amino acid mutations intended to increase or reduce constant domain interactions with Fc-gamma receptors, C1q and FcRn, and/or mutations intended to modulate protein stability or valency (full-length and half molecule, heterodimer molecule, etc.). Tables 4 and 5 disclose exemplary heavy and light chain acceptor framework sequences that can be used with any of the CDR sets disclosed herein (i.e., heavy chain acceptor sequences paired with any of the heavy chain CDRs 1-3 disclosed herein, and/or light chain acceptor sequences paired with any of the light chain CDRs 1-3 disclosed herein) to form functional binding sites for PDGF, VEGF, and/or their cognate receptors.







TABLE 1







Amino Acid and Nucleotide Sequences for VEGF-A










Sequence
Sequence


Kind of Sequence
Identifier
123456789012345678901234567890





Human VEGF-A 165
SEQ ID NO:
APMAEGGGQNHHEVVKFMDVYQRSYCHPIE


Amino Acid Sequence
253
TLVDIFQEYPDEIEYIFKPSCVPLMRCGGC




CNDEGLECVPTEESNITMQIMRIKPHQGQH




IGEMSFLQHNKCECRPKKDRARQENPCGPC




SERRKHLFVQDPQTCKCSCKNTDSRCKARQ




LELNERTCRCDKPRR


 


Human VEGF-A 121
SEQ ID NO:
APMAEGGGQNHHEVVKFMDVYQRSYCHPIE


Amino Acid Sequence
254
TLVDIFQEYPDEIEYIFKPSCVPLMRCGGC




CNDEGLECVPTEESNITMQIMRIKPHQGQH




IGEMSFLQHNKCECRPKKDRARQEKCDKPR




R


 


Human VEGF-A 110
SEQ ID NO:
APMAEGGGQNHHEVVKFMDVYQRSYCHPIE


Amino Acid Sequence
255
TLVDIFQEYPDEIEYIFKPSCVPLMRCGGC




CNDEGLECVPTEESNITMQIMRIKPHQGQH




IGEMSFLQHNKCECRCDKPRR


 


Cynomolgus monkey
SEQ ID NO:
APMAEGGGQNHHEVVKFMDVYQRSYCHPIE


VEGF-A 165 Amino Acid
256
TLVDIFQEYPDEIEYIFKPSCVPLMRCGGC


Sequence

CNDEGLECVPTEESNITMQIMRIKPHQGQH




IGEMSFLQHNKCECRPKKDRARQENPCGPC




SERRKHLFVQDPQTCKCSCKNTDSRCKARQ




LELNERTCRCDKPRR


 


Mouse VEGF-A 164
SEQ ID NO:
APTTEGEQKSHEVIKFMDVYQRSYCRPIET


Amino Acid Sequence
257
LVDIFQEYPDEIEYIFKPSCVPLMRCAGCC




NDEALECVPTSESNITMQIMRIKPHQSQHI




ERMSFLQHSRCECRPKKDRTKPENHCEPCS




ERRKHLFVQDPQTCKCSCKNTDSRCKARQL




ELNERTCRCDKPRR


 


Rat VEGF-A 164 Amino
SEQ ID NO:
APTTEGEQKAHEVVKFMDVYQRSYCRPIET


Acid Sequence
258
LVDIFQEYPDEIEYIFKPSCVPLMRCAGCC




NDEALECVPTSESNVTMQIMRIKPHQSQHI




GEMSFLQHSRCECRPKKDRTKPENHCEPCS




ERRKHLFVQDPQTCKCSCKNTDSRCKARQL




ELNERTCRCDKPRR


 


Rabbit VEGF-A Amino
SEQ ID NO:
MNFLLSWVHWSLALLLYLHHAKWSQAAPMA


Acid Sequence
259
EEGDNKPHEVVKFMEVYRRSYCQPIETLVD




IFQEYPDEIEYIFKPSCVPLVRCGGCCNDE




SLECVPTEEFNVTMQIMRIKPHQGQHIGEM




SFLQHNKCECRPKKDRARQENPCGPCSERR




KHLFVQDPQTCKCSCKNTDSRCKARQLELN




ERTCRCDKPRR
















TABLE 2







Amino Acid and Nucleotide Sequences for PDGF-BB










Sequence
Sequence


Kind of Sequence
Identifier
123456789012345678901234567890





Human PDGF-BB Amino
SEQ ID NO:
SLGSLTIAEPAMIAECKTRTEVFEISRRLI


Acid Sequence
260
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC




RPTQVQLRPVQVRKIEIVRKKPIFKKATVT




LEDHLACKCETVAAARPVT


 


Human PDGF-BB-RM
SEQ ID NO:
MNRCWALFLSLCCYLRLVSAEGDPIPEELY


(Retention Motif) Amino
261
EMLSDHSIRSFDDLQRLLHGDPGEEDGAEL


Acid Sequence

DLNMTRSHSGGELESLARGRRSLGSLTIAE




PAMIAECKTRTEVFEISRRLIDRTNANFLV




WPPCVEVQRCSGCCNNRNVQCRPTQVQLRP




VQVRKIEIVRKKPIFKKATVTLEDHLACKC




ETVAAARPVTRSPGGSQEQRAKTPQTRVTI




RTVRVRRPPKGKHRKFKHTHDKTALKETLG




A


 


Cynomolgus monkey
SEQ ID NO:
SLGSLTVAEPAMIAECKTRTEVFEISRRLI


PDGF-BB Amino Acid
262
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC


Sequence

RPTQVQLRPVQVRKIEIVRKKPIFKKATVT




LEDHLACKCETVAAARPVT


 


Mouse PDGF-BB Amino
SEQ ID NO:
SLGSLAAAEPAVIAECKTRTEVFQISRNLI


Acid Sequence
263
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC




RASQVQMRPVQVRKIEIVRKKPIFKKATVT




LEDHLACKCETIVTPRPVT


 


Rat PDGF-BB Amino
SEQ ID NO:
SLGSLAAAEPAVIAECKTRTEVFQISRNLI


Acid Sequence
264
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC




RASQVQMRPVQVRKIEIVRKKPVFKKATVT




LEDHLACKCETVVTPRPVT


 


Rabbit PDGF-BBA Amino
SEQ ID NO:
SLGSLAAAEPAVIAECKTRTEVFQISRNLI


Acid Sequence
265
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC




RASQVQMRPVQVRKIEIVRKKPVFKKATVT




LEDHLACKCETVVTPRPVT
















TABLE 3







Amino Acid Sequences of Human IgG Heavy Chain and


Light Chain Constant Domains










Sequence
Sequence


Protein
Identifier
123456789012345678901234567890





Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK


region
266
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS




GLYSLSSVVTVPSSSLGTQTYICNVNHKPS




NTKVDKKVEPKSCDKTHTCPPCPAPELLGG




PSVFLFPPKPKDTLMISRTPEVTCVVVDVS




HEDPEVKFNWYVDGVEVHNAKTKPREEQYN




STYRVVSVLTVLHQDWLNGKEYKCKVSNKA




LPAPIEKTISKAKGQPREPQVYTLPPSREE




MTKNQVSLTCLVKGFYPSDIAVEWESNGQP




ENNYKTTPPVLDSDGSFFLYSKLTVDKSRW




QQGNVFSCSVMHEALHNHYTQKSLSLSPGK


 


Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK


region L234A, L235A
267
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS




GLYSLSSVVTVPSSSLGTQTYICNVNHKPS




NTKVDKKVEPKSCDKTHTCPPCPAPEAAGG




PSVFLFPPKPKDTLMISRTPEVTCVVVDVS




HEDPEVKFNWYVDGVEVHNAKTKPREEQYN




STYRVVSVLTVLHQDWLNGKEYKCKVSNKA




LPAPIEKTISKAKGQPREPQVYTLPPSREE




MTKNQVSLTCLVKGFYPSDIAVEWESNGQP




ENNYKTTPPVLDSDGSFFLYSKLTVDKSRW




QQGNVFSCSVMHEALHNHYTQKSLSLSPGK


 


Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK


region L234A, L235A,
268
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS


H435A

GLYSLSSVVTVPSSSLGTQTYICNVNHKPS




NTKVDKKVEPKSCDKTHTCPPCPAPEAAGG




PSVFLFPPKPKDTLMISRTPEVTCVVVDVS




HEDPEVKFNWYVDGVEVHNAKTKPREEQYN




STYRVVSVLTVLHQDWLNGKEYKCKVSNKA




LPAPIEKTISKAKGQPREPQVYTLPPSREE




MTKNQVSLTCLVKGFYPSDIAVEWESNGQP




ENNYKTTPPVLDSDGSFFLYSKLTVDKSRW




QQGNVFSCSVMHEALHNAYTQKSLSLSPGK


 


Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK


region L234A, L235A,
269
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS


H435R

GLYSLSSVVTVPSSSLGTQTYICNVNHKPS




NTKVDKKVEPKSCDKTHTCPPCPAPEAAGG




PSVFLFPPKPKDTLMISRTPEVTCVVVDVS




HEDPEVKFNWYVDGVEVHNAKTKPREEQYN




STYRVVSVLTVLHQDWLNGKEYKCKVSNKA




LPAPIEKTISKAKGQPREPQVYTLPPSREE




MTKNQVSLTCLVKGFYPSDIAVEWESNGQP




ENNYKTTPPVLDSDGSFFLYSKLTVDKSRW




QQGNVFSCSVMHEALHNRYTQKSLSLSPGK


 


Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK


region C226A, C229A,
270
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS


N297A, F405R (Half

GLYSLSSVVTVPSSSLGTQTYICNVNHKPS


body)

NTKVDKKVEPKSCDKTHTAPPAPAPELLGG




PSVFLFPPKPKDTLMISRTPEVTCVVVDVS




HEDPEVKFNWYVDGVEVHNAKTKPREEQYA




STYRVVSVLTVLHQDWLNGKEYKCKVSNKA




LPAPIEKTISKAKGQPREPQVYTLPPSREE




MTKNQVSLTCLVKGFYPSDIAVEWESNGQP




ENNYKTTPPVLDSDGSFRLYSKLTVDKSRW




QQGNVFSCSVMHEALHNHYTQKSLSLSPGK


 


Ig Kappa constant region
SEQ ID NO:
RTVAAPSVFIFPPSDEQLKSGTASVVCLLN



271
NFYPREAKVQWKVDNALQSGNSQESVTEQD




SKDSTYSLSSTLTLSKADYEKHKVYACEVT




HQGLSSPVTKSFNRGEC


 


Ig Lambda constant region
SEQ ID NO:
GQPKAAPSVTLFPPSSEELQANKATLVCLI



272
SDFYPGAVTVAWKADSSPVKAGVETTTPSK




QSNNKYAASSYLSLTPEQWKSHRSYSCQVT




HEGSTVEKTVAPTECS
















TABLE 4







Amino Acid Sequences of Heavy Chain Acceptor Frameworks










Protein region/



SEQ ID
Closest
Amino Acid Sequence


NO:
Germline Family
12345678901234567890123456789012





273
VH3-7 FR1
EVQLVESGGGLVQPGGSLRLSCAASGFTFS


 


274
VH3-7 FR2
WVRQAPGKGLEWVA


 


275
VH3-7 FR3
RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR


 


276
JH4 FR4
WGQGTLVTVSS


 


277
VH3 CONSENUSUS FR1
EVQLVESGGGLVQPGGSLRLSCAASGFTFS


 


278
VH3 CONSENUSUS FR2
WVRQAPGKGLEWVS


 


279
VH3 CONSENUSUS FR3
RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR


 


280
JH4 FR4
WGQGTLVTVSS


 


281
VH1-46 FR1
QVQLVQSGAEVKKPGASVKVSCKASGYTFT


 


282
VH1-46 FR2
WVRQAPGQGLEWMG


 


283
VH1-46 FR3
RVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR


 


284
JH4 FR4
WGQGTLVTVSS


 


285
VH3-30 FR1
QVQLVESGGGVVQPGRSLRLSCAASGFTFS


 


286
VH3-30 FR2
WVRQAPGKGLEWVA


 


287
VH3-30 FR3
RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR


 


288
JH3 FR4
WGQGTMVTVSS


 


289
VH3 CONSENUSUS FR1
EVQLVESGGGLVQPGGSLRLSCAASGFTFS


 


290
VH3 CONSENUSUS FR2
WVRQAPGKGLEWVS


 


291
VH3 CONSENUSUS FR3
RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR


 


292
JH3 FR4
WGQGTMVTVSS


 


293
VH2-70/JH6 FR1
EVTLRESGPALVKPTQTLTLTCTFSGFSLS


 


294
VH2-70/JH6 FR2
WIRQPPGKALEWLA


 


295
VH2-70/JH6 FR3
RLTISKDTSKNQVVLTMTNMDPVDTATYYCAR


 


296
VH2-70/JH6 FR4
WGQGTTVTVSS


 


297
VH2-26/JH6 FR1
EVTLKESGPVLVKPTETLTLTCTVSGFSLS


 


298
VH2-26/JH6 FR2
WIRQPPGKALEWLA


 


299
VH2-26/JH6 FR3
RLTISKDTSKSQVVLTMTNMDPVDTATYYCAR


 


300
VH2-26/JH6 FR4
WGQGTTVTVSS


 


301
VH3-72/JH6 FR1
EVQLVESGGGLVQPGGSLRLSCAASGFTFS


 


302
VH3-72/JH6 FR2
WVRQAPGKGLEWVG


 


303
VH3-72/JH6 FR3
RFTISRDDSKNSLYLQMNSLKTEDTAVYYCAR


 


304
VH3-72/JH6 FR4
WGQGTTVTVSS


 


305
VH3-21/JH6 FR1
EVQLVESGGGLVKPGGSLRLSCAASGFTFS


 


306
VH3-21/JH6 FR2
WVRQAPGKGLEWVS


 


307
VH3-21/JH6 FR3
RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR


 


308
VH3-21/JH6 FR4
WGQGTTVTVSS


 


309
VH1-69/JH6 FR1
EVQLVQSGAEVKKPGSSVKVSCKASGGTFS


 


310
VH1-69/JH6 FR2
WVRQAPGQGLEWMG


 


311
VH1-69/JH6 FR3
RVTITADKSTSTAYMELSSLRSEDTAVYYCAR


 


312
VH1-69/JH6 FR4
WGQGTTVTVSS


 


313
VH1-18/JH6 FR1
EVQLVQSGAEVKKPGASVKVSCKASGYTFT


 


314
VH1-18/JH6 FR2
WVRQAPGQGLEWMG


 


315
VH1-18/JH6 FR3
RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR


 


316
VH1-18/JH6 FR4
WGQGTTVTVSS


 


317
IGHV4-59 FR1
EVQLQESGPGLVKPSETLSLTCTVSGGSIS


 


318
IGHV4-59 FR2
WIRQPPGKGLEWIG


 


319
IGHV4-59 FR3
RVTISVDTSKNQFSLKLSSVTAADTAVYYCAR


 


320
IGHV4-59/JH FR4
WGQGTLVTVSS


 


321
IGHV3-66 FW1
EVQLVESGGGLVQPGGSLRLSCAVSGGSIS


 


322
IGHV3-66 FW2
WIRQAPGKGLEWIG


 


323
IGHV3-66 FW3
RVTISVDTSKNSFYLQMNSLRAEDTAVYYCAR


 


324
IGHV3-66/JH FW4
WGQGTLVTVSS


 


325
IGHV4-59 FR1
EVQLQESGPGLVKPGETLSLTCTVSGGSIS


 


326
IGHV4-59 FR2
WIRQAPGKGLEWIG


 


327
IGHV4-59 FR3
RVTISVDTSKNQFYLKLSSVRAEDTAVYYCAR


 


328
IGHV4-59/JH FR4
WGQGTLVTVSS


 


329
IGHV5-51 FR1
EVQLVQSGTEVKKPGESLKISCKVSGGSIS


 


330
IGHV5-51 FR2
WIRQMPGKGLEWIG


 


331
IGHV5-51 FR3
QVTISVDTSFNTFFLQWSSLKASDTAMYYCAR


 


332
IGHV5-51/JH FR4
WGQGTMVTVSS


 


333
IGHV2-70 FR1
EVTLRESGPALVKPTQTLTLTCTVSGGSIS


 


334
IGHV2-70 FR2
WIRQPPGKGLEWIG


 


335
IGHV2-70 FR3
RVTISVDTSKNQFVLTMTNMDPVDTATYYCAR


 


336
IGHV2-70/JH FR4
WGQGTTVTVSS


 


337
IGHV3-15 FR1
EVQLLESGGGLVKSGGSLRLSCAASGFTFR


 


338
IGHV3-15 FR2
WVRQAPGKGLEWVA


 


339
IGHV3-15 FR3
RFTISRDNSKNTLYLQLNSLRAEDTAVYYCAK


 


340
IGHV3-15/JH FR4
WGQGTMVTVSS


 


341
IGHV3-43 FR1
EVQLVESGGGVVQPGGSLRLSCAASGFTFG


 


342
IGHV3-43 FR2
WVRQAPGKGLEWVA


 


343
IGHV3-43 FR3
RFTISRDNSKNTLYLQLNSLRAEDTAVYYCAK


 


344
IGHV3-43/JH FR4
WGQGTMVTVSS
















TABLE 5







Amino Acid Sequences


of Light Chain Acceptor Frameworks










Protein




region/


SEQ
Closest


ID
Germline
Sequence


NO:
Family
12345678901234567890123456789012





345
O2 FR1
DIQMTQSPSSLSASVGDRVTITC


 


346
O2 FR2
WYQQKPGKAPKLLIY


 


347
O2 FR3
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC


 


348
JK2 FR4
FGQGTKLEIK


 


349
L2 FR1
EIVMTQSPATLSVSPGERATLSC


 


350
L2 FR2
WYQQKPGQAPRLLIY


 


351
L2 FR3
GIPARFSGSGSGTEFTLTISSLQSEDFAVYYC


 


352
JK2 FR4
FGQGTKLEIK


 


353
B3/JK4 FR1
DIVMTQSPDSLAVSLGERATINC


 


354
B3/JK4 FR2
WYQQKPGQPPKLLIY


 


355
B3/JK4 FR3
GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC


 


356
B3/JK4 FR4
FGGGTKVEIKR


 


357
L2/JK4 FR1
EIVMTQSPATLSVSPGERATLSC


 


358
L2/JK4 FR2
WYQQKPGQAPRLLIY


 


359
L2/JK4 FR3
GIPARFSGSGSGTEFTLTISSLQSEDFAVYYC


 


360
L2/JK4 FR4
FGGGTKVEIKR


 


361
L15/JK4 FR1
DIQMTQSPSSLSASVGDRVTITC


 


362
L15/JK4 FR2
WYQQKPEKAPKSLIY


 


363
L15/JK4 FR3
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC


 


364
L15/JK4 FR4
FGGGTKVEIKR


 


365
L5/JK4 FR1
DIQMTQSPSSVSASVGDRVTITC


 


366
L5/JK4 FR2
WYQQKPGKAPKLLIY


 


367
L5/JK4 FR3
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC


 


368
L5/JK4 FR4
FGGGTKVEIKR


 


369
IGLV3-1 FR1
SYELTQPPSVSVSPGQTASITC


 


370
IGLV3-1 FR2
WYQQKPGQSPVLVIY


 


371
IGLV3-1 FR3
GIPERFSGSNSGDTATLTISGTQPMDEADYYC


 


372
IGLV3-1/JL FR4
FGYGTKVTVL


 


373
IGLV3-1 FR1
SYELTQPPSVSVSPGQTASITC


 


374
IGLV3-1 FR2
WYQQKPGQSPVLVIY


 


375
IGLV3-1 FR3
GIPERFSGSNSGDTATLTISGTQPMDEADYYC


 


376
IGLV3-1/JL FR4
GGGTKLTVLG


 


377
IGLV3-1 FR1
YELTQPPSVSVSPGQTASITC


 


378
IGLV3-1 FR2
WYQQKPGQSPVLVIY


 


379
IGLV3-1 FR3
GIPERFSGSNSGDTATLTISGTQPMDEADYYC


 


380
IGLV3-1/JL FR4
GGGTKLTVLG


 


381
IGLV3-1 FR1
LYVLTQPPSVSVSPGQTASITC


 


382
IGLV3-1 FR2
WYQQKPGQSPVLVIY


 


383
IGLV3-1 FR3
GIPERFSGSNSGDTATLTISGTQTMDEADYLC


 


384
IGLV3-1/JL FR4
FGGGTKVTVLG


 


385
IGKV6D-21 FR1
EYVLTQSPDFQSVTPKEKVTITC


 


386
IGKV6D-21 FR2
WYQQKPDQSPKLVIY


 


387
IGKV6D-21 FR3
GVPSRFSGSNSGDDATLTINSLEAEDAATYYC


 


388
IGKV6D-21/JK
FGQGTKVEIKR



FR4


 


389
IGKV3D-15 FR1
EYVLTQSPATLSVSPGERATLSC


 


390
IGKV3D-15 FR2
WYQQKPGQSPRLVIY


 


391
IGKV3D-15 FR3
DIPARFSGSNSGDEATLTISSLQSEDFAVYYC


 


392
IGKV3D-15/JK
FGQGTRLEIKR



FR4


 


393
IGKV4-1 FR1
DYVLTQSPDSLAVSLGERATINC


 


394
IGKV4-1 FR2
WYQQKPGQSPKLVIY


 


395
IGKV4-1 FR3
GIPDRFSGSNSGDDATLTISSLQAEDVAVYYC


 


396
IGKV4-1/JK FR4
FGGGTKVEIKR


 


397
IGLV3-1 FR1
LPVLTQPPSVSVSPGQTASITC


 


398
IGLV3-1 FR2
WYQQKPGQSPVLVIY


 


399
IGLV3-1 FR3
GIPERFSGSNSGNTATLTISGTQTMDEADYLC


 


400
IGLV3-1/JL FR4
FGGGTKVTVL


 


401
IGLV3-1 FR1
SYELTQPPSVSVSPGQTASITC


 


402
IGLV3-1 FR2
WYQQKPGQSPVLVIY


 


403
IGLV3-1 FR3
GIPERFSGSNSGNTATLTISGTQTMDEADYLC


 


404
IGLV3-1/JL FR4
FGGGTKLTVL
















TABLE A







Select Heavy Chain and Light Chain Variable Domain Sequences


(CDRs in bold)









SEQ

Sequence


ID NO
VD name
12345678901234567890123456789012












1
hBDI-9E8.4 VH
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEW



(PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCA




RIESIGTTYSFDYWGQGTMVTVSS


 


2
hBDI-9E8.4 VL
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLV



(PDGF)
IYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINID




IVFGGGTKVEIK


 


3
hBDI-5H1.9
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIRQPPGKALEW



VH (PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCA




RISTGISSYYVMDAWGQGTTVTVSS


 


4
hBDI-5H1.9 VL
DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVSWYQQKPGQPPKNV



(PDGF)
IYGNDQRPSGVPDRFSGSGSGNSATLTISSLQAEDVAVYFCQSYDSDID




IVFGGGTKVEIK


 


5
hBDI-9E8.12
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTYGMGVGWIRQAPGKGLEW



VH (PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCA




RIESIGTTYSFDYWGQGTLVTVSS


 


6
hBDI-9E8.12
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAPKNV



VL (PDGF)
IYADDQRPSGVPSRFSGSGSGNSASLTISSLQPEDFATYYCQSYDINID




IVFGQGTKVEIK


 


7
hBDI-9E8.9 VH
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEW



(PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCA




RIESIGTTYSFDYWGQGTTVTVSS


 


8
hBDI-9E8.9 VL
DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVSWYQQKPGQPPKNV



(PDGF)
IYADDQRPSGVPDRFSGSGSGNSASLTISSLQAEDVAVYFCQSYDINID




IVFGGGTKVEIK


 


9
hBDI-9E8.12
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTYGMGVGWIRQAPGKGLEW



VH (PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCA




RIESIGTTYSFDYWGQGTLVTVSS


 


10
hBDI-9E8.12
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAPKNV



VL (PDGF)
IYADDQRPSGVPSRFSGSGSGNSASLTISSLQPEDFATYYCQSYDINID




IVFGQGTKVEIK


 


11
hBDI-9E8.4E
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEW



VH (PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCA




RIESIGTTYSFDYWGQGTMVTVSS


 


12
hBDI-9E8.4E
EFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLV



VL (PDGF)
IYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINID




IVFGGGTKVEIK


 


13
hBFU-3E2.1
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIG



VH (PDGF)
RIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCAR




FGARSYFYPMDAWGQGTTVTVSS


 


14
hBFU-3E2.1 VL
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIY



(PDGF)
GASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTF




GGGTKVEIK


 


15
CL-33675 VH
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEW



(PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCA




RIESSGPKYSFDYWGQGTMVTVSS


 


16
CL-33675 VL
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLL



(PDGF)
IYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINID




VVFGGGTKVEIK


 


17
hBDB-4G8.3
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMG



VH (VEGF)
WINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCAR




TNYYYRSYIFYFDYWGQGTMVTVSS


 


18
hBDB-4G8.3
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIY



VL (VEGF)
GASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTF




GQGTKLEIK


 


19
hBDB-4G8.13
EIQLVQSGTEVKKPGESLKISCKASGYTFTNYGMYWVKQMPGKGLEYMG



VH (VEGF)
WINTETGKPTYADDFKGRFTFSLDKSFNTAFLQWSSLKASDTAMYFCAR




TNYYYRSYIFYFDYWGQGTMVTVSS


 


20
hBDB-4G8.13
ETVLTQSPATLSVSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIY



VL (VEGF)
GASNLESGVPARFSGSGSGTDFTLTISSLQSEDFAVYFCQQSWNDPFTF




GQGTRLEIK


 


21
hBDB-4G8.14
EIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQAPGKGLEYMG



VH (VEGF)
WINTETGKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFCAR




TNYYYRSYIFYFDYWGQGTLVTVSS


 


22
hBDB-4G8.14
DTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIY



VL (VEGF)
GASNLESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTF




GQGTKVEIK


 


23
hBDB-4G8.15
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQAPGKGLEYMG



VH (VEGF)
WINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYFCAR




TNYYYRSYIFYFDYWGQGTLVTVSS


 


24
hBDB-4G8.15
DTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIY



VL (VEGF)
GASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTF




GQGTKVEIK


 


25
hBEW-9A8.12
EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMG



VH (VEGF)
WINTETGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR




VDYDGSFWFAYWGQGTLVTVSS


 


26
hBEW-9A8.12
DTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIH



VL (VEGF)
GASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTF




GQGTKLEIK


 


27
hBDB-4G8.2
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMG



VH (VEGF)
WINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCAR




TNYYYRSYIFYFDYWGQGTMVTVSS


 


28
hBDB-4G8.2
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYG



VL (VEGF)
ASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFG




QGTKLEIK


 


29
hBDB-4G8.4
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMG



VH (VEGF)
WINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCAR




TNYYYRSYIFYFDYWGQGTMVTVSS


 


30
hBDB-4G8.4
AIQLTQSPSSLSASVGDRVTITCRASESVSTHMHWYQQKPGKAPKLLIY



VL (VEGF)
GASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSWNDPFTF




GQGTKLEIK


 


31
hBDB-4G8.5
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMG



VH (VEGF)
WINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCAR




TNYYYRSYIFYFDYWGQGTMVTVSS


 


32
hBDB-4G8.5
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYG



VL (VEGF)
ASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFG




QGTKLEIK


 


33
hBDB-4G8.12
EIQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMG



VH (VEGF)
WINTETGKPTYADDFKGRFTFTLDTSTSTAYMELRSLRSDDTAVYFCAR




TNYYYRSYIFYFDYWGQGTMVTVSS


 


34
hBDB-4G8.12
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIY



VL (VEGF)
GASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTF




GQGTKLEIK


 


35
hBEW-9E10.1
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMG



VH (VEGF)
WIDTETGRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCAR




WSGDTTGIRGPWFAYWGQGTLVTVSS


 


36
hBEW-9E10.1
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIY



VL (VEGF)
NANGLQNGVPSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTF




GQGTKLEIK


 


37
hBEW-9E10.6
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMG



VH (VEGF)
WIDTETGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDTAVYYCAR




WSGDTTGIRGPWFAYWGQGTLVTVSS


 


38
hBEW-9E10.6
DIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIY



VL (VEGF)
NANGLQNGVPSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTF




GQGTKLEIK


 


39
hBEW-1B10.1
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVA



VH (VEGF)
SITTSGVGTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCAR




GYGAMDAWGQGTTVTVSS


 


40
hBEW-1B10.1
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIY



VL (VEGF)
AATRLADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTF




GGGTKVEIK


 


41
hBEW-1E3.4
EIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMYWVKQAPGQGLEYMG



VH (VEGF)
WINTEAGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCAR




WGYISDNSYGWFDYWGQGTLVTVSS


 


42
hBEW-1E3.4
ATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIY



VL (VEGF)
KASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTF




GQGTKLEIK


 


43
CL-34565 VH
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGLEWMG



(VEGF)
WIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCAR




TNYYYRNYMFYFDYWGQGTMVTVSS


 


44
CL-34565 VL
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIY



(VEGF)
GASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITF




GQGTKLEIK


 


211
hBDI-5H1.12
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTFGMGVGWIRQAPGKGLEW



VH (PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCA




RISTGISSYYVMDAWGQGTLVTVSS


 


212
hBDI-5H1.12
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAPKNV



VL (PDGF)
IYGNDQRPSGVPSRFSGSGSGNSATLTISSLQPEDFATYFCQSYDSDID




IVFGQGTKVEIK









It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the methods described herein are obvious and may be made using suitable equivalents without departing from the scope of the embodiments disclosed herein. Having now described certain embodiments in detail, the same will be more clearly understood by reference to the following examples, which are included for purposes of illustration only and are not intended to be limiting.
EXAMPLES
Example 1: In Vitro Assays Used to Determine the Functional Activity of Anti-VEGF-A Antibodies, Anti-PDGF-BB Antibodies, Anti-VEGFR Antibodies, Anti-PDGFR-B Antibodies, and DVD-Ig Proteins
Example 1.1: Affinity Determination Using BIACORE® Surface Plasmon Resonance Technology for Antigen Binding
The BIACORE® surface plasmon resonance assay (Biacore, Inc., Piscataway, N.J.) determines the affinity of antibodies with kinetic measurements of on-rate and off-rate constants. Binding of anti-VEGF-A antibodies, anti-PDGF-BB antibodies, anti-VEGFR antibodies, anti-PDGFR-B antibodies, or anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules, to a purified recombinant VEGF-A, PDGF-BB, VEGFR extracellular domain (ECD), PDGFR-B ECD or their Fc fusion proteins was determined by surface plasmon resonance-based measurements with a Biacore® instrument (either a Biacore 2000, Biacore 3000, or Biacore T100; GE Healthcare, Piscataway, N.J.) using running buffer HBS-EPB (10 mM HEPES [pH 7.4], 150 mM NaCl, 3 mM EDTA, 0.1 mg/ml BSA and 0.005% surfactant P20) at 25° C. For example, approximately 9000 RU of goat anti-human Fc specific polyclonal antibody (Thermo Fisher Scientific Inc., Rockford, Ill.) diluted in 10 mM sodium acetate (pH 4.5) is directly immobilized across a CM5 research grade biosensor chip using a standard amine coupling kit according to manufacturer's instructions and procedures at 25 μg/ml. Unreacted moieties on the biosensor surface were blocked with ethanolamine. For kinetic analysis, rate equations derived from the 1:1 Langmuir binding model were fitted simultaneously to multiple antigen injections (using global fit analysis) with the use of Scrubber 2 (BioLogic Software), Biacore Biaevaluation 4.0.1 software or Biacore T100 Evaluation software. Purified antibodies or DVD-Ig molecules were diluted in running buffer for capture across goat anti-human Fc reaction surfaces. Antibodies or DVD-Ig molecules to be captured as a ligand (1 μg/ml) were injected over reaction matrices at a flow rate of 10 μl/minute. During the assay, all measurements were referenced against the capture surface alone (i.e., with no captured antibody or DVD-Ig molecule). The association and dissociation rate constants, Kon (M−1 s−1) and Koff (s−1) were determined under a continuous flow rate of 80 μl/minute. Rate constants were derived by making kinetic binding measurements at different antigen concentrations ranging from 1.23-900 nM, as a 3-fold dilution series, and included buffer-only injections (to be used for double referencing). The equilibrium dissociation constant KD (M) of the reaction between antibodies and the target antigen was then calculated from the kinetic rate constants by the following formula: KD=Koff/Kon. Binding was recorded as a function of time and kinetic rate constants were calculated. In this assay, on-rates as fast as 106M−1s−1 and off-rates as slow as 10−6 s−1 could be measured.
In some experiments, the conditions below were used for affinity determination:
Chip surface: CM5 chip with goat anti human Fc IgG (5000 RU).
Reference: Goat IgG (capture 5000 RU).
Running buffer: HBS-EP, 0.1 mg/ml BSA
DVD-Ig or mAbs were captured at 1 μg/ml, at 70-200 RU.
Recombinant ECD proteins were serially diluted 1:5 at 0.016-50 nM.
Association time was 5 min and dissociation time was observed for 10 and 30 min.
Flow rate was 50 ul/min.
Surface regeneration: two 30s pulses of 10 mM Glycine, pH 1.5, at 50 μl/min.
Example 1.2: Surface Resonance FcγRIIa, FcγRIIb, FcγRIIIa, and FcRn Binding Assay
The binding of VEGF/PDGF DVD-Ig molecules to recombinant FcγRs captured via 6×His-tag (SEQ ID NO: 405) was assessed using a Biacore T200 (GE Healthcare) instrument. A CM5 chip (GE Healthcare, Pittsburgh, Pa.) with mouse anti-6×His antibodies (“6×His” disclosed as SEQ ID NO: 405) that were directly immobilized on the chip via amine coupling according to the GE Healthcare protocol to the density of 10000RU (all flow cells) was used for experiments. Human FcγRs were captured on flow cells 2, 3 and 4. Flow cell 1 was used as a reference surface. HBS-EP+ was used as the running buffer. Anti VEGF/PDGF DVD-Igs were injected over all the flow cells at a flow rate of 50 μL/minute for 1-2 minutes at concentrations of 31.25; 62.5, 125, 250, 500, 1000, 2000 and 4000 nM, followed by 1-3 minutes of dissociation. The chip surfaces were regenerated with an injection of 10 mM glycine pH 1.5 at a flow rate of 100 μL/minute over all four flow cells after each cycle.
For FcRn binding analysis, VEGF/PDGF DVD-Igs were directly immobilized on a CM5 chip by amine coupling according to the manufacturer's (GE Healthcare) protocol to a density of approximately 750 RU. Flow cell 1, where blank immobilization was performed, did not contain DVD-Igs and was used as a reference surface. Human, cynomolgus, mouse, rat and rabbit recombinant FcRns were injected over all the flow cells at a flow rate of 50 μL/minute for 1 minute at a concentrations range of from 2.7 to 6000 nM (three fold serial dilution), followed by a 2 minute dissociation time. The surfaces were regenerated with an injection of 10 mM HCl at 100 μL/minute for 2 seconds followed by an injection of HBS-EP+, pH 7.4, at a flow rate of 50 μL/minute for 30 seconds over all four flow cells. Samples were prepared and run in two running buffer systems, pH 6.0 MES-EP+, and pH 7.4 HBS-EP-EP+. Recombinant human FcγRIIIa V158 and rat and mouse FcRn data were fitted to 1:1 kinetic model. Recombinant human FcγRIIa R131 and FcγRIIa H131, FcγRIIIa F158, and recombinant human, cynomolgus and rabbit FcRn binding data were fitted to a steady state affinity model. Biacore T200 Evaluation Software version 2.0 was used to fit all the data.
Example 1.3: VEGF-A Binding Activity Determined by Capture ELISA
To identify molecules that could bind hVEGF165, a direct binding ELISA was performed. 96-well high binding neutravidin plates (Thermo Scientific cat#15507) were coated with 0.25 μg/mL/6.51E-9 M biotinylated recombinant human VEGF165 (AP PR-1361002, 50 μL/well in D-PBS), and shaken for 1.5 hours at 25° C. During the coating step, supernatant, antibodies, benchmark compounds or DVD-Ig were diluted in 10% Superblock (Thermo Scientific, cat#37535) and an eight point titration of each sample molecule was performed. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20). The sample molecule titration was added to the coated plate at 50 μL in duplicate and incubated for one hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The appropriate anti-species-IgG HRP conjugate was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for forty-five minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, Lexington, Ky. cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, Radnor, Pa. cat#BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in optical density indicates the binding of the test molecule to biotinylated recombinant human VEGF165. Data was analyzed using Softmax Pro 4.8 software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.4: VEGF-A Blocking Activity Determined by Inhibition of VEGF-R2 Interaction with Human VEGF165 
To identify molecules that could block the binding of hVEGF165 to the hVEGF-R2 (KDR/Flk-1) receptor, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.27E-9 M recombinant human VEGF-R2-Fc (R&D Systems cat#357-KD), 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatant, antibodies, benchmark compounds or DVD-Ig were diluted in 1% Blocker BSA (Thermo Scientific cat#37525) and an eight point titration of each sample molecule was performed. The biotinylated human VEGF165 (AP, PR-1361002) was diluted in 1% Blocker BSA at 35 ng/mL. The sample molecule titration was added to the biotinylated human VEGF165 (17.5 ng/mL/4.56E-10 M final concentration) and pre-incubated for 45 minutes at 25° C. with shaking. The pre-incubated sample/hVEGF165 complex was added to the coated plate at 50 μL in duplicate and incubated for 30 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Streptavidin-polyHRP-40 (Fitzgerald cal#65r-s104phrp) was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the hVEGF165 binding to the hVEGF-R2-Fc. Data was analyzed using Softmax Pro 4.8 software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.5: Mouse VEGF-A Blocking Activity Determined by Inhibition of Mouse VEGF-R2 Interaction with Mouse VEGF164 
To identify molecules that could block the binding of mVEGF164 to the mVEGF-R2, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 2 μg/mL anti-human IgG-Fc (Thermo-Scientific, cat 31125) shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were washed four times with wash buffer (TBS, 0.05% Tween-20) and 1 μg/mL/4.55E-9 M recombinant mouse VEGF-R2-Fc (R&D Systems cat#443-KD)(50 μL/well in D-PBS) was added to wells and incubated for 1.5 hour at 25° C. with shaking. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, hybridoma supernatants were diluted in 1% Blocker BSA (Thermo Scientific cat#37525). The mouse VEGF164 (R&D Systems cat#493-MV-005) was diluted in 1% Blocker BSA to 20 ng/mL. The diluted sample was added to the mouse VEGF164 (10 ng/mL/5.15E-10 M final concentration) and pre-incubated for 45 minutes at 25° C. with shaking. The pre-incubated sample/mVEGF164 complex was added to the coated plate at 50 μL and incubated for 30 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The detection reagent biotinylated goat anti-mVEGF164 (R&D Systems cat#BAF-493) was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates for 1 hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Streptavidin-polyHRP-40 (Fitzgerald cat#65r-s104phrp) was diluted in assay diluent and added to plates (50 μK) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the mVEGF164 binding to the mouse VEGF-R2-Fc. Data was analyzed using Softmax Pro 4.8 software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.6: VEGF-A Blocking Activity Determined by VEGFR2 (Tyr1054) Phosphorylation
To test candidate molecules for the ability to neutralize hVEGF-A activity, a cell based human VEGF-R2 (KDR/Flk-1) phosphorylation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, 400 μg/mL geneticin and 10% FBS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 6 hours at 37° C., 5% CO2. Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO2. The following day, the MSD anti-VEGFR2-phospho assay plate (Mesoscale VEGFR2-Tyr1054 phospho-MSD kit cat# K151DJD-2) was blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in growth media and pre-incubated with recombinant human VEGF165 (AP, PR-1350437) (50 ng/ml/1.3E-9 M final concentration), hVEGF111 (R&DSystems, cat#5336-VE-10/CF) (50 ng/mL/1.9E-9 M final concentration) or rabbit VEGF165 (AbbVie, PR-1563693.0) (50 ng/mL/1.24E-9 M final concentration) for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO2 Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. Ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL) on ice. Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated for 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr1054-IgG-sulfotag reagent was diluted in detection solution (K151DJD-2 components) and 25 μL added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K151DJD-2 component) added to wells and plates read on MSD Sector Imager 6000. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF-A mediated activation. Data was analyzed using Graphpad Prism software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.7: VEGF-A Blocking Activity Determined by Inhibition of Human VEGF165 Stimulated VEGFR2-3T3 Cell Proliferation/Survival
To screen candidate molecules for the ability to neutralize hVEGF165 activity, a cell based proliferation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 8.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 4,250 cells/well (50 μL) on black 96-well plates and incubated for 24 hours at 37° C., 5% CO2. The following day, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant human VEGF165 (AP, PR-1350437) (40 ng/ml/1.04E-9 M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO2 for 72 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using an ATPlite kit (Perkin Elmer, Waltham, Mass.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF165 induced proliferation. Data was analyzed and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.8: VEGF-A Blocking Activity Determined by Inhibition of HumanVEGF111 and HumanVEGF121 Stimulated VEGFR2-3T3 Cell Proliferation/Survival
To test the ability of candidate molecules to neutralize hVEGF111 and hVEGF121 activity, a cell based proliferation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 8.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 4,250 cells/well (50 μL) on black 96-well plates and incubated for 24 hours at 37° C., 5% CO2. The following day, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with either recombinant human VEGF111 (R&D Systems, cat#5336-VE) (10 ng/ml/3.85E-10 M final concentration) or human VEGF121 (R&D Systems, cat#4644-VS) (10 ng/ml/3.57E-10 M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO2 for 72 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using an ATPlite kit (Perkin Elmer, Waltham, Mass.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF111 or hVEGF121 induced proliferation. Data was analyzed and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.9: VEGF-A Blocking Activity Determined by Inhibition of Rabbit VEGF165 Stimulated VEGFR2-3T3 Cell Proliferation/Survival
To screen candidates for the ability to neutralize rabbitVEGF165, a cell based proliferation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 8.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 4,250 cells/well (50 μL) on black 96-well plates and incubated for 24 hours at 37° C., 5% CO2. The following day, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant rabbit VEGF165 (AbbVie, PR-1563693.0) (40 ng/ml/9.92E-10M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO2 for 72 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using an ATPlite kit (Perkin Elmer, Waltham, Mass.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the rabbitVEGF165 induced proliferation. Data was analyzed and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.10: VEGF-A Blocking Activity Determined by Inhibition of Human VEGF165 Stimulated Endothelial Cell Proliferation/Survival
To test for the ability to neutralize hVEGF165, a cell based proliferation assay was performed. Human microvascular endothelial cells (Lonza, cat#CC-2516) were maintained in EBM-2 (Lonza cat#CC3156) supplemented with EGM-2V singlequots (Lonza cat#3202). The day of the assay, the cells (passage 2-7) were trypsinized, washed in D-PBS and resuspended at 1E5 cells/mL in assay media (M199, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 10 mM HEPES and 10% FBS). Cells were plated at 5,000 cells/well (50 μL) on 96-well gelatin coated plates (BD Biocoat cat#354689) and incubated at 37° C., 5% CO2. The anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant human VEGF165 (AP, PR-1350437) (5 ng/ml/1.3E-10 M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO2 for 72 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF165 induced proliferation. Data was analyzed and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.11: Generation of Naturally Derived Human VEGF-A and Reactivity to the Anti-VEGF Antibodies or Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Proteins
To identify molecules that could bind naturally derived human VEGF-A, a sandwich ELISA was performed. Native human VEGF-A was obtained from the supernatant of Y-79 cells (ATCC, cat#HTB-18) grown in the presence of dimethyloxalylglycine (Sigma-Aldrich, cat#D3695). The naturally derived material was quantified using the R&D Systems VEGF Duoset kit (cat#DY293B). 96-well Costar high binding plates (#3369) were coated with 13.3E-8 M antibodies, benchmark compounds or DVD-Ig in D-PBS, shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were blocked with Superblock blocking buffer (Thermo Scientific, cat#37535) followed by four washes with wash buffer (TBS, 0.05% Tween-20). The naturally derived human VEGF-A supernatant was serially diluted in assay diluent (1% Blocker BSA; Pierce, cat#37525) for final test concentrations of 2900 ng/mL-11.88 ng/mL. The dilutions were added to the plates (50 μL) and incubated for 2 hours at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Detection antibody from the R&D Systems Duoset kit (Part 840163, cat#DY293B) was diluted in assay diluent and added to plates (50 μL) for 2 hours at 25° C. with shaking. Plates were then washed four times with wash buffer. The streptavidin-HRP from the R&D Systems Duoset kit (Part 890803, cat#DY293B) was diluted in assay diluent and added to plates (50 μL) for 35 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in optical density indicates binding of the test molecule to the naturally derived human VEGF-A. Data was analyzed using Softmax Pro 4.8 software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.12: PDGF-BB Binding Activity Determined by Capture ELISA
To identify molecules that could bind hPDGF-BB, a direct binding ELISA was performed. 96-well high binding neutravidin plates (Thermo Scientific cat#15507) were coated with 0.5 μg/mL/1.99E-8 M recombinant human PDGF-BB-biotin (CST cat#8912BF; labeled at AbbVie, 50 μL/well in D-PBS), shaken for 2 hours at 25° C. During the coating step, supernatants, benchmark compounds or DVD-Ig were diluted in 10% Superblock (Thermo Scientific, cat#37525) and an eight point titration of each sample molecule was performed. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20). The sample molecule titration was added to the coated plate at 50 μL in duplicate and incubated for one hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The appropriate anti-species-IgG HRP conjugate was in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for one hour at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in optical density indicates binding of the test molecule to biotinylated recombinant human PDGF-BB. Data was analyzed using Softmax Pro 4.8 software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.13: PDGF-BB Blocking Activity Determined by Inhibition of PDGF-Rβ Interaction with Human PDGF-BB
To identify molecules that could block the binding of hPDGF-BB to the hPDGF-Rβ, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.98E-9 M recombinant human PDGF-Rβ-Fc (R&D Systems #385-PR, 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatants, antibodies, benchmark compounds or DVD-Ig were diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and an eight point titration of each sample molecule was performed. The recombinant human PDGF-BB-biotin (CST cat#8912BF; labeled at AbbVie) was diluted in assay diluent at 20 ng/mL. The sample molecule titration was added to the human PDGF-BB-biotin (10 ng/mL/3.97E-10 M final concentration) and pre-incubated for 45 minutes at 25° C. with shaking. The pre-incubated sample/PDGF-BB complex was added to the coated plate at 50 μL in duplicate and incubated for 35 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Detection reagent Streptavidin-polyHRP-40 (Fitzgerald, cat#65r-s104phrp) was diluted in assay diluent and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the hPDGF-BB binding to the human PDGF-Rβ-Fc. Data was analyzed using Softmax Pro 4.8 software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.14: PDGF-BB Blocking Activity Determined by PDGFRβ (Tyr751) Phosphorylation
To test candidate molecules for the ability to neutralize hPDGF-BB activity, a cell based PDGF-Rβ phosphorylation assay was performed. Balb-3T3 cells (ATCC cat# CCL-163) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, and 10% FCS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 20 hours at 37° C., 5% CO2. Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO2. The following day, the MSD anti-PDGF-Rβ phospho-assay plate (Mesoscale PDGF-Rβ-Tyr751 phospho-MSD kit cat# K150DVD-2) was blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, anti-PDGF-BB supernatants, monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in growth media and pre-incubated with recombinant human PDGF-BB (CST, cat#8912BF) (20 ng/ml/7.94E-10 M final concentration) and rat PDGF-BB (R&D Systems,cat#520-BB) (70 ng/ml/1.4E-9 M final concentration) for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO2. Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. On ice, ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL). Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr751-IgG-sulfotag reagent was diluted in detection solution (K150DVD-2 components) and 25 μl added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K150DVD-2 component) added to wells and plates read on MSD Sector Imager 6000. A decrease in observed reporter signal indicates the test molecule is neutralizing the hPDGF-BB mediated activation. Data was analyzed using Graphpad Prism software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.15: PDGF-BB Blocking Activity Determined by Inhibition of Human PDGF-BB Stimulated NIH-3T3 Cell Proliferation/Survival
To screen candidate molecules for the ability to neutralize hPDGF-BB activity, a cell based proliferation assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO2. During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant human PDGF-BB (CST, cat#8912BF) (1.67 ng/ml/6.63E-11 M final concentration) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO2 for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hPDGF-BB induced proliferation. Data was analyzed and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.16: PDGF-BB Blocking Activity Determined by Inhibition of Cynomolgus PDGF-BB Stimulated NIH-3T3 Cell Proliferation/Survival
To screen candidate molecules for the ability to neutralize cynomolgus PDGF-BB activity, a cell based proliferation assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO2. During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant cynomolgus PDGF-BB (AP, PR-1575400) (4 ng/ml/1.61E-10 M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO2 for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the cynoPDGF-BB induced proliferation. Data was analyzed and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.17: PDGF-BB Blocking Activity Determined by Inhibition of Murine PDGF-BB Stimulated NIH-3T3 Cell Proliferation/Survival
To test candidate molecules for the ability to neutralize mouse PDGF-BB activity, a cell based assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO2. During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant murine PDGF-BB (Abnova, cat#0309-200-58-S) (2 ng/ml/8.13E-11 M final concentration) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO2 for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the murine PDGF-BB induced proliferation. Data was analyzed and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.18: PDGF-BB Blocking Activity Determined by Inhibition of Rat PDGF-BB Stimulated NIH-3T3 Cell Proliferation/Survival
To test candidate molecules for the ability to neutralize rat PDGF-BB activity, a cell based assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO2. During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant rat PDGF-BB (R&D Systems,cat#520-BB) (2 ng/ml/8.0E-11 M final concentration) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO2 for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the rat PDGF-BB induced proliferation. Data was analyzed and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.19: Generation of Naturally Derived Human PDGF-BB and Reactivity to the Anti-PDGF-BB Antibodies or Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Proteins
The native form of human PDGF was purified from platelets by a modified protocol from Antoniades et al. (Antoniades et al. (1979) Proc. Natl. Acad. Sci. USA 76(4): 1809-1813. In the modified protocol, ten units of platelets (Bioreclamation Inc.) were thawed, washed with 12 ml of Platelet Wash Buffer (HBSS—Gibco #14175/0.3% BSA/10 mM EDTA) and centrifuged. The platelets were then suspended in 25 ml of Buffer A (20 mM NaHPO4, pH 7.4, 80 mM NaCl in a 50 ml tube). From here the platelet wash (50 ml tube) and the suspended platelets were worked up in parallel using the same protocol.
Both the suspended platelets and platelets wash tubes were placed into a boiling water bath for 10 minutes, after which the contents of the tubes were cooled on ice. The supernatant was separated from the pellet by centrifugation. The supernatant was placed aside at 4° C. and the pellet was extracted with 30 ml Buffer B (20 mM NaHPO4, pH 7.4, 1M NaCl) by stirring overnight at 4° C. The supernatant was separated from the pellet by centrifugation. The supernatant was placed aside (4° C.) and the pellet was extracted with 30 ml Buffer B by stirring overnight at 4° C. This was repeated two more times. All the supernatants were then dialyzed separately against Buffer A. After removal from dialysis, they were all analyzed for protein content and PDGF-BB (ELISA) (See Table 6).







TABLE 6







Native PDGF Extraction from Human Platelets
















Total






Volume
PDGF-BB
PDGF-BB
Protein
Total Protein
ng PDGF-BB


Sample
(ml)
(ng/mL)
(ng)
(mg/mL)
(mg)
per mg Protein
















Boiled platelet








Supernatant
50
4.52
226.18
0.63
31.50
7.18


Pellet


Extraction 1
35
8.77
306.95
0.31
10.85
28.29


Extraction 2
35
3.79
132.76
0.25
8.58
15.48


Extraction 3
35
1.26
44.03
0.10
3.43
12.83


Extraction 4
37
1.53
56.65
0.19
7.03
8.05


Platelet Wash


Boiled


Supernatant
27
7.49
202.12
0.64
17.28
11.70


Extracted Pellet
37
10.89
402.75
0.90
33.15
12.15


Total
256
5.36
1371.32
0.44
111.82
12.26
















TABLE 7







Native PDGF Purification from Human Platelets


















Specific






Total

Activity



PDGF-

PDGF-
Total
ng
Endotoxin Levels















Platelet
BB
Volume
BB
Protein
PDGF/mg

EU/mg



Purification
(ng/mL)
(mL)
(ng)
(mg)
Protein
EU/ml
protein
EU/μg PDGF


















Eluate 1
214.94
6.74
1449
0.443
3266.49
2.36
35.87
10.98


Flow
1.17
500
585
110.5
5.29


Thru 1









Due to low specific activity (ng PDGF-BB per mg protein), the supernatants were subjected to further purification by CM sepharose. The supernatants were applied (with washing Buffer A) to a 20 ml CM sepharose column (GE Healthcare cat#17-0719-01) and the PDGF was eluted with Buffer B. Subsequently the eluted protein was dialyzed against Buffer A. From here the protein that was eluted and subsequently dialyzed as well as the flow through were all analyzed for protein content and PDGF-BB (ELISA). At this point the specific activity (eluate 1) was high enough to be queried in the assay.
To identify molecules that could bind naturally derived human PDGF-BB, a sandwich ELISA was performed. The native human PDGF-BB was isolated and purified from human platelets (AbbVie, PR-1566692). This material was quantified using the R&D Systems PDGF-BB Duoset kit (cat#DY220). 96-well Costar high binding plates (#3369) were coated with 13.3E-8 M antibodies, benchmark compounds or DVD-Ig in D-PBS, shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were blocked with Superblock blocking buffer (Thermo Scientific, cat#37535) followed by four washes with wash buffer (TBS, 0.05% Tween-20). The native human PDGF-BB was serially diluted in assay diluent (1% Blocker BSA; Pierce, cat#37525) for final test concentrations of 2000 ng/mL-2.74 ng/mL (5.4E-8 M-7.5E-11 M). The dilutions were added to the plates (50 μL) and incubated for 2 hours at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Detection antibody from the R&D Systems Duoset kit (Part 840926, cat#DY220) was diluted in assay diluent and added to plates (50 μL) for 2 hours at 25° C. with shaking. Plates were then washed four times with wash buffer. The streptavidin-HRP from the R&D Systems Duoset kit (Part 890803, cat#DY220) was diluted in assay diluent and added to plates (50 μL) for 35 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in optical density indicates binding of the test molecule to the naturally derived human PDGF-BB. Data was analyzed using Softmax Pro 4.8 software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.20: hVEGF-A Neutralization Potency of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Proteins when Pre-Incubated with hPDGF-BB
To test candidate molecules for the ability to neutralize hVEGF-A activity in the presence of hPDGF-BB, a cell based VEGF-R2 (KDR/Flk-1) phosphorylation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, 400 μg/mL geneticin and 10% FBS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 6 hours at 37° C., 5% CO2 Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO2. The following day, the MSD anti-VEGFR2-phospho assay plate (Mesoscale VEGFR2-Tyr1054 phospho-MSD kit, cat#K151DJD-2) was blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in growth media and pre-incubated with recombinant human PDGF-BB (CST cat#8912BF) (0.992 μg/ml/3.94E-8 M final concentration) for 30 minutes at 25° C. with shaking. Following the first pre-incubation step, recombinant human VEGF165 (AP, PR-1350437) was added to the samples for a final concentration of human VEGF165 of 50 ng/ml/1.3E-9 M and of hPDGF-BB of 0.496 μg/ml/1.97E-8 M final concentration for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO2. Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. Ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL) on ice. Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr1054-IgG-sulfotag reagent was diluted in detection solution (K151DJD-2 components) and 25 L added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K151DJD-2 component) added to wells and plates read on MSD Sector Imager 6000. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF165 mediated activation in the presence of hPDGF-BB. Data was analyzed using Graphpad Prism software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.21: PDGF Neutralization Potency of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Proteins when Pre-Incubated with VEGF
To test candidate molecules for the ability to neutralize hPDGF-BB activity in the presence of hVEGF-A, a cell based proliferation assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO2. During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media containing hVEGF165 (4 μg/mL/104.2 nM). The samples were pre-incubated with recombinant human PDGF-BB in assay media (CST, cat#8912BF) (3.34 ng/ml/1.33E-10 M final concentration in well) for 1 hour at 25° C. with gentle shaking. The final concentrations of ligand in assay wells were hVEGF165 2.6E-8 M and hPDGF-BB 6.63E-11 M. The pre-incubated samples were added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO2 for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hPDGF-BB induced proliferation in the presence of hVEGF165. Data was analyzed and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.22: Human VEGF-R2 Binding Activity of the Anti-VEGF-R2 Antibodies
To identify molecules which could bind VEGF-R2 (KDR/Flk-1), a direct binding ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.27E-9 M recombinant human VEGF-R2-Fc (R&D Systems cat#357-KD), 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatant, antibodies or benchmark compounds were diluted in 1% Blocker BSA (Thermo Scientific cat#37525) and an eight point titration of each sample molecule was performed. The samples were added to wells and incubated for one hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The appropriate anti-species-IgG HRP conjugate was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for forty-five minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in observed optical density indicates the test molecule is binding the human VEGF-R2-Fc. Data was analyzed using Softmax Pro 4.8 software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.23: Human VEGF-R2 Blocking Activity of the Anti-VEGF-R2 Antibodies as Determined by Inhibition of Human VEGF-R2 Interaction with Human VEGF165 
To identify molecules which could block the binding of VEGF-R2 (KDR/Flk-1) to hVEGF165, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.27E-9 M recombinant human VEGF-R2-Fc (R&D Systems cat#357-KD), 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatant, antibodies or benchmark compounds were diluted in 1% Blocker BSA (Thermo Scientific cat#37525) and an eight point titration of each sample molecule was performed. The samples were added to wells and incubated for 30 minutes at 25° C. with shaking. The biotinylated human VEGF165 (AP, PR-1361002) was diluted in 1% BSA at 35 ng/mL. This was added to wells (17.5 ng/mL/4.56E-10 M final concentration) and incubation was continued for 30 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Streptavidin-polyHRP-40 (Fitzgerald cat#65r-s104phrp) was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the human VEGF-R2-Fc binding to hVEGF165. Data was analyzed using Softmax Pro 4.8 software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.24: VEGF-A Blocking Activity of the Anti-VEGF-R2 Antibodies as Determined by VEGFR2 (Tyr1054) Phosphorylation
To test candidate molecules for the ability to neutralize hVEGF-R2 activity, a cell based VEGF-R2 (KDR/Flk-1) phosphorylation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, 400 μg/mL geneticin and 10% FBS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 6 hours at 37° C., 5% CO2. Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO2. The following day, the MSD anti-VEGR2-phospho assay plate (Mesoscale VEGFR2-Tyr1054 phospho-MSD #kit cat K151DJD-2) was blocked with MSD Blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, anti-VEGF-R2 supernatant, monoclonal antibodies and benchmark compounds were serially diluted in growth media and pre-incubated with recombinant human VEGFR2-Fc (R&D Systems, cat#357-KD) (500 ng/ml/2.27E-9 M final concentration) for 30 minutes at 25° C. with shaking. Recombinant human VEGF165 (AP, PR-1350437) (50 ng/ml/1.3E-9 M final concentration) was added to the wells and incubation was continued for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO2. Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. Ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL) on ice. Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr1054-IgG-sulfotag reagent was diluted in detection solution (K151DJD-2 components) and 25 μL added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K151DJD-2 component) added to wells and plates read on MSD Sector Imager 6000. An increase in observed signal indicates the test molecule is neutralizing the exogeneous hVEGFR2 and allowing for hVEGF165 mediated activation. Data was analyzed using Graphpad Prism software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.25: Mouse VEGF-R2 Blocking Activity of the Anti-VEGF-R2
Antibodies as Determined by Inhibition of Mouse VEGF-R2 Interaction with Mouse VEGF164 
To identify molecules which could block the binding of mVEGF164 to the mVEGF-R2, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 1 μg/mL/4.55E-9 M recombinant mouse VEGF-R2-Fc (R&D Systems cat#443-KD)(50 μL/well in D-PBS) shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were washed four times with wash buffer (TBS, 0.05% Tween-20). Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, hybridoma supernatants and rat IgG were diluted in 1% Blocker BSA (Thermo Scientific cat#37525). The sample was added to the plates (50 μL) and incubated for 45 minutes at 25° C. with shaking. The mouse VEGF164 (R&D Systems cat#493-MV-005) was diluted in 1% Blocker BSA to 20 ng/mL and added to wells for a final concentration of 10 ng/mL/5.15E-10 M final concentration. Incubation was continued for 30 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The detection reagent biotinylated goat anti-mVEGF164 (R&D Systems cat#BAF-493) was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates for 1 hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Streptavidin-polyHRP-40 (Fitzgerald cat#65r-s104phrp) was diluted in assay diluent and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the mouse VEGF-R2-Fc binding to the mVEGF164. Data was analyzed using Softmax Pro 4.8 software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.26: PDGF-Rβ Binding Activity of the Anti-PDGF-Rβ Antibodies
To identify molecules which bind hPDGF-Rβ, a direct ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.98E-9 M recombinant human PDGF-Rβ-Fc (R&D Systems #385-PR, 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatants, antibodies and benchmark compounds were diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and an eight point titration of each sample molecule was performed. The samples were added to wells and incubated for one hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The appropriate anti-species-IgG HRP conjugate was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for forty-five minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in observed optical density indicates the test molecule is binding the human PDGF-Rβ-Fc. Data was analyzed using Softmax Pro 4.8 software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.27: PDGF-Rβ Blocking Activity of the Anti-PDGF-Rβ Antibodies as Determined by Inhibition of PDGF-Rβ Interaction with Human PDGF-BB
To identify molecules which could block the binding of hPDGF-Rβ to hPDGF-BB, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.98E-9 M recombinant human PDGF-Rβ-Fc (R&D Systems #385-PR, 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatants, antibodies and benchmark compounds were diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and an eight point titration of each sample molecule was performed. The samples were added to wells and incubated for 30 minutes at 25° C. with shaking. The recombinant human PDGF-BB-biotin (CST cat#8912BF; labeled at ABC) was diluted in assay diluent at 20 ng/mL. This was added to wells (10 ng/mL/3.97E-10 M final concentration) and incubation was continued for 35 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Detection reagent Streptavidin-polyHRP-40 (Fitzgerald, cat#65r-s104phrp) was diluted in assay diluent and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the human PDGF-Rβ-Fc binding to hPDGF-BB. Data was analyzed using Softmax Pro 4.8 software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.28: PDGF-Rβ Blocking Activity of the Anti-PDGF-Rβ Antibodies as Determined by PDGFRβ (Tyr751) Phosphorylation
To test candidate molecules for the ability to neutralize hPDGF-Rβ activity, a cell based PDGF-Rβ phosphorylation assay was performed. Balb-3T3 cells (ATCC cat# CCL-163) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, and 10% FCS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 20 hours at 37° C., 5% CO2. Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO2. The following day, the MSD anti-PDGFRβ-phospho-assay plate (Mesoscale PDGF-Rβ-Tyr751 phospho-MSD kit cat# K150DVD-2) was blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, supernatants, antibodies or benchmark compounds were serially diluted in growth media and pre-incubated with 500 ng/mL/2.98E-9 M hPDGF-Rβ (R&D System, cat 385-PR) for 30 minutes at 25° C. Recombinant human PDGF-BB (CST, cat#8912BF) (20 ng/ml/7.94E-10 nM final concentration) was added to the wells and incubation was continued for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO2. Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. Ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL) on ice. Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr751-IgG-sulfotag reagent was diluted in detection solution (K150DVD—2 components) and 25 μL added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K150DVD-2 components) added to wells and plates read on MSD Sector Imager 6000. An increase in observed signal indicates the test molecule is neutralizing the exogeneous hPDGF-Rβ and allowing for hPDGF-BB mediated activation. Data was analyzed using Graphpad Prism software and IC50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.29: Reactivity of Anti-PDGF-BB Antibodies and Anti-VEGF-A/anti-PDGF-BB DVD-Ig Molecules to ECM-associated PDGF-BB
Both recombinant cell line HEK293 cells over-expressing PDGFBB-RM and HUVEC naturally expressing ECM-associated PDGF-BB cells were used for staining.
HEK293 Cell Staining:
PDGFB-RM transient transfected HEK 293 cells and parental HEK293 cells were re-suspended at 1E6 cells/mL in PBS and fixed in 4% paraformaldehyde at RT for 10 minutes, washed with PBS and 2E5 cells/tube were incubated in blocking buffer (10% goat serum in PBS) for one hour on ice. Cells were washed with PBS and incubated with primary antibodies or DVD-Ig molecules at 33 nM in antibody dilution buffer (5% goat serum in PBS) for one hour on ice. Cells were washed three times with PBS and incubated with Alexa Fluo 488 conjugated Goat anti-Human IgG (Jackson Immune, code: 109-546-098; lot: 108427) 1:400 dilution in antibody dilution buffer, incubated on ice for 45 minutes, cells were washed three times with PBS and cytospin onto glass slides and mounted with mounting media with DAPI. Pictures were taken by fluorescent microscopy.
HUVEC Staining:
The anti-VEGF/anti-PDGF DVD-Ig was further assessed for its staining on naturally derived ECM-associated PDGF-BB on HUVEC cells. HUVECs (Lonza, cat#: C2519A lot: 181607) were trypsinized, resuspended at 2E4 cells/mL in culture media (Lonza, EGM2 MV Bulletkit: CC-3202). Cells were plated at 10,000 cells/500 μl/well in 8-chamber glass slide and incubated for 16 hours at 37° C., 5% CO2. After incubation, cells were fixed with 200 μl 4% paraformaldehyde at RT for 10 minutes, washed with PBS and incubated in blocking buffer (10% goat serum in PBS) for one hour on ice. Cells were washed with PBS 3× and incubated with primary antibodies or DVD-Ig molecules at 33 nM in antibody dilution buffer (5% goat serum in PBS) for one hour on ice. Cells were washed three times with PBS and incubated with Alexa Fluo 488 conjugated Goat anti-Human IgG (JacksonImmune, code: 109-546-098; lot: 108427) 1:400 dilution in antibody dilution buffer, incubate on ice for 45 minutes, cells were washed three times with PBS and mounted with mounting media with DAPI. Pictures were taken by fluorescent microscopy.
A. Example 1.30: Inhibition of Sprouting in HUVEC/MSC Co-culture Sprouting Assay by Anti-VEGF-A/anti-PDGF-BB DVD-Ig Molecules
In early therapeutic treatment mode, Cytodex-3 beads (Sigma-Aldrich, cat# C3275) were coated with HUVEC cells (Lonza) overnight, and then embedded (100 beads/well) with human mesenchymal stem cells (Lonza, 20,000 cells/well) in fibrin gel in 24-well tissue culture plates. A 1:1 mixture of fresh EGM-2 complete media (Lonza) and fibroblast (Lonza) conditioned EGM-2 media were added on top of the fibrin gel along with 2 ng/mL of recombinant human HGF. Medium was replaced every 2-3 days till the end of the experiment. After EC sprouts and pericyte covering were formed usually on day 4, anti-VEGF-A (4G8.4), anti-PDGFBB (9E8.) or anti-PDGFBB/VEGF-A DVD-Ig, were added to the culture medium at 10 nM starting. 10 days later cells were fixed in 4% PFA overnight at 4° C. Endothelial cells were stained with anti-PECAM (Abcam, ab32457), followed by fluorescence-conjugated secondary antibody, and pericytes were labeled with anti-aSMA-Cy3 (Sigma, C6198). Cells were then viewed by an inverted fluorescence microscope and 5× images were captured (FIGS. 2 and 3).
Example 2: Analytical Methods and Techniques for Physicochemical Property Characterizations of DVD-Ig Proteins
Example 2.1: Size Exclusion Chromatography Technique
Size exclusion chromatography (SEC) is used to separate proteins based on size. Proteins are carried in an aqueous mobile phase and through a porous stationary phase resin packed in a column. The retention time in the column is a function of the hydrodynamic size of the protein and the size of the pores in the packed resin bed. Smaller molecules can penetrate into smaller pores in the resin and are retained longer than larger molecules. Samples at 1 mg/ml, or diluted with formulation buffer to this concentration, are injected onto the SEC column at a volume of 10 μl. Upon elution from the column, the proteins are detected by UV absorbance. The SEC method uses a TSK gel guard (TOSOH Biosciences, Montgomeryville, Pa., cat. no. 08543) and a TSK gel G3000SWxL (TOSOH Biosciences, Montgomeryville, Pa., cat. no. 08541). The mobile phase was 100 mM Na2HPO4, 100 mM Na2SO4, pH 6.8. The flow rate is 0.25 ml/minute. The column temperature is room temperature. The autosampler temperature is 2-8° C. The total run time is 55 minutes. The detection is based on UV absorbance at 214 nm wavelength, with band width set at 8 nm, using reference wavelength at 360 nm with band width 100 nm. The resulting chromatogram is analysed for the distribution of different size species (aggregate, monomer, and fragment) by the percentage of the total area of the signal.
Example 2.2: Differential Scanning Calorimetry Technique
The thermal stability of the protein samples was assessed using a differential scanning calorimetry (DSC) instrument. The DSC instrument used was an automated VP-DSC equipment with Capillary Cell (Microcal, GE Healthcare Ltd./Microcal, Buckinghamshire, UK). Unfolding of molecules was studied applying a 1° C./minute scan rate over a 25° C.-95° C. temperature range for samples at 1 mg/mL. Additional measurement parameters applied were a fitting period of 16 seconds, a pre-scan wait time of 10 minutes, and measurements were performed in none-feedback mode. For each measurement, 420 μL of sample or blank buffer was filled into the designated receptacle within the DSC instrument. The thermograms obtained (heat capacity versus temperature) were fitted to a non-two state model to obtain the midpoint temperatures and enthalpies of the different transitions.
Example 2.3: Sample Preparation
The antibodies and DVD-Ig molecules were initially obtained as a solution and diluted below 10 mg/ml with the formulation buffer. Each sample was then inserted into a separate dialysis cartridge (Slide-a-lyzer cassette, 10,000 MWCO, 3-12 mL capacity, Thermo Scientific, USA, Cat. No. 66810) and dialyzed against 2 L of the formulation buffer with continuous stirring via a magnetic stir bar for 18-24 hours. The samples were then retrieved from the cartridge and briefly spun down in a centrifuge and/or passed through 0.45 μm PVDF filters to remove any precipitation or particles. This was followed by up-concentration of the DVD-Ig solutions with centrifuge spin filters (Amicon Ultra 30,000 MWCO Regenerated Cellulose) to reach the desired protein concentration which was confirmed by UV measurements at 280 nm. If the solutions were above the desired concentration, they were diluted to that concentration with the formulation buffer.
Example 2.4: Storage Stability Analysis Method
The antibodies and DVD-Ig molecule solutions prepared according to Example 2.3 were analyzed for their physical stability during storage at 40° C., 25° C., and/or 5° C. Both 25° C. (room temperature) and 5° C. (storage temperature) are typical temperatures at which the samples would be subjected either during preparation and storage for manufacture or as part of the final drug product presentation. Storage at 40° C. is considered an accelerated stability condition which provides an indication of long-term stability prospects. The samples were aliquoted into low volume containers (<0.1 ml), tightly sealed, and placed at the designated temperatures (sometimes in a water bath). The samples were then pulled at periodic intervals and a small portion was removed for analysis by SEC (Example 2.1).
Example 2.5: Freeze-Thaw Analysis Method
The antibody and DVD-Ig molecule solutions prepared according to Example 2.3 were analyzed for their physical stability during freeze/thaw stress. Samples were aliquoted into low volume containers (<1 ml) and tightly sealed. The samples were then placed at −80° C. for at least 6 hours and then thawed at 30° C. in a water bath. This was repeated three more times. After the second and fourth thaws, a small portion of each sample was removed for analysis by SEC (Example 2.1).
DVD-Ig solutions are typically frozen at −80° C. for long term storage as well as shipping to remote manufacturing sites. The samples are then thawed in order to complete the drug product manufacturing process. Stability due to freeze-thawing was assessed at low concentration in order to evaluate greater exposure of protein molecules to the denaturing ice-water interfaces. At higher concentrations, proportionally less protein encounters the ice-water interface, instead interacting with other protein molecules.
Example 2.6: Viscosity Determination Method
The antibody and DVD-Ig molecule solutions prepared according to Example 2.3 were analyzed for their viscosity at room temperature ( ̃23° C.) with a Malvern Viscosizer 200 instrument. The viscosity serves as an indication of the ease of delivery of the sample through a small diameter needle attached to a syringe, a likely drug product presentation. A higher viscosity requires a greater force for delivery, and vice-versa.
Example 2.7: Intact and Reduced Molecular Weight Determination
The intact molecular weights of the three samples shown in Table 8 were acquired. Each sample was diluted to 1 mg/mL with Milli-Q water. 1.0 μL of the 1 mg/mL sample was injected onto an Agilent 6510 Q-Tof LC/MS system with a C4 MicroTrap column. Table 9 shows the HPLC gradient for intact molecular weight analysis. Buffer A was 0.02% TFA, 0.08% FA in water. Buffer B was 0.02% TFA, 0.08% FA in acetonitrile. The flow rate was 50 μL/minute. The column temperature was set at 60° C. The mass spectrometer was operated at 5 kvolts spray voltage and the scan range was from 600 to 3200 mass to charge ratio. The deglycosylated intact molecular weights of all three samples were measured by Agilent 6510 Q-Tof LC/MS system after the samples were deglycosylated. 100 μL of 1 mg/mL sample was mixed with 5 μL of 10% N-octylglucoside and 2 μL of PNGase F enzyme. The sample was incubated at 37° C. for 18 hours. 1.0 μg of the deglycosylated sample was injected onto an Agilent 6510 Q-Tof LC/MS system with a C4 MicroTrap for deglycosylated intact molecular weight analysis.
The reduced molecular weights of all three samples were obtained. Each sample was diluted to 1 mg/mL with Milli-Q water. 1.0 μL of 1M DTT was added to 100 μL of a 1 mg/mL sample and incubated at 37° C. for 30 minutes. 2.0 μL of the reduced sample was injected onto an Agilent 6510 Q-Tof LC/MS system with a diphenyl column. The HPLC gradient for reduced molecular weight analysis is shown in Table 9. The mass spectrometer was operated at 5 kvolts spray voltage and the scan range was from 600 to 3200 mass to charge ratio.







TABLE 8







VEGF/PDGF DVD-Ig Formulations














Concentration



Sample ID
Lot
Detailed name
(mg/mL)
Formulation














PR-1572102
Lot 2211502
hu VEGF 4G8.3-GS-hu PDGF
6.5
30 mM histidine,




9E8.4 (germline) [hu IgG1/k]

8% sucrose pH




LALA H435A

5.2


PR-1572105
Lot 2211597
hu VEGF 4G8.3-SL-hu PDGF
1.5
30 mM Histidine,




9E8.4 (germline) [hu IgG1/k]

8% Sucrose pH




LALA H435A

5.2


PR-1610561
Lot 2213329
hu VEGF 9E10.1-GS-hu PDGF
5
30 mM Histidine,




33675 [hu IgG1/k] LALA H435A

8% sucrose, pH






5.2
















TABLE 9







PLC Operating Conditions For Intact And Reduced Molecular Weight










Intact/C4

Reduced/Diphenyl











Time (min)
% Buffer B
Time (min)
% Buffer B













0
5
0
5


5
5
5
30


5.5
95
30
40


10
95
32
90


10.5
5
37
90


15
5
39
5




44
5









Example 2.8: Oligosaccharide Profiles Determined by Fc Molecular Weight Measurement
Samples were partially digested with Lys-C enzyme, reduced and analyzed by LC/MS. Different oligosaccharide species were quantitated based on the peak intensity detected by mass spectrometry and the relative percentage of different oligosaccharide species was reported. Samples were diluted to 1 mg/mL with Milli-Q water. 100 μL of each sample was mixed with 2 μL of 0.005 mg/mL Lys-C enzyme and incubated at 37° C. for 30 minutes. 1 μL of 1 M DTT was added and incubated at 37° C. for 30 minutes for reduction. 2 μL of sample was injected onto an Agilent 6510 Q-Tof LC/MS system with a diphenyl column and a reduced HPLC gradient was used. The column temperature was set at 60° C. The mass spectrometer was operated at 5 kvolts spray voltage and the scan range was from 600 to 3200 mass to charge ratio.
Example 2.9: Charge Heterogeneity by Weak Cation Exchange Chromatography and Imaged Isoelectric Focusing (icIEF)
Charge heterogeneity was studied using a Propac WCX-10 column for weak cation exchange chromatography analysis. Mobile phase A was 20 mM MES, pH 5.5. Mobile phase B was 20 mM MES, 500 mM NaCl, pH 5.5. Each sample was diluted to 1 mg/mL in mobile phase A. 50 μg of each sample was loaded, and the HPLC gradient is shown in Table 10. The flow rate was 1 mL/minute flow rate and the UV detector was monitored at 280 nm.







TABLE 10







Gradient Used For Weak Cation Exchange Chromatography










Time (minutes)
Mobile phase B














0
20



5
20



25
40



27
100



32
100



34
20



38
20










Imaged isoelectric focusing was performed on an iCE instrument from ProteinSimple. All three samples were diluted to 1 mg/mL with Milli-Q water before mixing with amphalyte and other components as shown in Table 11. Each sample was vortexed briefly and centrifuged for 5 minutes at 10 k RPM before being transferred to glass inserts for analysis. Each sample was pre-focused at 1500 V for 1 minute and focused at 3000 V for 8 minutes.







TABLE 11







Sample Preparation for icIEF










Component
Volume (μL)














1% Methyl cellulose
70



Pharmalyte 3-10
4



Pharmalyte 5-8
4



Diluted pI 5.1 marker
8



Diluted pI 8.2 marker
8



1 mg/mL test sample
50



Water
6



8M Urea
50










Example 3: Generation of Rat Anti-VEGF-A, Anti-VEGFRII, Rat-Anti-PDGF-BB, Anti-PDGFR-B Monoclonal Antibodies by DNA Immunization and Rat Hybridoma Technology
Example 3.1: DNA Immunization, Hybridoma Fusion and Screening
Genetic immunization enables the development of antibodies against any protein target directly from a cDNA. A cDNA encoding the soluble human VEGFA-165, soluble human PDGF-BB, human VEGFR-II ECD (extracellular domain) or human PDGFR-BB ECD was cloned into a eukaryotic expression vector (Aldevron GmbH, Freiburg, Germany). Wistar rats were immunized by intradermal application of DNA-coated gold-particles using a hand-held device for particle-bombardment (“gene gun”). Antibody-producing splenocytes or lymph node cells were isolated and fused with fusion partner myeloma cells using polyethylene glycol (PEG) according to standard procedures. To help identify positive antisera and hybridomas, screening is done with the use of either cells transfected with screening vector encoding GPI anchored human VEGF-A165, human PDGF-BB, human VEGFR-II ECD or human PDGFR-BB ECD proteins, soluble recombinant human VEGF-A165 and human PDGF-BB protein or peptides. The tables below are the lists of antibodies generated using the rat DNA immunization approach.
Anti-VEGF-A antibodies derived from rat hybridomas were characterized for binding, function and cross-reactivity in a panel of assays. Supernatants were tested for the ability to bind hVEGF165 (Example 1.3) and block binding of hVEGF165 to hVEGFR2 in a competition ELISA format (Example 1.4). Select hybridomas were assessed for cross-reactivity by testing for the ability to block human VEGF111 and rabbit VEGF165 in a Tyr1054 phosphorylation assay (Example 1.6) and blocking of murine VEGF164 binding to mVEGFR2 (Example 1.5). Candidate rat IgG was then examined for potency in the hVEGF165-induced cell proliferation assay (Example 1.7), reactivity to native hVEGF165 (Example 1.11) and binding affinity measurement by Biacore analysis (Example 1.1). The data is summarized in Tables 12 and 13 below.







TABLE 12







A List of Anti-VEGF-A Antibodies Generated Using DNA Immunization and Rat


Hybridoma Technology
























huVEGF-











Receptor
A165








Competition
Neutralization






Phospho-
ELISA
ELISA
Potency in
ELISA
ELISA
Phospho-




ELISA
ELISA
Tyr1054/
Binding to
huVEGF-
hVEGF-
Mouse
Rat
Tyr1054/




huVEGF-
huVEGF-
huVEGF-
Naturally
A165/
R2 Over-
VEGF-
VEGF-
Rabbit


Hybridoma

A 165
A121
A111
Derived
huVEGF-
expressing
A164
A164
VEGF-A165


Clones
Isotype
Binding
Binding
Neutralization
huVEGF-A
R2 (nM)
Cells (nM)
Binding
Binding
Neutralization




















BEW-
IgG2b/κ
+
NT
+
+
0.18
0.09
−
NT
+


164-


C4


BEW-
IgG2b/κ
+
NT
+
+
0.62
0.39
−
NT
+


1E3-


D6


BEW-
IgG2b/κ
+
NT
+
+
0.156
0.88
−
NT
+


5C3-


E7


BEW-
IgG2b/κ
+
NT
+
+
0.197
<0.1
−
NT
+


6C2-


C8


BEW-
IgG2a/κ
+
NT
+
+
0.342
0.41
−
NT
+


8E6-


E4


BEW-
IgG2a/κ
+
NT
+
+
0.249
0.16
−
NT
+


9A8-


E2


BEW-
IgG2a/κ
+
NT
+
+
0.274
0.17
−
NT
+


9E10-


E7


BEW-
IgG2b/κ
+
NT
+
+
0.42
0.42
−
NT
+


10H2-


B9


BEW-
IgG2a/κ
+
NT
+
+
0.124
<0.1
−
NT
+


9E3--


B9


BEW-
IgG2b/κ
+
NT
+
+
0.207
0.14
−
NT
+


9E7-


B4


BEW-
IgG1/κ
+
NT
+
+
0.584
1.46
−
NT
+


1G1-


C2


BEW-
IgG2b/κ
+
NT
+
+
0.155
<0.1
−
NT
+


9C2-


D6


BEW-
IgG2a/κ
+
NT
+
+
0.127
0.09
−
NT
+


9D2-


E8


BEW-
IgG2a/κ
+
NT
+
+
0.326
2.8
−
NT
+


1B10-


B9-C3


BEW-
IgG2b/κ
+
NT
+
+
0.124
0.96
−
NT
+


3A1-


D10-


G9


BED-
IgG2b/κ
+
NT
+
+
0.13
0.38
−
NT
+


4G10-


C8


BDB-
IgG2b/κ
+
NT
+
+
0.13
0.617
−
NT
+


4G8-


D4





NT = not tested













TABLE 13







Biacore Binding of Rat Anti-VEGF Antibodies










Antibody
kon (M−1 s−1)
koff (M−1)
KD (M)













BDB-4G8-D4
≧1.0E+07
8.1E−06
≦8.1E−13


BDB-4G8-D4
1.4E+07
1.6E−05
1.2E−12


BED-4G10-C8
1.8E+07
1.1E−03
6.0E−11


BEW-1B4-C4
1.8E+07
1.3E−04
7.4E−12


BEW-1B10-B9-C3
4.4E+06
7.2E−05
1.6E−11


BEW-1E3-D6
1.4E+07
1.4E−04
1.0E−11


BEW-1G1-C2
1.6E+07
3.0E−05
1.9E−12


BEW-3A1-D10-G9
1.0E+07
1.4E−03
1.4E−10


BEW-5C3-E7
1.2E+07
4.8E−05
3.9E−12


BEW-6C2-C8
6.9E+06
8.4E−05
1.2E−11


BEW-8E6-E4
6.9E+06
1.2E−04
1.7E−11


BEW-9A8-E2
7.4E+06
7.1E−06
9.6E−13


BEW-9C2-D6
5.5E+06
≦1.0E−06
≦1.8E−13


BEW-9D2-E8
7.0E+06
9.8E−05
1.4E−11


BEW-9E10-E7
1.3E+07
3.9E−05
3.1E−12


BEW-9E3-B9
6.7E+06
9.5E−05
1.4E−11


BEW-9E7-B4
5.9E+06
2.5E−05
4.3E−12


BEW-10H2-B9
2.4E+07
2.7E−04
1.1E−11









Anti-PDGF-BB antibodies derived from rat hybridomas were characterized for binding, function and cross-reactivity in a panel of assays. Supernatants were tested for the ability to bind hPDGF-BB (Example 1.12) and block binding of hPDGF-BB to hPDGF-R in a competition ELISA format (Example 1.13). Select hybridomas were assessed for the ability to block human and rat PDGF-BB in a Tyr751 phosphorylation assay (Example 1.14). Candidate rat IgG was then examined for potency in the human, mouse and cynomolgus PDGF-BB-induced cell proliferation assay (Examples 1.15-1.17), reactivity to native hPDGF-BB (Example 1.19) and binding affinity measurement by Biacore analysis (Example 1.1). The data is summarized in Tables 14 and 15 below.







TABLE 14







A List of Anti-PDGF-BB Antibodies Generated using DNA Immunization and Rat


Hybridoma Technology



















ELISA
Receptor

huPDGF-

mPDGF-
cynoPDGF-





Binding
Competition

BB
Phospho-
BB
BB





to
ELISA
Phospho-
Neutralization
Tyr751/
Neutralization
Neutralization




ELISA
Naturally
huPDGF-
Tyr751/hPDGF-
Potency
ratPDGF-
Potency
Potency




huPDGF-
Derived
BB/
BB
(nM) in
BB
(nM) in
(nM) in


Hybridoma

BB
huPDGF-
huPDGF
Neutralization
NIH-3T3
Neutralization
NIH-3T3
NIH-3T3


Clones
Isotype
Binding
BB
Rβ (nM)
(nM)
Cells
(nM)
Cells
Cells



















BDI-
IgG2b/κ
+
+
1.121
0.629
0.195
0.333
0.026
0.194


9E8-E7


BDI-
IgG2b/κ
+
+
0.528
0.884
0.371
0.319
NT
NT


5H1-F6


BDI-
IgG2b
+
+
>10
>10
>5
>5
NT
NT


7H10-


D8


BDI-
IgG2b/κ
+
NT
>10
1.057
>5
+
NT
NT


1E1-D5


BDI-
IgG2b/λ
+
NT
1.065
0.923
0.741
+
NT
NT


5G2-F9


BDI-
IgG2b/λ
+
NT
3.228
1.618
>5
−
NT
NT


6A3-A9


BDI-
IgG2b
+
NT
>10
>10
>5
−
NT
NT


7F6-D3


BDI-
IgG2b/λ
+
NT
1.035
2.53
>5
−
NT
NT


10E7-


F9


BDI-
IgG2b/λ
+
NT
1.086
3.159
>5
−
NT
NT


8B8-F2


BFF-
IgG2b/κ
+
NT
>50
0.753
>5
NT
NT
NT


5C9-C7-


B5


BFF-
IgG2b/λ
+
NT
>50
1.745
>10
NT
NT
NT


7D7-D3-


E4


BFF-
IgG2b/κ
+
NT
>50
>10
>10
NT
NT
NT


7E9-C3-


B6


BFF-
IgG2b/λ
+
NT
>50
1.896
>10
NT
NT
NT


4G8-B4


BFF-
IgG2b/λ
+
NT
>50
0.739
>10
NT
NT
NT


4E8-E5


BFU-
IgG2b/κ
+
NT
>50
0.642
0.247
NT
NT
NT


3E2-B9-


B8


BFU-
IgG2b/κ
+
NT
7.095
0.736
0.344
NT
NT
NT


11A8-


D6-C3


BFU-
IgG2b
+
NT
2.287
0.639
>10
NT
NT
NT


3H6-D2
















TABLE 15







Biacore Binding of Rat Anti-PDGF Antibodies










Antibody
kon (M−1 s−1)
koff (M−1)
KD (M)













BDI-1E1-D5
≧1.0E+07
3.7E−04**
≦3.7E−11**


BDI-5G2-F9
≧1.0E+07
≦1.0E−06
≦1.0E−13


BDI-5H1-F6
≧1.0E+07
≦1.0E−06
≦1.0E−13


BDI-6A3-A9
≧1.0E+07
6.7E−03**
≦6.7E−10**


BDI-7F6-D3
≧1.0E+07
6.0E−03
≦6.0E−10


BDI-7H10-D8
≧1.0E+07
≦1.3E−02**
≦1.3E−09**


BDI-8B8-F2
≧1.0E+07*
≦1.0E−06*
≦1.0E−13*


BDI-9E8-E7
≧1.7E+07
≦1.0E−06
≦5.8E−14


BDI-9E8-E7
≧1.0E+07
≦1.0E−06
≦1.0E−13


BDI-10E7-F9
≧1.0E+07*
1.3E−04*
≦1.3E−11*


BFF-4E8-E5
≧1.0E+07
8.3E−03***
≦8.3E−10***


BFF-4G4-B8
≧1.0E+07
8.3E−03**
≦8.3E−10**


BFF-5C9-C7-B5
≧1.0E+07
5.8E−05
≦5.8E−12


BFF-7D7-D3-E4
≧1.0E+07
2.1E−02**
≦2.1E−09**


BFF-7E9-C3-B6
≧1.0E+07
1.2E−03**
≦1.2E−10**


BFU-3E2-B9-B8
≧1.0E+07
1.5E−06
≦1.5E−13


BFU-3H6-D2
≧1.0E+07
2.7E−04**
≦2.7E−11**


BFU-11A8-D6-C3
2.1E+07
≦1.0E−06
≦4.7E−14





*Low Ag response


**Heterogeneous off-rate


***Low Ag response and Heterogeneous off-rate






Anti-VEGFR2 antibodies derived from rat hybridomas were characterized for binding, function and cross-reactivity in a panel of assays. The subcloned rat antibodies were tested for the ability to bind hVEGFR2 (Example 1.22), block binding of hVEGF-R2 to hVEGF165 in a competition ELISA format (Example 1.23), and a hVEGF165 Tyr1054 phosphorylation assay (Example 1.24). Candidate molecules were then characterized for species cross-reactivity by testing their ability to block binding of mVEGFR2 to mVEGF164 in a competition ELISA format (Example 1.25). The data is summarized in Table 16 below.







TABLE 16







A List of Anti-VEGFR II Antibodies Generated Using


DNA Immunization and Rat Hybridoma Technology









Potency (nM)















hVEGF165/
mVEGF164/
Tyr1054


Hybridoma

hVEGFR2-
hVEGFR2-Fc
mVEGFR2-Fc
phospho-


Clones
Isotype
Fc Binding
Competition
Competition
assay





BCU-3D6-C9

+
NT
NT
NT


BCU-6B1-G6
IgG2a/κ
+
4.850
1.350
+


BCU-7A6-C2
IgG2b/κ
+
−
−
+









Anti-PDGF-Rβ antibodies derived from rat hybridomas were characterized for binding and function in a panel of assays. The subcloned rat antibodies were tested for the ability to bind hPDGF-Rβ (Example 1.26). Candidate IgG was also characterized for the ability to block binding of hPDGF-Rβ to hPDGF-BB in a competition ELISA format (Example 1.27) and an hPDGF-BB Tyr751 phosphorylation assay (Example 1.28). The data is summarized in Table 17 below.







TABLE 17







A List of Anti-PDGFR-B Antibodies Generated Using


DNA Immunization and Rat Hybridoma Technology









Potency (nM)














hPDGF-BB/
hPDGF-BB/


Hybridoma

hPDGFRβ-
hPDGFRβ-Fc
Tyr751


Clones
Isotype
Fc Binding
Competition
phospho-assay





BDE-3C9-G4
IgG2b/κ
+
0.832
4.696


BDE-4F2-D4
IgG2a/κ
+
0.527
+


BDE-8H6-F7

+
+
−









Example 4: Deduction of Variable Region Protein Sequences of Monoclonal Antibodies by DNA Cloning and Sequencing
Total RNA was extracted from hybridoma cell pellets using RNeasy mini kit (Qiagen, catalog #74104) using the following protocol. 600 μl of buffer RLT were added to disrupt cells by pipetting up and down several times. The cell lysate was homogenized by passing it 10 times through a 20-gauge needle fitted to an RNase-free syringe. One volume of 70% ethanol was added to the homogenized lysate and mixed well by pipetting. Up to 700 μl at a time of the sample were added to an RNeasy spin column and spun for 15 seconds at 10,000 rpm, discarding flow through. 700 μl of buffer RW1 were added to the column and spun for 15 seconds at 10,000 rpm, discarding flow through. 500 μl of buffer RPE were added to wash the column membrane and spun for 15 seconds at 10,000 rpm, discarding flow through. The same step was repeated one more time, but the column was centrifuged for 2 minutes. Sample was then centrifuged for 1 minute at 10,000 rpm to eliminate any carryover of buffer RPE. RNA was eluted with 30 μl of RNase-free water by centrifuging for 1 minute at 10,000 rpm. Subsequently, 2 μg of total RNA were used to synthesize first-strand cDNA using SuperScript First-Strand Synthesis System for RT-PCR (Invitrogen, catalog #11904-018) according to following protocol: 2 tag of RNA+2 μl dNTP+2 μl Oligo (dT)+DEPC-H2O (to 20 μl) were incubated at 65° C. for 5 minutes, then transferred to ice for at least 1 minute. The sample was then added to the following mixture: 4 μl of 10×RT buffer+8 μl 25 mM MgCl2+4 μl 0.1 M DTT+2 μl RNase OUT and incubated at 42° C. for 2 minutes. Then, 2 μl of SuperScript II RT were added to the sample and incubated at 42° C. for 50 minutes. Sample was then incubated at 70° C. for 15 minutes and chilled on ice. 2 μl of RNase H were then added and the sample was incubated at 37° C. for 20 minutes. cDNA was then used as template for PCR amplification of variable regions of antibodies. PCR was performed using first-strand cDNA, primers from Mouse Ig-Primer Set (Novagen, catalog #69831-3) and Platinum Super Mix High Fidelity (Invitrogen, catalog #12532-016). To amplify heavy chain variable regions, PCR samples were assembled as follows: 22.5 μl PCR Super Mix+0.25 μl reverse primer MuIgG VH3′-2+1 μl cDNA+1.25 μl of one the forward primers (VH-A, VH-B) or 0.5 μl of one of the forward primers (VH-C, VH-D, VH-E, VH-F). To amplify light chain variable regions, PCR samples were assembled as follows: 22.5 μl PCR Super Mix+0.25 μl reverse primer MuIgKVL-3′-1+1 μl cDNA+1.25 μl of one the forward primers (VL-A, VL-B) or 0.5 μl of one of the forward primers (VL-C, VL-D, VL-E, VL-F, VL-G).
For samples with primers VH-A, VH-B, VL-A and VL-B, the following PCR cycles were used (40-45 cycles, steps 2 through 4):
1—Denature 94° C. 2 minutes.
2—Denature 94° C. 30 seconds.
3—Anneal 50° C. 30 seconds.
4—Extend 68° C. 1 minute.
5—Final extension 68° C. 5 minutes.
6—Cool 4° C. forever
For samples with primers VH-C through VH-F, and VL-C through VL-G, the following PCR cycles were used (40-45 cycles, steps 2 through 4):
1—Denature 94° C. 2 minutes.
2—Denature 94° ° C. 30 seconds.
3—Anneal 60° C. 30 seconds.
4—Extend 68° C. 1 minute.
5—Final extension 68° C. 5 minutes.
6—Cool 4° C. forever
PCR products were run on a 1.2% agarose gel, and bands migrating at the expected size (400-500 bp) were excised for DNA extraction. DNA was purified using QIAquick Gel Extraction Kit (Qiagen, catalog #28704) according to the following protocol: gel slices were weighed. 3 volumes of buffer QG to 1 volume of gel were added to each gel slice. Samples were incubated at 50° C. for 10 minutes until gel slices were completely dissolved, mixing every 2-3 minutes. One gel volume of isopropanol was then added to each sample and mixed. Samples were then applied to QIAquick column and centrifuged for 1 minute at 13000 rpm. To wash, 750 μl of buffer PE were added to samples and spun for 1 minute at 13000 rpm. Columns were then centrifuged for an additional minute at 13,000 rpm to completely remove residual ethanol DNA was eluted by adding 30 μl of H2O to each column and by spinning 1 minute at 13,000 rpm. Purified PCR products were then sequenced to identify variable region sequences (see Tables below).







TABLE 18







VH and VL Amino Acid Sequences of Rat


Anti-Human VEGFA Monoclonal Antibodies










SEQ ID

Protein
V Region


NO:
Clone
Region
123456789012345678901234567





406
BDB-4G8-D4 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGMYW





VKQAPGQGLQYMGWINTETGKPTYADDFKGRFVFFL





ETSASTAYLQINNLKNEDMATYFCARTNYYYRSYIF





YFDYWGQGTMVTVSS


 


407
BDB-4G8-D4
CDR-H1
GYTFTNYGMY


 


408
BDB-4G8-D4
CDR-H2
WINTETGKPTYADDFKG


 


409
BDB-4G8-D4
CDR-H3
TNYYYRSYIFYFDY


 


410
BDB-4G8-D4 VL

DTVLTQSPALAVSPGERVSISCRASESVSTHMHWYQ





QKPGQQPKLLIYGASNLESGVPARFSGSGSGTDFTL





TIDPVEADDTATYFCQQSWNDPFTFGAVTKLELK


 


411
BDB-4G8-D4
CDR-L1
RASESVSTHMH


 


412
BDB-4G8-D4
CDR-L2
GASNLES


 


413
BDB-4G8-D4
CDR-L3
QQSWNDPFT


 


414
BED-4G10-C8 VH

QVQLQQSGTELVKPGSSVKISCKASGYTFTSNYMHW





IRQQPGNGLEWIGWIYPGDGDTNYNHNFNGKATLTA





DKSSSTAYMQLSSLTSEDFAVYFCASSTRAIPGWFT





YWGQGTLVTVSS


 


415
BED-4G10-C8
CDR-H1
GYTFTSNYMH


 


416
BED-4G10-C8
CDR-H2
WIYPGDGDTNYNHNFNG


 


417
BED-4G10-C8
CDR-H3
STRAIPGWFTY


 


418
BED-4G10-C8 VL

DTVLTQSPALAVSPGERVSISCWASESVSTLMHWYQ





QKLGQQPKLLIYGASNLESGVPARFRGSGSGTDFTL





TIDPVEADDTATYFCQQSWSDPYTFGAGTKLELK


 


419
BED-4G10-C8
CDR-L1
WASESVSTLMH


 


420
BED-4G10-C8
CDR-L2
GASNLES


 


421
BED-4G10-C8
CDR-L3
QQSWSDPYT


 


422
BEW-10H2-B9 VH

QIQLVQSGPELKKPGESVKISCKASGYSFTNFGLYW





VKQAPGQGLQYMGWIDTETGKPTYADDFRGRFVFFL





ETSASTAYLQINNLKNEDMATYFCARVYGYPSWYFD





FWGPGTMVTVSS


 


423
BEW-10H2-B9
CDR-H1
GYSFTNFGLY


 


424
BEW-10H2-B9
CDR-H2
WIDTETGKPTYADDFRG


 


425
BEW-10H2-B9
CDR-H3
VYGYPSWYFDF


 


426
BEW-10H2-B9 VL

DIQMTQSPASLSTSLEEIVTITCQASQDIDNYLSWY





QQKPGKSPQLLIHSATSLADGVPSRFSGSRSGTQFS





LKIHRLQVEDTGIYYCLQHFFPPWTFGGGTKLELK


 


427
BEW-10H2-B9
CDR-L1
QASQDIDNYLS


 


428
BEW-10H2-B9
CDR-L2
SATSLAD


 


429
BEW-10H2-B9
CDR-L3
LQHFFPPWT


 


430
BEW-1B10-B9-C3 VH

EVQLVESGGGLVQPGRSLKLSCAASGFSFSKYDMAW





FRQTPTKGLEWVASITTSGVGTYYRDSVKGRFTVSR





DNAKSTLYLQMDSLRSEDTATYYCARGYGAMDAWGQ





GTSVTVSS


 


431
BEW-1B10-B9-C3
CDR-H1
GFSFSKYDMA


 


432
BEW-1B10-B9-C3
CDR-H2
SITTSGVGTYYRDSVKG


 


433
BEW-1B10-B9-C3
CDR-H3
GYGAMDA


 


434
BEW-1B10-B9-C3 VL

DIQMTQSPASLSASLEEIVTITCKASQDIDDYLSWY





QQKPGKSPQLVIYAATRLADGVPSRFSGSGSGTQYS





LKISRLQVDDSGIYYCLQSSSTPWTFGGGTNLELK


 


435
BEW-1B10-B9-C3
CDR-L1
KASQDIDDYLS


 


436
BEW-1B10-B9-C3
CDR-L2
AATRLAD


 


437
BEW-1B10-B9-C3
CDR-L3
LQSSSTPWT


 


438
BEW-1B4-C4 VH

QIQLVQSGPELKKPGESVKISCKASGYSFTNYGMYW





VKQAPGQGLQYMGWIDTETGKPTYTDDFKGRFVFFL





ETSASTAYLQINNLKNEDMATYFCARWSGDTAGIRG





PWFAYWGQGTLVTVSS


 


439
BEW-1B4-C4
CDR-H1
GYSFTNYGMY


 


440
BEW-1B4-C4
CDR-H2
WIDTETGKPTYTDDFKG


 


441
BEW-1B4-C4
CDR-H3
WSGDTAGIRGPWFAY


 


442
BEW-1B4-C4 VL

DIRMTQSPASLSASLGETVNIECLASEDIYSDLAWY





QQKPGKSPQLLIYNANDLQKGVPSRFSGSGSGTQYS





LKINSLQSEDVATYFCQQYNYYPGTFGAGTKLELK


 


443
BEW-1B4-C4
CDR-L1
LASEDIYSDLA


 


444
BEW-1B4-C4
CDR-L2
NANDLQK


 


445
BEW-1B4-C4
CDR-L3
QQYNYYPGT


 


446
BEW-1C6-D2 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGMYW





VKQAPGQGLQYMGWINTETGKPTYADDFKGRFVFFL





ETSASTAYFQINNLKNEDLATYFCARPSDYYDGFWF





PYWGQGTLVTVSS


 


447
BEW-1C6-D2
CDR-H1
GYTFTNYGMY


 


448
BEW-1C6-D2
CDR-H2
WINTETGKPTYADDFKG


 


449
BEW-1C6-D2
CDR-H3
PSDYYDGFWFPY


 


450
BEW-1C6-D2 VL

DTALTQSPALAVSPGERVSISCRASEGVNSYMHWYQ





QSPGQQPKLLIYKASNLASGVPARFSGSGSGTDFTL





TIDPVEADDTATYFCQQSWYDPLTFGSGTKLEIK


 


451
BEW-1C6-D2
CDR-L1
RASEGVNSYMH


 


452
BEW-1C6-D2
CDR-L2
KASNLAS


 


453
BEW-1C6-D2
CDR-L3
QQSWYDPLT


 


454
BEW-1E3-D6 VH

QIQLVQSGPELKKPGESVKISCKASGYPFTNSGMYW





VKQAPGQGLQYMGWINTEAGKPTYADDFKGRFVFFL





ETSASTAYLQINNLKNEDMATYFCARWGYISDNSYG





WFDYWGQGTLVTVSS


 


455
BEW-1E3-D6
CDR-H1
GYPFTNSGMY


 


456
BEW-1E3-D6
CDR-H2
WINTEAGKPTYADDFKG


 


457
BEW-1E3-D6
CDR-H3
WGYISDNSYGWFDY


 


458
BEW-1E3-D6 VL

DTVLTQSPALAVSPGERVSISCRASEGVYSYMHWYQ





QNPGQQPKLLIYKASNLASGVPARFSGSGSGTDFTL





TIDPVEADDTATYFCHQNWNDPLTFGSGTKLEIK


 


459
BEW-1E3-D6
CDR-L1
RASEGVYSYMH


 


460
BEW-1E3-D6
CDR-L2
KASNLAS


 


461
BEW-1E3-D6
CDR-L3
HQNWNDPLT


 


462
BEW-3A1-D10-G9 VH

QVQLEQSGAELVKPGTSVKLSCMASGYTSSSNHMNW





MKQTTGQGLEWIGIINPGSGGTRYNVKFEGKATLTV





DKSSSTAFMQLNSLTPEDSAVYYCARAGFPGPFSYY





AMGAWGQGTSVTVSS


 


463
BEW-3A1-D10-G9
CDR-H1
GYTSSSNHMN


 


464
BEW-3A1-D10-G9
CDR-H2
IINPGSGGTRYNVKFEG


 


465
BEW-3A1-D10-G9
CDR-H3
AGFPGPFSYYAMGA


 


466
BEW-3A1-D10-G9 VL

DIQMTQSPPVLSASVGDRVTLSCKASQNIHNNLDWY





QQKHGEAPKLLIFYTNNLQTGIPSRFSGSGSGTDYT





LTISSLQPEDVATYYCYQYNSGYTFGAGTKLELK


 


467
BEW-3A1-D10-G9
CDR-L1
KASQNIHNNLD


 


468
BEW-3A1-D10-G9
CDR-L2
YTNNLQT


 


469
BEW-3A1-D10-G9
CDR-L3
YQYNSGYT


 


470
BEW-5C3-E7 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGVYW





VKQAPGQGLQYMGWINTETGKPTYADDFKGRFVFFL





ETSTNTAYLQINNLKNEDMATFFCARARQLDWFVYW





GQGTLVTVSS


 


471
BEW-5C3-E7
CDR-H1
GYTFTNYGVY


 


472
BEW-5C3-E7
CDR-H2
WINTETGKPTYADDFKG


 


473
BEW-5C3-E7
CDR-H3
ARQLDWFVY


 


474
BEW-5C3-E7 VL

DTVLTQSPALTVSPGERVSISCRARESLTTSLCWFQ





QKPGQQPKLLIYGASKLESGVPARFSGSGSGTDFTL





TIDPVEADDTATYFCQQSWYDPPTFGGGTKLELK


 


475
BEW-5C3-E7
CDR-L1
RARESLTTSLC


 


476
BEW-5C3-E7
CDR-L2
GASKLES


 


477
BEW-5C3-E7
CDR-L3
QQSWYDPPT


 


478
BEW-6C2-C8 VH

EVQLVESGGGLVQPGSSLKLSCAASGFTFSYYGMHW





IRQAPKKGLEWMALIYYDSSKMYYADSVKGRFTISR





DNSKNTLYLEMNSLRSEDTAMYYCAAGGTAPVYWGQ





GVMVTVSS


 


479
BEW-6C2-C8
CDR-H1
GFTFSYYGMH


 


480
BEW-6C2-C8
CDR-H2
LIYYDSSKMYYADSVKG


 


481
BEW-6C2-C8
CDR-H3
GGTAPVY


 


482
BEW-6C2-C8 VL

NIQLTQSPSLLSASVGDRVTLSCKGSQNIANYLAWY





QQKLGEAPKLLIYNTDSLQTGIPSRFSGSGSGTDYT





LTISSLQPEDVATYFCYQSNNGYTFGAGTKLELR


 


483
BEW-6C2-C8
CDR-L1
KGSQNIANYLA


 


484
BEW-6C2-C8
CDR-L2
NTDSLQT


 


485
BEW-6C2-C8
CDR-L3
YQSNNGYT


 


486
BEW-8E6-E4 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTDYAMHW





VKQAPGKVLKWMGWINTFTGKPTYIDDFKGRFVFSL





EASASTANLQISDLKNEDTATYFCARGNYYSGYWYF





DFWGPGTMVTMSS


 


487
BEW-8E6-E4
CDR-H1
GYTFTDYAMH


 


488
BEW-8E6-E4
CDR-H2
WINTFTGKPTYIDDFKG


 


489
BEW-8E6-E4
CDR-H3
GNYYSGYWYFDF


 


490
BEW-8E6-E4 VL

DIQMTQSPASLSASLGETISIECRASEDISSNLAWY





QQKSGKSPQLLIFAANRLQDGVPSRFSGSGSGTQFS





LKISGMQPEDEGDYFCLQGSKFYTFGAGTKLELK


 


491
BEW-8E6-E4
CDR-L1
RASEDISSNLA


 


492
BEW-8E6-E4
CDR-L2
AANRLQD


 


493
BEW-8E6-E4
CDR-L3
LQGSKFYT


 


494
BEW-9A8-E2 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGMYW





VKQAPGQGLQYMGWINTETGKPIYADDFKGRFVFFL





ETSASTAYLQINNLKNEDMATFFCARVDYDGSFWFA





YWGQGTLVTVSS


 


495
BEW-9A8-E2
CDR-H1
GYTFTNYGMY


 


496
BEW-9A8-E2
CDR-H2
WINTETGKPIYADDFKG


 


497
BEW-9A8-E2
CDR-H3
VDYDGSFWFAY


 


498
BEW-9A8-E2 VL

DTVLTQSPALAVSPGERVSISCRASESVSTVIHWYQ





QKPGQQPKLLIHGASNLESGVPARFSGSGSGTDFTL





TIDPVEADDTATYFCQQHWNDPPTFGAGTKLEMK


 


499
BEW-9A8-E2
CDR-L1
RASESVSTVIH


 


500
BEW-9A8-E2
CDR-L2
GASNLES


 


501
BEW-9A8-E2
CDR-L3
QQHWNDPPT


 


502
BEW-9C2-D6 VH

QIQLVQSGPELKKPGESVKVSCKASGYTFTNYGIHW





VKQAPGQGLQYVGWINTETGRPTYADDFKGRFVFFL





ETSASTAYLQINNLKNEDMATYFCARPLYYGYAHYF





DYWGQGVMVTVSS


 


503
BEW-9C2-D6
CDR-H1
GYTFTNYGIH


 


504
BEW-9C2-D6
CDR-H2
WINTETGRPTYADDFKG


 


505
BEW-9C2-D6
CDR-H3
PLYYGYAHYFDY


 


506
BEW-9C2-D6 VL

DIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWY





QQKPGKSPQLLIYGATSLADGVPSRFSGSRSGTQYS





LKISRLQVEDIGIYYCQQASSVTYTFGAGTKLELK


 


507
BEW-9C2-D6
CDR-L1
QASQDIGNWLA


 


508
BEW-9C2-D6
CDR-L2
GATSLAD


 


509
BEW-9C2-D6
CDR-L3
QQASSVTYT


 


510
BEW-9D2-E8 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGMYW





VKLAPGQGLQYLGWINTETGKPTYADDFKGRFVFFL





ETSASTAYLQINNLRNEDMATYFCARPSDYYDGFWF





AYWGQGTLVTVSS


 


511
BEW-9D2-E8
CDR-H1
GYTFTNYGMY


 


512
BEW-9D2-E8
CDR-H2
WINTETGKPTYADDFKG


 


513
BEW-9D2-E8
CDR-H3
PSDYYDGFWFAY


 


514
BEW-9D2-E8 VL

DTVLTQSPALTVSPGERVSISCRASEWVNSYMHWYQ





QNPGQQPKLLIYKASNLASGVPARFSGSGSGTDFTL





TLDPVEADDTATYFCQQSWNDPLTFGSGTKLEIK


 


515
BEW-9D2-E8
CDR-L1
RASEWVNSYMH


 


516
BEW-9D2-E8
CDR-L2
KASNLAS


 


517
BEW-9D2-E8
CDR-L3
QQSWNDPLT


 


518
BEW-9E10-E7 VH

QIQLLQSGPELKKPGESVKISCKASGYTFTNYGMYW





VKQAPGQGLQYMGWIDTETGRPTYADDFKGRFVFFL





ETSASTAYLQINNLKNEDMATYFCARWSGDTTGIRG





PWFAYWGQGTLVTVSS


 


519
BEW-9E10-E7
CDR-H1
GYTFTNYGMY


 


520
BEW-9E10-E7
CDR-H2
WIDTETGRPTYADDFKG


 


521
BEW-9E10-E7
CDR-H3
WSGDTTGIRGPWFAY


 


522
BEW-9E10-E7 VL

DIRMTQSPASLSASLGETVNIECLASEDIYSDLAWY





QQKPGRSPQLLIYNANGLQNGVPSRFGGSGSGTQYS





LKINSLQSEDVATYFCQQYNYFPGTFGAGTKLELK


 


523
BEW-9E10-E7
CDR-L1
LASEDIYSDLA


 


524
BEW-9E10-E7
CDR-L2
NANGLQN


 


525
BEW-9E10-E7
CDR-L3
QQYNYFPGT


 


526
BEW-9E3-B9 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGMYW





VKQAPGQGLQYMGWINTETGKPTYADDFKGRFVFFL





ETSASTAFLQINNLKNEDMATYFCARPSDYYDGFWF





PYWGQGALVTVSS


 


527
BEW-9E3-B9
CDR-H1
GYTFTNYGMY


 


528
BEW-9E3-B9
CDR-H2
WINTETGKPTYADDFKG


 


529
BEW-9E3-B9
CDR-H3
PSDYYDGFWFPY


 


530
BEW-9E3-B9 VL

DTILTQSPALAVSPGERISISCRASEGVNSYMHWYQ





QNPGQQPKLLIYKASNLASGVPARFSGSGSGTDFTL





TIDPVEADDTATYFCQQSWNDPLTFGSGTKLEIK


 


531
BEW-9E3-B9
CDR-L1
RASEGVNSYMH


 


532
BEW-9E3-B9
CDR-L2
KASNLAS


 


533
BEW-9E3-B9
CDR-L3
QQSWNDPLT


 


534
BEW-9E7-B4 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGMYW





VKQAPGQGLQYMGWIDTETGKPTYADDFKGRFVFFL





ETSASTAYLQINNLRNEDMATYFCARWGYTSDYYYG





WFPDWGQGTLVTVST


 


535
BEW-9E7-B4
CDR-H1
GYTFTNYGMY


 


536
BEW-9E7-B4
CDR-H2
WIDTETGKPTYADDFKG


 


537
BEW-9E7-B4
CDR-H3
WGYTSDYYYGWFPD


 


538
BEW-9E7-B4 VL

DTVLTQSPALAVSPGERVSISCRASEGVNSYMHWYQ





QNPGQQPKLLIYKASNLASGVPARFSGSGSGTDFTL





NIHPVEADDTATYFCQQNWNVPLTFGSGTKLEIK


 


539
BEW-9E7-B4
CDR-L1
RASEGVNSYMH


 


540
BEW-9E7-B4
CDR-L2
KASNLAS


 


541
BEW-9E7-B4
CDR-L3
QQNWNVPLT
















TABLE 19







VH and VL Amino Acid Sequences of Rat Anti-Human PDGF-BB Monoclonal


Antibodies










SEQ ID

Protein
V Region


NO:
Clone
Region
12345678901234567890123456





542
BDI-1E1-D5 VH

EVKLQQSGDELVRPGASVKMSCKASGYTFTDYVMHW





VKQSPGQGLEWIGTIIPLIDTTSYNQKFKGKATLTA





DKSSNTAYMELSRLTSEDSAVYYCARTSPYYYSSYD





VMDAWGQGASVTVSS


 


543
BDI-1E1-D5
CDR-H1
GYTFTDYVMH


 


544
BDI-1E1-D5
CDR-H2
TIIPLIDTTSYNQKFKG


 


545
BDI-1E1-D5
CDR-H3
TSPYYYSSYDVMDA


 


546
BDI-1E1-D5 VL

NIQLTQSPSLLSASVGDRVTLSCKGSQNINNYLAWY





QQKLGEAPKLLIYKTNNLQTGIPSRFSGCGSGTDYT





LTISSLHSEDLATYYCYQYDNGYTFGAGTKLELK


 


547
BDI-1E1-D5
CDR-L1
KGSQNINNYLA


 


548
BDI-1E1-D5
CDR-L2
KTNNLQT


 


549
BDI-1E1-D5
CDR-L3
YQYDNGYT


 


550
BDI-5G2-F9 VH

QVTLKESGPGILQPSQTLSLTCTFSGFSLSTFGMGV





GWIRQPSGKGLEWLANIWWDDDKYYNPSLKNRLTIS





KDTSNSQAFLEITNVDTADTATYYCARISTGISSYY





VMDAWGQGASVTVSS


 


551
BDI-5G2-F9
CDR-H1
GFSLSTFGMGVG


 


552
BDI-5G2-F9
CDR-H2
NIWWDDDKYYNPSLKN


 


553
BDI-5G2-F9
CDR-H3
ISTGISSYYVMDA


 


554
BDI-5G2-F9 VL

QFTLTQPKSVSGSLRSTITIPCERSSGDIGDTYVSW





YQQHLGRPPINVIYGNDQRPSEVSDRFSGSIDSSSN





SASLTITNLQMDDEADYFCQSYDSDIDIVFGGGTKL





TVL


 


555
BDI-5G2-F9
CDR-L1
ERSSGDIGDTYVS


 


556
BDI-5G2-F9
CDR-L2
GNDQRPS


 


557
BDI-5G2-F9
CDR-L3
QSYDSDIDIV


 


558
BDI-5H1-F6 VH

QVTLKESGPGILQPSQTLSLTCTFSGFSLSTFGMGV





GWIRQPSGKGLEWLANIWWDDDKYYNPSLKNRLTIS





KDTSNSQAFLEITNVDTADTATYYCARISTGISSYY





VMDAWGQGASVTVSS


 


559
BDI-5H1-F6
CDR-H1
GFSLSTFGMGVG


 


560
BDI-5H1-F6
CDR-H2
NIWWDDDKYYNPSLKN


 


561
BDI-5H1-F6
CDR-H3
ISTGISSYYVMDA


 


562
BDI-5H1-F6 VL

QFTLTQPKSVSGSLRSTITIPCERSSGDIGDTYVSW





YQQHLGRPPINVIYGNDQRPSEVSDRFSGSIDSSSN





SASLTITNLQMDDEADYFCQSYDSDIDIVFGGGTKL





TVL


 


563
BDI-5H1-F6
CDR-L1
ERSSGDIGDTYVS


 


564
BDI-5H1-F6
CDR-L2
GNDQRPS


 


565
BDI-5H1-F6
CDR-L3
QSYDSDIDIV


 


566
BDI-6A3-A9 VH

EVQLVESGGGLVQPGRSLKFSCAASGFSFSDSAMAW





VRQAPKKGLEWVATIIYDGSGTYYRDSVKGRFTISR





DNAKSTLYLQMDSLRSEDTATYYCARLGFNYGNYGY





YVMDAWGQGASVTVSS


 


567
BDI-6A3-A9
CDR-H1
GFSFSDSAMA


 


568
BDI-6A3-A9
CDR-H2
TIIYDGSGTYYRDSVKG


 


569
BDI-6A3-A9
CDR-H3
LGFNYGNYGYYVMDA


 


570
BDI-6A3-A9 VL

QFTLTQPKSVSGSLRNTITIPCERSSGDIGDSYVSW





YQQHLGRPPINVIFADDQRPSEVSDRFSGSIDSSSN





SASLTITNLQMDDEADYFCQSYDSNIDINIVFGGGT





KLTVL


 


571
BDI-6A3-A9
CDR-L1
ERSSGDIGDSYVS


 


572
BDI-6A3-A9
CDR-L2
ADDQRPS


 


573
BDI-6A3-A9
CDR-L3
QSYDSNIDINIV


 


574
BDI-7H10-D8 VH

EVKLQQSGDELVRPGASVKMSCKASGYTFTDYAMHW





VKQSPGQGLEWIGTIIPLIDTTSYNQKFKGKATLTA





DTSSNTAYMELSRLTSEDSAVYYCARDWDNNWGYFD





YWGQGVMVTVSS


 


575
BDI-7H10-D8
CDR-H1
GYTFTDYAMH


 


576
BDI-7H10-D8
CDR-H2
TIIPLIDTTSYNQKFKG


 


577
BDI-7H10-D8
CDR-H3
DWDNNWGYFDY


 


578
BDI-7H10-D8 VL

DVVLTQTPVSLSVTLGDQASISCRSSQSLEYSDGYT





YLEWYLQKPGQSPQLLIYGVSNRFSGVPDRFIGSGS





GTDFTLKISRVEPEDLGVYYCFQATHDPLTFGSGTK





LEIK


 


579
BDI-7H10-D8
CDR-L1
RSSQSLEYSDGYTYLE


 


580
BDI-7H10-D8
CDR-L2
GVSNRFS


 


581
BDI-7H10-D8
CDR-L3
FQATHDPLT


 


582
BDI-9E8-E7 VH

QVTLKESGPGILQPSQTLSLTCTFSGFSLSTYGMGV





GWIRQPSGKGLEWLANIWWDDDKYYNPSLKNRLTIS





KDTSNNQAFLKITNVDTADTATYYCARIESIGTTYS





FDYWGQGVMVTVSS


 


583
BDI-9E8-E7
CDR-H1
GFSLSTYGMGVG


 


584
BDI-9E8-E7
CDR-H2
NIWWDDDKYYNPSLKN


 


585
BDI-9E8-E7
CDR-H3
IESIGTTYSFDY


 


586
BDI-9E8-E7 VL

QFTLTQPKSVSGSLRSTITIPCERSSGDIGDSYVSW





YQQHLGRPPINVIYADDQRPSEVSDRFSGSIDSSSN





SASLTITNLQMDDEADYFCQSYDINIDIVFGGGTKL





TVL


 


587
BDI-9E8-E7
CDR-L1
ERSSGDIGDSYVS


 


588
BDI-9E8-E7
CDR-L2
ADDQRPS


 


589
BDI-9E8-E7
CDR-L3
QSYDINIDIV


 


590
BFU-11A8-D6-C3 VH

EVQLQQSGPELQRPGASVKLSCKASGYTFTESYIYW





VKQRPEQSLELIGRIDPEDGSTDYVEKFKNKATLTA





DTSSNTAYMQLSSLTSEDTATYFCARFGARSYFYPM





DAWGQGTSVTVSS


 


591
BFU-11A8-D6-C3
CDR-H1
GYTFTESYIY


 


592
BFU-11A8-D6-C3
CDR-H2
RIDPEDGSTDYVEKFKN


 


593
BFU-11A8-D6-C3
CDR-H3
FGARSYFYPMDA


 


594
BFU-11A8-D6-C3 VL

DTVLTQSPTLAVSPGERVSIPCRASESVSTLMHWYQ





QKPGQQPRLLIYGASNLESGVPARFSGSGSGTDFTL





TIDPVEADDTATYFCQQSWNDPWTFGGGTKLELK


 


595
BFU-11A8-D6-C3
CDR-L1
RASESVSTLMH


 


596
BFU-11A8-D6-C3
CDR-L2
GASNLES


 


597
BFU-11A8-D6-C3
CDR-L3
QQSWNDPWT


 


598
BFU-3E2-B9-B8 VH

EVQLQQSGPELQRPGASVKLSCKASGYTFTESYMYW





VKQRPEQSLELIGRIDPEDGSTDYVEKFKNKATLTA





DTSSNTAYMQLSSLTSEDSATYFCARFGARSYFYPM





DAWGQGTSVTVSS


 


599
BFU-3E2-B9-B8
CDR-H1
GYTFTESYMY


 


600
BFU-3E2-B9-B8
CDR-H2
RIDPEDGSTDYVEKFKN


 


601
BFU-3E2-B9-B8
CDR-H3
FGARSYFYPMDA


 


602
BFU-3E2-B9-B8 VL

DTVLTQPPALAVSPGERVSISCRASESVSTLMHWYQ





QKPGQQPRLLIYGASNLESGVPARFSGSGSGTDFTL





TIDPVEADDTATYFCQQSWNDPWTFGGGTKLELK


 


603
BFU-3E2-B9-B8
CDR-L1
RASESVSTLMH


 


604
BFU-3E2-B9-B8
CDR-L2
GASNLES


 


605
BFU-3E2-B9-B8
CDR-L3
QQSWNDPWT
















TABLE 20







VH and VL Amino Acid Sequences of Rat Anti-Human VEGFR II


Monoclonal Antibodies










SEQ ID

Protein
V Region


NO:
Clone
Region
12345678901234567890123456





606
BCU-3D6-C9 VH

QIQLVQSGPELKKPGESVKISCKASEYTFTDYAIHW





VKQAPGKGLKWMGWINTYTGKPTYADDFKGRFVFSL





EASASTANLQISNLKNEDTATYFCARDYGGYGERRD





YFDYWGQGVMVTVSS


 


607
BCU-3D6-C9
CDR-H1
EYTFTDYAIH


 


608
BCU-3D6-C9
CDR-H2
WINTYTGKPTYADDFKG


 


609
BCU-3D6-C9
CDR-H3
DYGGYGERRDYFDY


 


610
BCU-3D6-C9 VL

DIQMTQSPASLSASLGETVTIECRVSEDIYNGLAWY





QQKPGKSPQFLIYNANRLHTGVPSRFSGSGSGTQFS





LKINSLQSEDVANYFCQQYYDYPLTFGSATKLEIK


 


611
BCU-3D6-C9
CDR-L1
RVSEDIYNGLA


 


612
BCU-3D6-C9
CDR-L2
NANRLHT


 


613
BCU-3D6-C9
CDR-L3
QQYYDYPLT


 


614
BCU-6B1-G6 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGMYW





VKQAPGQALQFMGWINTETGQPTYADDFKGRFVFFL





ETSASTAYLQINNLKNEDMATYFCARLGNNYGIWFA





YWGQGTLVTVSS


 


615
BCU-6B1-G6
CDR-H1
GYTFTNYGMY


 


616
BCU-6B1-G6
CDR-H2
WINTETGQPTYADDFKG


 


617
BCU-6B1-G6
CDR-H3
LGNNYGIWFAY


 


618
BCU-6B1-G6 VL

DIQMTQSPASLSASLGETVTIECRASDDLYSTLAWY





QQKPGDSPQLLIFDANRLAAGVPSRFSGSGSGTQYS





LKINSLQSEDVASYFCQQYNKFPWTFGGGTKLELK


 


619
BCU-6B1-G6
CDR-L1
RASDDLYSTLA


 


620
BCU-6B1-G6
CDR-L2
DANRLAA


 


621
BCU-6B1-G6
CDR-L3
QQYNKFPWT


 


622
BCU-7A6-C2 VH

EVQLVESGGGLVQPRGSLKLSCAASGFDFNSYGMSW





VRQAPGKGLDLVADISSKSYNYATYYADSVKDRFTI





SRDDSQSMVYLQMDNLKTEDTALYYCTESLELGGAY





WGQGTLVTVSS


 


623
BCU-7A6-C2
CDR-H1
GFDFNSYGMS


 


624
BCU-7A6-C2
CDR-H2
DISSKSYNYATYYADSVKD


 


625
BCU-7A6-C2
CDR-H3
SLELGGAY


 


626
BCU-7A6-C2 VL

DIQMTQSPPSLSASLGDEVTITCQASQNINKFIAWY





QQKPGKAPRLLIRYTSTLKSGTPSRFSGSGSGRDYS





FSISNVESEDIASYYCLQYDSLPWTFGGGTKLELK


 


627
BCU-7A6-C2
CDR-L1
QASQNINKFIA


 


628
BCU-7A6-C2
CDR-L2
YTSTLKS


 


629
BCU-7A6-C2
CDR-L3
LQYDSLPWT
















TABLE 21







VH and VL Amino Acid Sequences of Rat Anti-Human PDGFR-B


Monoclonal Antibodies










SEQ ID

Protein
V Region


NO:
Clone
Region
12345678901234567890123456





630
BDE-3C9-G4 VH

EVQLVESGGGLVQPGRSLKLSCAASGFTFSNYGMA





WVRQAPTQGLEWVASITNSGGNTYYRDSVKGRFTI





SRDSAKNTQYLQMDSLRSEDTATYFCARHTPGANY





FDYWGQGLMVTVSS


 


631
BDE-3C9-G4
CDR-H1
GFTFSNYGMA


 


632
BDE-3C9-G4
CDR-H2
SITNSGGNTYYRDSVKG


 


633
BDE-3C9-G4
CDR-H3
HTPGANYFDY


 


634
BDE-3C9-G4 VL

DIQMTQSPPSLSASLGEKVTITCQASQSIKNYIAW





YQLKPGTAPRLLMRYTSTLESGTPSRFSGSGSGRD





YSFSISNVESEDIASYYCVQYANLYTFGGGTKLEL





K


 


635
BDE-3C9-G4
CDR-L1
QASQSIKNYIA


 


636
BDE-3C9-G4
CDR-L2
YTSTLES


 


637
BDE-3C9-G4
CDR-L3
VQYANLYT


 


638
BDE-4F2-D4 VH

QVQLKESGPGLMQPSQTLSLTCTVSGFSLTNYGVS





WVRQFPGKGLEWIAAISSGGSTYYNSALKSRLSIS





RDTSRSQVFLKMNSLLTEDTAFYFCTRVYYGSNYF





DYWGPGVMVTVSS


 


639
BDE-4F2-D4
CDR-H1
GFSLTNYGVS


 


640
BDE-4F2-D4
CDR-H2
AISSGGSTYYNSALKS


 


641
BDE-4F2-D4
CDR-H3
VYYGSNYFDY


 


642
BDE-4F2-D4 VL

DIVMTQTPSSQAVSAGEKVTMSCKSSQSLLYGGDQ





KNFLAWYQQKPGQSPKLLIYLASTRESGVPDRFIG





SGSGTDFTLTISSVQAEDLADYYCQQHYGYPFTFG





SGTKLEIK


 


643
BDE-4F2-D4
CDR-L1
KSSQSLLYGGDQKNFLA


 


644
BDE-4F2-D4
CDR-L2
LASTRES


 


645
BDE-4F2-D4
CDR-L3
QQHYGYPFT


 


646
BDE-8H6-F7 VH

EVQLVESGGGLVQPGSSLKLSCLASGFTFSNYNMY





WIRQAPKKGLEWIALIFYDNNNKYYADSVKGRFTI





SRDNSKNTLYLEMNSLRSEDTAMYYCLRDSGPFSY





WGQGTLVTVSS


 


647
BDE-8H6-F7
CDR-H1
GFTFSNYNMY


 


648
BDE-8H6-F7
CDR-H2
LIFYDNNNKYYADSVKG


 


649
BDE-8H6-F7
CDR-H3
DSGPFSY


 


650
BDE-8H6-F7 VL

DIQMTQSPPSLSASLGDKVTINCQAGQNIKKYIAW





YQQEPGKVPRLLIRYTSKLESDTPSRFSGSGSGRD





YSFSISNVESEDIASYYCLQYDNLPWTFGGGTKLE





LK


 


651
BDE-8H6-F7
CDR-L1
QAGQNIKKYIA


 


652
BDE-8H6-F7
CDR-L2
YTSKLES


 


653
BDE-8H6-F7
CDR-L3
LQYDNLPWT









Example 5: Generation of Chimeric Antibodies
The variable domains of the heavy and light chain of the rat mAbs were cloned in-frame to mutant human IgG1 (L234, 235A) heavy-chain and kappa light-chain constant regions, respectively. The activities of the resulting chimeric antibodies were confirmed in ELISA-based binding and competition assays or Biacore binding assay, and were comparable to their parental rat mAbs.
Chimeric anti-VEGF-A antibodies were characterized for binding, function and cross-reactivity in a panel of assays. Potency for all chimeric molecules was characterized in the hVEGF165-induced cell proliferation assay (Example 1.7). Binding affinity of these molecules to hVEGF165 was measured by Biacore analysis (Example 1.1). Select chimeric molecules were tested for the ability to block binding of hVEGF165 to hVEGF-R2 in a competition ELISA format (Example 1.4) and a hVEGF111 Tyr1054 phosphorylation assay (Example 1.6). Candidate molecules were then examined for potency in the HMVEC-d hVEGF165-induced proliferation assay (Example 1.10) and species cross-reactivity in the rabVEGF165-induced cell proliferation assay (Example 1.9). The data is summarized in Tables 22 and 23 below.







TABLE 22







Characterization of Chimeric Anti-Human VEGF-A Monoclonal Antibodies















Receptor



huVEGF-




Competition

huVEGF-A165
rabbitVEGF-A165
A165




ELISA
Phospho-
Neutralization
Neutralization
Neutralization



ELISA
huVEGF-
Tyr1054/
Potency in
Potency in
Potency



huVEGF-
A165/
huVEGF-A111
hVEGFR2
hVEGFR2
in


Chimeric
A165
huVEGFR2
Neuterlization
Overexpressing
Overexpressing
HMVEC-d


Clones
Binding
(nM)
(nM)
Cells (nM)
Cells (nM)
cells (nM)
















chBEW-1B4
NT
NT
NT
1.428
NT
NT


chBEW-1B4
NT
NT
NT
1.669
NT
NT


half-body


chBEW-1E3
NT
NT
NT
0.657
NT
NT


chBEW-1E3
NT
NT
NT
3.752
NT
NT


half-body


chBEW-5C3
NT
NT
NT
0.244
NT
NT


chBEW-5C3
NT
NT
NT
2.264
NT
NT


half-body


chBEW-6C2
NT
0.148
0.435
>10
0.58 
0.031


chBEW-6C2
NT
NT
NT
>10
NT
NT


half-body


chBEW-8E6
NT
NT
NT
0.499
NT
NT


chBEW-8E6
NT
NT
NT
>10
NT
NT


half-body


chBEW-9A8
NT
0.097
0.260
0.416
0.510
0.026


chBEW-9A82
NT
NT
NT
1.584
NT
NT


half-body


chBEW-9E10
NT
NT
NT
0.448
NT
NT


chBEW-9E10
NT
NT
NT
0.598
NT
NT


half-body


chBEW-10H2
NT
NT
NT
0.912
NT
NT


chBEW-
NT
NT
NT
2.562
NT
NT


10H2-B9 half-


body


chBEW-9C2
NT
NT
NT
2.090
NT
NT


chBEW-9C2
NT
NT
NT
2.740
NT
NT


half-body


chBEW-9D2
NT
NT
NT
1.556
0.740
2.150


chBEW-9D2
NT
NT
NT
>10
NT
NT


half-body


chBEW-1B10
NT
NT
NT
0.377
NT
NT


chBEW-3A1
NT
NT
NT
0.680
NT
NT


chBEW-3A1
NT
NT
NT
>10
NT
NT


half-body


chBDB-4G8
NT
0.157
0.575
0.687
NT
0.195


chBEW-1C6
NT
NT
NT
3.595
NT
NT


half-body





NT—Not tested













TABLE 23







Biacore Binding of Rat and Rat-Human Chimera Anti-VEGF










Antibody
kon (M−1 s−1)
koff (M−1)
KD (M)













chBDB-4G8
1.7E+07
2.4E−05
1.9E−12


chBDB-4G8
1.2E+07
4.7E−05
3.8E−12


chBED-4G10-C8
1.0E+07
5.9E−03
5.9E−10


chBEW-1B4-C4
1.1E+07
1.2E−04
1.1E−11


chBEW-1B10-B9-C3
5.5E+06
5.2E−05
9.4E−12


chBEW-1E3-D6
7.2E+06
8.0E−05
1.1E−11


chBEW-3A1-D10-G9
3.5E+07
8.0E−04
2.3E−11


chBEW-5C3-E7
6.8E+06
8.2E−05
1.2E−11


chBEW-6C2
4.9E+06
4.3E−05
8.8E−12


chBEW-8E6-E4
6.2E+06
1.0E−04
1.6E−11


chBEW-9A8
8.9E+06
≦1.0E−06
≦1.1E−13


chBEW-10H2-B9
2.8E+07
3.5E−04
1.3E−11









Chimeric anti-PDGF-BB antibodies were characterized for binding, function and cross-reactivity in a panel of assays. The chimeric molecules were first tested for the ability to bind hPDGF-BB in a direct binding ELISA (Example 1.12). Binding affinity of these molecules to hPDGF-BB was then measured by Biacore analysis (Example 1.1). Functional characterization of these molecules included testing of the ability to block binding of hPDGF-BB to hPDGF-Rβ in a competition ELISA format (Example 1.13) and an hPDGFRβ Tyr751 phosphorylation assay (Example 1.14). Potency was further characterized in the hPDGF-BB-induced cell proliferation assay (Example 1.15). Candidate molecules were advanced and cross-reactivity was determined for mouse and rat/rabbit PDGF-BB in the cell-based proliferation assay (Examples 1.17-1.18). The data is summarized in Tables 24 and 25 below.







TABLE 24







Characterization of Chimeric Anti-Human PDGF-BB Monoclonal Antibodies















Receptor
Phospho-
huPDGF-BB
ratPDGF-BB
mPDGF-BB



ELISA
Competition
Tyr751/hPDGF-
Neutralization
Neutralization
Neutralization



huPDGF-
ELISA
BB
Potency (nM)
Potency (nM)
Potency (nM)


Chimeric
BB
huPDGF-BB/
Neutralization
in NIH-3T3
in NIH-3T3
in NIH-3T3


Molecule
Binding
huPDGFR
(nM)
Cells
Cells B (nM)
Cells
















chBDI-9E8
0.38
0.791
0.388
0.058
0.075
0.08


chBDI-9E8
NT
NT
NT
1.84
NT
NT


half-body


chBDI-5H1
0.12
1.039
1.602
0.275
0.17 
NT


chBDI-5H1
NT
NT
NT
>10
NT
NT


half-body


chBDI-7H10
>10   
10.1  
2.476
>10
NT
NT


chBDI-5G2
NT
1.08 
NT
0.181
0.118
NT


chBDI-1E1
NT
0.417
NT
>5
NT
NT


chBDI-1E1
NT
NT
NT
>10
NT
NT


half body


chBDI-8B8
NT
0.179
NT
>10
NT
NT


chBFU-3E2
NT
NT
NT
0.099
NT
NT


chBFU-3E2
NT
NT
NT
2.494
NT
NT


half-body


chBFU-11A8
NT
NT
NT
0.086
NT
NT


chBFU-11A8
NT
NT
NT
>10
NT
NT


half-body





NT—Not tested













TABLE 25







Biacore Binding Of Rat And Rat-Human Chimera Anti-PDGF










Antibody
kon (M−1 s−1)
koff (M−1)
KD (M)













BFU-11A8-D6-C3
2.1E+07
≦1.0E−06
≦4.7E−14


chBDI-5H1
≧1.0E+07
1.5E−04
≦1.5E−11


chBDI-9E8
≧1.0E+07
1.2E−04
≦1.2E−11


chBFU-3E2-B9-B8
≧1.0E+07
1.9E−04
≦1.9E−11


chBFU-11A8-D6-C3
≧1.0E+07
1.5E−04
≦1.5E−11









Chimeric anti-VEGFR2 antibodies were tested for the ability to block binding of VEGFR2 to hVEGF165 in a competition ELISA format, as described in Example 1.22. The data is summarized in Table 26.







TABLE 26







Characterization of Chimeric Anti-Human


VEGFR II Monoclonal Antibodies











hVEGF165/hVEGFR2-Fc



Chimeric Molecules
Competition







chBCU-6B1-G6
0.498



chBCU-7A6-C2
NT










Example 6: Humanization of Rat Monoclonal Antibodies
Below are the humanization designs for the rat monoclonal antibodies, followed by summaries of amino acid sequences and characterization of selected humanized antibodies.
Example 6.1: Humanization of PDGF-BB Antibodies
Example 6.1.1: Humanization Method
Antibody humanization is achieved by grafting CDRs of the rodent antibody onto a “similar” human framework (acceptor) and incorporating minimal number of key framework residues (back-mutation) from the rodent antibody that are selected to maintain the original CDR conformation in order to minimize the immunogenicity while retaining the optimal antigen binding.
Example 6.1.2: Human Germline Sequence Selections for Constructing CDR-Grafted, Humanized PDGF Antibodies
By applying the aforementioned method, the CDR sequences of VH and VL chains of monoclonal antibodies BDI-5H1-F6, BDI-9E8-E7, BDI-7H10-D8, BDI-1E1-D5, BDI-6A3-A9, BFU-3E2 and BFU-11A8 were grafted onto different human heavy and light chain acceptor sequences.
Example 6.1.2.1: BDI-5H1-F6
Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-5H1-F6 of the present invention, the following known human sequences are selected:
1. IGHV2-70*01 and IGHJ6*01 for constructing heavy chain acceptor sequences
2. IGHV2-70*04 and IGHJ6*01 as alternative acceptor sequence for constructing heavy chain
3. IGHV3-66*01 and IGHJ1*01 as alternative acceptor sequence for constructing heavy chain
4. IGLV6-57*01 and IGJL2*01 for constructing light chain acceptor sequences
5. IGKV3-20*01 and IGJK4*01 as alternative acceptor sequences for constructing light chain
6. IGKV4-1*01 and IGJK4*01 as alternative acceptor sequences for constructing light chain
7. IGKV1-39*01 and IGJK1*01 as alternative acceptor sequences for constructing light chain
By grafting the corresponding VH and VL CDRs of BDI-5H1-F6 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.1.2.2: BDI-9E8-E7
Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-9E8-E7 of the present invention, the following known human sequences are selected:
1. IGHV2-70*01 and IGHJ3*01 for constructing heavy chain acceptor sequences
2. IGHV2-70*04 and IGHJ6*01 as alternative acceptor sequence for constructing heavy chain
3. IGHV3-66*01 and IGHJ1*01 as alternative acceptor sequence for constructing heavy chain
4. IGLV6-57*01 and IGJL2*01 for constructing light chain acceptor sequences
5. IGKV3-20*01 and IGJK4*01 as alternative acceptor for constructing light chain sequences
6. IGKV4-1*01 and IGJK4*01 as alternative acceptor sequences for constructing light chain
7. IGKV1-39*01 and IGJK1*01 as alternative acceptor sequences for constructing light chain
By grafting the corresponding VH and VL CDRs of BDI-9E8-E7 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.1.2.3: BDI-7H10-D8
Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-7H10-D8 of the present invention, the following known human sequences are selected:
1. IGHV1-69*01 and IGHJ3*01 for constructing heavy chain acceptor sequences
2. IGKV2-29*02 and IGK2*01 for constructing light chain acceptor sequences
By grafting the corresponding VH and VL CDRs of BDI-7H10-D8 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.1.2.4: BDI-1E1-D5
Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-1E1-D5 of the present invention the following known human sequences are selected:
1. IGHV1-69*06 and IGHJ6*01 for constructing heavy chain acceptor sequences
2. IGKV1D-13*01 and IGKJ2*01 for constructing light chain acceptor sequences
3. IGKV3-11*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain
By grafting the corresponding VH and VL CDRs of BDI-1E1-D5 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.1.2.5: BDI-6A3-A9
Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-6A3-A9 of the present invention the following known human sequences are selected:
1. IGHV3-7*01 and IGHJ6*01 for constructing heavy chain acceptor sequences
2. IGHV1-3*01 and IGHJ6*01 as alternative acceptor sequence for constructing heavy chain
3. IGLV6-57*01 and IGJL2*01 for constructing light chain acceptor sequences
By grafting the corresponding VH and VL CDRs of BDI-6A3-A9 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.1.2.6: BFU-3E2
Based on the alignments with the VH and VL sequences of monoclonal antibody BFU-3E2 of the present invention, the following known human sequences are selected:
1. IGHV1-69*01 and IGHJ6*01 for constructing heavy chain acceptor sequences
2. IGKV3-11*01 and IGKJ4*01 for constructing light chain acceptor sequences
3. IGKV1-13*01 and IGKJ4*01 as alternative acceptor sequence for constructing light chain
By grafting the corresponding VH and VL CDRs of BFU-3E2 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.1.2.7: BFU-11A8
Based on the alignments with the VH and VL sequences of monoclonal antibody BFU-11A8 of the present invention, the following known human sequences are selected:
1. IGHV1-69*01 and IGHJ6*01 for constructing heavy chain acceptor sequences
2. IGKV3-11*01 and IGKJ4*01 for constructing light chain acceptor sequences
3. IGKV1-5*01 and IGKJ4*01 as alternative acceptor sequence for constructing light chain
By grafting the corresponding VH and VL CDRs of BFU-11A8 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.1.3: Introducing Potential Framework Back-Mutations in CDR-Grafted Antibodies
To generate humanized antibody with potential framework back-mutations, the mutations were identified and introduced into the CDR-grafted antibody sequences by de novo synthesis of the variable domain, or mutagenic oligonucleotide primers and polymerase chain reactions, or by methods well known in the art. Different combinations of back mutations and other mutations are constructed for each of the CDR-grafts as follows. Residue numbers for these mutations are based on the Kabat numbering system.
BDI-5H1-F6
When IGHV2-70*01 and IGHJ6*01 selected as BDI-5H1-F6 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, A44→G, K75→N, V78→A, M82→I with or without N65→T (CDR change).
When IGHV2-70*04 and IGHJ6*01 selected as BDI-5H1-F6 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q→1E, K5→R, K75→N, N76→S, V78→A and M82→I.
When IGHV3-66*01 and IGHJ1*01 selected as BDI-5H1-F6 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: A24→F, V37→I, V48→L, S49→A, F67→L, R71→K, N73→T, T77→Q, L78→A, and M82→I.
When IGLV6-57*01 and IGJL2*01 selected as BDI-5H1-F6 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: N1→Q, S22→P, S43→P, T464→N, G57→E, P59→S, and Y87→F.
When IGKV3-20*01 and IGJK4*01 selected as BDI-5H1-F6 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→F, A43→P, L46→N, L47→V, I58→V, G66→I, G68→S, T69→N, F71→A, Y87→F and with or without two residues insertion D66a, S66b and deletion of T10.
When IGKV4-1*01 and IGJK4*01 selected as BDI-5H1-F6 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→F, M4→L, L46→N, L47→V, T69→N, D70→S, F71→A, Y87→F.
When IGKV1-39*01 and IGJK1*01 selected as BDI-5H1-F6 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→F, M4→L, L46→N, L47→V, T69→N, D70→S, F71→A, and Y87→F.
BDI-9E8-E7
When IGHV2-70*01 and IGHJ6*01 selected as BDI-9E8-E7 heavy chain acceptor sequences, one or more of following residues could be back-mutated as follows: Q1→E, A44→G, V78→A M82→I with or without N65→T (CDR change).
When IGHV2-70*04 and IGHJ6*01 selected as BDI-9E8-E7 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, K5→R, V78→A, and M82→I.
When IGHV3-66*01 and IGHJ1*01 selected as BDI-9E8-E7 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: A24→F, V37→I, V48→L, S49→A, F67→L, R71→K, N73→T, T77→Q, L78→A, and M82→I.
When IGLV6-57*01 and IGJL2*01 selected as BDI-9E8-E7 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: S43→P, T46→N and Y87→F.
When IGKV3-20*01 and IGJK4*01 selected as BDI-9E8-E7 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→F, A43→P, L46→N, L47→V, I58→V, G66→I, T69→N, F71→A, Y87→F and W/WO two residues insertion (D66a, S66b) and deletion of T10.
When IGKV4-1*01 and IGJK4*01 selected as BDI-9E8-E7 light chain acceptor sequences, one or more of the following residues could be back mutated as follows: I2→F, M4→L, L46→N, L47→V, T69→N, D70→S, F71→A, T72→S, and Y87→F.
When IGKV1-39*01 and IGJK1*01 selected as BDI-9E8-E7 light chain acceptor sequences, one or more of the following residues could be back mutated as follows: I2→F, M4→L, L46→N, L47→V, T69→N, D70→S, F71→A, and T72→S.
BDI-7H10-D8
When IGHV1-69*01 and IGHJ3*01 selected as BDI-7H10-D8 heavy chain acceptor sequences, one or more of following residues could be back-mutated as follows: Q1→E, M48→I, V67→A, I69→L, E73→T, S76→N, with or without CDR changes Y27→G and T30→S.
When IGKV2-29*02 and IGKJ2*01 selected as BDI-7H10-D8 light chain acceptor sequences, one or more of following residues could be back-mutated as follows: I2→V and M4→L.
BDI-1E1-D5
When IGHV1-69*06 and IGHJ6*01 selected as BDI-1E1-D5 heavy chain acceptor sequence, one or more of the following residues could be back-mutated as follows: Q1→E M48→I, V67→A, I69→L and S76→N.
When IGKV1D-13*01 and IGKJ2*01 selected as BDI-1E1-D5 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V58→I and F71→Y.
When IGKV3-11*01 and IGKJ2*01 selected as BDI-1E1-D5 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: F71→Y and V85→T.
BDI-6A3-A9
When IGHV3-7*01 and IGHJ6*01 selected as BDI-6A3-A9 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: S28→T, R60→V, N76→S.
When IGHV1-3*01 and IGHJ6*01 selected as BDI-6A3-A9 heavy chains acceptor sequences, one or more of following residues could be back-mutated as follows: Q1→E, R44→G, M48→V, G49→A, V67→F, T73→N, A78→L and M80→L.
When IGLV6-57*01 and IGJL2*01 selected as BDI-6A3-A9 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: S43→P, T46→N, Y49→F and Y87→F.
BFU-3E2
When IGHV1-69*01 and IGHJ6*01 selected as BFU-3E2 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: R38→K, G44→S, W47→L, M48→I, R66→K, V67→A, 169→L, S76→N, Y91→F.
When IGKV3-11*01 and IGKJ4*01 selected as BFU-3E2 light chain acceptor sequences, one or more of the following could be back-mutated as follows: I2→T, A43→Q, 158→V, Y87→F.
When IGKV1-13*01 and IGKJ4*01 selected as BFU-3E2 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, T22→S, A43→Q, K45→R, Y87→F.
BFU-11A8
When IGHV1-69*01 and IGHJ6*01 selected as BFU-11A8 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: R38→K, W47→L, M48→I, R66→K, V67→A, 169→L, S76→N, and Y91→F.
When IGKV3-11*01 and IGKJ4*01 selected as BFU-11A8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, S22→P, A43→Q, 158→V, Y87→F.
When IGKV1-5*01 and IGKJ4*01 selected as BFU-11A8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, M4→L, T22→P, A43→Q, Y87→F.
Example 6.1.4: Generation of Humanized Antibodies to PDGF Containing Framework Back-Mutations in CDR-Grafted Antibodies
The following humanized variable regions of the murine monoclonal PDGF antibodies were cloned into IgG expression vectors for functional characterization.
Example 6.1.4.1: BDI-5H1-F6







TABLE 1.4.1







Sequences of Humanized BDI-5H1-F6 Variable Regions











Sequence


SEQ ID

12345678901234567890123


NO:
Protein region
4567890





3882
hBDI-5H1-F6VH.1z
QVTLRESGPALVKPTQTLTLTCT




FSGFSLS




TFGMGVGWIRQPPGKALEWLANI




WWDDDKY




YNPSLKNRLTISKDTSKNQVVLT




MTNMDPV




DTATYYCARISTGISSYYVMDAW




GQGTTVT




VSS


 


3883
hBDI-5H1-F6VH.1
EVTLRESGPALVKPTQTLTLTCT




FSGFSLS




TFGMGVGWIRQPPGKALEWLANI




WWDDDKY




YNPSLKNRLTISKDTSKNQVVLT




MTNMDPV




DTATYYCARISTGISSYYVMDAW




GQGTTVT




VSS


 


3884
hBDI-5H1-F6VH.1a
EVTLRESGPALVKPTQTLTLTCT




FSGFSLS




TFGMGVGWIRQPPGKGLEWLANI




WWDDDKY




YNPSLKNRLTISKDTSNNQAVLT




ITNMDPV




DTATYYCARISTGISSYYVMDAW




GQGTTVT




VSS


 


3885
hBDI-5H1-F6VH.1b
EVTLRESGPALVKPTQTLTLTCT




FSGFSLS




TFGMGVGWIRQPPGKGLEWLANI




WWDDDKY




YNPSLKNRLTISKDTSKNQVVLT




ITNMDPV




DTATYYCARISTGISSYYVMDAW




GQGTTVT




VSS


 


3886
hBDI-5H1-F6VH.1c
EVTLRESGPALVKPTQTLTLTCT




FSGFSLS




TFGMGVGWIRQPPGKGLEWLANI




WWDDDKY




YNPSLKTRLTISKDTSKNQVVLT




ITNMDPV




DTATYYCARISTGISSYYVMDAW




GQGTTVT




VSS


 


3887
hBDI-5H1-F6VH.2z
QVTLKESGPALVKPTQTLTLTCT




FSGFSLS




TFGMGVGWIRQPPGKALEWLANI




WWDDDKY




YNPSLKNRLTISKDTSKNQVVLT




MTNMDPV




DTATYYCARISTGISSYYVMDAW




GQGTTVT




VSS


 


3888
hBDI-5H1-F6VH.2
EVTLKESGPALVKPTQTLTLTCT




FSGFSLS




TFGMGVGWIRQPPGKALEWLANI




WWDDDKY




YNPSLKNRLTISKDTSKNQVVLT




MTNMDPV




DTATYYCARISTGISSYYVMDAW




GQGTTVT




VSS


 


3889
hBDI-5H1-F6VH.2a
EVTLKESGPALVKPTQTLTLTCT




FSGFSLS




TFGMGVGWIRQPPGKGLEWLANI




WWDDDKY




YNPSLKNRLTISKDTSNSQAVLT




ITNMDPV




DTATYYCARISTGISSYYVMDAW




GQGTTVT




VSS


 


3890
hBDI-5H1-F6VH.2b
EVTLKESGPALVKPTQTLTLTCT




FSGFSLS




TFGMGVGWIRQPPGKALEWLANI




WWDDDKY




YNPSLKNRLTISKDTSKNQAVLT




ITNMDPV




DTATYYCARISTGISSYYVMDAW




GQGTTVT




VSS


 


3891
hBDI-5H1-F6VH.2c
EVTLRESGPALVKPTQTLTLTCT




FSGFSLS




TFGMGVGWIRQPPGKALEWLANI




WWDDDKY




YNPSLKNRLTISKDTSKNQAVLT




ITNMDPV




DTATYYCARISTGISSYYVMDAW




GQGTTVT




VSS


 


3892
hBDI-5H1-F6VH.v7
EVQLVESGGGLVQPGGSLRLSCA




FSGFSLS




TFGMGVGWIRQAPGKGLEWLANI




WWDDDKY




YNPSLKNRLTISKDTSKNQAYLQ




INSLRAE




DTAVYYCARISTGISSYYVMDAW




GQGTLVT




VSS


 


3893
hBDI-5H1-F6VL.1
NFMLTQPHSVSESPGKTVTISCE




RSSGDIG




DTYVSWYQQRPGSSPTTVIYGND




QRPSGVP




DRFSGSIDSSSNSASLTISGLKT




EDEADYY




CQSYDSDIDIVFGGGTKLTVL


 


3894
hBDI-5H1-F6VL.1a
NFMLTQPHSVSESPGKTVTISCE




RSSGDIG




DTYVSWYQQRPGSPPTNVIYGND




QRPSGVP




DRFSGSIDSSSNSASLTISGLKT




EDEADYF




CQSYDSDIDIVFGGGTKLTVL


 


3895
hBDI-5H1-F6VL.1b
QFMLTQPHSVSESPGKTVTIPCE




RSSGDIG




DTYVSWYQQRPGSPPTNVIYGND




QRPSEVS




DRFSGSIDSSSNSASLTISGLKT




EDEADYF




CQSYDSDIDIVFGGGTKLTVL


 


3896
hBDI-5H1-F6VL.1c
QFMLTQPHSVSESPGKTVTISCE




RSSGDIG




DTYVSWYQQRPGSSPTTVIYGND




QRPSGVP




DRFSGSIDSSSNSASLTISGLKT




EDEADYF




CQSYDSDIDIVFGGGTKLTVL


 


3897
hBDI-5H1-F6VL.2
EIVLTQSPGTLSLSPGERATLSC




ERSSGDI




GDTYVSWYQQKPGQAPRLLIYGN




DQRPSGI




PDRFSGSGSGTDFTLTISRLEPE




DFAVYYC




QSYDSDIDIVFGGGTKVEIK


 


3898
hBDI-5H1-F6L.2a
EFVLTQSPGLSLSPGERATLSCE




RSSGDIG




DTYVSWYQQKPGQPPRNVIYGND




QRPSGVP




DRFSGSIDSSSNDATLTISRLEP




EDFAVYF




CQSYDSDIDIVFGGGTKVEIK


 


3899
hBDI-5H1-F6L.2b
EFVLTQSPGTLSLSPGERATLSC




ERSSGDI




GDTYVSWYQQKPGQAPRLVIYGN




DQRPSGI




PDRFSGSGSGTDFTLTISRLEPE




DFAVYYC




QSYDSDIDIVFGGGTKVEIK


 


3900
hBDI-5H1-F6L.2c
EFVLTQSPGTLSLSPGERATLSC




ERSSGDI




GDTYVSWYQQKPGQPPRNVIYGN




DQRPSGV




PDRFSGSGSGTDFTLTISRLEPE




DFAVYFC




QSYDSDIDIVFGGGTKVEIK


 


3901
hBDI-5H1-F6VL.v6
DFVLTQSPDSLAVSLGERATINC




ERSSGDI




GDTYVSWYQQKPGQPPKNVIYGN




DQRPSGV




PDRFSGSGSGNSATLTISSLQAE




DVAVYFC




QSYDSDIDIVFGGGTKVEIK


 


3902
hBDI-5H1-F6VL.v7
DFQLTQSPSSLSASVGDRVTITC




ERSSGDI




GDTYVSWYQQKPGKAPKNVIYGN




DQRPSGV




PSRFSGSGSGNSATLTISSLQPE




DFATYFC




QSYDSDIDIVFGQGTKVEIK









    
    
        hBDI-5H1-F6VH.1z is a CDR-grafted, humanized BDI-5H1-F6 VH containing IGHV2-70*01 and IGHJ6 framework sequences.
        hBDI-5H1-F6VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBDI-5H1-F6VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (A44G, K75N, V78A and M82I).
        hBDI-5H1-F6VH.1b is an intermediate design between .1 and .1a and only has two proposed framework back-mutations (A44G and M82I).
        hBDI-5H1-F6VH.1c is based on .1b with additional one CDR germlining change N65T to improve identity to human germline sequence.
        hBDI-5H1-F6VH.2z is a CDR-grafted, humanized BDI-5H1-F6 VH containing IGHV2-70*04 and IGHJ6 framework sequences.
        hBDI-5H1-F6VH.2 is based on .2z with Q1E change to prevent pyroglutamate formation.
        hBDI-5H1-F6VH.2a (hBDI-5H1-F6VH.1d) is based on .2 and contains four proposed framework back-mutations (K75N, N76S, V78A and M82I).
        hBDI-5H1-F6VH.2b (hBDI-5H1-F6VH.v2) is an intermediate design between .2 and .2a and only has two proposed framework back-mutations (V78A and M82I).
        hBDI-5H1-F6VH.2c (hBDI-5H1-F6VH.v6) is based on .2 and contains three proposed framework back-mutations (K5R, V78A, M82I).
        hBDI-5H1-F6VH.v7 is a humanized BDI-5H1-F6 VH containing IGHV3-66*01 and IGHJ1 framework sequences with ten proposed framework back-mutations (A24F, V37I, V48L, S49A, F67L, R71K, N73T, T77Q, L78A, and M82I).
        hBDI-5H1-F6VL.1 is a CDR-grafted humanized BDI-5H1-F6 VL containing IGLV6-57*01 and IGJL2*01 framework sequences.
        hBDI-5H1-F6VL.1a is a humanized design based on .1 with 3 proposed framework back-mutations (S43P, T46N and Y87F).
        hBDI-5H1-F6VL.1b is a humanized design based on .1 with 7 proposed framework back-mutations (N1Q, S22P, S43P, T46N, G57E, P59S, Y87F).
        hBDI-5H1-F6VL.1c is an intermediate design between .1 and .1b with 2 back-mutations (N1Q and Y87F).
        hBDI-5H1-F6VL.2 is a CDR-grafted humanized BDI-5H1-F6 VL containing IGKV3-20*01 and IGJK4*01 framework sequences.
        hBDI-5H1-F6VL.2a is a humanized design based on .2 with 10 proposed framework back-mutations (I2F, A43P, L46N, L47V, I58V, G66I, G68S, T69N, F71A, Y87F) and one residue deletion (T10) and two residues insertion (D66a and S66b).
        hBDI-5H1-F6VL.2b is based on .2a only with 2 proposed framework back-mutations (12F, L47V) and without residues deletion (T10) and insertion (D66a, S66b).
        hBDI-5H1-F6VL.2c is a humanized design on .2 with 6 proposed framework back-mutations (I2F, A43P, L46N, L47V, I58V, Y87F) and without residues deletion (T10) and insertion (D66a, S66b).
        hBDI-5H1-F6VL.v6 is a humanized BDI-5H1-F6 VL containing IGKV4-1*01 and IGJK4*01 framework sequences with eight proposed framework back-mutations (I2F, M4L, L46N, L47V, T69N, D70S, F71A, Y87F).
        hBDI-5H1-F6VL.v7 is a humanized BDI-5H1-F6 VL containing IGKV1-39*01 and IGJK1*01 framework sequences with eight proposed framework back-mutations (I2F, M4L, L46N, L47V, T69N, D70S, F71A, and Y87F).
    
    


Example 6.1.4.2: BDI-9E8-E7







TABLE 1.4.2







Sequences of Humanized BDI-9E8-E7 Variable Regions









SEQ
Protein
Sequence


ID NO:
region
123456789012345678901234567890





3903
hBDI-9E8-
QVTLRESGPALVKPTQTLTLTCTFSGFSLS



E7VH.1z
TYGMGVGWIRQPPGKALEWLANIWWDDDKY




YNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTV




SS


 


3904
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFSGFSLS



E7VH.1
TYGMGVGWIRQPPGKALEWLANIWWDDDKY




YNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTV




SS


 


3905
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFSGFSLS



E7VH.1a
TYGMGVGWIRQPPGKGLEWLANIWWDDDKY




YNPSLKNRLTISKDTSKNQAVLTITNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTV




SS


 


3906
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFSGFSLS



E7VH.1b
TYGMGVGWIRQPPGKGLEWLANIWWDDDKY




YNPSLKNRLTISKDTSKNQVVLTITNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTV




SS


 


3907
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFSGFSLS



E7VH.1c
TYGMGVGWIRQPPGKGLEWLANIWWDDDKY




YNPSLKTRLTISKDTSKNQVVLTITNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTV




SS


 


3908
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFSGFSLS



E7VH.v6
TYGMGVGWIRQPPGKALEWLANIWWDDDKY




YNPSLKNRLTISKDTSKNQAVLTITNMDPV




DTATYYCARIESIGTTYSFDYWGQGTTVTV




SS


 


3909
hBDI-9E8-
EVQLVESGGGLVQPGGSLRLSCAFSGFSLS



E7VH.v7
TYGMGVGWIRQAPGKGLEWLANIWWDDDKY




YNPSLKNRLTISKDTSKNQAYLQINSLRAE




DTAVYYCARIESIGTTYSFDYWGQGTLVTV




SS


 


3910
hBDI-9E8-
NFMLTQPHSVSESPGKTVTISCERSSGDIG



E7VL.1
DSYVSWYQQRPGSSPTTVIYADDQRPSGVP




DRFSGSIDSSSNSASLTISGLKTEDEADYY




CQSYDINIDIVFGGGTKLTVL


 


3911
hBDI-9E8-
NFMLTQPHSVSESPGKTVTISCERSSGDIG



E7VL.1a
DSYVSWYQQRPGSPPTNVIYADDQRPSGVP




DRFSGSIDSSSNSASLTISGLKTEDEADYF




CQSYDINIDIVFGGGTKLTVL


 


3912
hBDI-9E8-
EIVLTQSPGTLSLSPGERATLSCERSSGDI



E7VL.2
GDSYVSWYQQKPGQAPRLLIYADDQRPSGI




PDRFSGSGSGTDFTLTISRLEPEDFAVYYC




QSYDINIDIVFGGGTKVEIK


 


3913
hBDI-9E8-
EFVLTQSPGLSLSPGERATLSCERSSGDIG



E7VL.2a
DSYVSWYQQKPGQPPRNVIYADDQRPSGVP




DRFSGSIDSSGNDATLTISRLEPEDFAVYF




CQSYDINIDIVFGGGTKVEIK


 


3914
hBDI-9E8-
EFVLTQSPGTLSLSPGERATLSCERSSGDI



E7VL.2b
GDSYVSWYQQKPGQAPRLVIYADDQRPSGI




PDRFSGSGSGTDFTLTISRLEPEDFAVYYC




QSYDINIDIVFGGGTKVEIK


 


3915
hBDI-9E8-
DFVLTQSPDSLAVSLGERATINCERSSGDI



E7VL.v6
GDSYVSWYQQKPGQPPKNVIYADDQRPSGV




PDRFSGSGSGNSASLTISSLQAEDVAVYFC




QSYDINIDIVFGGGTKVEIK


 


3916
hBDI-9E8-
DFQLTQSPSSLSASVGDRVTITCERSSGDI



E7VL.v7
GDSYVSWYQQKPGKAPKNVIYADDQRPSGV




PSRFSGSGSGNSASLTISSLQPEDFATYYC




QSYDINIDIVFGQGTKVEIK









    
    
        hBDI-9E8-E7VH.1z is a CDR-grafted, humanized BDI-9E8-E7 VH containing IGHV2-70*01 and IGHJ3*01 framework sequences.
        hBDI-9E8-E7VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBDI-9E8-E7VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations (A44G, V78A and M82I).
        hBDI-9E8-E7VH.1b is an intermediate design between .1 and .1a and only has two proposed framework back-mutations (A44G and M82I).
        hBDI-9E8-E7VH.1c is based on .1b with additional one CDR germlining change N65T to improve identity to human germline sequence.
        hBDI-9E8-E7VH.v6 is a humanized BDI-9E8-E7 VH containing IGHV2-70*04 and IGHJ6 framework sequences with four proposed framework back-mutations (Q1E, K5R, V78A, and M82I).
        hBDI-9E8-E7VH.v7 is a humanized BDI-9E8-E7 VH containing IGHV3-66*01 and IGHJ1 framework sequences with ten proposed framework back-mutations (A24F, V37I, V48L, S49A, F67L, R71K, N73T, T77Q, L78A, and M82I).
        hBDI-9E8-E7VL.1 is a CDR-grafted humanized BDI-9E8-E7 VL containing IGLV6-57*01 and IGJL2*01 framework sequences.
        hBDI-9E8-E7VL.1a is a humanized design based on .1 with three proposed framework back-mutations (S43P, T46N and Y87F).
        hBDI-9E8-E7VL.2 is a CDR-grafted humanized BDI-9E8-E7 VL containing IGKV3-20*01 and IGJK4*01 framework sequences.
        hBDI-9E8-E7VL.2a is a humanized design based on .2 with 9 proposed framework back-mutations (I2F, A43P, L46N, L47V, I58V, G66I, T69N, F71A, Y87F) and one residue deletion (T10) and two residues insertion (D66a and S66b).
        hBDI-9E8-E7VL.2b is based on .2a only with 2 proposed framework back-mutations (I2F, L47V) and without residues deletion (T10) and insertion (D66a, S66b).
        hBDI-9E8-E7VL.v6 is a humanized BDI-9E8-E7 VL containing IGKV4-1*01 and IGJK4*01 framework sequences with nine proposed framework back-mutations: (I2F, M4L, L46N, L47V, T69N, D70S, F71A, T72S, and Y87F).
        hBDI-9E8-E7VL.v7 is a humanized BDI-9E8-E7 VL containing IGKV1-39*01 and IGJK1*01 framework sequences with eight proposed framework back-mutations: I2F, M4L, L46N, L47V, T69N, D70S, F71A, and T72S.
    
    


Example 6.1.4.3: BDI-7H10-D8







TABLE 1.4.3







Sequences of Humanized BDI-7H10-D8 Variable


Regions









SEQ ID
Protein
Sequence


NO:
region
123456789012345678901234567890





3917
hBDI-7H10-
QVQLVQSGAEVKKPGSSVKVSCKASGYTFT



D8VH.1z
DYAMHWVRQAPGQGLEWMGTIIPLIDTTSY




NQKFKGRVTITADESTSTAYMELSSLRSED




TAVYYCARDWDNNWGYFDYWGQGTMVTVSS


 


3918
hBDI-7H10-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT



D8VH.1
DYAMHWVRQAPGQGLEWMGTIIPLIDTTSY




NQKFKGPVTITADESTSTAYMELSSLRSED




TAVYYCARDWDNNWGYFDYWGQGTMVTVSS


 


3919
hBDI-7H10-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT



D8VH.1a
DYAMHWVRQAPGQGLEWIGTIIPLIDTTSY




NQKFKGRATLTADTSTNTAYMELSSLRSED




TAVYYCARDWDNNWGYFDYWGQGTMVTVSS


 


3920
hBDI-7H10-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT



D8VH.1b
DYAMHWVRQAPGQGLEWIGTIIPLIDTTSY




NQKFKGPVTITADESTSTAYMELSSLRSED




TAVYYCARDWDNNWGYFDYWGQGTMVTVSS


 


3921
hBDI-7H10-
EVQLVQSGAEVKKPGSSVKVSCKASGGTFS



D8VH.1c
DYAMHWVRQAPGQGLEWIGTIIPLIDTTSY




NQKFKGRVTITADESTSTAYMELSSLRSED




TAVYYCARDWDNNWGYFDYWGQGTMVTVSS


 


3922
hBDI-7H10-
DIVMTQTPLSLSVTPGQPASISCRSSQSLE



D8VL.1
YSDGYTYLEWYLQKPGQSPQLLIYGVSNRF




SGVPDPFSGSGSGTDFTLKISPVEAEDVGV




YYCFQATHDPLTFGQGTKLEIK


 


3923
hBDI-7H10-
DVVLTQTPLSLSVTPGQPASISCRSSQSLE



D8VL.1a
YSDGYTYLEWYLQKPGQSPQLLIYGVSNRF




SGVPDPFSGSGSGTDFTLKISPVEAEDVGV




YYCFQATHDPLTFGQGTKLEIK


 


3924
hBDI-7H10-
DVVMTQTPLSLSVTPGQPASISCRSSQSLE



D8VL.1b
YSDGYTYLEWYLQKPGQSPQLLIYGVSNRF




SGVPDPFSGSGSGTDFTLKISPVEAEDVGV




YYCFQATHDPLTFGQGTKLEIK









    
    
        hBDI-7H10-D8VH.1z is a CDR-grafted, humanized BDI-7H10-D8 VH containing IGHV1-69*01 and IGHJ3 framework sequences.
        hBDI-7H10-D8VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBDI-7H10-D8VH.1a is a humanized design based on .1 and contains five proposed framework back-mutations (M48I, V67A, I69L, E73T and S76N).
        hBDI-7H10-D8VH.1b is an intermediate design between .1 and .1a and only has one proposed framework back-mutation M48I.
        hBDI-7H10-D8VH.1c is based on .1b with two additional CDR germlining changes Y27G and T30S.
        hBDI-7H10-D8VL.1 is a CDR-grafted humanized BDI-7H10-D8 VL containing IGKV2-29*02 and IGKJ2 framework sequences.
        hBDI-7H10-D8VL.1a is a humanized design based on .1 with 2 proposed framework back-mutations 12V and M4L.
        hBDI-7H10-D8VL.1b is an intermediate design between .1 and .1a with only one proposed framework back-mutation 12V.
    
    


Example 6.1.4.4: BDI-1E1-D5







TABLE 1.4.4







Sequences of Humanized BDI-1E1-D5 Variable Regions









SEQ ID
Protein
Sequence


NO:
region
123456789012345678901234567890





3925
hBDI-1E1-
QVQLVQSGAEVKKPGSSVKVSCKASGYTFT



D5VH.1z
DYVMHWVRQAPGQGLEWMGTIIPLIDTTSY




NQKFKGRVTITADKSTSTAYMELSSLRSED




TAVYYCARTSPYYYSSYDVMDAWGQGTTVT




VSS


 


3926
hBDI-1E1-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT



D5VH.1
DYVMHWVRQAPGQGLEWMGTIIPLIDTTSY




NQKFKGRVTITADKSTSTAYMELSSLRSED




TAVYYCARTSPYYYSSYDVMDAWGQGTTVT




VSS


 


3927
hBDI-1E1-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT



D5VH.1a
DYVMHWVRQAPGQGLEWIGTIIPLIDTTSY




NQKFKGRATLTADKSTNTAYMELSSLRSED




TAVYYCARTSPYYYSSYDVMDAWGQGTTVT




VSS


 


3928
hBDI-1E1-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT



D5VH.1b
DYVMHWVRQAPGQGLEWIGTIIPLIDTTSY




NQKFKGRVTITADKSTSTAYMELSSLRSED




TAVYYCARTSPYYYSSYDVMDAWGQGTTVT




VSS


 


3929
hBDI-1E1-
AIQLTQSPSSLSASVGDRVTITCKGSQNIN



D5VL.1
NYLAWYQQKPGKAPKLLIYKTNNLQTGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCYQ




YDNGYTFGQGTKLEIK


 


3930
hBDI-
AIQLTQSPSSLSASVGDRVTITCKGSQNIN



1E1-D5VL.1a
NYLAWYQQKPGKAPKLLIYKTNNLQTGIPS




RFSGSGSGTDYTLTISSLQPEDFATYYCYQ




YDNGYTFGQGTKLEIK


 


3931
hBDI-1E1-
EIVLTQSPATLSLSPGERATLSCKGSQNIN



D5VL.2
NYLAWYQQKPGQAPRLLIYKTNNLQTGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCYQ




YDNGYTFGQGTKLEIK


 


3932
hBDI-
EIVLTQSPATLSLSPGERATLSCKGSQNIN



1E1-D5VL.2a
NYLAWYQQKPGQAPRLLIYKTNNLQTGIPA




RFSGSGSGTDYTLTISSLEPEDFATYYCYQ




YDNGYTFGQGTKLEIK









    
    
        hBDI-1E1-D5VH.1z is a CDR-grafted, humanized BDI-1E1-D5 VH containing IGHV1-69*06 and JH6 framework sequences.
        hBDI-1E1-D5VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBDI-1E1-D5VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (M48I, V67A, I69L and S76N).
        hBDI-1E1-D5VH.1b is an intermediate design between .1 and .1a and only has one back-mutations M48I. This design eliminates Carter residue back-mutations.
        hBDI-1E1-D5VL.1 is a CDR-grafted humanized BDI-1E1-D5 VL containing IGKV1D-13*01 and Jk2 framework sequences.
        hBDI-1E1-D5VL.1a is a humanized design based on .1 with 2 proposed framework back-mutations (V58I and F71Y).
        hBDI-1E1-D5VL.2 is a CDR-grafted humanized BDI-1E1-D5 VL containing IGKV3-11*01 and Jk2 framework sequences.
        hBDI-1E1-D5VL.2a is a humanized design based on .2 with 2 proposed framework back-mutations (F71Y and V85T).
    
    


Example 6.1.4.5: BDI-6A3-A9







TABLE 1.4.5







Sequences of Humanized BDI-6A3-A9 Variable Regions









SEQ
Protein
Sequence


ID NO:
region
123456789012345678901234567890





3933
BDI-6A3-
EVQLVESGGGLVQPGGSLRLSCAASGFSFS



A9VH.1
DSAMAWVRQAPGKGLEWVATIIYDGSGTYY




RDSVKGRFTISRDNAKNSLYLQMNSLRAED




TAVYYCARLGFNYGNYGYYVMDAWGQGTTV




TVSS


 


3934
hBDI-6A3-
EVQLVESGGGLVQPGGSLRLSCAASGFSFS



A9VH.1a
DSAMAWVRQAPGKGLEWVATIIYDGSGTYY




RDSVKGRFTISRDNAKSSLYLQMNSLRAED




TAVYYCARLGFNYGNYGYYVMDAWGQGTTV




TVSS


 


3935
hBDI-6A3-
EVQLVESGGGLVQPGGSLRLSCAASGFTFS



A9VH.1b
DSAMAWVRQAPGKGLEWVATIIYDGSGTYY




VDSVKGRFTISRDNAKNSLYLQMNSLRAED




TAVYYCARLGFNYGNYGYYVMDAWGQGTTV




TVSS


 


3936
hBDI-6A3-
QVQLVQSGAEVKKPGASVKVSCKASGFSFS



A9VH.2z
DSAMAWVRQAPGQRLEWMGTIIYDGSGTYY




RDSVKGRVTITRDTSASTAYMELSSLRSED




TAVYYCARLGFNYGNYGYYVMDAWGQGTTV




TVSS


 


3937
hBDI-6A3-
EVQLVQSGAEVKKPGASVKVSCKASGFSFS



A9VH.2
DSAMAWVRQAPGQRLEWMGTIIYDGSGTYY




RDSVKGRVTITRDTSASTAYMELSSLRSED




TAVYYCARLGFNYGNYGYYVMDAWGQGTTV




TVSS


 


3938
hBDI-6A3-
EVQLVQSGAEVKKPGASVKVSCKASGFSFS



A9VH.2a
DSAMAWVRQAPGQGLEWVATIIYDGSGTYY




RDSVKGRFTITRDNSASTLYLELSSLRSED




TAVYYCARLGFNYGNYGYYVMDAWGQGTTV




TVSS


 


3939
hBDI-6A3-
EVQLVQSGAEVKKPGASVKVSCKASGFSFS



A9VH.2b
DSAMAWVRQAPGQGLEWVGTIIYDGSGTYY




RDSVKGRVTITRDTSASTAYLELSSLRSED




TAVYYCARLGFNYGNYGYYVMDAWGQGTTV




TVSS


 


3940
hBDI-6A3-
NFMLTQPHSVSESPGKTVTISCERSSGDIG



A9VL.1
DSYVSWYQQRPGSSPTTVIYADDQRPSGVP




DRFSGSIDSSSNSASLTISGLKTEDEADYY




CQSYDSNIDINIVFGGGTKLTVL


 


3941
hBDI-6A3-
NFMLTQPHSVSESPGKTVTISCERSSGDIG



A9VL.1a
DSYVSWYQQRPGSPPTNVIFADDQRPSGVP




DRFSGSIDSSSNSASLTISGLKTEDEADYF




CQSYDSNIDINIVFGGGTKLTVL


 


3942
hBDI-6A3-
NFMLTQPHSVSESPGKTVTISCERSSGDIG



A9VL.1b
DSYVSWYQQRPGSSPTTVIFADDQRPSGVP




DRFSGSIDSSSNSASLTISGLKTEDEADYY




CQSYDSNIDINIVFGGGTKLTVL









    
    
        hBDI-6A3-A9VH.1 is a CDR-grafted, humanized BDI-6A3-A9 VH containing IGHV3-7*01 and JH6 framework sequences.
        hBDI-6A3-A9VH.1a is a humanized design based on .1 and contains one proposed framework back-mutation N76S.
        hBDI-6A3-A9VH.1b is based on .1 with additional two CDR germlining changes S28T and R60V to improve identity to human germline sequence.
        hBDI-6A3-A9VH.2z is a CDR-grafted, humanized BDI-6A3-A9 VH containing IGHV1-3*01 and JH6 framework sequences.
        hBDI-6A3-A9VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
        hBDI-6A3-A9VH.2a is a humanized design based on .2 and contains seven proposed framework back-mutations R44G, M48V, G49A, V67F, T73N, A78L and M80L.
        hBDI-6A3-A9VH.2b is an intermediate design between .2 and .2a with only three proposed framework back-mutations R44G, M48V and M80L.
        hBDI-6A3-A9VL.1 is a CDR-grafted humanized BDI-6A3-A9 VL containing IGLV6-57*01 and JL2 framework sequences.
        hBDI-6A3-A9VL.1a is a humanized design based on .1 with 4 proposed framework back-mutations (S43P, T46N, Y49F and Y87F).
        hBDI-6A3-A9VL.1b is an intermediate design between .1 and .1a with only 1 proposed framework back-mutation Y49F.
    
    


Example 6.1.4.6: BFU-3E2







TABLE 1.4.6







Sequences of Humanized BFU-3E2 Variable Regions









SEQ ID
Protein
Sequence


NO:
region
123456789012345678901234567890












3943
hBFU-3E2VH.1z
QVQLVQSGAEVKKPGSSVKVSCKASGYTFT




ESYMYWVRQAPGQGLEWMGRIDPEDGSTDY




VEKFKNRVTITADESTSTAYMELSSLRSED




TAVYYCARFGARSYFYPMDAWGQGTTVTVS




S


 


3944
hBFU-3E2VH.1
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT




ESYMYWVRQAPGQGLEWMGRIDPEDGSTDY




VEKFKNRVTITADESTSTAYMELSSLRSED




TAVYYCARFGARSYFYPMDAWGQGTTVTVS




S


 


3945
hBFU-3E2VH.1a
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT




ESYMYWVKQAPGQGLELIGRIDPEDGSTDY




VEKFKNRVTITADESTSTAYMELSSLRSED




TAVYYCARFGARSYFYPMDAWGQGTTVTVS




S


 


3946
hBFU-3E2VH.1b
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT




ESYMYWVRQAPGQGLELIGRIDPEDGSTDY




VEKFKNRVTLTADESTSTAYMELSSLRSED




TAVYYCARFGARSYFYPMDAWGQGTTVTVS




S


 


3947
hBFU-3E2VH.1c
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT




ESYMYWVRQAPGQGLELIGRIDPEDGSTDY




VEKFKNRVTITADESTSTAYMELSSLRSED




TAVYYCARFGARSYFYPMDAWGQGTTVTVS




S


 


3948
hBFU-3E2VH.1d
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT




ESYMYWVKQAPGQSLELIGRIDPEDGSTDY




VEKFKNKATLTADESTNTAYMELSSLRSED




TAVYFCARFGARSYFYPMDAWGQGTTVTVS




S


 


3949
hBFU-3E2VL.1
EIVLTQSPATLSLSPGERATLSCRASESVS




TLMHWYQQKPGQAPRLLIYGASNLESGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ




SWNDPWTFGGGTKVEIK


 


3950
hBFU-3E2VL.1a
ETVLTQSPATLSLSPGERATLSCRASESVS




TLMHWYQQKPGQQPRLLIYGASNLESGVPA




RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ




SWNDPWTFGGGTKVEIK


 


3951
hBFU-3E2VL.1b
ETVLTQSPATLSLSPGERATLSCRASESVS




TLMHWYQQKPGQAPRLLIYGASNLESGVPA




RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ




SWNDPWTFGGGTKVEIK


 


3952
hBFU-3E2VL.1c
ETVLTQSPATLSLSPGERATLSCRASESVS




TLMHWYQQKPGQAPRLLIYGASNLESGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ




SWNDPWTFGGGTKVEIK


 


3953
hBFU-3E2VL.2
AIQLTQSPSSLSASVGDRVTITCRASESVS




TLMHWYQQKPGKAPKLLIYGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCQQ




SWNDPWTFGGGTKVEIK


 


3954
hBFU-3E2VL.2a
ATQLTQSPSSLSASVGDRVTISCRASESVS




TLMHWYQQKPGKQPRLLIYGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYFCQQ




SWNDPWTFGGGTKVEIK


 


3955
hBFU-3E2VL.2b
ATQLTQSPSSLSASVGDRVTITCRASESVS




TLMHWYQQKPGKAPRLLIYGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYFCQQ




SWNDPWTFGGGTKVEIK


 


3956
hBFU-3E2VL.2c
ATQLTQSPSSLSASVGDRVTITCRASESVS




TLMHWYQQKPGKAPRLLIYGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCQQ




SWNDPWTFGGGTKVEIK









    
    
        hBFU-3E2VH.1z is a CDR-grafted, humanized BFU-3E2 VH containing IGHV1-69*01 and IGHJ6*01 framework sequences.
        hBFU-3E2VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBFU-3E2VH.1a is a humanized design based on .1 and contains 7 proposed framework back-mutations (R38K, W47L, M48I, R66K, V67A, 169L, Y91F).
        hBFU-3E2VH.1b is an intermediate design between .1 and .1a and contains 3 proposed framework back-mutations (W47L, M48I, I69L).
        hBFU-3E2VH.1c is an intermediate design between .1 and .1a and contains 2 proposed framework back-mutations (W47L, M48I.)
        hBFU-3E2VH.1d is a humanized design based on .1 and contains 9 proposed framework back-mutations (R38K, G44S, W47L, M48I, R66K, V67A, I69L, S76N, Y91F)
        hBFU-3E2VL.1 is a CDR-grafted, humanized BFU-3E2 VL containing IGKV3-11*01 and IGKJ4*01 framework sequences.
        hBFU-3E2VL.1a is a humanized design based on .1 and contains 4 proposed framework back-mutations (I2T, A43Q, I58V, Y87F).
        hBFU-3E2VL.1b is an intermediate design between .1 and .1a. It contains 3 proposed framework back-mutations (I2T, I58V, Y87F).
        hBFU-3E2VL.1c is a design based on .1b and contains 1 proposed framework back-mutations: I2T.
        hBFU-3E2VL.2 is a CDR-grafted, humanized BFU-3E2 VL containing IGKV1-13*01 and IGKJ4*01 framework sequences.
        hBFU-3E2VL.2a is a humanized design based on .2 and contains 5 proposed framework back-mutations (I2T, T22S, A43Q, K45R, Y87F).
        hBFU-3E2VL.2b is an intermediate design between .2 and 2a. It contains 3 proposed framework back-mutations (I2T, K45R, Y87F).
        hBFU-3E2VL.2c is a design based on .2b and contains 2 proposed framework back-mutations (I2T, K45R).
    
    


Example 6.1.4.7: BFU-11A8







TABLE 1.4.7







Sequences of Humanized BFU-11A8 Variable Regions









SEQ




ID
Protein
Sequence


NO:1 
region
1234567891234567891234567890












3957
hBFU-11A8VH.1z
QVQLVQSGAEVKKPGSSVKVSCKASGYTFT




ESYIYWVRQAPGQGLEWMGRIDPEDGSTDY




VEKFKNRVTITADESTSTAYMELSSLRSED




TAVYYCARFGARSYFYPMDAWGQGTTVTVS




S


 


3958
hBFU-11A8VH.1
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT




ESYIYWVRQAPGQGLEWMGRIDPEDGSTDY




VEKFKNRVTITADESTSTAYMELSSLRSED




TAVYYCARFGARSYFYPMDAWGQGTTVTVS




S


 


3959
hBFU-11A8VH.1a
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT




ESYIYWVKQAPGQGLELIGRIDPEDGSTDY




VEKFKNKATLTADESTNTAYMELSSLRSED




TAVYFCARFGARSYFYPMDAWGQGTTVTVS




S


 


3960
hBFU-11A8VH.1b
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT




ESYIYWVRQAPGQGLELIGRIDPEDGSTDY




VEKFKNRVTLTADESTNTAYMELSSLRSED




TAVYYCARFGARSYFYPMDAWGQGTTVTVS




S


 


3961
hBFU-11A8VH.1c
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT




ESYIYWVRQAPGQGLELIGRIDPEDGSTDY




VEKFKNRVTITADESTSTAYMELSSLRSED




TAVYYCARFGARSYFYPMDAWGQGTTVTVS




S


 


3962
hBFU-11A8VL.1
EIVLTQSPATLSLSPGERATLSCRASESVS




TLMHWYQQKPGQAPRLLIYGASNLESGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ




SWNDPWTFGGGTKVEIK


 


3963
hBFU-11A8VL.1a
ETVLTQSPATLSLSPGERATLPCRASESVS




TLMHWYQQKPGQQPRLLIYGASNLESGVPA




RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ




SWNDPWTFGGGTKVEIK


 


3964
hBFU-11A8VL.1b
ETVLTQSPATLSLSPGERATLSCRASESVS




TLMHWYQQKPGQAPRLLIYGASNLESGVPA




RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ




SWNDPWTFGGGTKVEIK


 


3965
hBFU-11A8VL.1c
ETVLTQSPATLSLSPGERATLSCRASESVS




TLMHWYQQKPGQAPRLLIYGASNLESGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ




SWNDPWTFGGGTKVEIK


 


3966
hBFU-11A8VL.2
DIQMTQSPSTLSASVGDRVTITCRASESVS




TLMHWYQQKPGKAPKLLIYGASNLESGVPS




RFSGSGSGTEFTLTISSLQPDDFATYYCQQ




SWNDPWTFGGGTKVEIK


 


3967
hBFU-11A8VL.2a
DTQLTQSPSTLSASVGDRVTIPCRASESVS




TLMHWYQQKPGKQPKLLIYGASNLESGVPS




RFSGSGSGTEFTLTISSLQPDDFATYFCQQ




SWNDPWTFGGGTKVEIK


 


3968
hBFU-11A8VL.2b
DTQLTQSPSTLSASVGDRVTITCRASESVS




TLMHWYQQKPGKAPKLLIYGASNLESGVPS




RFSGSGSGTEFTLTISSLQPDDFATYFCQQ




SWNDPWTFGGGTKVEIK


 


3969
hBFU-11A8VL.2c
DTQMTQSPSTLSASVGDRVTITCRASESVS




TLMHWYQQKPGKAPKLLIYGASNLESGVPS




RFSGSGSGTEFTLTISSLQPDDFATYYCQQ




SWNDPWTFGGGTKVEIK









    
    
        hBFU-11A8VH.1z is a CDR-grafted, humanized BFU-11A8 VH containing IGHV1-69*01 and IGHJ6*01 framework sequences.
        hBFU-11A8VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBFU-11A8VH.1a is a humanized design based on .1 and contains 8 proposed framework back-mutations: R38K, W47L, M48I, R66K, V67A, 169L, S76N, Y91F.
        hBFU-11A8VH.1b is an intermediate design between .1 and .1a and contains 4 proposed framework back-mutations: W47L, M48I, I69L, S76N.
        hBFU-11A8VH.1c is a design based on .1b and contains 2 proposed framework back-mutations: W47L, M48I.
        hBFU-11A8VL.1 is a CDR-grafted, humanized BFU-11A8 VL containing IGKV3-11*01 and IGKJ4*01 framework sequences.
        hBFU-11A8VL.1a is a humanized design based on .1 and contains 5 proposed framework back-mutations: I2T, S22P, A43Q, 158V, Y87F.
        hBFU-11A8VL.1b is an intermediate design between .1 and .1a. It contains 3 proposed framework back-mutations: I2T, 158V, Y87F.
        hBFU-11A8VL.1c is a design based on .1b and contains 1 proposed framework back-mutations: I2T.
        hBFU-11A8VL.2 is a CDR-grafted, humanized BFU-11A8 VL containing IGKV1-5*01 and IGKJ4*01 framework sequences.
        hBFU-11A8VL.2a is a humanized design based on .2 and contains 5 proposed framework back-mutations: I2T, M4L, T22P, A43Q, Y87F.
        hBFU-11A8VL.2b is an intermediate design between .2 and 2a. It contains 3 proposed framework back-mutations: I2T, M4L, Y87F.
        hBFU-11A8VL.2c is a design based on .2b and contains 1 proposed framework back-mutations: I2T.
    
    


Example 6.2: Humanization of VEGF Antibodies
Example 6.2.1: Humanization Method
Antibody humanization is achieved by grafting CDRs of the rodent antibody onto a “similar” human framework (acceptor) and incorporating minimal number of key framework residues (back-mutation) from the rodent antibody that are selected to maintain the original CDR conformation in order to minimize the immunogenicity while retaining the optimal antigen binding.
Example 6.2.2: Human Germline Sequence Selections for Constructing CDR-Grafted, Humanized VEGF Antibodies
By applying the aforementioned method, the CDR sequences of VH and VL chains of monoclonal antibodies BDB-4G8-D4, BEW-9A8-E2, BEW-6C2-C8, BEW-9D2-E8, BEW-9E3-B9, BEW-5C3, BEW-9E10, BEW-1B10, and BEW-1E3 were grafted onto different human heavy and light chain acceptor sequences.
Example 6.2.2.1: BDB-4G8-D4
Based on the alignments with the VH and VL sequences of monoclonal antibody BDB-4G8-D4 of the present invention, the following known human sequences are selected:
1. IGHV7-4-1*02 and IGHJ3*01 for constructing heavy chain acceptor sequences
2. IGHV1-18*01 and IGHJ3*01 as backup acceptor sequences for constructing heavy chain
3. IGHV5-51*01 and IGHJ3*01 as backup acceptor sequences for constructing heavy chain
4. IGHV3-66*01 and IGHJ1*01 as backup acceptor sequences for constructing heavy chain
5. IGKV1D-13*01 and IGKJ2*01 for constructing light chain acceptor sequences
6. IGKV3-11*01 and IGKJ2*01 as alternative acceptor sequences for constructing light chain
7. IGKV3-15*01 and IGKJ5*01 as alternative acceptor sequences for constructing light chain
8. IGKV3-15*01 and IGKJ1*01 as alternative acceptor sequences for constructing light chain
9. IGKV1-39*01 and IGKJ1*01 as alternative acceptor sequences for constructing light chain.
By grafting the corresponding VH and VL CDRs of BDB-4G8-D4 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.2: BEW-9A8-E2
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-9A8-E2 of the present invention the following known human sequences are selected:
1. IGHV7-81*01 and IGHJ1*01 for constructing heavy chain acceptor sequences
2. IGHV1-18*01 and IGHJ1*01 as alternative acceptor sequence for constructing heavy chain
3. IGHV7-4-1*01 and IGHJ1*01 as alternative acceptor sequence for constructing heavy chain
4. IGKV6-21*01 and IGKJ2*01 for constructing light chain acceptor sequences
5. IGKV1-39*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain
6. IGKV3-11*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain
7. IGKV1-13*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain
By grafting the corresponding VH and VL CDRs of BEW-9A8-E2 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.3: BEW-6C2-C8
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-6C2-C8 of the present invention the following known human sequences are selected:
1. IGHV3-7*01 and IGHJ3*01 for constructing heavy chain acceptor sequences
2. IGKV3-11*01 and IGKJ2*01 for constructing light chain acceptor sequences
3. IGKV1-39*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain
By grafting the corresponding VH and VL CDRs of BEW-6C2-C8 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.4: BEW-9D2-E8
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-9D2-E8 of the present invention the following known human sequences are selected:
1. IGHV7-81*01 and IGHJ4*01 for constructing heavy chain acceptor sequences
2. IGHV1-18*01 and IGHJ4*01 as alternative acceptor sequence for constructing heavy chain
3. IGKV3-11*01 and IGKJ2*01 for constructing light chain acceptor sequences
4. IGKV1-39*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain
By grafting the corresponding VH and VL CDRs of BEW-9D2-E8 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.5: BEW-9E3-B9
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-9E3-B9 of the present invention the following known human sequences are selected:
1. IGHV7-81*01 and IGHJ4*01 for constructing heavy chain acceptor sequences
2. IGHV1-18*01 and IGHJ4*01 as alternative acceptor sequence for constructing heavy chain
3. IGKV3-11*01 and IGKJ2*01 for constructing light chain acceptor sequences
4. IGKV1-39*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain
By grafting the corresponding VH and VL CDRs of BEW-9E3-B9 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.6: BEW-5C3
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-5C3 of the present invention, the following known human sequences are selected:
1. IGHV7-4-1*01 and IGHJ1*01 for constructing heavy chain acceptor sequences
2. IGHV1-69*06 and IGHJ1*01 as alternative acceptor for constructing heavy chain
3. IGKV3-11*01 and IGKJ4*01 for constructing light chain acceptor sequences
4. IGKV1-13*01 and IGKJ4*01 as alternative acceptor for constructing light chain
By grafting the corresponding VH and VL CDRs of BEW-5C3 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.7: BEW-9E10
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-9E10 of the present invention, the following known human sequences are selected:
1. IGHV7-4-1*01 and IGHJ1*01 for constructing heavy chain acceptor sequences
2. IGHV1-69*06 and IGHJ1*01 as alternative acceptor for constructing heavy chain
3. IGKV1-27*01 and IGKJ2*01 for constructing light chain acceptor sequences
By grafting the corresponding VH and VL CDRs of BEW-9E10 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.8: BEW-1B10
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-1B10 of the present invention, the following known human sequences are selected:
1. IGHV3-7*01 and IGHJ6*01 for constructing heavy chain acceptor sequences
2. IGKV1-39*01 and IGKJ4*01 for constructing light chain acceptor sequences
By grafting the corresponding VH and VL CDRs of BEW-1B10 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.9: BEW-1E3
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-1E3 of the present invention, the following known human sequences are selected:
1. IGHV7-4-1*01(0-1) and IGHJ1*01 for constructing heavy chain acceptor sequences
2. IGHV1-18*01 and IGHJ1*01 as alternative acceptor for constructing heavy chain
3. IGKV3-11*01 and IGKJ2*01 for constructing light chain acceptor sequences
4. IGKV1-13*01 and IGKJ2*01 as alternative acceptor for constructing light chain
By grafting the corresponding VH and VL CDRs of BEW-1E3 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.3: Introducing Potential Framework Back-Mutations in CDR-Grafted Antibodies
To generate humanized antibody with potential framework back-mutations, the mutations were identified and introduced into the CDR-grafted antibody sequences by de novo synthesis of the variable domain, or mutagenic oligonucleotide primers and polymerase chain reactions, or by methods well known in the art. Different combinations of back mutations and other mutations are constructed for each of the CDR-grafts as follows. Residue numbers for these mutations are based on the Kabat numbering system.
Example 6.2.3.1: BDB-4G8-D4
When IGHV7-4-1*02 and IGHJ3*01 selected as BDB-4G8-D4 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→, V2→I, W47→Y, and Y91→F.
When IGHV1-18*01 and IGHJ3*01 selected as BDB-4G8-D4 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, W47→Y, V67→F, M69→F, T71→L and Y91→F.
When IGHV5-51*01 and IGHJ3*01 selected as BDB-4G8-D4 heavy chain acceptor sequences, one or more following residues could be back-mutated as follows: V2→I, A9→T, G24→A, R38→K, W47→Y, Q66→R, V67→F, I69→F, A71→L, I75→F, S76→N, Y79→F and Y91→F.
When IGHV3-66*01 and IGHJ1*01 selected as BDB-4G8-D4 heavy chain acceptor sequences, one or more following residues could be back-mutated as follows: V2→I, E6→Q, L11→V, R38→K, W47→Y, V48→M, S49→G, I69→F, R71→L, N73→T, N76→S, L78→A, M82→L and Y91→F.
When IGKV1D-13*01 and IGKJ2*01 selected as BDB-4G8-D4 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, A43→Q and Y87→F with or without one residue deletion (S10).
When IGKV3-11*01 and IGKJ2*01 selected as BDB-4G8-D4 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: E1→D, I2→T, I58→V, and Y87→F.
When IGKV3-15*01 and IGKJ5*01 or IGKJ5*01 selected as BDB-4G8-D4 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: E1→D, I2→T, M4→L, A9→S, L13→A, L21→I, R45→K, I58→V, A60→S, G66→R, E70→D, E79→Q and Y87→F.
When IGKV1-39*01 and IGKJ1*01 selected as BDB-4G8-D4 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, M4→L, T22→S, and Y87→F.
Example 6.2.3.2: BEW-9A8-E2
When IGHV7-81*01 and IGHJ1*01 selected as BEW-9A8-E2 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E V2→I, P38→K, W47→Y, M71→L, Y90→F and Y91→F with or without CDR change T28→S.
When IGHV1-18*01 and IGHJ1*01 selected as BEW-9A8-E2 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, R38→K, W47→Y, V67→F, M69→F, T71→L, Y90→F and Y91→F.
When IGHV7-4-1*01 and IGHJ1*01 selected as BEW-9A8-E2 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, R38→K, W47→Y, Y90→F, Y91→F.
When IGKV6-21*01 and IGKJ2*01 selected as BEW-9A8-E2 light chain accepter sequences, one or more of the following residues could be back-mutated as follows: I2→T, S434Q, K49→H and Y87→F. Additional mutations include the following: F10 deletion.
When IGKV1-39*01 and IGKJ2*01 selected as BEW-9A8-E2 light chain accepter sequences, one or more of the following residues could be back-mutated as follows: I2→T, M4→L, A43→Q, Y49→H and Y87→F. Additional mutations include the following: S10 deletion.
When IGKV3-11*01 and IGKJ2*01 selected as BEW-9A8-E2 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, Y49→H, I58→V, V85→T, and Y87→F.
When IGKV1-13*01 and IGKJ2*01 selected as BEW-9A8-E2 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, T22→S, Y49→H, Y87→F.
Example 6.2.3.3: BEW-6C2-C8
When IGHV3-7*01 and IGHJ3*01 selected as BEW-6C2-C8 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V37→I, V48→M and R94→A.
When IGKV3-11*01 and IGKJ2*01 selected as BEW-6C2-C8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: F71→Y and Y87→F.
When IGKV1-39*01 and IGKJ2*01 selected as BEW-6C2-C8 light chain acceptor sequence, one or more of the following residues could be back-mutated as follows: M4→L, V58→I, F71→Y and Y87→F.
Example 6.2.3.4: BEW-9D2-E8
When IGHV7-81*01 and IGHJ4*01 selected as BEW-9D2-E8 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, P38→K, Q39→L, W47→Y, M48→L, M71→L and Y91→F with or without CDR change T28→S.
When IGHV1-18*01 and IGHJ4*01 selected as BEW-9D2-E8 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, R38→K, Q39→L, W47→Y, M48→L, V67→F, M69→F, T71→L, M80→L and Y91→F.
When IGKV3-11*01 and IGKJ2*01 selected as BEW-9D2-E8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, A43→Q, I58→V and Y87→F. Additional mutations include the following: T10 deletion.
When IGKV1-39*01 and IGKJ2*01 selected as BEW-9D2-E8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, M4→L, A43→Q and Y87→F. Additional mutations include the following: T10 deletion.
Example 6.2.3.5: BEW-9E3-B9
When IGHV7-81*01 and IGHJ4*01 selected as BEW-9E3-B9 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1E, V2→I, W47→Y, M71→L and Y91→F with or without CDR change T28→S.
When IGHV1-18*01 and IGHJ4*01 selected as BEW-9E3-B9 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, W47→Y, V67→F, M69→F, T71→L and Y91→F.
When IGKV3-11*01 and IGKJ2*01 selected as BEW-9E3-B9 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, A43→Q, I58→V and Y87→F. Additional mutations include the following: S10 deletion.
When IGKV1-39*01 and IGKJ2*01 selected as BEW-9E3-B9 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, M4→L, A43→Q and Y87→F. Additional mutations include the following: S10 deletion.
Example 6.2.3.6: BEW-5C3
When IGHV7-4-1*01 and IGHJ1*01 selected as BEW-5C3 heavy chain accepter sequences, one or more of the following residues could be back-mutated as follows: V2→I, R38→K, W47→Y, Y90→F, Y91→F.
When IGHV1-69*01 and IGHJ1*01 selected as BEW-5C3 heavy chain accepter sequences, one or more of the following residues could be back-mutated as follows: V67→F, I69→F, A71→L. Additional mutations include the following: V2→I, R38→K, W47→Y, T68→V, M80→L, Y90→F, Y91→F.
When IGKV3-11*01 and IGKJ4*01 selected as BEW-5C3 light chain accepter sequences, one or more of the following residues could be back-mutated as follows: E1→D, I2→T, Y36→F, Y87→F. Additional mutations include the following: A43→Q, I58→V, C34→S (CDR change).
When IGKV1-13*01 and IGKJ4*01 selected as BEW-5C3 light chain accepter sequences, one or more of the following residues could be back-mutated as follows: A1→D, I2→T, T22→S, Y36→F, A43→Q, Y87→F with CDR change C34→S.
Example 6.2.3.7: BEW-9E10
When IGHV7-4-1*01 and IGHJ1*01 selected as BEW-9E10 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V2→I, R38→K, W47→Y, Y91→F.
When IGHV1-69*06 and IGHJ1*01 selected as BEW-9E10 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V67→F, I69→F. Additional mutations include the following: V2→I, R38→K, W47→Y, Y91→F.
When IGKV1-27*01 and IGKJ2*01 selected as BEW-9E10 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q3→R, V43→S, F71→Y, Y87→F. Additional mutations include the following: T22→E, T72→S.
Example 6.2.3.8: BEW-1B10
When IGHV3-7*01 and IGHJ6*01 selected as BEW-1B10 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V37→F, I69→V. Additional mutations include the following: N76→S, S77→T.
When IGKV1-39*01 and IGKJ4*01 selected as BEW-1B10 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: A43→S, F71→Y. Additional mutations include the following: L47→V.
Example 6.2.3.9: BEW-1E3
When IGHV7-4-1*01 and IGHJ1*01 selected as BEW-1E3 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V2→I, R38→K, W47→Y, Y91→F.
When IGHV1-18*01 and IGHJ1*01 selected as BEW-1E3 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V67→F, M69→F, T71→L. Additional mutations include the following: V2→I, R38→K, W47→Y, Y91→F.
When IGKV3-11*01 and IGKJ2*01 selected as BEW-1E3 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I58→V, Y87→F. Additional mutations include the following: I2→T, A43→Q.
When IGKV1-13*01 and IGKJ2*01 selected as BEW-1E3 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Y87→F. Additional mutations include the following: I2→T, T22→S, A43→Q.
Example 6.2.4: Generation of Humanized Antibodies to VEGF Containing Framework Back-Mutations in CDR-Grafted Antibodies
The following humanized variable regions of the murine monoclonal VEGF antibodies were cloned into IgG expression vectors for functional characterization.
Example 6.2.4.1: BDB-4G8-D4







TABLE 2.4.1







Sequences of Humanized BDB-4G8-D4 Variable Regions









SEQ




ID

Sequence


NO:
Protein region
123456789012345678901234567890












654
hBDB-4G8-D4VH.1z
QVQLVQSGSELKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWINTETGKPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSS


 


655
hBDB-4G8-D4VH.1
EVQLVQSGSELKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWINTETGKPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSS


 


656
hBDB-4G8-D4VH.1a
EIQLVQSGSELKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEYMGWINTETGKPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYFCARTNYYYRSYIFYFDYWGQGTMVT




VSS


 


657
hBDB-4G8-D4VH.1b
EVQLVQSGSELKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEYMGWINTETGKPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSS


 


658
hBDB-4G8-D4VH.2z
QVQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWINTETGKPTY




ADDFKGRVTMTTDTSTSTAYMELRSLRSDD




TAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSS


 


659
hBDB-4G8-D4VH.2
EVQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWINTETGKPTY




ADDFKGRVTMTTDTSTSTAYMELRSLRSDD




TAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSS


 


660
hBDB-4G8-D4VH.2a
EIQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEYMGWINTETGKPTY




ADDFKGRFTFTLDTSTSTAYMELRSLRSDD




TAVYFCARTNYYYRSYIFYFDYWGQGTMVT




VSS


 


661
hBDB-4G8-D4VH.2b
EVQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEYMGWINTETGKPTY




ADDFKGRVTMTLDTSTSTAYMELRSLRSDD




TAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSS


 


662
hBDB-4G8-D4VH.v3
EIQLVQSGTEVKKPGESLKISCKASGYTFT




NYGMYWVKQMPGKGLEYMCWINTETGKPTY




ADDFKGRFTFSLDKSFNTAFLQWSSLKASD




TAMYFCARTNYYYRSYIFYFDYWGQGTMVT




VSS


 


663
hBDB-4G8-D4VH.v4
EIQLVQSGGGVVQPGGSLRLSCAASGYTFT




NYGMYWVKQAPGKGLEYMCWINTETGKPTY




ADDFKGRFTFSLDTSKSTAYLQLNSLRAED




TAVYFCARTNYYYRSYIFYFDYWGQGTLVT




VSS


 


664
hBDB-4G8-D4VH.v5
EVQLVESGGGLVQPGGSLRLSCAASGYTFT




NYGMYWVKQAPGKGLEYMGWINTETGKPTY




ADDFKGRFTFSLDTSKSTAYLQMNSLRAED




TAVYFCARTNYYYRSYIFYFDYWGQGTLVT




VSS


 


665
hBDB-4G8-D4VL.1
AIQLTQSPSSLSASVGDRVTITCRASESVS




THMHWYQQKPGKAPKLLIYGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCQQ




SWNDPFTFGQGTKLEIK


 


666
hBDB-4G8-D4VL.1a
ATQLTQSPSLSASVGDRVTITCRASESVST




HMHWYQQKPGKQPKLLIYGASNLESGVPSR




FSGSGSGTDFTLTISSLQPEDFATYFCQQS




WNDPFTFGQGTKLEIK


 


667
hBDB-4G8-D4VL.1b
ATQLTQSPSLSASVGDRVTITCRASESVST




HMHWYQQKPGKAPKLLIYGASNLESGVPSR




FSGSGSGTDFTLTISSLQPEDFATYYCQQS




WNDPFTFGQGTKLEIK


 


668
hBDB-4G8-D4VL.1c
ATQLTQSPSSLSASVGDRVTITCRASESVS




THMHWYQQKPGKAPKLLIYGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCQQ




SWNDPFTFGQGTKLEIK


 


669
hBDB-4G8-D4VL.v2
DTVLTQSPATLSLSPGERATLSCRASESVS




THMHWYQQKPGQAPRLLIYGASNLESGVPA




RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ




SWNDPFTFGQGTKLEIK


 


670
hBDB-4G8-D4VL.v3
ETVLTQSPATLSVSPGERATLSCRASESVS




THMHWYQQKPGQAPRLLIYGASNLESGVPA




RFSGSGSGTDFTLTISSLQSEDFAVYFCQQ




SWNDPFTFGQGTRLEIK


 


671
hBDB-4G8-D4VL.v4
DTVLTQSPSTLSASPGERATISCRASESVS




THMHWYQQKPGQAPKLLIYGASNLESGVPS




RFSGSRSGTDFTLTISSLQPEDFAVYFCQQ




SWNDPFTFGQGTKVEIK


 


672
hBDB-4G8-D4VL.v5
DTQLTQSPSSLSASVGDRVTISCRASESVS




THMHWYQQKPGKAPKLLIYGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYFCQQ




SWNDPFTFGQGTKVEIK









    
    
        hBDB-4G8-D4VH.1z is a CDR-grafted, humanized BDB-4G8-D4 VH containing IGHV7-4-1*02 and IGHJ3*01 framework sequences.
        hBDB-4G8-D4VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBDB-4G8-D4VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations (V2I, W47Y and Y91F).
        hBDB-4G8-D4VH.1b is an intermediate design between .1 and .1a and only has one back-mutations W47Y.
        hBDB-4G8-D4VH.2z is a CDR-grafted, humanized BDB-4G8-D4 VH containing IGHV1-18*01 and IGHJ3*01 framework sequences.
        hBDB-4G8-D4VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
        hBDB-4G8-D4VH.2a is a humanized design based on .2 and contains six proposed framework back-mutations (V2I, W47Y, V67F, M69F, T71L and Y91F).
        hBDB-4G8-D4VH.2b is an intermediate design between .2 and .2a and only has two proposed framework back-mutations (W47Y and T71L).
        hBDB-4G8-D4VH.v3 is a humanized BDB-4G8-D4 VH containing IGHV5-51*01 and
    
    


IGHJ3*01 framework sequences with thirteen proposed framework back-mutations (V21, A9T, G24A, R38K, W47Y, Q66R, V67F, 169F, A71L, I75F, S76N, Y79F and Y91F).

    
    
        hBDB-4G8-D4VH.v4 is a humanized BDB-4G8-D4 VH containing IGHV3-66*01 and IGHJ1*01 framework sequences with thirteen proposed framework back-mutations (V21, E6Q, L11V, W47Y, V48M, S49G, 169F, R71L, N73T, N76S, L78A, M82L and Y91F).
        hBDB-4G8-D4VH.v5 is a humanized BDB-4G8-D4 containing IGHV3-66*01 and IGHJ1*01 framework sequences with ten proposed framework back-mutations (R38K, W47Y, V48M, S49G, 169F, R71L, N73T, N76S, L78A and Y91F).
        hBDB-4G8-D4VL.1 is a CDR-grafted humanized BDB-4G8-D4 VL containing IGKV1D-13*01 and IGKJ2*01 framework sequences.
        hBDB-4G8-D4VL.1a is a humanized design based on .1 with 3 proposed framework back-mutations (I2T, A43Q and Y87F) and one residue deletion (S10).
        hBDB-4G8-D4VL.1b is an intermediate design between .1 and .1a with only one proposed framework back-mutation 12T.
        hBDB-4G8-D4VL.1c is a humanized design based on .1b with one residue insertion (S10).
        hBDB-4G8-D4VL.v2 is a humanized BDB-4G8-D4 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences with four proposed framework back-mutations (E1D, 12T, I58V, and Y87F).
        hBDB-4G8-D4VL.v3 is a humanized BDB-4G8-D4 VL design containing IGKV3-15*01 and IGKJ5*01 framework sequences with five proposed framework back-mutations (I2T, M4L, I58V, E70D, and Y87F).
        hBDB-4G8-D4VL.v4 is a humanized BDB-4G8-D4 VL containing IGKV3-15*01 and IGKJ1*01 framework sequences with eleven proposed framework back-mutations (E1D, 12T, A9S, L13A, L21I, R45K, I58V, A605, G66R, E79Q, and Y87F).
        hBDB-4G8-D4VL.v5 is a humanized BDB-4G8-D4 VL containing IGKV1-39*01 and IGKJ1*01 framework sequences with four proposed framework back-mutations (I2T, M4L, T22S, and Y87F).
    
    


Example 6.2.4.2: BEW-9A8-E2







TABLE 2.4.2







Sequences of Humanized BEW-9A8-E2 Variable Regions









SEQ ID
Protein
Sequence


NO:
region
123456789012345678901234567890












673
hBEW-9A8-
QVQLVQSGHEVKQPGASVKVSCKASGYTFT



E2VH.1z
NYGMYWVPQAPGQGLEWMGWINTETGKPIY




ADDFKGRFVFSMDTSASTAYLQISSLKAED




MAMYYCARVDYDGSFWFAYWGQGTLVTVSS


 


674
hBEW-9A8-
EVQLVQSGHEVKQPGASVKVSCKASGYTFT



E2VH.1
NYGMYWVPQAPGQGLEWMGWINTETGKPIY




ADDFKGRFVFSMDTSASTAYLQISSLKAED




MAMYYCARVDYDGSFWFAYWGQGTLVTVSS


 


675
hBEW-9A8-
EIQLVQSGHEVKQPGASVKVSCKASGYTFT



E2VH.1a
NYGMYWVKQAPGQGLEYMGWINTETGKPIY




ADDFKGRFVFSLDTSASTAYLQISSLKAED




MAMFFCARVDYDGSFWFAYWGQGTLVTVSS


 


676
hBEW-9A8-
EVQLVQSGHEVKQPGASVKVSCKASGYTFT



E2VH.1b
NYGMYWVPQAPGQGLEYMGWINTETGKPIY




ADDFKGRFVFSLDTSASTAYLQISSLKAED




MAMFYCARVDYDGSFWFAYWGQGTLVTVSS


 


677
hBEW-9A8-
EVQLVQSGHEVKQPGASVKVSCKASGYSFT



E2VH.1c
NYGMYWVPQAPGQGLEYMGWINTETGKPIY




ADDFKGRFVFSLDTSASTAYLQISSLKAED




MAMFYCARVDYDGSFWFAYWGQGTLVTVSS


 


678
hBEW-9A8-
QVQLVQSGAEVKKPGASVKVSCKASGYTFT



E2VH.2z
NYGMYWVRQAPGQGLEWMGWINTETGKPIY




ADDFKGRVTMTTDTSTSTAYMELRSLRSDD




TAVYYCARVDYDGSFWFAYWGQGTLVTVSS


 


679
hBEW-9A8-
EVQLVQSGAEVKKPGASVKVSCKASGYTFT



E2VH.2
NYGMYWVRQAPGQGLEWMGWINTETGKPIY




ADDFKGRVTMTTDTSTSTAYMELRSLRSDD




TAVYYCARVDYDGSFWFAYWGQGTLVTVSS


 


680
hBEW-9A8-
EIQLVQSGAEVKKPGASVKVSCKASGYTFT



E2VH.2a
NYGMYWVKQAPGQGLEYMGWINTETGKPIY




ADDFKGRFTFTLDTSTSTAYMELRSLRSDD




TAVFFCARVDYDGSFWFAYWGQGTLVTVSS


 


681
hBEW-9A8-
EVQLVQSGAEVKKPGASVKVSCKASGYTFT



E2VH.2b
NYGMYWVRQAPGQGLEYMGWINTETGKPIY




ADDFKGRVTMTLDTSTSTAYMELRSLRSDD




TAVFYCARVDYDGSFWFAYWGQGTLVTVSS


 


682
hBEW-9A8-
EIQLVQSGAEVKKPGASVKVSCKASGYTFT



E2VH.2c
NYGMYWVKQAPGQGLEYMGWINTETGKPIY




ADDFKGRFTFTLDTSTSTAYMELRSLRSDD




TAVYYCARVDYDGSFWFAYWGQGTLVTVSS


 


683
hBEW-9A8-
EIQLVQSGAEVKKPGASVKVSCKASGYTFT



E2VH.2d
NYGMYWVRQAPGQGLEWMGWINTETGKPIY




ADDFKGRFTFTLDTSTSTAYMELRSLRSDD




TAVYYCARVDYDGSFWFAYWGQGTLVTVSS


 


684
hBEW-9A8-
QVQLVQSGSELKKPGASVKVSCKASGYTFT



E2VH.3z
NYGMYWVRQAPGQGLEWMGWINTETGKPIY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARVDYDGSFWFAYWGQGTLVTVSS


 


685
hBEW-9A8-
EVQLVQSGSELKKPGASVKVSCKASGYTFT



E2VH.3
NYGMYWVRQAPGQGLEWMGWINTETGKPIY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARVDYDGSFWFAYWGQGTLVTVSS


 


686
hBEW-9A8-
EIQLVQSGSELKKPGASVKVSCKASGYTFT



E2VH.3a
NYGMYWVKQAPGQGLEYMGWINTETGKPIY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARVDYDGSFWFAYWGQGTLVTVSS


 


687
hBEW-9A8-
EIQLVQSGSELKKPGASVKVSCKASGYTFT



E2VH.3b
NYGMYWVRQAPGQGLEWMGWINTETGKPIY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARVDYDGSFWFAYWGQGTLVTVSS


 


688
hBEW-9A8-
EIQLVQSGSELKKPGASVKVSCKASGYTFT



E2VH.3c
NYGMYWVKQAPGQGLEYMGWINTETGKPIY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVFFCARVDYDGSFWFAYWGQGTLVTVSS


 


689
hBEW-9A8-
EIVLTQSPDFQSVTPKEKVTITCRASESVS



E2VL.1
TVIHWYQQKPDQSPKLLIKGASNLESGVPS




RFSGSGSGTDFTLTINSLEAEDAATYYCQQ




HWNDPPTFGQGTKLEIK


 


690
hBEW-9A8-
ETVLTQSPDFQSVTPKEKVTITCRASESVS



E2VL.1a
TVIHWYQQKPDQQPKLLIHGASNLESGVPS




RFSGSGSGTDFTLTINSLEAEDAATYFCQQ




HWNDPPTFGQGTKLEIK


 


691
hBEW-9A8-
ETVLTQSPDFQSVTPKEKVTITCRASESVS



E2VL.1b
TVIHWYQQKPDQSPKLLIHGASNLESGVPS




RFSGSGSGTDFTLTINSLEAEDAATYYCQQ




HWNDPPTFGQGTKLEIK


 


692
hBEW-9A8-
ETVLTQSPDQSVTPKEKVTITCRASESVST



E2VL.1c
VIHWYQQKPDQSPKLLIHGASNLESGVPSR




FSGSGSGTDFTLTINSLEAEDAATYYCQQH




WNDPPTFGQGTKLEIK


 


693
hBEW-9A8-
DIQMTQSPSSLSASVGDRVTITCRASESVS



E2VL.2
TVIHWYQQKPGKAPKLLIYGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCQQ




HWNDPPTFGQGTKLEIK


 


694
hBEW-9A8-
DTQLTQSPSSLSASVGDRVTITCRASESVS



E2VL.2a
TVIHWYQQKPGKQPKLLIHGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYFCQQ




HWNDPPTFGQGTKLEIK


 


695
hBEW-9A8-
DTQMTQSPSSLSASVGDRVTITCRASESVS



E2VL.2b
TVIHWYQQKPGKAPKLLIHGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCQQ




HWNDPPTFGQGTKLEIK


 


696
hBEW-9A8-
DTQMTQSPSLSASVGDRVTITCRASESVST



E2VL.2c
VIHWYQQKPGKAPKLLIHGASNLESGVPSR




FSGSGSGTDFTLTISSLQPEDFATYYCQQH




WNDPPTFGQGTKLEIK


 


697
hBEW-9A8-
EIVLTQSPATLSLSPGERATLSCRASESVS



E2VL.3
TVIHWYQQKPGQAPRLLIYGASNLESGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ




HWNDPPTFGQGTKLEIK


 


698
hBEW-9A8-
ETVLTQSPATLSLSPGERATLSCRASESVS



E2VL.3a
TVIHWYQQKPGQAPRLLIHGASNLESGVPA




RFSGSGSGTDFTLTISSLEPEDFATYFCQQ




HWNDPPTFGQGTKLEIK


 


699
hBEW-9A8-
ETVLTQSPATLSLSPGERATLSCRASESVS



E2VL.3b
TVIHWYQQKPGQAPRLLIYGASNLESGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ




HWNDPPTFGQGTKLEIK


 


700
hBEW-9A8-
ETVLTQSPATLSLSPGERATLSCRASESVS



E2VL.3c
TVIHWYQQKPGQAPRLLIYGASNLESGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ




HWNDPPTFGQGTKLEIK


 


701
hBEW-9A8-
AIQLTQSPSSLSASVGDRVTITCRASESVS



E2VL.4
TVIHWYQQKPGKAPKLLIYGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCQQ




HWNDPPTFGQGTKLEIK


 


702
hBEW-9A8-
ATQLTQSPSSLSASVGDRVTISCRASESVS



E2VL.4a
TVIHWYQQKPGKAPKLLIHGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYFCQQ




HWNDPPTFGQGTKLEIK


 


703
hBEW-9A8-
ATQLTQSPSSLSASVGDRVTITCRASESVS



E2VL.4b
TVIHWYQQKPGKAPKLLIYGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYFCQQ




HWNDPPTFGQGTKLEIK


 


704
hBEW-9A8-
ATQLTQSPSSLSASVGDRVTITCRASESVS



E2VL.4c
TVIHWYQQKPGKAPKLLIYGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCQQ




HWNDPPTFGQGTKLEIK









    
    
        hBEW-9A8-E2VH.1z is a CDR-grafted, humanized BEW-9A8-E2 VH containing IGHV7-81*01 and IGHJ1*01 framework sequences.
        hBEW-9A8-E2VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBEW-9A8-E2VH.1a is a humanized design based on .1 and contains six proposed framework back-mutations (V2I, P38K, W47Y, M71L, Y90F and Y91F).
        hBEW-9A8-E2VH.1b is an intermediate design between .1 and .1a and only has three proposed framework back-mutations (W47Y, M71L and Y90F).
        hBEW-9A8-E2VH.1c is based on .1b with additional one CDR germlining change T28S to improve identity to human germline sequence.
        hBEW-9A8-E2VH.2z is a CDR-grafted, humanized BEW-9A8-E2 VH containing IGHV1-18*01 and IGHJ1*01 framework sequences.
        hBEW-9A8-E2VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
        hBEW-9A8-E2VH.2a is a humanized design based on .2 and contains eight proposed framework back-mutations (V2I, R38K, W47Y, V67F, M69F, T71L, Y90F and Y91F).
        hBEW-9A8-E2VH.2b is an intermediate design between .2 and .2a and contains three back-mutations (W47Y, M71L and Y90F).
        hBEW-9A8-E2VH.2c (hBEW-9A8VH.4a) is an intermediate design between .2 and .2a and contains six proposed framework back-mutations (V21, R38K, W47Y, V67F, M69F, and T71L).
        hBEW-9A8-E2VH.2d (hBEW-9A8VH.4b) is an intermediate design between .2 and .2a contains four proposed framework back-mutations (V2I, V67F, M69F, and T71L).
        hBEW-9A8VH.3z is a CDR-grafted, humanized BEW-9A8 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
        hBEW-9A8VH.3 is based on .3z with a Q1E change to prevent pyroglutamate formation.
        hBEW-9A8VH.3a is a humanized design based on .3 and contains 3 proposed framework back-mutations (V2I, R38K, W47Y).
        hBEW-9A8VH.3b is an intermediate design between .3 and .3a and contains 1 proposed framework back-mutations: V21.
        hBEW-9A8VH.3c is a humanized design based on .3 and contains 5 proposed framework back-mutations (V2I, R38K, W47Y, Y90F, Y91F).
        hBEW-9A8-E2VL.1 is a CDR-grafted humanized BEW-9A8-E2 VL containing IGKV6-21*01 and IGKJ2*01 framework sequences.
        hBEW-9A8-E2VL.1a is a humanized design based on .1 with four proposed framework back-mutations (I2T, S43Q, K49H and Y87F).
        hBEW-9A8-E2VL.1b is an intermediate design between .1 and .1a with only two proposed framework back-mutation (I2T and K49H).
        hBEW-9A8-E2VL.1c is based on .1b with one residue deletion of F10.
        hBEW-9A8-E2VL.2 is a CDR-grafted humanized BEW-9A8-E2 VL containing IGKV1-39*01 and IGKJ2*01 framework sequences.
        hBEW-9A8-E2VL.2a is a humanized design based on .2 with five proposed framework back-mutations (I2T, M4L, A43Q, Y49H and Y87F).
        hBEW-9A8-E2VL.2b is an intermediate design between .1 and .1a with only two proposed framework back-mutation (I2T and Y49H).
        hBEW-9A8-E2VL.2c is based on .2b with one residue deletion of S10.
        hBEW-9A8VL.3 is a CDR-grafted, humanized BEW-9A8 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
        hBEW-9A8VL.3a is a humanized design based on .3 and contains 5 proposed framework back-mutations: (I2T, Y49H, I58V, V85T, Y87F).
        hBEW-9A8VL.3b is an intermediate design between .3 and 3a. It contains 2 proposed framework back-mutations: (I2T, Y87F).
        hBEW-9A8VL.3c is a design based on .3b and contains 1 proposed framework back-mutations: I2T.
        hBEW-9A8VL.4 is a CDR-grafted, humanized BEW-9A8 VL containing IGKV1-13*01 and IGKJ2*01 framework sequences.
        hBEW-9A8VL.4a is a humanized design based on .4 and contains 4 proposed framework back-mutations: I2T, T22S, Y49H, Y87F.
        hBEW-9A8VL.4b is an intermediate design between .4 and 4a. It contains 2 proposed framework back-mutations: I2T, Y87F.
        hBEW-9A8VL.4c is a design based on .4b and eliminated Carter residue back-mutations. It contains 1 proposed framework back-mutations: I2T.
    
    


Example 6.2.4.3: BEW-6C2-C8







TABLE 2.4.3







Sequences of Humanized BEW-6C2-C8 Variable Regions









SEQ




ID
Protein
Sequence


NO:
region
123456789012345678901234567890












705
hBEW-6C2-C8VH.1
EVQLVESGGGLVQPGGSLRLSCAASGFTFS




YYGMHWVRQAPGKGLEWVALIYYDSSKMYY




ADSVKGRFTISRDNAKNSLYLQMNSLRAED




TAVYYCARGGTAPVYWGQGTMVTVSS


 


706
hBEW-6C2-
EVQLVESGGGLVQPGGSLRLSCAASGFTFS



C8VH.1a
YYGMHWIRQAPGKGLEWMALIYYDSSKMYY




ADSVKGRFTISRDNAKNSLYLQMNSLRAED




TAVYYCAAGGTAPVYWGQGTMVTVSS


 


707
hBEW-6C2-
EVQLVESGGGLVQPGGSLRLSCAASGFTFS



C8VH.1b
YYGMHWVRQAPGKGLEWMALIYYDSSKMYY




ADSVKGRFTISRDNAKNSLYLQMNSLRAED




TAVYYCAAGGTAPVYWGQGTMVTVSS


 


708
hBEW-6C2-C8VL.1
EIVLTQSPATLSLSPGERATLSCKGSQNIA




NYLAWYQQKPGQAPRLLIYNTDSLQTGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCYQ




SNNGYTFGQGTKLEIK


 


709
hBEW-6C2-
EIVLTQSPATLSLSPGERATLSCKGSQNIA



C8VL.1a
NYLAWYQQKPGQAPRLLIYNTDSLQTGIPA




RFSGSGSGTDYTLTISSLEPEDFAVYFCYQ




SNNGYTFGQGTKLEIK


 


710
hBEW-6C2-C8VL.2
DIQMTQSPSSLSASVGDRVTITCKGSQNIA




NYLAWYQQKPGKAPKLLIYNTDSLQTGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCYQ




SNNGYTFGQGTKLEIK


 


711
hBEW-6C2-
DIQLTQSPSSLSASVGDRVTITCKGSQNIA



C8VL.2a
NYLAWYQQKPGKAPKLLIYNTDSLQTGIPS




RFSGSGSGTDYTLTISSLQPEDFATYFCYQ




SNNGYTFGQGTKLEIK









    
    
        hBEW-6C2-C8VH.1 is a CDR-grafted, humanized BEW-6C2-C8 VH containing IGHV3-7*01 and IGHJ3*01 framework sequences.
        hBEW-6C2-C8VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations V37I, V48M and R94A.
        hBEW-6C2-C8VH.1b is an intermediate design between .1 and .1a and only has two back-mutations V48M and R94A. This design eliminates Carter residue back-mutations.
        hBEW-6C2-C8VL.1 is a CDR-grafted humanized BEW-6C2-C8 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
        hBEW-6C2-C8VL.1a is a humanized design based on .1 with 2 proposed framework back-mutations (F71Y and Y87F).
        hBEW-6C2-C8VL.2 is a CDR-grafted humanized BEW-6C2-C8 VL containing IGKV1-39*01 and IGKJ2*01 framework sequences.
        hBEW-6C2-C8VL.2a is a humanized design based on .2 with 4 proposed framework back-mutations (M4L, V58I, F71Y and Y87F).
    
    


Example 6.2.4.4: BEW-9D2-E8







TABLE 2.4.4







Sequences of Humanized BEW-9D2-E8 Variable Regions









SEQ




ID
Protein
Sequence


NO:
region
123456789012345678901234567890












712
hBEW-9D2-E8VH.1z
QVQLVQSGHEVKQPGASVKVSCKASGYTFT




NYGMYWVPQAPGQGLEWMGWINTETGKPTY




ADDFKGRFVFSMDTSASTAYLQISSLKAED




MAMYYCARPSDYYDGFWFAYWGQGTLVTVS




S


 


713
hBEW-9D2-E8VH.1
EVQLVQSGHEVKQPGASVKVSCKASGYTFT




NYGMYWVPQAPGQGLEWMGWINTETGKPTY




ADDFKGRFVFSMDTSASTAYLQISSLKAED




MAMYYCARPSDYYDGFWFAYWGQGTLVTVS




S


 


714
hBEW-9D2-E8VH.1a
EIQLVQSGHEVKQPGASVKVSCKASGYTFT




NYGMYWVKLAPGQGLEYLGWINTETGKPTY




ADDFKGRFVFSLDTSASTAYLQISSLKAED




MAMYFCARPSDYYDGFWFAYWGQGTLVTVS




S


 


715
hBEW-9D2-E8VH.1b
EVQLVQSGHEVKQPGASVKVSCKASGYTFT




NYGMYWVKQAPGQGLEYLGWINTETGKPTY




ADDFKGRFVFSLDTSASTAYLQISSLKAED




MAMYYCARPSDYYDGFWFAYWGQGTLVTVS




S


 


716
hBEW-9D2-E8VH.1c
EVQLVQSGHEVKQPGASVKVSCKASGYSFT




NYGMYWVKQAPGQGLEYLGWINTETGKPTY




ADDFKGRFVFSLDTSASTAYLQISSLKAED




MAMYYCARPSDYYDGFWFAYWGQGTLVTVS




S


 


717
hBEW-9D2-E8VH.2z
QVQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWINTETGKPTY




ADDFKGRVTMTTDTSTSTAYMELRSLRSDD




TAVYYCARPSDYYDGFWFAYWGQGTLVTVS




S


 


718
hBEW-9D2-E8VH.2
EVQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWINTETGKPTY




ADDFKGRVTMTTDTSTSTAYMELRSLRSDD




TAVYYCARPSDYYDGFWFAYWGQGTLVTVS




S


 


719
hBEW-9D2-E8VH.2a
EIQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVKLAPGQGLEYLGWINTETGKPTY




ADDFKGRFTFTLDTSTSTAYLELRSLRSDD




TAVYFCARPSDYYDGFWFAYWGQGTLVTVS




S


 


720
hBEW-9D2-E8VH.2B
EVQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVKQAPGQGLEYLGWINTETGKPTY




ADDFKGRVTMTLDTSTSTAYLELRSLRSDD




TAVYYCARPSDYYDGFWFAYWGQGTLVTVS




S


 


721
hBEW-9D2-E8VL.1
EIVLTQSPATLSLSPGERATLSCRASEWVN




SYMHWYQQKPGQAPRLLIYKASNLASGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ




SWNDPLTFGQGTKLEIK


 


722
hBEW-9D2-E8VL.1a
ETVLTQSPATLSLSPGERATLSCRASEWVN




SYMHWYQQKPGQQPRLLIYKASNLASGVPA




RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ




SWNDPLTFGQGTKLEIK


 


723
hBEW-9D2-E8VL.1b
ETVLTQSPATLSLSPGERATLSCRASEWVN




SYMHWYQQKPGQAPRLLIYKASNLASGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ




SWNDPLTFGQGTKLEIK


 


724
hBEW-9D2-E8VL.2
DIQMTQSPSSLSASVGDRVTITCRASEWVN




SYMHWYQQKPGKAPKLLIYKASNLASGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCQQ




SWNDPLTFGQGTKLEIK


 


725
hBEW-9D2-E8VL.2a
DTQLTQSPSSLSASVGDRVTITCRASEWVN




SYMHWYQQKPGKQPKLLIYKASNLASGVPS




RFSGSGSGTDFTLTISSLQPEDFATYFCQQ




SWNDPLTFGQGTKLEIK


 


726
hBEW-9D2-E8VL.2b
DTQMTQSPSSLSASVGDRVTITCRASEWVN




SYMHWYQQKPGKAPKLLIYKASNLASGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCQQ




SWNDPLTFGQGTKLEIK









    
    
        hBEW-9D2-E8VH.1z is a CDR-grafted, humanized BEW-9D2-E8 VH containing IGHV7-81*01 and IGHJ4*01 framework sequences.
        hBEW-9D2-E8VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBEW-9D2-E8VH.1a is a humanized design based on .1 and contains seven proposed framework back-mutations (V2I, P38K, Q39L, W47Y, M48L, M71L and Y91F).
        hBEW-9D2-E8VH.1b is an intermediate design between .1 and .1a and only has four proposed framework back-mutations (P38K, W47Y, M48L, M71L).
        BEW-9D2-E8VH.1c is based on .1b with additional one CDR germlining change T28S to improve identity to human germline sequence.
        hBEW-9D2-E8VH.2z is a CDR-grafted, humanized BEW-9D2-E8 VH containing IGHV1-18*01 and IGHJ4*01 framework sequences.
        hBEW-9D2-E8VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
        hBEW-9D2-E8VH.2a is a humanized design based on .2 and contains ten proposed framework back-mutations (V21, R38K, Q39L, W47Y, M48L, V67F, M69F, T71L, M80L and Y91F).
        hBEW-9D2-E8VH.2b is an intermediate design between .2 and .2a and only has five proposed framework back-mutations (R38K, W47Y, M48L, T71L and M80L).
        hBEW-9D2-E8VL.1 is a CDR-grafted humanized BEW-9D2-E8 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
        hBEW-9D2-E8VL.1a is a humanized design based on .1 with four proposed framework back-mutations (I2T, A43Q, I58V and Y87F).
        hBEW-9D2-E8VL.1b is an intermediate design between .1 and .1a with one proposed framework back-mutation 12V.
        hBEW-9D2-E8VL.2 is a CDR-grafted humanized BEW-9D2-E8 VL containing IGKV1-39*01 and IGKJ2*01 framework sequences.
        hBEW-9D2-E8VL.2a is a humanized design based on .2 with four proposed framework back-mutations (I2T, M4L, A43Q and Y87F).
        hBEW-9D2-E8VL.2b is an intermediate design between .2 and .2a with one proposed framework back-mutation 12V.
    
    


Example 6.2.4.5: BEW-9E3-B9







TABLE 2.4.5







Sequences of Humanized BEW-9E3-B9 Variable Regions









SEQ




ID
Protein
Sequence


NO:
region
123456789012345678901234567890












727
hBEW-9E3-B9VH.1z
QVQLVQSGHEVKQPGASVKVSCKASGYTFT




NYGMYWVPQAPGQGLEWMGWINTETGKPTY




ADDFKGRFVFSMDTSASTAYLQISSLKAED




MAMYYCARPSDYYDGFWFPYWGQGTLVTVS




S


 


728
hBEW-9E3-B9VH.1
EVQLVQSGHEVKQPGASVKVSCKASGYTFT




NYGMYWVPQAPGQGLEWMGWINTETGKPTY




ADDFKGRFVFSMDTSASTAYLQISSLKAED




MAMYYCARPSDYYDGFWFPYWGQGTLVTVS




S


 


729
hBEW-9E3-B9VH.1a
EIQLVQSGHEVKQPGASVKVSCKASGYTFT




NYGMYWVPQAPGQGLEYMGWINTETGKPTY




ADDFKGRFVFSLDTSASTAYLQISSLKAED




MAMYFCARPSDYYDGFWFPYWGQGTLVTVS




S


 


730
hBEW-9E3-B9VH.1b
EVQLVQSGHEVKQPGASVKVSCKASGYTFT




NYGMYWVPQAPGQGLEYMGWINTETGKPTY




ADDFKGPFVFSLDTSASTAYLQISSLKAED




MAMYYCARPSDYYDGFWFPYWGQGTLVTVS




S


 


731
hBEW-9E3-B9VH.1c
EVQLVQSGHEVKQPGASVKVSCKASGYSFT




NYGMYWVPQAPGQGLEYMGWINTETGKPTY




ADDFKGRFVFSLDTSASTAYLQISSLKAED




MAMYYCARPSDYYDGFWFPYWGQGTLVTVS




S


 


732
hBEW-9E3-B9VH.2z
QVQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWINTETGKPTY




ADDFKGPVTMTTDTSTSTAYMELRSLPSDD




TAVYYCARPSDYYDGFWFPYWGQGTLVTVS




S


 


733
hBEW-9E3-B9VH.2
EVQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWINTETGKPTY




ADDFKGRVTMTTDTSTSTAYMELRSLRSDD




TAVYYCARPSDYYDGFWFPYWGQGTLVTVS




S


 


734
hBEW-9E3-B9VH.2a
EIQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEYMGWINTETGKPTY




ADDFKGRFTFTLDTSTSTAYMELRSLRSDD




TAVYFCARPSDYYDGFWFPYWGQGTLVTVS




S


 


735
hBEW-9E3-B9VH.2b
EVQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEYMGWINTETGKPTY




ADDFKGRVTMTLDTSTSTAYMELRSLRSDD




TAVYYCARPSDYYDGFWFPYWGQGTLVTVS




S


 


736
hBEW-9E3-B9VL.1
EIVLTQSPATLSLSPGERATLSCRASEGVN




SYMHWYQQKPGQAPRLLIYKASNLASGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ




SWNDPLTFGQGTKLEIK


 


737
hBEW-9E3-B9VL.1a
ETVLTQSPATLSLSPGERATLSCRASEGVN




SYMHWYQQKPGQQPRLLIYKASNLASGVPA




RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ




SWNDPLTFGQGTKLEIK


 


738
hBEW-9E3-B9VL.1b
ETVLTQSPATLSLSPGERATLSCRASEGVN




SYMHWYQQKPGQAPRLLIYKASNLASGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ




SWNDPLTFGQGTKLEIK


 


739
hBEW-9E3-B9VL.2
DIQMTQSPSSLSASVGDRVTITCRASEGVN




SYMHWYQQKPGKAPKLLIYKASNLASGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCQQ




SWNDPLTFGQGTKLEIK


 


740
hBEW-9E3-B9VL.2a
DTQLTQSPSSLSASVGDRVTITCRASEGVN




SYMHWYQQKPGKQPKLLIYKASNLASGVPS




RFSGSGSGTDFTLTISSLQPEDFATYFCQQ




SWNDPLTFGQGTKLEIK


 


741
hBEW-9E3-B9VL.2b
DTQMTQSPSSLSASVGDRVTITCRASEGVN




SYMHWYQQKPGKAPKLLIYKASNLASGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCQQ




SWNDPLTFGQGTKLEIK









    
    
        hBEW-9E3-B9VH.1z is a CDR-grafted, humanized BEW-9E3-B9 VH containing IGHV7-81*01 and IGHJ4*01 framework sequences.
        hBEW-9E3-B9VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBEW-9E3-B9VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (V2I, W47Y, M71L and Y91F).
        hBEW-9E3-B9VH.1b is an intermediate design between .1 and .1a and only has two back-mutations (W47Y and M71L).
        hBEW-9E3-B9VH.1c is based on .1b with additional one CDR germlining change T28S to improve identity to human germline sequence.
        hBEW-9E3-B9VH.2z is a CDR-grafted, humanized BEW-9E3-B9 VH containing IGHV1-18*01 and IGHJ4*01 framework sequences.
        hBEW-9E3-B9VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
        hBEW-9E3-B9VH.2a is a humanized design based on .2 and contains six proposed framework back-mutations (V2I, W47Y, V67F, M69F, T71L and Y91F).
        hBEW-9E3-B9VH.2b is an intermediate design between .2 and .2a and only has two back-mutations W47Y and T71L.
        hBEW-9E3-B9VL.1 is a CDR-grafted humanized BEW-9E3-B9 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
        hBEW-9E3-B9VL.1a is a humanized design based on .1 with four proposed framework back-mutations (I2T, A43Q, I58V and Y87F).
        hBEW-9E3-B9VL.1b is an intermediate design between .1 and .1a with 1 proposed framework back-mutation 12T.
        hBEW-9E3-B9VL.2 is a CDR-grafted humanized BEW-9E3-B9 VL containing IGKV1-39*01 and IGKJ2*01 framework sequences.
        hBEW-9E3-B9VL.2a is a humanized design based on .1 with four proposed framework back-mutations (I2T, M4L, A43Q and Y87F).
        hBEW-9E3-B9VL.2b is an intermediate design between .1 and .1a with 1 proposed framework back-mutation 12T.
    
    


Example 6.2.4.6: BEW-5C3







TABLE 2.4.6







Sequences of Humanized BEW-5C3 Variable Regions









SEQ




ID

Sequence


NO:
Protein region
123456789012345678901234567890












742
hBEW-5c3VH.1z
QVQLVQSGSELKKPGASVKVSCKASGYTFT




NYGVYWVRQAPGQGLEWMGWINTETGKPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARARQLDWFVYWGQGTLVTVSS


 


743
hBEW-5C3VH.1
EVQLVQSGSELKKPGASVKVSCKASGYTFT




NYGVYWVRQAPGQGLEWMGWINTETGKPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARARQLDWFVYWGQGTLVTVSS


 


744
hBEW-5C3VH.1a
EIQLVQSGSELKKPGASVKVSCKASGYTFT




NYGVYWVKQAPGQGLEYMGWINTETGKPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARARQLDWFVYWGQGTLVTVSS


 


745
hBEW-5C3VH.1b
EIQLVQSGSELKKPGASVKVSCKASGYTFT




NYGVYWVKQAPGQGLEYMGWINTETGKPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVFFCARARQLDWFVYWGQGTLVTVSS


 


746
hBEW-5C3VH.2z
QVQLVQSGAEVKKPGSSVKVSCKASGYTFT




NYGVYWVRQAPGQGLEWMGWINTETGKPTY




ADDFKGRVTITADKSTSTAYMELSSLRSED




TAVYYCARARQLDWFVYWGQGTLVTVSS


 


747
hBEW-5C3VH.2
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT




NYGVYWVRQAPGQGLEWMGWINTETGKPTY




ADDFKGRVTITADKSTSTAYMELSSLRSED




TAVYYCARARQLDWFVYWGQGTLVTVSS


 


748
hBEW-5C3VH.2a
EIQLVQSGAEVKKPGSSVKVSCKASGYTFT




NYGVYWVKQAPGQGLEYMGWINTETGKPTY




ADDFKGRFTFTLDKSTSTAYMELSSLRSED




TAVYFCARARQLDWFVYWGQGTLVTVSS


 


749
hBEW-5C3VH.2b
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT




NYGVYWVRQAPGQGLEWMGWINTETGKPTY




ADDFKGRFTFTLDKSTSTAYMELSSLRSED




TAVYYCARARQLDWFVYWGQGTLVTVSS


 


750
hBEW-5C3VH.2C
EIQLVQSGAEVKKPGSSVKVSCKASGYTFT




NYGVYWVKQAPGQGLEYMGWINTETGKPTY




ADDFKGRFVFTLDKSTSTAYLELSSLRSED




TAVFFCARARQLDWFVYWGQGTLVTVSS


 


751
hBEW-5C3VL.1
EIVLTQSPATLSLSPGERATLSCRARESLT




TSLCWYQQKPGQAPRLLIYGASKLESGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ




SWYDPPTFGGGTKVEIK


 


752
hBEW-5C3VL.1a
DTVLTQSPATLSLSPGERATLSCRARESLT




TSLSWFQQKPGQQPRLLIYGASKLESGVPA




RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ




SWYDPPTFGGGTKVEIK


 


753
hBEW-5C3VL.1b
DTVLTQSPATLSLSPGERATLSCRARESLT




TSLSWFQQKPGQAPRLLIYGASKLESGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ




SWYDPPTFGGGTKVEIK


 


754
hBEW-5C3VL.1c
DTVLTQSPATLSLSPGERATLSCRARESLT




TSLSWYQQKPGQAPRLLIYgasklesGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ




SWYDPPTFGGGTKVEIK


 


755
hBEW-5C3VL.2
AIQLTQSPSSLSASVGDRVTITCRARESLT




TSLSWYQQKPGKAPKLLIYGASKLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCQQ




SWYDPPTFGGGTKVEIK


 


756
hBEW-5C3VL.2a
DTQLTQSPSSLSASVGDRVTISCRARESLT




TSLSWFQQKPGKQPKLLIYGASKLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYFCQQ




SWYDPPTFGGGTKVEIK


 


757
hBEW-5C3VL.2b
DTQLTQSPSSLSASVGDRVTITCRARESLT




TSLSWFQQKPGKAPKLLIYGASKLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYFCQQ




SWYDPPTFGGGTKVEIK


 


758
hBEW-5C3VL.2c
DTQLTQSPSSLSASVGDRVTITCRARESLT




TSLSWYQQKPGKAPKLLIYGASKLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCQQ




SWYDPPTFGGGTKVEIK









    
    
        hBEW-5C3VH.1z is a CDR-grafted, humanized BEW-5C3 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
        hBEW-5C3VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBEW-5C3VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations (V2I, R38K, W47Y).
        hBEW-5C3VH.1b is a humanized design based on .1 and contains five proposed framework back-mutations (V2I, R38K, W47Y, Y90F, Y91F).
        hBEW-5C3VH.2z is a CDR-grafted, humanized BEW-5C3 VH containing IGHV1-69*06 and IGHJ1*01 framework sequences.
        hBEW-5C3VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
        hBEW-5C3VH.2a is a humanized design based on .2 and contains seven proposed framework back-mutations (V2I, R38K, W47Y, V67F, I69F, A71L, Y91F).
        hBEW-5C3VH.2b is an intermediate design between .2 and .2a and contains three proposed framework back-mutations (V67F, I69F, A71L).
        hBEW-5C3VH.2c is a humanized design based on .2 and contains ten proposed framework back-mutations (V2I, R38K, W47Y, V67F, T68V, I69F, A71L, M80L, Y90F, Y91F).
        hBEW-5C3VL.1 is a CDR-grafted, humanized BEW-5C3 VL containing IGKV3-11*01 and IGKJ4*01 framework sequences.
        hBEW-5C3VL.1a is a humanized design based on .1 and contains six proposed framework back-mutations (E1D, I2T, Y36F, A43Q, I58V, Y87F).
        hBEW-5C3VL.1b is an intermediate design between .1 and .1a. It contains four proposed framework back-mutations (E1D, I2T, Y36F, Y87F).
        hBEW-5C3VL.1c is a design based on .1b and contains two proposed framework back-mutations (E1D, I2T)
        hBEW-5C3VL.2 is a CDR-grafted, humanized BEW-5C3 VL containing IGKV1-13*01 and IGKJ4*01 framework sequences.
        hBEW-5C3VL.2a is a humanized design based on .2 and contains six proposed framework back-mutations (A1D, I2T, T22S, Y36F, A43Q, Y87F).
        hBEW-5C3VL.2b is an intermediate design between .2 and 2a. It contains four proposed framework back-mutations (A1D, I2T, Y36F, Y87F).
        hBEW-5C3VL.2c is a design based on .2b and contains two proposed framework back-mutations (A1D, I2T)
    
    


Example 6.2.4.7: BEW-9E10







TABLE 2.4.7







Sequences of Humanized BEW-9E10 Variable Regions









SEQ




ID

Sequence


NO:
Protein region
123456789012345678901234567890












759
hBEW-9E10VH.1z
QVQLVQSGSELKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWIDTETGRPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARWSGDTTGIRGPWFAYWGQGTLV




TVSS


 


760
hBEW-9E10VH.1
EVQLVQSGSELKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWIDTETGRPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARWSGDTTGIRGPWFAYWGQGTLV




TVSS


 


761
hBEW-9E10VH.1a
EIQLVQSGSELKKPGASVKVSCKASGYTFT




NYGMYWVKQAPGQGLEYMGWIDTETGRPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYFCARWSGDTTGIRGPWFAYWGQGTLV




TVSS


 


762
hBEW-9E10VH.2z
QVQLVQSGAEVKKPGSSVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWIDTETGRPTY




ADDFKGRVTITADKSTSTAYMELSSLRSED




TAVYYCARWSGDTTGIRGPWFAYWGQGTLV




TVSS


 


763
hBEW-9E10VH.2
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWIDTETGRPTY




ADDFKGRVTITADKSTSTAYMELSSLRSED




TAVYYCARWSGDTTGIRGPWFAYWGQGTLV




TVSS


 


764
hBEW-9E10VH.2a
EIQLVQSGAEVKKPGSSVKVSCKASGYTFT




NYGMYWVKQAPGQGLEYMGWIDTETGRPTY




ADDFKGRFTFTADKSTSTAYMELSSLRSED




TAVYFCARWSGDTTGIRGPWFAYWGQGTLV




TVSS


 


765
hBEW-9E10VH.2b
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWIDTETGRPTY




ADDFKGRFTFTADKSTSTAYMELSSLRSED




TAVYYCARWSGDTTGIRGPWFAYWGQGTLV




TVSS


 


766
hBEW-9E10VL.1
DIQMTQSPSSLSASVGDRVTITCLASEDIY




SDLAWYQQKPGKVPKLLIYNANGLQNGVPS




RFSGSGSGTDFTLTISSLQPEDVATYYCQQ




YNYFPGTFGQGTKLEIK


 


767
hBEW-9E10VL.1a
DIRMTQSPSSLSASVGDRVTIECLASEDIY




SDLAWYQQKPGKSPKLLIYNANGLQNGVPS




RFSGSGSGTDYSLTISSLQPEDVATYFCQQ




YNYFPGTFGQGTKLEIK


 


768
hBEW-9E10VL.1b
DIRMTQSPSSLSASVGDRVTITCLASEDIY




SDLAWYQQKPGKSPKLLIYNANGLQNGVPS




RFSGSGSGTDYTLTISSLQPEDVATYFCQQ




YNYFPGTFGQGTKLEIK









    
    
        hBEW-9E10VH.1z is a CDR-grafted, humanized BEW-9E10 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
        hBEW-9E10VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBEW-9E10VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (V2I, R38K, W47Y, Y91F).
        hBEW-9E10VH.2z is a CDR-grafted, humanized BEW-9E10 VH containing IGHV1-69*06 and IGHJ1*01 framework sequences.
        hBEW-9E10VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
        hBEW-9E10VH.2a is a humanized design based on .2 and contains six proposed framework back-mutations (V2I, R38K, W47Y, V67F, I69F, Y91F).
        hBEW-9E10VH.2b is an intermediate design between .2 and .2a and contains two proposed framework back-mutations: (V67F, I69F).
        hBEW-9E10VL.1 is a CDR-grafted, humanized BEW-9E10 VL containing IGKV1-27*01 and IGKJ2*01 framework sequences.
        hBEW-9E10VL.1a is a humanized design based on .1 and contains six proposed framework back-mutations (Q3R, T22E, V43S, F71Y, T72S, Y87F).
        hBEW-9E10VL.1b is an intermediate design between .1 and .1a. It contains four proposed framework back-mutations (Q3R, V43S, F71Y, Y87F).
    
    


Example 6.2.4.8: BEW-1B10







TABLE 2.4.8







Sequences of Humanized BEW-1B10 Variable Regions









SEQ




ID

Sequence


NO:
Protein region
123456789012345678901234567890












769
hBEW-1B10VH.1
EVQLVESGGGLVQPGGSLRLSCAASGFSFS




KYDMAWVRQAPGKGLEWVASITTSGVGTYY




RDSVKGRFTISRDNAKNSLYLQMNSLRAED




TAVYYCARGYGAMDAWGQGTTVTVSS


 


770
hBEW-1B10VH.1a
EVQLVESGGGLVQPGGSLRLSCAASGFSFS




KYDMAWFRQAPGKGLEWVASITTSGVGTYY




RDSVKGRFTVSRDNAKSTLYLQMNSLRAED




TAVYYCARGYGAMDAWGQGTTVTVSS


 


771
hBEW-1B10VH.1b
EVQLVESGGGLVQPGGSLRLSCAASGFSFS




KYDMAWFRQAPGKGLEWVASITTSGVGTYY




RDSVKGRFTVSRDNAKNSLYLQMNSLRAED




TAVYYCARGYGAMDAWGQGTTVTVSS


 


772
hBEW-1B10VL.1
DIQMTQSPSSLSASVGDRVTITCKASQDID




DYLSWYQQKPGKAPKLLIYAATRLADGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCLQ




SSSTPWTFGGGTKVEIK


 


773
hBEW-1B10VL.1a
DIQMTQSPSSLSASVGDRVTITCKASQDID




DYLSWYQQKPGKSPKLVIYAATRLADGVPS




RFSGSGSGTDYTLTISSLQPEDFATYYCLQ




SSSTPWTFGGGTKVEIK


 


774
hBEW-1B10VL.1b
DIQMTQSPSSLSASVGDRVTITCKASQDID




DYLSWYQQKPGKSPKLLIYAATRLADGVPS




RFSGSGSGTDYTLTISSLQPEDFATYYCLQ




SSSTPWTFGGGTKVEIK









    
    
        hBEW-1B10VH.1 is a CDR-grafted, humanized BEW-1B10 VH containing IGHV3-7*01 and IGHJ6*01 framework sequences.
        hBEW-1B10VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (V37F, I69V, N76S, S77T).
        hBEW-1B10VH.1b is an intermediate design between .1 and .1a and contains two proposed framework back-mutations: (V37F, I69V).
        hBEW-9E10VH.1z is a CDR-grafted, humanized BEW-9E10 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
        hBEW-9E10VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBEW-1B10VL.1 is a CDR-grafted, humanized BEW-1B10 VL containing IGKV1-39*01 and IGKJ4*01 framework sequences.
        hBEW-1B10VL.1a is a humanized design based on .1 and contains three proposed framework back-mutations: (A43S, L47V, F71Y).
        hBEW-1B10VL.1b is an intermediate design between .1 and .1a. It contains two proposed framework back-mutations (A43S, F71Y).
    
    


Example 6.2.4.9: BEW-1E3







TABLE 2.4.9







Sequences of Humanized BEW-1E3 Variable Regions









SEQ




ID

Sequence


NO:
Protein region
123456789012345678901234567890












775
hBEW-1E3VH.1z
QVQLVQSGSELKKPGASVKVSCKASGYPFT




NSGMYWVRQAPGQGLEWMGWINTEAGKPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARWGYISDNSYGWFDYWGQGTLVT




VSS


 


776
hBEW-1E3VH.1
EVQLVQSGSELKKPGASVKVSCKASGYPFT




NSGMYWVRQAPGQGLEWMGWINTEAGKPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARWGYISDNSYGWFDYWGQGTLVT




VSS


 


777
hBEW-1E3VH.1a
EIQLVQSGSELKKPGASVKVSCKASGYPFT




NSGMYWVKQAPGQGLEYMGWINTEAGKPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYFCARWGYISDNSYGWFDYWGQGTLVT




VSS


 


778
hBEW-1E3VH.2z
QVQLVQSGAEVKKPGASVKVSCKASGYPFT




NSGMYWVRQAPGQGLEWMGWINTEAGKPTY




ADDFKGRVTMTTDTSTSTAYMELRSLRSDD




TAVYYCARWGYISDNSYGWFDYWGQGTLVT




VSS


 


779
hBEW-1E3VH.2
EVQLVQSGAEVKKPGASVKVSCKASGYPFT




NSGMYWVRQAPGQGLEWMGWINTEAGKPTY




ADDFKGRVTMTTDTSTSTAYMELRSLRSDD




TAVYYCARWGYISDNSYGWFDYWGQGTLVT




VSS


 


780
hBEW-1E3VH.2a
EIQLVQSGAEVKKPGASVKVSCKASGYPFT




NSGMYWVKQAPGQGLEYMGWINTEAGKPTY




ADDFKGRFTFTLDTSTSTAYLEIRSLRSDD




TAVYFCARWGYISDNSYGWFDYWGQGTLVT




VSS


 


781
hBEW-1E3VH.2b
EVQLVQSGAEVKKPGASVKVSCKASGYPFT




NSGMYWVRQAPGQGLEWMGWINTEAGKPTY




ADDFKGRFTFTLDTSTSTAYLEIRSLRSDD




TAVYYCARWGYISDNSYGWFDYWGQGTLVT




VSS


 


782
hBEW-1E3VL.1
EIVLTQSPATLSLSPGERATLSCRASEGVY




SYMHWYQQKPGQAPRLLIYKASNLASGIPA




RFSGSGSGTDFTLTISSLEPEDFAVYYCHQ




NWNDPLTFGQGTKLEIK


 


783
hBEW-1E3VL.1a
ETVLTQSPATLSLSPGERATLSCRASEGVY




SYMHWYQQKPGQQPRLLIYKASNLASGVPA




RFSGSGSGTDFTLTISSLEPEDFAVYFCHQ




NWNDPLTFGQGTKLEIK


 


784
hBEW-1E3VL.1b
EIVLTQSPATLSLSPGERATLSCRASEGVY




SYMHWYQQKPGQAPRLLIYKASNLASGVPA




RFSGSGSGTDFTLTISSLEPEDFAVYFCHQ




NWNDPLTFGQGTKLEIK


 


785
hBEW-1E3VL.2
AIQLTQSPSSLSASVGDRVTITCRASEGVY




SYMHWYQQKPGKAPKLLIYKASNLASGVPS




RFSGSGSGTDFTLTISSLQPEDFATYYCHQ




NWNDPLTFGQGTKLEIK


 


786
hBEW-1E3VL.2a
ATQLTQSPSSLSASVGDRVTISCRASEGVY




SYMHWYQQKPGKQPKLLIYKASNLASGVPS




RFSGSGSGTDFTLTISSLQPEDFATYFCHQ




NWNDPLTFGQGTKLEIK


 


787
hBEW-1E3VL.2b
AIQLTQSPSSLSASVGDRVTITCRASEGVY




SYMHWYQQKPGKAPKLLIYKASNLASGVPS




RFSGSGSGTDFTLTISSLQPEDFATYFCHQ




NWNDPLTFGQGTKLEIK









    
    
        hBEW-1E3VH.1z is a CDR-grafted, humanized BEW-1E3 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
        hBEW-1E3VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBEW-1E3VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (V2I, R38K, W47Y, Y91F).
        hBEW-1E3VH.2z is a CDR-grafted, humanized BEW-1E3 VH containing IGHV1-18*01 and IGHJ1*01 framework sequences.
        hBEW-1E3VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
        hBEW-1E3VH.2a is a humanized design based on .2 and contains seven proposed framework back-mutations (V2I, R38K, W47Y, V67F, M69F, T71L, Y91F).
        hBEW-1E3VH.2b is an intermediate design between .2 and .2a and contains three proposed framework back-mutations (V67F, M69F, T71L).
        hBEW-1E3VL.1 is a CDR-grafted, humanized BEW-1E3 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
        hBEW-1E3VL.1a is a humanized design based on .1 and contains four proposed framework back-mutations (I2T, A43Q, I58V, Y87F).
        hBEW-1E3VL.1b is an intermediate design between .1 and .1a. It contains two proposed framework back-mutations (I58V, Y87F).
        hBEW-1E3VL.2 is a CDR-grafted, humanized BEW-1E3 VL containing IGKV1-13*01 and IGKJ2*01 framework sequences.
        hBEW-1E3VL.2a is a humanized design based on .2 and contains four proposed framework back-mutations (I2T, T22S, A43Q, Y87F).
        hBEW-1E3VL.2b is an intermediate design between .2 and 2a. It contains one proposed framework back-mutations Y87F.
    
    


Example 6.3: Humanization of VEGFRII Antibodies
Example 6.3.1: Humanization Method
Antibody humanization is achieved by grafting CDRs of the rodent antibody onto a “similar” human framework (acceptor) and incorporating minimal number of key framework residues (back-mutation) from the rodent antibody that are selected to maintain the original CDR conformation in order to minimize the immunogenicity while retaining the optimal antigen binding.
Example 6.3.2: Human Germline Sequence Selections for Constructing CDR-Grafted, Humanized VEGFRII Antibodies
By applying the aforementioned method, the CDR sequences of VH and VL chains of monoclonal antibody BCU-6B1-G6 were grafted onto different human heavy and light chain acceptor sequences.
Example 6.3.2.1: BCU-6B1-G6
Based on the alignments with the VH and VL sequences of monoclonal antibody BCU-6B1-G6 of the present invention, the following known human sequences are selected:
1. IGHV7-4-1*01 and IGHJ1*01 for constructing heavy chain acceptor sequences
2. IGHV1-18*01 and IGHJ1*01 as alternative acceptor for constructing heavy chain
3. IGKV1-27*01 and IGKJ4*01 for constructing light chain acceptor sequences
By grafting the corresponding VH and VL CDRs of BCU-6B1-G6 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.3.3: Introducing Potential Framework Back-Mutations in CDR-Grafted Antibodies
To generate humanized antibody with potential framework back-mutations, the mutations were identified and introduced into the CDR-grafted antibody sequences by de novo synthesis of the variable domain, or mutagenic oligonucleotide primers and polymerase chain reactions, or by methods well known in the art. Different combinations of back mutations and other mutations are constructed for each of the CDR-grafts as follows. Residue numbers for these mutations are based on the Kabat numbering system.
Example 6.3.3.1: BCU-6B1-G6
When IGHV7-4-1*01 and IGHJ1*01 selected as BCU-6B1-G6 heavy chain acceptor sequence, one or more of the following residues could back-mutated as follows: W47→F. Additional mutations include the following: R38→K, Y91→F.
When IGHV1-18*01 and IGHJ1*01 selected as BCU-6B1-G6 heavy chain acceptor sequence, one or more of the following residues could back-mutated as follows: W47→F, V67→F, M69→F, T71→L. Additional mutations include the following: R38→K, Y91→F.
When IGKV1-27*01 and IGKJ4*01 selected as BCU-6B1-G6 light chain acceptor sequence, one or more of the following residues could back-mutated as follows: V43→S, Y49→F, F71→Y, Y87→F. Additional mutations include the following: T22→E, T72→S.
Example 6.3.4: Generation of Humanized Antibodies to VEGFRII Containing Framework Back-Mutations in CDR-Grafted Antibodies
The following humanized variable regions of the murine monoclonal VEGFRII antibodies were cloned into IgG expression vectors for functional characterization.
Example 6.3.4.1: BCU-6B1-G6







TABLE 3.4.1







Sequences of Humanized BCU-6B1-G6 Variable Regions









SEQ




ID
Protein
Sequence


NO:
region
123456789012345678901234567890












788
hBCU-6B1-G6VH.1z
QVQLVQSGSELKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWINTETGQPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARLGNNYGIWFAYWGQGTLVTVSS


 


789
hBCU-6B1-G6VH.1
EVQLVQSGSELKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWINTETGQPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARLGNNYGIWFAYWGQGTLVTVSS


 


790
hBCU-6B1-G6VH.1a
EVQLVQSGSELKKPGASVKVSCKASGYTFT




NYGMYWVKQAPGQGLEFMGWINTETGQPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYFCARLGNNYGIWFAYWGQGTLVTVSS


 


791
hBCU-6B1-G6VH.1b
EVQLVQSGSELKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEFMGWINTETGQPTY




ADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARLGNNYGIWFAYWGQGTLVTVSS


 


792
hBCU-6B1-G6VH.2z
QVQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWINTETGQPTY




ADDFKGRVTMTTDTSTSTAYMELRSLRSDD




TAVYYCARLGNNYGIWFAYWGQGTLVTVSS


 


793
hBCU-6B1-G6VH.2
EVQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEWMGWINTETGQPTY




ADDFKGRVTMTTDTSTSTAYMELRSLRSDD




TAVYYCARLGNNYGIWFAYWGQGTLVTVSS


 


794
hBCU-6B1-G6VH.2a
EVQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVKQAPGQGLEFMGWINTETGQPTY




ADDFKGRFTFTLDTSTSTAYMELRSLRSDD




TAVYFCARLGNNYGIWFAYWGQGTLVTVSS


 


795
hBCU-6B1-G6VH.2b
EVQLVQSGAEVKKPGASVKVSCKASGYTFT




NYGMYWVRQAPGQGLEFMGWINTETGQPTY




ADDFKGRFTFTLDTSTSTAYMELRSLRSDD




TAVYYCARLGNNYGIWFAYWGQGTLVTVSS


 


796
hBCU-6B1-
DIQMTQSPSSLSASVGDRVTITCRASDDLY



G6VL.1
STLAWYQQKPGKVPKLLIYDANRLAAGVPS




RFSGSGSGTDFTLTISSLQPEDVATYYCQQ




YNKFPWTFGGGTKVEIK


 


797
hBCU-6B1-
DIQMTQSPSSLSASVGDRVTIECRASDDLY



G6VL.1a
STLAWYQQKPGKSPKLLIFDANRLAAGVPS




RFSGSGSGTDYSLTISSLQPEDVATYFCQQ




YNKFPWTFGGGTKVEIK


 


798
hBCU-6B1-
DIQMTQSPSSLSASVGDRVTITCRASDDLY



G6VL.1b
STLAWYQQKPGKSPKLLIFDANRLAAGVPS




RFSGSGSGTDYTLTISSLQPEDVATYFCQQ




YNKFPWTFGGGTKVEIK









    
    
        hBCU-6B1-G6VH.1z is a CDR-grafted, humanized BCU-6B1-G6 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
        hBCU-6B1-G6VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
        hBCU-6B1-G6VH.1a is a humanized design based on .1 and contains 3 proposed framework back-mutations: (R38K, W47F, Y91F).
        hBCU-6B1-G6VH.1b is an intermediate design between .1 and .1a and contains 1 proposed framework back-mutations: W47F
        hBCU-6B1-G6VH.2z is a CDR-grafted, humanized BCU-6B1-G6 VH containing IGHV1-18*01 and IGHJ1*01 framework sequences.
        hBCU-6B1-G6VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
        hBCU-6B1-G6VH.2a is a humanized design based on .2 and contains six proposed framework back-mutations (R38K, W47F, V67F, M69F, T71L, Y91F).
        hBCU-6B1-G6VH.2b is an intermediate design between .2 and .2a and contains four proposed framework back-mutations: W47F, V67F, M69F, T71L.
        hBCU-6B1-G6VL.1 is a CDR-grafted, humanized BCU-6B1-G6 VL containing IGKV1-27*01 and IGKJ4*01 framework sequences.
        hBCU-6B1-G6VL.1a is a humanized design based on .1 and contains six proposed framework back-mutations (T22E, V43S, Y49F, F71Y, T72S, Y87F).
        hBCU-6B1-G6VL.1b is an intermediate design between .1 and .1a. It contains four proposed framework back-mutations (V43S, Y49F, F71Y, Y87F).
    
    


Example 6.4: Humanization of PDGFRB Antibodies
Example 6.4.1: Humanization Method
Antibody humanization is achieved by grafting CDRs of the rodent antibody onto a “similar” human framework (acceptor) and incorporating minimal number of key framework residues (back-mutation) from the rodent antibody that are selected to maintain the original CDR conformation in order to minimize the immunogenicity while retaining the optimal antigen binding.
Example 6.4.2: Human Germline Sequence Selections for Constructing CDR-Grafted, Humanized PDGFRB Antibodies
By applying the aforementioned method, the CDR sequences of VH and VL chains of monoclonal antibody BDE-3C9-G4 was grafted onto different human heavy and light chain acceptor sequences.
Example 6.4.2.1: BDE-3C9-G4
Based on the alignments with the VH and VL sequences of monoclonal antibody BDE-3C9-G4 of the present invention, the following known human sequences are selected:
1. IGHV3-7*01 and IGHJ3*01 for constructing heavy chain acceptor sequences
2. IGKV1-33*01 and IGKJ4*01 for constructing light chain acceptor sequences
By grafting the corresponding VH and VL CDRs of BDE-3C9-G4 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.4.3: Introducing Potential Framework Back-Mutations in CDR-Grafted Antibodies
To generate humanized antibody with potential framework back-mutations, the mutations were identified and introduced into the CDR-grafted antibody sequences by de novo synthesis of the variable domain, or mutagenic oligonucleotide primers and polymerase chain reactions, or by methods well known in the art. Different combinations of back mutations and other mutations are constructed for each of the CDR-grafts as follows. Residue numbers for these mutations are based on the Kabat numbering system.
Example 6.4.3.1: BDE-3C9-G4
When IGHV3-7*01 and IGHJ3*01 selected as BDE-3C9-G4 heavy chain acceptor sequence, one or more of the following residues could back-mutated as follows: S77→T, L78→Q, Y91→F.
When IGKV1-33*01 and IGKJ4*01 selected as BDE-3C9-G4 light chain acceptor sequence, one or more of the following residues could back-mutated as follows: Q38→L, K45→R, I48→M, Y49→R, T69→R, F71→Y. Additional mutations include the following: V584T.
Example 6.4.4: Generation of Humanized Antibodies to PDGFRB Containing Framework Back-Mutations in CDR-Grafted Antibodies
The following humanized variable regions of the murine monoclonal PDGFRB antibodies were cloned into IgG expression vectors for functional characterization.
Example 6.4.4.1: BDE-3C9-G4







TABLE 4.4.1







Sequences of Humanized BDE-3C9-G4


Variable Regions









SEQ ID
Protein
Sequence


NO:
region
123456789012345678901234567890





799
hBDE-3C9-
EVQLVESGGGLVQPGGSLRLSCAASGFTFS



G4VH.1
NYGMAWVRQAPGKGLEWVASITNSGGNTYY




RDSVKGRFTISRDNAKNSLYLQMNSLRAED




TAVYYCARHTPGANYFDYWGQGTMVTVSS


 


800
hBDE-3C9-
EVQLVESGGGLVQPGGSLRLSCAASGFTFS



G4VH.1a
NYGMAWVRQAPGKGLEWVASITNSGGNTYY




RDSVKGRFTISRDNAKNTQYLQMNSLRAED




TAVYFCARHTPGANYFDYWGQGTMVTVSS


 


801
hBDE-3C9-
DIQMTQSPSSLSASVGDRVTITCQASQSIK



G4VL.1
NYIAWYQQKPGKAPKLLIYYTSTLESGVPS




RFSGSGSGTDFTFTISSLQPEDIATYYCVQ




YANLYTFGGGTKVEIK


 


802
hBDE-3C9-
DIQMTQSPSSLSASVGDRVTITCQASQSIK



G4VL.1a
NYIAWYQLKPGKAPRLLMRYTSTLESGTPS




RFSGSGSGRDYTFTISSLQPEDIATYYCVQ




YANLYTFGGGTKVEIK


 


803
hBDE-3C9-
DIQMTQSPSSLSASVGDRVTITCQASQSIK



G4VL.1b
NYIAWYQQKPGKAPRLLIRYTSTLESGVPS




RFSGSGSGRDYTFTISSLQPEDIATYYCVQ




YANLYTFGGGTKVEIK









    
    
        hBDE-3C9-G4VH.1 is a CDR-grafted, humanized BDE-3C9-G4 VH containing IGHV3-7*01 and IGHJ3*01 framework sequences.
        hBDE-3C9-G4VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations (S77T, L78Q, Y91F).
        hBDE-3C9-G4VL.1 is a CDR-grafted, humanized BDE-3C9-G4 VL containing IGKV1-33*01 and IGKJ4*01 framework sequences.
        hBDE-3C9-G4VL.1a is a humanized design based on .1 and contains seven proposed framework back-mutations (Q38L, K45R, 148M, Y49R, V58T, T69R, F71Y).
        hBDE-3C9-G4VL.1b is an intermediate design between .1 and .1a. It contains four proposed framework back-mutations (K45R, Y49R, T69R, F71Y).

Summary of VH and VL Amino Acid Sequences of Humanized Rat Anti-Human VEGF-A and Humanized Rat Anti-Human PDGF-BB Monoclonal Antibodies

    
    









TABLE 27







VH and VL Amino Acid Sequences of Humanized


Rat Anti-Human VEGF-A Monoclonal Antibodies


(CDRs in bold)










SEQ ID

Protein
V Region


NO:
Clone
Region
123456789012345678901234567890













804
hBDB-4G8.1 VH

EVQLVQSGSELKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEWMGWIN





TETGKPTYADDFKGRFVFSLDTSVST





AYLQISSLKAEDTAVYYCARTNYYYR





SYIFYFDYWGQGTMVTVSS


 


805
hBDB-4G8.1
CDR-H1
GYTFTNYGMY


 


806
hBDB-4G8.1
CDR-H2
WINTETGKPTYADDFKG


 


807
hBDB-4G8.1
CDR-H3
TNYYYRSYIFYFDY


 


808
hBDB-4G8.1 VL

AIQLTQSPSSLSASVGDRVTITCRAS





ESVSTHMHWYQQKPGKAPKLLIYGAS





NLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYYCQQSWNDPFTFGQGTKL





EIK


 


809
hBDB-4G8.1
CDR-L1
RASESVSTHMH


 


810
hBDB-4G8.1
CDR-L2
GASNLES


 


811
hBDB-4G8.1
CDR-L3
QQSWNDPFT


 


812
hBDB-4G8.10 VH

EIQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEYMGWIN





TETGKPTYADDFKGRFTFTLDTSTST





AYMELRSLRSDDTAVYFCARTNYYYR





SYIFYFDYWGQGTMVTVSS


 


813
hBDB-4G8.10
CDR-H1
GYTFTNYGMY


 


814
hBDB-4G8.10
CDR-H2
WINTETGKPTYADDFKG


 


815
hBDB-4G8.10
CDR-H3
TNYYYRSYIFYFDY


 


816
hBDB-4G8.10 VL

AIQLTQSPSSLSASVGDRVTITCRAS





ESVSTHMHWYQQKPGKAPKLLIYGAS





NLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYYCQQSWNDPFTFGQGTKL





EIK


 


817
hBDB-4G8.10
CDR-L1
RASESVSTHMH


 


818
hBDB-4G8.10
CDR-L2
GASNLES


 


819
hBDB-4G8.10
CDR-L3
QQSWNDPFT


 


820
hBDB-4G8.11 VH

EIQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEYMGWIN





TETGKPTYADDFKGRFTFTLDTSTST





AYMELRSLRSDDTAVYFCARTNYYYR





SYIFYFDYWGQGTMVTVSS


 


821
hBDB-4G8.11
CDR-H1
GYTFTNYGMY


 


822
hBDB-4G8.11
CDR-H2
WINTETGKPTYADDFKG


 


823
hBDB-4G8.11
CDR-H3
TNYYYRSYIFYFDY


 


824
hBDB-4G8.11 VL

ATQLTQSPSLSASVGDRVTITCRASE





SVSTHMHWYQQKPGKQPKLLIYGASN





LESGVPSRFSGSGSGTDFTLTISSLQ





PEDFATYFCQQSWNDPFTFGQGTKLE





IK


 


825
hBDB-4G8.11
CDR-L1
RASESVSTHMH


 


826
hBDB-4G8.11
CDR-L2
GASNLES


 


827
hBDB-4G8.11
CDR-L3
QQSWNDPFT


 


828
hBDB-4G8.12 VH

EIQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEYMGWIN





TETGKPTYADDFKGRFTFTLDTSTST





AYMELRSLRSDDTAVYFCARTNYYYR





SYIFYFDYWGQGTMVTVSS


 


829
hBDB-4G8.12
CDR-H1
GYTFTNYGMY


 


830
hBDB-4G8.12
CDR-H2
WINTETGKPTYADDFKG


 


831
hBDB-4G8.12
CDR-H3
TNYYYRSYIFYFDY


 


832
hBDB-4G8.12 VL

DTVLTQSPATLSLSPGERATLSCRAS





ESVSTHMHWYQQKPGQAPRLLIYGAS





NLESGVPARFSGSGSGTDFTLTISSL





EPEDFAVYFCQQSWNDPFTFGQGTKL





EIK


 


833
hBDB-4G8.12
CDR-L1
RASESVSTHMH


 


834
hBDB-4G8.12
CDR-L2
GASNLES


 


835
hBDB-4G8.12
CDR-L3
QQSWNDPFT


 


836
hBDB-4G8.13 VH

EIQLVQSGTEVKKPGESLKISCKASG





YTFTNYGMYWVKQMPGKGLEYMGWIN





TETGKPTYADDFKGRFTFSLDKSFNT





AFLQWSSLKASDTAMYFCARTNYYYR





SYIFYFDYWGQGTMVTVSS


 


837
hBDB-4G8.13
CDR-H1
GYTFTNYGMY


 


838
hBDB-4G8.13
CDR-H2
WINTETGKPTYADDFKG


 


839
hBDB-4G8.13
CDR-H3
TNYYYRSYIFYFDY


 


840
hBDB-4G8.13 VL

ETVLTQSPATLSVSPGERATLSCRAS





ESVSTHMHWYQQKPGQAPRLLIYGAS





NLESGVPARFSGSGSGTDFTLTISSL





QSEDFAVYFCQQSWNDPFTFGQGTRL





EIK


 


841
hBDB-4G8.13
CDR-L1
RASESVSTHMH


 


842
hBDB-4G8.13
CDR-L2
GASNLES


 


843
hBDB-4G8.13
CDR-L3
QQSWNDPFT


 


844
hBDB-4G8.14 VH

EIQLVQSGGGVVQPGGSLRLSCAASG





YTFTNYGMYWVKQAPGKGLEYMGWIN





TETGKPTYADDFKGRFTFSLDTSKST





AYLQLNSLRAEDTAVYFCARTNYYYR





SYIFYFDYWGQGTLVTVSS


 


845
hBDB-4G8.14
CDR-H1
GYTFTNYGMY


 


846
hBDB-4G8.14
CDR-H2
WINTETGKPTYADDFKG


 


847
hBDB-4G8.14
CDR-H3
TNYYYRSYIFYFDY


 


848
hBDB-4G8.14 VL

DTVLTQSPSTLSASPGERATISCRAS





ESVSTHMHWYQQKPGQAPKLLIYGAS





NLESGVPSRFSGSRSGTDFTLTISSL





QPEDFAVYFCQQSWNDPFTFGQGTKV





EIK


 


849
hBDB-4G8.14
CDR-L1
RASESVSTHMH


 


850
hBDB-4G8.14
CDR-L2
GASNLES


 


851
hBDB-4G8.14
CDR-L3
QQSWNDPFT


 


852
hBDB-4G8.15 VH

EVQLVESGGGLVQPGGSLRLSCAASG





YTFTNYGMYWVKQAPGKGLEYMGWIN





TETGKPTYADDFKGRFTFSLDTSKST





AYLQMNSLRAEDTAVYFCARTNYYYR





SYIFYFDYWGQGTLVTVSS


 


853
hBDB-4G8.15
CDR-H1
GYTFTNYGMY


 


854
hBDB-4G8.15
CDR-H2
WINTETGKPTYADDFKG


 


855
hBDB-4G8.15
CDR-H3
TNYYYRSYIFYFDY


 


856
hBDB-4G8.15 VL

DTQLTQSPSSLSASVGDRVTISCRAS





ESVSTHMHWYQQKPGKAPKLLIYGAS





NLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYFCQQSWNDPFTFGQGTKV





EIK


 


857
hBDB-4G8.15
CDR-L1
RASESVSTHMH


 


858
hBDB-4G8.15
CDR-L2
GASNLES


 


859
hBDB-4G8.15
CDR-L3
QQSWNDPFT


 


860
hBDB-4G8.2 VH

EVQLVQSGSELKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEWMGWIN





TETGKPTYADDFKGRFVFSLDTSVST





AYLQISSLKAEDTAVYYCARTNYYYR





SYIFYFDYWGQGTMVTVSS


 


861
hBDB-4G8.2
CDR-H1
GYTFTNYGMY


 


862
hBDB-4G8.2
CDR-H2
WINTETGKPTYADDFKG


 


863
hBDB-4G8.2
CDR-H3
TNYYYRSYIFYFDY


 


864
hBDB-4G8.2 VL

ATQLTQSPSLSASVGDRVTITCRASE





SVSTHMHWYQQKPGKQPKLLIYGASN





LESGVPSRFSGSGSGTDFTLTISSLQ





PEDFATYFCQQSWNDPFTFGQGTKLE





IK


 


865
hBDB-4G8.2
CDR-L1
RASESVSTHMH


 


866
hBDB-4G8.2
CDR-L2
GASNLES


 


867
hBDB-4G8.2
CDR-L3
QQSWNDPFT


 


868
hBDB-4G8.3 VH

EVQLVQSGSELKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEWMGWIN





TETGKPTYADDFKGRFVFSLDTSVST





AYLQISSLKAEDTAVYYCARTNYYYR





SYIFYFDYWGQGTMVTVSS


 


869
hBDB-4G8.3
CDR-H1
GYTFTNYGMY


 


870
hBDB-4G8.3
CDR-H2
WINTETGKPTYADDFKG


 


871
hBDB-4G8.3
CDR-H3
TNYYYRSYIFYFDY


 


872
hBDB-4G8.3 VL

DTVLTQSPATLSLSPGERATLSCRAS





ESVSTHMHWYQQKPGQAPRLLIYGAS





NLESGVPARFSGSGSGTDFTLTISSL





EPEDFAVYFCQQSWNDPFTFGQGTKL





EIK


 


873
hBDB-4G8.3
CDR-L1
RASESVSTHMH


 


874
hBDB-4G8.3
CDR-L2
GASNLES


 


875
hBDB-4G8.3
CDR-L3
QQSWNDPFT


 


876
hBDB-4G8.4 VH

EIQLVQSGSELKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEYMGWIN





TETGKPTYADDFKGRFVFSLDTSVST





AYLQISSLKAEDTAVYFCARTNYYYR





SYIFYFDYWGQGTMVTVSS


 


877
hBDB-4G8.4
CDR-H1
GYTFTNYGMY


 


878
hBDB-4G8.4
CDR-H2
WINTETGKPTYADDFKG


 


879
hBDB-4G8.4
CDR-H3
TNYYYRSYIFYFDY


 


880
hBDB-4G8.4 VL

AIQLTQSPSSLSASVGDRVTITCRAS





ESVSTHMHWYQQKPGKAPKLLIYGAS





NLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYYCQQSWNDPFTFGQGTKL





EIK


 


881
hBDB-4G8.4
CDR-L1
RASESVSTHMH


 


882
hBDB-4G8.4
CDR-L2
GASNLES


 


883
hBDB-4G8.4
CDR-L3
QQSWNDPFT


 


884
hBDB-4G8.5 VH

EIQLVQSGSELKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEYMGWIN





TETGKPTYADDFKGRFVFSLDTSVST





AYLQISSLKAEDTAVYFCARTNYYYR





SYIFYFDYWGQGTMVTVSS


 


885
hBDB-4G8.5
CDR-H1
GYTFTNYGMY


 


886
hBDB-4G8.5
CDR-H2
WINTETGKPTYADDFKG


 


887
hBDB-4G8.5
CDR-H3
TNYYYRSYIFYFDY


 


888
hBDB-4G8.5 VL

ATQLTQSPSLSASVGDRVTITCRASE





SVSTHMHWYQQKPGKQPKLLIYGASN





LESGVPSRFSGSGSGTDFTLTISSLQ





PEDFATYFCQQSWNDPFTFGQGTKLE





IK


 


889
hBDB-4G8.5
CDR-L1
RASESVSTHMH


 


890
hBDB-4G8.5
CDR-L2
GASNLES


 


891
hBDB-4G8.5
CDR-L3
QQSWNDPFT


 


892
hBDB-4G8.6 VH

EIQLVQSGSELKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEYMGWIN





TETGKPTYADDFKGRFVFSLDTSVST





AYLQISSLKAEDTAVYFCARTNYYYR





SYIFYFDYWGQGTMVTVSS


 


893
hBDB-4G8.6
CDR-H1
GYTFTNYGMY


 


894
hBDB-4G8.6
CDR-H2
WINTETGKPTYADDFKG


 


895
hBDB-4G8.6
CDR-H3
TNYYYRSYIFYFDY


 


896
hBDB-4G8.6 VL

DTVLTQSPATLSLSPGERATLSCRAS





ESVSTHMHWYQQKPGQAPRLLIYGAS





NLESGVPARFSGSGSGTDFTLTISSL





EPEDFAVYFCQQSWNDPFTFGQGTKL





EIK


 


897
hBDB-4G8.6
CDR-L1
RASESVSTHMH


 


898
hBDB-4G8.6
CDR-L2
GASNLES


 


899
hBDB-4G8.6
CDR-L3
QQSWNDPFT


 


900
hBDB-4G8.7 VH

EVQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEWMGWIN





TETGKPTYADDFKGRVTMTTDTSTST





AYMELRSLRSDDTAVYYCARTNYYYR





SYIFYFDYWGQGTMVTVSS


 


901
hBDB-4G8.7
CDR-H1
GYTFTNYGMY


 


902
hBDB-4G8.7
CDR-H2
WINTETGKPTYADDFKG


 


903
hBDB-4G8.7
CDR-H3
TNYYYRSYIFYFDY


 


904
hBDB-4G8.7 VL

AIQLTQSPSSLSASVGDRVTITCRAS





ESVSTHMHWYQQKPGKAPKLLIYGAS





NLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYYCQQSWNDPFTFGQGTKL





EIK


 


905
hBDB-4G8.7
CDR-L1
RASESVSTHMH


 


906
hBDB-4G8.7
CDR-L2
GASNLES


 


907
hBDB-4G8.7
CDR-L3
QQSWNDPFT


 


908
hBDB-4G8.8 VH

EVQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEWMGWIN





TETGKPTYADDFKGRVTMTTDTSTST





AYMELRSLRSDDTAVYYCARTNYYYR





SYIFYFDYWGQGTMVTVSS


 


909
hBDB-4G8.8
CDR-H1
GYTFTNYGMY


 


910
hBDB-4G8.8
CDR-H2
WINTETGKPTYADDFKG


 


911
hBDB-4G8.8
CDR-H3
TNYYYRSYIFYFDY


 


912
hBDB-4G8.8 VL

ATQLTQSPSLSASVGDRVTITCRASE





SVSTHMHWYQQKPGKQPKLLIYGASN





LESGVPSRFSGSGSGTDFTLISSLQ





PEDFATYFCQQSWNDPFTFGQGTKLE





IK


 


913
hBDB-4G8.8
CDR-L1
RASESVSTHMH


 


914
hBDB-4G8.8
CDR-L2
GASNLES


 


915
hBDB-4G8.8
CDR-L3
QQSWNDPFT


 


916
hBDB-4G8.9 VH

EVQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEWMGWIN





TETGKPTYADDFKGRVTMTTDTSTST





AYMELRSLRSDDTAVYYCARTNYYYR





SYIFYFDYWGQGTMVTVSS


 


917
hBDB-4G8.9
CDR-H1
GYTFTNYGMY


 


918
hBDB-4G8.9
CDR-H2
WINTETGKPTYADDFKG


 


919
hBDB-4G8.9
CDR-H3
TNYYYRSYIFYFDY


 


920
hBDB-4G8.9 VL

DTVLTQSPATLSLSPGERATLSCRAS





ESVSTHMHWYQQKPGQAPRLLIYGAS





NLESGVPARFSGSGSGTDFTLTISSL





EPEDFAVYFCQQSWNDPFTFGQGTKL





EIK


 


921
hBDB-4G8.9
CDR-L1
RASESVSTHMH


 


922
hBDB-4G8.9
CDR-L2
GASNLES


 


923
hBDB-4G8.9
CDR-L3
QQSWNDPFT


 


924
hBEW-1B10.1 VH

EVQLVESGGGLVQPGGSLRLSCAASG





FSFSKYDMAWFRQAPGKGLEWVASIT





TSGVGTYYRDSVKGRFTVSRDNAKST





LYLQMNSLRAEDTAVYYCARGYGAMD





AWGQGTTVTVSS


 


925
hBEW-1B10.1
CDR-H1
GFSFSKYDMA


 


926
hBEW-1B10.1
CDR-H2
SITTSGVGTYYRDSVKG


 


927
hBEW-1B10.1
CDR-H3
GYGAMDA


 


928
hBEW-1B10.1 VL

DIQMTQSPSSLSASVGDRVTITCKAS





QDIDDYLSWYQQKPGKSPKLVIYAAT





RLADGVPSRFSGSGSGTDYTLTISSL





QPEDFATYYCLQSSSTPWTFGGGTKV





EIK


 


929
hBEW-1B10.1
CDR-L1
KASQDIDDYLS


 


930
hBEW-1B10.1
CDR-L2
AATRLAD


 


931
hBEW-1B10.1
CDR-L3
LQSSSTPWT


 


932
hBEW-1B10.2 VH

EVQLVESGGGLVQPGGSLRLSCAASG





FSFSKYDMAWFRQAPGKGLEWVASIT





TSGVGTYYRDSVKGRFTVSRDNAKNS





LYLQMNSLRAEDTAVYYCARGYGAMD





AWGQGTTVTVSS


 


933
hBEW-1B10.2
CDR-H1
GFSFSKYDMA


 


934
hBEW-1B10.2
CDR-H2
SITTSGVGTYYRDSVKG


 


935
hBEW-1B10.2
CDR-H3
GYGAMDA


 


936
hBEW-1B10.2 VL

DIQMTQSPSSLSASVGDRVTITCKAS





QDIDDYLSWYQQKPGKSPKLVIYAAT





RLADGVPSRFSGSGSGTDYTLTISSL





QPEDFATYYCLQSSSTPWTFGGGTKV





EIK


 


937
hBEW-1B10.2
CDR-L1
KASQDIDDYLS


 


938
hBEW-1B10.2
CDR-L2
AATRLAD


 


939
hBEW-1B10.2
CDR-L3
LQSSSTPWT


 


940
hBEW-1E3.1 VH

EIQLVQSGSELKKPGASVKVSCKASG





YPFTNSGMYWVKQAPGQGLEYMGWIN





TEAGKPTYADDFKGRFVFSLDTSVST





AYLQISSLKAEDTAVYFCARWGYISD





NSYGWFDYWGQGTLVTVSS


 


941
hBEW-1E3.1
CDR-H1
GYPFTNSGMY


 


942
hBEW-1E3.1
CDR-H2
WINTEAGKPTYADDFKG


 


943
hBEW-1E3.1
CDR-H3
WGYISDNSYGWFDY


 


944
hBEW-1E3.1 VL

ETVLTQSPATLSLSPGERATLSCRAS





EGVYSYMHWYQQKPGQQPRLLIYKAS





NLASGVPARFSGSGSGTDFTLTISSL





EPEDFAVYFCHQNWNDPLTFGQGTKL





EIK


 


945
hBEW-1E3.1
CDR-L1
RASEGVYSYMH


 


946
hBEW-1E3.1
CDR-L2
KASNLAS


 


947
hBEW-1E3.1
CDR-L3
HQNWNDPLT


 


948
hBEW-1E3.2 VH

EIQLVQSGAEVKKPGASVKVSCKASG





YPFTNSGMYWVKQAPGQGLEYMGWIN





TEAGKPTYADDFKGRFTFTLDTSTST





AYLEIRSLRSDDTAVYFCARWGYISD





NSYGWFDYWGQGTLVTVSS


 


949
hBEW-1E3.2
CDR-H1
GYPFTNSGMY


 


950
hBEW-1E3.2
CDR-H2
WINTEAGKPTYADDFKG


 


951
hBEW-1E3.2
CDR-H3
WGYISDNSYGWFDY


 


952
hBEW-1E3.2 VL

ETVLTQSPATLSLSPGERATLSCRAS





EGVYSYMHWYQQKPGQQPRLLIYKAS





NLASGVPARFSGSGSGTDFTLTISSL





EPEDFAVYFCHQNWNDPLTFGQGTKL





EIK


 


953
hBEW-1E3.2
CDR-L1
RASEGVYSYMH


 


954
hBEW-1E3.2
CDR-L2
KASNLAS


 


955
hBEW-1E3.2
CDR-L3
HQNWNDPLT


 


956
hBEW-1E3.3 VH

EVQLVQSGAEVKKPGASVKVSCKASG





YPFTNSGMYWVRQAPGQGLEWMGWIN





TEAGKPTYADDFKGRFTFTLDTSTST





AYLEIRSLRSDDTAVYYCARWGYISD





NSYGWFDYWGQGTLVTVSS


 


957
hBEW-1E3.3
CDR-H1
GYPFTNSGMY


 


958
hBEW-1E3.3
CDR-H2
WINTEAGKPTYADDFKG


 


959
hBEW-1E3.3
CDR-H3
WGYISDNSYGWFDY


 


960
hBEW-1E3.3 VL

ETVLTQSPATLSLSPGERATLSCRAS





EGVYSYMHWYQQKPGQQPRLLIYKAS





NLASGVPARFSGSGSGTDFTLTISSL





EPEDFAVYFCHQNWNDPLTFGQGTKL





EIK


 


961
hBEW-1E3.3
CDR-L1
RASEGVYSYMH


 


962
hBEW-1E3.3
CDR-L2
KASNLAS


 


963
hBEW-1E3.3
CDR-L3
HQNWNDPLT


 


964
hBEW-1E3.4 VH

EIQLVQSGSELKKPGASVKVSCKASG





YPFTNSGMYWVKQAPGQGLEYMGWIN





TEAGKPTYADDFKGRFVFSLDTSVST





AYLQISSLKAEDTAVYFCARWGYISD





NSYGWFDYWGQGTLVTVSS


 


965
hBEW-1E3.4
CDR-H1
GYPFTNSGMY


 


966
hBEW-1E3.4
CDR-H2
WINTEAGKPTYADDFKG


 


967
hBEW-1E3.4
CDR-H3
WGYISDNSYGWFDY


 


968
hBEW-1E3.4 VL

ATQLTQSPSSLSASVGDRVTISCRAS





EGVYSYMHWYQQKPGKQPKLLIYKAS





NLASGVPSRFSGSGSGTDFTLTISSL





QPEDFATYFCHQNWNDPLTFGQGTKL





EIK


 


969
hBEW-1E3.4
CDR-L1
RASEGVYSYMH


 


970
hBEW-1E3.4
CDR-L2
KASNLAS


 


971
hBEW-1E3.4
CDR-L3
HQNWNDPLT


 


972
hBEW-1E3.5 VH

EIQLVQSGAEVKKPGASVKVSCKASG





YPFTNSGMYWVKQAPGQGLEYMGWIN





TEAGKPTYADDFKGRFTFTLDTSTST





AYLEIRSLRSDDTAVYFCARWGYISD





NSYGWFDYWGQGTLVTVSS


 


973
hBEW-1E3.5
CDR-H1
GYPFTNSGMY


 


974
hBEW-1E3.5
CDR-H2
WINTEAGKPTYADDFKG


 


975
hBEW-1E3.5
CDR-H3
WGYISDNSYGWFDY


 


976
hBEW-1E3.5 VL

ATQLTQSPSSLSASVGDRVTISCRAS





EGVYSYMHWYQQKPGKQPKLLIYKAS





NLASGVPSRFSGSGSGTDFTLTISSL





QPEDFATYFCHQNWNDPLTFGQGTKL





EIK


 


977
hBEW-1E3.5
CDR-L1
RASEGVYSYMH


 


978
hBEW-1E3.5
CDR-L2
KASNLAS


 


979
hBEW-1E3.5
CDR-L3
HQNWNDPLT


 


980
hBEW-5C3.1 VH

EIQLVQSGSELKKPGASVKVSCKASG





YTFTNYGVYWVKQAPGQGLEYMGWIN





TETGKPTYADDFKGRFVFSLDTSVST





AYLQISSLKAEDTAVYYCARARQLDW





FVYWGQGTLVTVSS


 


981
hBEW-5C3.1
CDR-H1
GYTFTNYGVY


 


982
hBEW-5C3.1
CDR-H2
WINTETGKPTYADDFKG


 


983
hBEW-5C3.1
CDR-H3
ARQLDWFVY


984
hBEW-5C3.1 VL

DTVLTQSPATLSLSPGERATLSCRAR





ESLTTSLSWFQQKPGQQPRLLIYGAS





KLESGVPARFSGSGSGTDFTLTISSL





EPEDFAVYFCQQSWYDPPTFGGGTKV





EIK


 


985
hBEW-5C3.1
CDR-L1
RARESLTTSLS


 


986
hBEW-5C3.1
CDR-L2
GASKLES


 


987
hBEW-5C3.1
CDR-L3
QQSWYDPPT


 


988
hBEW-5C3.2 VH

EIQLVQSGAEVKKPGSSVKVSCKASG





YTFTNYGVYWVKQAPGQGLEYMGWIN





TETGKPTYADDFKGRFTFTLDKSTST





AYMELSSLRSEDTAVYFCARARQLDW





FVYWGQGTLVTVSS


 


989
hBEW-5C3.2
CDR-H1
GYTFTNYGVY


 


990
hBEW-5C3.2
CDR-H2
WINTETGKPTYADDFKG


 


991
hBEW-5C3.2
CDR-H3
ARQLDWFVY


 


992
hBEW-5C3.2 VL

DTVLTQSPATLSLSPGERATLSCRAR





ESLTTSLSWFQQKPGQQPRLLIYGAS





KLESGVPARFSGSGSGTDFTLTISSL





EPEDFAVYFCQQSWYDPPTFGGGTKV





EIK


 


993
hBEW-5C3.2
CDR-L1
RARESLTTSLS


 


994
hBEW-5C3.2
CDR-L2
GASKLES


 


995
hBEW-5C3.2
CDR-L3
QQSWYDPPT


 


996
hBEW-5C3.3 VH

EVQLVQSGAEVKKPGSSVKVSCKASG





YTFTNYGVYWVRQAPGQGLEWMGWIN





TETGKPTYADDFKGRFTFTLDKSTST





AYMELSSLRSEDTAVYYCARARQLDW





FVYWGQGTLVTVSS


 


997
hBEW-5C3.3
CDR-H1
GYTFTNYGVY


 


998
hBEW-5C3.3
CDR-H2
WINTETGKPTYADDFKG


 


999
hBEW-5C3.3
CDR-H3
ARQLDWFVY


 


1000
hBEW-5C3.3 VL

DTVLTQSPATLSLSPGERATLSCRAR





ESLTTSLSWFQQKPGQQPRLLIYGAS





KLESGVPARFSGSGSGTDFTLTISSL





EPEDFAVYFCQQSWYDPPTFGGGTKV





EIK


 


1001
hBEW-5C3.3
CDR-L1
RARESLTTSLS


 


1002
hBEW-5C3.3
CDR-L2
GASKLES


 


1003
hBEW-5C3.3
CDR-L3
QQSWYDPPT


 


1004
hBEW-5C3.4 VH

EIQLVQSGSELKKPGASVKVSCKASG





YTFTNYGVYWVKQAPGQGLEYMGWIN





TETGKPTYADDFKGRFVFSLDTSVST





AYLQISSLKAEDTAVYYCARARQLDW





FVYWGQGTLVTVSS


 


1005
hBEW-5C3.4
CDR-H1
GYTFTNYGVY


1006
hBEW-5C3.4
CDR-H2
WINTETGKPTYADDFKG


 


1007
hBEW-5C3.4
CDR-H3
ARQLDWFVY


 


1008
hBEW-5C3.4 VL

DTQLTQSPSSLSASVGDRVTISCRAR





ESLTTSLSWFQQKPGKQPKLLIYGAS





KLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYFCQQSWYDPPTFGGGTKV





EIK


 


1009
hBEW-5C3.4
CDR-L1
RARESLTTSLS


 


1010
hBEW-5C3.4
CDR-L2
GASKLES


 


1011
hBEW-5C3.4
CDR-L3
QQSWYDPPT


 


1012
hBEW-5C3.5 VH

EIQLVQSGAEVKKPGSSVKVSCKASG





YTFTNYGVYWVKQAPGQGLEYMGWIN





TETGKPTYADDFKGRFTFTLDKSTST





AYMELSSLRSEDTAVYFCARARQLDW





FVYWGQGTLVTVSS


 


1013
hBEW-5C3.5
CDR-H1
GYTFTNYGVY


 


1014
hBEW-5C3.5
CDR-H2
WINTETGKPTYADDFKG


 


1015
hBEW-5C3.5
CDR-H3
ARQLDWFVY


 


1016
hBEW-5C3.5 VL

DTQLTQSPSSLSASVGDRVTISCRAR





ESLTTSLSWFQQKPGKQPKLLIYGAS





KLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYFCQQSWYDPPTFGGGTKV





EIK


 


1017
hBEW-5C3.5
CDR-L1
RARESLTTSLS


 


1018
hBEW-5C3.5
CDR-L2
GASKLES


 


1019
hBEW-5C3.5
CDR-L3
QQSWYDPPT


 


1020
hBEW-5C3.6 VH

EVQLVQSGAEVKKPGSSVKVSCKASG





YTFTNYGVYWVRQAPGQGLEWMGWIN





TETGKPTYADDFKGRFTFTLDKSTST





AYMELSSLRSEDTAVYYCARARQLDW





FVYWGQGTLVTVSS


 


1021
hBEW-5C3.6
CDR-H1
GYTFTNYGVY


 


1022
hBEW-5C3.6
CDR-H2
WINTETGKPTYADDFKG


 


1023
hBEW-5C3.6
CDR-H3
ARQLDWFVY


 


1024
hBEW-5C3.6 VL

DTQLTQSPSSLSASVGDRVTISCRAR





ESLTTSLSWFQQKPGKQPKLLIYGAS





KLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYFCQQSWYDPPTFGGGTKV





EIK


 


1025
hBEW-5C3.6
CDR-L1
RARESLTTSLS


 


1026
hBEW-5C3.6
CDR-L2
GASKLES


 


1027
hBEW-5C3.6
CDR-L3
QQSWYDPPT


 


1028
hBEW-6C2.1 VH

EVQLVESGGGLVQPGGSLRLSCAASG





FTFSYYGMHWVRQAPGKGLEWVALIY





YDSSKMYYADSVKGRFTISRDNAKNS





LYLQMNSLRAEDTAVYYCARGGTAPV





YWGQGTMVTVSS


 


1029
hBEW-6C2.1
CDR-H1
GFTFSYYGMH


 


1030
hBEW-6C2.1
CDR-H2
LIYYDSSKMYYADSVKG


 


1031
hBEW-6C2.1
CDR-H3
GGTAPVY


 


1032
hBEW-6C2.1 VL

EIVLTQSPATLSLSPGERATLSCKGS





QNIANYLAWYQQKPGQAPRLLIYNTD





SLQTGIPARFSGSGSGTDFTLTISSL





EPEDFAVYYCYQSNNGYTFGQGTKLE





IK


 


1033
hBEW-6C2.1
CDR-L1
KGSQNIANYLA


 


1034
hBEW-6C2.1
CDR-L2
NTDSLQT


 


1035
hBEW-6C2.1
CDR-L3
YQSNNGYT


 


1036
hBEW-6C2.2 VH

EVQLVESGGGLVQPGGSLRLSCAASG





FTFSYYGMHWVRQAPGKGLEWVALIY





YDSSKMYYADSVKGRFTISRDNAKNS





LYLQMNSLRAEDTAVYYCARGGTAPV





YWGQGTMVTVSS


 


1037
hBEW-6C2.2
CDR-H1
GFTFSYYGMH


 


1038
hBEW-6C2.2
CDR-H2
LIYYDSSKMYYADSVKG


 


1039
hBEW-6C2.2
CDR-H3
GGTAPVY


 


1040
hBEW-6C2.2 VL

EIVLTQSPATLSLSPGERATLSCKGS





QNIANYLAWYQQKPGQAPRLLIYNTD





SLQTGIPARFSGSGSGTDYTLTISSL





EPEDFAVYFCYQSNNGYTFGQGTKLE





IK


 


1041
hBEW-6C2.2
CDR-L1
KGSQNIANYLA


 


1042
hBEW-6C2.2
CDR-L2
NTDSLQT


 


1043
hBEW-6C2.2
CDR-L3
YQSNNGYT


 


1044
hBEW-6C2.3 VH

EVQLVESGGGLVQPGGSLRLSCAASG





FTFSYYGMHWVRQAPGKGLEWVALIY





YDSSKMYYADSVKGRFTISRDNAKNS





LYLQMNSLRAEDTAVYYCARGGTAPV





YWGQGTMVTVSS


 


1045
hBEW-6C2.3
CDR-H1
GFTFSYYGMH


 


1046
hBEW-6C2.3
CDR-H2
LIYYDSSKMYYADSVKG


 


1047
hBEW-6C2.3
CDR-H3
GGTAPVY


 


1048
hBEW-6C2.3 VL

DIQMTQSPSSLSASVGDRVTITCKGS





QNIANYLAWYQQKPGKAPKLLIYNTD





SLQTGVPSRFSGSGSGTDFTLTISSL





QPEDFATYYCYQSNNGYTFGQGTKLE





IK


 


1049
hBEW-6C2.3
CDR-L1
KGSQNIANYLA


 


1050
hBEW-6C2.3
CDR-L2
NTDSLQT


 


1051
hBEW-6C2.3
CDR-L3
YQSNNGYT


 


1052
hBEW-6C2.4 VH

EVQLVESGGGLVQPGGSLRLSCAASG





FTFSYYGMHWVRQAPGKGLEWVALIY





YDSSKMYYADSVKGRFTISRDNAKNS





LYLQMNSLRAEDTAVYYCARGGTAPV





YWGQGTMVTVSS


 


1053
hBEW-6C2.4
CDR-H1
GFTFSYYGMH


 


1054
hBEW-6C2.4
CDR-H2
LIYYDSSKMYYADSVKG


 


1055
hBEW-6C2.4
CDR-H3
GGTAPVY


 


1056
hBEW-6C2.4 VL

DIQLTQSPSSLSASVGDRVTITCKGS





QNIANYLAWYQQKPGKAPKLLIYNTD





SLQTGIPSRFSGSGSGTDYTLTISSL





QPEDFATYFCYQSNNGYTFGQGTKLE





IK


 


1057
hBEW-6C2.4
CDR-L1
KGSQNIANYLA


 


1058
hBEW-6C2.4
CDR-L2
NTDSLQT


 


1059
hBEW-6C2.4
CDR-L3
YQSNNGYT


 


1060
hBEW-6C2.5 VH

EVQLVESGGGLVQPGGSLRLSCAASG





FTFSYYGMHWIRQAPGKGLEWMALIY





YDSSKMYYADSVKGRFTISRDNAKNS





LYLQMNSLRAEDTAVYYCAAGGTAPV





YWGQGTMVTVSS


 


1061
hBEW-6C2.5
CDR-H1
GFTFSYYGMH


 


1062
hBEW-6C2.5
CDR-H2
LIYYDSSKMYYADSVKG


 


1063
hBEW-6C2.5
CDR-H3
GGTAPVY


 


1064
hBEW-6C2.5 VL

EIVLTQSPATLSLSPGERATLSCKGS





QNIANYLAWYQQKPGQAPRLLIYNTD





SLQTGIPARFSGSGSGTDFTLTISSL





EPEDFAVYYCYQSNNGYTFGQGTKLE





IK


 


1065
hBEW-6C2.5
CDR-L1
KGSQNIANYLA


 


1066
hBEW-6C2.5
CDR-L2
NTDSLQT


 


1067
hBEW-6C2.5
CDR-L3
YQSNNGYT


 


1068
hBEW-6C2.6 VH

EVQLVESGGGLVQPGGSLRLSCAASG





FTFSYYGMHWIRQAPGKGLEWMALIY





YDSSKMYYADSVKGRFTISRDNAKNS





LYLQMNSLRAEDTAVYYCAAGGTAPV





YWGQGTMVTVSS


 


1069
hBEW-6C2.6
CDR-H1
GFTFSYYGMH


 


1070
hBEW-6C2.6
CDR-H2
LIYYDSSKMYYADSVKG


 


1071
hBEW-6C2.6
CDR-H3
GGTAPVY


 


1072
hBEW-6C2.6 VL

EIVLTQSPATLSLSPGERATLSCKGS





QNIANYLAWYQQKPGQAPRLLIYNTD





SLQTGIPARFSGSGSGTDYTLTISSL





EPEDFAVYFCYQSNNGYTFGQGTKLE





IK


 


1073
hBEW-6C2.6
CDR-L1
KGSQNIANYLA


 


1074
hBEW-6C2.6
CDR-L2
NTDSLQT


 


1075
hBEW-6C2.6
CDR-L3
YQSNNGYT


 


1076
hBEW-6C2.7 VH

EVQLVESGGGLVQPGGSLRLSCAASG





FTFSYYGMHWIRQAPGKGLEWMALIY





YDSSKMYYADSVKGRFTISRDNAKNS





LYLQMNSLRAEDTAVYYCAAGGTAPV





YWGQGTMVTVSS


 


1077
hBEW-6C2.7
CDR-H1
GFTFSYYGMH


 


1078
hBEW-6C2.7
CDR-H2
LIYYDSSKMYYADSVKG


 


1079
hBEW-6C2.7
CDR-H3
GGTAPVY


 


1080
hBEW-6C2.7 VL

DIQMTQSPSSLSASVGDRVTITCKGS





QNIANYLAWYQQKPGKAPKLLIYNTD





SLQTGVPSRFSGSGSGTDFTLTISSL





QPEDFATYYCYQSNNGYTFGQGTKLE





IK


 


1081
hBEW-6C2.7
CDR-L1
KGSQNIANYLA


 


1082
hBEW-6C2.7
CDR-L2
NTDSLQT


 


1083
hBEW-6C2.7
CDR-L3
YQSNNGYT


 


1084
hBEW-6C2.8 VH

EVQLVESGGGLVQPGGSLRLSCAASG





FTFSYYGMHWIRQAPGKGLEWMALIY





YDSSKMYYADSVKGRFTISRDNAKNS





LYLQMNSLRAEDTAVYYCAAGGTAPV





YWGQGTMVTVSS


 


1085
hBEW-6C2.8
CDR-H1
GFTFSYYGMH


 


1086
hBEW-6C2.8
CDR-H2
LIYYDSSKMYYADSVKG


 


1087
hBEW-6C2.8
CDR-H3
GGTAPVY


 


1088
hBEW-6C2.8 VL

DIQLTQSPSSLSASVGDRVTITCKGS





QNIANYLAWYQQKPGKAPKLLIYNTD





SLQTGIPSRFSGSGSGTDYTLTISSL





QPEDFATYFCYQSNNGYTFGQGTKLE





IK


 


1089
hBEW-6C2.8
CDR-L1
KGSQNIANYLA


 


1090
hBEW-6C2.8
CDR-L2
NTDSLQT


 


1091
hBEW-6C2.8
CDR-L3
YQSNNGYT


 


1092
hBEW-9A8.1 VH

EVQLVQSGHEVKQPGASVKVSCKASG





YTFTNYGMYWVPQAPGQGLEWMGWIN





TETGKPIYADDFKGRFVFSMDTSAST





AYLQISSLKAEDMAMYYCARVDYDGS





FWFAYWGQGTLVTVSS


 


1093
hBEW-9A8.1
CDR-H1
GYTFTNYGMY


 


1094
hBEW-9A8.1
CDR-H2
WINTETGKPIYADDFKG


 


1095
hBEW-9A8.1
CDR-H3
VDYDGSFWFAY


 


1096
hBEW-9A8.1 VL

EIVLTQSPDFQSVTPKEKVTITCRAS





ESVSTVIHWYQQKPDQSPKLLIKPGAS





NLESGVPSRFSGSGSGTDFTLTINSL





EAEDAATYYCQQHWNDPPTFGQGTKL





EIK


 


1097
hBEW-9A8.1
CDR-L1
RASESVSTVIH


 


1098
hBEW-9A8.1
CDR-L2
GASNLES


 


1099
hBEW-9A8.1
CDR-L3
QQHWNDPPT


 


1100
hBEW-9A8.10 VH

EVQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEWMGWIN





TETGKPIYADDFKGRVTMTTDTSTST





AYMELRSLRSDDTAVYYCARVDYDGS





FWFAYWGQGTLVTVSS


 


1101
hBEW-9A8.10
CDR-H1
GYTFTNYGMY


 


1102
hBEW-9A8.10
CDR-H2
WINTETGKPIYADDFKG


 


1103
hBEW-9A8.10
CDR-H3
VDYDGSFWFAY


 


1104
hBEW-9A8.10 VL

ETVLTQSPDFQSVTPKEKVTITCRAS





ESVSTVIHWYQQKPDQQPKLLIHGAS





NLESGVPSRFSGSGSGTDFTLTINSL





EAEDAATYFCQQHWNDPPTFGQGTKL





EIK


 


1105
hBEW-9A8.10
CDR-L1
RASESVSTVIH


 


1106
hBEW-9A8.10
CDR-L2
GASNLES


 


1107
hBEW-9A8.10
CDR-L3
QQHWNDPPT


 


1108
hBEW-9A8.11 VH

EVQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEWMGWIN





TETGKPIYADDFKGRVTMTTDTSTST





AYMELRSLRSDDTAVYYCARVDYDGS





FWFAYWGQGTLVTVSS


 


1109
hBEW-9A8.11
CDR-H1
GYTFTNYGMY


 


1110
hBEW-9A8.11
CDR-H2
WINTETGKPIYADDFKG


 


1111
hBEW-9A8.11
CDR-H3
VDYDGSFWFAY


 


1112
hBEW-9A8.11 VL

DIQMTQSPSSLSASVGDRVTITCRAS





ESVSTVIHWYQQKPGKAPKLLIYGAS





NLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYYCQQHWNDPPTFGQGTKL





EIK


 


1113
hBEW-9A8.11
CDR-L1
RASESVSTVIH


 


1114
hBEW-9A8.11
CDR-L2
GASNLES


 


1115
hBEW-9A8.11
CDR-L3
QQHWNDPPT


 


1116
hBEW-9A8.12 VH

EVQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEWMGWIN





TETGKPIYADDFKGRVTMTTDTSTST





AYMELRSLRSDDTAVYYCARVDYDGS





FWFAYWGQGTLVTVSS


 


1117
hBEW-9A8.12
CDR-H1
GYTFTNYGMY


 


1118
hBEW-9A8.12
CDR-H2
WINTETGKPIYADDFKG


 


1119
hBEW-9A8.12
CDR-H3
VDYDGSFWFAY


 


1120
hBEW-9A8.12 VL

DTQLTQSPSSLSASVGDRVTITCRAS





ESVSTVIHWYQQKPGKQPKLLIHGAS





NLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYFCQQHWNDPPTFGQGTKL





EIK


 


1121
hBEW-9A8.12
CDR-L1
RASESVSTVIH


 


1122
hBEW-9A8.12
CDR-L2
GASNLES


 


1123
hBEW-9A8.12
CDR-L3
QQHWNDPPT


 


1124
hBEW-9A8.13 VH

EIQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVKQAPGQGLEYMGWIN





TETGKPIYADDFKGRFTFTLDTSTST





AYMELRSLRSDDTAVFFCARVDYDGS





FWFAYWGQGTLVTVSS


 


1125
hBEW-9A8.13
CDR-H1
GYTFTNYGMY


 


1126
hBEW-9A8.13
CDR-H2
WINTETGKPIYADDFKG


 


1127
hBEW-9A8.13
CDR-H3
VDYDGSFWFAY


 


1128
hBEW-9A8.13 VL

EIVLTQSPDFQSVTPKEKVTITCRAS





ESVSTVIHWYQQKPDQSPKLLIKGAS





NLESGVPSRFSGSGSGTDFTLTINSL





EAEDAATYYCQQHWNDPPTFGQGTKL





EIK


 


1129
hBEW-9A8.13
CDR-L1
RASESVSTVIH


 


1130
hBEW-9A8.13
CDR-L2
GASNLES


 


1131
hBEW-9A8.13
CDR-L3
QQHWNDPPT


 


1132
hBEW-9A8.14 VH

EIQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVKQAPGQGLEYMGWIN





TETGKPIYADDFKGRFTFTLDTSTST





AYMELRSLRSDDTAVFFCARVDYDGS





FWFAYWGQGTLVTVSS


 


1133
hBEW-9A8.14
CDR-H1
GYTFTNYGMY


 


1134
hBEW-9A8.14
CDR-H2
WINTETGKPIYADDFKG


 


1135
hBEW-9A8.14
CDR-H3
VDYDGSFWFAY


 


1136
hBEW-9A8.14 VL

ETVLTQSPDFQSVTPKEKVTITCRAS





ESVSTVIHWYQQKPDQQPKLLIHGAS





NLESGVPSRFSGSGSGTDFTLTINSL





EAEDAATYFCQQHWNDPPTFGQGTKL





EIK


 


1137
hBEW-9A8.14
CDR-L1
RASESVSTVIH


 


1138
hBEW-9A8.14
CDR-L2
GASNLES


 


1139
hBEW-9A8.14
CDR-L3
QQHWNDPPT


 


1140
hBEW-9A8.15 VH

EIQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVKQAPGQGLEYMGWIN





TETGKPIYADDFKGRFTFTLDTSTST





AYMELRSLRSDDTAVFFCARVDYDGS





FWFAYWGQGTLVTVSS


 


1141
hBEW-9A8.15
CDR-H1
GYTFTNYGMY


 


1142
hBEW-9A8.15
CDR-H2
WINTETGKPIYADDFKG


 


1143
hBEW-9A8.15
CDR-H3
VDYDGSFWFAY


 


1144
hBEW-9A8.15 VL

DIQMTQSPSSLSASVGDRVTITCRAS





ESVSTVIHWYQQKPGKAPKLLIYGAS





NLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYYCQQHWNDPPTFGQGTKL





EIK


 


1145
hBEW-9A8.15
CDR-L1
RASESVSTVIH


 


1146
hBEW-9A8.15
CDR-L2
GASNLES


 


1147
hBEW-9A8.15
CDR-L3
QQHWNDPPT


 


1148
hBEW-9A8.16 VH

EIQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVKQAPGQGLEYMGWIN





TETGKPIYADDFKGRFTFTLDTSTST





AYMELRSLRSDDTAVFFCARVDYDGS





FWFAYWGQGTLVTVSS


 


1149
hBEW-9A8.16
CDR-H1
GYTFTNYGMY


 


1150
hBEW-9A8.16
CDR-H2
WINTETGKPIYADDFKG


 


1151
hBEW-9A8.16
CDR-H3
VDYDGSFWFAY


 


1152
hBEW-9A8.16 VL

DTQLTQSPSSLSASVGDRVTITCRAS





ESVSTVIHWYQQKPGKQPKLLIHGAS





NLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYFCQQHWNDPPTFGQGTKL





EIK


 


1153
hBEW-9A8.16
CDR-L1
RASESVSTVIH


 


1154
hBEW-9A8.16
CDR-L2
GASNLES


 


1155
hBEW-9A8.16
CDR-L3
QQHWNDPPT


 


1156
hBEW-9A8.17 VH

EIQLVQSGSELKKPGASVKVSCKASG





YTFTNYGMYWVKQAPGQGLEYMGWIN





TETGKPIYADDFKGRFVFSLDTSVST





AYLQISSLKAEDTAVYYCARVDYDGS





FWFAYWGQGTLVTVSS


 


1157
hBEW-9A8.17
CDR-H1
GYTFTNYGMY


 


1158
hBEW-9A8.17
CDR-H2
WINTETGKPIYADDFKG


 


1159
hBEW-9A8.17
CDR-H3
VDYDGSFWFAY


 


1160
hBEW-9A8.17 VL

ETVLTQSPATLSLSPGERATLSGRAS





ESVSTVIHWYQQKPGQQPRLLIHGAS





NLESGVPARFSGSGSGTDFTLTISSL





EPEDFAVYFCQQHWNDPPTFGQGTKL





EIK


 


1161
hBEW-9A8.17
CDR-L1
RASESVSTVIH


 


1162
hBEW-9A8.17
CDR-L2
GASNLES


 


1163
hBEW-9A8.17
CDR-L3
QQHWNDPPT


 


1164
hBEW-9A8.2 VH

EVQLVQSGHEVKQPGASVKVSCKASG





YTFTNYGMYWVPQAPGQGLEWMGWIN





TETGKPIYADDFKGRFVFSMDTSAST





AYLQISSLKAEDMAMYYCARVDYDGS





FWFAYWGQGTLVTVSS


 


1165
hBEW-9A8.2
CDR-H1
GYTFTNYGMY


 


1166
hBEW-9A8.2
CDR-H2
WINTETGKPIYADDFKG


 


1167
hBEW-9A8.2
CDR-H3
VDYDGSFWFAY


 


1168
hBEW-9A8.2 VL

ETVLTQSPDFQSVTPKEKVTITGRAS





ESVSTVIHWYQQKPDQQPKLLIHGAS





NLESGVPSRFSGSGSGTDFTLTINSL





EAEDAATYFCQQHWNDPPTFGQGTKL





EIK


 


1169
hBEW-9A8.2
CDR-L1
RASESVSTVIH


 


1170
hBEW-9A8.2
CDR-L2
GASNLES


 


1171
hBEW-9A8.2
CDR-L3
QQHWNDPPT


 


1172
hBEW-9A8.20 VH

EIQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVKQAPGQGLEYMGWIN





TETGKPIYADDFKGRFTFTLDTSTST





AYMELRSLRSDDTAVYYCARVDYDGS





FWFAYWGQGTLVTVSS


 


1173
hBEW-9A8.20
CDR-H1
GYTFTNYGMY


 


1174
hBEW-9A8.20
CDR-H2
WINTETGKPIYADDFKG


 


1175
hBEW-9A8.20
CDR-H3
VDYDGSFWFAY


 


1176
hBEW-9A8.20 VL

ETVLTQSPATLSLSPGERATLSCRAS





ESVSTVIHWYQQKPGQQPRLLIHGAS





NLESGVPARFSGSGSGTDFTLTISSL





EPEDFAVYFCQQHWNDPPTFGQGTKL





EIK


 


1177
hBEW-9A8.20
CDR-L1
RASESVSTVIH


 


1178
hBEW-9A8.20
CDR-L2
GASNLES


 


1179
hBEW-9A8.20
CDR-L3
QQHWNDPPT


 


1180
hBEW-9A8.21 VH

EIQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEWMGWIN





TETGKPIYADDFKGRFTFTLDTSTST





AYMELRSLRSDDTAVYYCARVDYDGS





FWFAYWGQGTLVTVSS


 


1181
hBEW-9A8.21
CDR-H1
GYTFTNYGMY


 


1182
hBEW-9A8.21
CDR-H2
WINTETGKPIYADDFKG


 


1183
hBEW-9A8.21
CDR-H3
VDYDGSFWFAY


 


1184
hBEW-9A8.21 VL

ETVLTQSPATLSLSPGERATLSCRAS





ESVSTVIHWYQQKPGQQPRLLIHGAS





NLESGVPARFSGSGSGTDFTLTISSL





EPEDFAVYFCQQHWNDPPTFGQGTKL





EIK


 


1185
hBEW-9A8.21
CDR-L1
RASESVSTVIH


 


1186
hBEW-9A8.21
CDR-L2
GASNLES


 


1187
hBEW-9A8.21
CDR-L3
QQHWNDPPT


 


1188
hBEW-9A8.3 VH

EVQLVQSGHEVKQPGASVKVSCKASG





YTFTNYGMYWVPQAPGQGLEWMGWIN





TETGKPIYADDFKGRFVFSMDTSAST





AYLQISSLKAEDMAMYYCARVDYDGS





FWFAYWGQGTLVTVSS


 


1189
hBEW-9A8.3
CDR-H1
GYTFTNYGMY


 


1190
hBEW-9A8.3
CDR-H2
WINTETGKPIYADDFKG


 


1191
hBEW-9A8.3
CDR-H3
VDYDGSFWFAY


 


1192
hBEW-9A8.3 VL

DIQMTQSPSSLSASVGDRVTITCRAS





ESVSTVIHWYQQKPGKAPKLLIYGAS





NLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYYCQQHWNDPPTFGQGTKL





EIK


 


1193
hBEW-9A8.3
CDR-L1
RASESVSTVIH


 


1194
hBEW-9A8.3
CDR-L2
GASNLES


 


1195
hBEW-9A8.3
CDR-L3
QQHWNDPPT


 


1196
hBEW-9A8.4 VH

EVQLVQSGHEVKQPGASVKVSCKASG





YTFTNYGMYWVPQAPGQGLEWMGWIN





TETGKPIYADDFKGRFVFSMDTSAST





AYLQISSLKAEDMAMYYCARVDYDGS





FWFAYWGQGTLVTVSS


 


1197
hBEW-9A8.4
CDR-H1
GYTFTNYGMY


 


1198
hBEW-9A8.4
CDR-H2
WINTETGKPIYADDFKG


 


1199
hBEW-9A8.4
CDR-H3
VDYDGSFWFAY


 


1200
hBEW-9A8.4 VL

DTQLTQSPSSLSASVGDRVTITCRAS





ESVSTVIHWYQQKPGKQPKLLIHGAS





NLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYFCQQHWNDPPTFGQGTKL





EIK


 


1201
hBEW-9A8.4
CDR-L1
RASESVSTVIH


 


1202
hBEW-9A8.4
CDR-L2
GASNLES


 


1203
hBEW-9A8.4
CDR-L3
QQHWNDPPT


 


1204
hBEW-9A8.5 VH

EIQLVQSGHEVKQPGASVKVSCKASG





YTFTNYGMYWVKQAPGQGLEYMGWIN





TETGKPIYADDFKGRFVFSLDTSAST





AYLQISSLKAEDMAMFFCARVDYDGS





FWFAYWGQGTLVTVSS


 


1205
hBEW-9A8.5
CDR-H1
GYTFTNYGMY


 


1206
hBEW-9A8.5
CDR-H2
WINTETGKPIYADDFKG


 


1207
hBEW-9A8.5
CDR-H3
VDYDGSFWFAY


 


1208
hBEW-9A8.5 VL

EIVLTQSPDFQSVTPKEKVTITCRAS





ESVSTVIHWYQQKPDQSPKLLIKGAS





NLESGVPSRFSGSGSGTDFTLTINSL





EAEDAATYYCQQHWNDPPTFGQGTKL





EIK


 


1209
hBEW-9A8.5
CDR-L1
RASESVSTVIH


 


1210
hBEW-9A8.5
CDR-L2
GASNLES


 


1211
hBEW-9A8.5
CDR-L3
QQHWNDPPT


 


1212
hBEW-9A8.6 VH

EIQLVQSGHEVKQPGASVKVSCKASG





YTFTNYGMYWVKQAPGQGLEYMGWIN





TETGKPIYADDFKGRFVFSLDTSAST





AYLQISSLKAEDMAMFFCARVDYDGS





FWFAYWGQGTLVTVSS


 


1213
hBEW-9A8.6
CDR-H1
GYTFTNYGMY


 


1214
hBEW-9A8.6
CDR-H2
WINTETGKPIYADDFKG


 


1215
hBEW-9A8.6
CDR-H3
VDYDGSFWFAY


 


1216
hBEW-9A8.6 VL

ETVLTQSPDFQSVTPKEKVTITCRAS





ESVSTVIHWYQQKPDQQPKLLIHGAS





NLESGVPSRFSGSGSGTDFTLTINSL





EAEDAATYFCQQHWNDPPTFGQGTKL





EIK


 


1217
hBEW-9A8.6
CDR-L1
RASESVSTVIH


 


1218
hBEW-9A8.6
CDR-L2
GASNLES


 


1219
hBEW-9A8.6
CDR-L3
QQHWNDPPT


 


1220
hBEW-9A8.7 VH

EIQLVQSGHEVKQPGASVKVSCKASG





YTFTNYGMYWVKQAPGQGLEYMGWIN





TETGKPIYADDFKGRFVFSLDTSAST





AYLQISSLKAEDMAMFFCARVDYDGS





FWFAYWGQGTLVTVSS


 


1221
hBEW-9A8.7
CDR-H1
GYTFTNYGMY


 


1222
hBEW-9A8.7
CDR-H2
WINTETGKPIYADDFKG


 


1223
hBEW-9A8.7
CDR-H3
VDYDGSFWFAY


 


1224
hBEW-9A8.7 VL

DIQMTQSPSSLSASVGDRVTITCRAS





ESVSTVIHWYQQKPGKAPKLLIYGAS





NLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYYCQQHWNDPPTFGQGTKL





EIK


 


1225
hBEW-9A8.7
CDR-L1
RASESVSTVIH


 


1226
hBEW-9A8.7
CDR-L2
GASNLES


 


1227
hBEW-9A8.7
CDR-L3
QQHWNDPPT


 


1228
hBEW-9A8.8 VH

EIQLVQSGHEVKQPGASVKVSCKASG





YTFTNYGMYWVKQAPGQGLEYMGWIN





TETGKPIYADDFKGRFVFSLDTSAST





AYLQISSLKAEDMAMFFCARVDYDGS





FWFAYWGQGTLVTVSS


 


1229
hBEW-9A8.8
CDR-H1
GYTFTNYGMY


 


1230
hBEW-9A8.8
CDR-H2
WINTETGKPIYADDFKG


 


1231
hBEW-9A8.8
CDR-H3
VDYDGSFWFAY


 


1232
hBEW-9A8.8 VL

DTQLTQSPSSLSASVGDRVTITCRAS





ESVSTVIHWYQQKPGKQPKLLIHGAS





NLESGVPSRFSGSGSGTDFTLTISSL





QPEDFATYFCQQHWNDPPTFGQGTKL





EIK


 


1233
hBEW-9A8.8
CDR-L1
RASESVSTVIH


 


1234
hBEW-9A8.8
CDR-L2
GASNLES


 


1235
hBEW-9A8.8
CDR-L3
QQHWNDPPT


 


1236
hBEW-9A8.9 VH

EVQLVQSGAEVKKPGASVKVSCKASG





YTFTNYGMYWVRQAPGQGLEWMGWIN





TETGKPIYADDFKGRVTMTTDTSTST





AYMELRSLRSDDTAVYYCARVDYDGS





FWFAYWGQGTLVTVSS


 


1237
hBEW-9A8.9
CDR-H1
GYTFTNYGMY


 


1238
hBEW-9A8.9
CDR-H2
WINTETGKPIYADDFKG


 


1239
hBEW-9A8.9
CDR-H3
VDYDGSFWFAY


 


1240
hBEW-9A8.9 VL

EIVLTQSPDFQSVTPKEKVTITCRAS





ESVSTVIHWYQQKPDQSPKLLIKGAS





NLESGVPSRFSGSGSGTDFTLTINSL





EAEDAATYYCQQHWNDPPTFGQGTKL





EIK


 


1241
hBEW-9A8.9
CDR-L1
RASESVSTVIH


 


1242
hBEW-9A8.9
CDR-L2
GASNLES


 


1243
hBEW-9A8.9
CDR-L3
QQHWNDPPT


 


1244
hBEW-9E10.1 VH

EIQLVQSGSELKKPGASVKVSCKASG





YTFTNYGMYWVKQAPGQGLEYMGWID





TETGRPTYADDFKGRFVFSLDTSVST





AYLQISSLKAEDTAVYFCARWSGDTT





GIRGPWFAYWGQGTLVTVSS


 


1245
hBEW-9E10.1
CDR-H1
GYTFTNYGMY


 


1246
hBEW-9E10.1
CDR-H2
WIDTETGRPTYADDFKG


 


1247
hBEW-9E10.1
CDR-H3
WSGDTTGIRGPWFAY


 


1248
hBEW-9E10.1 VL

DIRMTQSPSSLSASVGDRVTIECLAS





EDIYSDLAWYQQKPGKSPKLLIYNAN





GLQNGVPSRFSGSGSGTDYSLTISSL





QPEDVATYFCQQYNYFPGTFGQGTKL





EIK


 


1249
hBEW-9E10.1
CDR-L1
LASEDIYSDLA


 


1250
hBEW-9E10.1
CDR-L2
NANGLQN


 


1251
hBEW-9E10.1
CDR-L3
QQYNYFPGT


 


1252
hBEW-9E10.2 VH

EIQLVQSGAEVKKPGSSVKVSCKASG





YTFTNYGMYWVKQAPGQGLEYMGWID





TETGRPTYADDFKGRFTFTADKSTST





AYMELSSLRSEDTAVYFCARWSGDTT





GIRGPWFAYWGQGTLVTVSS


 


1253
hBEW-9E10.2
CDR-H1
GYTFTNYGMY


 


1254
hBEW-9E10.2
CDR-H2
WIDTETGRPTYADDFKG


 


1255
hBEW-9E10.2
CDR-H3
WSGDTTGIRGPWFAY


 


1256
hBEW-9E10.2 VL

DIRMTQSPSSLSASVGDRVTIECLAS





EDIYSDLAWYQQKPGKSPKLLIYNAN





GLQNGVPSRFSGSGSGTDYSLTISSL





QPEDVATYFCQQYNYFPGTFGQGTKL





EIK


 


1257
hBEW-9E10.2
CDR-L1
LASEDIYSDLA


 


1258
hBEW-9E10.2
CDR-L2
NANGLQN


 


1259
hBEW-9E10.2
CDR-L3
QQYNYFPGT


 


1260
hBEW-9E10.3 VH

EVQLVQSGAEVKKPGSSVKVSCKASG





YTFTNYGMYWVRQAPGQGLEWMGWID





TETGRPTYADDFKGRFTFTADKSTST





AYMELSSLRSEDTAVYYCARWSGDTT





GIRGPWFAYWGQGTLVTVSS


 


1261
hBEW-9E10.3
CDR-H1
GYTFTNYGMY


 


1262
hBEW-9E10.3
CDR-H2
WIDTETGRPTYADDFKG


 


1263
hBEW-9E10.3
CDR-H3
WSGDTTGIRGPWFAY


 


1264
hBEW-9E10.3 VL

DIRMTQSPSSLSASVGDRVTIECLAS





EDIYSDLAWYQQKPGKSPKLLTYNAN





GLQNGVPSRFSGSGSGTDYSLTISSL





QPEDVATYFCQQYNYFPGTFGQGTKL





EIK


 


1265
hBEW-9E10.3
CDR-L1
LASEDIYSDLA


 


1266
hBEW-9E10.3
CDR-L2
NANGLQN


 


1267
hBEW-9E10.3
CDR-L3
QQYNYFPGT


 


1268
hBEW-9E10.4 VH

EIQLVQSGSELKKPGASVKVSCKASG





YTFTNYGMYWVKQAPGQGLEYMGWID





TETGRPTYADDFKGRFVFSLDTSVST





AYLQISSLKAEDTAVYFCARWSGDTT





GIRGPWFAYWGQGTLVTVSS


 


1269
hBEW-9E10.4
CDR-H1
GYTFTNYGMY


 


1270
hBEW-9E10.4
CDR-H2
WIDTETGRPTYADDFKG


 


1271
hBEW-9E10.4
CDR-H3
WSGDTTGIRGPWFAY


 


1272
hBEW-9E10.4 VL

DIRMTQSPSSLSASVGDRVTITCLAS





EDIYSDLAWYQQKPGKSPKLLTYNAN





GLQNGVPSRFSGSGSGTDYTLTISSL





QPEDVATYFCQQYNYFPGTFGQGTKL





EIK


 


1273
hBEW-9E10.4
CDR-L1
LASEDIYSDLA


 


1274
hBEW-9E10.4
CDR-L2
NANGLQN


 


1275
hBEW-9E10.4
CDR-L3
QQYNYFPGT


 


1276
hBEW-9E10.5 VH

EIQLVQSGAEVKKPGSSVKVSCKASG





YTFTNYGMYWVKQAPGQGLEYMGWID





TETGRPTYADDFKGRFTFTADKSTST





AYMELSSLRSEDTAVYFCARWSGDTT





GIRGPWFAYWGQGTLVTVSS


 


1277
hBEW-9E10.5
CDR-H1
GYTFTNYGMY


 


1278
hBEW-9E10.5
CDR-H2
WIDTETGRPTYADDFKG


 


1279
hBEW-9E10.5
CDR-H3
WSGDTTGIRGPWFAY


 


1280
hBEW-9E10.5 VL

DIRMTQSPSSLSASVGDRVTITCLAS





EDIYSDLAWYQQKPGKSPKLLTYNAN





GLQNGVPSRFSGSGSGTDYTLTISSL





QPEDVATYFCQQYNYFPGTFGQGTKL





EIK


 


1281
hBEW-9E10.5
CDR-L1
LASEDIYSDLA


 


1282
hBEW-9E10.5
CDR-L2
NANGLQN


 


1283
hBEW-9E10.5
CDR-L3
QQYNYFPGT


 


1284
hBEW-9E10.6 VH

EVQLVQSGAEVKKPGSSVKVSCKASG





YTFTNYGMYWVRQAPGQGLEWMGWID





TETGRPTYADDFKGRFTFTADKSTST





AYMELSSLRSEDTAVYYCARWSGDTT





GIRGPWFAYWGQGTLVTVSS


 


1285
hBEW-9E10.6
CDR-H1
GYTFTNYGMY


 


1286
hBEW-9E10.6
CDR-H2
WIDTETGRPTYADDFKG


 


1287
hBEW-9E10.6
CDR-H3
WSGDTTGIRGPWFAY


 


1288
hBEW-9E10.6 VL

DIRMTQSPSSLSASVGDRVTITCLAS





EDIYSDLAWYQQKPGKSPKLLIYNAN





GLQNGVPSRFSGSGSGTDYTLTISSL





QPEDVATYFCQQYNYFPGTFGQGTKL





EIK


 


1289
hBEW-9E10.6
CDR-L1
LASEDIYSDLA


 


1290
hBEW-9E10.6
CDR-L2
NANGLQN


 


1291
hBEW-9E10.6
CDR-L3
QQYNYFPGT


 


1292
AB014 VH

EVQLVESGGGLVQPGGSLR





LSCAASGYTFTNYGMNWVR





QAPGKGLEWVGWINTYTGE





PTYAADFKRRFTFSLDTSK





STAYLQMNSLRAEDTAVYY





CAKYPHYYGSSHWYFDVWG





QGTLVTVSS


 


1293
AB014
CDR-H1
GYTFTNYGMN


 


1294
AB014
CDR-H2
WINTYTGEPTYAADFKR


 


1295
AB014
CDR-H3
YPHYYGSSHWYFDV


 


1296
AB014 VL

DIQMTQSPSSLSASVGDRV





TITCSASQDISNYLNWYQQ





KPGKAPKVLIYFTSSLHSG





VPSRFSGSGSGTDFTLTIS





SLQPEDFATYYCQQYSTVP





WTFGQGTKVEIK


 


1297
AB014
CDR-L1
SASQDISNYLN


 


1298
AB014
CDR-L2
FTSSLHS


 


1299
AB014
CDR-L3
QQYSTVPWT
















TABLE 28







VH and VL Amino Acid Sequences of Humanized Versions of


Rat Anti-Human PDGF-BB Monoclonal Antibodies (CDRs in bold)










SEQ ID

Protein
V Region


NO:
Clone
Region
123456789012345678901234567890





1300
hBDI-1E1.1 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW





VRQAPGQGLEWMGTIIPLIDTTSYNQKFKGRVTITA





DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD





VMDAWGQGTTVTVSS


 


1301
hBDI-1E1.1
CDR-H1
GYTFTDYVMH


 


1302
hBDI-1E1.1
CDR-H2
TIIPLIDTTSYNQKFKG


 


1303
hBDI-1E1.1
CDR-H3
TSPYYYSSYDVMDA


 


1304
hBDI-1E1.1 VL

AIQLTQSPSSLSASVGDRVTITCKGSQNINNYLAWY





QQKPGKAPKLLIYKTNNLQTGVPSRFSGSGSGTDFT





LTISSLQPEDFATYYCYQYDNGYTFGQGTKLEIK


 


1305
hBDI-1E1.1
CDR-L1
KGSQNINNYLA


 


1306
hBDI-1E1.1
CDR-L2
KTNNLQT


 


1307
hBDI-1E1.1
CDR-L3
YQYDNGYT


 


1308
hBDI-1E1.10 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW





VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRVTITA





DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD





VMDAWGQGTTVTVSS


 


1309
hBDI-1E1.10
CDR-H1
GYTFTDYVMH


 


1310
hBDI-1E1.10
CDR-H2
TIIPLIDTTSYNQKFKG


 


1311
hBDI-1E1.10
CDR-H3
TSPYYYSSYDVMDA


 


1312
hBDI-1E1.10 VL

AIQLTQSPSSLSASVGDRVTITCKGSQNINNYLAWY





QQKPGKAPKLLIYKTNNLQTGIPSRFSGSGSGTDYT





LTISSLQPEDFATYYCYQYDNGYTFGQGTKLEIK


 


1313
hBDI-1E1.10
CDR-L1
KGSQNINNYLA


 


1314
hBDI-1E1.10
CDR-L2
KTNNLQT


 


1315
hBDI-1E1.10
CDR-L3
YQYDNGYT


 


1316
hBDI-1E1.11 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW





VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRVTITA





DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD





VMDAWGQGTTVTVSS


 


1317
hBDI-1E1.11
CDR-H1
GYTFTDYVMH


 


1318
hBDI-1E1.11
CDR-H2
TIIPLIDTTSYNQKFKG


 


1319
hBDI-1E1.11
CDR-H3
TSPYYYSSYDVMDA


 


1320
hBDI-1E1.11 VL

EIVLTQSPATLSLSPGERATLSCKGSQNINNYLAWY





QQKPGQAPRLLIYKTNNLQTGIPARFSGSGSGTDFT





LTISSLEPEDFAVYYCYQYDNGYTFGQGTKLEIK


 


1321
hBDI-1E1.11
CDR-L1
KGSQNINNYLA


 


1322
hBDI-1E1.11
CDR-L2
KTNNLQT


 


1323
hBDI-1E1.11
CDR-L3
YQYDNGYT


 


1324
hBDI-1E1.12 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW





VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRVTITA





DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD





VMDAWGQGTTVTVSS


 


1325
hBDI-1E1.12
CDR-H1
GYTFTDYVMH


 


1326
hBDI-1E1.12
CDR-H2
TIIPLIDTTSYNQKFKG


 


1327
hBDI-1E1.12
CDR-H3
TSPYYYSSYDVMDA


 


1328
hBDI-1E1.12 VL

EIVLTQSPATLSLSPGERATLSCKGSQNINNYLAWY





QQKPGQAPRLLIYKTNNLQTGIPARFSGSGSGTDYT





LTISSLEPEDFATYYCYQYDNGYTFGQGTKLEIK


 


1329
hBDI-1E1.12
CDR-L1
KGSQNINNYLA


 


1330
hBDI-1E1.12
CDR-L2
KTNNLQT


 


1331
hBDI-1E1.12
CDR-L3
YQYDNGYT


 


1332
hBDI-1E1.2 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW





VRQAPGQGLEWMGTIIPLIDTTSYNQKFKGRVTITA





DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD





VMDAWGQGTTVTVSS


 


1333
hBDI-1E1.2
CDR-H1
GYTFTDYVMH


 


1334
hBDI-1E1.2
CDR-H2
TIIPLIDTTSYNQKFKG


 


1335
hBDI-1E1.2
CDR-H3
TSPYYYSSYDVMDA


 


1336
hBDI-1E1.2 VL

AIQLTQSPSSLSASVGDRVTITCKGSQNINNYLAWY





QQKPGKAPKLLIYKTNNLQTGIPSRFSGSGSGTDYT





LTISSLQPEDFATYYCYQYDNGYTFGQGTKLEIK


 


1337
hBDI-1E1.2
CDR-L1
KGSQNINNYLA


 


1338
hBDI-1E1.2
CDR-L2
KTNNLQT


 


1339
hBDI-1E1.2
CDR-L3
YQYDNGYT


 


1340
hBDI-1E1.3 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW





VRQAPGQGLEWMGTIIPLIDTTSYNQKFKGRVTITA





DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD





VMDAWGQGTTVTVSS


 


1341
hBDI-1E1.3
CDR-H1
GYTFTDYVMH


 


1342
hBDI-1E1.3
CDR-H2
TIIPLIDTTSYNQKFKG


 


1343
hBDI-1E1.3
CDR-H3
TSPYYYSSYDVMDA


 


1344
hBDI-1E1.3 VL

EIVLTQSPATLSLSPGERATLSCKGSQNINNYLAWY





QQKPGQAPRLLIYKTNNLQTGIPARFSGSGSGTDFT





LTISSLEPEDFAVYYCYQYDNGYTFGQGTKLEIK


 


1345
hBDI-1E1.3
CDR-L1
KGSQNINNYLA


 


1346
hBDI-1E1.3
CDR-L2
KTNNLQT


 


1347
hBDI-1E1.3
CDR-L3
YQYDNGYT


 


1348
hBDI-1E1.4 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW





VRQAPGQGLEWMGTIIPLIDTTSYNQKFKGRVTITA





DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD





VMDAWGQGTTVTVSS


 


1349
hBDI-1E1.4
CDR-H1
GYTFTDYVMH


 


1350
hBDI-1E1.4
CDR-H2
TIIPLIDTTSYNQKFKG


 


1351
hBDI-1E1.4
CDR-H3
TSPYYYSSYDVMDA


 


1352
hBDI-1E1.4 VL

EIVLTQSPATLSLSPGERATLSCKGSQNINNYLAWY





QQKPGQAPRLLIYKTNNLQTGIPARFSGSGSGTDYT





LTISSLEPEDFATYYCYQYDNGYTFGQGTKLEIK


 


1353
hBDI-1E1.4
CDR-L1
KGSQNINNYLA


 


1354
hBDI-1E1.4
CDR-L2
KTNNLQT


 


1355
hBDI-1E1.4
CDR-L3
YQYDNGYT


 


1356
hBDI-1E1.5 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW





VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRATLTA





DKSTNTAYMELSSLRSEDTAVYYCARTSPYYYSSYD





VMDAWGQGTTVTVSS


 


1357
hBDI-1E1.5
CDR-H1
GYTFTDYVMH


 


1358
hBDI-1E1.5
CDR-H2
TIIPLIDTTSYNQKFKG


 


1359
hBDI-1E1.5
CDR-H3
TSPYYYSSYDVMDA


 


1360
hBDI-1E1.5 VL

AIQLTQSPSSLSASVGDRVTITCKGSQNINNYLAWY





QQKPGKAPKLLIYKTNNLQTGVPSRFSGSGSGTDFT





LTISSLQPEDFATYYCYQYDNGYTFGQGTKLEIK


 


1361
hBDI-1E1.5
CDR-L1
KGSQNINNYLA


 


1362
hBDI-1E1.5
CDR-L2
KTNNLQT


 


1363
hBDI-1E1.5
CDR-L3
YQYDNGYT


 


1364
hBDI-1E1.6 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW





VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRATLTA





DKSTNTAYMELSSLRSEDTAVYYCARTSPYYYSSYD





VMDAWGQGTTVTVSS


 


1365
hBDI-1E1.6
CDR-H1
GYTFTDYVMH


 


1366
hBDI-1E1.6
CDR-H2
TIIPLIDTTSYNQKFKG


 


1367
hBDI-1E1.6
CDR-H3
TSPYYYSSYDVMDA


 


1368
hBDI-1E1.6 VL

AIQLTQSPSSLSASVGDRVTITCKGSQNINNYLAWY





QQKPGKAPKLLIYKTNNLQTGIPSRFSGSGSGTDYT





LTISSLQPEDFATYYCYQYDNGYTFGQGTKLEIK


 


1369
hBDI-1E1.6
CDR-L1
KGSQNINNYLA


 


1370
hBDI-1E1.6
CDR-L2
KTNNLQT


 


1371
hBDI-1E1.6
CDR-L3
YQYDNGYT


 


1372
hBDI-1E1.7 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW





VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRATLTA





DKSTNTAYMELSSLRSEDTAVYYCARTSPYYYSSYD





VMDAWGQGTTVTVSS


 


1373
hBDI-1E1.7
CDR-H1
GYTFTDYVMH


 


1374
hBDI-1E1.7
CDR-H2
TIIPLIDTTSYNQKFKG


 


1375
hBDI-1E1.7
CDR-H3
TSPYYYSSYDVMDA


 


1376
hBDI-1E1.7 VL

EIVLTQSPATLSLSPGERATLSCKGSQNINNYLAWY





QQKPGQAPRLLIYKTNNLQTGIPARFSGSGSGTDFT





LTISSLEPEDFAVYYCYQYDNGYTFGQGTKLEIK


 


1377
hBDI-1E1.7
CDR-L1
KGSQNINNYLA


 


1378
hBDI-1E1.7
CDR-L2
KTNNLQT


 


1379
hBDI-1E1.7
CDR-L3
YQYDNGYT


 


1380
hBDI-1E1.8 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW





VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRATLTA





DKSTNTAYMELSSLRSEDTAVYYCARTSPYYYSSYD





VMDAWGQGTTVTVSS


 


1381
hBDI-1E1.8
CDR-H1
GYTFTDYVMH


 


1382
hBDI-1E1.8
CDR-H2
TIIPLIDTTSYNQKFKG


 


1383
hBDI-1E1.8
CDR-H3
TSPYYYSSYDVMDA


 


1384
hBDI-1E1.8 VL

EIVLTQSPATLSLSPGERATLSCKGSQNINNYLAWY





QQKPGQAPRLLIYKTNNLQTGIPARFSGSGSGTDYT





LTISSLEPEDFATYYCYQYDNGYTFGQGTKLEIK


 


1385
hBDI-1E1.8
CDR-L1
KGSQNINNYLA


 


1386
hBDI-1E1.8
CDR-L2
KTNNLQT


 


1387
hBDI-1E1.8
CDR-L3
YQYDNGYT


 


1388
hBDI-1E1.9 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW





VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRVTITA





DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD





VMDAWGQGTTVTVSS


 


1389
hBDI-1E1.9
CDR-H1
GYTFTDYVMH


 


1390
hBDI-1E1.9
CDR-H2
TIIPLIDTTSYNQKFKG


 


1391
hBDI-1E1.9
CDR-H3
TSPYYYSSYDVMDA


 


1392
hBDI-1E1.9 VL

AIQLTQSPSSLSASVGDRVTITCKGSQNINNYLAWY





QQKPGKAPKLLIYKTNNLQTGVPSRFSGSGSGTDFT





LTISSLQPEDFATYYCYQYDNGYTFGQGTKLEIK


 


1393
hBDI-1E1.9
CDR-L1
KGSQNINNYLA


 


1394
hBDI-1E1.9
CDR-L2
KTNNLQT


 


1395
hBDI-1E1.9
CDR-L3
YQYDNGYT


 


1396
hBDI-5H1.1 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQVVLTMTNMDPVDTATYYCARISTGISSYY





VMDAWGQGTTVTVSS


 


1397
hBDI-5H1.1
CDR-H1
GFSLSTFGMGVG


 


1398
hBDI-5H1.1
CDR-H2
NIWWDDDKYYNPSLKN


 


1399
hBDI-5H1.1
CDR-H3
ISTGISSYYVMDA


 


1400
hBDI-5H1.1 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDTYVSW





YQQRPGSSPTTVIYGNDQRPSGVPDRFSGSIDSSSN





SASLTISGLKTEDEADYYCQSYDSDIDIVFGGGTKL





TVL


 


1401
hBDI-5H1.1
CDR-L1
ERSSGDIGDTYVS


 


1402
hBDI-5H1.1
CDR-L2
GNDQRPS


 


1403
hBDI-5H1.1
CDR-L3
QSYDSDIDIV


 


1404
hBDI-5H1.10 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAVLTITNMDPVDTATYYCARISTGISSYY





VMDAWGQGTTVTVSS


 


1405
hBDI-5H1.10
CDR-H1
GFSLSTFGMGVG


 


1406
hBDI-5H1.10
CDR-H2
NIWWDDDKYYNPSLKN


 


1407
hBDI-5H1.10
CDR-H3
ISTGISSYYVMDA


 


1408
hBDI-5H1.10 VL

DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVS





WYQQKPGKAPKNVIYGNDQRPSGVPSRFSGSGSGNS





ATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVE





IK


 


1409
hBDI-5H1.10
CDR-L1
ERSSGDIGDTYVS


 


1410
hBDI-5H1.10
CDR-L2
GNDQRPS


 


1411
hBDI-5H1.10
CDR-L3
QSYDSDIDIV


 


1412
hBDI-5H1.11 VH

EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTFGMGV





GWIRQAPGKGLEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAYLQINSLRAEDTAVYYCARISTGISSYY





VMDAWGQGTLVTVSS


 


1413
hBDI-5H1.11
CDR-H1
GFSLSTFGMGVG


 


1414
hBDI-5H1.11
CDR-H2
NIWWDDDKYYNPSLKN


 


1415
hBDI-5H1.11
CDR-H3
ISTGISSYYVMDA


 


1416
hBDI-5H1.11 VL

DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVS





WYQQKPGQPPKNVIYGNDQRPSGVPDRFSGSGSGNS





ATLTISSLQAEDVAVYFCQSYDSDIDIVFGGGTKVE





IK


 


1417
hBDI-5H1.11
CDR-L1
ERSSGDIGDTYVS


 


1418
hBDI-5H1.11
CDR-L2
GNDQRPS


 


1419
hBDI-5H1.11
CDR-L3
QSYDSDIDIV


 


1420
hBDI-5H1.12 VH

EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTFGMGV





GWIRQAPGKGLEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAYLQINSLRAEDTAVYYCARISTGISSYY





VMDAWGQGTLVTVSS


 


1421
hBDI-5H1.12
CDR-H1
GFSLSTFGMGVG


 


1422
hBDI-5H1.12
CDR-H2
NIWWDDDKYYNPSLKN


 


1423
hBDI-5H1.12
CDR-H3
ISTGISSYYVMDA


 


1424
hBDI-5H1.12 VL

DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVS





WYQQKPGKAPKNVIYGNDQRPSGVPSRFSGSGSGNS





ATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVE





IK


 


1425
hBDI-5H1.12
CDR-L1
ERSSGDIGDTYVS


 


1426
hBDI-5H1.12
CDR-L2
GNDQRPS


 


1427
hBDI-5H1.12
CDR-L3
QSYDSDIDIV


 


1428
hBDI-5H1.13 VH

EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAVLTITNMDPVDTATYYCARISTGISSYY





VMDAWGQGTTVTVSS


 


1429
hBDI-5H1.13
CDR-H1
GFSLSTFGMGVG


 


1430
hBDI-5H1.13
CDR-H2
NIWWDDDKYYNPSLKN


 


1431
hBDI-5H1.13
CDR-H3
ISTGISSYYVMDA


 


1432
hBDI-5H1.13 VL

DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVS





WYQQKPGKAPKNVIYGNDQRPSGVPSRFSGSGSGNS





ATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVE





IK


 


1433
hBDI-5H1.13
CDR-L1
ERSSGDIGDTYVS


 


1434
hBDI-5H1.13
CDR-L2
GNDQRPS


 


1435
hBDI-5H1.13
CDR-L3
QSYDSDIDIV


 


1436
hBDI-5H1.16 VH

EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV





GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTIS





KDTSNSQAVLTITNMDPVDTATYYCARISTGISSYY





VMDAWGQGTTVTVSS


 


1437
hBDI-5H1.16
CDR-H1
GFSLSTFGMGVG


 


1438
hBDI-5H1.16
CDR-H2
NIWWDDDKYYNPSLKN


 


1439
hBDI-5H1.16
CDR-H3
ISTGISSYYVMDA


 


1440
hBDI-5H1.16 VL

EFVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVS





WYQQKPGQPPRNVIYGNDQRPSGVPDRFSGSGSGTD





FTLTISRLEPEDFAVYFCQSYDSDIDIVFGGGTKVE





IK


 


1441
hBDI-5H1.16
CDR-L1
ERSSGDIGDTYVS


 


1442
hBDI-5H1.16
CDR-L2
GNDQRPS


 


1443
hBDI-5H1.16
CDR-L3
QSYDSDIDIV


 


1444
hBDI-5H1.17 VH

EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV





GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTIS





KDTSNSQAVLTITNMDPVDTATYYCARISTGISSYY





VMDAWGQGTTVTVSS


 


1445
hBDI-5H1.17
CDR-H1
GFSLSTFGMGVG


 


1446
hBDI-5H1.17
CDR-H2
NIWWDDDKYYNPSLKN


 


1447
hBDI-5H1.17
CDR-H3
ISTGISSYYVMDA


 


1448
hBDI-5H1.17 VL

EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVS





WYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGSGTD





FTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVE





IK


 


1449
hBDI-5H1.17
CDR-L1
ERSSGDIGDSYVS


 


1450
hBDI-5H1.17
CDR-L2
ADDQRPS


 


1451
hBDI-5H1.17
CDR-L3
QSYDINIDIV


 


1452
hBDI-5H1.2 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQVVLTMTNMDPVDTATYYCARISTGISSYY





VMDAWGQGTTVTVSS


 


1453
hBDI-5H1.2
CDR-H1
GFSLSTFGMGVG


 


1454
hBDI-5H1.2
CDR-H2
NIWWDDDKYYNPSLKN


 


1455
hBDI-5H1.2
CDR-H3
ISTGISSYYVMDA


 


1456
hBDI-5H1.2 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDTYVSW





YQQRPGSPPTNVIYGNDQRPSGVPDRFSGSIDSSSN





SASLTISGLKTEDEADYFCQSYDSDIDIVFGGGTKL





TVL


 


1457
hBDI-5H1.2
CDR-L1
ERSSGDIGDTYVS


 


1458
hBDI-5H1.2
CDR-L2
GNDQRPS


 


1459
hBDI-5H1.2
CDR-L3
QSYDSDIDIV


 


1460
hBDI-5H1.3 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQVVLTMTNMDPVDTATYYCARISTGISSYY





VMDAWGQGTTVTVSS


 


1461
hBDI-5H1.3
CDR-H1
GFSLSTFGMGVG


 


1462
hBDI-5H1.3
CDR-H2
NIWWDDDKYYNPSLKN


 


1463
hBDI-5H1.3
CDR-H3
ISTGISSYYVMDA


 


1464
hBDI-5H1.3 VL

EIVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVS





WYQQKPGQAPRLLIYGNDQRPSGIPDRFSGSGSGTD





FTLTISRLEPEDFAVYYCQSYDSDIDIVFGGGTKVE





IK


 


1465
hBDI-5H1.3
CDR-L1
ERSSGDIGDTYVS


 


1466
hBDI-5H1.3
CDR-L2
GNDQRPS


 


1467
hBDI-5H1.3
CDR-L3
QSYDSDIDIV


 


1468
hBDI-5H1.4 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQVVLTMTNMDPVDTATYYCARISTGISSYY





VMDAWGQGTTVTVSS


 


1469
hBDI-5H1.4
CDR-H1
GFSLSTFGMGVG


 


1470
hBDI-5H1.4
CDR-H2
NIWWDDDKYYNPSLKN


 


1471
hBDI-5H1.4
CDR-H3
ISTGISSYYVMDA


 


1472
hBDI-5H1.4 VL

EFVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVS





WYQQKPGQAPRLVIYGNDQRPSGIPDRFSGSGSGTD





FTLTISRLEPEDFAVYYCQSYDSDIDIVFGGGTKVE





IK


 


1473
hBDI-5H1.4
CDR-L1
ERSSGDIGDTYVS


 


1474
hBDI-5H1.4
CDR-L2
GNDQRPS


 


1475
hBDI-5H1.4
CDR-L3
QSYDSDIDIV


 


1476
hBDI-5H1.5 VH

EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAVLTITNMDPVDTATYYCARISTGISSYY





VMDAWGQGTTVTVSS


 


1477
hBDI-5H1.5
CDR-H1
GFSLSTFGMGVG


 


1478
hBDI-5H1.5
CDR-H2
NIWWDDDKYYNPSLKN


 


1479
hBDI-5H1.5
CDR-H3
ISTGISSYYVMDA


 


1480
hBDI-5H1.5 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDTYVSW





YQQRPGSSPTTVIYGNDQRPSGVPDRFSGSIDSSSN





SASLTISGLKTEDEADYYCQSYDSDIDIVFGGGTKL





TVL


 


1481
hBDI-5H1.5
CDR-L1
ERSSGDIGDTYVS


 


1482
hBDI-5H1.5
CDR-L2
GNDQRPS


 


1483
hBDI-5H1.5
CDR-L3
QSYDSDIDIV


 


1484
hBDI-5H1.6 VH

EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAVLTITNMDPVDTATYYCARISTGISSYY





VMDAWGQGTTVTVSS


 


1485
hBDI-5H1.6
CDR-H1
GFSLSTFGMGVG


 


1486
hBDI-5H1.6
CDR-H2
NIWWDDDKYYNPSLKN


 


1487
hBDI-5H1.6
CDR-H3
ISTGISSYYVMDA


 


1488
hBDI-5H1.6 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDTYVSW





YQQRPGSPPTNVIYGNDQRPSGVPDRFSGSIDSSSN





SASLTISGLKTEDEADYFCQSYDSDIDIVFGGGTKL





TVL


 


1489
hBDI-5H1.6
CDR-L1
ERSSGDIGDTYVS


 


1490
hBDI-5H1.6
CDR-L2
GNDQRPS


 


1491
hBDI-5H1.6
CDR-L3
QSYDSDIDIV


 


1492
hBDI-5H1.7 VH

EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAVLTITNMDPVDTATYYCARISTGISSYY





VMDAWGQGTTVTVSS


 


1493
hBDI-5H1.7
CDR-H1
GFSLSTFGMGVG


 


1494
hBDI-5H1.7
CDR-H2
NIWWDDDKYYNPSLKN


 


1495
hBDI-5H1.7
CDR-H3
ISTGISSYYVMDA


 


1496
hBDI-5H1.7 VL

EIVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVS





WYQQKPGQAPRLLIYGNDQRPSGIPDRFSGSGSGTD





FTLTISRLEPEDFAVYYCQSYDSDIDIVFGGGTKVE





IK


 


1497
hBDI-5H1.7
CDR-L1
ERSSGDIGDTYVS


 


1498
hBDI-5H1.7
CDR-L2
GNDQRPS


 


1499
hBDI-5H1.7
CDR-L3
QSYDSDIDIV


 


1500
hBDI-5H1.8 VH

EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAVLTITNMDPVDTATYYCARISTGISSYY





VMDAWGQGTTVTVSS


 


1501
hBDI-5H1.8
CDR-H1
GFSLSTFGMGVG


 


1502
hBDI-5H1.8
CDR-H2
NIWWDDDKYYNPSLKN


 


1503
hBDI-5H1.8
CDR-H3
ISTGISSYYVMDA


 


1504
hBDI-5H1.8 VL

EFVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVS





WYQQKPGQAPRLVIYGNDQRPSGIPDRFSGSGSGTD





FTLTISRLEPEDFAVYYCQSYDSDIDIVFGGGTKVE





IK


 


1505
hBDI-5H1.8
CDR-L1
ERSSGDIGDTYVS


 


1506
hBDI-5H1.8
CDR-L2
GNDQRPS


 


1507
hBDI-5H1.8
CDR-L3
QSYDSDIDIV


 


1508
hBDI-5H1.9 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAVLTITNMDPVDTATYYCARISTGISSYY





VMDAWGQGTTVTVSS


 


1509
hBDI-5H1.9
CDR-H1
GFSLSTFGMGVG


 


1510
hBDI-5H1.9
CDR-H2
NIWWDDDKYYNPSLKN


 


1511
hBDI-5H1.9
CDR-H3
ISTGISSYYVMDA


 


1512
hBDI-5H1.9 VL

DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVS





WYQQKPGQPPKNVIYGNDQRPSGVPDRFSGSGSGNS





ATLTISSLQAEDVAVYFCQSYDSDIDIVFGGGTKVE





IK


 


1513
hBDI-5H1.9
CDR-L1
ERSSGDIGDTYVS


 


1514
hBDI-5H1.9
CDR-L2
GNDQRPS


 


1515
hBDI-5H1.9
CDR-L3
QSYDSDIDIV


 


1516
hBDI-9E8.1 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYS





FDYWGQGTMVTVSS


 


1517
hBDI-9E8.1
CDR-H1
GFSLSTYGMGVG


 


1518
hBDI-9E8.1
CDR-H2
NIWWDDDKYYNPSLKN


 


1519
hBDI-9E8.1
CDR-H3
IESIGTTYSFDY


 


1520
hBDI-9E8.1 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDSYVSW





YQQRPGSSPTTVIYADDQRPSGVPDRFSGSIDSSSN





SASLTISGLKTEDEADYYCQSYDINIDIVFGGGTKL





TVL


 


1521
hBDI-9E8.1
CDR-L1
ERSSGDIGDSYVS


 


1522
hBDI-9E8.1
CDR-L2
ADDQRPS


 


1523
hBDI-9E8.1
CDR-L3
QSYDINIDIV


 


1524
hBDI-9E8.10 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYS





FDYWGQGTTVTVSS


 


1525
hBDI-9E8.10
CDR-H1
GFSLSTYGMGVG


 


1526
hBDI-9E8.10
CDR-H2
NIWWDDDKYYNPSLKN


 


1527
hBDI-9E8.10
CDR-H3
IESIGTTYSFDY


 


1528
hBDI-9E8.10 VL

DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVS





WYQQKPGKAPKNVIYADDQRPSGVPSRFSGSGSGNS





ASLTISSLQPEDFATYYCQSYDINIDIVFGQGTKVE





IK


 


1529
hBDI-9E8.10
CDR-L1
ERSSGDIGDSYVS


 


1530
hBDI-9E8.10
CDR-L2
ADDQRPS


 


1531
hBDI-9E8.10
CDR-L3
QSYDINIDIV


 


1532
hBDI-9E8.11 VH

EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTYGMGV





GWIRQAPGKGLEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAYLQINSLRAEDTAVYYCARIESIGTTYS





FDYWGQGTLVTVSS


 


1533
hBDI-9E8.11
CDR-H1
GFSLSTYGMGVG


 


1534
hBDI-9E8.11
CDR-H2
NIWWDDDKYYNPSLKN


 


1535
hBDI-9E8.11
CDR-H3
IESIGTTYSFDY


 


1536
hBDI-9E8.11 VL

DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVS





WYQQKPGQPPKNVIYADDQRPSGVPDRFSGSGSGNS





ASLTISSLQAEDVAVYFCQSYDINIDIVFGGGTKVE





IK


 


1537
hBDI-9E8.11
CDR-L1
ERSSGDIGDSYVS


 


1538
hBDI-9E8.11
CDR-L2
ADDQRPS


 


1539
hBDI-9E8.11
CDR-L3
QSYDINIDIV


 


1540
hBDI-9E8.12 VH

EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTYGMGV





GWIRQAPGKGLEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAYLQINSLRAEDTAVYYCARIESIGTTYS





FDYWGQGTLVTVSS


 


1541
hBDI-9E8.12
CDR-H1
GFSLSTYGMGVG


 


1542
hBDI-9E8.12
CDR-H2
NIWWDDDKYYNPSLKN


 


1543
hBDI-9E8.12
CDR-H3
IESIGTTYSFDY


 


1544
hBDI-9E8.12 VL

DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVS





WYQQKPGKAPKNVIYADDQRPSGVPSRFSGSGSGNS





ASLTISSLQPEDFATYYCQSYDINIDIVFGQGTKVE





IK


 


1545
hBDI-9E8.12
CDR-L1
ERSSGDIGDSYVS


 


1546
hBDI-9E8.12
CDR-L2
ADDQRPS


 


1547
hBDI-9E8.12
CDR-L3
QSYDINIDIV


 


1548
hBDI-9E8.13 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV





GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYS





FDYWGQGTMVTVSS


 


1549
hBDI-9E8.13
CDR-H1
GFSLSTYGMGVG


 


1550
hBDI-9E8.13
CDR-H2
NIWWDDDKYYNPSLKN


 


1551
hBDI-9E8.13
CDR-H3
IESIGTTYSFDY


 


1552
hBDI-9E8.13 VL

DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVS





WYQQKPGKAPKNVIYADDQRPSGVPSRFSGSGSGNS





ASLTISSLQPEDFATYYCQSYDINIDIVFGQGTKVE





IK


 


1553
hBDI-9E8.13
CDR-L1
ERSSGDIGDSYVS


 


1554
hBDI-9E8.13
CDR-L2
ADDQRPS


 


1555
hBDI-9E8.13
CDR-L3
QSYDINIDIV


 


1556
hBDI-9E8.2 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYS





FDYWGQGTMVTVSS


 


1557
hBDI-9E8.2
CDR-H1
GFSLSTYGMGVG


 


1558
hBDI-9E8.2
CDR-H2
NIWWDDDKYYNPSLKN


 


1559
hBDI-9E8.2
CDR-H3
IESIGTTYSFDY


 


1560
hBDI-9E8.2 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDSYVSW





YQQRPGSPPTNVIYADDQRPSGVPDRFSGSIDSSSN





SASLTISGLKTEDEADYFCQSYDINIDIVFGGGTKL





TVL


 


1561
hBDI-9E8.2
CDR-L1
ERSSGDIGDSYVS


 


1562
hBDI-9E8.2
CDR-L2
ADDQRPS


 


1563
hBDI-9E8.2
CDR-L3
QSYDINIDIV


 


1564
hBDI-9E8.3 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYS





FDYWGQGTMVTVSS


 


1565
hBDI-9E8.3
CDR-H1
GFSLSTYGMGVG


 


1566
hBDI-9E8.3
CDR-H2
NIWWDDDKYYNPSLKN


 


1567
hBDI-9E8.3
CDR-H3
IESIGTTYSFDY


 


1568
hBDI-9E8.3 VL

EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVS





WYQQKPGQAPRLLIYADDQRPSGIPDRFSGSGSGTD





FTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVE





IK


 


1569
hBDI-9E8.3
CDR-L1
ERSSGDIGDSYVS


 


1570
hBDI-9E8.3
CDR-L2
ADDQRPS


 


1571
hBDI-9E8.3
CDR-L3
QSYDINIDIV


 


1572
hBDI-9E8.4 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYS





FDYWGQGTMVTVSS


 


1573
hBDI-9E8.4
CDR-H1
GFSLSTYGMGVG


 


1574
hBDI-9E8.4
CDR-H2
NIWWDDDKYYNPSLKN


 


1575
hBDI-9E8.4
CDR-H3
IESIGTTYSFDY


 


1576
hBDI-9E8.4 VL

EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVS





WYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGSGTD





FTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVE





IK


 


1577
hBDI-9E8.4
CDR-L1
ERSSGDIGDSYVS


 


1578
hBDI-9E8.4
CDR-L2
ADDQRPS


 


1579
hBDI-9E8.4
CDR-L3
QSYDINIDIV


 


1580
hBDI-9E8.5 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV





GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYS





FDYWGQGTMVTVSS


 


1581
hBDI-9E8.5
CDR-H1
GFSLSTYGMGVG


 


1582
hBDI-9E8.5
CDR-H2
NIWWDDDKYYNPSLKN


 


1583
hBDI-9E8.5
CDR-H3
IESIGTTYSFDY


 


1584
hBDI-9E8.5 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDSYVSW





YQQRPGSSPTTVIYADDQRPSGVPDRFSGSIDSSSN





SASLTISGLKTEDEADYYCQSYDINIDIVFGGGTKL





TVL


 


1585
hBDI-9E8.5
CDR-L1
ERSSGDIGDSYVS


 


1586
hBDI-9E8.5
CDR-L2
ADDQRPS


 


1587
hBDI-9E8.5
CDR-L3
QSYDINIDIV


 


1588
hBDI-9E8.6 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV





GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYS





FDYWGQGTMVTVSS


 


1589
hBDI-9E8.6
CDR-H1
GFSLSTYGMGVG


 


1590
hBDI-9E8.6
CDR-H2
NIWWDDDKYYNPSLKN


 


1591
hBDI-9E8.6
CDR-H3
IESIGTTYSFDY


 


1592
hBDI-9E8.6 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDSYVSW





YQQRPGSPPTNVIYADDQRPSGVPDRFSGSIDSSSN





SASLTISGLKTEDEADYFCQSYDINIDIVFGGGTKL





TVL


 


1593
hBDI-9E8.6
CDR-L1
ERSSGDIGDSYVS


 


1594
hBDI-9E8.6
CDR-L2
ADDQRPS


 


1595
hBDI-9E8.6
CDR-L3
QSYDINIDIV


 


1596
hBDI-9E8.7 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV





GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYS





FDYWGQGTMVTVSS


 


1597
hBDI-9E8.7
CDR-H1
GFSLSTYGMGVG


 


1598
hBDI-9E8.7
CDR-H2
NIWWDDDKYYNPSLKN


 


1599
hBDI-9E8.7
CDR-H3
IESIGTTYSFDY


 


1600
hBDI-9E8.7 VL

EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVS





WYQQKPGQAPRLLIYADDQRPSGIPDRFSGSGSGTD





FTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVE





IK


 


1601
hBDI-9E8.7
CDR-L1
ERSSGDIGDSYVS


 


1602
hBDI-9E8.7
CDR-L2
ADDQRPS


 


1603
hBDI-9E8.7
CDR-L3
QSYDINIDIV


 


1604
hBDI-9E8.8 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV





GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYS





FDYWGQGTMVTVSS


 


1605
hBDI-9E8.8
CDR-H1
GFSLSTYGMGVG


 


1606
hBDI-9E8.8
CDR-H2
NIWWDDDKYYNPSLKN


 


1607
hBDI-9E8.8
CDR-H3
IESIGTTYSFDY


 


1608
hBDI-9E8.8 VL

EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVS





WYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGSGTD





FTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVE





IK


 


1609
hBDI-9E8.8
CDR-L1
ERSSGDIGDSYVS


 


1610
hBDI-9E8.8
CDR-L2
ADDQRPS


 


1611
hBDI-9E8.8
CDR-L3
QSYDINIDIV


 


1612
hBDI-9E8.9 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYS





FDYWGQGTTVTVSS


 


1613
hBDI-9E8.9
CDR-H1
GFSLSTYGMGVG


 


1614
hBDI-9E8.9
CDR-H2
NIWWDDDKYYNPSLKN


 


1615
hBDI-9E8.9
CDR-H3
IESIGTTYSFDY


 


1616
hBDI-9E8.9 VL

DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVS





WYQQKPGQPPKNVIYADDQRPSGVPDRFSGSGSGNS





ASLTISSLQAEDVAVYFCQSYDINIDIVFGGGTKVE





IK


 


1617
hBDI-9E8.9
CDR-L1
ERSSGDIGDSYVS


 


1618
hBDI-9E8.9
CDR-L2
ADDQRPS


 


1619
hBDI-9E8.9
CDR-L3
QSYDINIDIV


 


1620
hBDI-9E8.4E VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV





GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS





KDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYS





FDYWGQGTMVTVSS


 


1621
hBDI-9E8.4E
CDR-H1
GFSLSTYGMGVG


 


1622
hBDI-9E8.4E
CDR-H2
NIWWDDDKYYNPSLKN


 


1623
hBDI-9E8.4E
CDR-H3
IESIGTTYSFDY


 


1624
hBDI-9E8.4E VL

EFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVS





WYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGSGTD





FTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVE





IK


 


1625
hBDI-9E8.4E
CDR-L1
ERSSGDIGESYVS


 


1626
hBDI-9E8.4E
CDR-L2
ADDQRPS


 


1627
hBDI-9E8.4E
CDR-L3
QSYDINIDIV


 


1628
hBFU-3E2.1 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYW





VKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTA





DKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPM





DAWGQGTTVTVSS


 


1629
hBFU-3E2.1
CDR-H1
GYTFTESYMY


 


1630
hBFU-3E2.1
CDR-H2
RIDPEDGSTDYVEKFKN


 


1631
hBFU-3E2.1
CDR-H3
FGARSYFYPMDA


 


1632
hBFU-3E2.1 VL

ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWY





QQKPGQQPRLLIYGASNLESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIK


 


1633
hBFU-3E2.1
CDR-L1
RASESVSTLMH


 


1634
hBFU-3E2.1
CDR-L2
GASNLES


 


1635
hBFU-3E2.1
CDR-L3
QQSWNDPWT


 


1636
hBFU-3E2.2 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYW





VRQAPGQGLELIGRIDPEDGSTDYVEKFKNRVTLTA





DKSTSTAYMELSSLRSEDTAVYYCARFGARSYFYPM





DAWGQGTTVTVSS


 


1637
hBFU-3E2.2
CDR-H1
GYTFTESYMY


 


1638
hBFU-3E2.2
CDR-H2
RIDPEDGSTDYVEKFKN


 


1639
hBFU-3E2.2
CDR-H3
FGARSYFYPMDA


 


1640
hBFU-3E2.2 VL

ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWY





QQKPGQQPRLLIYGASNLESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIK


 


1641
hBFU-3E2.2
CDR-L1
RASESVSTLMH


 


1642
hBFU-3E2.2
CDR-L2
GASNLES


 


1643
hBFU-3E2.2
CDR-L3
QQSWNDPWT


 


1644
hBFU-3E2.3 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYW





VKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTA





DKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPM





DAWGQGTTVTVSS


 


1645
hBFU-3E2.3
CDR-H1
GYTFTESYMY


 


1646
hBFU-3E2.3
CDR-H2
RIDPEDGSTDYVEKFKN


 


1647
hBFU-3E2.3
CDR-H3
FGARSYFYPMDA


 


1648
hBFU-3E2.3 VL

ATQLTQSPSSLSASVGDRVTISCRASESVSTLMHWY





QQKPGKQPRLLIYGASNLESGVPSRFSGSGSGTDFT





LTISSLQPEDFATYFCQQSWNDPWTFGGGTKVEIK


 


1649
hBFU-3E2.3
CDR-L1
RASESVSTLMH


 


1650
hBFU-3E2.3
CDR-L2
GASNLES


 


1651
hBFU-3E2.3
CDR-L3
QQSWNDPWT


 


1652
hBFU-3E2.4 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYW





VRQAPGQGLELIGRIDPEDGSTDYVEKFKNRVTLTA





DKSTSTAYMELSSLRSEDTAVYYCARFGARSYFYPM





DAWGQGTTVTVSS


 


1653
hBFU-3E2.4
CDR-H1
GYTFTESYMY


 


1654
hBFU-3E2.4
CDR-H2
RIDPEDGSTDYVEKFKN


 


1655
hBFU-3E2.4
CDR-H3
FGARSYFYPMDA


 


1656
hBFU-3E2.4 VL

ATQLTQSPSSLSASVGDRVTISCRASESVSTLMHWY





QQKPGKQPRLLIYGASNLESGVPSRFSGSGSGTDFT





LTISSLQPEDFATYFCQQSWNDPWTFGGGTKVEIK


 


1657
hBFU-3E2.4
CDR-L1
RASESVSTLMH


 


1658
hBFU-3E2.4
CDR-L2
GASNLES


 


1659
hBFU-3E2.4
CDR-L3
QQSWNDPWT
















TABLE 29







VH and VL Amino Acid Sequences of Humanized Versions of


Rat Anti-Human VEGFR II Monoclonal Antibodies (CDRs in bold)










SEQ ID

Protein
V Region


NO:
Clone
Region
12345678901234567890123456





1660
hBCU-6B1.1 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY





WVKQAPGQGLEFMGWINTETGQPTYADDFKGRFVF





SLDTSVSTAYLQISSLKAEDTAVYFCARLGNNYGI





WFAYWGQGTLVTVSS


 


1661
hBCU-6B1.1
CDR-H1
GYTFTNYGMY


 


1662
hBCU-6B1.1
CDR-H2
WINTETGQPTYADDFKG


 


1663
hBCU-6B1.1
CDR-H3
LGNNYGIWFAY


 


1664
hBCU-6B1.1 VL

DIQMTQSPSSLSASVGDRVTIECRASDDLYSTLAW





YQQKPGKSPKLLIFDANRLAAGVPSRFSGSGSGTD





YSLTISSLQPEDVATYFCQQYNKFPWTFGGGTKVE





IK


 


1665
hBCU-6B1.1
CDR-L1
RASDDLYSTLA


 


1666
hBCU-6B1.1
CDR-L2
DANRLAA


 


1667
hBCU-6B1.1
CDR-L3
QQYNKFPWT


 


1668
hBCU-6B1.2 VH

EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMY





WVKQAPGQGLEFMGWINTETGQPTYADDFKGRFTF





TLDTSTSTAYMELRSLRSDDTAVYFCARLGNNYGI





WFAYWGQGTLVTVSS


 


1669
hBCU-6B1.2
CDR-H1
GYTFTNYGMY


 


1670
hBCU-6B1.2
CDR-H2
WINTETGQPTYADDFKG


 


1671
hBCU-6B1.2
CDR-H3
LGNNYGIWFAY


 


1672
hBCU-6B1.2 VL

DIQMTQSPSSLSASVGDRVTIECRASDDLYSTLAW





YQQKPGKSPKLLIFDANRLAAGVPSRFSGSGSGTD





YSLTISSLQPEDVATYFCQQYNKFPWTFGGGTKVE





IK


 


1673
hBCU-6B1.2
CDR-L1
RASDDLYSTLA


 


1674
hBCU-6B1.2
CDR-L2
DANRLAA


 


1675
hBCU-6B1.2
CDR-L3
QQYNKFPWT


 


1676
hBCU-6B1.3 VH

EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMY





WVRQAPGQGLEFMGWINTETGQPTYADDFKGRFTF





TLDTSTSTAYMELRSLRSDDTAVYYCARLGNNYGI





WFAYWGQGTLVTVSS


 


1677
hBCU-6B1.3
CDR-H1
GYTFTNYGMY


 


1678
hBCU-6B1.3
CDR-H2
WINTETGQPTYADDFKG


 


1679
hBCU-6B1.3
CDR-H3
LGNNYGIWFAY


 


1680
hBCU-6B1.3 VL

DIQMTQSPSSLSASVGDRVTIECRASDDLYSTLAW





YQQKPGKSPKLLIFDANRLAAGVPSRFSGSGSGTD





YSLTISSLQPEDVATYFCQQYNKFPWTFGGGTKVE





IK


 


1681
hBCU-6B1.3
CDR-L1
RASDDLYSTLA


 


1682
hBCU-6B1.3
CDR-L2
DANRLAA


 


1683
hBCU-6B1.3
CDR-L3
QQYNKFPWT


 


1684
hBCU-6B1.4 VH

EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMY





WVRQAPGQGLEFMGWINTETGQPTYADDFKGRFTF





TLDTSTSTAYMELRSLRSDDTAVYYCARLGNNYGI





WFAYWGQGTLVTVSS


 


1685
hBCU-6B1.4
CDR-H1
GYTFTNYGMY


 


1686
hBCU-6B1.4
CDR-H2
WINTETGQPTYADDFKG


 


1687
hBCU-6B1.4
CDR-H3
LGNNYGIWFAY


 


1688
hBCU-6B1.4 VL

DIQMTQSPSSLSASVGDRVTITCRASDDLYSTLAW





YQQKPGKSPKLLIFDANRLAAGVPSRFSGSGSGTD





YTLTISSLQPEDVATYFCQQYNKFPWTFGGGTKVE





IK


 


1689
hBCU-6B1.4
CDR-L1
RASDDLYSTLA


 


1690
hBCU-6B1.4
CDR-L2
DANRLAA


 


1691
hBCU-6B1.4
CDR-L3
QQYNKFPWT
















TABLE 30







VH and VL Amino Acid Sequences of Humanized Versions of


Rat Anti-Human PDGFR b Monoclonal Antibodies (CDRs in bold)










SEQ ID

Protein
V Region


NO:
Clone
Region
123456789012345678901234567890





1692
hBDE-3C9.1 VH

EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGMA





WVRQAPGKGLEWVASITNSGGNTYYRDSVKGRFTI





SRDNAKNTQYLQMNSLRAEDTAVYFCARHTPGANY





FDYWGQGTMVTVSS


 


1693
hBDE-3C9.1
CDR-H1
GFTFSNYGMA


 


1694
hBDE-3C9.1
CDR-H2
SITNSGGNTYYRDSVKG


 


1695
hBDE-3C9.1
CDR-H3
HTPGANYFDY


 


1696
hBDE-3C9.1 VL

DIQMTQSPSSLSASVGDRVTITCQASQSIKNYIAW





YQLKPGKAPRLLMRYTSTLESGTPSRFSGSGSGRD





YTFTISSLQPEDIATYYCVQYANLYTFGGGTKVEI





K


 


1697
hBDE-3C9.1
CDR-L1
QASQSIKNYIA


 


1698
hBDE-3C9.1
CDR-L2
YTSTLES


 


1699
hBDE-3C9.1
CDR-L3
VQYANLYT


 


1700
hBDE-3C9.2 VH

EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGMA





WVRQAPGKGLEWVASITNSGGNTYYRDSVKGRFTI





SRDNAKNSLYLQMNSLRAEDTAVYYCARHTPGANY





FDYWGQGTMVTVSS


 


1701
hBDE-3C9.2
CDR-H1
GFTFSNYGMA


 


1702
hBDE-3C9.2
CDR-H2
SITNSGGNTYYRDSVKG


 


1703
hBDE-3C9.2
CDR-H3
HTPGANYFDY


 


1704
hBDE-3C9.2 VL

DIQMTQSPSSLSASVGDRVTITCQASQSIKNYIAW





YQQKPGKAPRLLIRYTSTLESGVPSRFSGSGSGRD





YTFTISSLQPEDIATYYCVQYANLYTFGGGTKVEI





K


 


1705
hBDE-3C9.2
CDR-L1
QASQSIKNYIA


 


1706
hBDE-3C9.2
CDR-L2
YTSTLES


 


1707
hBDE-3C9.2
CDR-L3
VQYANLYT









Generation of Humanized Antibodies
All variants were cloned into pHybE vectors and were transiently transfected into 50 mls of HEK 2936e suspension cell cultures in a ratio of 60% to 40% light to heavy chain construct. 1 mg/ml PEI was used to transfect the cells. Cell supernatants were harvested after six days in shaking flasks, spun down to pellet cells, and filtered through 0.22 μm filters to separate IgG from culture contaminates. All were batch purified by adding 1 supernatant volume of protein A IgG binding buffer (Thermo Scientific 21001) and 1 ml of rProteinA sepharose fast flow beads (GE Healthcare, 17-1279-04). Supernatants, with beads and buffer added, were rocked overnight at 4° C., and the day after beads were collected by gravity over poly prep chromatography columns (Bio Rad, 731-1550). Once supernatants had passed through the columns the beads were washed with 10 column volumes of binding buffer, and IgG was eluted with Immunopure IgG elution buffer (Pierce, 185 1520) and collected in 1 ml aliquots. Fractions containing IgG were pooled and dialyzed in 15 mM Histidine pH 6 overnight at 4° C.
Purified variants were further characterized for their affinities for recombinant human target proteins by binding ELISA, by Biacore, and by cell-based potency assays.







TABLE 31







Summary of Protein Expression and Purification for


Humanized Anti-Human VEGF-A And Humanized


Anti-Human PDGF-BB Monoclonal Antibodies













Octet Titer
~Yield
SEC



Name
(mg/L)1
(mg/L)2
(% monomer)3
















hBDB-4G8.1
19.9
19.7
100.0



hBDB-4G8.2
105.3
95.8
100.0



hBDB-4G8.3
34.8
31.9
100.0



hBDB-4G8.4
45.8
34.2
100.0



hBDB-4G8.5
24.7
27.4
100.0



hBDB-4G8.6
28.6
34.2
100.0



hBDB-4G8.7
75.8
63.4
100.0



hBDB-4G8.8
145.9
101.4
100.0



hBDB-4G8.9
38.8
39.0
100.0



hBDB-4G8.10
40.7
32.9
89.1



hBDB-4G8.11
47.9
38.0
87.2



hBDB-4G8.12
37.5
38.3
100.0



hBDB-4G8.13
44.8
35.1
100.0



hBDB-4G8.14
73.0
47.0
100.0



hBDB-4G8.15
161.2
94.9
100.0



hBDI-5H1.1
49.8
38.7
100.0



hBDI-5H1.2
63.4
62.0
100.0



hBDI-5H1.3
94.2
86.5
99.1



hBDI-5H1.4
109.0
123.1
99.2



hBDI-5H1.5
23.0
27.7
100.0



hBDI-5H1.6
41.2
46.0
100.0



hBDI-5H1.7
9.6
9.6
88.1



hBDI-5H1.8
36.0
41.5
100.0



hBDI-5H1.9
56.0
60.2
85.6



hBDI-5H1.10
34.2
31.1
85.2



hBDI-5H1.11
41.0
34.4
96.3



hBDI-5H1.12
37.7
30.2
100.0



hBDI-9E8.1
90.0
72.4
100.0



hBDI-9E8.2
89.9
89.1
99.3



hBDI-9E8.3
28.8
24.4
97.1



hBDI-9E8.4
52.8
54.8
98.2



hBDI-9E8.5
78.0
57.7
100.0



hBDI-9E8.6
60.6
61.4
100.0



hBDI-9E8.7
30.4
27.9
88.1



hBDI-9E8.8
37.1
38.0
98.4



hBDI-9E8.9
50.3
44.9
94.6



hBDI-9E8.10
93.0
56.2
94.7



hBDI-9E8.11
78.4
52.7
99.1



hBDI-9E8.12
92.3
68.5
100.0



hBDI-5H1.13
13.6
10.5
88.1



hBDI-9E8.13
53.5
66.9
100.0



hBDI-1E1.1
133.5
ND
ND



hBDI-1E1.2
115.6
ND
ND



hBDI-1E1.3
83.4
ND
ND



hBDI-1E1.4
137.6
ND
ND



hBDI-1E1.5
97.4
ND
ND



hBDI-1E1.6
70.6
ND
ND



hBDI-1E1.7
91.9
ND
ND



hBDI-1E1.8
71.2
ND
ND



hBDI-1E1.9
94.3
ND
ND



hBDI-1E1.10
72.7
ND
ND



hBDI-1E1.11
57.4
ND
ND



hBDI-1E1.12
151.6
ND
ND



hBEW-9A8.1
0.2
ND
ND



hBEW-9A8.2
0.2
ND
ND



hBEW-9A8.3
0.2
ND
ND



hBEW-9A8.4
0.2
ND
ND



hBEW-9A8.5
0.5
ND
ND



hBEW-9A8.6
0.2
ND
ND



hBEW-9A8.7
0.3
ND
ND



hBEW-9A8.8
3.5
ND
ND



hBEW-9A8.9
15.3
18.6
ND



hBEW-9A8.10
5.2
ND
ND



hBEW-9A8.11
30.6
18.9
ND



hBEW-9A8.12
38.3
28.4
ND



hBEW-9A8.13
0.4
ND
ND



hBEW-9A8.14
0.3
ND
ND



hBEW-9A8.15
0.3
ND
ND



hBEW-9A8.16
3.2
ND
ND



hBEW-6C2.1
5.4
ND
ND



hBEW-6C2.2
1.5
ND
ND



hBEW-6C2.3
14.8
7.8
ND



hBEW-6C2.4
79.6
29.5
ND



hBEW-6C2.5
4.7
ND
ND



hBEW-6C2.6
3.9
ND
ND



hBEW-6C2.7
140.8
39.7
ND



hBEW-6C2.8
75.3
24.8
ND



hBDI-5H1.16
ND
23.9
93.4



hBDI-5H1.17
ND
21.0
92.1



hBFU-3E2.1
ND
40.2
88.1



hBFU-3E2.2
ND
34.6
93.6



hBFU-3E2.3
ND
33.6
84.2



hBFU-3E2.4
ND
38.4
94.7



hBEW-9A8.17
ND
20.0
98.7



hBEW-9A8.20
ND
17.6
86.6



hBEW-9A8.21
ND
13.3
97.5



hBEW-5C3.1
ND
20.8
85.0



hBEW-5C3.2
ND
17.7
74.6



hBEW-5C3.3
ND
6.9
93.7



hBEW-5C3.4
ND
32.0
88.7



hBEW-5C3.5
ND
30.6
85.1



hBEW-5C3.6
ND
19.4
75.4



hBEW-9E10.1
ND
42.7
98.0



hBEW-9E10.2
ND
46.1
98.0



hBEW-9E10.3
ND
45.9
97.6



hBEW-9E10.4
ND
47.1
98.0



hBEW-9E10.5
ND
56.2
97.9



hBEW-9E10.6
ND
52.9
97.6



hBEW-1B10.1
ND
34.1
97.8



hBEW-1B10.2
ND
45.3
98.1



hBEW-1E3.1
ND
29.6
95.5



hBEW-1E3.2
ND
20.9
98.3



hBEW-1E3.3
ND
22.0
98.5



hBEW-1E3.4
ND
48.0
98.1



hBEW-1E3.5
ND
23.8
98.5



hBEW-1E3.6
ND
17.0
98.7







ND = Not Determined



1Octet titer is the amout of IgG in the unpurified supernatant as determined by protein A binding compared to a standard curve using an Octet instrument.



2Yield is determined by the total amount of purified protein in mg divided by the total cell culture volume in liters.



3SEC % monomer is determined using HPLC size exclusion chromatography.






Humanized anti-VEGF antibodies were tested for their binding to human VEGF-A according to the method described in Example 1.1. The on-rate, off-rate and binding kinetics are summarized in Table 32 below.







TABLE 32







Biacore Binding of Humanized Anti-VEGF Antibodies












Antibody
kon (M−1 s−1)
koff (M−1)
KD (M)
















hBDB-4G8.1
1.8E+07
1.0E−04
5.8E−12



hBDB-4G8.2
1.7E+07
6.2E−05
3.6E−12



hBDB-4G8.3
1.0E+07
4.8E−05
4.8E−12



hBDB-4G8.4
2.7E+07
1.5E−04
5.5E−12



hBDB-4G8.5
2.5E+07
4.0E−05
1.6E−12



hBDB-4G8.6
2.6E+07
3.7E−05
1.4E−12



hBDB-4G8.7
3.7E+07
1.3E−03
3.4E−11



hBDB-4G8.8
1.8E+07
8.6E−04
4.7E−11



hBDB-4G8.9
1.4E+07
8.8E−04
6.2E−11



hBDB-4G8.10
2.7E+07
2.2E−04
8.1E−12



hBDB-4G8.11
2.6E+07
3.4E−05
1.3E−12



hBDB-4G8.12
2.6E+07
3.2E−05
1.2E−12



hBDB-4G8.13
2.2E+07
1.7E−04
7.6E−12



hBDB-4G8.14
1.5E+07
5.6E−05
3.7E−12



hBDB-4G8.15
2.0E+07
8.7E−05
4.4E−12



hBEW-9A8.9
1.0E+07
8.2E−03
8.2E−10



hBEW-9A8.11
1.5E+07
1.1E−03
7.4E−11



hBEW-9A8.12
9.6E+06
1.4E−04
1.5E−11



hBEW-9A8.17
7.9E+06
1.4E−05
1.7E−12



hBEW-9A8.20
7.6E+06
1.2E−05
1.6E−12



hBEW-9A8.21
5.8E+06
3.9E−05
6.7E−12



hBEW-5C3.1
1.1E+07
6.9E−05
6.0E−12



hBEW-5C3.4
9.9E+06
8.5E−05
8.6E−12



hBEW-5C3.5
1.2E+07
9.7E−05
8.5E−12



hBEW-9E10.1
1.2E+07
2.5E−05
2.1E−12



hBEW-9E10.2
1.6E+07
1.9E−04
1.2E−11



hBEW-9E10.3
1.3E+07
4.2E−05
3.2E−12



hBEW-9E10.4
1.2E+07
2.5E−05
2.1E−12



hBEW-9E10.5
1.6E+07
2.3E−04
1.5E−11



hBEW-9E10.6
1.5E+07
4.0E−05
2.6E−12



hBEW-1B10.1
7.6E+06
1.4E−04
1.8E−11



hBEW-1B10.2
7.5E+06
1.5E−04
2.0E−11



hBEW-1E3.1
1.1E+07
8.5E−05
7.7E−12



hBEW-1E3.2
1.1E+07
1.0E−04
9.2E−12



hBEW-1E3.4
9.8E+06
9.6E−05
9.7E−12



hBEW-1E3.5
1.0E+07
1.0E−04
1.0E−11










Humanized anti-VEGF-A antibodies were tested for potency against hVEGF165-induced cell proliferation in one of two cellular assay formats. The HMVEC-d bioassay utilizes cells which natively express VEGFR2 (Example 1.10). The VEGFR2-3T3 cells are stably transfected with VEGFR2 (Example 1.7). The data is summarized in Table 33 below.







TABLE 33







Summary of Characterization of Humanized


Anti-Human VEGF-A Monoclonal Antibodies.










hVEGF165 IC50 (nM)














VEGFR2-



Humanized Molecules
HMVEC-d
3T3















hBDB-4G8.1
NT
0.847



hBDB-4G8.2
NT
0.603



hBDB-4G8.3
NT
0.665



hBDB-4G8.3 half-body
NT
>10



hBDB-4G8.4
NT
0.918



hBDB-4G8.5
NT
0.620



hBDB-4G8.6
NT
0.488



hBDB-4G8.7
NT
>10



hBDB-4G8.8
NT
>10



hBDB-4G8.9
NT
>10



hBDB-4G8.10
NT
>10



hBDB-4G8.11
NT
0.385



hBDB-4G8.12
NT
0.563



hBDB-4G8.13
NT
0.791



hBDB-4G8.14
NT
0.499



hBDB-4G8.15
NT
0.963



hBEW-1B10.1
0.168
NT



hBEW-1B10.2
0.222
NT



hBEW-1E3.1
0.138
NT



hBEW-1E3.4
0.212
NT



hBEW-1E3.2
0.161
NT



hBEW-1E3.3
0.205
NT



hBEW-1E3.5
0.184
NT



hBEW-1E3.6
0.26
NT



hBEW-5C3.1
0.071
NT



hBEW-5C3.2
0.162
NT



hBEW-5C3.3
>2
NT



hBEW-5C3.4
0.098
NT



hBEW-5C3.5
0.123
NT



hBEW-5C3.6
>2
NT



hBEW-9A8.9
NT
>10



hBEW-9A8.11
NT
>10



hBEW-9A8.12
NT
0.598



hBEW-9A8.17
0.059
NT



hBEW-9A8.20
0.064
NT



hBEW-9A8.21
0.09
NT



hBEW-9E10.1
0.064
NT



hBEW-9E10.2
0.181
NT



hBEW-9E10.3
0.062
NT



hBEW-9E10.4
0.071
NT



hBEW-9E10.5
0.229
NT



hBEW-9E10.6
0.068
NT







NT = Not tested






Humanized anti-PDGF-BB antibodies were tested for their binding to human PDGF-BB according to the method described in Example 1.1. The on-rate, off-rate and binding kinetics are summarized in Table 34 below.







TABLE 34







Biacore Binding of Humanized Anti-PDGF Antibodies












Antibody
kon (M−1 s−1)
koff (M−1)
KD (M)
















hBDI-9E8.1
≧1.0E+07
5.6E−03
≦5.6E−10



hBDI-9E8.2
≧1.0E+07
5.1E−03
≦5.1E−10



hBDI-9E8.3
≧1.0E+07
6.5E−04
≦6.5E−11



hBDI-9E8.4
>1.0E+07
2.1E−04
≦2.1E−11



hBDI-9E8.5
≧1.0E+07
2.1E−03
≦2.1E−10



hBDI-9E8.6
≧1.0E+07
2.1E−03
≦2.1E−10



hBDI-9E8.7
≧1.0E+07
4.5E−04
≦4.5E−11



hBDI-9E8.8
≧1.0E+07
1.7E−04
≦1.7E−11*



hBDI-9E8.9
≧1.0E+07
1.5E−03
≦1.5E−10



hBDI-9E8.10
≧1.0E+07
1.8E−03
≦1.8E−10



hBDI-9E8.11
≧1.0E+07
7.4E−04
≦7.4E−11



hBDI-9E8.12
≧1.0E+07
2.1E−03
≦2.1E−10



hBDI-9E8.13
≧1.0E+07
1.0E−03*
≦1.0E−10*



hBDI-5H1.1
≧1.0E+07
4.1E−03
≦4.1E−10



hBDI-5H1.2
≧1.0E+07
1.9E−03
≦1.9E−10



hBDI-5H1.3
≧1.0E+07
4.5E−03
≦4.5E−10



hBDI-5H1.4
≧1.0E+07
1.4E−02
≦1.4E−09



hBDI-5H1.5
≧1.0E+07
1.7E−03
≦1.7E−10



hBDI-5H1.6
≧1.0E+07
8.2E−04
≦8.2E−11



hBDI-5H1.7
≧1.0E+07
2.9E−02*
≦2.9E−09*



hBDI-5H1.8
≧1.0E+07
7.2E−01*
≦7.2E−08*



hBDI-5H1.9
≧1.0E+07
3.1E−03
≦3.1E−10



hBDI-5H1.10
≧1.0E+07
2.3E−03
≦2.3E−10



hBDI-5H1.11
≧1.0E+07
3.7E−03
≦3.7E−10



hBDI-5H1.12
≧1.0E+07
2.3E−03
≦2.3E−10



hBDI-5H1.13
≧1.0E+07
4.9E−03*
≦4.9E−10*







*Heterogeneous off-rate






Humanized anti-PDGF-BB antibodies were tested for potency against hPDGF-BB in functional assays. The ability to neutralize hPDGF-BB-induced cell proliferation was assessed (Example 1.15) as well as the ability to block binding of hPDGF-BB to hPDGF-Rβ in a competition ELISA format (Example 1.13). The data is summarized in Table 35 below.







TABLE 35







Summary of Characterization of Humanized


Anti-Human PDGF-BB Monoclonal Antibodies













hPDGF-





BB/hPDGFRβ




hPDGF-BB
Competition



Humanized Molecules
IC50 (nM)
IC50 (nM)















hBDI-9E8.1
>5
+



hBDI-9E8.2
>5
+



hBDI-9E8.3
1.583
+



hBDI-9E8.4
0.061
4.301



hBDI-9E8.4 half body
>5
NT



hBDI-9E8.5
>5
+



hBDI-9E8.6
>5
+



hBDI-9E8.7
0.350
+



hBDI-9E8.8
0.105
+



hBDI-9E8.9
0.574
+



hBDI-9E8.10
0.562
+



hBDI-9E8.11
0.309
1.730



hBDI-9E8.12
0.525
+



hBDI-5H1.1
<10
+



hBDI-5H1.2
<10
+



hBDI-5H1.3
<10
−



hBDI-5H1.4
<10
−



hBDI-5H1.9
<10
+



hBDI-5H1.10
<10
−



hBDI-5H1.11
<10
−



hBDI-5H1.12
<10
−



hBDI-5H1.5
<10
+



hBDI-5H1.6
<10
+



hBDI-5H1.7
<10
−



hBDI-5H1.8
<10
−



hBDI-5H1.13
<10
+



hBDI-5H1.16
<10
NT



hBDI-5H1.17
<10
NT



hBFU-3E2.1
0.183
NT



hBFU-3E2.2
0.659
NT



hBFU-3E2.3
0.335
NT



hBFU-3E2.4
0.571
NT







NT—Not tested






Humanized anti-VEGFR2 antibodies were tested for potency against hVEGFR2 in functional assay formats. The antibodies were characterized for the ability to block VEGFR2 binding to hVEGF165 in a competition ELISA format (Example 1.22). The antibodies were also tested for the ability to bind exogeneous hVEGFR2 and allow signaling in response to hVEGF165 (Example 1.23). The data is summarized in Table 36 below.







TABLE 36







Summary of Characterization of Humanized


Anti-Human VEGFR II Monoclonal Antibodies.










Potency (nM)













hVEGF165/
hVEGF165/



Humanized
hVEGFR2-Fc
Tyr1054



Molecules
Competition
phospho-assay







hBCU-6B1.1
0.474
NT



hBCU-6B1.2
0.340
NT



hBCU-6B1.3
0.319
NT



hBCU-6B1.4
0.335
NT







NT—Not tested






Humanized anti-PDGF-Rβ antibodies were characterized for activity in functional assays. Antibodies were assessed for the ability to bind hPDGF-Rβ (Example 1.26) and block binding of hPDGF-Rβ to hPDGF-BB in a competition ELISA format (Example 1.27). They were also tested for the ability to bind exogenoeous hPDGF-Rβ and allow signaling in response to hPDGF-BB (Example 1.28). The data is summarized in Table 37 below.







TABLE 37







Summary of Characterization of Humanized


Anti-Human PDGFR-B Monoclonal Antibodies









Potency (nM)












hPDGF-BB/
hPDGF-BB



hPDGFRβ-Fc
hPDGFRβ-Fc
Tyr751


Humanized Molecules
Binding
Competition
phospho-assay





hBDE-3C9.1
NT
0.217
1.053


hBDE-3C9.2
NT
0.260
0.882





NT—Not tested






Example 7: Affinity Maturation of Anti-Human VEGF-A Antibody 4G8
Library Designs And Strategy
Two different hBDB-4G8.3 parental sequences were made: One with “DT” and another with “EI” at the beginning of VL. Both parentals were tested as scFv, and the “EI” was chosen as the template for the libraries. Two libraries were made by dope primers: HC and LC. After library selection and diversity reduction, libraries were combined into one recombined library (rHC+LC). Final selected clones from each of 3 libraries were converted to IgG.
HC Library

    
    
        Doping (X) 11 residues at 76080808: 30, 31, 33, 53, 56, 58, 95, 96, 100, 100a and 100c
        Co-evolve (1): D61Q/D62G/K64T. Library will contain DDFKG (SEQ ID NO: 1708) or QGFTG (SEQ ID NO: 1709)
    
    


A 109 library will be able to sample mutants carrying up to 4 doped residues at least 4 times. On average, library members will have 5 doped residues.
LC Library

    
    
        Doping (X) 10 residues at 76080808: 30, 31, 32, 50, 53, 91-94 and 96
        Germline toggle (Z): E27Q, V58I and F87Y
        Co-evolve (1): M33L/H34A. Library will contain HMHW (SEQ ID NO: 1710) or YLAW (SEQ ID NO: 1711)
    
    


A 109 library will be able to sample mutants carrying up to 4 doped residues at least 4 times. On average, library members will have 5 doped residues.
Recombined Library
H1+H2 library is recombined with H3 library into a HC library. HC library is combined with LC library for a total recombined library rHC+LC.
Codons Specified for Residues to be Doped
For instance, if a proline is to be doped, the doping oligo will have C(5-85-5-5)C(5-85-5-5)S codon regardless of the original codon in the antibody sequence. These codons are selected based on the following criteria: Increase non-synonymous mutation; increase coverage of more amino acids when mutated; and uses high frequency codons and avoid SSS and WWW codons
Doping Order is A-C-G-T















A(70-10-10-10)
C(10-70-10-10)
G(10-10-70-10)
T(10-10-10-70)








Alanine (A):



GCN
G(10-10-70-10) C(10-70-10-10) S


Threonine (T):



ACN
A(70-10-10-10) C(10-70-10-10) S


Proline (P):



CCN
C(10-70-10-10) C(10-70-10-10) S


Serine (S):



TCN
T(10-10-10-70) C(10-70-10-10) S


AGY
A(70-10-10-10) G(10-10-70-10) C(10-70-10-10)


Valine (V):



GTN
G(10-10-70-10) T(10-10-10-70) S


Glycine (G):



GGN
G(10-10-70-10) G(10-10-70-10) S


Leucine (L):



CTN
C(10-70-10-10) T(10-10-10-70) S


TTR
T(10-10-10-70) T(10-10-10-70) G(10-10-70-10)


Arginine (R):



CGN
C(10-70-10-10) G(10-10-70-10) S


AGR
A(70-10-10-10) G(10-10-70-10) G(10-10-70-10)


Methionine (M):



ATG
A(70-10-10-10) T(10-10-10-70) G(10-10-70-10)


Tryptophan (W):



TGG
T(10-10-10-70) G(10-10-70-10) G(10-10-70-10)


Pheylalanine (F):



TTY
T(10-10-10-70) T(10-10-10-70) C(10-70-10-10)


Isoleucine (I):



50% ATY
A(70-10-10-10) T(10-10-10-70) C(10-70-10-10)


50% ATA
A(70-10-10-10) T(10-10-10-70) A(70-10-10-10)


Tyrosine (Y):



TAY
T(10-10-10-70) A(70-10-10-10) C


Histidine (H):



CAY
C(10-70-10-10) A(70-10-10-10) C(10-70-10-10)


Glutamine (Q):



CAR
C(10-70-10-10) A(70-10-10-10) G(10-10-70-10)


Asparagine (N):



AAY
A(70-10-10-10) A(70-10-10-10) C(10-70-10-10)


Lysine (K):



AAR
A(70-10-10-10) A(70-10-10-10) G(10-10-70-10)


Aspartic Acid (D):



GAY
G(10-10-70-10) A(70-10-10-10) C(10-70-10-10)


Glutamic acid (E):



GAR
G(10-10-70-10) A(70-10-10-10) G(10-10-70-10)


Cysteine (C):


TGY
NNS









List of Amino Acid Sequences of Affinity Matured H4g8.3 VH Variants.

Table 38 provides a list of amino acid sequences of unique, functional VH regions of affinity matured humanized anti-VEGF antibodies derived from hBDB-4G8.3. Amino acid residues of individual CDRs of each VH sequence are indicated in bold.







TABLE 38







List of Amino Acid Sequences of


Affinity Matured H4g8.3 VH Variants









Clone
SEQ ID NO:
VH





CL-27663
1712
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYRMYWVRQAPGQGL




EWMGWINTETGXPAYADDFKRRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTKYYYSSYIFYFDYWGQGTMVTVSS


 


CL-27664
1713
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYSMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTKYYYRFYLFYFDYWGQGTMVTVSS


 


CL-27665
1714
EVQLVQSGSELKKPGASVKVSCKASGYTFTYYGMYWVRQAPGQGL




EWMGWINTKTGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYGSYIFYFDYWGQGTMVTVSS


 


CL-27666
1715
EVQLVQSGSELKKPGASVKVSCKASGYTFINYRMYWVRQAPGQGL




EWMGWINTETGKPVYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYKFYFDYWGQGTMVTVSS


 


CL-27667
1716
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYAMYWVRQAPGQGL




EWMGWINTETGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTIYYYXKYIFYFDYWGQGTMVTVSS


 


CL-27668
1717
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARPTYYYWIYIFYFDYWGQGTMVTVSS


 


CL-27669
1718
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYCMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARRNYYYXCYIFYFDYWGQGTMVTVSS


 


CL-27670
1719
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYDMYWVRQAPGQGL




EWMGWINTVTGSPAYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTTYYYCSYTFYFDYWGQGTMVTVSS


 


CL-27671
1720
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTGTGXPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARXNYYYXSYXFYFDYWGQGTMVTVSS


 


CL-27672
1721
EVQLVQSGSELKKPGASVKVSCKASGYTFSKYGMYWVRQAPGQGL




EWMGWINTYTGKPLYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYMGYRFYFDYWGQGTMVTVSS


 


CL-27673
1722
EVQLVQSGSELKKPGASVKVSCKASGYTFTPYGMYWVRQAPGQGL




EWMGWINTETGVPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYRSYRFYFDYWGQGTMVTVSS


 


CL-27674
1723
EVQLVQSGSELKKPGASVKVSCKASGYTFINYVMYWVRQAPGQGL




EWMGWINTATGXPSYAQGFTGRFVFSFDTSVSTTYLQISSLKAED




TAVYYCARTTYYYRRYIFYFDYWGQGTMVTVSS


 


CL-27675
1724
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYDMYWVRQAPGQGL




EWMGWINTATGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTLYYYRRYIFYFDYWGQGTMVTVSS


 


CL-27676
1725
EVQLVQSGSELKKPGASVKVSCKASGYTFIKYGMYWVRQAPGQGL




EWMGWINTETGRPAYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARIRYYYGSYIFYFDYWGQGTMVTVSS


 


CL-27677
1726
EVQLVQSGSELKKPGASVKVSCKASGYTFKNYEMYWVRQAPGQGL




EWMGWINTETGKPRYADDFKGRFVFSLDTSVNTAYLQISSLKAED




TAVYYCARTNYYYRSYVFYFDYWGQGTMVTVSS


 


CL-27678
1727
EVQLVQSGSELKKPGASVKVSCKASGYTFPLYSMYWVRQAPGQGL




EWMGWINTHTGNPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYTFYFDYWGQGTMVTVSS


 


CL-27679
1728
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTATGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARMNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-27680
1729
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYCMYWVRQAPGQGL




EWMGWINTETGKPLYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARRNYYYGGYIFYFDYWGQGTMVTVSS


 


CL-27681
1730
EVQLVQSGSELKKPGASVKVSCKASGYTFTXYGMYWVRQAPGQGL




EWMGWINTQTGPPPYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTYYYYRWYIFYFDYWGQGTMVTVSS


 


CL-27682
1731
EVQLVQSGSELKKPGASVKVSCKASGYTFTIYEMYWVRQAPGQGL




EWMGWINTETGTPPYAXDFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARXXYYYXSYIFYFDYWGQGTMVTVSS


 


CL-27683
1732
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYVMYWVRQAPGQGL




EWMGWINTDTGNPAYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTTYYYRVYMFYFDYWGQGTMVTVSS


 


CL-27685
1733
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYCMYWVRQAPGQGL




EWMGWINTATGNPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYASYIFYFDYWGQGTMVTVSS


 


CL-27686
1734
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYAMYWVRQAPGQGL




EWMGWINTPTGMPNYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTSYYYSSYLFYFDYWGQGTMVTVSS


 


CL-27687
1735
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTDTGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTEYYYRSYIFYFDYWGQGTMVTVSS


 


CL-27688
1736
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYEMYWVRQAPGQGL




EWMGWINTATGKPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTIYYYVRYIFYFDYWGQGTMVTVSS


 


CL-27689
1737
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGTPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTVYYYRSYLFYFDYWGQGTMVTVSS


 


CL-27690
1738
EVQLVQSGSELKKPGASVKVSCKASGYTFATYGMYWVGQAPGQGL




EWMGWINTETGMPAYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARIRYYYGRYLFYFDYWGQGTMVTVSS


 


CL-27691
1739
EVQLVQSGSELKKPGASVKVSCKASGYTFSIYYMYWVRQAPGQGL




EWMGWINTGTGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTSYYYRSYLFYFDYWGQGTMVTVSS


 


CL-27692
1740
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYAMYWVRQAPGQGL




EWMGWINTQTGKPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARPQYYYTSYIFYFDYWGQGTMVTVSS


 


CL-27694
1741
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTXTGXPTYAXDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARXXYYYRSYXFYFDYWGQGTMVTVSS


 


CL-27695
1742
EVQLVQSGSELKKPGASVKVSCKASGYTFTYYNMYWVRQAPGQGL




EWMGWINTATGSPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSTYYYRSYIFYFDYWGQGTMVTVSS


 


CL-27696
1743
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYGMYWVRQAPGQGL




EWMGWINTQTGKPRYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYWSYIFYFDYWGQGTMVTVSS


 


CL-27697
1744
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYPMYWVRQAPGQGL




EWMGWINTETGXPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARXXYYYXRYIFYFDYWGQGTMVTVSS


 


CL-27699
1745
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYDMYWVRQAPGQGL




EWMGWINTATGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRSYLFYFDYWGQGTMVTVSS


 


CL-27700
1746
EVQLVQSGSELKKPGASVKVSCKASGYTFAHYGMYWVRQAPGQGL




EWMGWINTETGNPDYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRCYIFYFDYWGQGTMVTVSS


 


CL-27701
1747
EVQLVQSGSELKKPGASVKVSCKASGYTFTIYGMYWVRQAPGQGL




EWMGWINTETGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRCYMFYFDYWGQGTMVTVSS


 


CL-27702
1748
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTVTGAPIYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYWGYRFYFDYWGQGTMVTVSS


 


CL-27703
1749
EVQLVQSGSELKKPGASVKVSCKASGYTFRSYVMYWVRQAPGQGL




EWMGWINTDTGTPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARPYYYYRRYIFYFDYWGQGTMVTVSS


 


CL-27704
1750
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYCMYWVRQAPGQGL




EWMGWINTKTGNPAYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARXIYYYRRYVLYFDYWGQGTMVTVSS


 


CL-27705
1751
EVQLVQSGSELKKPGASVKVSCKASGYTFANYSMYWVRQAPGQGL




EWMGWINTETGKPKYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRRYSFYFDYWGQGTMVTVSS


 


CL-27706
1752
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYCMYWVRQAPGQGL




EWMGWINTTTGKPNYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYRRYLFYFDYWGQGTMVTVSS


 


CL-27708
1753
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTMTGKPNYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTDYYYRSYDFYFDYWGQGTMVTVSS


 


CL-27709
1754
EVQLVQSGSELKKPGASVKVSCKASGYTFPKYAMYWVRQAPGQGL




EWMGWINTETGXPRYAHDFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRGYIFYFDYWGQGTMVTVSS


 


CL-27710
1755
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYVMYWVRQAPGQGL




EWMGWINTETGTPMYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARRDYYYRRYVFYFDYWGQGTMVTVSS


 


CL-27711
1756
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYDMYWVRQVPGQGL




EWMGWVNTDTGKPPYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSKYYYWTYVFYFDYWGQGTMVTVSS


 


CL-27712
1757
EVQLVQSGSELKKPGASVKVSCKASGYTFTYYDMYWVRQAPGQGL




EWMGWINTXTGKPIYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTIYYYGRYSFYFDYWGQGTMVTVSS


 


CL-27713
1758
EVQLVQSGSELKKPGASVKVSCKASGYTFPFYVMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRRYIFYFDYWGQGTMVTVSS


 


CL-27714
1759
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYSMYWVRQAPGQGL




EWMGWINTKTGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTIYYYMCYVFYFDYWGQGTMVTVSS


 


CL-27715
1760
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGNPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARKHYYYGSYLFYFDYWGQGTMVTVSS


 


CL-27716
1761
EVQLVQSGSELKKPGASVKVSCKASGYTFPDYDMYWVRQAPGQGL




EWMGWINTETGMPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRGYIFYFDYWGQGTMVTVSS


 


CL-27717
1762
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTDTGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTYYYYKKYIFYFDYWGQGTMVTVSS


 


CL-27718
1763
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTGTGRPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTQYYYRRYIFYFDYWGQGTMVTVSS


 


CL-27719
1764
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL




EWMGWINTKTGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARKNYYYKSYVFYFDYWGQGTMVTVSS


 


CL-27721
1765
EVQLVQSVSELKKPGASVKVSCKASGYTFTKYTMYWVRQAPGQGL




EWMGWINTETGNPMYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRIYIFYFDYWGQGTMVTVSS


 


CL-27722
1766
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTATGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSSYYYRNYIFYFDYWGQGTMVTVSS


 


CL-27723
1767
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTVTGKPDYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARQKYYYRSYFFYFDYWGQGTMVTVSS


 


CL-27725
1768
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYDMYWVRQAPGQGL




EWMGWINTDTGKPAYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARPSYYYVXYIFYFDYWGQGTMVTVSS


 


CL-27726
1769
EVQLVQSGSELKKPGASVKVSCKASGYTFTLYXMYWVRQAPGQGL




EWMGWINTATGKPTYAHDFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTXYYYRSYIFYFDYWGQGTMVTVSS


 


CL-27727
1770
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYGMYWVRQAPGQGL




EWMGWINTHTGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRCYIFYFDYWGQGTMVTVSS


 


CL-27728
1771
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGKPEYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARPNYYYRSYFFYFDYWGQGTMVTVSS


 


CL-27729
1772
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGRPGYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARLWYYYWMYIFYFDYWGQGTMVTVSS


 


CL-27730
1773
EVQLVQSGSELKKPGASVKVSCKASGYTFTYYGMYWVRQAPGQGL




EWMGWINTETGTPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARVYYYYGSYSFYFDYWGQGTMVTVSS


 


CL-27731
1774
EVQLVQSGSELKKPGASVKVSCKASGYTFVNYAMYWVRQAPGQGL




EWMGWINTXTGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARKTYYYRGYIFYFDYWGQGTMVTVSS


 


CL-27733
1775
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYYMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSKYYYRSYTFYFDYWGQGTMVTVSS


 


CL-27734
1776
EVQLVQSGSELKKPGASVKVSCKASGYTFLHYGMYWVRQAPGQGL




EWMGWINTETGWPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTSYYYVSYIFYFDYWGQGTMVTVSS


 


CL-27735
1777
EVQLVQSGSELKKPGASVKVSCKASGYTFTIYGMYWVRQAPGQGL




EWMGWINTATGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTXYYYRSYVFYFDYWGQGTMVTVSS


 


CL-27736
1778
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGNPIYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARAHYYYRTYXFYFDYWGQGTMVTVSS


 


CL-27737
1779
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGNPIYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARAHYYYRTYNFYFDYWGQGTMVTVSS


 


CL-27738
1780
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYWMYWVRQAPGQGL




EWMGWINTETGRPRYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARVYYYYRCYSFYFDYWGQGTMVTVSS


 


CL-27739
1781
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYWMYWVRQAPGQGL




EWMGWINTETGTPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTTYYYRSYIFYFDYWGQGTMVTVSS


 


CL-27741
1782
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYGMYWVRQAPGQGL




EWMGWINTNTGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARAYYYYWSYIFYFDYWGQGTMVTVSS


 


CL-27742
1783
EVQLVQSGSELKKPGASVKVSCKASGYTFTSYVMYWVRQAPGQGL




EWMGWINTKTGMPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTTYYYMSYIFYFDYWGQGTMVTVSS


 


CL-27744
1784
EVQLVQSGSELKKPGASVKVSCKASGYTFTQYGMYWVRQAPGQGL




EWMGWINTETGKPKYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYWSYKFYFDYWGQGTMVTVSS


 


CL-27747
1785
EVQLVQSGSELKKPGASVKVSCKASGYTFSTYMMYWVRQAPGQGL




EWMGWINTETGXPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-27750
1786
EVQLVQSGSELKKPGASVKVSCKASGYTFMNYVMYWVRQAPGQGL




EWMGWINTKTGMPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYMRYIFYFDYWGQGTMVTVSS


 


CL-27751
1787
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYGMYWVRQAPGQGL




EWMGWINTQTGEPPYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTGYYYWNYLFYFDYWGQGTMVTVSS


 


CL-27752
1788
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYRMYWVRQAPGQGL




EWMGWINTETGKPPYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYMSYIFYFDYWGQGTMVTVSS


 


CL-27753
1789
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGSPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYVSYIFYFDYWGQGTMVTVSS


 


CL-27755
1790
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGXPTYAHDFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARXNYYYXXYIFYFDYWGQGTMVTVSS


 


CL-27756
1791
EVQLVQSGSELKKPGASVKVSCKASGYTFTIYGMYWVRQAPGQGL




EWMGWINTDTGRPIYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARIIYYYCSYIFYFDYWGQGTMVTVSS


 


CL-27757
1792
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL




EWMGWINTETGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-27758
1793
EVQLVQSGSELKKPGASVKVSCKASGYTFSLYAMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGQFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYNFYFDYWGQGTMVTVSS


 


CL-27760
1794
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-27824
1795
EVQLVQSGSELNXPGASLKVSCKASGYTFXNYGXYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-27833
1796
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGIYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-29884
1797
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRLYMFYFDYWGQGTMVTVSS


 


CL-29885
1798
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYQSYMFYFDYWGQGTMVTVSS


 


CL-29887
1799
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL




EWMGWINTETGEPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-29888
1800
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRTYMFYFDYWGQGTMVTVSS


 


CL-29889
1801
EVQLVQSGSELKKPGASVKVSCKASGYTFADYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYRTYMFYFDYWGQGTMVTVSS


 


CL-29890
1802
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYGMYWVRQAPGQGL




EWMGWINTETGXPTYAXDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARRXYYYXSYXFYFDYWGQGTMVTVSS


 


CL-29891
1803
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-29892
1804
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTETGQPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-29893
1805
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARVNYYYRNYMFYFDYWGQGTMVTVSS


 


CL-29895
1806
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARVNYYYMSYMFYFDYWGQGTMVTVSS


 


CL-29896
1807
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRMYMFYFDYWGQGTMVTVSS


 


CL-29897
1808
EVQLVQSGSELKKPGASVKVSCKASGYTFLNYGMYWVRQAPGQGL




EWMGWINTETGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTKYYYWRYIFYFDYWGQGTMVTVSS


 


CL-29898
1809
EVQLVQSGSELKKPGASVKVSCKASGYTFNDYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29899
1810
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARINYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29901
1811
EVQLVQSGSELKKPGASVKVSCKASGYTFMNYGMYWVRQAPGQGL




EWMGWIDTETGXXXYAHDFTGRFVFSLDTSVSTAYLEISSLKAED




TAVYYCARXNYYYXXYMFYFDYWGQGTMVTVSS


 


CL-29902
1812
EVQLVQSGSELKKPGASVKVSCKASGYTFTSYGMYWVRQAPGQGL




EWMGWINTETGQPMYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARRIYYYRCYLFYFDYWGQGTMVTVSS


 


CL-29904
1813
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTDTGMPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29906
1814
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS


 


CL-29907
1815
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGEPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29908
1816
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS


 


CL-29909
1817
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29910
1818
EVQLVQSGSELKKPGASVKVSCKASGYTFNYYGMYWVRQAPGQRL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYESYMFYFDYWGQGTMVTVSS


 


CL-29912
1819
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29913
1820
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYRMYWVRQAPGQGL




EWMGWINTVTGKPKYADDFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARFKYYYGSYFFYFDYWGQGTMVTVSS


 


CL-29914
1821
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-29915
1822
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS


 


CL-29916
1823
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29917
1824
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL




EWMGWIDTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPRYMFYFDYWGQGTMVTVSS


 


CL-29918
1825
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTDTGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYASYMFYFDYWGQGTMVTVSS


 


CL-29919
1826
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYQSYMFYFDYWGQGTMVTVSS


 


CL-29921
1827
EVQLVQSGSELKKPGASVKVSCKASGYTFSHYGMYWVRQAPGQGL




EWMGWINTETGSPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-29922
1828
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-29924
1829
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29925
1830
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTETGEPTYAXGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29926
1831
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYTSYMFYFDYWGQGTMVTVSS


 


CL-29927
1832
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRMYMFYFDYWGQGTMVTVSS


 


CL-29928
1833
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGEPYYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPKYMFYFDYWGQGTMVTVSS


 


CL-29929
1834
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYWMYWVRQAPGQGL




EWMGWINTETGKPAYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYIYYLFYFDYWGQGTMVTVSS


 


CL-29931
1835
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL




EWMGWINTGTGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS


 


CL-29932
1836
EVQLVQSGSELKKPGASVKVSCKASGYTFTPYGMYWVRQAPGQGL




EWMGWINTDTGXPPYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYTCYIFYFDYWGQGTMVTVSS


 


CL-29934
1837
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYWVRQAPGQGL




EWMGWINTETGXPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPRYMFYFDYWGQGTMVTVSS


 


CL-29935
1838
EVQLVQSGSELKKPGASVKVSCKASGYTFPDYGMYWVRQAPGQGL




EWMGWIDTETGMPXYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS


 


CL-29936
1839
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29937
1840
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARXNYYYRXYMFYFDYWGQGTMVTVSS


 


CL-29938
1841
EVQLVQSGSELKKPGASVKVSCKASGYTFNKYDMYWVRQAPGQGL




EWMGWINTKTGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTAYYYRNYKSTLITGGQGTMVTVSS


 


CL-29939
1842
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYKGYMFYFDYWGQGTMVTVSS


 


CL-29940
1843
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTYYYYRTYIFYFDYWGQGTMVTVSS


 


CL-29941
1844
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS


 


CL-29942
1845
EVQLVQSGSELKKPGASVKVSCKASGYNFTKYEMYWVRQAPGQGL




EWMGWINTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTKYYYRSYVFYFDYWGQGTMVTVSS


 


CL-29943
1846
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYLSYMFYFDYWGQGTMVTVSS


 


CL-29946
1847
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYWVRQAPGQGL




EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-29947
1848
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTDTGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRTYMFYFDYWGQGTMVTVSS


 


CL-29948
1849
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-29949
1850
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARVNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29950
1851
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTQTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYRLYMFYFDYWGQGTMVTVSS


 


CL-29951
1852
EVQLVQSGSELKKPGASVKVSCKASGYTFPDYGMYWVRQAPGQGL




EWMGWIDTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARADYYYPTYMFYFDYWGQGTMVTVSS


 


CL-29952
1853
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPTYMFYFDYWGQGTMVTVSS


 


CL-29955
1854
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29957
1855
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTVTGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTHYYYRTYLFYFDYWGQGTMVTVSS


 


CL-29958
1856
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29959
1857
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS


 


CL-29960
1858
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYSMYWVRQAPGQGL




EWMGWINTXTGKPIYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTKYYYRTYRFYFDYWGQGTMVTVSS


 


CL-29961
1859
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWIDTETGTPVYADDFKGRFVFSLDTSVNTAYLQISSLKAED




TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS


 


CL-29962
1860
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-29963
1861
EVQLVQSGSELKKPGASVKVSCKASGYTFSEYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29966
1862
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARVNYYYRWYMFYFDYWGQGTMVTVSS


 


CL-29967
1863
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL




EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-29968
1864
EVQLVQSGSELKKPGASVKVSCKAYGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYEKYMFYFDYWGQGTMVTVSS


 


CL-29969
1865
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYRGYMFYFDYWGQGTMVTVSS


 


CL-29970
1866
EVQLVQSGSELKKPGASVKVSCKASGYTFMTYVMYWVRQAPGQGL




EWMGWINTETGKPSYAHDFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARMXYYYXIYMFYFDYWGQGTMVTVSS


 


CL-29971
1867
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29972
1868
EVQLVQSGSELKKPGASVKVSCNASGXTFTNYGMYWVRQAPGQGL




EWMGWINTETGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARINYYYRSYIFYFDYWGQGTMVTVSS


 


CL-29973
1869
EVQLVQSGSELKKPGASVKVSCKASGYTFNDYGMYWVRQAPGQGL




EWMGWINTETGEPTYAXXFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYEGYMFYFDYWGQGTMVTVSS


 


CL-29974
1870
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-29975
1871
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS


 


CL-29976
1872
EVQLVQSGSELRKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL




EWMGWIDTETGRPWYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYQGYMFYFDYWGQGTMVTVSS


 


CL-29980
1873
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMHWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30036
1874
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSHIFYFDYWGQGTMVTVSS


 


CL-30060
1875
EVQLVQSGSELKKPGASVRVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30075
1876
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTXTGKPTYAXGFTGRFVFSLDTSVSTAYLQIXXLXAXD




TAVYYCARXKYYYXSYIFYFDYWGQGTMVTVSS


 


CL-30076
1877
EVQLVQSGSELKKPGASVKVSCKASGYTFYNYCMYWVRQAPGQGL




EWMGWINTETGIPKYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARINYYYKRYIFYFDYWGQGTMVTVSS


 


CL-30077
1878
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYYMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTXYYYXRYXFYFDYWGQGTMVTVSS


 


CL-30078
1879
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVFS


 


CL-30079
1880
EVQLVQSGSELKKPGASVKVSCKASGYTFIHYGMYWVRQAPGQGL




EWMGWINTETGRPTYADDFKGRFVFSLDTSVSTAYLQISSLKXED




TAVYYCARTVYYYPRYTFYFDYWGQGTMVTVSS


 


CL-30082
1881
EVQLVQSGSELKKPGASVKVSCKASGYTFMNYGMYWVRQAPGQGL




EWMGWINTETGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPGYIFYFDYWGQGTMVTVSS


 


CL-30083
1882
EVQLVQSGSELKKPGASVKVSCKASGYTFTLYGMYWVRQAPGQGL




EWMGWINTDTGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYXSYIFYFDYWGQGTMVTVSS


 


CL-30084
1883
EVQLVQSGSELKKPGASVKVSCKASGYTFNKYGMYWVRQAPGQGL




EWMGWINTETGKPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARAKYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30086
1884
EVQLVQSGSELKKPGASVKVSCKASGYTFLNYGMYWVRQAPGQGL




EWMGWINTETGRPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRIYRFYFDYWGQGTMVTVSS


 


CL-30087
1885
EVQLVQSGSELKKPGASVKVSCKASGYTFYNYGMYWVRQAPGQGL




EWMGWINTATGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARXKYYYXSXXFYFDYWGQGTMVTVSS


 


CL-30091
1886
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYDMYWVRQAPGQGL




EWMGWINTVTGLPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTIYYYKSYIFYFDYWGQGTMVTVSS


 


CL-30092
1887
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTGTGIPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTSYYYRNYLFYFDYWGQGTMVTVSS


 


CL-30093
1888
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYGMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTTYYYRRYIFYFDYWGQGTMVTVSS


 


CL-30096
1889
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYAMYWVRQAPGQGL




EWMGWINTETGKPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30097
1890
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQIXXLKTED




TAVYYCARSNYYYRGYIFYFDYWGQGTMVTVSS


 


CL-30103
1891
EVQLVQSGSELKKPGASVKVSCKASGYTFAIYRMYWVRQAPGQGL




EWMGWINTDTGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSKYYYGFYMFYFDYWGQGTMVTVSS


 


CL-30107
1892
EVQLVQSGSELKKPGASVKVSCKASGYTFMNYGMYWVRQAPGQGL




EWMGWINTETGRPVYAQGFTGRFVFSLDTSVSTAYLQISSLKAXD




TAVYYCARTNYYYLRYVFYFDYWGQGTMVTVSS


 


CL-30108
1893
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTGTGMPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARNKYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30110
1894
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYDMYWVRQAPGQGL




EWMGWINTETGKPPYADGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30113
1895
EVQLVQSGSELKKPGASVKVSCKASGYTFTSYGMYWVRQAPGQGL




EWMGWINTETGIPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARWDYYYTSYKFYFDYWGQGTMVTVSS


 


CL-30114
1896
EVQLVQSGSELKKPGASVKVSCKASGYTFTIYGMYWVRQAPGQGL




EWMGWINTVTGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTEYYYMNYIFYFDYWGQGTMVTVSS


 


CL-30116
1897
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYDMYWVRQAPGQGL




EWMGWINTGTGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYSRYDFYFDYWGQGTMVTVSS


 


CL-30119
1898
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYGMYWVRQAPGQGL




EWMGWINTQTGKPAYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARAIYYYRIYIFYFDYWGQGTMVTVSS


 


CL-30124
1899
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYAMYWVRQAPGQGL




EWMGWINTQTGEPSYAQGFTGXFVFSLDTSASTEYLXISILXDXD




TAVYYCARXTYYYXNYIFYFDYWGXGTMVTVSS


 


CL-30127
1900
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYGMYWVRQAPGQGL




EWMGWINTETGRPTYADDFNGWFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRIYIFYFDYWGQGTMVTVSS


 


CL-30128
1901
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30129
1902
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL




EWMGWINTGTGKPTYAQGFTGRFVFSLDTSVSTAYLQIXSLKAED




TAVYYCARPIYYYIRYIFYFDYWGQGTMVTVSS


 


CL-30130
1903
EVQLVQSGSELKKPGASVKVSCKASGYTFADYPMYWVRQAPGQGL




EWMGWINTXTGQPLYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTSYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30135
1904
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAXD




TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30136
1905
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYSMYWVRQAPGQGL




EWMGWINTETGKPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTSYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30138
1906
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYWMYWVRQAPGQGL




EWMGWINTETGEPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTEYYYKSYNFYFDYWGQGTMVTVSS


 


CL-30140
1907
EVQLVQSGSELKKPGASVKVSCKASGYTFTAYGMYWVRQAPGQGL




EWMGWINTETGMPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTKYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30141
1908
EVQLVQSGSELKKPGASVKVSCKASGYTFHNYGMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTSYYYRSYFFYFDYWGQGTMVTVSS


 


CL-30142
1909
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYVMYWVRQAPGQGL




EWMGWINTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARLIYYYXTYIFYFDYWGQGTMVTVSS


 


CL-30145
1910
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYAMYWVRQAPGQGL




EWMGWINTETGKPPYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTLYYYRTYIFYFDYWGQGTMVTVSS


 


CL-30147
1911
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRRYIFYFDYWGQGTMVTVXS


 


CL-30148
1912
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTETGQPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRCYIFYFDYWGQGTMVTVSS


 


CL-30151
1913
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGKPNYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARPNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30154
1914
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYAMYWVRQAPGQGL




EWMGWINTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYGIYLFYFDYWGQGTMVTVSS


 


CL-30156
1915
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYDMYWVRQAPGQGL




EWMGWINTVTGRPAYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARITYYYRMYRFYFDYWGQGTMVTVSS


 


CL-30159
1916
EVQLVQSGSELKKPGASVKVSCKASGYTFIDYLMYWVRQAPGQGL




EWMGWINTVTGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTHYYYRSYAFYFDYWGQGTMVTVSS


 


CL-30161
1917
EVQLVQSGSELKKPGASVKVSCKASGYTFAKYEMYWVRQAPGQGL




EWMGWINTETGNPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRDYTFYFDYWGQGTMVTVSS


 


CL-30162
1918
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYRMYWVRQAPGQGL




EWMGWINTVTGRPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARNIYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30164
1919
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30165
1920
EVQLVQSGSELKKPGASVKVSCKASGYTFRNYVMYWVRQAPGQGL




EWMGWINTQTGEPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYGIYIFYFDYWGQGTMVTVSS


 


CL-30166
1921
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLQAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30168
1922
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGMPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYRGYIFYFDYWGQGTMVTVSS


 


CL-30169
1923
EVQLVQSGSELKKPGASVKVSCKASGYTFLGYSMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARKFYYYESYIFYFDYWGQGTMVTVSS


 


CL-30170
1924
EVQLVQSGSELKKPGASVKVSCKASGYTFTYYCMYWVRQAPGQGL




EWMGWINTHTGKPMYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARKKYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30593
1925
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL




EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYMSYMFYFDYWGQGTMVTVSS


 


CL-30594
1926
EVQLVQSGSELKKPGASVKVSCKASGYTFMNYGMYWVRQAPGQGL




EWMGWINTETGKPMYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTIYYYPRYIFYFDYWGQGTMVTVSS


 


CL-30595
1927
EVQLVQSGSELKKPGASVKVSCKASGYTFAMYKMYWVRQAPGQGL




EWMGWINTQTGGPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTKYYYWRYVFYFDYWGQGTMVTVSS


 


CL-30597
1928
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTETGQPMYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-30599
1929
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-30600
1930
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTATGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYMYYLFYFDYWGQGTMVTVSS


 


CL-30602
1931
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRLYMFYFDYWGQGTMVTVSS


 


CL-30604
1932
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL




EWMGWINTWTGKPTYAXDFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-30605
1933
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRTYMFYFDYWGQGTMVTVSS


 


CL-30606
1934
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYRMYWVRQAPGQGL




EWMGWINTETGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-30608
1935
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYDMYWVRQAPGQGL




EWMGWINTVTGXPTYAXXFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSXYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30609
1936
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL




EWMGWINTETGKPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTDYYYRRYTFYFDYWGQGTMVTVSS


 


CL-30611
1937
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTYTGIPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARVNYYYSTYIFYFDYWGQGTMVTVSS


 


CL-30613
1938
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGIYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYRGYMFYFDYWGQGTMVTVSS


 


CL-30614
1939
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30615
1940
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL




EWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARVNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30616
1941
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYGMYWVRQAPGQGL




EWMGWINTLTGAPMYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYIFYFDYWGQGTMVTVSS


 


CL-30617
1942
EVQLVQSGSELKKPGASVKVSCKASGYTFKNYSMYWVRQAPGQGL




EWMGWINTDTGMPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRFYIFYFDYWGQGTMVTVSS


 


CL-30618
1943
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARVNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30619
1944
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30620
1945
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS


 


CL-30623
1946
EVQLVQSGSELKKPGASVKVSCKASGYTFANYGMYWVRQAPGQGL




EWMGWINTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYQSYMFYFDYWGQGTMVTVSS


 


CL-30624
1947
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTDTGTPAYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYTRYNFYFDYWGQGTMVTVSS


 


CL-30626
1948
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30628
1949
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30629
1950
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYDMYWVRQAPGQGL




EWMGWINTETGNPTYAXXFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARXNYYYSSYIFYFDYWGQGTMVTVSS


 


CL-30630
1951
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARSNYYYRTYMFYFDYWGQGTMVTVSS


 


CL-30631
1952
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL




EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-30632
1953
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-30634
1954
EVQLVQSGSELKKPGASVKVSCKASGYTFTYYGMYWVRQAPGQGL




EWMGWINTETGKPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTIYYYTTYIFYFDYWGQGTMVTVSS


 


CL-30635
1955
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL




EWMGWIDTETGEPIYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARINYYYPNYMFYFDYWGQGTMVTVSS


 


CL-30636
1956
EVQLVQSGSELKKPGASVKVSCKTSGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS


 


CL-30637
1957
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-30638
1958
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWIDTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30639
1959
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30640
1960
EVQLVQSGSELKKPGASVKVSCKASGYTFSSYGMYWVRQAPGQGL




EWMGWIDTETGEPKYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-30642
1961
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARYNYYYRIYLFYFDYWGQGTMVTVSS


 


CL-30643
1962
EVQLVQSGSELKKPGASVKVSCKASGYTFPYYSMYWVRQAPGQGL




EWMGWINTDTGTPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTTYYYWSYIFYFDYWGQGTMVTVSS


 


CL-30644
1963
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-30645
1964
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTXTGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTSYYYRCYIFYFDYWGQGTMVTVSS


 


CL-30647
1965
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGQPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30649
1966
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWIDTDTGKPTYAXDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYTGYMFYFDYWGQGTMVTVSS


 


CL-30651
1967
EVQLVQSGSELEKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL




EWMGWIDTDTGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30653
1968
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL




EWMGWIDTETGDPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYLSYMFYFDYWGQGTMVTVSS


 


CL-30654
1969
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS


 


CL-30655
1970
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGEPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-30657
1971
EVQLVQSGSELKKPGASVKVSCKASGYTFANYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS


 


CL-30658
1972
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30659
1973
EVQLVQSGSELKKPGASVKVSCKASGYTFPYYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRMYMFYFDYWGQGTMVTVSS


 


CL-30660
1974
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS


 


CL-30662
1975
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGSPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARIIYYYLSYLFYFDYWGQGTMVTVSS


 


CL-30663
1976
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWINTETGDPTYAQGFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-30664
1977
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYSGYMFYFDYWGQGTMVTVSS


 


CL-30665
1978
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRYYMFYFDYWGQGTMVTVSS


 


CL-30666
1979
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-30669
1980
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYAMYWVRQAPGQGL




EWMGWINTYTGVPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARGHYYYMMYIFYFDYWGQGTMVTVSS


 


CL-30670
1981
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWIDTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARYKYYYRSYKFYFDYWGQGTMVTVSS


 


CL-30671
1982
EVQLVQSGSELKKPGASVKVSCKASGYTFPDYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS


 


CL-30674
1983
EVQLVQSGSELKKPGASVKVSCKASGYTFSHYGMYWVRQAPGQGL




EWMGWINTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-30675
1984
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL




EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30676
1985
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGYPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRTYMFYFDYWGQGTMVTVSS


 


CL-30677
1986
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRTYMFYFDYWGQGTMVTVSS


 


CL-30678
1987
EVQLVQSGSELKKPGASVKVSCKASGYTFSHYGMYWVRQAPGQGL




EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS


 


CL-30679
1988
EVQLVQSGSELKKPGASVKVSCKASGYTFTSYRMYWVRQAPGQGL




EWMRWINTETGWPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTSYYYRNYMFYFDYWGQGTMVTVSS


 


CL-30682
1989
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGNPMYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-30684
1990
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS


 


CL-30685
1991
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCVRTNYYYRTYMFYFDYWGQGTMVTVSS


 


CL-32447
1992
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWXRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-32466
1993
EVQLVQSGSELKKPGASVKVSCKASGYTFHDYGMYWVRQAPGQGL




EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-32470
1994
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGXPTYAXXFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-32507
1995
EVQLVQSGSELKKPGASVKVSCKASGYTFNDYGMYWVRQAPGQGL




EWMGWIDTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-34445
1996
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34457
1997
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYAHDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARXNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34458
1998
EVQLVQSGSELKKPGAPVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34465
1999
EVQLVQSGSELKKPGASVKVSCKASGYTFPDYGMYWVRQAPGQGL




EWMGWIDTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRTYMFYFDYWGQGTMVTVSS


 


CL-34466
2000
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPIYAQGFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYNSYMFYFDYWGQGTMVTVSS


 


CL-34468
2001
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-34478
2002
EVQLVQSGSELKKPGASVKVSCKASGYTFPHYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-34480
2003
EVQLVQSGSELKKPGASVKVSCKASGYTFEDYGMYWVRQAPGQGL




EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS


 


CL-34482
2004
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRTYMFYFDYWGQGTMVTVSS


 


CL-34488
2005
EVQLVQSGSELKKPGASVKVSCKASGYTFDDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34490
2006
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGTPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34493
2007
EVQLVQSGSELKKPGASVKVSCKASGYTFGDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARVNYYYRNYMFYFDYWGQGTMVTVSS


 


CL-34495
2008
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS


 


CL-34496
2009
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS


 


CL-34499
2010
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL




EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34502
2011
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34503
2012
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL




EWMGWIDTETGTPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS


 


CL-34505
2013
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-34510
2014
EVQLVQSGSELKKPGASVKVSCKASGYTFSHYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYMSYMFYFDYWGQGTMVTVSS


 


CL-34512
2015
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTDTGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPKYMFYFDYWGQGTMVTVSS


 


CL-34527
2016
EVQLVQSGSELKKPGASVKVSCKASGYTFANYGMYWVRQAPGQGL




EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34528
2017
EVHLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWIDTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34529
2018
EVQLVQSGSELNKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPSYADDFKGRFVFSLDTXVSTAYXQISSLKAED




XAVYXCARTNYYYSSYMFYFDYWGQGTXVTVSS


 


CL-34534
2019
EVQLVQSGSELKKPGASVKVSCKASGYTFNDYGMYWVRQAPGQGL




EWMGWIDTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34539
2020
EVQLVPSGSHFNNPGASXKVSCSASGYTFSDYGMYWVRQAPGQGL




EWMGWIDTETGDPTYADDFKGXFVFSLDTSVXXAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34548
2021
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-34562
2022
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGKPTYADDFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRTYMFYFDYWGQGTMVTVSS


 


CL-34568
2023
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGQPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34577
2024
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYESYMFYFDYWGQGTMVTVSS


 


CL-34582
2025
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-34586
2026
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYAXXFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34590
2027
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34592
2028
EVQLVQSGSELKKPGASVKVSCKASGYTFNDYGMYWVRQAPGQGL




EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-34595
2029
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRTYMFYFDYWGQGTMVTVSS


 


CL-34596
2030
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS


 


CL-34597
2031
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34599
2032
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-34600
2033
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISNLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-34617
2034
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPRYMFYFDYWGQGTMVTVSS


 


CL-40631
2035
EVQLVQSGSELKKPGASVKVSCXASGYTFSDYGMYWVRQAPGQGL




EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40642
2036
RVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40646
2037
EVQLVQSGSELKKPGASVKVSCEASGYTFSDYGMYWVRQAPGQGL




EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40665
2038
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTSLQ


 


CL-40668
2039
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKVED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40671
2040
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-40687
2041
ASAAVQSGSELKKPGASVKVSCKASGYTFENYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-40688
2042
EVQLVQSGSELKKPGASVKVSCKASGYTFENYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-40694
2043
EVQLVQSGSELKKPGASVKVSCKASGYTFENYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLGTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-40708
2044
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-40716
2045
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL




EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40717
2046
EVQLVQSGSELKKPGASVKVSCKASGYTFDDYGMYWVRQAPGQGL




EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-40721
2047
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-40722
2048
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40723
2049
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40736
2050
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYXVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40740
2051
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL




EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-40741
2052
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGP




EWMGWIDTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-40742
2053
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEN




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40745
2054
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40746
2055
EVQLVQSGSXLKXPGXSXKVSCXVSGYTFQNYGMYCVRPAPGQWL




XWMGWIDXXTGEPTYAYDFKGWFLFSLHTSVSMSSLQNXSLKXDD




TAVYYCAKTNYYYNSYMFYFDYWGQGTXXTVSS


 


CL-40747
2056
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS


 


CL-40753
2057
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS


 


CL-40758
2058
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED




TAVHYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40760
2059
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-40763
2060
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40764
2061
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-40765
2062
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40766
2063
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEG




TAVYYCARTNYYYSSYMFCFDYWGQGTMVTVSS


 


CL-40768
2064
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYMFYFDYWGQGAMVTVSS


 


CL-40770
2065
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYWVRRAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40774
2066
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKVED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40779
2067
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-40780
2068
EVQLVQSGSELEKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRGYMFYFDYWGQGTMVTSLQ


 


CL-40788
2069
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDAETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS


 


CL-40790
2070
EGHLGQSGSELKNPGASVKVSCXASGYTFXNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYAXDFKGRFVFSLGTSVSTAYLQIXSLRAED




TAVYYCEXTNYYYSRYMFYFXYWGQGTMVTVSS


 


CL-40791
2071
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGXIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS


 


CL-40793
2072
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVFS


 


CL-40795
2073
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRGYMLYFDYWGQGTMVTVSS


 


CL-40796
2074
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS


 


CL-40800
2075
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRRAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS


 


CL-40801
2076
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRLVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS


 


CL-40805
2077
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS


 


CL-40806
2078
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS


 


CL-40811
2079
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS


 


CL-40812
2080
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYXSYMFYFDYWGQGTMVTVSS


 


CL-40815
2081
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS


 


CL-40816
2082
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGQFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS


 


CL-40817
2083
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYPSHMFYFDYWGQGTMVTVSS


 


CL-40819
2084
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL




EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED




TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS









List of Amino Acid Sequences of Affinity Matured h4G8.3 VL Variants

Table 39 provides a list of amino acid sequences of unique, functional VL regions of affinity matured humanized VEGF antibodies derived from hBDB-4G8.3. Amino acid residues of individual CDRs of each VL sequence are indicated in bold.







TABLE 39







List of Amino Acid Sequences of Affinity Matured


H4g8.3 VL Variants









Clone
SEQ ID NO:
VL





CL-27686
2085
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGXA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPFTFGQGTKLEIK


 


CL-27698
2086
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSRSGTDFTLTISSLEPEDFAVY




FCQQSWNDPFTFGQGTKLEIK


 


CL-27717
2087
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPFTFGQGAKLEIK


 


CL-27741
2088
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPFTFGLGTKLEIK


 


CL-27758
2089
EIVLTQFPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPFTFGQGTKLEIK


 


CL-27762
2090
EIVLTQSPATLSLSPGERATLSCRASQSVTPHMHWYQQKPGQA




PRLLIYGASTLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSCNDPFTFGQGTKLEIK


 


CL-27763
2091
EIVLTQSPATLSLSPGERATLSGRASESVDKYMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSRNDPLTFGQGTKLEIK


 


CL-27764
2092
EIVLTQSPATLSLSPGERATLSCRASQSVKTDMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSRNEPFTFGQGTKLEIK


 


CL-27765
2093
EIVLTQSPATLSLSPGERATLSCRASQSVSTHLAWYQQKPGQA




PRLLIYRASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQNWNDPLTFGQGTKLEIK


 


CL-27766
2094
EIVLTQSPATLSLSPGERATLSCRASQSVRTHMHWYQQKPGQA




PRLLIYGASALESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQGCNXPFTFGQGTKLEIK


 


CL-27767
2095
EIVLTQSPATLSLSPGERATLSCRASQSVRTHMHWYQQKPGQA




PRLLIYEASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSCNDPFTFGQGTKLEIK


 


CL-27768
2096
EIVLTQSPATLSLSPGERATLSCRASQSVSTDMHWYQQKPGQA




PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPFTFGQGTKLEIK


 


CL-27770
2097
EIVLTQSPATLSLSPGERATLSCRASQSVSPHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTSNEPFTFGQGTKLEIK


 


CL-27771
2098
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASDLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSXIDPVTFGQGTKLEIK


 


CL-27772
2099
EIVLTQSPATPSLSPGERATLSCRASESVNAHMHWYQQKPGQA




PRLLIYDASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWSDPFTFGQGTKLEIK


 


CL-27773
2100
EIVLTQSPATLSLSPGERATLSCRASESVRTQLAWYQQKPGQA




PRLLIYSASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSRTEPFTFGQGTKLEIK


 


CL-27774
2101
EIVLTQSPATLSLSPGERATLSCRASQSVSTPMHWYQQKPGQA




PRLLIYSASNLESGIPARFSDSGSGTDFTLTISSLEPEDFAVY




YCQQFWDDPYTFGQGTKLEIK


 


CL-27775
2102
EIVLTQSPATLSLSPGERATLSCRASESVITHLAWYQQKPGQA




PRLLIYSASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQCCIDPFTFGQGTKLEIK


 


CL-27776
2103
EIVLTQSPATLSLSPGERATLSCRASQSVRSQLAWYQQKPGQA




PRLLIYVASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSXNDPFTFGQGTKLEIK


 


CL-27779
2104
EIVLTQSPATLSLSPGERATLSCRASESVRTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWIDPFTFGQGTKLEIK


 


CL-27780
2105
EIVLTQSPATLSLSPGERATLSCRASESVSIHLAWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPFTFGQGTKLEIK


 


CL-27781
2106
EIVLTQSPATLSLSPGERATLSCRASQSVSTPMHWYQQKPGQA




PRLLIYGASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNEPYTFGQGTKLEIK


 


CL-27782
2107
EIVLTQSPATLSLSPGERATLSCRASESVSAHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWIYPFTFGQGTKLEIK


 


CL-27783
2108
EIVLTQSPATLSLSPGERATLSCRASQSVRTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGIDFTLTISSLEPEDFAVY




YCQQSXRYPFTFGQGTKLEIK


 


CL-27784
2109
EIVLTQSPATLSLSPGERATLSCRASQSVRTHMHWYQQKPGQA




PRLLIYRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQRSNEPFTFGQGTKLEIK


 


CL-27785
2110
EIVLTQSPATLSLSPGERATLSCRASQSVRSHMHWYQQKPGQA




PRLLIYGASGLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQRWNEPSTFGQGTKLEIK


 


CL-27786
2111
EIVLTQSPATLSLSPGERATLSCRASQSVRFHMHWYQQKPGQA




PRLLIYGASPLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSRRHPFTFGQGTKLEIK


 


CL-27787
2112
EIVLTQSPATLSLSPGERATLSCRASQSVSIQMHWYQQKPGQA




PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQQWNVPFTFGQGTKLEIK


 


CL-27788
2113
EIVLTQSPATLSLSPGERATLSCRASQSVSTPMHWYQQKPGQA




PRLLIYRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQGGNDPYTFGQGTKLEIK


 


CL-27790
2114
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYWASDLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQCWNGPLTFGQGTKLEIK


 


CL-27791
2115
EIVLTQSPATLSLSPGERATFSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGCGTDFTLTISSLEPEDFAVY




XCQQSGNDPFTFGQGTKLEIK


 


CL-27792
2116
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQGGNVPCTFGQGTKLEIK


 


CL-27794
2117
EIVLTQSPATLSLSPGERATLSCRASESVSWHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQIRADPFTFGQGTKLEIK


 


CL-27795
2118
EIVLTQSPATLSLSPGERATLSCRASESVCAHMHWYQQKPGQA




PRLLIYWASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSGLDPVTFGQGTKLEIK


 


CL-27796
2119
EIVLTQSPATLSLSPGERATLSCRASESVSTQMHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSGNNPFTFGQGTKLEIK


 


CL-27797
2120
EIVLTQSPATLSLSPGERATLSCRASQSVSTLMHWYQQKPGQA




PRLLIYRASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQGWNKPFTFGQGTKLEIK


 


CL-27798
2121
EIVLTQSPATLSLSPGERATLSCRASQSVTTHLAWYQQKPGQA




PRLLIYWASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSSKNPFTFGQGTKLEIK


 


CL-27799
2122
EIVLTQSPATLSLSPGERATLSCRASESVSXHMHWYQQKPGQA




PRLLIYWASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPPTFGQGTKLEIK


 


CL-27800
2123
EIVLTQSPATLSLSPGERATLSCRASQSVSSHLAWYQQKPGQA




PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSSRDPFTFGQGTKLEIK


 


CL-27801
2124
EIVLTQSPATLSLSPGERATLSCRASQSVTTNMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQRWNDPFTFGQGTKLEIK


 


CL-27802
2125
EIVLTQSPATLSLSPGERATLSCRASQSVSTHLAWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQKSNXPFTFGQGTKLEIK


 


CL-27803
2126
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYRASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWKDPYTFGQGTKLEIK


 


CL-27805
2127
EIVLTQSPATLSLSPGERATLSCRASQSVSAHLAWYQQKPGQA




PRLLIYEASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNVPFTFGQGTKLEIK


 


CL-27806
2128
EIVLTQSPATLSLSPGERATLSCRASESVLILMHWYQQKPGQA




PRLLIYEASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSSNDPFTFGQGTKLEIK


 


CL-27807
2129
EIVLTQSPATLSLSPGERATLSCRASQSVSSLMHWYQQKPGQA




PRLLIYGASCLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQYXNDPYTFGQGTKLEIK


 


CL-27809
2130
EIVLTQSPATLSLSPGERATLSCRASQSVITHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQRWKFPFTFGQGTKLEIK


 


CL-27810
2131
EIVLTQSPATLSLSPGERATLSCRASESVSTQLAWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQNWNNPLTFGQGTKLEIK


 


CL-27811
2132
EIVLTQSPATLSLSPGERATLSCRASQSVSRDMHWYQQKPGQA




PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQRWKEPFTFGQGTKLEIK


 


CL-27812
2133
EIVLTQSPATLSLSPGERATLSCRASQSVTTLMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQGCNDPLTFGQGTKLEIK


 


CL-27813
2134
EIVLTQSPATLSLSPGERATLSCRASESVVTHMHWYQQKPGQA




PRLLIYRASGLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWQHPFTFGQGTKLEIK


 


CL-27814
2135
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSGNDPCTFGQGTKLEIK


 


CL-27815
2136
EIVLTQSPATLSLSPGERATLSCRASQSVNSYLAWYQQKPGQA




PRLLIYWASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQAWNDPSTFGQGTKLEIK


 


CL-27816
2137
EIVLTQSPATLSLSPGERATLSCRASQSVSNPMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPFTFGQGTKLEIK


 


CL-27818
2138
EIVLTQSPATLSLSPGERATLSCRASQSVSTLMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQGLTDPFTFGQGTKLEIK


 


CL-27819
2139
EIVLTQSPATLSLSPGERATLSCRASESVSPPLAWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSENDPLTFGQGTKLEIK


 


CL-27820
2140
EIVLTQSPATLSLSPGERATLSCRASESVNTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWNHPFTFGQGTKLEIK


 


CL-27821
2141
EIVLTQSPATLSLSPGERATLSCRASESVSYPMHWYQQKPGQA




PRLLIYGASRLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQRWSDPFTFGQGTKLEIK


 


CL-27822
2142
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYIASFLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSXFEPSTFGQGTKLEIK


 


CL-27823
2143
EIVLTQSPATLSLSPGERATLSCRASESVSTQMHWYQQKPGQA




PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWKDPFTFGQGTKLEIK


 


CL-27824
2144
EIVLTQSPATLSLSPGERATLSCRASQSVSTKMHWYQQKPGQA




PRLLIYRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWIDPFTFGQGTKLEIK


 


CL-27826
2145
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYRASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWKDPFTFGQGTKLEIK


 


CL-27827
2146
EIVLTQSPATLSLSPGERATLSCRASQSVMTHLAWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNEPFTFGQGTKLEIK


 


CL-27828
2147
EIVLTQSPATLSLSPGERATLSCRASQSVXTHLAWYQQKPGQA




PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWQDPITFGQGTKLEIK


 


CL-27833
2148
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYAASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




XXQQSWNDPFTFGQGTKLEIK


 


CL-27838
2149
EIVLTQSPATLSLSPGERATLSCRASQSVSSLMHWYQQKPGQA




PRLLIYVASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNYPFTFGQGTKLEIK


 


CL-27840
2150
EIVLTQSPATLSLSPGERATLSCRASQSVITPLAWYQQKPGQA




PRLLIYGASRLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQIWNDPFTFGQGTKLEIK


 


CL-27841
2151
EIVLTQSPATLSLSPGERATLSCRASQSVSPLLAWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQRWNEPFTFGQGTKLEIK


 


CL-27842
2152
EIVLTQSPATLSLSPGERATLSCRASQSVNPHLAWYQQKPGQA




PRLLIYWASSLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQNWNDPFTFGQGTKLEIK


 


CL-27843
2153
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASRLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQGWNYPFTFGQGTKLEIK


 


CL-27844
2154
EIVLTQSPATLSLSPGERATLSCRASQSVSTRMHWYQQKPGQA




PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTRYDPFTFGQGTKLEIK


 


CL-27845
2155
EIVLTQSPATLSLSPGERATLSCRASESVSSHMHWYQQKPGQA




PRLLIYGASRLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPFTFGQGTKLEIK


 


CL-27846
2156
EIVLTQSPATLSLSPGERATLSCRASQSVTTHMHWYQQKPGQA




PRLLIYAASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNHPFTFGQGTKLEIK


 


CL-27847
2157
EIVLTQSPATLSLSPGERATLSCRASQSVKTQLAWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQRCNGPFTFGQGTKLEIK


 


CL-27848
2158
EIVLTQSPATLSLSPGERATLSCRASQSVSTQLAWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTGNDPFTFGQGTKLEIK


 


CL-27849
2159
EIVLTQSPATLSLSPGERATLSCRASESVSPLMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWKDPFTFGQGTKLEIK


 


CL-27850
2160
EIVLTQSPATLSLSPGERATLSCRASESVSAHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQWWNNPFTFGQGTKLEIK


 


CL-27851
2161
EIVLTQSPATLSLSPGERATLSCRASQSVNTHMHWYQQKPGQA




PRLLIYRASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNEPLTFGQGTKLEIK


 


CL-29979
2162
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWQDPLTFGQGTKLEIK


 


CL-29980
2163
EIVLTQSPATLSLSPGERATLSCRASQSVNTNMHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWNVPFTFGQGTKLEIK


 


CL-29981
2164
EIVLTQSPATLSLSPGERATLSCRASESVSTAMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWNVPITFGQGTKLEIK


 


CL-29982
2165
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASMLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-29983
2166
EIVLTQSPATLSLSPGERATLSCRASESVNDHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNNPITFGQGTKLEIK


 


CL-29984
2167
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPLTFGQGTKLEIK


 


CL-29985
2168
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWDDPITFGQGTKLEIK


 


CL-29986
2169
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSFLDPITFGQGTKLEIK


 


CL-29987
2170
EIVLTQSPATLSLSPGERATLSCRASESVSTNMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQGWSDPLTFGQGTKLEIK


 


CL-29988
2171
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWIDPLTFGQGTKLEIK


 


CL-29989
2172
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWIDPITFGQGTKLEIK


 


CL-29990
2173
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGCGTDFTLTISSLEPEDFAVY




FCQQSWHDPLTFGQGTKLEIK


 


CL-29991
2174
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWDDPITFGQGTKLEIK


 


CL-29992
2175
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASELESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWNDPITFGQGTKLEIK


 


CL-29993
2176
EIVLTQSPATLSLSPGERATLSCRASESVNTLMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWNEPITFGQGTKLEIK


 


CL-29994
2177
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWSDPLTFGQGTKLEIK


 


CL-29995
2178
EIVLTQSPATLSLSPGERATLSCRASQSVSKHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNNPITFGQGTKLEIK


 


CL-29996
2179
EIVLTQSPATLSLSPGERATLSCRASQSVDTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWHDPITFGQGTKLEIK


 


CL-29997
2180
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWTDPLTFGQGTKLEIK


 


CL-29998
2181
EIVLTQSPATLSLSPGERATLSCRASQSVSSHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPLTFGQGTKLEIK


 


CL-29999
2182
EIVLTQSPATLSLSPGERATLSCRASESVSTNMHWYQQKPGQA




PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNEPFTFGQGTKLEIK


 


CL-30000
2183
EIVLTQSPATLSLSPGERATLSCRASQSVDTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWGDPLTFGQGTKLEIK


 


CL-30001
2184
EIVLTQSPATLSLSPGERATLSCRASESVSNNLAWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWNDPITFGQGTKLEIK


 


CL-30002
2185
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPITFGQGTKLEIK


 


CL-30003
2186
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNEPWTFGQGTKLEIK


 


CL-30004
2187
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWIDPLTFGQGTKLEIK


 


CL-30005
2188
EIVLTQSPATLSLSPGERATLSCRASQSVGNNMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30006
2189
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFGGSGSGTDFTLTISSLEPEDFAVY




YCQQSWTDPLTFGQGTKLEIK


 


CL-30007
2190
EIVLTQSPATLSLSPGERATLSCRASESVYTXLAWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQILNDPFTFGQGTKLEIK


 


CL-30009
2191
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30010
2192
EIVLTQSPATLSLSPGERATLSCRASQSVGTNMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPITFGQGTKLEIK


 


CL-30011
2193
EIVLTQSPATLSLSPGERATLSCRASESVATHMHWYQQKPGQA




PRLLIYGASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30012
2194
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30013
2195
EIVLTQSPATLSLSPGERATLSCRASESVMNHLAWYQQKPGQA




PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWSDPLTFGQGTKLEIK


 


CL-30014
2196
EIVLTQSPATLSLSPGERATLSCRASQSVGTSMHWYQQKPGQA




PRLLIYAASELESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPFTFGQGTKLEIK


 


CL-30015
2197
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPLTFGQGTKLEIK


 


CL-30017
2198
EIVLTQSPATLSLSPGERATLSCRASESVSNNMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWSDPFTFGQGTKLEIK


 


CL-30018
2199
EIVLTQSPATLSLSPGERATLSCRASQSVSSHMHWYQQKPGQA




PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSFSDPITFGQGTKLEIK


 


CL-30019
2200
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWSDPLTFGQGTKLEIK


 


CL-30020
2201
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30021
2202
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNPPITFGQGTKLEIK


 


CL-30022
2203
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNEPFTFGQGTKLEIK


 


CL-30023
2204
EIVLTQSPATLSLSPGERATLSCRASQSVGTNMHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWNEPITFGQGTKLEIK


 


CL-30024
2205
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPVTFGQGTKLEIK


 


CL-30025
2206
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWNDPLTFGQGTKLEIK


 


CL-30026
2207
EIVLTQSPATLSLSPGERATLSCRASQSVSSHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-30027
2208
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-30028
2209
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWSDPLTFGQGTKLEIK


 


CL-30029
2210
EIVLTQSPATLSLSPGERATLSCRASESVSTHMNWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNVPYTFGQGTKLEIK


 


CL-30030
2211
EIVLTQSPATLSLSPGERATLSCRASESVTSNMHWYQQKPGQA




PRLLIYAASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWQNPITFGQGTKLEIK


 


CL-30031
2212
EIVLTQSPATLSLSPGERATLSCRASESVSDHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWTDPLTFGQGTKLEIK


 


CL-30032
2213
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30033
2214
EIVLTQSPATLSLSPGERATLSCRASESVSNYMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWTDPLTFGQGTKLEIK


 


CL-30034
2215
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWNDPITFGQGTKLEIK


 


CL-30035
2216
EIVLTQSPATLSLSPGERATLSCRASQSVGTAMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWDAPFTFGQGTKLEIK


 


CL-30036
2217
EIVLTQSPATLSLSPGERATLSCRASQSVRSHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWTPPITFGQGTKLEIK


 


CL-30037
2218
EIVLTQSPATLSLSPGERATLSCRASESVSTSMNWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWKDPITFGQGTKLEIK


 


CL-30038
2219
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNVPWTFGQGTKLEIK


 


CL-30039
2220
EIVLTQSPATLSLSPGERATLSCRASESVSNSMHWYQQKPGQA




PRLLIYGASTLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWTDPLTFGQGTKLEIK


 


CL-30040
2221
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWNDPSTFGQGTKLEIK


 


CL-30041
2222
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30042
2223
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASTLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWSDPLTFGQGTKLEIK


 


CL-30043
2224
EIVLTQSPATLSLSPGERATLSCRASESVDSNMHWYQQKPGQA




PRLLIYRASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWGDPITFGQGTKLEIK


 


CL-30044
2225
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30045
2226
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30046
2227
EIVLTQSPATLSLSPGERATLSCRASESVSDHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWTDPLTFGQGTKLEIK


 


CL-30047
2228
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30048
2229
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWSDPLTFGQGTKLEIK


 


CL-30049
2230
EIVLTQSPATLSLSPGERATLSCRASESVNTHLAWYQQKPGQA




PRLLIYGASMLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWSLPYTFGQGTKLEIK


 


CL-30050
2231
EIVLTQSPATLSLSPGERATLSCRASQSVSSHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30053
2232
EIVLTQSPATLSLSPGERATLSCRASESVSTHMNWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPFTFGQGTKLEIK


 


CL-30054
2233
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNEPYTFGQGTKLEIK


 


CL-30055
2234
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWGDPITFGQGTKLEIK


 


CL-30056
2235
EIVLTQSPATLSLSPGERATLSCRASQSVSTNMHWYQQKPGQA




PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWNEPITFGQGTKLEIK


 


CL-30057
2236
EIVLTQSPATLSLSPGERATLSCRASESVGKHMHWYQQKPGQA




PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWNDPITFGQGTKLEIK


 


CL-30058
2237
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASFLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWTNPITFGQGTKLEIK


 


CL-30059
2238
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWDDPLTFGQGTKLEIK


 


CL-30060
2239
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWTDPITFGQGTKLEIK


 


CL-30061
2240
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWIDPITFGQGTKLEIK


 


CL-30062
2241
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPITFGQGTKLEIK


 


CL-30063
2242
EIVLTQSPATLSLSPGERATLSCRASESVCTRMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPYTFGQGTKLEIK


 


CL-30064
2243
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTFDDPLTFGQGTKLEIK


 


CL-30066
2244
EIVLTQSPATLSLSPGERATLSCRASQSVGDSLAWYQQKPGQA




PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWNVPITFGQGTKLEIK


 


CL-30067
2245
EIVLTQSPATLSLSPGERATLSCRASESVANHLAWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPITFGQGTKLEIK


 


CL-30068
2246
EIVLTQSPATLSLSPGERATLSCRASESVSTHMNWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQGWYDPLTFGQGTKLEIK


 


CL-30069
2247
EIVLTQSPATLSLSPGERATLSCRASESVSSHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPITFGQGTKLEIK


 


CL-30070
2248
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNVPFTFGQGTKLEIK


 


CL-30071
2249
EIVLTQSPATLSLSPGERATLSCRASESVNKHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWIDPFTFGQGTKLEIK


 


CL-30072
2250
EIVLTQSPATLSLSPGERATLSCRASQSVGNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNMPITFGQGTKLEIK


 


CL-30073
2251
EIVLTQSPATLSLSPGERATLSCRASESVGEHMHWYQQKPGQA




PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-30074
2252
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWDVPLTFGQGTKLEIK


 


CL-30078
2253
ENVLTQSPATLSLSPGERATLSCRASESVITHMNWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPFTFGQGTKLEIK


 


CL-30090
2254
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-30095
2255
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASELESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWSDPLTFGQGTKLEIK


 


CL-30098
2256
EIVLTQSPATLSLSPGERATLSCRASQSVDTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWIDPITFGQGTKLEIK


 


CL-30099
2257
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWIDPLTFGQGTKLEIK


 


CL-30103
2258
EIVLTQSPATPSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPFTFGQGTKLEIK


 


CL-30104
2259
EIVLTQSPATLSLSPGERATLSCRASESVSSHMHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWNDPITFGQGTKLEIK


 


CL-30106
2260
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30109
2261
EIVLTQSPATLSLSPGERATLSCRASQSVITHMNWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWNDPITFGQGTKLEIK


 


CL-30115
2262
EIVLTQSPATLSLSPGERATLSCRASESVQTHMNWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPFTFGQGTKLEIK


 


CL-30120
2263
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-30121
2264
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPLTFGQGTKLEIK


 


CL-30123
2265
EIVLTQSPATLSLSPGERATLSCRASESVITHMNWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWDNPITFGQGTKLEIK


 


CL-30126
2266
EIVLTQSPATLSLSPGERATLSCRASQSVHKHMNWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQGWDDPLTFGQGTKLEIK


 


CL-30128
2267
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30131
2268
EIVLTQSPATLSLSPGERATLSCRASESVLTHMNWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYEPWTFGQGTKLEIK


 


CL-30132
2269
EIVLTQSPATLSLSPGERATLSCRASESVDTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPITFGQGTKLEIK


 


CL-30133
2270
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWSDPITFGQGTKLEIK


 


CL-30134
2271
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMNWYQQKPGQA




PRLLIYGASFLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWSDPITFGQGTKLEIK


 


CL-30135
2272
EIVLTQSPATLSLSPGERATLSCRASQSVGTPMHWYQQKPGQA




PRLLIYGASTLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-30137
2273
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPITFGQGTKLEIK


 


CL-30143
2274
EIVLTQSPATLSLSPGERATLSCRASESVDTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPITFGQGTKLEIK


 


CL-30144
2275
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASMLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWTDPITFGQGTKLEIK


 


CL-30147
2276
EIVLTQSPATLSLXPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLEYGVPARFSGSGCGTDFTLTISSIEHEDFAVY




FCQQSWNDPFTFGQGTKLEIK


 


CL-30150
2277
EIVLTQSPATLSLSPGERATLSCRASQSVANHLAWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWTDPITFGQGTKLEIK


 


CL-30152
2278
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASMLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNNPITFGQGTKLEIK


 


CL-30155
2279
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYAASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWDDPLTFGQGTKLEIK


 


CL-30158
2280
EIVLTQSPATLSLSPGERVTLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPITFGQGTKLEIK


 


CL-30160
2281
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30163
2282
EIVLTQSPATLSLSPGERATLSCRASQSVSSHMHWYQQKPGQA




PRLLIYAASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-30164
2283
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWMDPITFGQGTKLEIK


 


CL-30166
2284
EIVLTQSPATLSLSPGERATLSCRASESVSTNMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWSEPWTFGQGTKLEIK


 


CL-30167
2285
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWSDPLTFGQGTKLEIK


 


CL-30593
2286
EIVLTQSPATLSLSPGERATLSCRASQSVDTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-30594
2287
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNEPFTFGQGTKLEIK


 


CL-30595
2288
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPITFGQGTKLEIK


 


CL-30597
2289
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASTLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30598
2290
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASVLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWDDPLTFGQGTKLEIK


 


CL-30600
2291
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWLDPITFGQGTKLEIK


 


CL-30601
2292
EIVLTQSPATLSLSPGERATLSCRASQSVNTHLAWYQQKPGQA




PRLLIYAASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWTDPLTFGQGTKLEIK


 


CL-30602
2293
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWSDPLTFGQGTKLEIK


 


CL-30604
2294
EIVLTQSPATLSLSPGERATLSCRASQSVSNPMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNXPFTFGQGTKLEIK


 


CL-30606
2295
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWDDPFTFGQGTKLEIK


 


CL-30608
2296
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWSDPLTFGQGTKLEIK


 


CL-30609
2297
EIVLTQSPATLSLSPGERATLSCRASESVNSNMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-30610
2298
EIVLTQSPATLSLSPGERATLSCRASQSVRNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWDDPLTFGQGTKLEIK


 


CL-30611
2299
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWDDPLTFGQGTKLEIK


 


CL-30613
2300
EIVLTQSPATLSLSPGERATLSCRASQSVNTAMHWYQQKPGQA




PRLLIYGASSLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30614
2301
EIVLTQSPATLSLSPGERATLSCRASESVGSHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNLPLTFGQGTKLEIK


 


CL-30615
2302
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPITFGQGTKLEIK


 


CL-30616
2303
EIVLTQSPATLSLSPGERATLSCRASQSVITHMNWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWGDPWTFGQGTKLEIK


 


CL-30617
2304
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWIDPLTFGQGTKLEIK


 


CL-30618
2305
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASMLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWDDPLTFGQGTKLEIK


 


CL-30619
2306
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYAASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPITFGQGTKLEIK


 


CL-30620
2307
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPITFGQGTKLEIK


 


CL-30624
2308
EIVLTQSPATPSLSPGERATLSCRASESVGSCMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPLTFGQGTKLEIK


 


CL-30626
2309
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPLTFGQGTKLEIK


 


CL-30627
2310
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30628
2311
EIVLTQSPATLSLSPGERATLSCRASESVSRHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNNPLTFGQGTKLEIK


 


CL-30629
2312
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPATFGQGTKLEIK


 


CL-30630
2313
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30631
2314
EIVLTQSPATLSLSPGERATLSCRASQSVGRHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWTDPLTFGQGTKLEIK


 


CL-30632
2315
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWSDPITFGQGTKLEIK


 


CL-30634
2316
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30635
2317
EIVLTQSPATLSLSPGERATLSCRASESVSSNMNWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSFYDPITFGQGTKLEIK


 


CL-30636
2318
EIVLTQSPATLSLSPGERATLSCRASESVSSHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWSDPLTFGQGTKLEIK


 


CL-30637
2319
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWHDPLTFGQGTKLEIK


 


CL-30638
2320
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYAASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWIDPITFGQGTKLEIK


 


CL-30639
2321
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWTDPLTFGQGTKLEIK


 


CL-30640
2322
EIVLTQSPATLSLSPGERATLSCRASESVRSHLAWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSIEPEDFAVY




FCQQSWNAPFTFGQGTKLEIK


 


CL-30641
2323
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWSDPLTFGQGTKLEIK


 


CL-30642
2324
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWDDPITFGQGTKLEIK


 


CL-30643
2325
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNEPLTFGQGTKLEIK


 


CL-30644
2326
EIVLTQSPATLSLSPGERATLSCRASESVSTHMPWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30645
2327
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWSDPLTFGQGTKLEIK


 


CL-30647
2328
EIVLTQSPATLSLSPGERATLSCRASQSVSTAMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWFDPLTFGQGTKLEIK


 


CL-30648
2329
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWSDPITFGQGTKLEIK


 


CL-30649
2330
EIVLTQSPATLSLSPGERATLSCRASESVNSDMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-30650
2331
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNVPITFGQGTKLEIK


 


CL-30651
2332
EIVLTQSPATLSLSPGERATLSCRASESVSTNLAWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWNDPITFGQGTKLEIK


 


CL-30653
2333
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYAASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWTDPITFGQGTKLEIK


 


CL-30654
2334
EIVLTQSPATLSLSPGERATLSCRASESVSTHMNWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWTDPITFGQGTKLEIK


 


CL-30655
2335
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWDVPFTFGQGTKLEIK


 


CL-30657
2336
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWSDPITFGQGTKLEIK


 


CL-30658
2337
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQCRNDPFTFGQGTKLEIK


 


CL-30659
2338
EIVLTQSPATLSLSPGERATLSCRASESVSKHMNWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWTDPLTFGQGTKLEIK


 


CL-30660
2339
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASRLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30662
2340
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWDDPLTFGQGTKLEIK


 


CL-30663
2341
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNEPYTFGQGTKLEIK


 


CL-30664
2342
EIVLTQSPATLSLSPGERATLSCRASESVGMHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30665
2343
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMNWYQQKPGQA




PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSFNNPLTFGQGTKLEIK


 


CL-30666
2344
EIVLTQSPATLSLSPGERATLSCRASQSVNTHLHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWFDPLTFGQGTKLEIK


 


CL-30667
2345
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPLTFGQGTKLEIK


 


CL-30669
2346
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-30670
2347
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWLDPLTFGQGTKLEIK


 


CL-30671
2348
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASILESGVLARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30672
2349
EIVLTQSPATLSLSPGERATLSCRASESVSSHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWNYPITFGQGTKLEIK


 


CL-30673
2350
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPITFGQGTKLEIK


 


CL-30674
2351
EIVLTQSPATLSLSPGERATLSCRASESVGNHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWIDPLTFGQGTKLEIK


 


CL-30675
2352
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYAASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWVEPFTFGQGTKLEIK


 


CL-30676
2353
EIVLTQSPATLSLSPGERATLSCRASQSVETHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWRDPLTFGQGTKLEIK


 


CL-30677
2354
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMNWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWDDPLTFGQGTKLEIK


 


CL-30678
2355
EIVLTQSPATLSLSPGERATLSCRASQSVGSSMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPLTFGQGTKLEIK


 


CL-30679
2356
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30681
2357
EIVLTQSPATLSLSPGERATLSCRASQSVTNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWHDPLTFGQGTKLEIK


 


CL-30682
2358
EIVLTQSPATLSLSPGERATLSCRASESVSSHLAWYQQKPGQA




PRLLIYGASTLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWGDPFTFGQGTKLEIK


 


CL-30683
2359
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWSDPLTFGQGTKLEIK


 


CL-30684
2360
EIVLTQSPATLSLSPGERATLSCRASESVHDHMHWYQQKPGQA




PRLLIYAASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPLTFGQGTKLEIK


 


CL-30685
2361
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWADPLTFGQGTKLEIK


 


CL-34444
2362
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34445
2363
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPFTFGQGTKLEIK


 


CL-34446
2364
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSFYDPLTFGQGTKLEIK


 


CL-34447
2365
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34448
2366
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASMLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWMDPITFGQGTKLEIK


 


CL-34450
2367
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWMDPLTFGQGTKLEIK


 


CL-34451
2368
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34452
2369
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWHDPLTFGQGTKLEIK


 


CL-34453
2370
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSFTNPLTFGQGTKLEIK


 


CL-34454
2371
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34457
2372
EIVLTQSPATLSLSPGERATLSCRASXSVNTHMHWYQQKPGQA




PRLLIYGASXLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQXWYDPITFGQGTKLEIK


 


CL-34458
2373
EIVLTQSPATLSLSPGERATLSCRASESVRTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34459
2374
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-34460
2375
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34461
2376
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34462
2377
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASVLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34464
2378
EIVLTQSPATLSLSPGERATLSCRASQSVSRHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPITFGQGTKLEIK


 


CL-34465
2379
EIVLTQSPATLSLSPGERATLSCRASQSVSSHMHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWDDPITFGQGTKLEIK


 


CL-34467
2380
EIVLTQSPATLSLSPGERATLSCRASESVSTSMHWYQQKPGQA




PRLLIYGASQLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNVPFTFGQGTKLEIK


 


CL-34468
2381
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASRLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWTVPLTFGQGTKLEIK


 


CL-34472
2382
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-34473
2383
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASVLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-34474
2384
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASTLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-34478
2385
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPLTFGQGTKLEIK


 


CL-34479
2386
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASTLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-34480
2387
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34481
2388
EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34482
2389
EIVLTQSPATLSLSPGERATLSCRASQSVGEHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPITFGQGTKLEIK


 


CL-34485
2390
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-34487
2391
EIVLTQSPATLSLSPGERATLSCRASQSVSTNMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPITFGQGTKLEIK


 


CL-34488
2392
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASTLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34490
2393
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-34494
2394
EIVLTQSPATLSLSPGERATLSCRASQSVGSHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPITFGQGTKLEIK


 


CL-34496
2395
EIVLTQSPATLSLSPGERATLSCRASQSVGNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-34498
2396
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-34499
2397
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPITFGQGTKLEIK


 


CL-34500
2398
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPITFGQGTKLEIK


 


CL-34502
2399
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34504
2400
EIVLTQSPATLSLSPGERATLSCRASESVSRHMNWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPITFGQGTNLEIK


 


CL-34505
2401
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPITFGQGTKLEIK


 


CL-34506
2402
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPITFGQGTKLEIK


 


CL-34508
2403
EIVLTQSPATLSLSPGERATLSCRASESVDTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34509
2404
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPITFGQGTKLEIK


 


CL-34511
2405
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34512
2406
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34514
2407
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34515
2408
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPITFGQGTKLEIK


 


CL-34517
2409
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34520
2410
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-34521
2411
EIVLTQSPATLSLSPGERATLSCRASESVDRHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-34523
2412
EIVLTQSPATLSLSPGERATLSCRASQSVTNHMHWYQQKPGQA




PRLLIYGASVLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34524
2413
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPITFGQGTKLEIK


 


CL-34525
2414
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPITFGQGTKLEIK


 


CL-34526
2415
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-34529
2416
EIVLTQSPATLYLXPGERATLSCRASQSVSTHMHWYQQKPGQA




ARLVMYGASNLEFGVPARFSGSGSGTEFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34533
2417
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPITFGQGTKLEIK


 


CL-34534
2418
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34536
2419
EIVLTQSPATLSLSPGERATLSCRASQSVGAHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-34539
2420
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWSDPLTFGQGTKLEIK


 


CL-34541
2421
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPITFGQGTKLEIK


 


CL-34548
2422
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34556
2423
EIVLTQSPATLSLSPGERATLSCRASESVSXHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34558
2424
EIVLTQSPATLSLSPGERATLSCRASESVSTAMHWYQQKPGQA




PRLLIYAASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34561
2425
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPITFGQGTKLEIK


 


CL-34562
2426
EIVLTQSPATLSLSPGERATLSCRASQSVGSHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-34563
2427
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-34566
2428
EIVLTQSPATLSLSPGERATLSCRASQSVGTNMHWYQQKPGQA




PRLLIYGASVLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPITFGQGTKLEIK


 


CL-34568
2429
EIVLTQSPATLSLSPGERATLSCRASESVGKHMHWYQQKPGQA




PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWMDPLTFGQGTKLEIK


 


CL-34573
2430
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASFLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34574
2431
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWGDPLTFGQGTKLEIK


 


CL-34577
2432
EIVLTQSPATLSLSPGERATLSCRASESVSKHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34580
2433
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASMLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWDDPLTFGQGTKLEIK


 


CL-34582
2434
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34585
2435
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-34586
2436
EIVLTQSPATLSLSPGERATLSCRASQSVXXHMHWYQQKPGQA




PRLLIYGASTLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWTDPXTFGQGTKLEIK


 


CL-34587
2437
EIVLTQSPATLSLSPGERATLSCRASESVSTHLHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34590
2438
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34591
2439
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPITFGQGTKLEIK


 


CL-34592
2440
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPITFGQGTKLEIK


 


CL-34593
2441
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASMLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34594
2442
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPITFGQGTKLEIK


 


CL-34598
2443
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWIEPYTFGQGTKLEIK


 


CL-34599
2444
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPITFGQGTKLEIK


 


CL-34600
2445
EIVLTQSPATLSLSPGERATLSCRASESVNTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWNDPFTFGQGTKLEIK


 


CL-34601
2446
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-34602
2447
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPGTFGQGTKLEIK


 


CL-34604
2448
EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-34610
2449
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-34612
2450
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMQWYQQKPGQA




PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEHEDFAVY




XCQQSWYDPLTFGQGTKLEIK


 


CL-34613
2451
EIVLTQSPATLSLSPGERATLSCRASESVGRHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPITFGQGTKLEIK


 


CL-34614
2452
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-34617
2453
EIVLTQSPATLSLSPGERATLSCRASESVDSSMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-34618
2454
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPITFGQGTKLEIK


 


CL-40245
2455
EIVLTQSPATLSLSPGERAALSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40250
2456
EIVLTQSPATLSLSPGERATLSYRASQSVGTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-40251
2457
EIVLTQSPGTLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40253
2458
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGADFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40255
2459
EIVLTQSPGTLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40258
2460
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASHPESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-40266
2461
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPMTFGQGTKLEIK


 


CL-40271
2462
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLGSN


 


CL-40272
2463
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLRSN


 


CL-40283
2464
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPMTFGQGTKLEIK


 


CL-40284
2465
EIVLTQSPATLSLSPGERAILSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLAFGQGTKLEIK


 


CL-40286
2466
EIVLPQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLEPGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPFTFGQGTKLEIK


 


CL-40287
2467
EIVLTQSPGTLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPFTFGQGTKLEIK


 


CL-40288
2468
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40299
2469
RNCVTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-40302
2470
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWCDPLTFGQGTKLEIK


 


CL-40303
2471
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLPIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40317
2472
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLGPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40324
2473
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-40327
2474
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPMTFGQGTKLEIK


 


CL-40328
2475
EIVLTQSPGTLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40331
2476
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQRTKLEIK


 


CL-40332
2477
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPMAFGQGTKLEIK


 


CL-40335
2478
RNCVDKSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-40336
2479
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40337
2480
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQRSWYDPLTFGQGTKLEIK


 


CL-40338
2481
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWNDPFTFGQGTKLEIK


 


CL-40339
2482
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40341
2483
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFVVY




YCQQSWYDPITFGQGTKLEIK


 


CL-40342
2484
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTCYDPLTFGQGTKLEIK


 


CL-40350
2485
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGADFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-40356
2486
EIVLTQSPATLSLSPGERATLSCRASESVGKHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPITFGQGTKLEIK


 


CL-40357
2487
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-40364
2488
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSFYDPLTFGQGTKLEIK


 


CL-40367
2489
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPLTFGQGTKLEIK


 


CL-40370
2490
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFILTISSLEPEDFAVY




YCQQSFYDPLTFGQGTKLEIK


 


CL-40373
2491
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-40381
2492
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAIY




FCQQTWYDPLTFGQGTKLEIK


 


CL-40382
2493
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGIDFTLTISSLEPEDFAVY




FCQQTWYDPLTFGQGTKLEIK


 


CL-40390
2494
EIVLTQSPATLSLSPGERATLSCRASGSVGKHMHWYQQKPGQA




PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40394
2495
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEEFAVY




FCQQTWYDPLTFGQGTKLEIK


 


CL-40399
2496
EIVLTQSPATLSLSPGERATLSCRASQSVSKHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDSTLTISSLEPEDFAVY




FCQQTWYDPITFGQGTKLEIK


 


CL-40408
2497
EIVLTQSPATLSLPPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSFYDPLTFGQGTKLEIK


 


CL-40414
2498
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFGGSGSGTDFTLTISSLEPEDFAVY




YCQQSFYDPLTFGQGTKLEIK


 


CL-40426
2499
EIVSTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTIGSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-40440
2500
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTNLEIK


 


CL-40441
2501
EIVLTQSPATLSLSPGERATFSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40443
2502
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAAY




FCQQTWYDPLTFGQGTKLEIK


 


CL-40445
2503
EIVLTQSPSTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPLTFGQGTKLEIK


 


CL-40447
2504
EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIX


 


CL-40453
2505
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWCQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPLTFGQGTKLEIK


 


CL-40463
2506
EIVLTQSPGTLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-40466
2507
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-40470
2508
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-40472
2509
EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40476
2510
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLRSN


 


CL-40479
2511
EIVLTQSPATLSLSPGERATLSCRASQSVATHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLRSN


 


CL-40480
2512
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQEPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40484
2513
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40485
2514
RNLLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPLTFGQGTKLEIK


 


CL-40489
2515
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPLTFGQGTKLVIK


 


CL-40494
2516
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGADFTLTISSLEPEDFAVY




FCQQTWYDPLTFGQGTKLEIK


 


CL-40498
2517
EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSRYDPLTFGQGTKLEIK


 


CL-40503
2518
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPLTFGQGTKLEIK


 


CL-40505
2519
EIVLTQSPGTLSLSPGERATLSCRASQSVATHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40511
2520
AIVLTQSPATLSLSPGERATLSCRASQSVATHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-40526
2521
EIVLTQSPAALSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPLTFGQGTKLEIK


 


CL-40531
2522
EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA




PRLLIYGASIPESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-41836
2523
AIVLTQSPGTLSLSPGERATLSCRASQSVATHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-41845
2524
EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-41849
2525
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-41850
2526
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK


 


CL-41852
2527
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-41854
2528
EIVLTQSPATLSLSPGERATLSCRASQSVATHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-41855
2529
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPLTFGQGTKLEIK


 


CL-41885
2530
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTITSLEPEDFAVY




FCXQTWYDPLTFGQGTKLEIK


 


CL-41886
2531
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPITFGQGTKLRSN


 


CL-41888
2532
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-41920
2533
EIVLTQSPGTLSLSPGERASLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSFYDPLTFGRGTKLEIK


 


CL-41923
2534
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIN


 


CL-41928
2535
EIVLTQSPATLSLSPGERATLSCRTSESVGKHMHWYQQKPGQA




PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-41938
2536
EIVLTQSPATLSLSPGERATLSCRASESVGKHMHWYQQKPGQA




PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPLTFGQGTKLEIK


 


CL-41940
2537
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSWYDPITFGQGTKLEIK


 


CL-41941
2538
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPLTFGQGTKLEIK


 


CL-41947
2539
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSFYDPLTFGQGTKLEIQ


 


CL-41949
2540
EIVLTQSPATLSLSPGERATLSCRASQSVSKHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQTWYDPITFGQGTKLEIK


 


CL-41950
2541
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQTWYDPLTFGQGTKLEIK


 


CL-41951
2542
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




YCQQSFYDPLTFGQGTKLEIK


 


CL-41952
2543
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA




PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY




FCQQSWYDPLTFGQGTKLEIK
















TABLE 40







Amino Acid Residues Found In Each Position of the Heavy


Chain Variable Region During The Affinity Maturation Of


Humanized Anti-Human VEGF Antibody Hbdb-4G8.3


hBDB-4G8|Heavy Chain Variable Region








SEQ ID NO:
Sequence





2544
         1         2         3         4         5         6



123456789012345678901234567890123456789012345678901234567890



EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTETGKPTY



           R          S       S S                    Y  N I



                      N      QK D                    L  D M



                             DY K                    V  T K



                             ET C                    W  P A



                             NM V                    A  W N



                             AG E                    Q  Y P



                             GA L                    H  V L



                             HI W                    G  S V



                             KL P                    K  M W



                             ME Y                    N  A D



                             LP M                    M  I Y



                             RQ N                    T  G G



                             IF T                    P  R E



                             Y                          L



                             V



         7         8         9        10        11        12



123456789012345678901234567890123456789012345678901234567890



ADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT



 Y  N             T        D           H    N L



 H                         T          YI   ST N



                                      GT   NK T



                                      ID   EM V



                                      S    MY A



                                      KF   LC R



                                      NL   TI F



                                      PE   WF D



                                      LV   QL



                                      WY   GD S



                                      MA   IW



                                      FG   AX



                                      RW   CV



                                      QQ   V



                                       R



123



VSS



SFQ



 L
















TABLE 41







Amino Acid Residues Found In Each Position of the Light


Chain Variable Region During The Affinity Maturation Of


Humanized Anti-Human VEGF Antibody Hbdb-4G8.3


hBDB-4G8|Light Chain Variable Region








SEQ ID NO:
Sequence





2545
         1         2         3         4         5         6



123456789012345678901234567890123456789012345678901234567890



EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESGVPA



                   A         NSA A               W  H  Y



                             DRD P               V  Y



                               C                 I  M



                             TAP                 E  T



                             RER                 S  F



                             HDY                 D  V



                             EM                     R



                             IPL                    Q



                             LYQ                    A



                             QIK                    S



                             CW                     E



                             MF                     G



                             Y                      C



                             K                      D



                             V                      P



         7         8         9        10



12345678901234567890123456789012345678901234567



RFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIK



                              CCIN M        G



                              GLTY G



                              IGDA Y



                              W GL



                              REM  A



                              NSSM W



                              A HP S



                              Y AG V



                              K RH C



                              Q VF P



                              F LK



                                F



                                K



                                Q
















TABLE 42







Variable Region Sequences of hBDB-4G8.3 Affinity


Matured Clones Converted To IgG










SEQ ID

Protein
V Region


NO:
Clone
Region
123456789012345678901234567890





2546
CL-32416 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW





VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF





YFDYWGQGTMVTVSS


 


2547
CL-32416
CDR-H1
GYTFTDYGMY


 


2548
CL-32416
CDR-H2
WIDTETGEPTYADDFKG


 


2549
CL-32416
CDR-H3
TNYYYRSYMFYFDY


 


2550
CL-32416 VL

EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWY





QQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIK


 


2551
CL-32416
CDR-L1
RASESVSTHMH


 


2552
CL-32416
CDR-L2
GASNLES


 


2553
CL-32416
CDR-L3
QQSWNDPFT


 


2554
CL-34449 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW





VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF





YFDYWGQGTMVTVSS


 


2555
CL-34449
CDR-H1
GYTFTDYGMY


 


2556
CL-34449
CDR-H2
WIDTETGEPTYADDFKG


 


2557
CL-34449
CDR-H3
TNYYYRSYMFYFDY


 


2558
CL-34449 VL

EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWY





QQKPGQAPRLLIYGASHLESGIPARFSGSGSGTDFT





LTISSLEPEDFAVYYCQQTWYDPLTFGQGTKLEIK


 


2559
CL-34449
CDR-L1
RASQSVGTHMH


 


2560
CL-34449
CDR-L2
GASHLES


 


2561
CL-34449
CDR-L3
QQTWYDPLT


 


2562
CL-34455 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYW





VRQAPGQGLEWMGWIDTETGEPTYAQGFTGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYPSYMF





YFDYWGQGTMVTVSS


 


2563
CL-34455
CDR-H1
GYTFTNYGMY


 


2564
CL-34455
CDR-H2
WIDTETGEPTYAQGFTG


 


2565
CL-34455
CDR-H3
TNYYYPSYMFYFDY


 


2566
CL-34455 VL

EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWY





QQKPGQAPRLLIYGASKLESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK


 


2567
CL-34455
CDR-L1
RASQSVGTHMH


 


2568
CL-34455
CDR-L2
GASKLES


 


2569
CL-34455
CDR-L3
QQSWYDPLT


 


2570
CL-34463 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW





VRQAPGQGLEWMGWIDTETGNPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYPSYMF





YFDYWGQGTMVTVSS


 


2571
CL-34463
CDR-H1
GYTFTDYGMY


 


2572
CL-34463
CDR-H2
WIDTETGNPTYADDFKG


 


2573
CL-34463
CDR-H3
TNYYYPSYMFYFDY


 


2574
CL-34463 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSKHMHWY





QQKPGQAPRLLIYGASNLESGIPARFSGSGSGTDFT





LTISSLEPEDFAVYFCQQTWYDPITFGQGTKLEIK


 


2575
CL-34463
CDR-L1
RASQSVSKHMH


 


2576
CL-34463
CDR-L2
GASNLES


 


2577
CL-34463
CDR-L3
QQTWYDPIT


 


2578
CL-34469 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYW





VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF





YFDYWGQGTMVTVSS


 


2579
CL-34469
CDR-H1
GYTFTNYGMY


 


2580
CL-34469
CDR-H2
WIDTETGEPTYADDFKG


 


2581
CL-34469
CDR-H3
TNYYYRSYMFYFDY


 


2582
CL-34469 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY





QQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK


 


2583
CL-34469
CDR-L1
RASQSVSTHMH


 


2584
CL-34469
CDR-L2
GASNLES


 


2585
CL-34469
CDR-L3
QQSWYDPLT


 


2586
CL-34475 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW





VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYSSYMF





YFDYWGQGTMVTVSS


 


2587
CL-34475
CDR-H1
GYTFTDYGMY


 


2588
CL-34475
CDR-H2
WIDTETGEPTYADDFKG


 


2589
CL-34475
CDR-H3
TNYYYSSYMFYFDY


 


2590
CL-34475 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY





QQKPGQAPRLLIYGASNLESGIPARFSGSGSGTDFT





LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK


 


2591
CL-34475
CDR-L1
RASQSVSTHMH


 


2592
CL-34475
CDR-L2
GASNLES


 


2593
CL-34475
CDR-L3
QQSWYDPLT


 


2594
CL-34483 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYW





VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF





YFDYWGQGTMVTVSS


 


2595
CL-34483
CDR-H1
GYTFPNYGMY


 


2596
CL-34483
CDR-H2
WIDTETGEPTYADDFKG


 


2597
CL-34483
CDR-H3
TNYYYRSYMFYFDY


 


2598
CL-34483 VL

EIVLTQSPATLSLSPGERATLSCRASQSVATHMHWY





QQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK


 


2599
CL-34483
CDR-L1
RASQSVATHMH


 


2600
CL-34483
CDR-L2
GASNLES


 


2601
CL-34483
CDR-L3
QQSWYDPLT


 


2602
CL-34489 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYW





VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYSSYMF





YFDYWGQGTMVTVSS


 


2603
CL-34489
CDR-H1
GYTFSNYGMY


 


2604
CL-34489
CDR-H2
WIDTETGEPTYADDFKG


 


2605
CL-34489
CDR-H3
TNYYYSSYMFYFDY


 


2606
CL-34489 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY





QQKPGQAPRLLIYGASNLESGIPARFSGSGSGTDFT





LTISSLEPEDFAVYFCQQSWYDPLTFGQGTKLEIK


 


2607
CL-34489
CDR-L1
RASQSVSTHMH


 


2608
CL-34489
CDR-L2
GASNLES


 


2609
CL-34489
CDR-L3
QQSWYDPLT


 


2610
CL-34501 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYW





VRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYPSYMF





YFDYWGQGTMVTVSS


 


2611
CL-34501
CDR-H1
GYTFSDYGMY


 


2612
CL-34501
CDR-H2
WIDTETGDPTYADDFKG


 


2613
CL-34501
CDR-H3
TNYYYPSYMFYFDY


 


2614
CL-34501 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY





QQKPGQAPRLLIYGASILESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYFCQQTWYDPLTFGQGTKLEIK


 


2615
CL-34501
CDR-L1
RASQSVSTHMH


 


2616
CL-34501
CDR-L2
GASILES


 


2617
CL-34501
CDR-L3
QQTWYDPLT


 


2618
CL-34513 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW





VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRGYMF





YFDYWGQGTMVTVSS


 


2619
CL-34513
CDR-H1
GYTFTDYGMY


 


2620
CL-34513
CDR-H2
WIDTETGEPTYADDFKG


 


2621
CL-34513
CDR-H3
TNYYYRGYMFYFDY


 


2622
CL-34513 VL

EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWY





QQKPGQAPRLLIYGASILESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYFCQQSWYDPLTFGQGTKLEIK


 


2623
CL-34513
CDR-L1
RASQSVNNHMH


 


2624
CL-34513
CDR-L2
GASILES


 


2625
CL-34513
CDR-L3
QQSWYDPLT


 


2626
CL-34518 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYW





VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYKSYMF





YFDYWGQGTMVTVSS


 


2627
CL-34518
CDR-H1
GYTFTNYGMY


 


2628
CL-34518
CDR-H2
WIDTETGEPTYADDFKG


 


2629
CL-34518
CDR-H3
TNYYYKSYMFYFDY


 


2630
CL-34518 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY





QQKPGQAPRLLIYGASKLESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK


 


2631
CL-34518
CDR-L1
RASQSVSTHMH


 


2632
CL-34518
CDR-L2
GASKLES


 


2633
CL-34518
CDR-L3
QQSWYDPLT


 


2634
CL-34522 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFENYGMYW





VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYSSYMF





YFDYWGQGTMVTVSS


 


2635
CL-34522
CDR-H1
GYTFENYGMY


 


2636
CL-34522
CDR-H2
WIDTETGEPTYADDFKG


 


2637
CL-34522
CDR-H3
TNYYYSSYMFYFDY


 


2638
CL-34522 VL

EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWY





QQKPGQAPRLLIYGASKLESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK


 


2639
CL-34522
CDR-L1
RASQSVGTHMH


 


2640
CL-34522
CDR-L2
GASKLES


 


2641
CL-34522
CDR-L3
QQSWYDPLT


 


2642
CL-34537 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYW





VRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARANYYYRSYMF





YFDYWGQGTMVTVSS


 


2643
CL-34537
CDR-H1
GYTFSDYGMY


 


2644
CL-34537
CDR-H2
WIDTETGDPTYADDFKG


 


2645
CL-34537
CDR-H3
ANYYYRSYMFYFDY


 


2646
CL-34537 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY





QQKPGQAPRLLIYGASNLESGIPARFSGSGSGTDFT





LTISSLEPEDFAVYFCQQSWYDPMTFGQGTKLEIK


 


2647
CL-34537
CDR-L1
RASQSVSTHMH


 


2648
CL-34537
CDR-L2
GASNLES


 


2649
CL-34537
CDR-L3
QQSWYDPMT


 


2650
CL-34538 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW





VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYPSYMF





YFDYWGQGTMVTVSS


 


2651
CL-34538
CDR-H1
GYTFTDYGMY


 


2652
CL-34538
CDR-H2
WIDTETGEPTYADDFKG


 


2653
CL-34538
CDR-H3
TNYYYPSYMFYFDY


 


2654
CL-34538 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY





QQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYFCQQTWYDPLTFGQGTKLEIK


 


2655
CL-34538
CDR-L1
RASQSVSTHMH


 


2656
CL-34538
CDR-L2
GASNLES


 


2657
CL-34538
CDR-L3
QQTWYDPLT


 


2658
CL-34540 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW





VRQAPGQGLEWMGWIDTETGQPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF





YFDYWGQGTMVTVSS


 


2659
CL-34540
CDR-H1
GYTFTDYGMY


 


2660
CL-34540
CDR-H2
WIDTETGQPTYADDFKG


 


2661
CL-34540
CDR-H3
TNYYYRSYMFYFDY


 


2662
CL-34540 VL

EIVLTQSPATLSLSPGERATLSCRASESVGKHMHWY





QQKPGQAPRLLIYAASNLESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK


 


2663
CL-34540
CDR-L1
RASESVGKHMH


 


2664
CL-34540
CDR-L2
AASNLES


 


2665
CL-34540
CDR-L3
QQSWYDPLT


 


2666
CL-34565 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW





VRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRNYMF





YFDYWGQGTMVTVSS


 


2667
CL-34565
CDR-H1
GYTFTDYGMY


 


2668
CL-34565
CDR-H2
WIDTETGDPTYADDFKG


 


2669
CL-34565
CDR-H3
TNYYYRNYMFYFDY


 


2670
CL-34565 VL

EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWY





QQKPGQAPRLLIYGASILESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIK


 


2671
CL-34565
CDR-L1
RASQSVSNHMH


 


2672
CL-34565
CDR-L2
GASILES


 


2673
CL-34565
CDR-L3
QQSWYDPIT


 


2674
CL-34570 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFDDYGMYW





VRQAPGQGLEWMGWIDTETGTPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYSSYMF





YFDYWGQGTMVTVSS


 


2675
CL-34570
CDR-H1
GYTFDDYGMY


 


2676
CL-34570
CDR-H2
WIDTETGTPTYADDFKG


 


2677
CL-34570
CDR-H3
TNYYYSSYMFYFDY


 


2678
CL-34570 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY





QQKPGQAPRLLIYGASNLESGIPARFSGSGSGTDFT





LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK


 


2679
CL-34570
CDR-L1
RASQSVSTHMH


 


2680
CL-34570
CDR-L2
GASNLES


 


2681
CL-34570
CDR-L3
QQSWYDPLT


 


2682
CL-34603 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW





VRQAPGQGLEWMGWIDTETGEPTYAQGFTGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF





YFDYWGQGTMVTVSS


 


2683
CL-34603
CDR-H1
GYTFTDYGMY


 


2684
CL-34603
CDR-H2
WIDTETGEPTYAQGFTG


 


2685
CL-34603
CDR-H3
TNYYYRSYMFYFDY


 


2686
CL-34603 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY





QQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYYCQQTWYDPLTFGQGTKLEIK


 


2687
CL-34603
CDR-L1
RASQSVSTHMH


 


2688
CL-34603
CDR-L2
GASNLES


 


2689
CL-34603
CDR-L3
QQTWYDPLT


 


2690
CL-34605 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYW





VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF





YFDYWGQGTMVTVSS


 


2691
CL-34605
CDR-H1
GYTFTHYGMY


 


2692
CL-34605
CDR-H2
WIDTETGEPTYADDFKG


 


2693
CL-34605
CDR-H3
TNYYYRSYMFYFDY


 


2694
CL-34605 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY





QQKPGQAPRLLIYGASNLESGIPARFSGSGSGTDFT





LTISSLEPEDFAVYYCQQSFYDPLTFGQGTKLEIK


 


2695
CL-34605
CDR-L1
RASQSVSTHMH


 


2696
CL-34605
CDR-L2
GASNLES


 


2697
CL-34605
CDR-L3
QQSFYDPLT


 


2698
CL-34633 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYW





VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL





DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF





YFDYWGQGTMVTVSS


 


2699
CL-34633
CDR-H1
GYTFSDYGMY


 


2700
CL-34633
CDR-H2
WIDTETGEPTYADDFKG


 


2701
CL-34633
CDR-H3
TNYYYRSYMFYFDY


 


2702
CL-34633 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY





QQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFT





LTISSLEPEDFAVYFCQQSWYDPLTFGQGTKLEIK


 


2703
CL-34633
CDR-L1
RASQSVSTHMH


 


2704
CL-34633
CDR-L2
GASNLES


 


2705
CL-34633
CDR-L3
QQSWYDPLT
















TABLE 43







Summary of Protein Expression and Purification Affinity


Matured Humanized Anti-Human VEGF-A Antibodies












Yield
SEC (%



Name
(mg/L)1
monomer)2















CL-32416-IgG
28.5
100.0



CL-34449-IgG
16.1
100.0



CL-34455-IgG
34.1
100.0



CL-34469-IgG
21.3
100.0



CL-34475-IgG
33.6
100.0



CL-34522-IgG
18.4
100.0



CL-34538-IgG
40.8
100.0



CL-34540-IgG
80.0
100.0



CL-34565-IgG
133.6
100.0



CL-34570-IgG
28.3
100.0



CL-34633-IgG
49.9
100.0







1Yield is determined by the total amount of purified protein in mg divided by the total cell culture volume in liters.



2SEC % monomer is determined using HPLC size exclusion chromatography.













TABLE 44







Biacore Binding of Affinity Matured Humanized


Anti-VEGF Antibodies












Antibody
kon (M−1 s−1)
koff (M−1)
KD (M)







CL-28815-IgG
9.2E+06
1.1E−04
1.2E−11



(El version of



parent mAb)



CL-32416-IgG
2.0E+07
1.1E−05
5.4E−13



CL-34449-IgG
1.1E+07
9.1E−06
8.5E−13



CL-34455-IgG
2.2E+07
1.0E−05
4.6E−13



CL-34469-IgG
1.5E+07
9.5E−06
6.2E−13



CL-34475-IgG
2.7E+07
1.4E−05
5.2E−13



CL-34522-IgG
2.0E+07
1.0E−05
5.3E−13



CL-34538-IgG
3.3E+07
8.1E−06
2.4E−13



CL-34540-IgG
8.4E+06
7.1E−06
8.5E−13



CL-34565-IgG
2.0E+07
7.8E−06
4.0E−13



CL-34570-IgG
1.9E+07
5.5E−06
2.9E−13



CL-34633-IgG
1.7E+07
4.1E−06
2.4E−13










Affinity matured humanized anti-VEGF antibodies were characterized for hVEGF165 binding and potency. Binding affinity of these molecules to hVEGF165 was determined by Biacore analysis (Example 1.1). Potency was evaluated in both cell-based and ELISA formats. The ability to block binding of hVEGF165 to hVEGFR2 was evaluated in a competition ELISA (Example 1.4) Inhibition of hVEGF165-induced cell proliferation was assessed using HMVEC-d cells (Example 1.10). The data is summarized in Table 45 below.







TABLE 45







Summary of Characterization of Affinity Matured Humanized


Anti-Human VEGF-A Antibodies









hVEGF165 IC50 (nM)










Affinity Matured
VEGFR2
Potency
Potency


Humanized IgG
Competition
HMVEC-d
VEGFR2-3T3













CL-32416-IgG
<0.1
0.117
NT


CL-34449-IgG
<0.1
0.077
NT


CL-34455-IgG
<0.1
0.105
NT


CL-34469-IgG
<0.1
0.094
NT


CL-34475-IgG
<0.1
0.106
NT


CL-34522-IgG
<0.1
0.116
NT


CL-34540-IgG
<0.1
0.139
NT


CL-34633-IgG
<0.1
0.138
NT


CL-34538-IgG
<0.1
0.127
NT


CL-34570-IgG
<0.1
0.11
NT


CL-34565-IgG
<0.1
0.126
NT









Example 8: Affinity Maturation of Anti-Human PDGF-BB Antibody hBDI-9E8
The PDGF-β antibody hBDI-9E8.4 was obtained from rat hybridomas generated at Aldevron and was humanized at AbbVie Bioresearch Center (100 Research Drive, Worcester, Mass. 01605). The human germlines for this clone are VH2-70 and IGKV3-20. To improve the affinity of hBDI-9E8.4, hypermutated CDR residues were identified from other human antibody sequences in the IgBLAST database that also shared high identity to germlines VHVH2-70 and IGKV3-20. The corresponding h9E8.4 CDR residues were then subjected to limited mutagenesis by PCR with primers having low degeneracy at these positions to create three antibody libraries in the scFv format suitable for surface display. To improve the affinity of hBDI-9E8.4 to PDGFβ we generated three antibody libraries in scFv format suitable for surface display. In the first library, residues 30, 32, 34, 35, and 35b in the VH CDR1 and residues 50, 52, 54, 56, 57, 58, 60, 61 and 65 (Kabat numbering) in the VH CDR2 were subjected to limited mutagenesis by primers. In the second library residues 95-100a, 100c and 102 (Kabat numbering) in the VH CDR3 were subjected to limited mutagenesis by primers. In the third library residues 24, 25, 27b, and 29-32 in the VL CDR1, residues 47, 50, 51, 53, 55, and 56 in the VL CDR2 and residues 90, 93-95a, 96 and 97 (Kabat numbering) in the VL CDR3 were subjected to limited mutagenesis by primers.
These hBDI-9E8.4 libraries were displayed to be selected against a low concentration of biotinylated PDGFβ by magnetic then fluorescence activated cell sorting. Selections for improved on-rate, off-rate, or both were carried out and antibody protein sequences of affinity-modulated hBDI-9E8.4 clones.
Table 46 provides a list of amino acid sequences of VH regions of affinity matured humanized PDGF antibodies derived from hBDI-9E8.4. Amino acid residues of individual CDRs of each VH sequence are indicated in bold.







TABLE 46







List of amino Acid Sequences Of Affinity Matured


hBDI-9E8.4 VH Variants









Clone
SEQ ID NO:
VH





CL-22556
2706
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVGVGWIRQPPGK




ALEWLANIWWVDEIFYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22557
2707
EVTLRESGPALVKPTQTLTLTCTFSGFSLWTSGMGVVWIRQPPGK




ALEWLALIDWADVKSYNPSLKNRLTISEDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22558
2708
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVSVGWIRQPPGK




ALEWLALIDWYDDMYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22559
2709
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVRVVWIRQPPGK




ALEWLANIWWDDYLDYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22560
2710
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMSVGWIRQPPGK




ALEWLALIDWADDTYYNPSLNNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22561
2711
EVTLRESGPALVKPTQTLTLTCTFSGFSLATYGMSVAWIRQPPGK




ALEWLALIDWYDDEYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22562
2712
EVTLRESGPALVKPTQTLTLTCTFSGFSLXTYGVGVGWIRQPPGK




ALEWLANIWWVDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22563
2713
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGK




ALEWLALIDWADDKYYNPSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22564
2714
EVTLRESGPALVKPTQTLTLTCTFSGFSLCTSGVRVRWIRQPPGK




ALEWLALIDWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22565
2715
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGK




ALEWLANIWWDDNXYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22567
2716
EVTLRESGPALVKPTQTLTLTCTFSGFSLATSGVSVGWIRQPPGK




ALEWLALIDWEDDKGYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22569
2717
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMRVGWIRQPPGK




ALEWLALIDWDDHKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22570
2718
EVTLRESGPALVKPTQTLTLTCTFSGFSLCTSGVGVGWIRQPPGK




ALEWLALIDWDDDNYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22571
2719
EVTLRESGPALVKPTQTLTLTCTFSGFSLFTYGMGVGWIRQPPGK




ALEWLALIDWVDDKFYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22572
2720
EVTLRESGPALVKPTQTLTLTCTFSGFSLCTSGVGVGWIRQPPGK




ALEWLANIWWDDDRYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22573
2721
EVTLRESGPALVKPTQTLTLTCTFSGFSLCTSGMSVGWIRQPPGK




ALEWLALICWDDDRYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22575
2722
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMRVGWIRQPPGK




ALEWLALIDWGDDMSYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22576
2723
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK




ALEWLALIDWEDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22578
2724
EVTLRESGPALVKPTQTLTLTCTFSGFSLLTYGVGVCWIRQPPGK




ALEGWLNIWWADGKCYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22581
2725
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVRVSWIRQPPGK




ALEWLALIDWDDEECYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22582
2726
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMSVSWIRQPPGK




ALEWLALIDWVDDMGYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22583
2727
EVTLRESGPALVKPTQTLTLTCTFSGFSLXTYGMGVGWIRQPPGK




ALEWLALIDWADYRSYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22584
2728
EVTLRESGPALVKPTQTLTLTCTFSGFSLATYGVGVGWIRQPPGK




ALEWLALIDWEDAVNYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22585
2729
EVTLRESGPALVKPTQTLTLTCTFSGFSLCTYGMGVCWIRQPPGK




ALEWLALIGWDDENYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22586
2730
EVTLRESGPALVKPTQTLTLTCTFSGFSLTTYGVRVGWIRQPPGK




ALEWLALIDWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22587
2731
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMSVCWIRQPPGK




ALEWLANIWWDDGCCYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22588
2732
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMRVGWIRQPPGK




ALEWLALIDWCDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22589
2733
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVSWIRQPPGK




ALEWLALIDWDDHXHYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22591
2734
EVTLRESGPALVKPTQTLTLTCTFSGFSLWTSGVGVGWIRQPPGK




ALEWLALIDWEDNKDYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22593
2735
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVRVGWIRQPPGK




ALEWLALIDWVDDMYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22595
2736
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVEWIRQPPGK




ALEWLALIDWDDDKDYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22596
2737
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK




ALEWLALIDWCDNRYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22597
2738
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMRVGWIRQPPGK




ALEWLALIDWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22598
2739
EVTLRESGPALVKPTQTLTLTCTFSGFSLRTYGVSVGWIRQPPGK




ALEWLALIDWYDGKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22599
2740
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVDWIRQPPGK




ALEWLALIDWEDDKSYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22600
2741
EVTLRESGPALVKPTQTLTLTCTFSGFSLWTYGVSVRWIRQPPGK




ALEWLALIDWDDVKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22601
2742
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGK




ALEWLALIDWDDDKFYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22602
2743
EVTLRESGPALVKPTQTLTLTCTFSGFSLPTYGVRVGWIRQPPGK




ALEWLANIWWVDNKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22603
2744
EVTLRESGPALVKPTQTLTLTCTFSGFSLXTSGVRVGWIRQPPGK




ALEWLALIDWDDYQYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22604
2745
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVSVGWIRQPPGK




ALEWLANIWWYDLKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22605
2746
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVGVGWIRQPPGK




ALEWLALIDWDDDKCYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22606
2747
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVGWIRQPPGK




ALEWLANIWWDDEKAYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22607
2748
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVSWIRQPPGK




ALEWLALIDWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22608
2749
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLALIDWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22609
2750
EVTLRESGPALVKPTQTLTLTCTFSGFSLPTSGVSVGWIRQPPGK




ALEWLANIWWADSKFYSTSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22610
2751
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVSVDWIRQPPGK




ALEWLALIDWGDQTNYNPSLKNRLTISKDTSKNQVVXTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22611
2752
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVGVEWIRQPPGK




ALEWLALIDWYDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22612
2753
EVTLRESGPALVKPTQTLTLTCTFSGFSLPTSGVGVGWIRQPPGK




ALEWLALIDWEDHMDYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22614
2754
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMRVGWIRQPPGK




ALEWLALIDWXDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22615
2755
EVTLRESGPALVKPTQTLTLTCTFSGFSLTTSGVGVGWIRQPPGK




ALEWLALIDWYDERFYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22617
2756
EVTLRESGPALVKPTQTLTLTXTFSGFSLSTYGMRVGWIRQPPGK




ALEWLANIWWADNXSYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22618
2757
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMSVGWIRQPPGK




ALEWLALIDWADDNYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22619
2758
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVGWIRQPPGK




ALEWLALIDWEDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22620
2759
EVTLRESGPALVKPTQTLTLTCTFSGFSLWTSGMGVGWIRQPPGK




ALEWLALIDWDDEKAYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22621
2760
EVTLRESGPALVKPTQTLTLTCTFSGFSLWTSGMRVGWIRQPPGK




ALEWLANIWWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22622
2761
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVSVGWIRQPPGK




ALEWLALIDWHDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22624
2762
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMSVGWIRQPPGK




ALEWLALIDWNDNKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22625
2763
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGK




ALEWLALIDWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22626
2764
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVRVCWIRQPPGK




ALEWLALIDWDDDKSYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22627
2765
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVSVTWIRQPPGK




ALEWLALIDWNDDNHYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22628
2766
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVVWIRQPPGK




ALEWLANIWWDDEKCYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22629
2767
EVTLRESGPALVKPTQTLTLTCTFTGFSLYTSGMGVGWIRQPPGK




ALEWLALIDWDDDKNYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22630
2768
EVTLRESGPALVKPTQTLTLTCTFSGFSLFTYGVGVDWIRQPPGK




ALEWLANIWWPDDNYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22631
2769
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGK




ALEWLALIDWDDDXCYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22633
2770
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVSVGWIRQPPGK




ALEWLALIDWDDEKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22634
2771
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGK




ALEWLALIDWIDDEDYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22635
2772
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVRWIRQPPGK




ALEWLANIWWDDNKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22636
2773
EVTLRESGPALVKPTQTLTLTCTFSGFSLCTSGMGVGWIRQPPGK




ALEWLANIWWDDDNYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22637
2774
EVTLRESGPALVKPTQTLTLTCTFSGFSLLTYGMGVGWIRQPPGK




ALEWLANIWWHDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22638
2775
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVAWIRQPPGK




ALEWLANIWWDDDKYYSTSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22639
2776
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVRVGWIRQPPGK




ALEWLALIDWEDYLCYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22640
2777
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGK




ALEWLALIDWDDDYYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22641
2778
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22642
2779
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK




ALEWLANIWWVDDNYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22643
2780
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVYWIRQPPGK




ALEWLALIDWDDDNYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22644
2781
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVGWIRQPPGK




ALEWLALIDWDDGKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22645
2782
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVRVVWIRQPPGK




ALEWLALIDWNDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22646
2783
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVVWIRQPPGK




ALEWLANIWWHDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22648
2784
EVTLRESGPALVKPTQTLTLTCTFSGFSLMTSGMSVCWIRQPPGK




ALEWLANIWWYDHKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22649
2785
EVTLRESGPALVKPTQTLTLTCTFSGFSLRTYGVSVGWIRQPPGK




ALEWLANIWWDDAKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22650
2786
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVRVAWIRQPPGK




ALEWLANIWWDDVKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22651
2787
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIAASYSFDYWGQGTMVTVSS


 


CL-22652
2788
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARFEYLGAMYXFDYWGQGTMVTVSS


 


CL-22653
2789
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARXDSFRKPYSFDYWGQGTMVTVSS


 


CL-22654
2790
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIXSIGSTYWFDYWGQGTMVTVSS


 


CL-22655
2791
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARLVSIVTKYSFDYWGQGTMVTVSS


 


CL-22656
2792
XVTLXESGPALXKPTXTLTLTCTFSGFXLSTXGMGVGWIRQPPRK




ALXWLANXWWDDDKYYNPSLXNRLXISKDTSKNQVVLTMTNMDPV




DTAXYYCARXXXXXMXYSFDYWGQGTMVTXSX


 


CL-22658
2793
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARLEPIPMTYSFDYWGQGTMVTVSS


 


CL-22659
2794
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIEWSAITYSFDYWGQGTMVTVSS


 


CL-22660
2795
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIECTXNRYXFDYWGQGTMVTVSS


 


CL-22661
2796
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIECNSTTYSFDYWGQGTMVTVSS


 


CL-22664
2797
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARLASLCATYYFDYWGQGTMVTVSS


 


CL-22665
2798
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIGWRLRMYSFDYWGQGTMVTVSS


 


CL-22666
2799
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIVSIGGTYSFDYWGQGTMVTVSS


 


CL-22668
2800
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARVESIGTTYYFDYWGQGTMVTVSS


 


CL-22669
2801
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARYAPIGTTYWFDYWGQGTMVTVSS


 


CL-22670
2802
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTRTTYLFDYWGQGTMVTVSS


 


CL-22671
2803
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTGTAYSFDYWGQGTMVTVSS


 


CL-22672
2804
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIASVGTSYSFDYWGQGTMVTVSS


 


CL-22673
2805
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCAREESTCPTYYFDYWGQGTMVTVSS


 


CL-22675
2806
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARTESIDRAYSFDYWGQGTMVTVSS


 


CL-22677
2807
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIGSTGISYSFDYWGQGTMVTVSS


 


CL-22678
2808
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARRESIGTTYSFDYWGQGTMVTVSS


 


CL-22679
2809
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARKVTIETAYYFDYWGQGTMVTVSS


 


CL-22680
2810
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATXYCARFASIGTTYSFDYWGQGTMVTVSS


 


CL-22681
2811
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARMKSIATTYSFDYWGQGTMVTVSS


 


CL-22682
2812
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESRRATYSFDYWGQGTMVTVSS


 


CL-22683
2813
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIGXIGSAYTFDYWGQGTMVTVSS


 


CL-22685
2814
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARTGSGVTTYSFDYWGQGTMVTVSS


 


CL-22688
2815
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIGSIESAYSFDYWGQGTMVTVSS


 


CL-22689
2816
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARVYSKGTTYSFDYWGQGTMVTVSS


 


CL-22691
2817
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARFEALGLSYSFDYWGQGTMVTVSS


 


CL-22692
2818
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATXYCARRGTIRTTYSFDYWGQGTMVTVSS


 


CL-22694
2819
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIYWIGPTYCFDYWGQGTMVTVSS


 


CL-22695
2820
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESMRTTYSFDYWGQGTMVTVSS


 


CL-22696
2821
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIRSIVTTYSFDYWGQGTMVTVSS


 


CL-22698
2822
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARTQSSAMTYSFDYWGQGTMVTVSS


 


CL-22702
2823
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARNESMGTSYSFDYWGQGTMVTVSS


 


CL-22703
2824
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIEFVRAIYSFDYWGQGTMVTVSS


 


CL-22704
2825
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARFESLGETYSFDYWGQGTMVTVSS


 


CL-22705
2826
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIEAIGNQYSFDYWGQGTMVTVSS


 


CL-22706
2827
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARKDSMVTTYLFDYWGQGTMVTVSS


 


CL-22707
2828
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARVEWQGSTYSFDYWGQGTMVTVSS


 


CL-22708
2829
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYMFDYWGQGTMVTVSS


 


CL-22709
2830
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARCASVSTTYCFDYWGQGTMVTVSS


 


CL-22710
2831
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARILSIGNTYSFDYWGQGTMVTVSS


 


CL-22711
2832
EVTLRESGPALVKPTQTLTLTCTFFGFSLSTYGMGVGWIRQPPGK




ALEWLANIWCDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESNGNTYSFDYWGQGTMVTVSS


 


CL-22712
2833
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARRDSTGTPYSFDYWGQGTMVTVSS


 


CL-22713
2834
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARVESIVTTYYFDYWGQGTMVTVSS


 


CL-22714
2835
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARLEKFGRTYPFDYWGQGTMVTVSS


 


CL-22715
2836
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARFKSNRPSYSFDYWGQGTMVTVSS


 


CL-22716
2837
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSXKNRLXISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLDTTYXFDXXGQGXMXTVSS


 


CL-22717
2838
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIXATGMLYSFDYWGQGTMVTVSS


 


CL-22718
2839
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIETTYXFDYWGQGTMVTVSS


 


CL-22719
2840
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIEXMAPMYSFDYWGQGTMVTVSS


 


CL-22720
2841
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARVRPLVTIYSFDYWGQGTMVTVSS


 


CL-22721
2842
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIDSVWTTYSFDYWGQGTMVTVSS


 


CL-22722
2843
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARVEEIGNTYNFDYWGQGTMVTVSS


 


CL-22723
2844
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARRGLFRIRYSFDYWGQGTMVTVSS


 


CL-22724
2845
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRXTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22725
2846
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIEVIGTAYSFDYWGQGTMVTVSS


 


CL-22726
2847
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARLDVIGMLYAFDYWGQGTMVTVSS


 


CL-22728
2848
EVTLRESGPALVKPTKTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIMSIGSSYXFDYWGQGTMVTVSS


 


CL-22729
2849
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIDWIGTTYSFDYWGQGTMVTVSS


 


CL-22730
2850
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARNSSIGSTYSFDYWGQGTMVTVSS


 


CL-22731
2851
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESPGTWYSFDYWGQGTMVTVSS


 


CL-22732
2852
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIEWIGITYCFDYWGQGTMVTVSS


 


CL-22733
2853
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIEXLGTTYSFDYWGQGTMVTVSS


 


CL-22734
2854
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARKELTCSTYSFDYWGQGTMVTVSS


 


CL-22736
2855
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIEXIRMRYSFDYWGQGTMVTVSS


 


CL-22737
2856
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARKAAIATLYLFDYWGQGTMVTVSS


 


CL-22738
2857
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARRRPIVTTYSFDYWGQGTMVTVSS


 


CL-22740
2858
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTVYSFDYWGQGTMVTVSS


 


CL-22741
2859
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIASIGSMYSFDYWGQGTMVTVSS


 


CL-22742
2860
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESRATTYSFDYWGQGTMVTVSS


 


CL-22743
2861
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARNVWLGTTYSFDYWGQGTMVTVSS


 


CL-22744
2862
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIMSIGTAYSFDYWGQGTMVTVSS


 


CL-22745
2863
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIKWIWTTYSFDYWGQGTMVTVSS


 


CL-22746
2864
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIEXRGSTYIFDYWGQGTMVTVSS


 


CL-22759
2865
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCXRIESIGTTYSFDYWGQGTMVTVSS


 


CL-22763
2866
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNXDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-22806
2867
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYXFXYWGQGTMVTVSS


 


CL-22812
2868
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATXYCARIESIGTTYSFDYXGQGTMVTVSS


 


CL-22819
2869
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCAXIESIGTTYSFDYWGQGTMVTVSS


 


CL-22833
2870
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYXCARIESIGTTYSXDYWGQGTXVTVSS


 


CL-25629
2871
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRKPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25633
2872
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNVDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25645
2873
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ELEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25649
2874
EVTLRESGPALVKPTQTLTLTCTFSGFSLATSGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25656
2875
EVTLRESGPALVKPTQTLTLTCTFSGFRLSTYGMGVGWIRKPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25657
2876
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTANYYCARIASIPTMYAFDYWGQGTMVTVSS


 


CL-25676
2877
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWMANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25679
2878
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDHDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25684
2879
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25696
2880
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVGVGWIRQPPGK




ALEWLANIWWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25697
2881
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRKPPGK




ALEWLANIWWDDDKYYNPSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25699
2882
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK




ALEWLANIWWDDDRYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25700
2883
EVTLRESGPALVKPTQTLTLTCTFSGFSLMTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25702
2884
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNTSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25710
2885
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLENIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25738
2886
EVTLKKSGPALVKPXQTLTLTCTFSGFSLSTYGMGVGWIRXPPGK




GLEWLANIWWDDDKYYNPSLKNRLTIXKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25739
2887
EVTLKESGPALVKPTXTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25745
2888
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSX


 


CL-25749
2889
EVTLRESGPALVKPTXTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25755
2890
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARMKSIGSTYSFDYWGQGTMVTVSS


 


CL-25763
2891
EVTLKESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25765
2892
EVTLRESGPALVKPTXTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGXMVTVSS


 


CL-25769
2893
EVTLKESGPALVKPTXTLTLTCTFSGFSLSTYGMGVGWIRHPPGK




ALEWLANIWWNNDNYYNPSLKNRLTINKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25773
2894
EVTLKESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEGLANIWWDDDKYYNPSLKNRLTINKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25789
2895
EVTLRESGPALVKPTHTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25791
2896
EVTLKESGPALVKPTQTLTLTCTFSGFRLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25797
2897
EVTLXESGPALVKPTXTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-25815
2898
EVTLKESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTINKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-28144
2899
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESGWTTYSFDYWGQGTMVTVSS


 


CL-28145
2900
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIWTSYSFDYWGQGTMVTVSS


 


CL-28146
2901
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIVSSWTIYSFDYWGQGTMVTVSS


 


CL-28147
2902
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIYSSGTVYSFDYWGQGTMVTVSS


 


CL-28148
2903
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGISYSFDYWGQGTMVTVSS


 


CL-28149
2904
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTGTSYSFDYWGQGTMVTVSS


 


CL-28151
2905
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGPSYSFDYWGQGTMVTVSS


 


CL-28152
2906
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGSSYSFDYWGQGTMVTVSS


 


CL-28155
2907
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIVSIGWSYSFDYWGQGTMVTVSS


 


CL-28156
2908
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIYSDWTIYSFDYWGQGTMVTVSS


 


CL-28157
2909
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWITYSFDYWGQGTMVTVSS


 


CL-28160
2910
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESEWTTYNFDYWGQGTMVTVSS


 


CL-28161
2911
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSPTTYSFDYWGQGTMVTVSS


 


CL-28162
2912
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGISYSFDYWGQGTMVTVSS


 


CL-28163
2913
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSATIYSFDYWGQGTMVTVSS


 


CL-28164
2914
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTGTTYSFDYWGQGTMVTVSS


 


CL-28167
2915
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTSYSFDYWGQGTMVTVSS


 


CL-28169
2916
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIVSTWTTYSFDYWGQGTMVTVSS


 


CL-28170
2917
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGTSYNFDYWGQGTMVTVSS


 


CL-28173
2918
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTWWTYSFDYWGQGTMVTVSS


 


CL-28175
2919
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSGWSYAFDYWGQGTMVTVSS


 


CL-28177
2920
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGYSYSFDYWGQGTMVTVSS


 


CL-28180
2921
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWMANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIETLGISYSFDYWGQGTMVTVSS


 


CL-28181
2922
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESMWSSYSFDYWGQGTMVTVSS


 


CL-28182
2923
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIETIGTSYSFDYWGQGTMVTVSS


 


CL-28186
2924
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIVSDVTTYSFDYWGQGTMVTVSS


 


CL-28187
2925
EVTLRESGPALVKPTKTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESFGTSYSFDYWGQGTMVTVSS


 


CL-28189
2926
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIKSIGWTYSFDYWGQGTMVTVSS


 


CL-28190
2927
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESNFWSYSFDYWGQGTMVTVSS


 


CL-28195
2928
EVTLRESGPALVKPTHTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIMSLETRYDFYYWGQGTMVTVSS


 


CL-28196
2929
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESVETSYNFDYWGQGTMVTVSS


 


CL-28198
2930
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESFWTTYSFDYWGQGTMVTVSS


 


CL-28204
2931
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESMGTSYSFDYWGQGTMVTVSS


 


CL-28205
2932
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIWSSYSFDYWGQGTMVTVSS


 


CL-28208
2933
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGFSYSFDYWGQGTMVTVSS


 


CL-28212
2934
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESVGPSYSFDYWGQGTMVTVSS


 


CL-28213
2935
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGWTYSFDYWGQGTMVTVSS


 


CL-28215
2936
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESDWTTYSFDYWGQGTMVTVSS


 


CL-28219
2937
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGPSYSFDYWGQGTMVTVSS


 


CL-28233
2938
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLVTSYDFDYWGQGTMVTVSS


 


CL-28235
2939
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESVGTSYNFDYWGQGTMVTVSS


 


CL-29595
2940
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTEASYSFDYWGQGTMVTVSS


 


CL-29596
2941
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESNGASYSFDYWGQGTMVTVSS


 


CL-29597
2942
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSVTTYSFDYWGQGTMVTVSS


 


CL-29598
2943
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDNYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARXESXWTSYSFDYWGQGTMVTVSS


 


CL-29600
2944
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGASYSFDYWGQGTMVTVSS


 


CL-29601
2945
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTGRSYGFDYWGQGTMVTVSS


 


CL-29607
2946
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIETLGTSYSFDYWGQGTMVTVSS


 


CL-29608
2947
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGTTYSFDYWGQGTMVTVSS


 


CL-29611
2948
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIPTAYSFDYWGQGTMVTVSS


 


CL-29612
2949
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGTTYSFDYWGQGTMVTVSS


 


CL-29613
2950
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARLESIATTYSFDYWGQGTMVTVSS


 


CL-29614
2951
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGPSYSFDYWGHGTMVTVSS


 


CL-29617
2952
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSYTSYSFDYWGQGTMVTVSS


 


CL-29618
2953
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTWTSYSFDYWGQGTMVTVSS


 


CL-29620
2954
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSVTNYQFDYWGQGTMVTVSS


 


CL-29621
2955
EVTLRESGPALVKPTQTLTLICTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTSYSFDYWGQGTMVTVSS


 


CL-29625
2956
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGPAYSFDYWGQGTMVTVSS


 


CL-29627
2957
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSNNQVVLTMTNMDPV




DTATYYCARIESFGSSYSFDYWGQGTMVTVSS


 


CL-29629
2958
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSETTYTFDYWGQGTMVTVSS


 


CL-29630
2959
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIWTTYSFDYWGQGTMVTVSS


 


CL-29631
2960
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNLLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESFGTSYSFDYWGQGTMVTVSS


 


CL-29632
2961
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIASXGTSYSFDYWGQGTMVTVSS


 


CL-29634
2962
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDEKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTSYSFDYWGQGTMVTVSS


 


CL-29635
2963
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSPTSYSFDYWGQGTMVTVSS


 


CL-29636
2964
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGWSYAFDYWGQGTMVTVSS


 


CL-29637
2965
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGWTYSFDYWGQGTMVTVSS


 


CL-29638
2966
EVTLRESGPALVKPTQTLTLTCTFSGFSLATSGVSVLWIRQPPGK




ALEWLANIWWDDGXYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESFGTSYSFDYWGQGTMVTVSS


 


CL-29639
2967
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLWTTYSFDYWGQGTMVTVSS


 


CL-29643
2968
EVTLRESGPALVKPTQTLTLTCTFSGFSLDTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSGYTYSFDYWGQGTMVTVSS


 


CL-29644
2969
EVTLRESGPALVKPTQTLTLTCTFSGFSLTTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSGSSYSFDYWGQGTMVTVSS


 


CL-29645
2970
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARVASSWVEYSFDYWGQGTMVTVSS


 


CL-29647
2971
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESFGTSYSFDYWGQGTMVTVSS


 


CL-29648
2972
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSGTTYSFDYWGQGTMVTVSS


 


CL-29649
2973
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRKPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESMGISYSFDYWGQGTMVTVSS


 


CL-29651
2974
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGIAYSFDYWGQGTMVTVSS


 


CL-29654
2975
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIXWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIVTTYSFDYWGQGTMVTVSS


 


CL-29658
2976
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESGWTIYSFDYWGQGTMVTVSS


 


CL-29662
2977
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGPTYSFDYWGQGTMVTVSS


 


CL-29663
2978
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESVGTSYSFDYWGQGTMVTVSS


 


CL-29665
2979
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK




ALEWLANIWWDDDQYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTTYSFDYWGQGTMVTVSS


 


CL-29667
2980
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESFGPSYSFDYWGQGTMVTVSS


 


CL-29668
2981
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSGTSYSFDYWGQGTMVTVSS


 


CL-29673
2982
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARXXSIVTTYSFDYWGQGTMVTVSS


 


CL-29674
2983
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTSYSFDYWGQGTMVTVSS


 


CL-29676
2984
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGLIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESVGTSYSFDYWGQGTMVTVSS


 


CL-29678
2985
EVTLKESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIGSSGTTYSFDYWGQGTMVTVSS


 


CL-29679
2986
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNTSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIDSFGAIYSFDYWGQGTMVTVSS


 


CL-29680
2987
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ELEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




ETATYYCARIESIGTAYNFDYWGQGTMVTVSS


 


CL-29683
2988
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGTSYSFDYWGQGTMFTVSS


 


CL-29688
2989
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGTSYSFDYWGQGTMVTVSS


 


CL-29689
2990
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIEAKGTTYSFDYWGQGTMVTVSS


 


CL-29699
2991
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESRGTSYSFDYWGQGTMVTVSS


 


CL-29706
2992
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESMGPTYSFDYWGQGTMVTVSS


 


CL-29707
2993
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIETSYSFDYWGQGTMVTVSS


 


CL-29709
2994
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYRARIESLGTTYSFDYWGQGTMVTVSS


 


CL-29711
2995
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRHPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESMGTSYSFDYWGQGTMVTVSS


 


CL-29713
2996
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESMGTTYSFDYWGQGTMVTVSS


 


CL-29714
2997
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCALIESSGTTYSFDYWGQGTMVTVSS


 


CL-29720
2998
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESKGVSYSFDYWGQGTMVTVSS


 


CL-29721
2999
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIPTTYSFDYWGQGTMVTVSS


 


CL-29727
3000
EVTLRESXPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ELEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGTTYSFDYWGQGTMVTVSS


 


CL-29728
3001
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGITYSFDYWGQGTMVTVSS


 


CL-29730
3002
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESMGRSYSFDYWGQGTMVTVSS


 


CL-29731
3003
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIATSYSFDYWGQGTMVTVSS


 


CL-29732
3004
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYNFDYWGQGTMVTVSS


 


CL-29735
3005
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESMGPMYSFDYWGQGTMVTVSS


 


CL-29736
3006
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTAYSFDYWGQGTMVTVSS


 


CL-29738
3007
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARMESSWTTYSFDYWGQGTMVTVSS


 


CL-29739
3008
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTGATYSFDYWGQGTMVTVSS


 


CL-29740
3009
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESMGPKYSFDYWGQGTMVTVSS


 


CL-29742
3010
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESMGMSYSFDYWGQGTMVTVSS


 


CL-29744
3011
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGLSYSFDYWGQGTMVTVSS


 


CL-29745
3012
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYRARIESLGMSYSFDYWGQGTMVTVSS


 


CL-29746
3013
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARLXSTGTNYSFDYWGQGTMVTVSS


 


CL-29748
3014
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSDTIYSFDYWGQGTMVTVSS


 


CL-29749
3015
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVDWIRQPPGK




ALEWLALIDWDDDIHYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-29751
3016
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESVGTTYSFDYWGQGTMVTVSS


 


CL-29753
3017
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWYDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTGTTYSFDYWGQGTMVTVSS


 


CL-29756
3018
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARNESFGRMYXFDYWGQGTMVTVSS


 


CL-29757
3019
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARXESIGTTYSFDYWGQGTMVTVSS


 


CL-29758
3020
EVTLRESGPSLVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESFGTTYSFDYWGQGTMVTVSS


 


CL-29759
3021
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIETLGTAYSFDYWGQGTMVTVSS


 


CL-29761
3022
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESFGSSYSFDYWGQGTMVTVSS


 


CL-29763
3023
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESGPTTYSFDYWGQGTMVTVSS


 


CL-29765
3024
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTMYSFDYWGQGTMVTVSS


 


CL-29771
3025
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTXTTYSXDYWGQGTMVTVSS


 


CL-29772
3026
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGITYSFDYWGQGTMVTVSS


 


CL-29773
3027
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESMETTYSFDYWGQGTMVTVSS


 


CL-29776
3028
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESNAITYSFDYWGQGTMVTVSS


 


CL-29777
3029
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSETTYMFDYWGQGTMVTVSS


 


CL-29780
3030
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLTNIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESMGTSYSFDYWGQGTMVTVSS


 


CL-29786
3031
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIYSIGTSYSFDYWGQGTMVTVSS


 


CL-33292
3032
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSPWTYSFDYWGQGTMVTVSS


 


CL-33332
3033
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESRPDTYSFDYWGQGTMVTVSS


 


CL-33361
3034
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIQSSASNYEFDYWGQGTMVTVSS


 


CL-33368
3035
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIQSGWTNXEFDYWGQGTMVTVSS


 


CL-33583
3036
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIQSIWTRYDFDYWGQGTMVTVSS


 


CL-33588
3037
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIQSFATNYEFDYWGQGTMVTVSS


 


CL-33591
3038
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESVPWSYSFDYWGQGTMVTVSS


 


CL-33592
3039
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTPFSYSFDYWGQGTMVTVSS


 


CL-33599
3040
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTSYDFDYWGQGTMVTVSS


 


CL-33601
3041
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIQSSSTNYEFDYWGQGTMVTVSS


 


CL-33612
3042
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIQSSWRRYEFDYWGQGTMVTVSS


 


CL-33616
3043
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIKTSATNYDFDYWGQGTMVTVSS


 


CL-33618
3044
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSAFSYNFDYWGQGTMVTVSS


 


CL-33626
3045
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVFLTMTNMDPV




DTATYYCARIVSSLTEYNFDYWGQGTMVTVSS


 


CL-33627
3046
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESRVDSYSFDYWGQGTMVTVSS


 


CL-33628
3047
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTWTSYDFDYWGQGTMVTVSS


 


CL-33654
3048
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESVAWRYDFDYWGQGTMVTVSS


 


CL-33657
3049
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLPTSYNFDYWGQGTMVTVSS


 


CL-33663
3050
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSPFTYSFDYWGQGTMVTVSS


 


CL-33665
3051
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESDYTKYDFDYWGQGTMVTVSS


 


CL-33667
3052
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLPTRYDFDYWGQGTMVTVSS


 


CL-33674
3053
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWMANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIPTSYSFDYWGQGTMVTVSS


 


CL-33679
3054
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESKPTSYSFDYWGQGTMVTVSS


 


CL-33680
3055
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTTYSFDYWGQGTMVTVSS


 


CL-33687
3056
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTSYSFDYWGQGTMVTVSS


 


CL-33688
3057
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTFKNQVVLTMTNMDPV




DTATYYCARIESIPTSYSFDYWGQGTMVTVSS


 


CL-33690
3058
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDETYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESDFTSYMFDYWGQGTMVTVSS


 


CL-33693
3059
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESNWWSYSFDYWGQGTMVTVSS


 


CL-33696
3060
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSFTTYSFDYWGQGTMVTVSS


 


CL-33698
3061
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESXGXSYSFDYWGQGTMVTVSS


 


CL-33705
3062
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESRLDTYSFDYWGQGTMVTVSS


 


CL-33707
3063
EVTLRESGPALVKPTQTLTLTCTFSGFSLDTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTSYSFDYWGQGTMVTVSS


 


CL-33709
3064
EVTLRESGPALVKPTQTLTLTCTFSGFSLATSGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIPWSYSFDYWGQGTMVTVSS


 


CL-33711
3065
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTGYSYSFDYWGQGTMVTVSS


 


CL-33712
3066
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRKPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTSYSFDYWGQGTMVTVSS


 


CL-33722
3067
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSFFSYSFDYWGQGTMVTVSS


 


CL-33725
3068
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDEYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGTSYSFDYWGQGTMVTVSS


 


CL-33734
3069
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLPGSYDFDYWGQGTMVTVSS


 


CL-33735
3070
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ELEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESNPLTYSFDYWGQGTMVTVSS


 


CL-33741
3071
EVTLRESGPALVKPTKTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGISYSFDYWGQGTMVTVSS


 


CL-33743
3072
EVTLRESGPALVKPTQTLTLTCTFSGFSLATYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLPTSYSFDYWGQGTMVTVSS


 


CL-33745
3073
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSPFAYSFDYWGQGTMVTVSS


 


CL-33746
3074
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWFTYAFDYWGQGTMVTVSS


 


CL-33747
3075
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIETIXPKYSFDYWGQGTMVTVSS


 


CL-33754
3076
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTTYAFDYWGQGTMVTVSS


 


CL-33755
3077
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSEWTYSFDYWGQGTMVTVSS


 


CL-33756
3078
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIQSSWTTYEFDYWGQGTMVTVSS


 


CL-33760
3079
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIETLGSSYSFDYWGQGTMVTVSS


 


CL-33766
3080
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRKPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSFTSYSFDYWGQGTMVTVSS


 


CL-33770
3081
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESGGISYSFDYWGQGTMVTVSS


 


CL-33773
3082
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLPTTYSFDYWGQGTMVTVSS


 


CL-33777
3083
EVTLRESGPALVKPTQTLTLTCTFSGFSLYTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESVGTSYSFDYWGQGTMVTVSS


 


CL-33781
3084
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWYSYNFDYWGQGTMVTVSS


 


CL-33782
3085
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWRSYCFDYWGQGTMVTVSS


 


CL-33784
3086
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSPMSYSFDYWGQGTMVTVSS


 


CL-33789
3087
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLPTSYCFDYWGQGTMVTVSS


 


CL-33791
3088
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWWTYSFDYWGQGTMVTVSS


 


CL-33794
3089
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESRPTSYCFDYWGQGTMVTVSS


 


CL-33795
3090
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESVPTSYSFDYWGQGTMVTVSS


 


CL-33798
3091
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIQSDGPMYSFDYWGQGTMVTVSS


 


CL-33802
3092
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESTGASYSFDYWGQGTMVTVSS


 


CL-33813
3093
EVTLRESGPALVKPTQTLTLTCTFSGFSLYTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLPTSYSFDYWGQGTMVTVSS


 


CL-33814
3094
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDTV




DTATYYCARIESTPWSYSFDYWGQGTMVTVSS


 


CL-33816
3095
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTSYAFDYWGQGTMVTVSS


 


CL-33823
3096
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ELEWLANIWWDDDKYYNPSLNNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSGPKYSFDYWGQGTMVTVSS


 


CL-33833
3097
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGWSYSFDYWGQGTMVTVSS


 


CL-33840
3098
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSAWTYSFDYWGQGTMVTVSS


 


CL-33842
3099
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESYGPKYSFDYWGQGTMVTVSS


 


CL-33844
3100
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKTRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIETSWWKYSFDYWGQGTMVTVSS


 


CL-33847
3101
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNLSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSPTSYSFDYWGQGTMVTVSS


 


CL-33849
3102
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIVSSYFTYSFDYWGQGTMVTVSS


 


CL-33858
3103
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDEEYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGISYSFDYWGQGTMVTVSS


 


CL-33861
3104
EVTLRESGPALVKPTQTLTLTCTFSGFSLYTSGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTTYSFDYWGQGTMVTVSS


 


CL-33862
3105
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIPTRYDFDYWGQGTMVTVSS


 


CL-41180
3106
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNRVVLTMTNMDPV




DTATYYCARIVSDWTTYSFDYWGQGTMVTVSS


 


CL-41185
3107
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTDMDPV




DTATYYCARIESSWTTYSFDYWGQGTMVTVSS


 


CL-41193
3108
RXHWRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIETFGPKYSFDYWGQGTMVTVSS


 


CL-41204
3109
RGNTEESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTTTYYCARIESLPTSYSFDYWGQGTMVTVSS


 


CL-41213
3110
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLXTNYSFDYWGQGTMVTVSS


 


CL-41224
3111
EVTLREGGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESHWWSYAFDYWGQGTMVTVSS


 


CL-41229
3112
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSFTSYSFDYWGQGTMVTEXC


 


CL-41232
3113
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESHWWSYAFDYWGQGTMVTVSS


 


CL-41233
3114
RXHXGESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTTYSFDYWGQGTMVTVSS


 


CL-41246
3115
EVTLRESGPALAKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESHWWSYAFDYWGQGTMVTVSS


 


CL-41252
3116
EVTLRESGPALVKPTQTLTLTCAFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTTYSFDYWGQGTMVTVSS


 


CL-41255
3117
EVTLRESGPALVEPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESNPWKYSFDYWGQGTMVTVSS


 


CL-41257
3118
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESNWRTYSFDYWGQGTMVTVSS


 


CL-41260
3119
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSFTSYSFDYWGQGTMVTVSS


 


CL-41261
3120
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESHWWSYAFDYWGQGTMVTVSI


 


CL-41262
3121
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIVSDWTTYSFDYWGQGTMVTVSS


 


CL-41268
3122
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGWSYSFDYWGQGTMVTVSS


 


CL-41269
3123
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLPTSYSFDYWGQGTMVTVSS


 


CL-41270
3124
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTTYSFDYWGQGTMVTVSS


 


CL-41272
3125
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESNPWKYSFDYWGQGTMVTVSS


 


CL-41273
3126
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIETFGPKYSFDYWGQGTMVTVSS


 


CL-41276
3127
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGIGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESMGPKYAFDYWGQGTMVTVSS


 


CL-41283
3128
EVTLRESGPALVKPTQTLTLTRTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIPTSYSFDYWGQGTMVTVSS


 


CL-41325
3129
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRKPPGK




ALEWLANIWWDGDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSGPKYSFDYWGQGTMVTVSS


 


CL-41342
3130
EVTLRESGPALVKPTQTLTLACTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESVWTKYYFDXGGQGTMVTVSS


 


CL-41348
3131
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYEMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTPKNQVVLTMTNMDPV




DTATYYCARIESVWTRYDFDYWGQGTMVKXVV


 


CL-41353
3132
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESLGTSYSFDYWGQGTMVTVSS


 


CL-41358
3133
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGPKYSFDYWGQGTMVTVSS


 


CL-41361
3134
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESVWTRYDFDYWGQGTMVTVSS


 


CL-41362
3135
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIETMGPKYSFDYWGQGTMVTVSS


 


CL-41365
3136
RGNTRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALKWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGPKYSFDYWGQGTMVTVSS


 


CL-41366
3137
EVTLRESGPAQVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIPTSYSFDYWGQGTMVTVSS


 


CL-41367
3138
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRKPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSGPKYSFDYWGQGTMVTVSS


 


CL-41368
3139
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGPKYSFDXGGQGTMVTVSS


 


CL-41369
3140
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIPTSYSFDYWGQGTMVTVSS


 


CL-41376
3141
EVKLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIQTIGTNYSFDYWGQGTMVTVSS


 


CL-41377
3142
EGQLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTSYSFDYWGQGTMVTVSS


 


CL-41381
3143
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTSYSFDYWGQSTMVTVSS


 


CL-41385
3144
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTSYSFDYWGQGTIVTVSS


 


CL-41399
3145
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKSRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTSYSFDYWGQGTMVTVSS


 


CL-41405
3146
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTAAYYCARIETIGPKYSFDYWGQGTMVTVSS


 


CL-41411
3147
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIQSGWTNYEFDYWGQGTMVTVVV


 


CL-41420
3148
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIQSMWTRYDFDYWGQGTMVTVSS


 


CL-41425
3149
RXHXRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSGPKYSFDYWGQGTMVTVSS


 


CL-41427
3150
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DAATYYCARIQSGWTNYEFDYWGQGTMVTVSS


 


CL-41436
3151
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTSYSFDYWSQGTMVTVSS


 


CL-41439
3152
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIETIGPKYSFDYWGQGTMVTVSS


 


CL-41443
3153
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSGPKYSFDYWGQGTMVTVSS


 


CL-41446
3154
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTSYSFDYWGQGTMVTVSS


 


CL-41447
3155
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQAVLTMTNMDPV




DTATYYCARIQSGWTNYEFDYWGQGTMVTVSS


 


CL-41448
3156
RGNTEKSGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSWTSYSFDYWGQGTMVTVSS


 


CL-41449
3157
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIQSGWTNYEFDYWGQGTMVTVSS


 


CL-41452
3158
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMEXVVR


 


CL-41459
3159
EVTLRESGPALVKPTQTLTLTCTFSGFILSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-41463
3160
EVTLRESGPALVKSTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


CL-41465
3161
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSS









Table 47 provides a list of amino acid sequences of VL regions of affinity matured humanized PDGF antibodies derived from hBDI-9E8.4. Amino acid residues of individual CDRs of each VL sequence are indicated in bold.







TABLE 47







List of Amino Acid Sequences Of Affinity


Matured hBDI-9E8.4 VL Variants









Clone
SEQ ID NO:
VL





CL-22656
3162
EIVLTQSXGTLSLSPGXRXTLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-22715
3163
EIVLXQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-22747
3164
EIVLTQSPGTLSLSPGERATLSCERSSGSIWYSYVSWYQQKPGQ




APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINKDLTFGGGTKVEIK


 


CL-22748
3165
EIVLTQSPGTLSLSPGERATLSCERSSGSIGYSYVSWYQQKPGQ




APRLVIYAADQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGIIIDITFGGGTKVEIK


 


CL-22749
3166
EIVLTQSPGTLSLSPGERATLSCERSSGSIEHAYVSWYQQKPGQ




APRLLIYGADHRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDFNNTITFGGGTKVEIK


 


CL-22750
3167
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHCYVSWYQQKPGQ




APRLVIYAADHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGKNIDGTFGGGTKVEIK


 


CL-22752
3168
EIVLTQSPGTLSLSPGERATLSCRASSGDIGDFCVSWYQQKPGQ




APRLLIYVDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGRRLDITFGGGTKVEIK


 


CL-22753
3169
EIVLTQSPGTLSLSPGERATLSCERSSGDIVLPYVSWYQQKPGQ




APRLVIYAADWRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDITIDTVFGGGTKVEIK


 


CL-22754
3170
EIVLTQSPGTLSLSPGERATLSCRASSGSIGYECVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDRQIVFGGGTKVEIK


 


CL-22755
3171
EIVLTQSPGTLSLSPGERATLSCRASSGSIVGSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGVHIDITFGGGTKVEIK


 


CL-22756
3172
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHSDVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIGQVFGGGTKVEIK


 


CL-22758
3173
EIVLTQSPGTLSLSPGERATLSCRASSGSIGHPYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGCHIYNVFGGGTKVEIK


 


CL-22759
3174
EIVLTQSPGTLSLSPGERATLSCERSSGSICDTYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIYIHIVFGGGTKVEIK


 


CL-22760
3175
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSCVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGIDIVIVFGGGTKVEIK


 


CL-22761
3176
EIVLTQSPGTLSLSPGERATLSCERSSGSIGYSDVSWYQQKPGQ




APRLLIYADDKRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDKYIVFGGGTKVEIK


 


CL-22763
3177
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHFYVSWYQQKPGQ




APRLVIYAADHRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGTNIEIVFGGGTKVEIK


 


CL-22764
3178
EIVLTQSPGTLSLSPGERATLSCERSSGDIGXADVSWYQQKPGQ




APRLVIYVDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGEYIDRTFGGGTKVEIK


 


CL-22765
3179
EIVLTQSPGTLSLSPGERATLSCRASSGSIGGSYVSWYQQKPGQ




APRLLIYADDHRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGINIGTVFGGGTKVEIK


 


CL-22766
3180
EIVLTQSPGTLSLSPGERATLSCERSSGDIECDFVSWYQQKPGQ




APRLVIYADDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGINNDITFGGGTKVEIK


 


CL-22767
3181
EIVLTQSPGTLSLSPGERATLSCERSSGDIGCSYVSWYQQKPGQ




APRLVIYGDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINKEITFGGGTKVEIK


 


CL-22768
3182
EIVLTQSPGTLSLSPGERATLSCERSSGSIGHSRVSWYQQKPGQ




APRLVIYVDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDNNIATVFGGGTKVEIK


 


CL-22769
3183
EIVLTQSPGTLSLSPGERATLSCERSSGSINHCHVSWYQQKPGQ




APRLVIYAADXRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIILDITFGGGTKVEIK


 


CL-22770
3184
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDHRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDFDIDITFGGGTKVEIK


 


CL-22771
3185
EIVLTQSPGTLSLSPGERATLSCRASSGSIRYTYVSWYQQKPGQ




APRLVIYAADEPPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINRNIVFGGGTKVEIK


 


CL-22772
3186
EIVLTQSPGTLSLSPGERATLSCERSSGDIGCTYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGISTVLVFGGGTKVEIK


 


CL-22773
3187
EIVLTQSPGTLSLSPGERATLSCERSSGDIRYCYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDVDIVFGGGTKVEIK


 


CL-22774
3188
EIVLTQSPGTLSLSPGERATLSCRASSGSISQSYVSWYQQKPGQ




APRLVIYADDLRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGINIDITFGGGTKVEIK


 


CL-22775
3189
EIVLTQSPGTLSLSPGERATLSCERSSGSIFYGCVSWYQQKPGQ




APRLLIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDINIVITFGGGTKVEIK


 


CL-22776
3190
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSYVSWYQQKPGQ




APRLVIYAADQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINKYAVFGGGTKVEIK


 


CL-22777
3191
EIVLTQSPGTLSLSPGERATLSCRASSGDISYSYVSWYQQKPGQ




APRLVIYVDDERASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDIYKDLTFGGGTKVEIK


 


CL-22778
3192
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDXRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDSNIDIVFGGGTKVEIK


 


CL-22779
3193
EIVLTQSPGTLSLSPGERATLSCERSSGSICYXYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDVNLEHTFGGGTKVEIK


 


CL-22780
3194
EIVLTQSPGTLSLSPGERATLSCRASSGDIRHCYVSWYQQKPGQ




APRLLIYPDDLRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-22781
3195
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYVDDHRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGTSLDNTFGGGTKVEIK


 


CL-22782
3196
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHSYVSWYQQKPGQ




APRLVIYAADHRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGVNIYITFGGGTKVEIK


 


CL-22783
3197
EIVLTQSPGTLSLSPGERATLSCRASSGSIRYSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDINKVIVFGGGTKVEIK


 


CL-22784
3198
EIVLTQSPGTLSLSPGERATLSCERSSGDIGKPTSPWYQQKPGQ




APRLVIYSADERPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGVNRDIVFGGGTKVEIK


 


CL-22785
3199
EIVLTQSPGTLSLSPGERATLSCERSSGSIGPCYVSWYQQKPGQ




APRLVIYADDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDINLVITFGGGTKVEIK


 


CL-22786
3200
EIVLTQSPGTLSLSPGERATLSCERSSGSIHYSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGISIDITFGGGTKVEIK


 


CL-22787
3201
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDPYVSWYQQKPGQ




APRLVIYAADPRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDISIYIVFGGGTKVEIK


 


CL-22788
3202
EIVLTQSPGTLSLSPGERATLSCERSSGDIKHCCVSWYQQKPGQ




APRLVIYLDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDISIDITFGGGTKVEIK


 


CL-22789
3203
EIVLTQSPGTLSLSPGERATLSCRASSGSIVQSYVSWYQQKPGQ




APRLLIYSDDPRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGLYRDITFGGGTKVEIK


 


CL-22790
3204
EIVLTQSPGTLSLSPGERATLSCRASSGSISYSYVSWYQQKPGQ




APRLLIYADDXRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQHYDIHINITFGGGTKVEIK


 


CL-22791
3205
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYAHVSWYQQKPGQ




APRLLIYGDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGKNSEITFGGGTKVEIK


 


CL-22792
3206
EIVLTQSPGTLSLSPGERATLSCRASSGSIGHSYVSWYQQKPGQ




APRLLIYDDDPRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGINVDIVFGGGTKVEIK


 


CL-22794
3207
EIVLTQSPGTLSLSPGERATLSCRASSGSIGHSCVSWYQQKPGQ




APRLVIYSADERASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDLNTLFVFGGGTKVEIK


 


CL-22795
3208
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHXYVSWYQQKPGQ




APRLVIYAADHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGISIAVVFGGGTKVEIK


 


CL-22796
3209
EIVLTQSPGTLSLSPGERATLSCERSSGSIGLSYVSWYQQKPGQ




APRLVIYAADQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDRHLDATFGGGTKVEIK


 


CL-22797
3210
EIVLTQSPGTLSLSPGERATLSCERSSGDIGCSYVSWYQQKPGQ




APRLLIYGADHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGIDIDITFGGGTKVEIK


 


CL-22798
3211
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDASVSWYQQKPGQ




APRLLIYAADQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDITIGVVFGGGTKVEIK


 


CL-22799
3212
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYCFVSWYQQKPGQ




APRLVIYAADLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIKIGITFGGGTKVEIK


 


CL-22800
3213
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYWDVSWYQQKPGQ




APRLLIYADDERASGIPDRFSGSGSGTDFTLTISRLEPEDFSVY




YCQSYGINKDFVFGGGTKVEIK


 


CL-22801
3214
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHTYVSWYQQKPGQ




APRLVIYTDDLRASGIPDRFSGSGSGTDFTLTISRLDPEDFAVY




YCQQYDLNIDIVFGGGTKVEIK


 


CL-22802
3215
EIVLTQSPGTLSLSPGERATLSCERSSGSIGXSHVSWYQQKPGQ




APRLLIYVDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIKKGXTFGGGTKVEIK


 


CL-22803
3216
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHSFVSWYQQKPGQ




APRLVIYADDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGVNIDITFGGGTKVEIK


 


CL-22804
3217
EIVLTQSPGTLSLSPGERATLSCRASSGSIFQSDVSWYQQKPGQ




APRLVIYADDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGKNIYIVFGGGTKVEIK


 


CL-22805
3218
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYSAVSWYQQKPGQ




APRLVXYVDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIKLDFVFGGGTKVEIK


 


CL-22806
3219
EIVLTQSPGTLSLSPGERATLSCRASSGSIVYSSVSWYQQKPGQ




APRLVIYVXDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDIHIDITFGGGTKVEIK


 


CL-22807
3220
EIVLTQSPGTLSLSPGERATLSCRASSGSIRDFYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGINLDNTFGGGTKVEIK


 


CL-22808
3221
EIVLTQSPGTLSLSPGERATLSCERSSGDISDSHVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDITFGGGTKVEIK


 


CL-22811
3222
EIVLTQSPGTLSLSPGERATLSCERSSGSIALSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINLDIVFGGGTKVEIK


 


CL-22812
3223
EIVLTQSPGTLSLSPGERATLSCERSSGDMRYSDVSWYQQKPGQ




APRMVIYAVDQRASGIPDRLSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDVGMVLTFGGGTKVEIK


 


CL-22813
3224
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHFYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGISIDLTFGGGTKVEIK


 


CL-22815
3225
EIVLTQSPGTLSLSPGERATLSCERSSGDIDHSYVSWYQQKPGQ




APRLVIYADDPRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGLNIDLTFGGGTKVEIK


 


CL-22816
3226
EIVLTQSPGTLSLSPGERATLSCERSSGSIRHSCVSWYQQKPGQ




APRLVIYADDHRASGIPDRFSDSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-22818
3227
EIVLTQSPGTLSLSPGERATLSCRASSGDIWHSYVSWYQQKPGQ




APRLVIYTDDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGCDKDITFGGGTKVEIK


 


CL-22819
3228
EIVLTQSPGTLSLSPGERATLSCRASSGSIGDFYVSWYQQKPGQ




APRLVIYADDQRPTGIPDRLSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGIHIEIVFGGGTKVEIK


 


CL-22820
3229
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHSAVSWYQQKPGQ




APRLLIYADDPRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGKNKELVFGGGTKVEIK


 


CL-22821
3230
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGINSYLVFGGGTKVEIK


 


CL-22822
3231
EIVLTQSPGTLSLSPGERATLSCRASSGDIGPSYVSWYQQKPGQ




APRLLIYPDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDINKELVFGGGTKVEIK


 


CL-22823
3232
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGKNVDIVFGGGTKVEIK


 


CL-22824
3233
EIVLTQSPGTLSLSPGERATLSCRASSGSILDTYVSWYQQKPGQ




APRLVIYADDSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDVNVDIVFGGGTKVEIK


 


CL-22825
3234
EIVLTQSPGTLSLSPGERATLSCRASSGSISQSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDXTIGIVFGGGTKVEIK


 


CL-22826
3235
EIVLTQSPGTLSLSPGERATLSCERSSGSIGFSYVSWYQQKPGQ




APRLVIYEDDPRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGANIEIVFGGGTKVEIK


 


CL-22827
3236
EIVLTQSPGTLSLSPGERATLSCRASSGYISHEYVSWYQQKPGQ




APRLVIYAADQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGIHIHVTFGGGTKVEIK


 


CL-22828
3237
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHSYVSWYQQKPGQ




APRLVIYEDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGGNIGIVFGGGTKVEIK


 


CL-22829
3238
EIVLTQSPGTLSLSPGERATLSCRASSGSIDASYVSWYQQKPGQ




APRLLIYTDDRRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGIILDIVFGGGTKVEIK


 


CL-22830
3239
EIVLTQSPGTLSLSPGERATLSCRASSGSIGYSYVSWYQQKPGQ




APRLLIYADDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGVIIYITFGGGTKVEIK


 


CL-22832
3240
EIVLTQSPGTLSLSPGERATLSCRASSGDIFYSYVSWYQQKPGQ




APRLVIYADDXRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-22833
3241
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYLYVSWYQQKPGQ




APXLVIYPDDXRASGIPDRFSGSGSGXDFTLTISRLEPEDXAVY




YCQQYDKTIDIVFGGGTKVEIK


 


CL-22834
3242
EIVLTQSPGTLSLSPGERATLSCRASSGDICESCVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINKDIVFGGGTKVEIK


 


CL-22835
3243
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSNVSWYQQKPGQ




APRLLIYEDDKRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGXLVPIVFGGGTKVEIK


 


CL-22836
3244
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYGIKVDSTFGGGTKVEIK


 


CL-22837
3245
EIVLTQSPGTLSLSPGERATLSCERSSGSIQSLHVSWYQQKPGQ




APRLLIYADDXRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGRHIGLVFGGGTKVEIK


 


CL-22838
3246
EIVLTQSPGTLSLSPGERATLSCERSSGSIGYCYVSWYQQKPGQ




APRLVIYADDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDLCIYITFGGGTKVEIK


 


CL-22839
3247
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSHVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIAITFGGGTKVEIK


 


CL-22840
3248
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYTYVSWYQQKPGQ




APRLLIYPDDKRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIRPTTFGGGTKVEIK


 


CL-22841
3249
EIVLTQSPGTLSLSPGERATLSCERSSGDIAHSYVSWYQQKPGQ




APRLVIYAADYRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDSHNNIVFGGGTKVEIK


 


CL-22842
3250
EIVLTQSPGTLSLSPGERATLSCRASSGSIRGLRVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGLNFDIVFGGGTKVEIK


 


CL-25631
3251
EIVLTQSPGTLSLSPGERATLSCRASSGSITYYYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINTDIVFGGGTKVEIK


 


CL-25634
3252
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-25648
3253
EIVLTQSPGTLSLSPGEXATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYVDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-25655
3254
EIVLTQSPGTLSLSPGERXTLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-25666
3255
EIVLTQXPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-25690
3256
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYSDDQRPGGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-25721
3257
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGYGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-25724
3258
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLLIYVDDWRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDVVFGGGTKVEIK


 


CL-25725
3259
EIVLTQSPGTLSLSPGERATLSCERSSGDIDYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDIVFGGGTKVEIK


 


CL-25726
3260
EIVLTQSPGTLSLSPGERATLSCRASSGSIGYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINTDVVFGGGTKVEIK


 


CL-25727
3261
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIYIDVTFGGGTKVEIK


 


CL-25728
3262
EIVLTQSPGTLSLSPGERATLSCERSSGSIGYSYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDIVFGGGTKVEIK


 


CL-25729
3263
EIVLTQSPGTLSLSPGERATLSCERSSGDIAGYYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDITFGGGTKVEIK


 


CL-25730
3264
EIVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQ




APRLVIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIVIDIXFGGGTKVEIK


 


CL-25731
3265
EIVLTQSPGTLSLSPGERATLSCRASSGSIVYSYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIYIDITFGGGTKVEIK


 


CL-25732
3266
EIVLTQSPGTLSLSPGERATLSCRASSGDIVYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDVTFGGGTKVEIK


 


CL-25733
3267
EIVLTQSPGTLSLSPGERATLSCRASSGDIWDAYVSWYQQKPGQ




APRLLIYADDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDITFGGGTKVEIK


 


CL-25734
3268
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYAYVSWYQQKPGQ




APRLVIYADDYRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDVDIVFGGGTKVEIK


 


CL-25735
3269
EIVLTQSPGTLSLSPGERATLSCRASSGDILDSYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDTIIDITFGGGTKVEIK


 


CL-25736
3270
EIVLTQSPGTLSLSPGERATLSCERSSGDIDDYYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIYIDVTFGGGTKVEIK


 


CL-25737
3271
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDFYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDVTIDVTFGGGTKVEIK


 


CL-25738
3272
EIVLTQSPGTLSLSPGERATLSCERSSGDIGLSYVSWYQQKPGQ




APRLVIYSDDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDVDIDVTFGGGTKVEIK


 


CL-25739
3273
EIVLTQSPGTLSLSPGERATLSCERSSGDIFYTYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDITFGGGTKVEIK


 


CL-25740
3274
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLLIYADDQRAIGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIYVDVVFGGGTKVEIK


 


CL-25741
3275
EIVLTQSPGTLSLSPGERATLSCRASSGDIEGSYVSWYQQKPGQ




APRLVIYSDDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-25742
3276
EIVLTQSPGTLSLSPGERATLSCRASSGDISCSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINTDIVFGGGTKVEIK


 


CL-25743
3277
EIVLTQSPGTLSLSPGERATLSCRASSGSIGSYYVSWYQQKPGQ




APRLVIYSDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIYIDVVFGGGTKVEIK


 


CL-25745
3278
EIVLTQSPGTLSLSPGERATLSCRASSGDIWYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIEIDVTFGGGTKVEIK


 


CL-25747
3279
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYSYVSWYQQKPGQ




APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIISDITFGGGTKVEIK


 


CL-25748
3280
EIVLTQSPGTLSLSPGERATLSCRASSGSIDYAYVSWYQQKPGQ




APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGITIDVVFGGGTKVEIK


 


CL-25749
3281
EIVLTQSPGTLSLSPGERATLSCRASSGSIYFAYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGITIDVVFGGGTKVEIK


 


CL-25751
3282
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINVDIVFGGGTKVEIK


 


CL-25752
3283
EIVLTQSPGTLSLSPGERATLSCRASSGDIAHSYVSWYQQKPGQ




APRLVIYTDDARASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIVDIVFGGGTKVEIK


 


CL-25754
3284
EIVLTQSPGTLSLSPGERATLSCERSSGDICQYYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLNIDVTFGGGTKVEIK


 


CL-25756
3285
EIVLTQSPGTLSLSPGERATLSCERSSGSIGDSYVSWYQQKPGQ




APRLLIYNDDDRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLTIDVTFGGGTKVEIK


 


CL-25758
3286
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ




APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-25759
3287
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDVDIVFGGGTKVEIK


 


CL-25760
3288
EIVLTQSPGTLSLSPGERATLSCERSSGSIWDMYVSWYQQKPGQ




APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIEIDITFGGGTKVEIK


 


CL-25761
3289
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYGDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDITFGGGTKVEIK


 


CL-25763
3290
EIVLTQSPGTLSLSPGERATLSCERSSGDIWESYVSWYQQKPGQ




APRLVIYADDERATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDIVFGGGTKVEIK


 


CL-25765
3291
EIVLTQSPGTLSLSPGERATLSCRASSGDIAYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-25767
3292
EIVLTQSPGTLSLSPGERATLSCRASSGSIFGAYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIITDIVFGGGTKVEIK


 


CL-25769
3293
EIVLTQSPGTLSLSPGERATLSCRASSGSIADSLVSWYQQKPGQ




APRLVIYTDDWRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-25770
3294
EIVLTQSPGTLSLSPGERATLSCERSSGSIGDSYVSWYQQKPGQ




APRLLIYTDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDITIDIVFGGGTKVEIK


 


CL-25771
3295
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDYYVSWYQQKPGQ




APRLVIYSDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDITFGGGTKVEIK


 


CL-25772
3296
EIVLTQSPGTLSLSPGERATLSCERSSGSIVHSYVSWYQQKPGQ




APRLVXYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIXVDIVFGGGTKVEIK


 


CL-25773
3297
EIVLTQSPGTLSLSPGERATLSCRASSGDIWYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGITVDIVFGGGTKVEIK


 


CL-25775
3298
EIVLTQSPGTLSLSPGERATLSCERSSGDIFYSYVSWYQQKPGQ




APRLVIYADDERASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIEIDIVFGGGTKVEIK


 


CL-25776
3299
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDVDIVFGGGTKVEIK


 


CL-25778
3300
EIVLTQSPGTLSLSPGERATLSCERSSGDIGLSYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLIIDIVFGGGTKVEIK


 


CL-25779
3301
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDIVFGGGTKVEIK


 


CL-25780
3302
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYSYVSWYQQKPGQ




APRLVIYADDERASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIEIDITFGGGTKVEIK


 


CL-25782
3303
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYSYVSWYQQKPGQ




APRLLIYFDDYRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIEIDIVFGGGTKVEIK


 


CL-25783
3304
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYYYVSWYQQKPGQ




APRLVIYADDERATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIYIDVVFGGGTKVEIK


 


CL-25784
3305
EIVLTQSPGTLSLSPGERATLSCRASSGDISDSYVSWYQQKPGQ




APRLVIYTDDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDIVFGGGTKVEIK


 


CL-25785
3306
EIVLTQSPGTLSLSPGERATLSCERSSGSIGDSYVSWYQQKPGQ




APRLVIYVDDWRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDVDIVFGGGTKVEIK


 


CL-25786
3307
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHSYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-25787
3308
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDIIDDIVFGGGTKVEIK


 


CL-25788
3309
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYSYVSWYQQKPGQ




APRLLIYADDFRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIITDITFGGGTKVEIK


 


CL-25789
3310
EIVLTQSPGTLSLSPGERATLSCERSSGDIYYSYVSWYQQKPGQ




APRLVIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDVTFGGGTKVEIK


 


CL-25790
3311
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGL




APRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGTYVDIVFGGGTKVEIK


 


CL-25791
3312
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVSWYQQKPGQ




APRLVIYADDQRASGIPDRXSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDXVFGGGTKVEIK


 


CL-25792
3313
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQYYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-25793
3314
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDWRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIYIDIVFGGGTKVEIK


 


CL-25794
3315
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDTIIDIVFGGGTKVEIK


 


CL-25795
3316
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDYYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVVFGGGTKVEIK


 


CL-25796
3317
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDTIIDIVFGGGTKVEIK


 


CL-25797
3318
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQYYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLNIDITFGGGTKVEIK


 


CL-25798
3319
EIVLTQSPGTLSLSPGERATLSCRASSGDIGESYVSWYQQKPGQ




APRLVIYSDDSRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-25799
3320
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYSYVSWYQQKPGQ




APRLVIYADDLRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIIDIVFGGGTKVEIK


 


CL-25800
3321
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDYYVSWYQQKPGQ




APRLVIYWDDYRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDVILDITFGGGTKVEIK


 


CL-25801
3322
EIVLTQSPGTLSLSPGERATLSCERSSGDISYTYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIITDIVFGGGTKVEIK


 


CL-25802
3323
EIVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQ




APRLVIYTDDWRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGSNIDVVFGGGTKVEIK


 


CL-25803
3324
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGILTDITFGGGTKVEIK


 


CL-25804
3325
EIVLTQSPGTLSLSPGERATLSCRASSGSIAHSYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIVDIVFGGGTKVEIK


 


CL-25805
3326
EIVLTQSPGTLSLSPGERATLSCRASSGSIVYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIITDIVFGGGTKVEIK


 


CL-25806
3327
EIVLTQSPGTLSLSPGERATLSCERSSGDISYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDITFGGGTKVEIK


 


CL-25807
3328
EIVLTQSPGTLSLSPGERATLSCRASSGSIGDTYVSWYQQKPGQ




APRLLIYADDWRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIEIDIVFGGGTKVEIK


 


CL-25808
3329
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDIVFGGGTKVEIK


 


CL-25809
3330
EIVLTQSPGTLSLSPGERATLSCERSSGSIGETYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGTIIDIVFGGGTKVEIK


 


CL-25810
3331
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-25812
3332
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-25813
3333
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLLIYADDYRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIVDITFGGGTKVEIK


 


CL-25814
3334
EIVLTQSPGTLSLSPGERATLSCERSSGDIGQSYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-25815
3335
EIVLTQSPGTLSLSPGERATLSCRESSGDILYTYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIEIDITFGGGTKVEIK


 


CL-25816
3336
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHSYVSWYQQKPGQ




APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIIDVTFGGGTKVEIK


 


CL-25818
3337
EIVLTQSPGTLSLSPGERATLSCRASSGDISDSYVSWYQQKPGQ




APRLLIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIIDIVFGGGTKVEIK


 


CL-25819
3338
EIVLTQSPGTLSLSPGERATLSCRASSGSIGHSYVSWYQQKPGQ




APRLVIYGDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDVDIDVVFGGGTKVEIK


 


CL-28175
3339
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYVDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-28178
3340
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVCGGGTKVEIK


 


CL-28195
3341
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPGRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-28212
3342
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDFYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-28215
3343
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDYYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTINRMEPEDFAVY




YCQSYDINMDIVFGGGTKVEIK


 


CL-28233
3344
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYGDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-29595
3345
EIVLTQSPGTLSLSPGERATLSCRASSGSISYSYVSWYQQKPGQ




APRLVIYADDLRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-29596
3346
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ




APRLLIYADDQRASGIPYRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINVDTVFGGGTKVEIK


 


CL-29597
3347
EIVLTQSPGTLSLSPGERATLSCERSSGSIGDAYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIVDVVFGGGTKVEIK


 


CL-29598
3348
EIVLTQSPGTLSLSPGERATLSCRASSGSIGDSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIAIDIVFGGGTKVEIK


 


CL-29599
3349
EIVLTQSPGTLSLSPGERATLSCRASSGSIEYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIVDIVFGGGTKVEIK


 


CL-29600
3350
EIVLTQSPGTLSLSPGERATLSCRASSGSIEGAYVSWYQQKPGQ




APRLVIYSDDERATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIITDIVFGGGTKVEIK


 


CL-29601
3351
EIVLTQSPGTLSLSPGERATLSCERSSGSIGGTYVSWYQQKPGQ




APRLVIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIEIDITFGGGTKVEIK


 


CL-29602
3352
EIVLTQSPGTLSLSPGERATLSCERSSGDIGSCYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVVFGGGTKVEIK


 


CL-29603
3353
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYTYVSWYQQKPGQ




APRLVIYADDVRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDVDIVFGGGTKVEIK


 


CL-29604
3354
EIVLTQSPGTLSLSPGERATLSCERSSGSIWGYYVSWYQQKPGQ




APRLVIYADDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDITFGGGTKVEIK


 


CL-29605
3355
EIVLTQSPGTLSLSPGERATLSCERSSGDIGEAYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDITFGGGTKVEIK


 


CL-29606
3356
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ




APRLLIYSDDNRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGTIIDITFGGGTKVEIK


 


CL-29607
3357
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDITIDIVFGGGTKVEIK


 


CL-29608
3358
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ




APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLIIDVVFGGGTKVEIK


 


CL-29609
3359
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDITFGGGTKVEIK


 


CL-29610
3360
EIVLTQSPGTLSLSPGERATLSCRASSGDIGDSYVSWYQQKPGQ




APRLVIYADDDRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDVDVTFGGGTKVEIK


 


CL-29611
3361
EIVLTQSPGTLSLSPGERATLSCRASSGDIAHSYVSWYQQKPGQ




APRLLIYVDDLRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDITIDIVFGGGTKVEIK


 


CL-29612
3362
EIVLTQSPGTLSLSPGERATLSCERSSGDIYSYYVSWYQQKPGQ




APRLLIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLNIDVVFGGGTKVEIK


 


CL-29613
3363
EIVLTQSPGTLSLSPGERATLSCRASSGDISESYVSWYQQKPGQ




APRLLIYTDDLRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDTDIVFGGGTKVEIK


 


CL-29614
3364
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSLVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGVIVDIVFGGGTKVEIK


 


CL-29615
3365
EIVLTQSPGTLSLSPGERATLSCRASSGDIYESYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDVTIDIVFGGGTKVEIK


 


CL-29617
3366
EIVLTQSPGTLSLSPGERATLSCERSSGDIGFAYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDIVFGGGTKVEIK


 


CL-29618
3367
EIVLTQSPGTLSLSPGERAPLSCERSSGSIWDSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDVDIDIVFGGGTKVEIK


 


CL-29620
3368
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDSYVSWYQQKPGQ




APRLVIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIIDITFGGGTKVEIK


 


CL-29621
3369
EIVLTQSPGTLSLSPGERATLSCRASSGSIGYSYVSWYQQKPGQ




APRLVIYADDRRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIRDIVFGGGTKVEIK


 


CL-29622
3370
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIVDIVFGGGTKVEIK


 


CL-29623
3371
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVTFGGGTKVEIK


 


CL-29624
3372
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDSYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIIDIVFGGGTKVEIK


 


CL-29625
3373
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYFYVSWYQQKPGQ




APRLVIYVDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-29626
3374
EIVLTQSPGTLSLSPGERATLSCRASSGSIGDTYVSWYQQKPGQ




APRLLIYSDDHRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-29627
3375
EIVLTQSPGTLSLSPGERATLSCRASSGDIWYSFVSWYQQKPGQ




APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIISDIVFGGGTKVEIK


 


CL-29628
3376
EIVLTQSPGTLSLSPGERATLSCERSSGSIGETYVSWYQQKPGQ




APRLVIYADDLRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIVDIVFGGGTKVEIK


 


CL-29629
3377
EIVLTQSPGTLSLSPGERATLSCRASSGDIGDCFVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-29630
3378
EIVLTQSPGTLSLSPGERATLSCRASSGDIRHSFVSWYQQKPGQ




APRLVIYWDDYRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVTFGGGTKVEIK


 


CL-29631
3379
EIVLTQSPGTLSLSPGERATLSCERSSGSIDECYVSWYQQKPGQ




APRLVIYADDDRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVVFGGGTKVEIK


 


CL-29632
3380
EIVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQ




APRLVIYTDDRRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGSNIDVVFGGGTKVEIK


 


CL-29634
3381
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQQYDIDTDIVFGGGTKVEIK


 


CL-29635
3382
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHSYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDITFGGGTKVEIK


 


CL-29636
3383
EIVLTQSPGTLSLSPGERATLSCRASSGDICHSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIVDIVFGGGTKVEIK


 


CL-29637
3384
EIVLTQSPGTLSLSPGERATLSCERSSGSINESYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDIVFGGGTKVEIK


 


CL-29638
3385
EIVLTQSPGTLSLSPGERATLSCERSSGSIWYSYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVTFGGGTKVEIK


 


CL-29639
3386
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ




APRLLIYADDERASRIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDVVFGGGTKVEIK


 


CL-29640
3387
EIVLTQSPGTLSLSPGERATLSCRASSGDIWYSYVSWYQQKPGQ




APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDITFGGGTKVEIK


 


CL-29641
3388
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQSYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIVIDITFGGGTKVEIK


 


CL-29642
3389
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ




APRLLIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-29643
3390
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDYYVSWYQQKPGQ




APRLVIYSDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLIIDITFGGGTKVEIK


 


CL-29644
3391
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYTYVSWYQQKPGQ




APRLVIYSDDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIVDIVFGGGTKVEIK


 


CL-29645
3392
EIVLTQSPGTLSLSPGERATLSCERSSGDISGAYVSWYQQKPGQ




APRLVIYGDDERASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDVTFGGGTKVEIK


 


CL-29646
3393
EIVLTQSPGTLSLSPGERATLSCRASSGDIGRSYVSWYQQKPGQ




APRLVIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDVNTDIVFGGGTKVEIK


 


CL-29647
3394
EIVLTQSPGTLSLSPGERATLSCERSSGSIWHTYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIIDITFGGGTKVEIK


 


CL-29648
3395
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYAYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIILDVTFGGGTKVEIK


 


CL-29649
3396
EIVLTQSPGTLSLSPGERATLSCRASSGDIEHSYVSWYQQKPGQ




APRLLIYVDDQRPTGIPDRFSGSGSGTDFTLTISRLXPEDFAVY




YCQSYGIREDIVFGGGTKVEIK


 


CL-29650
3397
EIVLTQSPGTLSLSPGERATLSCERSSGSIGFSYVSWYQQKPGQ




APRLVIYADDLRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGTYVDVVFGGGTKVEIK


 


CL-29651
3398
EIVLTQSPGTLSLSPGERATLSCRASSGDIWYSYVSWYQQKPGQ




APRLVIYSDDERPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGVDVDVVFGGGTKVEIK


 


CL-29652
3399
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-29653
3400
EIVLTQSPGTLSLSPGERATLSCRASSGDIEHSYVSWYQQKPGQ




APRLLIYADDYRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDPDITFGGGTKVEIK


 


CL-29654
3401
EIVLTQSPGTLSLSPGERATLSCRASSGDISHSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDITFGGGTKVEIK


 


CL-29655
3402
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDAYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIFIDIVFGGGTKVEIK


 


CL-29656
3403
EIVLTQSPGTLSLSPGERATLSCERSSGDIGEYYVSWYQQKPGQ




APRLVIYADDRRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVTFGGGTKVEIK


 


CL-29657
3404
EIVLTQSPGTLSLSPGERATLSCERSSGSIDYAYVSWYQQKPGQ




APRLVIYSDDYRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDITFGGGTKVEIK


 


CL-29658
3405
EIVLTQSPGTLSLSPGERATLSCRASSGDIWYSYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIVIDIVFGGGTKVEIK


 


CL-29659
3406
EIVLTQSPGTLSLSPGERATLSCERSSGSIGYSYVSWYQQKPGQ




APRLVMYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDVIIDVVFGGGTKVEIK


 


CL-29660
3407
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYSYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDVTFGGGTKVEIK


 


CL-29661
3408
EIVLTQSPGTLSLSPGERATLSCRASSGSIWHSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCKSYGINIDVTFGGGTKVEIK


 


CL-29662
3409
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDVVFGGGTKVEIK


 


CL-29663
3410
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDITFGGGTKVEIK


 


CL-29664
3411
EIVLTQSPGTLSLSPGERATLSCRASSGDIRHSYVSWYQQKPGQ




APRLVIYADDDRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINTDIVFGGGTKVEIK


 


CL-29665
3412
EIVLTQSPGTLSLSPGERATLSCRASSGDIGGSYVSWYQQKPGQ




APRLVIYTDDWRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-29666
3413
EIVLTQSPGTLSLSPGERATLSCRASSGDISYSYVSWYQQKPGQ




APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIIDVVFGGGTKVEIK


 


CL-29667
3414
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDMYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-29668
3415
EIVLTQSPGTLSLSPGERATLSCERSSGDIDYTYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLTLDITFGGGTKVEIK


 


CL-29669
3416
EIVLTQSPGTLSLSPGERATLSCERSSSSIWHSYVSWYQQKPGQ




APRLVIYADDYRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVVFGGGTKVEIK


 


CL-29670
3417
EIVLTQSPGTLSLSPGERATLSCRASSGSIDYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIYIDVVFGGGTKVEIK


 


CL-29671
3418
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGQYIDVVFGGGTKVEIK


 


CL-29672
3419
EIVLTQSPGTLSLSPGERATLSCRASSGDIDESYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIIDIVFGGGTKVEIK


 


CL-29673
3420
EIVLTQSPGTLSLSPGERATLSCRASSGDIXYSYVSWYQQKPGQ




APRLVIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDSIIDVTFGGGTKVEIK


 


CL-29674
3421
EIVLTQSPGTLSLSPGERATLSCRASSGDIWYSYVSWYQQKPGQ




APRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINVDIVFGGGTKVEIK


 


CL-29675
3422
EIVLTQSPGTLSLSPGERATLSCERSSGSIMYAYVSWYQQKPGQ




APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLIIDVTFGGGTKVEIK


 


CL-29676
3423
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVSWYQQKPGQ




APRLVIYADDARATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDITFGGGTKVEIK


 


CL-29677
3424
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDISIDVTFGGGTKVEIK


 


CL-29678
3425
EIVLTQSPGTLSLSPGERATLSCERSSGSIGETYVSWYQQKPGQ




APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDIVFGGGTKVEIK


 


CL-29679
3426
EIVLTQSPGTLSLSPGERATLSCRASSGSIGDSYVSWYQQKPGQ




APRLLIYSDDDRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGISIDVTFGGGTKVEIK


 


CL-29681
3427
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHSYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDITFGGGTKVEIK


 


CL-29682
3428
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIIDIVFGGGTKVEIK


 


CL-29683
3429
EIVLTQSPGTLSLSPGERATLSCERSSGDIYSYYVSWYQQKPGQ




APRLLIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVTFGGGTKVEIK


 


CL-29684
3430
EIVLTQSPGTLSLSPGERATLSCERSSGSIWHSYVSWYQQKPGQ




APRLVIYSDDQQASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-29685
3431
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIVIDIVFGGGTKVEIK


 


CL-29686
3432
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVSWYQQKPGQ




APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLTIDIVFGGGTKVEIK


 


CL-29687
3433
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDICIDVTFGGGTKVEIK


 


CL-29688
3434
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLLIYSDDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIIDIVFGGGTKVEIK


 


CL-29689
3435
EIVLTQSPGTLSLSPGERATLSCERSSGSIGGYYVSWYQQKPGQ




APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIIDIVFGGGTKVEIK


 


CL-29690
3436
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ




APRLVIYGADLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDIVFGGGTKVEIK


 


CL-29722
3437
EIVLTQSPGTLSLSPGERATLSCERSXGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-29732
3438
EIVLTQSPGTLSLSPGERATLSCERSSVDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-29741
3439
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIHADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-29746
3440
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPVQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-29756
3441
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




ATRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-29759
3442
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYAYDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-29765
3443
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-29771
3444
EXXLTQSPGTLSLSPGERATXSCERSSGDXGDSYVSWYQQKPGQ




APRLVIYXDDQRPSGIPDRFSGSGSGTDFTLTISGLEPEDFAVY




YCQSXDINMDIVFGGGTKVEIK


 


CL-29780
3445
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGVGTKVEIK


 


CL-29781
3446
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFVVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-33580
3447
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYXDDQRPSGIPDRFSGSGSGGDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-33673
3448
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLEVDIVFGGGTKVEIK


 


CL-33674
3449
EIVLTQSPGTLSLSPGERATLSCERSSGSIWDTYVSWYQQKPGQ




APRLVIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINVDIVFGGGTKVEIK


 


CL-33676
3450
EIVLTQSPGTLSLSPGERATLSCERSSGDIWGYYVSWYQQKPGQ




APRLLIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDVVFGGGTKVEIK


 


CL-33677
3451
EIVLTQSPGTLSLSPGERATLSCERSSGSIYYTYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDVDVVFGGGTKVEIK


 


CL-33678
3452
EIVLTQSPGTLSLSPGERATLSCERSSGDIWGYYVSWYQQKPGQ




APRLLIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDITFGGGTKVEIK


 


CL-33679
3453
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGLNVDVVFGGGTKVEIK


 


CL-33680
3454
EIVLTQSPGTLSLSPGERATLSCERSSGDIYETYVSWYQQKPGQ




APRLVIYSDDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVVFGGGTKVEIK


 


CL-33681
3455
EIVLTQSPGTLSLSPGERATLSCERSSGSIWYSYVSWYQQKPGQ




APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIITDVTFGGGTKVEIK


 


CL-33684
3456
EIVLTQSPGTLSLSPGERATLSCERSSGDIWGYYVSWYQQKPGQ




APRLLIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDVVFGGGTEVEIK


 


CL-33685
3457
EIVLTQSPGTLSLSPGERATLSCERSSGDIYYTYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-33687
3458
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDVVFGGGTKVEIK


 


CL-33688
3459
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-33690
3460
EIVLTQSPGTLSLSPGERATLSCKRSSGSIYDTYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDVDSDIVFGGGTKVEIK


 


CL-33691
3461
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDVTFGGGTKVEIK


 


CL-33692
3462
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDVTFGGGTKVEIK


 


CL-33693
3463
EIVLTQSPGTLSLSPGERATLSCERSSGSIYESYVSWYQQKPGQ




APRLLIYSDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDVVFGGGTKVEIK


 


CL-33694
3464
EIVLTQSPGTLSLSPGERATLSCERSSGSIYHTYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDVTFGGGTKVEIK


 


CL-33695
3465
EIVLTQSPGTLSLSPGERATLSCERSSGSIYDTYVSWYQQKPGQ




APRLVIYSDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDIVFGGGTKVEIK


 


CL-33697
3466
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDVDIVFGGGTKVEIK


 


CL-33698
3467
EIVLTQSPGTLSLSPGERATLSCERSSGDIWXYYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLFIDVTFGGGTKVEIK


 


CL-33700
3468
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHYYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLEIDVTFGGGTKVEIK


 


CL-33704
3469
EIVLTQSPGTLSLSPGERATLSCERSSGDIWSYYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLTVDVVFGGGTKVEIK


 


CL-33707
3470
EIVLTQSPGTLSLSPGERATLSCERSSGDIWSYYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDVTFGGGTKVEIK


 


CL-33708
3471
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVTFGGGTKVEIK


 


CL-33709
3472
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVTFGGGTKVEIK


 


CL-33710
3473
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDVVFGGGTKVEIK


 


CL-33712
3474
EIVLTQSPGTLSLSPGERATLSCRASSGSIYYSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVVFGGGTKVEIK


 


CL-33713
3475
EIVLTQSPGTLSLSPGERATLSCERYSGDIWYTYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDVDVVFGGGTKVEIK


 


CL-33716
3476
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLVIYADDLRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDVTFGGGTKVEIK


 


CL-33718
3477
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLNIDVVFGGGTKVEIK


 


CL-33719
3478
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLVIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDVTFGGGTKVEIK


 


CL-33720
3479
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLVIYTDDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIETDIVFGGGTKVEIK


 


CL-33721
3480
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDVDVTFGGGTKVEIK


 


CL-33722
3481
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIYIDVVFGGGTKVEIK


 


CL-33723
3482
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDVCIDVVFGGGTKVEIK


 


CL-33725
3483
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDVVFGGGTKVEIK


 


CL-33726
3484
EIVLTQSPGTLSLSPGERATLSCERSSGSIWYSYVSWYQQKPGQ




APRLVIYSDDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDVVFGGGTKVEIK


 


CL-33727
3485
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYWDDYRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDVDIVFGGGTKVEIK


 


CL-33729
3486
EIVLTQSPGTLSLSPGERATLSCERSSGDIWSYYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDITFGGGTKVEIK


 


CL-33730
3487
EIVLTQSPGTLSLSPGERATLSCERSSGDIWSYYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLNIDTVFGGGTKVEIK


 


CL-33732
3488
EIVLTQSPGTLSLSPGERATLSCERSSCDIWQYYVSWYQQKPGQ




APRLLIYADDQRATGIPDRFSGSGSGTDFTLIISRLEPEDFAVY




YCQSYDLDIDVVFGGGTKVEIK


 


CL-33733
3489
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIITDVVFGGGTKVEIK


 


CL-33734
3490
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHTYVSWYQQKPGQ




APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDVNIDVVFGGGTKVEIK


 


CL-33740
3491
EIVLTQSPGTLSLSPGERATLSCERSSGSIWSTYVSWYQQKPGQ




APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDVVIDIVFGGGTKVEIK


 


CL-33741
3492
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLLIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLIIDIVFGGGTKVEIK


 


CL-33742
3493
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHYYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDVTFGGGTKVEIK


 


CL-33743
3494
EIVLTQSPGTLSLSPGERATLSCERSSGSIWGYYVSWYQQKPGQ




APRLVIYADDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDETIDIVFGGGTKVEIK


 


CL-33745
3495
EIVLTQSPGTLSLSPGERATLSCERSSGDIYYTYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDITFGGGTKVEIK


 


CL-33746
3496
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQSYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDVDIVFGGGTKVEIK


 


CL-33747
3497
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-33755
3498
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGTNIDVVFGGGTKVEIK


 


CL-33756
3499
EIVLTQSPGTLSLSPGERATLSCERSSGDIWESYVSWYQQKPGQ




APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIDDIVFGGGTKVEIK


 


CL-33757
3500
EIVLTQSPGTLSLSPGERATLSCERSSGDIWETYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVTFGGGTKVEIK


 


CL-33758
3501
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVVFGGGTKVEIK


 


CL-33760
3502
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGLNIDVVFGGGTKVEIK


 


CL-33761
3503
EIVLTQSPGTLSLSPGERATLSCERSSGDIWSYYVSWYQQKPGQ




APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDICIDVTFGGGTKVEIK


 


CL-33763
3504
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDIVFGGGTKVEIK


 


CL-33766
3505
EIVLTQSPGTLSLSPGERATLSCERSSGDIYDAYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDVDVVFGGGTKVEIK


 


CL-33768
3506
EIVLTQSPGTLSLSPGERATLSCERSSGSIWDTYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVVFGGGTKVEIK


 


CL-33771
3507
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQYYVSWYQQKPGQ




APRLLIYADDKRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDEDIDITFGGGTKVEIK


 


CL-33773
3508
EIVLTQSPGTLSLSPGERATLSCERSSGDIWSYYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLNIDVTFGGGTKVEIK


 


CL-33774
3509
EIVLTQSPGTLSLSPGERATLSCERSSGDIWSYYVSWYQQKPGQ




APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLYIDIVFGGGTKVEIK


 


CL-33775
3510
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ




APRLVIYADDMRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLNIDVTFGGGTKVEIK


 


CL-33776
3511
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIIDIVFGGGTKVEIK


 


CL-33777
3512
EIVLTQSPGTLSLSPGERATLSCERSSGDIYETYVSWYQQKPGQ




APRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVVFGGGTKVEIK


 


CL-33778
3513
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGLITDVTFGGGTKVEIK


 


CL-33779
3514
EIVLTQSPGTLSLSPGERATLSCERSSGSIWETYVSWYQQKPGQ




APRLVIYADDRRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDVVFGGGTKVEIK


 


CL-33781
3515
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDTDIVFGGGTKVEIK


 


CL-33782
3516
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-33785
3517
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQTYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIVIDVVFGGGTKVEIK


 


CL-33787
3518
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQYYVSWYQQKPGQ




APRLVIYADDHRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDVTFGGGTKVEIK


 


CL-33790
3519
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHTYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDVDIDITFGGGTKVEIK


 


CL-33791
3520
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQAYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIEDITFGGGTKVEIK


 


CL-33792
3521
EIVLTQSPGTLSLSPGERATLSCERSSGDIYETYVSWYQQKPGQ




APRLVIYSDDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIITDIVFGGGTKVEIK


 


CL-33794
3522
EIVLTQSPGTLSLSPGERATLSCERSSGSIWDYYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLITDIVFGGGTKVEIK


 


CL-33795
3523
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-33796
3524
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLIRDIVFGGGTKVEIK


 


CL-33799
3525
EIVLTQSPGTLSLSPGERATLSCERSSGSIYETYVSWYQQKPGQ




APRLLIYADDWRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDITVDVVFGGGTKVEIK


 


CL-33801
3526
EIVLTQSPGTLSLSPGERATLSCERSSGDIWESYVSWYQQKPGQ




APRLVIYSDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIIDDIVFGGGTKVEIK


 


CL-33802
3527
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDITFGGGTKVEIK


 


CL-33813
3528
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDVVFGGGTKVEIK


 


CL-33814
3529
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-33815
3530
EIVLTQSPGTLSLSPGERATLSCERSSGDIYETYVSWYQQKPGQ




APRLVIYSDDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDVDVVFGGGTKVEIK


 


CL-33816
3531
EIVLTQSPGTLSLSPGERATLSCERSSGDIYETYVSWYQQKPGQ




APRLVIYSDDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINVDVVFGGGTKVEIK


 


CL-33817
3532
EIVLTQSPGTLSLSPGERATLSCRASSGDISDKYVSWYQQKPGQ




APRLVIYADDYRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLCIDVTFGGGTKVEIK


 


CL-33819
3533
EIVLTQSPGTLSLSPGERATLSCRASSGDISDKYVSWYQQKPGQ




APRLLIYADDWRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDVDVVFGGGTKVEIK


 


CL-33825
3534
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQYYVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLDIDVTFGGGTKVEIK


 


CL-33826
3535
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLEIDVVFGGGTKVEIK


 


CL-33828
3536
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ




APRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDITVDVVFGGGTKVEIK


 


CL-33829
3537
EIVLTQSPGTLSLSPGERATLSCERSSGSIWYSYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVTFGGGTKVEIK


 


CL-33832
3538
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLIIDVTFGGGTKVEIK


 


CL-33833
3539
EIVLTQSPGTLSLSPGERATLSCERSSGDIWETYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDVDIVFGGGTKVEIK


 


CL-33834
3540
EIVLTQSPGTLSLSPGERATLSCERSSGSIWYSYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDSDIVFGGGTKVEIK


 


CL-33836
3541
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINVDIVFGGGTKVEIK


 


CL-33837
3542
EIVLTQSPGTLSLSPGERATLSCERSSGDIYQTYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDVVFGGGTKVEIK


 


CL-33839
3543
EIVLTQSPGTLSLSPGERATLSCERSSGSIWETYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGVDIDVVFGGGTKVEIK


 


CL-33840
3544
EIVLTQSPGTLSLSPGERATLSCERSSGDIYETYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVVFGGGTKVEIK


 


CL-33841
3545
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQYYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLFIDVTFGGGTKVEIK


 


CL-33844
3546
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ




APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIYVDIVFGGGTKVEIK


 


CL-33847
3547
EIVLTQSPGTLSLSPGERATLSCERSSGSIYYTYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIEIDITFGGGTKVEIK


 


CL-33848
3548
EIVLTQSPGTLSLSPGERATLSCERSSGDIYETYVSWYQQKPGQ




APRLVIYSDDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDTDIVFGGGTKVEIK


 


CL-33849
3549
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-33854
3550
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHTYVSWYQQKPGQ




APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINVDVVFGGGTKVEIK


 


CL-33857
3551
EIVLTQSPGTLSLSPGERATLSCERSSGDIWESYVSWYQQKPGQ




APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-33858
3552
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHTYVSWYQQKPGQ




APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIISDVVFGGGTKVEIK


 


CL-33862
3553
EIVLTQSPGTLSLSPGERATLSCERSSGSIWGTYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVTFGGGTKVEIK


 


CL-41468
3554
EIVLTQSPGTLSLPPGERATLSCKRSSGSIYDTYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLTIDITFGGGTKVEIK


 


CL-41469
3555
EIVLTQSPGTLSLSPGERATLSCERSSGSIWHSYVSWYQQKPGQ




APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIYIDVVFGGGTRSKLS


 


CL-41472
3556
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ




APRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLTIDITFGGGTKVEIK


 


CL-41477
3557
EIVLTQSPGTLSLSPGERATPSCRASSGSIWYSFVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-41479
3558
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQPYDLFIDVTFGGGTKVEIK


 


CL-41480
3559
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQSYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAGY




YCQSYGINIDVVFGGGTKVEIK


 


CL-41486
3560
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDYYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLFIDVTFGGGTKVEIK


 


CL-41505
3561
EIVLTQSPGTLSLSPGERATLSCERSSGSIWHSYVSWYQQKPGQ




APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIETDIVFGGGTKVEIK


 


CL-41509
3562
EIVLTQSPGTWSLSPGERATLSCERSSGSNYDTYVSWYQQKPGQ




APRLLIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIETDIVFGGGTKVEIK


 


CL-41528
3563
EIVLTQSPGTLSLSPGERATLSCERSSGSIWHSYVSWYQQKPGQ




APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIYIDVVFGGDTKVEIK


 


CL-41529
3564
EIVLTQSPGTLSLSSGERATLSCERSSGSNYDTYVSWYQQKPGQ




APRLLIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIETDIVFGGGTKVEIK


 


CL-41532
3565
EIVLTQSPGTLSLSPGERATLSCRASSGSTWYSFVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-41535
3566
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLTIDITFGGGTKVEIK


 


CL-41536
3567
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLFIDXTFGGGTKVEIK


 


CL-41539
3568
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ




APRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEGFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-41543
3569
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ




ASRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-41547
3570
EIVLTQSPGTLSLSPGERATLSCERSSGSIWHSYVSWYQQKPGQ




APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIYIDVVFGGGTNVEIK


 


CL-41550
3571
EIVLTQSPGTLSLSPGERATLSCKRSSGSIYDTYVSWYQQKPGQ




APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLTIDITFGGGTKVEIK


 


CL-41554
3572
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQSYVSWYQQKPGQ




APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-41556
3573
EIVLTQSPGTLSLSPGERATLSCERSSGSIWHSYVSWYQQKPGQ




APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIYIDVVFGGGTKVEIK


 


CL-41557
3574
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ




APRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIIIDIVFGGGTKVEIK


 


CL-41560
3575
EIFLTQSPGTLSLSPGKKATLSGKRSSGSIYNTYFSGYQQKPGQ




APKRVIYSDDRRPSGIPDRFSGSGXGTDFTLTISXLEPKDFAVY




YCQSYDLTINLXFGGGTKVXIX


 


CL-41561
3576
EIVLTQSPGTLSLSPGERATLSCERSSGSNYDTYVSWYQQKPGQ




APRLLIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIETDIVFGGGTKVEIK


 


CL-41562
3577
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




SPRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-41569
3578
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPRGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-41577
3579
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVVFGGGTKVEIS


 


CL-41581
3580
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSRYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-41591
3581
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGIDIDVVFGGGTKVEIK


 


CL-41599
3582
KSSLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-41600
3583
EIVLTQSLGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-41615
3584
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQMYVSWYQQKPGQ




APRLVIYGDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDITFGGGTKVEIK


 


CL-41616
3585
EIVLTQSPGTLSLPPGERATLSCERSSGDIWQTYVSWYQQKPGQ




APRLVIYGDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDITFGGGHKGRNX


 


CL-41639
3586
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDSAVY




YCQSYDLFIDVTFGGGTKVEIK


 


CL-41642
3587
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQRKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-41645
3588
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ




APRLVIYGDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDITFGGGTKVEIK


 


CL-41646
3589
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQSYVSWYQQKPGQ




APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDIDIDVVFGGGTKVEIK


 


CL-41649
3590
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDLFIDVTFGGGTKVEIK


 


CL-41654
3591
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVH




YCQSYGINIDVVFGGGTKVEIK


 


CL-41655
3592
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ




APRLVIYGDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-41668
3593
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVC




YCQSYGINIDVVFGGGTKVEIK


 


CL-41673
3594
EIVLTQSPGTLSLSPGERAPLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIX


 


CL-41685
3595
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTINRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-41705
3596
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ




APRLLIYADDQRASGIPDRLSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-41707
3597
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADGQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-41710
3598
EIVLTQSPSTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-41713
3599
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIN


 


CL-41714
3600
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVELS


 


CL-41720
3601
EIVLTQIPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-41725
3602
EIVLTQSPGTLSLSPGERATLSCERSSGSNYDTYVSWYQQKPGQ




APRLLIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-41727
3603
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YRQSYGINIDVVFGGGTKVEIK


 


CL-41729
3604
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ




APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYGINIDVVFGGGTKVEIK


 


CL-41732
3605
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPIGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-41735
3606
EIVLTQSPGTLSLSPVERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-41737
3607
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY




YCQSYDINIDIVFGGGTKVEIK


 


CL-41738
3608
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQAP




RLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC




QQSWYDPLTFGQGTKLEIK


 


CL-41739
3609
EIVLTQSPATLSLSPGERAALSCRASQSVSTHMHWYQQKPGQAP




RLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC




QQSWYDPLTFGQGTKLEIK


 


CL-41740
3610
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQAP




RLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC




QQSRYDPLTFGQGTKLEIK


 


CL-41742
3611
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQAP




RLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC




QQSWYDPLTFGQGTKLEIK


 


CL-41751
3612
AKLCXPVPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQAP




RLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC




QQSWYDPLTFGQGTKLEIK


 


CL-41752
3613
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQAP




RLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC




QQSWYDPLTFGQGTKLRSN
















TABLE 48







Amino Acid Residues Found In Each Position Of The Heavy


Chain Variable Region During The Affinity Maturation


Of Anti-PDGF-BB Antibody hBDI-9E8.4


hBDI-9E8.4-2I|CL-22843 Heavy Chain Variable Region








SEQ ID NO:
Sequence





3614
         1         2         3         4         5         6



123456789012345678901234567890123456789012345678901234567890



EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWDDDKY



                           I Y SEVSIDL             L DCYGEEH



                           R A    R L                C NNGTC



                             D      A                G HHVID



                             T      C                  V AQN



                             M      V                  E HVS



                             R      Y                  I YNA



                             L      R                  P NRF



                             C      T                  A QYG



                             F      E                  C SL



                             W      S                  G LM



                             P                            C


 



         7         8         9        10        11        12



12345678901234567890123456789012345678901234567890123456789012



YNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSS



 SL  NS                                 LYQTGWPN E Y



  T   T                                NVASPWS D



                                       LKYMFRK Y



                                       MYWVCIR A



                                       VLPLYFM C



                                       RDLFAAA N



                                       KGVNEME M



                                       FAEDLYI W



                                       CMKHVSV T



                                       TRFYSLL Q



                                       ESCTDGW G



                                         RRDP I



                                         Q KQ L



                                         K V  P



                                         E N



                                         P E
















TABLE 49







Amino Acid Residues Found In Each Position Of The Light Chain


Variable Region During The Affinity Maturation


Of Anti-PDGF Antibody hBDI-9E8.4


hBDI-9E8.4-2I|CL-22843 Light Chain Variable Region








SEQ ID NO:
Sequence





3615
         1         2         3         4         5         6



123456789012345678901234567890123456789012345678901234567890



EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGI



 F                     RAY CSNWYTFFPR  R         MHGYGLQAIR



                       KE  VYTYQYLS G              SA RP T



                           S MSNMR                 WV H  R



                              MHKH                 T  W  G



                              HGAN                 L  Y



                              DECC                 V  M



                              RSFA                 F  K



                              EKLD                 N  D



                              NFES                 P  A



                              CRWT                 E  E



                              ALD                  D  N



                              LCP                     V



                              VAG                     S



                              FP                      F



                              T                       P



                              Q



                              K


 



         7         8         9         10         11



12345678901234567890123456789012345678901234567890



PDRFSGSGSGTDFTLTISRLEFEDFAVYYCQSYDINIDIVFGGGTKVEIK



                             RKP GLFTNVT



                               Q  VDSPL



                               H  EEVAG



                                  TTDYT



                                  SIRGS



                                  QYEHN



                                  RCMEF



                                  NVLVA



                                  KSPLH



                                  GRFQR



                                  AANTQ



                                  CLK



                                  FG



                                   H



                                   K
















TABLE 50







Variable Region Sequences of h9E8.4 Affinity


Matured Clones Converted to IgG












Protein
V Region


SEQ ID NO:
Clone
Region
123456789012345678901234567890





3616
CL-33578 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIQSGW





TNYEFDYWGQGTMVTVSS


 


3617
CL-33578
CDR-H1
GFSLSTYGMGVG


 


3618
CL-33578
CDR-H2
NIWWDDDKYYNPSLKN


 


3619
CL-33578
CDR-H3
IQSGWTNYEFDY


 


3620
CL-33578 VL

EIVLTQSPGTLSLSPGERATLSCERS





SGDIGDSYVSWYQQKPGQAPRLVIYA





DDQRPSGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYDINIDIVFGGG





TKVEIK


 


3621
CL-33578
CDR-L1
ERSSGDIGDSYVS


 


3622
CL-33578
CDR-L2
ADDQRPS


 


3623
CL-33578
CDR-L3
QSYDINIDIV


 


3624
CL-33587 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIQSMW





TRYDFDYWGQGTMVTVSS


 


3625
CL-33587
CDR-H1
GFSLSTYGMGVG


 


3626
CL-33587
CDR-H2
NIWWDDDKYYNPSLKN


 


3627
CL-33587
CDR-H3
IQSMWTRYDFDY


 


3628
CL-33587 VL

EIVLTQSPGTLSLSPGERATLSCERS





SGDIGDSYVSWYQQKPGQAPRLVIYA





DDQRPSGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYDINIDIVFGGG





TKVEIK


 


3629
CL-33587
CDR-L1
ERSSGDIGDSYVS


 


3630
CL-33587
CDR-L2
ADDQRPS


 


3631
CL-33587
CDR-L3
QSYDINIDIV


 


3632
CL-33675 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIESSG





PKYSFDYWGQGTMVTVSS


 


3633
CL-33675
CDR-H1
GFSLSTYGMGVG


 


3634
CL-33675
CDR-H2
NIWWDDDKYYNPSLKN


 


3635
CL-33675
CDR-H3
IESSGPKYSFDY


 


3636
CL-33675 VL

EIVLTQSPGTLSLSPGERATLSCRAS





SGSIWYSFVSWYQQKPGQAPRLLIYA





DDQRASGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYGINIDVVFGGG





TKVEIK


 


3637
CL-33675
CDR-L1
RASSGSIWYSFVS


 


3638
CL-33675
CDR-L2
ADDQRAS


 


3639
CL-33675
CDR-L3
QSYGINIDVV


 


3640
CL-33682 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTIKDTSKN





QVVLTMTNMDPVDTATYYCARIESSW





TSYSFDYWGQGTMVTVSS


 


3641
CL-33682
CDR-H1
GFSLSTYGMGVG


 


3642
CL-33682
CDR-H2
NIWWDDDKYYNPSLKN


 


3643
CL-33682
CDR-H3
IESSWTSYSFDY


 


3644
CL-33682 VL

EIVLTQSPGTLSLSPGERATLSCERS





SGSNYDTYVSWYQQKPGQAPRLLIYA





DDLRASGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYGINIDVVFGGG





TKVEIK


 


3645
CL-33682
CDR-L1
ERSSGSNYDTYVS


 


3646
CL-33682
CDR-L2
ADDLRAS


 


3647
CL-33682
CDR-L3
QSYGINIDVV


 


3648
CL-33683 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIETIG





PKYSFDYWGQGTMVTVSS


 


3649
CL-33683
CDR-H1
GFSLSTYGMGVG


 


3650
CL-33683
CDR-H2
NIWWDDDKYYNPSLKN


 


3651
CL-33683
CDR-H3
IETIGPKYSFDY


 


3652
CL-33683 VL

EIVLTQSPGTLSLSPGERATLSCRAS





SGSIWYSFVSWYQQKPGQAPRLLIYA





DDQRASGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYGINIDVVFGGG





TKVEIK


 


3653
CL-33683
CDR-L1
RASSGSIWYSFVS


 


3654
CL-33683
CDR-L2
ADDQRAS


 


3655
CL-33683
CDR-L3
QSYGINIDVV


 


3656
CL-33699 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGIGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIESMG





PKYAFDYWGQGTMVTVSS


 


3657
CL-33699
CDR-H1
GFSLSTYGMGIG


 


3658
CL-33699
CDR-H2
NIWWDDDKYYNPSLKN


 


3659
CL-33699
CDR-H3
IESMGPKYAFDY


 


3660
CL-33699 VL

EIVLTQSPGTLSLSPGERATLSCRAS





SGSIWYSFVSWYQQKPGQAPRLLIYA





DDQRASGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYGINIDVVFGGG





TKVEIK


 


3661
CL-33699
CDR-L1
RASSGSIWYSFVS


 


3662
CL-33699
CDR-L2
ADDQRAS


 


3663
CL-33699
CDR-L3
QSYGINIDVV


 


3664
CL-33701 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIESLG





TSYSFDYWGQGTMVTVSS


 


3665
CL-33701
CDR-H1
GFSLSTYGMGVG


 


3666
CL-33701
CDR-H2
NIWWDDDKYYNPSLKN


 


3667
CL-33701
CDR-H3
IESLGTSYSFDY


 


3668
CL-33701 VL

EIVLTQSPGTLSLSPGERATLSCERS





SGDIWDYYVSWYQQKPGQAPRLVIYA





DDQRPSGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYDLFIDVTFGGG





TKVEIK


 


3669
CL-33701
CDR-L1
ERSSGDIWDYYVS


 


3670
CL-33701
CDR-L2
ADDQRPS


 


3671
CL-33701
CDR-L3
QSYDLFIDVT


 


3672
CL-33706 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIETMG





PKYSFDYWGQGTMVTVSS


 


3673
CL-33706
CDR-H1
GFSLSTYGMGVG


 


3674
CL-33706
CDR-H2
NIWWDDDKYYNPSLKN


 


3675
CL-33706
CDR-H3
IETMGPKYSFDY


 


3676
CL-33706 VL

EIVLTQSPGTLSLSPGERATLSCRAS





SGSIWYSFVSWYQQKPGQAPRLLIYA





DDQRASGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYGINIDVVFGGG





TKVEIK


 


3677
CL-33706
CDR-L1
RASSGSIWYSFVS


 


3678
CL-33706
CDR-L2
ADDQRAS


 


3679
CL-33706
CDR-L3
QSYGINIDVV


 


3680
CL-33731 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIESIP





TSYSFDYWGQGTMVTVSS


 


3681
CL-33731
CDR-H1
GFSLSTYGMGVG


 


3682
CL-33731
CDR-H2
NIWWDDDKYYNPSLKN


 


3683
CL-33731
CDR-H3
IESIPTSYSFDY


 


3684
CL-33731 VL

EIVLTQSPGTLSLSPGERATLSCERS





SGSIWQSYVSWYQQKPGQAPRLVIYA





DDQRATGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYDIDIDVVFGGG





TKVEIK


 


3685
CL-33731
CDR-L1
ERSSGSIWQSYVS


 


3686
CL-33731
CDR-L2
ADDQRAT


 


3687
CL-33731
CDR-L3
QSYDIDIDVV


 


3688
CL-33737 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRKPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIESSG





PKYSFDYWGQGTMVTVSS


 


3689
CL-33737
CDR-H1
GFSLSTYGMGVG


 


3690
CL-33737
CDR-H2
NIWWDDDKYYNPSLKN


 


3691
CL-33737
CDR-H3
IESSGPKYSFDY


 


3692
CL-33737 VL

EIVLTQSPGTLSLSPGERATLSCRAS





SGSIWYSFVSWYQQKPGQAPRLLIYA





DDQRASGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYGINIDVVFGGG





TKVEIK


 


3693
CL-33737
CDR-L1
RASSGSIWYSFVS


 


3694
CL-33737
CDR-L2
ADDQRAS


 


3695
CL-33737
CDR-L3
QSYGINIDVV


 


3696
CL-33759 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIESVW





TRYDFDYWGQGTMVTVSS


 


3697
CL-33759
CDR-H1
GFSLSTYGMGVG


 


3698
CL-33759
CDR-H2
NIWWDDDKYYNPSLKN


 


3699
CL-33759
CDR-H3
IESVWTRYDFDY


 


3700
CL-33759 VL

EIVLTQSPGTLSLSPGERATLSCERS





SGDIWQTYVSWYQQKPGQAPRLVIYG





DDQRASGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYDIDIDITFGGG





TKVEIK


 


3701
CL-33759
CDR-L1
ERSSGDIWQTYVS


 


3702
CL-33759
CDR-L2
GDDQRAS


 


3703
CL-33759
CDR-L3
QSYDIDIDIT


 


3704
CL-33767 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIESIG





PKYSFDYWGQGTMVTVSS


 


3705
CL-33767
CDR-H1
GFSLSTYGMGVG


 


3706
CL-33767
CDR-H2
NIWWDDDKYYNPSLKN


 


3707
CL-33767
CDR-H3
IESIGPKYSFDY


 


3708
CL-33767 VL

EIVLTQSPGTLSLSPGERATLSCRAS





SGSIWYSFVSWYQQKPGQAPRLLIYA





DDQRASGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYGINIDVVFGGG





TKVEIK


 


3709
CL-33767
CDR-L1
RASSGSIWYSFVS


 


3710
CL-33767
CDR-L2
ADDQRAS


 


3711
CL-33767
CDR-L3
QSYGINIDVV


 


3712
CL-33769 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIESIG





PKYSFDYWGQGTMVTVSS


 


3713
CL-33769
CDR-H1
GFSLSTYGMGVG


 


3714
CL-33769
CDR-H2
NIWWDDDKYYNPSLKN


 


3715
CL-33769
CDR-H3
IESIGPKYSFDY


 


3716
CL-33769 VL

EIVLTQSPGTLSLSPGERATLSCRAS





SGSIWYSFVSWYQQKPGQAPRLLIYA





DDQRASGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYGINIDVVFGGG





TKVEIK


 


3717
CL-33769
CDR-L1
RASSGSIWYSFVS


 


3718
CL-33769
CDR-L2
ADDQRAS


 


3719
CL-33769
CDR-L3
QSYGINIDVV


 


3720
CL-33797 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIESLG





WSYSFDYWGQGTMVTVSS


 


3721
CL-33797
CDR-H1
GFSLSTYGMGVG


 


3722
CL-33797
CDR-H2
NIWWDDDKYYNPSLKN


 


3723
CL-33797
CDR-H3
IESLGWSYSFDY


 


3724
CL-33797 VL

EIVLTQSPGTLSLSPGERATLSCERS





SGDIWDYYVSWYQQKPGQAPRLVIYA





DDQRPSGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYDLFIDVTFGGG





TKVEIK


 


3725
CL-33797
CDR-L1
ERSSGDIWDYYVS


 


3726
CL-33797
CDR-L2
ADDQRPS


 


3727
CL-33797
CDR-L3
QSYDLFIDVT


 


3728
CL-33803 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIESLP





TSYSFDYWGQGTMVTVSS


 


3729
CL-33803
CDR-H1
GFSLSTYGMGVG


 


3730
CL-33803
CDR-H2
NIWWDDDKYYNPSLKN


 


3731
CL-33803
CDR-H3
IESLPTSYSFDY


 


3732
CL-33803 VL

EIVLTQSPGTLSLSPGERATLSCERS





SGDIWDTYVSWYQQKPGQAPRLLIYA





DDQRPSGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYDIIIDIVFGGG





TKVEIK


 


3733
CL-33803
CDR-L1
ERSSGDIWDTYVS


 


3734
CL-33803
CDR-L2
ADDQRPS


 


3735
CL-33803
CDR-L3
QSYDIIIDIV


 


3736
CL-33805 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIESHW





WSYAFDYWGQGTMVTVSS


 


3737
CL-33805
CDR-H1
GFSLSTYGMGVG


 


3738
CL-33805
CDR-H2
NIWWDDDKYYNPSLKN


 


3739
CL-33805
CDR-H3
IESHWWSYAFDY


 


3740
CL-33805 VL

EIVLTQSPGTLSLSPGERATLSCERS





SGSNYDTYVSWYQQKPGQAPRLLIYA





DDLRASGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYGIETDIVFGGG





TKVEIK


 


3741
CL-33805
CDR-L1
ERSSGSNYDTYVS


 


3742
CL-33805
CDR-L2
ADDLRAS


 


3743
CL-33805
CDR-L3
QSYGIETDIV


 


3744
CL-33811 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIESSW





TTYSFDYWGQGTMVTVSS


 


3745
CL-33811
CDR-H1
GFSLSTYGMGVG


 


3746
CL-33811
CDR-H2
NIWWDDDKYYNPSLKN


 


3747
CL-33811
CDR-H3
IESSWTTYSFDY


 


3748
CL-33811 VL

EIVLTQSPGTLSLSPGERATLSCERS





SGSIWHSYVSWYQQKPGQAPRLLIYS





DDQRATGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYGIYIDVVFGGG





TKVEIK


 


3749
CL-33811
CDR-L1
ERSSGSIWHSYVS


 


3750
CL-33811
CDR-L2
SDDQRAT


 


3751
CL-33811
CDR-L3
QSYGIYIDVV


 


3752
CL-33812 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIESNP





WKYSFDYWGQGTMVTVSS


 


3753
CL-33812
CDR-H1
GFSLSTYGMGVG


 


3754
CL-33812
CDR-H2
NIWWDDDKYYNPSLKN


 


3755
CL-33812
CDR-H3
IESNPWKYSFDY


 


3756
CL-33812 VL

EIVLTQSPGTLSLSPGERATLSCERS





SGDIWQSYVSWYQQKPGQAPRLVIYS





DDQRASGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYGINIDVVFGGG





TKVEIK


 


3757
CL-33812
CDR-L1
ERSSGDIWQSYVS


 


3758
CL-33812
CDR-L2
SDDQRAS


 


3759
CL-33812
CDR-L3
QSYGINIDVV


 


3760
CL-33820 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIESSF





TSYSFDYWGQGTMVTVSS


 


3761
CL-33820
CDR-H1
GFSLSTYGMGVG


 


3762
CL-33820
CDR-H2
NIWWDDDKYYNPSLKN


 


3763
CL-33820
CDR-H3
IESSFTSYSFDY


 


3764
CL-33820 VL

EIVLTQSPGTLSLSPGERATLSCKRS





SGSIYDTYVSWYQQKPGQAPRLVIYS





DDQRPSGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYDLTIDITFGGG





TKVEIK


 


3765
CL-33820
CDR-L1
KRSSGSIYDTYVS


 


3766
CL-33820
CDR-L2
SDDQRPS


 


3767
CL-33820
CDR-L3
QSYDLTIDIT


 


3768
CL-33845 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIVSDW





TTYSFDYWGQGTMVTVSS


 


3769
CL-33845
CDR-H1
GFSLSTYGMGVG


 


3770
CL-33845
CDR-H2
NIWWDDDKYYNPSLKN


 


3771
CL-33845
CDR-H3
IVSDWTTYSFDY


 


3772
CL-33845 VL

EIVLTQSPGTLSLSPGERATLSCRAS





SGSIWYSFVSWYQQKPGQAPRLLIYA





DDQRASGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYGINIDVVFGGG





TKVEIK


 


3773
CL-33845
CDR-L1
RASSGSIWYSFVS


 


3774
CL-33845
CDR-L2
ADDQRAS


 


3775
CL-33845
CDR-L3
QSYGINIDVV


 


3776
CL-33855 VH

EVTLRESGPALVKPTQTLTLTCTFSG





FSLSTYGMGVGWIRQPPGKALEWLAN





IWWDDDKYYNPSLKNRLTISKDTSKN





QVVLTMTNMDPVDTATYYCARIETFG





PKYSFDYWGQGTMVTVSS


 


3777
CL-33855
CDR-H1
GFSLSTYGMGVG


 


3778
CL-33855
CDR-H2
NIWWDDDKYYNPSLKN


 


3779
CL-33855
CDR-H3
IETFGPKYSFDY


 


3780
CL-33855 VL

EIVLTQSPGTLSLSPGERATLSCRAS





SGSIWYSFVSWYQQKPGQAPRLLIYA





DDQRASGIPDRFSGSGSGTDFTLTIS





RLEPEDFAVYYCQSYGINIDVVFGGG





TKVEIK


 


3781
CL-33855
CDR-L1
RASSGSIWYSFVS


 


3782
CL-33855
CDR-L2
ADDQRAS


 


3783
CL-33855
CDR-L3
QSYGINIDVV
















TABLE 51







Summary of Protein Expression And Purification Of


Affinity Matured Humanized Anti-Human PDGF-BB


Antibodies













Octet Titer
~Yield
SEC (%



Name
(mg/L)1
(mg/L)2
monomer)3
















CL-33578-IgG
176.5
98.9
91.3



CL-33587-IgG
155.7
109.1
94.2



CL-33675-IgG
275.2
57.7
96.9



CL-33682-IgG
203.6
80.7
94.6



CL-33683-IgG
136.7
24.5
48.1



CL-33701-IgG
114.9
79.2
97.9



CL-33706-IgG
169.8
25.8
100.0



CL-33731-IgG
137.0
73.6
95.8



CL-33803-IgG
98.0
50.5
96.7



CL-33805-IgG
227.5
66.5
97.9



CL-33811-IgG
190.2
31.7
99.0



CL-33812-IgG
171.0
76.4
96.7



CL-33820-IgG
135.3
75.0
95.7



CL-33855-IgG
50.9
13.8
94.3



CL-33699-IgG
ND
10.5
81.7



CL-33737-IgG
ND
5.0
88.0



CL-33759-IgG
ND
18.5
100.0



CL-33767-IgG
ND
16.5
50.9



CL-33845-IgG
ND
0.8
60.6







ND = Not Determined



1Octet titer is the amount of IgG in the unpurified supernatant as determined by protein A binding compared to a standard curve using an Octet instrument.



2Yield is determined by the total amount of purified protein in mg divided by the total cell culture volume in liters.



3SEC % monomer is determined using HPLC size exclusion chromatography.













TABLE 52







Biacore Binding of Affinity-Matured Humanized


Anti-PDGF Antibodies












Antibody
kon (M−1 s−1)
koff (M−1)
KD (M)







CL-33578
≧9.0E+07 
2.70E−05
≦3.0E−13 



CL-33587
≧9.0E+07 
2.00E−05
≦2.2E−13 



CL-33675
3.60E+07
2.20E−05
6.10E−13



CL-33682
≧9.0E+07 
2.20E−05
≦2.4E−13 



CL-33683
1.90E+07
8.20E−06
4.40E−13



CL-33701
7.30E+07
1.80E−05
2.40E−13



CL-33706
1.80E+07
1.20E−05
6.90E−13



CL-33731
8.10E+07
1.60E−05
2.00E−13



CL-33803
≧9.0E+07 
1.40E−05
≦1.6E−13 



CL-33805
6.80E+07
1.50E−05
2.10E−13



CL-33811
2.70E+07
1.20E−05
4.50E−13



CL-33812
6.30E+07
1.90E−05
3.00E−13



CL-33820
≧9.8E+07 
1.60E−05
≦1.6E−13 



CL-33855
2.00E+07
≦1.0E−06 
≦5.0E−14 







*Heterogeneous off-rate






Affinity matured humanized anti-PDGF-BB antibodies were characterized for PDGF-BB binding and potency. Human PDGF-BB binding affinity was determined by Biacore analysis (Example 1.1). Potency was evaluated in both cell-based and ELISA formats. The ability to block binding of hPDGF-BB to hPDGF-Rβ was tested in a competition ELISA format (Example 1.13) Inhibition of human and cynomolgus PDGF-BB-induced cell proliferation was assessed using NIH-3T3 cells (Examples 1.15 and 1.16). The data is summarized in Table 53 below.







TABLE 53







Summary of Characterization of Affinity Matured Humanized


Anti-Human PDGF-BB Antibodies









PDGF-BB IC50 Potency (nM)











hPDGF-BB
cynoPDGF-BB
hPDGF-BB/


Affinity Matured
NIH-3T3
NIH-3T3
hPDGFR□


Humanized IgG
Proliferation
Proliferation
Competition













CL-33578-Ig
0.033
0.023
0.049


CL-33587-Ig
0.046
0.029
<0.1


CL-33675-Ig
0.04
0.024
0.054


CL-33682-Ig
0.03
0.019
0.069


CL-33683-Ig
0.029
0.028
0.126


CL-33699-Ig
0.033
0.016
0.072


CL-33706-Ig
0.035
0.019
0.081


CL-33731Ig
0.036
0.023
0.068


CL-33759-Ig
0.293
0.18
1.267


CL-33811-Ig
0.032
0.012
0.1


CL-33812-Ig
0.033
0.028
0.043


CL-33820-Ig
0.017
0.013
0.066


CL-33855-Ig
0.037
0.019
0.162


CL-33701-Ig
0.056
0.012
0.059


CL-33737-Ig
0.03
0.024
0.092


CL-33803-Ig
0.024
0.018
0.044


C-L33767-Ig
0.09
0.042
0.114


CL-33845-Ig
0.171
0.073
0.409


CL-33805-Ig
0.039
0.018
0.063









Example 9: Methods of Selecting Preferred Humanized Antibodies as DVD-Ig Building Blocks
Example 9.1: A Technique for Assessing the Stability of Regions of the Parental Antibodies Intended for DVD-Ig Protein Incorporation
The technique of differential scanning calorimetry (DSC) can be used to determine the thermal stabilities of the different domains of an antibody (e.g. CH2, CH3, CH1-CL, and VH-VL). The temperature of the highest peak in a DSC thermogram (plotted as heat capacity versus temperature) of an antibody has been shown to correspond to the midpoint of the unfolding transition or process of that antibody's VH-VL region due to increasing temperature. This may be interpreted as a measure of VH-VL thermal stability. VH-VL regions with high thermal stability in the antibody format will also likely have high thermal stability when incorporated into the DVD-Ig format as one of the binding domains. Therefore, antibodies can be screened to determine those with VH-VL regions of high thermal stability. Those regions can then be incorporated into the DVD-Ig format to increase the probability of generating a more stable DVD-Ig molecule.
Example 9.2: Determination of the Thermal Stability of the VH-VL Regions of Anti-VEGF mAbs and Anti-PDGF mAbs by Differential Scanning Calorimetry
A total of 73 mAbs (45 anti-VEGF and 28 anti-PDGF) were selected and analyzed by DSC (Example 2.2) and the thermal stabilities of their VH-VL regions were quantitated by determining the temperature of the highest peak in the DSC thermograms as detailed in Example 9.1 (Table 54).







TABLE 54







Thermal Stability of Anti-VEGF and Anti-PDGF Antibodies











Temperature of highest peak in


Name
Target Antigen
DSC thermogram (° C.)












hBDB-4G8.1
VEGF
71.97


hBDB-4G8.2
VEGF
69.13


hBDB-4G8.3
VEGF
65.65


hBDB-4G8.4
VEGF
75.27


hBDB-4G8.5
VEGF
73.07


hBDB-4G8.6
VEGF
68.68


hBDB-4G8.7
VEGF
76.27


hBDB-4G8.8
VEGF
73.16


hBDB-4G8.9
VEGF
68.95


hBDB-4G8.10
VEGF
73.44


hBDB-4G8.11
VEGF
69.77


hBDB-4G8.12
VEGF
67.48


hBDB-4G8.13
VEGF
67.12


hBDB-4G8.14
VEGF
63.4


hBDB-4G8.15
VEGF
69.41


h4G8.3 EI
VEGF
68.31


h4G8 CL-32416
VEGF
68.95


h4G8 CL-34449
VEGF
72.7


h4G8 CL-34455
VEGF
70.69


h4G8 CL-34469
VEGF
70.23


h4G8 CL-34475
VEGF
70.69


h4G8 CL-34522
VEGF
67.49


h4G8 CL-34540
VEGF
69.87


h4G8 CL-34633
VEGF
69.22


h4G8 CL-34538
VEGF
71.15


h4G8 CL-34570
VEGF
66.84


h4G8 CL-34565
VEGF
71.15


hBEW-9A8.17
VEGF
64.56


hBEW-9A8.21
VEGF
54.25


hBEW-5C3.4
VEGF
66.94


hBEW-9E10.1
VEGF
71.88


hBEW-9E10.3
VEGF
71.24


hBEW-9E10.4
VEGF
71.77


hBEW-9E10.6
VEGF
71.24


hBEW-9A8.20
VEGF
61.85


hBEW-5C3.1
VEGF
63.15


hBEW-5C3.5
VEGF
64.83


hBEW-9E10.2
VEGF
71.37


hBEW-9E10.5
VEGF
71.24


hBEW-1B10.1
VEGF
87.95


hBEW-1B10.2
VEGF
86.38


hBEW-1E3.1
VEGF
62.74


hBEW-1E3.2
VEGF
66.29


hBEW-1E3.4
VEGF
66.11


hBEW-1E3.5
VEGF
68.83


hBDI-9E8.1
PDGF
77.6


hBDI-9E8.2
PDGF
76.28


hBDI-9E8.3
PDGF
87.4


hBDI-9E8.4
PDGF
84.2


hBDI-9E8.5
PDGF
77.69


hBDI-9E8.6
PDGF
75.91


hBDI-9E8.7
PDGF
87.4


hBDI-9E8.8
PDGF
84.29


hBDI-9E8.9
PDGF
82.09


hBDI-9E8.10
PDGF
83.37


hBDI-9E8.11
PDGF
80.9


hBDI-9E8.12
PDGF
82.64


hBDI-9E8.13
PDGF
85.39


CL-33578-IgG
PDGF
75.03


CL-33587-IgG
PDGF
76.37


CL-33675-IgG
PDGF
87.4


CL-33682-IgG
PDGF
78.52


CL-33683-IgG
PDGF
82.55


CL-33701-IgG
PDGF
73.62


CL-33706-IgG
PDGF
86.85


CL-33731-IgG
PDGF
77.33


CL-33803-IgG
PDGF
74.26


CL-33805-IgG
PDGF
80.35


CL-33811-IgG
PDGF
79.71


CL-33812-IgG
PDGF
78.15


CL-33820-IgG
PDGF
78.88


CL-33855-IgG
PDGF
82.18


hBFU-3E2.1
PDGF
68.31









Example 10: Generation of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules
The variable domain sequences from humanized anti-human VEGF-A and anti-human PDGF-BB mAbs were used to design the VH and VL domains of anti-human VEGF-A/anti-human PDGF-BB DVD-Ig molecules. In some cases, variable regions were synthesized using two-step PCR. Primers were designed with homologous flanking regions to the cloning vector and the linker region between each DVD variable pair. In some cases, variable regions were generated using gene synthesis. Bacterial transformations were performed to identify positive clones and constructs were harvested and purified for use in mammalian transfection using standard protocols known in the art.
The variable domains of the heavy and light chain were cloned in-frame into mutant human IgG1 (L234, 235A) heavy-chain or mutant human IgG1 (L234, 235A, H435A) heavy-chain, and kappa light-chain constant regions, respectively, into pHybE vectors to generate anti-human VEGF-A/anti-human PDGF-BB DVD-Ig molecules.







TABLE 55







Amino Acid Sequences of DVD-Ig Linkers









Seq ID




No
Name
Sequence





3784
HG-short
ASTKGP


 


3785
HG-long
ASTKGPSVFPLAP


 


3786
GS-H10
GGGGSGGGGS


 


3787
LK-short
RTVAAP


 


3788
LK-long
RTVAAPSVFIFPP


 


3789
GS-L10
RGGSGGGGSG


 


3790
GS-L10(dR)
GGSGGGGSGG


 


3791
GS-L11
RGGSGGGGSGG


 


3792

AKTTPKLEEGEFSEAR


 


3793

AKTTPKLEEGEFSEARV


 


3794

AKTTPKLGG


 


3795

SAKTTPKLGG


 


3796

SAKTTP


 


3797

RADAAP


 


3798

RADAAPTVS


 


3799

RADAAAAGGPGS


 


3800

RADAAAA(G4S)4


 


3801

SAKTTPKLEEGEFSEARV


 


3802

ADAAP


 


3803

ADAAPTVSIFPP


 


3804

TVAAP


 


3805

TVAAPSVFIFPP


 


3806

QPKAAP


 


3807

QPKAAPSVTLFPP


 


3808

AKTTPP


 


3809

AKTTPPSVTPLAP


 


3810

AKTTAP


 


3811

AKTTAPSVYPLAP


 


3812

ASTKGP


 


3813

ASTKGPSVFPLAP


 


3814

GGGGSGGGGSGGGGS


 


3815

GENKVEYAPALMALS


 


3816

GPAKELTPLKEAKVS


 


3817

GHEAAAVMQVQYPAS


 


3818

TVAAPSVFIFPPTVAAPSVFIFPP


 


3819

ASTKGPSVFPLAPASTKGPSVFPLAP


 


3820

GGGGSGGGGS


 


3821

GGSGGGGSG




G/S based sequences




(e.g., G4S (SEQ ID NO: 3822)




and G4S repeats (“G4S”




disclosed as SEQ ID NO: 3822))
















TABLE 56







Heavy (H) and Light Chain (L) Composition of Anti-VEGF-A/Anti-PDGF-BB DVD-


Ig Molecules (first and second polypeptide chains are listed in alternating rows of the table)



















SEQ ID NO








VD1-X1-


SEQ ID

DVD-Ig Variable Domain
Outer Variable

Inner Variable
VD2


NO
Corporate ID
Name
Domain Name
Linker
Domain Name
Formula






NA
AB014-GS-9E8.4a
AB014 VH
GS-H10
hBDI-9E8.4 VH






AB014 VL
GS-L10
hBDI-9E8.4 VL



NA
9E8.4-GS-AB014a
hBDI-9E8.4 VH
GS-H10
AB014 VH





hBDI-9E8.4 VL
GS-L10
AB014 VL



NA
AB014-SS-9E8.4a
AB014 VH
HG-short
hBDI-9E8.4 VH





AB014 VL
LK-short
hBDI-9E8.4 VL



NA
9E8.4-SS-AB014a
hBDI-9E8.4 VH
HG-short
AB014 VH





hBDI-9E8.4 VL
LK-short
AB014 VL



NA
AB014-SL-9E8.4a
AB014 VH
HG-short
hBDI-9E8.4 VH





AB014 VL
LK-long
hBDI-9E8.4 VL



NA
9E8.4-SL-AB014a
hBDI-9E8.4 VH
HG-short
AB014 VH





hBDI-9E8.4 VL
LK-long
AB014 VL



NA
AB014-LS-9E8.4a
AB014 VH
HG-long
hBDI-9E8.4 VH





AB014 VL
LK-short
hBDI-9E8.4 VL



NA
9E8.4-LS-AB014a
hBDI-9E8.4 VH
HG-long
AB014 VH





hBDI-9E8.4 VL
LK-short
AB014 VL



PR-1563988
9E8.4-GS-4G8.3a
hBDI-9E8.4 VH
GS-H10
hBDB-4G8.3 VH





hBDI-9E8.4 VL
GS-L10
hBDB-4G8.3 VL



PR-1563990
9E8.4-SS-4G8.3a
hBDI-9E8.4 VH
HG-short
hBDB-4G8.3 VH





hBDI-9E8.4 VL
LK-short
hBDB-4G8.3 VL



PR-1563998
9E8.4-SL-4G8.3a
hBDI-9E8.4 VH
HG-short
hBDB-4G8.3 VH





hBDI-9E8.4 VL
LK-long
hBDB-4G8.3 VL



PR-1564009
9E8.4-LS-4G8.3a
hBDI-9E8.4 VH
HG-long
hBDB-4G8.3 VH





hBDI-9E8.4 VL
LK-short
hBDB-4G8.3 VL



PR-1564010
4G8.3-GS-9E8.4a
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4 VH





hBDB-4G8.3 VL
GS-H10
hBDI-9E8.4 VL



PR-1564011
4G8.3-SS-9E8.4a
hBDB-4G8.3 VH
HG-short
hBDI-9E8.4 VH





hBDB-4G8.3 VL
LK-short
hBDI-9E8.4 VL



PR-1564012
4G8.3-SL-9E8.4a
hBDB-4G8.3 VH
HG-short
hBDI-9E8.4 VH





hBDB-4G8.3 VL
LK-long
hBDI-9E8.4 VL



PR-1564013
4G8.3-LS-9E8.4a
hBDB-4G8.3 VH
HG-long
hBDI-9E8.4 VH





hBDB-4G8.3 VL
LK-short
hBDI-9E8.4 VL



PR-1569574
9E8.4-GS-4G8.3
hBDI-9E8.4 VH
GS-H10
hBDB-4G8.3 VH





hBDI-9E8.4 VL
GS-L10
hBDB-4G8.3 VL



PR-1569579
9E8.4-SL-4G8.3
hBDI-9E8.4 VH
HG-short
hBDB-4G8.3 VH





hBDI-9E8.4 VL
LK-long
hBDB-4G8.3 VL



PR-1575573
9E8.4-LS-4G8.3
hBDI-9E8.4 VH
HG-long
hBDB-4G8.3 VH





hBDI-9E8.4 VL
LK-short
hBDB-4G8.3 VL



PR-1572102
4G8.3-GS-9E8.4 (g)
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4 VH





hBDB-4G8.3 VL
GS-L10
hBDI-9E8.4 VL



PR-1572103
4G8.3-GS(11)-9E8.4 (g)
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4 VH





hBDB-4G8.3 VL
GS-L11
hBDI-9E8.4 VL



PR-1572104
4G8.3-GS(noR)-9E8.4 (g)
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4 VH





hBDB-4G8.3 VL
GS-
hBDI-9E8.4 VL






L10 (dR)



PR-1572105
4G8.3-SL-9E8.4 (g)
hBDB-4G8.3 VH
HG-short
hBDI-9E8.4 VH





hBDB-4G8.3 VL
LK-long
hBDI-9E8.4 VL



PR-1572106
4G8.3-LS-9E8.4 (g)
hBDB-4G8.3 VH
HG-long
hBDI-9E8.4 VH





hBDB-4G8.3 VL
LK-short
hBDI-9E8.4 VL



PR-1575832
4G8.3-GS-9E8.4E
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4E VH





hBDB-4G8.3 VL
GS-L10
hBDI-9E8.4E VL



PR-1575834
4G8.3-SL-9E8.4E
hBDB-4G8.3 VH
HG-short
hBDI-9E8.4E VH





hBDB-4G8.3 VL
LK-long
hBDI-9E8.4E VL



PR-1575835
4G8.3-LS-9E8.4E
hBDB-4G8.3 VH
HG-long
hBDI-9E8.4E VH





hBDB-4G8.3 VL
LK-short
hBDI-9E8.4E VL



PR-1577165
9A8.12-GS-9E8.4E
hBEW-9A8.12
GS-H10
hBDI-9E8.4E VH





VH





hBEW-9A8.12 VL
GS-L10
hBDI-9E8.4E VL



PR-1577166
9A8.12-SL-9E8.4E
hBEW-9A8.12
HG-short
hBDI-9E8.4E VH





VH





hBEW-9A8.12 VL
LK-long
hBDI-9E8.4E VL



PR-1577547
9A8.12-LS-9E8.4E
hBEW-9A8.12
HG-long
hBDI-9E8.4E VH





VH





hBEW-9A8.12 VL
LK-short
hBDI-9E8.4E VL



PR-1578137
9E8.4E-GS-9A8.12
hBDI-9E8.4E VH
GS-H10
hBEW-9A8.12 VH





hBDI-9E8.4E VL
GS-L10
hBEW-9A8.12 VL



PR-1577548
9E8.4E-SL-9A8.12
hBDI-9E8.4E VH
HG-short
hBEW-9A8.12 VH





hBDI-9E8.4E VL
LK-long
hBEW-9A8.12 VL



PR-1577550
9E8.4E-LS-9A8.12
hBDI-9E8.4E VH
HG-long
hBEW-9A8.12 VH





hBDI-9E8.4E VL
LK-short
hBEW-9A8.12 VL



PR-1598261
4G8.2-GS-9E8.4
hBDB-4G8.2 VH
GS-H10
hBDI-9E8.4 VH





hBDB-4G8.2 VL
GS-L10
hBDI-9E8.4 VL



PR-1598262
4G8.4-GS-9E8.4
hBDB-4G8.4 VH
GS-H10
hBDI-9E8.4 VH





hBDB-4G8.4 VL
GS-L10
hBDI-9E8.4 VL



PR-1598263
4G8.5-GS-9E8.4
hBDB-4G8.5 VH
GS-H10
hBDI-9E8.4 VH





hBDB-4G8.5 VL
GS-L10
hBDI-9E8.4 VL



PR-1598264
4G8.12-GS-9E8.4
hBDB-4G8.12 VH
GS-H10
hBDI-9E8.4 VH





hBDB-4G8.12 VL
GS-L10
hBDI-9E8.4 VL



PR-1598265
4G8.13-GS-9E8.4
hBDB-4G8.13 VH
GS-H10
hBDI-9E8.4 VH





hBDB-4G8.13 VL
GS-L10
hBDI-9E8.4 VL



PR-1598266
4G8.14-GS-9E8.4
hBDB-4G8.14 VH
GS-H10
hBDI-9E8.4 VH





hBDB-4G8.14 VL
GS-L10
hBDI-9E8.4 VL



PR-1613183
CL-34565_GS_CL-33675
CL-34565 VH
GS-H10
CL-33675 VH





CL-34565 VL
GS-
CL-33675 VL






L10 (dR)



PR-1613184
CL-34565_GS_9E8.4
CL-34565 VH
GS-H10
hBDI-9E8.4 VH





CL-34565 VL
GS-
hBDI-9E8.4 VL






L10 (dR)



PR-1613185
CL-34565_GS_3E2.1
CL-34565 VH
GS-H10
hBFU-3E2.1 VH





CL-34565 VL
GS-
hBFU-3E2.1 VL






L10 (dR)



PR-1611291
4G8.5_GS_CL-33675
hBDB-4G8.5 VH
GS-H10
CL-33675 VH





hBDB-4G8.5 VL
GS-
CL-33675 VL






L10 (dR)



PR-1612489
4G8.5_GS_9E8.4
hBDB-4G8.5 VH
GS-H10
hBDI-9E8.4 VH





hBDB-4G8.5 VL
GS-
hBDI-9E8.4 VL






L10 (dR)



PR-1610560
4G8.5_GS_3E2.1
hBDB-4G8.5 VH
GS-H10
hBFU-3E2.1 VH





hBDB-4G8.5 VL
GS-
hBFU-3E2.1 VL






L10 (dR)



PR-1610561
9E10.1_GS_CL-33675
hBEW-9E10.1 VH
GS-H10
CL-33675 VH





hBEW-9E10.1 VL
GS-
CL-33675 VL






L10 (dR)



PR-1612491
9E10.1_GS_9E8.4
hBEW-9E10.1 VH
GS-H10
hBDI-9E8.4 VH





hBEW-9E10.1 VL
GS-
hBDI-9E8.4 VL






L10 (dR)



PR-1610562
9E10.1_GS_3E2.1
hBEW-9E10.1 VH
GS-H10
hBFU-3E2.1 VH





hBEW-9E10.1 VL
GS-
hBFU-3E2.1 VL






L10 (dR)



PR-1612492
9E10.6_GS_CL-33675
hBEW-9E10.6 VH
GS-H10
CL-33675 VH





hBEW-9E10.6 VL
GS-
CL-33675 VL






L10 (dR)



PR-1612493
9E10.6_GS_9E8.4
hBEW-9E10.6 VH
GS-H10
hBDI-9E8.4 VH





hBEW-9E10.6 VL
GS-
hBDI-9E8.4 VL






L10 (dR)



PR-1610563
9E10.6_GS_3E2.1
hBEW-9E10.6 VH
GS-H10
hBFU-3E2.1 VH





hBEW-9E10.6 VL
GS-
hBFU-3E2.1 VL






L10 (dR)



PR-1611292
1B10.1_GS_CL-33675
hBEW-1B10.1 VH
GS-H10
CL-33675 VH





hBEW-1B10.1 VL
GS-
CL-33675 VL






L10 (dR)



PR-1612494
1B10.1_GS_9E8.4
hBEW-1B10.1 VH
GS-H10
hBDI-9E8.4 VH





hBEW-1B10.1 VL
GS-
hBDI-9E8.4 VL






L10 (dR)



PR-1610564
1B10.1_GS_3E2.1
hBEW-1B10.1 VH
GS-H10
hBFU-3E2.1 VH





hBEW-1B10.1 VL
GS-
hBFU-3E2.1 VL






L10 (dR)



PR-1611293
1E3.4_GS_CL-33675
hBEW-1E3.4 VH
GS-H10
CL-33675 VH





hBEW-1E3.4 VL
GS-
CL-33675 VL






L10 (dR)



PR-1611294
1E3.4_GS_9E8.4
hBEW-1E3.4 VH
GS-H10
hBDI-9E8.4 VH





hBEW-1E3.4 VL
GS-
hBDI-9E8.4 VL






L10 (dR)



PR-1612495
1E3.4_GS_3E2.1
hBEW-1E3.4 VH
GS-H10
hBFU-3E2.1 VH





hBEW-1E3.4 VL
GS-
hBFU-3E2.1 VL






L10 (dR)



PR-1613186
CL-33675_GS_CL-34565
CL-33675 VH
GS-H10
CL-34565 VH





CL-33675 VL
GS-
CL-34565 VL






L10 (dR)



PR-1612496
CL-33675_GS_4G8.5
CL-33675 VH
GS-H10
hBDB-4G8.5 VH





CL-33675 VL
GS-
hBDB-4G8.5 VL






L10 (dR)



PR-1611295
CL-33675_GS_9E10.1
CL-33675 VH
GS-H10
hBEW-9E10.1 VH





CL-33675 VL
GS-
hBEW-9E10.1 VL






L10 (dR)



PR-1611296
CL-33675_GS_9E10.6
CL-33675 VH
GS-H10
hBEW-9E10.6 VH





CL-33675 VL
GS-
hBEW-9E10.6 VL






L10 (dR)



PR-1612498
CL-33675_GS_1B10.1
CL-33675 VH
GS-H10
hBEW-1B10.1 VH





CL-33675 VL
GS-
hBEW-1B10.1






L10 (dR)
VL



PR-1611297
CL-33675_GS_1E3.4
CL-33675 VH
GS-H10
hBEW-1E3.4







VH





CL-33675 VL
GS-
hBEW-1E3.4 VL






L10 (dR)



PR-1613187
9E8.4_GS_CL-34565
hBDI-9E8.4 VH
GS-H10
CL-34565 VH





hBDI-9E8.4 VL
GS-
CL-34565 VL






L10 (dR)



PR-1613188
9E8.4_GS_4G8.5
hBDI-9E8.4 VH
GS-H10
hBDB-4G8.5 VH





hBDI-9E8.4 VL
GS-
hBDB-4G8.5 VL






L10 (dR)



PR-1611298
9E8.4_GS_9E10.1
hBDI-9E8.4 VH
GS-H10
hBEW-9E10.1







VH






GS-
hBEW-9E10.1H






L10 (dR)
VL



PR-1611299
9E8.4_GS_9E10.6
hBDI-9E8.4 VH
GS-H10
hBEW-9E10.6







VH





hBDI-9E8.4 VL
GS-
hBEW-9E10.6






L10 (dR)
VL



PR-1611300
9E8.4_GS_1B10.1
hBDI-9E8.4 VH
GS-H10
hBEW-1B10.1 VH





hBDI-9E8.4 VL
GS-
hBEW-1B10.1






L10 (dR)
VL



PR-1611301
9E8.4_GS_1E3.4
hBDI-9E8.4 VH
GS-H10
hBEW-1E3.4







VH





hBDI-9E8.4 VL
GS-
hBEW-1E3.4 VL






L10 (dR)



PR-1613189
3E2.1_GS_CL-34565
hBFU-3E2.1 VH
GS-H10
CL-34565 VH





hBFU-3E2.1 VL
GS-
CL-34565 VL






L10 (dR)



PR-1612499
3E2.1_GS_4G8.5
hBFU-3E2.1 VH
GS-H10
hBDB-4G8.5 VH





hBFU-3E2.1 VL
GS-
hBDB-4G8.5 VL






L10 (dR)



PR-1612500
3E2.1_GS_9E10.1
hBFU-3E2.1 VH
GS-H10
hBEW-9E10.1







VH





hBFU-3E2.1 VL
GS-
hBEW-9E10.1






L10 (dR)
VL



PR-1612501
3E2.1_GS_9E10.6
hBFU-3E2.1 VH
GS-H10
hBEW-9E10.6







VH





hBFU-3E2.1 VL
GS-
hBEW-9E10.6






L10 (dR)
VL



PR-1612502
3E2.1_GS_1B10.1
hBFU-3E2.1 VH
GS-H10
hBEW-1B10.1 VH





hBFU-3E2.1 VL
GS-
hBEW-1B10.1






L10 (dR)
VL



PR-1613190
3E2.1_GS_1E3.4
hBFU-3E2.1 VH
GS-H10
hBEW-1E3.4







VH





hBFU-3E2.1 VL
GS-
hBEW-1E3.4 VL






L10 (dR)



PR-1629646
9E10.1_SL_CL-33675
hBEW-9E10.1 VH
HG-short
CL-33675 VH





hBEW-9E10.1 VL
LK-long
CL-33675 VL



PR-1629647
1B10.1_SL_CL-33675
hBEW-1B10.1 VH
HG-short
CL-33675 VH





hBEW-1B10.1 VL
LK-long
CL-33675 VL



PR-1629648
9E10.1_LS_CL-33675
hBEW-9E10.1 VH
HG-long
CL-33675 VH





hBEW-9E10.1 VL
LK-short
CL-33675 VL



PR-1629649
1B10.1_LS_CL-33675
hBEW-1B10.1 VH
HG-long
CL-33675 VH





hBEW-1B10.1 VL
LK-short
CL-33675 VL



PR-1564883
DVD3896a
hBDI-5H1.9 VH
HG-short
hBDB-4G8.13







VH





hBDI-5H1.9 VL
LK-long
hBDB-4G8.13







VL



PR-1564893
DVD3897a
hBDI-5H1.9 VH
HG-short
hBDB-4G8.14







VH





hBDI-5H1.9 VL
LK-long
hBDB-4G8.14







VL



PR-1564896
DVD3898a
hBDI-5H1.9 VH
HG-short
hBDB-4G8.15







VH





hBDI-5H1.9 VL
LK-long
hBDB-4G8.15







VL



PR-1564898
DVD3899a
hBDI-9E8.12 VH
HG-short
hBDB-4G8.14







VH





hBDI-9E8.12 VL
LK-long
hBDB-4G8.14







VL



PR-1564899
DVD3900a
hBDI-9E8.12 VH
HG-short
hBDB-4G8.15







VH





hBDI-9E8.12 VL
LK-long
hBDB-4G8.15







VL



PR-1565023
DVD3901a
hBDI-9E8.9 VH
HG-short
hBDB-4G8.13







VH





hBDI-9E8.9 VL
LK-long
hBDB-4G8.13







VL



PR-1565029
DVD3902a
hBDI-9E8.9 VH
HG-short
hBDB-4G8.14







VH





hBDI-9E8.9 VL
LK-long
hBDB-4G8.14







VL



PR-1565030
DVD3903a
hBDI-9E8.9 VH
HG-short
hBDB-4G8.15







VH





hBDI-9E8.9 VL
LK-long
hBDB-4G8.15







VL



PR-1565031
DVD3904a
hBDI-5H1.13 VH
HG-short
hBDB-4G8.14







VH





hBDI-5H1.13 VL
LK-long
hBDB-4G8.14







VL



PR-1565032
DVD3905a
hBDI-9E8.12 VH
HG-short
hBDB-4G8.15







VH





hBDI-9E8.12 VL
LK-long
hBDB-4G8.15







VL



PR-1565035
DVD3906a
hBDI-5H1.13 VH
HG-short
hBDB-4G8.15







VH





hBDI-5H1.13 VL
LK-long
hBDB-4G8.15







VL



PR-1565033
DVD3907a
hBDI-9E8.13 VH
HG-short
hBDB-4G8.15







VH





hBDI-9E8.13 VL
LK-long
hBDB-4G8.15







VL





aThese DVDs were made with Ig gamma-1 constant region L234A, L235A, all other DVDs made with Ig gamma-1 constant region L234A, L235A, and H435A.













TABLE 57







Heavy (H) and Light Chain (L) Amino Acid Composition of


Some Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules


(Linker sequence in italics; CDR sequences in bold;


HC = heavy chain and LC = light chain)









Sequence
DVD-Ig Variable
Sequence


Identifier
Domain (Corporate ID)
12345678901234567890123456789012





SEQ ID NO: 3823
4G8.3-GS-9E8.4 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNY



(PR-1569574)
GMYWVRQAPGQGLEWMGWINTETGKPTYADDF




KGRFVFSLDTSVSTAYLQISSLKAEDTAVYYC




ARTNYYYRSYIFYFDYWGQGTMVTVSSGGGGS




GGGGSEVTLRESGPALVKPTQTLTLTCTFSGF




SLSTYGMGVGWIRQPPGKALEWLANIWWDDDK




YYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD




TATYYCARIESIGTTYSFDYWGQGTMVTVSSA




STKGPSVFPLAPSSKSTSGGTAALGCLVKDYF




PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL




SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK




VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPK




PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY




VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH




QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ




PREPQVYTLPPSREEMTKNQVSLTCLVKGFYP




SDIAVEWESNGQPENNYKTTPPVLDSDGSFFL




YSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQ




KSLSLSPGK


 


SEQ ID NO: 3824
4G8.3-GS-9E8.4 LC
DTVLTQSPATLSLSPGERATLSCRASESVSTH



(PR-1569574)
MHWYQQKPGQAPRLLIYGASNLESGVPARFSG




SGSGTDFTLTISSLEPEDFAVYFCQQSWNDPF




TFGQGTKLEIKRGGSGGGGSGEFVLTQSPGTL




SLSPGERATLSCERSSGDIGDSYVSWYQQKPG




QAPRLVIYADDQRPSGIPDRFSGSGSGTDFTL




TISRLEPEDFAVYYCQSYDINIDIVFGGGTKV




EIKGTVAAPSVFIFPPSDEQLKSGTASVVCLL




NNFYPREAKVQWKVDNALQSGNSQESVTEQDS




KDSTYSLSSTLTLSKADYEKHKVYACEVTHQG




LSSPVTKSFNRGEC


 


SEQ ID NO: 3825
4G8.3-SL-9E8.4 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNY



(PR-1569579)
GMYWVRQAPGQGLEWMGWINTETGKPTYADDF




KGRFVFSLDTSVSTAYLQISSLKAEDTAVYYC




ARTNYYYRSYIFYFDYWGQGTMVTVSSASTKG




PEVTLRESGPALVKPTQTLTLTCTFSGFSLST




YGMGVGWIRQPPGKALEWLANIWWDDDKYYNP




SLKNRLTISKDTSKNQVVLTMTNMDPVDTATY




YCARIESIGTTYSFDYWGQGTMVTVSSASTKG




PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV




TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV




TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK




SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDT




LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV




EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL




NGKEYKCKVSNKALPAPIEKTISKAKGQPREP




QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA




VEWESNGQPENNYKTTPPVLDSDGSFFLYSKL




TVDKSRWQQGNVFSCSVMHEALHNAYTQKSLS




LSPGK


 


SEQ ID NO: 3826
4G8.3-SL-9E8.4 LC
DTVLTQSPATLSLSPGERATLSCRASESVSTH



(PR-1569579)
MHWYQQKPGQAPRLLIYGASNLESGVPARFSG




SGSGTDFTLTISSLEPEDFAVYFCQQSWNDPF




TFGQGTKLEIKRTVAAPSVFIFPPEFVLTQSP




GTLSLSPGERATLSCERSSGDIGDSYVSWYQQ




KPGQAPRLVIYADDQRPSGIPDRFSGSGSGTD




FTLTISRLEPEDFAVYYCQSYDINIDIVFGGG




TKVEIKGTVAAPSVFIFPPSDEQLKSGTASVV




CLLNNFYPREAKVQWKVDNALQSGNSQESVTE




QDSKDSTYSLSSTLTLSKADYEKHKVYACEVT




HQGLSSPVTKSFNRGEC


 


SEQ ID NO: 3827
4G8.3-LS-9E8.4 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNY



(PR-1575573)
GMYWVRQAPGQGLEWMGWINTETGKPTYADDF




KGRFVFSLDTSVSTAYLQISSLKAEDTAVYYC




ARTNYYYRSYIFYFDYWGQGTMVTVSSASTKG




PSVFPLAPEVTLRESGPALVKPTQTLTLTCTF




SGFSLSTYGMGVGWIRQPPGKALEWLANIWWD




DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMD




PVDTATYYCARIESIGTTYSFDYWGQGTMVTV




SSASTKGPSVFPLAPSSKSTSGGTAALGCLVK




DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL




YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV




DKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLF




PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF




NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT




VLHQDWLNGKEYKCKVSNKALPAPIEKTISKA




KGQPREPQVYTLPPSREEMTKNQVSLTCLVKG




FYPSDIAVEWESNGQPENNYKTTPPVLDSDGS




FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNA




YTQKSLSLSPGK


 


SEQ ID NO: 3828
4G8.3-LS-9E8.4 LC
DTVLTQSPATLSLSPGERATLSCRASESVSTH



(PR-1575573)
MHWYQQKPGQAPRLLIYGASNLESGVPARFSG




SGSGTDFTLTISSLEPEDFAVYFCQQSWNDPF




TFGQGTKLEIKRTVAAPEFVLTQSPGTLSLSP




GERATLSCERSSGDIGDSYVSWYQQKPGQAPR




LVIYADDQRPSGIPDRFSGSGSGTDFTLTISR




LEPEDFAVYYCQSYDINIDIVFGGGTKVEIKG




TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY




PREAKVQWKVDNALQSGNSQESVTEQDSKDST




YSLSSTLTLSKADYEKHKVYACEVTHQGLSSP




VTKSFNRGEC


 


SEQ ID NO: 3829
4G8.3-GS-9E8.4 (g)
EVQLVQSGSELKKPGASVKVSCKASGYTFTNY



HC (PR-1572102)
GMYWVRQAPGQGLEWMGWINTETGKPTYADDF




KGRFVFSLDTSVSTAYLQISSLKAEDTAVYYC




ARTNYYYRSYIFYFDYWGQGTMVTVSSGGGGS




GGGGSEVTLRESGPALVKPTQTLTLTCTFSGF




SLSTYGMGVGWIRQPPGKALEWLANIWWDDDK




YYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD




TATYYCARIESIGTTYSFDYWGQGTMVTVSSA




STKGPSVFPLAPSSKSTSGGTAALGCLVKDYF




PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL




SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK




VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPK




PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY




VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH




QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ




PREPQVYTLPPSREEMTKNQVSLTCLVKGFYP




SDIAVEWESNGQPENNYKTTPPVLDSDGSFFL




YSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQ




KSLSLSPGK


 


SEQ ID NO: 3830
4G8.3-GS-9E8.4 (g) LC
DTVLTQSPATLSLSPGERATLSCRASESVSTH



(PR-1572102)
MHWYQQKPGQAPRLLIYGASNLESGVPARFSG




SGSGTDFTLTISSLEPEDFAVYFCQQSWNDPF




TFGQGTKLEIKRGGSGGGGSGEFVLTQSPGTL




SLSPGERATLSCERSSGDIGDSYVSWYQQKPG




QAPRLVIYADDQRPSGIPDRFSGSGSGTDFTL




TISRLEPEDFAVYYCQSYDINIDIVFGGGTKV




EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL




NNFYPREAKVQWKVDNALQSGNSQESVTEQDS




KDSTYSLSSTLTLSKADYEKHKVYACEVTHQG




LSSPVTKSFNRGEC


 


SEQ ID NO: 3831
4G8.3-SL-9E8.4 (g) HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNY



(PR-1572105)
GMYWVRQAPGQGLEWMGWINTETGKPTYADDF




KGRFVFSLDTSVSTAYLQISSLKAEDTAVYYC




ARTNYYYRSYIFYFDYWGQGTMVTVSSASTKG




PEVTLRESGPALVKPTQTLTLTCTFSGFSLST




YGMGVGWIRQPPGKALEWLANIWWDDDKYYNP




SLKNRLTISKDTSKNQVVLTMTNMDPVDTATY




YCARIESIGTTYSFDYWGQGTMVTVSSASTKG




PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV




TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV




TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK




SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDT




LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV




EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL




NGKEYKCKVSNKALPAPIEKTISKAKGQPREP




QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA




VEWESNGQPENNYKTTPPVLDSDGSFFLYSKL




TVDKSRWQQGNVFSCSVMHEALHNAYTQKSLS




LSPGK


 


SEQ ID NO: 3832
4G8.3-SL-9E8.4 (g) LC
DTVLTQSPATLSLSPGERATLSCRASESVSTH



(PR-1572105)
MHWYQQKPGQAPRLLIYGASNLESGVPARFSG




SGSGTDFTLTISSLEPEDFAVYFCQQSWNDPF




TFGQGTKLEIKRTVAAPSVFIFPPEFVLTQSP




GTLSLSPGERATLSCERSSGDIGDSYVSWYQQ




KPGQAPRLVIYADDQRPSGIPDRFSGSGSGTD




FTLTISRLEPEDFAVYYCQSYDINIDIVFGGG




TKVEIKrTVAAPSVFIFPPSDEQLKSGTASVV




CLLNNFYPREAKVQWKVDNALQSGNSQESVTE




QDSKDSTYSLSSTLTLSKADYEKHKVYACEVT




HQGLSSPVTKSFNRGEC


 


SEQ ID NO: 3833
9E10.1_GS_CL-33675
EIQLVQSGSELKKPGASVKVSCKASGYTFTNY



HC (PR-1610561)
GMYWVKQAPGQGLEYMGWIDTETGRPTYADDF




KGRFVFSLDTSVSTAYLQISSLKAEDTAVYFC




ARWSGDTTGIRGPWFAYWGQGTLVTVSSGGGG




SGGGGSEVTLRESGPALVKPTQTLTLTCTFSG




FSLSTYGMGVGWIRQPPGKALEWLANIWWDDD




KYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSGPKYSFDYWGQGTMVTVSS




ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY




FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS




LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK




KVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPP




KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW




YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL




HQDWLNGKEYKCKVSNKALPAPIEKTISKAKG




QPREPQVYTLPPSREEMTKNQVSLTCLVKGFY




PSDIAVEWESNGQPENNYKTTPPVLDSDGSFF




LYSKLTVDKSRWQQGNVFSCSVMHEALHNAYT




QKSLSLSPGK


 


SEQ ID NO: 3834
9E10.1_GS_CL-33675
DIRMTQSPSSLSASVGDRVTIECLASEDIYSD



LC (PR-1610561)
LAWYQQKPGKSPKLLIYNANGLQNGVPSRFSG




SGSGTDYSLTISSLQPEDVATYFCQQYNYFPG




TFGQGTKLEIKGGSGGGGSGGEIVLTQSPGTL




SLSPGERATLSCRASSGSIWYSFVSWYQQKPG




QAPRLLIYADDQRASGIPDRFSGSGSGTDFTL




TISRLEPEDFAVYYCQSYGINIDVVFGGGTKV




EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL




NNFYPREAKVQWKVDNALQSGNSQESVTEQDS




KDSTYSLSSTLTLSKADYEKHKVYACEVTHQG




LSSPVTKSFNRGEC


 


SEQ ID NO: 3835
1B10.1_GS_CL-33675
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKY



HC (PR-1611292)
DMAWFRQAPGKGLEWVASITTSGVGTYYRDSV




KGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYC




ARGYGAMDAWGQGTTVTVSSGGGGSGGGGSEV




TLRESGPALVKPTQTLTLTCTFSGFSLSTYGM




GVGWIRQPPGKALEWLANIWWDDDKYYNPSLK




NRLTISKDTSKNQVVLTMTNMDPVDTATYYCA




RIESSGPKYSFDYWGQ




GTMVTVSSASTKGPSVFPLAPSSKSTSGGTAA




LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV




LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK




PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGG




PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE




DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR




VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE




KTISKAKGQPREPQVY




TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEW




ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD




KSRWQQGNVFSCSVMHEALHNAYTQKSLSLSP




GK


 


SEQ ID NO: 3836
1B10.1_GS_CL-33675
DIQMTQSPSSLSASVGDRVTITCKASQDIDDY



LC (PR-1611292)
LSWYQQKPGKSPKLVIYAATRLADGVPSRFSG




SGSGTDYTLTISSLQPEDFATYYCLQSSSTPW




TFGGGTKVEIKGGSGGGGSGGEIVLTQSPGTL




SLSPGERATLSCRASSGSIWYSFVSWYQQKPG




QAPRLLIYADDQRASGIPDRFSGSGSGTDFTL




TISRLEPEDFAVYYCQSYGINIDVVFGGGTKV




EIKRTVAAPSVFIFPP




SDEQLKSGTASVVCLLNNFYPREAKVQWKVDN




ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA




DYEKHKVYACEVTHQGLSSPVTKSFNRGEC









Example 11: Generation of CO-DVD-Ig Molecules
Cross-over DVD-Ig binding proteins are constructed as shown below. Each of VD1, VD2, VD3 and VD4 could be the VH or VL from a mAb. In cross-over DVD-Ig, VD1 and VD4 form one antigen binding domain. VD2 and VD3 form another binding domain.











TABLE 58







Heavy Chain and Light Chain Amino Acid Sequences of Anti-Human


VEGF-A/Anti-Human PDGF-BB Cross-over DVD-Ig Molecules


(Linker sequence in italics; CDR sequences in bold)









Seq ID
Name (Corporate
Sequence


No
ID)
1234567890123456789012345678901234567890












3844
CODV001 HC
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA



(PR-1565040)
PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAY




LQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT




VSSGEVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV




GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTS




KNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWGQG




TTVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV




PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP




CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH




EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV




LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV




YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE




NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM




HEALHNHYTQKSLSLSPGK


 


3845
CODV001 LC
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQ



(PR-1565040)
KPGKAPKNVIYGNDQRPSGVPSRFSGSGSGNSATLTISSL




QPEDFATYFCQSYDSDIDIVFGQGTKVEIKGGGSGGGDIQ




MTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKA




PKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDF




ATYYCQQYSTVPWTFGQGTKVEIKGGGSGRTVAAPSVFIF




PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN




SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH




QGLSSPVTKSFNRGEC


 


3837
CODV002 HC
EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIR



(PR-1565042)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQA




VLTITNMDPVDTATYYCARISTGISSYYVMDAWGQGTTVT




VSSGEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNW




VRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSK




STAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQG




TLVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV




PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP




CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH




EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV




LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV




YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE




NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM




HEALHNHYTQKSLSLSPGK


 


3838
CODV002 LC
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKP



(PR-1565042)
GKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQP




EDFATYYCQQYSTVPWTFGQGTKVEIKGGGSGGGDFQLTQ




SPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAP




KNVIYGNDQRPSGVPSRFSGSGSGNSATLTISSLQPEDFA




TYFCQSYDSDIDIVFGQGTKVEIKGGGSGRTVAAPSVFIF




PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN




SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH




QGLSSPVTKSFNRGEC


 


213
CODV003 HC
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA



(PR-1565044)
PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAY




LQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT




VSSGEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV




GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTISKDTS




KNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWGQGT




MVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY




FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP




SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC




PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE




DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL




HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY




TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN




NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH




EALHNHYTQKSLSLSPGK


 


214
CODV003 LC
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQ



(PR-1565044)
KPGKAPKNVIYADDQRPSGVPSRFSGSGSGNSASLTISSL




QPEDFATYFCQSYDINIDIVFGQGTKVEIKGGGSGGGDIQ




MTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKA




PKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDF




ATYYCQQYSTVPWTFGQGTKVEIKGGGSGRTVAAPSVFIF




PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN




SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH




QGLSSPVTKSFNRGEC


 


215
CODV004 HC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR



(PR-1565051)
QPPGKGLEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQA




VLTITNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV




SSGEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWV




RQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKS




TAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGT




LVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY




FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP




SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC




PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE




DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL




HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY




TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN




NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH




EALHNHYTQKSLSLSPGK


 


216
CODV004 LC
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKP



(PR-1565051)
GKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQP




EDFATYYCQQYSTVPWTFGQGTKVEIKGGGSGGGDFQLTQ




SPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAP




KNVIYADDQRPSGVPSRFSGSGSGNSASLTISSLQPEDFA




TYFCQSYDINIDIVFGQGTKVEIKGGGSGRTVAAPSVFIF




PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN




SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH




QGLSSPVTKSFNRGEC


 


217
CODV005 HC
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQA



(PR-1565083)
PGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAY




LQMNSLRAEDTAVYFCARTNYYYRSYIFYFDYWGQGTLVT




VSSGEVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV




GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTS




KNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWGQG




TTVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV




PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP




CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH




EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV




LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV




YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE




NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM




HEALHNHYTQKSLSLSPGK


 


218
CODV005 LC
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQ



(PR-1565083)
KPGKAPKNVIYGNDQRPSGVPSRFSGSGSGNSATLTISSL




QPEDFATYFCQSYDSDIDIVFGQGTKVEIKGGGSGGGDTQ




LTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKA




PKLLIYGASNLESGVPSRFSGSGSGTDFTLTISSLQPEDF




ATYFCQQSWNDPFTFGQGTKVEIKGGGSGRTVAAPSVFIF




PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN




SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH




QGLSSPVTKSFNRGEC


 


219
CODV006 HC
EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIR



(PR-1565084)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQA




VLTITNMDPVDTATYYCARISTGISSYYVMDAWGQGTTVT




VSSGEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYW




VKQAPGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSK




STAYLQMNSLRAEDTAVYFCARTNYYYRSYIFYFDYWGQG




TLVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV




PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP




CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH




EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV




LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV




YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE




NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM




HEALHNHYTQKSLSLSPGK


 


220
CODV006 LC
DTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKP



(PR-1565084)
GKAPKLLIYGASNLESGVPSRFSGSGSGTDFTLTISSLQP




EDFATYFCQQSWNDPFTFGQGTKVEIKGGGSGGGDFQLTQ




SPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAP




KNVIYGNDQRPSGVPSRFSGSGSGNSATLTISSLQPEDFA




TYFCQSYDSDIDIVFGQGTKVEIKGGGSGRTVAAPSVFIF




PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN




SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH




QGLSSPVTKSFNRGEC


 


221
CODV007 HC
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQA



(PR-1565085)
PGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAY




LQMNSLRAEDTAVYFCARTNYYYRSYIFYFDYWGQGTLVT




VSSGEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV




GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTISKDTS




KNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWGQGT




MVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY




FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP




SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC




PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE




DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL




HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY




TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN




NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH




EALHNHYTQKSLSLSPGK


 


222
CODV007 LC
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQ



(PR-1565085)
KPGKAPKNVIYADDQRPSGVPSRFSGSGSGNSASLTISSL




QPEDFATYFCQSYDINIDIVFGQGTKVEIKGGGSGGGDTQ




LTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKA




PKLLIYGASNLESGVPSRFSGSGSGTDFTLTISSLQPEDF




ATYFCQQSWNDPFTFGQGTKVEIKGGGSGRTVAAPSVFIF




PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN




SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH




QGLSSPVTKSFNRGEC


 


223
CODV008 HC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR



(PR-1565086)
QPPGKGLEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQA




VLTITNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV




SSGEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWV




KQAPGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKS




TAYLQMNSLRAEDTAVYFCARTNYYYRSYIFYFDYWGQGT




LVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY




FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP




SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC




PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE




DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL




HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY




TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN




NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH




EALHNHYTQKSLSLSPGK


 


224
CODV008 LC
DTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKP



(PR-1565086)
GKAPKLLIYGASNLESGVPSRFSGSGSGTDFTLTISSLQP




EDFATYFCQQSWNDPFTFGQGTKVEIKGGGSGGGDFQLTQ




SPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAP




KNVIYADDQRPSGVPSRFSGSGSGNSASLTISSLQPEDFA




TYFCQSYDINIDIVFGQGTKVEIKGGGSGRTVAAPSVFIF




PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN




SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH




QGLSSPVTKSFNRGEC


 


225
CODV009 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA



(PR-1571821)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY




LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSSGEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV




GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTS




KNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGT




MVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY




FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP




SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC




PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE




DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL




HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY




TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN




NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH




EALHNAYTQKSLSLSPGK


 


226
CODV009 LC
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQ



(PR-1571821)
KPGQAPRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRL




EPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGGSGGGDTV




LTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDF




AVYFCQQSWNDPFTFGQGTKLEIKGGGSGRTVAAPSVFIF




PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN




SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH




QGLSSPVTKSFNRGEC


 


227
CODV010 HC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR



(PR-1571823)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV




VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV




SSGEVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWV




RQAPGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVS




TAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGT




MVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY




FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP




SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC




PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE




DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL




HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY




TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN




NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH




EALHNAYTQKSLSLSPGK


 


228
CODV010 LC
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKP



(PR-1571823)
GQAPRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEP




EDFAVYFCQQSWNDPFTFGQGTKLEIKGGGSGGGEFVLTQ




SPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAP




RLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFA




VYYCQSYDINIDIVFGGGTKVEIKGGGSGRTVAAPSVFIF




PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN




SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH




QGLSSPVTKSFNRGEC


 


229
CODV011 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA



(PR-1575521)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY




LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSSGGGGSGGGGSEFVLTQSPGTLSLSPGERATLSCERSS




GDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGS




GSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKV




EIKGGGSGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY




FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP




SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC




PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE




DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL




HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY




TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN




NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH




EALHNAYTQKSLSLSPGK


 


230
CODV011 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR



(PR-1575521)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV




VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV




SSGGGGSGGGGSDTVLTQSPATLSLSPGERATLSCRASES




VSTHMHWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSG




TDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKG




GGSGRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE




AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK




ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


231
CODV012 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA



(PR-1571824)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY




LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSSGGGGSGGGEFVLTQSPGTLSLSPGERATLSCERSSGD




IGDSYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGS




GTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEI




KGGGSGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP




EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS




SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA




PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP




EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ




DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL




PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY




KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA




LHNAYTQKSLSLSPGK


 


232
CODV012 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR



(PR-1571824)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV




VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV




SSGGGGSGGGDTVLTQSPATLSLSPGERATLSCRASESVS




THMHWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSGTD




FTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGG




SGRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK




VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD




YEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


233
CODV013 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA



(PR-1571825)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY




LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSSGGGGSGGGEFVLTQSPGTLSLSPGERATLSCERSSGD




IGDSYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGS




GTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEI




KGGSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP




VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL




GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE




AAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV




KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW




LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP




SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT




TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH




NAYTQKSLSLSPGK


 


234
CODV013 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR



(PR-1571825)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV




VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV




SSGGGGSGGGDTVLTQSPATLSLSPGERATLSCRASESVS




THMHWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSGTD




FTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGG




SGRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK




VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD




YEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


235
CODV014 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA



(PR-1571826)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY




LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSSGGGGSEFVLTQSPGTLSLSPGERATLSCERSSGDIGD




SYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGSGTD




FTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGG




SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV




SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ




TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAG




GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN




WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG




KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE




EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP




VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAY




TQKSLSLSPGK


 


236
CODV014 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR



(PR-1571826)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV




VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV




SSGGGGSGGGDTVLTQSPATLSLSPGERATLSCRASESVS




THMHWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSGTD




FTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGG




SGRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK




VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD




YEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


237
CODV015 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA



(PR-1571827)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY




LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSSGGGGSGGGEFVLTQSPGTLSLSPGERATLSCERSSGD




IGDSYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGS




GTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEI




KGGGSGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP




EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS




SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA




PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP




EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ




DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL




PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY




KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA




LHNAYTQKSLSLSPGK


 


238
CODV015 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR



(PR-1571827)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV




VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV




SSGGGGSGGGDTVLTQSPATLSLSPGERATLSCRASESVS




THMHWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSGTD




FTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGS




RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ




WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE




KHKVYACEVTHQGLSSPVTKSFNRGEC


 


239
CODV016 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA



(PR-1571828)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY




LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSSGGGGSGGGEFVLTQSPGTLSLSPGERATLSCERSSGD




IGDSYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGS




GTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEI




KGGGSGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP




EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS




SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA




PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP




EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ




DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL




PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY




KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA




LHNAYTQKSLSLSPGK


 


240
CODV016 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR



(PR-1571828)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV




VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV




SSGGGGSDTVLTQSPATLSLSPGERATLSCRASESVSTHM




HWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFTL




TISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGSRTV




AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV




DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK




VYACEVTHQGLSSPVTKSFNRGEC


 


241
CODV017 HC
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKP



(PR-1571830)
GQAPRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEP




EDFAVYFCQQSWNDPFTFGQGTKLEIKGGGSGGGEFVLTQ




SPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAP




RLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFA




VYYCQSYDINIDIVFGGGTKVEIKGGGSGASTKGPSVFPL




APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH




TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN




TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPK




DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK




TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL




PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL




VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS




KLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPGK


 


242
CODV017 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR



(PR-1571830)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV




VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV




SSGEVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWV




RQAPGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVS




TAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGT




MVTVSSGGRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF




YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL




TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


243
CODV018 HC
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQ



(PR-1571831)
KPGQAPRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRL




EPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGGSGGGDTV




LTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA




PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDF




AVYFCQQSWNDPFTFGQGTKLEIKGGGSGASTKGPSVFPL




APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH




TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN




TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPK




DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK




TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL




PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL




VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS




KLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPGK


 


244
CODV018 LC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA



(PR-1571831)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY




LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSSGEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV




GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTS




KNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGT




MVTVSSGGRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF




YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL




TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


245
CODV019 HC
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKP



(PR-1571832)
GQAPRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEP




EDFAVYFCQQSWNDPFTFGQGTKLEIKGGGSGGGGEVTLR




ESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMT




NMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSLGG




CGGGSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE




PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS




LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP




EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE




VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP




PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK




TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL




HNAYTQKSLSLSPGK


 


246
CODV019 LC
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQ



(PR-1571832)
KPGQAPRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRL




EPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGGSGGGGEV




QLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPG




QGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQ




ISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVTVS




SLGGCGGGSRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN




FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST




LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


247
CODV020 HC
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQ



(PR-1571836)
KPGQAPRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRL




EPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGGSGGGGEV




QLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPG




QGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQ




ISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVTVS




SLGGCGGGSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV




PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP




CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH




EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV




LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV




YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE




NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM




HEALHNAYTQKSLSLSPGK


 


248
CODV020 LC
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKP



(PR-1571836)
GQAPRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEP




EDFAVYFCQQSWNDPFTFGQGTKLEIKGGGSGGGGEVTLR




ESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK




ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMT




NMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSLGG




CGGGSRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR




EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS




KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


249
CODV021 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA



(PR-1577053)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY




LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSSGGGGSGGGEFVLTQSPGTLSLSPGERATLSCERSSGD




IGESYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGS




GTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEI




KGGGSGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP




EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS




SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA




PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP




EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ




DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL




PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY




KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA




LHNAYTQKSLSLSPGK


 


250
CODV021 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR



(PR-1577053)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV




VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV




SSGGGGSGGGDTVLTQSPATLSLSPGERATLSCRASESVS




THMHWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSGTD




FTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGS




RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ




WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE




KHKVYACEVTHQGLSSPVTKSFNRGEC


 


251
CODV022 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA



(PR-1577056)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY




LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT




VSSGGGGSGGGEFVLTQSPGTLSLSPGERATLSCERSSGD




IGESYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGS




GTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEI




KGGGSGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP




EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS




SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA




PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP




EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ




DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL




PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY




KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA




LHNAYTQKSLSLSPGK


 


252
CODV022 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR



(PR-1577056)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV




VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV




SSGGGGSDTVLTQSPATLSLSPGERATLSCRASESVSTHM




HWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFTL




TISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGSRTV




AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV




DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK




VYACEVTHQGLSSPVTKSFNRGEC









Example 12: Generation of scFv-IgG Fusion Proteins
All Ig-scFv molecules used the same anti-VEGF-A mAb AB014 as the IgG molecule. A single chain Fv (scFv) anti-PDGF-BB antibody was fused to the C-terminus of AB014 heavy chain using various length of GS linker using standard molecular cloning techniques. Four different heavy chains and one common light chain were made, as shown in the table below. Each heavy chain and the common light chain were co-transfected into HEK293 cells and the resulting Ig-scFv fusion proteins were purified using rProtein-A chromatography.







TABLE 59







Heavy Chain and Light Chain Amino Acid Sequences of Anti-human


VEGF-A/anti-human PDGF-BB Ig-scFv Molecules


(Linker sequence in italics; CDR sequences in bold)









Seq ID
Name
Sequence


No
(Corporate ID)
1234567890123456789012345678901234567890





3839
AB014-GS6-9E8.4
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA



VH-VK HC
PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAY



(PR-1599234)
LQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT




VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV




TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG




TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA




AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK




FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL




NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS




REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT




PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN




AYTQKSLSLSPGKGGSGGGEVTLRESGPALVKPTQTLTLT




CTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWDDDKYY




NPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIE




SIGTTYSFDYWGQGTMVTVSSGGGGSGGGGSGGGGSEIVL




TQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ




APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPED




FAVYYCQSYDINIDIVFGGGTKVEIK


 


3940
AB014-GS10-9E8.4
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA



VH-VK HC
PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAY



(PR-1599236)
LQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT




VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV




TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG




TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA




AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK




FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL




NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS




REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT




PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN




AYTQKSLSLSPGKGGSGGGGSGGEVTLRESGPALVKPTQT




LTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWDD




DKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYC




ARIESIGTTYSFDYWGQGTMVTVSSGGGGSGGGGSGGGGS




EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQ




KPGQAPRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRL




EPEDFAVYYCQSYDINIDIVFGGGTKVEIK


 


3841
AB014-GS15-9E8.4
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA



VH-VK HC
PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAY



(PR-1599239)
LQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT




VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV




TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG




TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA




AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK




FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL




NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS




REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT




PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN




AYTQKSLSLSPGKGGSGGGGSGGGGSGGEVTLRESGPALV




KPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLAN




IWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDT




ATYYCARIESIGTTYSFDYWGQGTMVTVSSGGGGSGGGGS




GGGGSEIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYV




SWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGSGTDFTL




TISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIK


 


3842
AB014-GS10-9E8.4
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA



VK-VH HC
PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAY



(PR-1599240)
LQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT




VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV




TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG




TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA




AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK




FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL




NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS




REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT




PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN




AYTQKSLSLSPGKGGSGGGGSGGEIVLTQSPGTLSLSPGE




RATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP




SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINI




DIVFGGGTKVEIKGGGGSGGGGSGGGGSEVTLRESGPALV




KPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLAN




IWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDT




ATYYCARIESIGTTYSFDYWGQGTMVTVSS


 


3843
AB014 LC
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKP




GKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQP




EDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPP




SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ




ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG




LSSPVTKSFNRGEC









All HC use the exact same LC (last sequence in Table 59). The naming of the HC follows the following convention: VH name—Linker length (between Fc and scFv)—scFv name with orientation of scFv.

Example 13: In Vitro Characterization of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules and Other Bispecific Molecules
Example 13.1: Expression and Purification of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules and CO-DVD-Ig Molecules
All variants were transiently transfected into 200-500 mls of HEK 293 6e suspension cell cultures in a ratio of 60% to 40% light to heavy chain construct. 1 mg/ml PEI was used to transfect the cells. Alternatively variants were transiently transfected into 500 mls of Expi293 suspension cell cultures using the ExpiFectamine kit (LifeTechnologies A14524). Supernatants were harvested after six days in shaking flasks, spun down to pellet cells, and filtered through 0.22 μm filters to separate IgG from culture contaminates. All was purified via gravity flow using 1-2 ml of rProteinA sepharose fast flow beads (GE Healthcare, 17-1279-04) over poly prep chromatography columns (Bio Rad, 731-1550). Once supernatants had passed through the columns the beads were washed with 10 column volumes of binding buffer, and IgG was eluted with Immunopure IgG elution buffer (Pierce, 185 1520) and collected in 1 ml aliquots. Fractions containing DVD-Ig were pooled and dialyzed in PBS or 15 mM Histidine pH 6 overnight at 4° C.







TABLE 60







Expression Level and SEC Profile of Anti-VEGF-A/Anti-


PDGF-BB DVD-Ig, CO-DVD-Ig and IgG-scFv Fusion Proteins













Octet






Titer
Yield
SEC (%


Name
Corporate ID
(mg/L)
(mg/L)
monomer)














AB014-GS-9E8.4
NA
4.2
ND
ND


9E8.4-GS-AB014
NA
1.2
ND
ND


AB014-SS-9E8.4
NA
3.5
0.4
ND


9E8.4-SS-AB014
NA
3.5
0.6
ND


AB014-SL-9E8.4
NA
2.0
ND
ND


9E8.4-SL-AB014
NA
2.8
0.1
ND


AB014-LS-9E8.4
NA
3.3
ND
ND


9E8.4-LS-AB014
NA
3.6
ND
ND


9E8.4-GS-4G8.3
PR-1563988
6.5
2.8
94.5


9E8.4-SS-4G8.3
PR-1563990
5.9
4.5
92.1


9E8.4-SL-4G8.3
PR-1563998
3.4
2.0
94.0


9E8.4-LS-4G8.3
PR-1564009
10.7
8.0
93.3


4G8.3-GS-9E8.4
PR-1564010
3.6
2.1
98.4


4G8.3-SS-9E8.4
PR-1564011
5.7
3.1
99.4


4G8.3-SL-9E8.4
PR-1564012
2.6
0.7
99.4


4G8.3-LS-9E8.4
PR-1564013
6.7
3.1
99.2


DVD3896
PR-1564883
ND
2.8
100.0


DVD3897
PR-1564893
ND
2.7
79.1


DVD3898
PR-1564896
ND
22.0
93.0


DVD3899
PR-1564898
ND
14.7
87.4


DVD3900
PR-1564899
ND
12.1
72.4


DVD3901
PR-1565023
ND
1.3
99.1


DVD3902
PR-1565029
ND
3.2
98.3


DVD3903
PR-1565030
ND
2.9
98.0


DVD3904
PR-1565031
ND
13.8
97.8


DVD3905
PR-1565032
ND
15.1
92.5


DVD3906
PR-1565035
ND
28.2
85.5


DVD3907
PR-1565033
ND
0.5
ND


CODV001
PR-1565040
ND
88.4
87.6


CODV002
PR-1565042
ND
46.5
97.0


CODV003
PR-1565044
ND
37.3
77.3


CODV004
PR-1565051
ND
75.8
77.4


CODV005
PR-1565083
ND
104.5
86.9


CODV006
PR-1565084
ND
83.9
96.4


CODV007
PR-1565085
ND
43.9
77.4


CODV008
PR-1565086
ND
44.5
75.5


CODV009
PR-1571821
2.0
1.2
86.6


CODV010
PR-1571823
4.5
3.6
94.8


CODV011
PR-1575521
3.7
2.0
100.0


CODV012
PR-1571824
2.0
0.7
98.9


CODV013
PR-1571825
0.7
0.4
90.6


CODV014
PR-1571826
4.5
0.5
89.6


CODV015
PR-1571827
0.7
0.9
91.7


CODV016
PR-1571828
2.6
1.4
93.6


CODV017
PR-1571830
4.2
2.6
99.8


CODV018
PR-1571831
2.6
1.5
88.8


CODV019
PR-1571832
0.4
0.2
87.1


CODV020
PR-1571836
2.1
0.3
58.1


4G8.3-GS-9E8.4
PR-1569574
4.4
4.3
ND


4G8.3-SL-9E8.4
PR-1569579
0.7
0.5
ND


4G8.3-LS-9E8.4
PR-1575573
3.8
2.7
ND


4G8.3-GS-9E8.4 (g)
PR-1572102
2.5
0.4
98.8


4G8.3-GS(11)-9E8.4 (g)
PR-1572103
5.3
1.4
100.0


4G8.3-GS(noR)-9E8.4 (g)
PR-1572104
4.1
0.7
99.5


4G8.3-SL-9E8.4 (g)
PR-1572105
1.4
0.3
98.6


4G8.3-LS-9E8.4 (g)
PR-1572106
4.0
0.8
100.0


4G8.3-GS-9E8.4E
PR-1575832
9.8
8.1
99.2


4G8.3-SL-9E8.4E
PR-1575834
4.5
2.6
99.0


4G8.3-LS-9E8.4E
PR-1575835
16.0
9.7
99.6


CODV021
PR-1577053
2.6
0.3
92.8


CODV022
PR-1577056
2.0
0.2
93.2


9A8.12-GS-9E8.4E
PR-1577165
3.3
2.4
82.99


9A8.12-SL-9E8.4E
PR-1577166
1.1
0.2
51.54


9A8.12-LS-9E8.4E
PR-1577547
10.6
1.1
97.35


9E8.4E-GS-9A8.12
PR-1578137
12.0
3.8
97.3


9E8.4E-SL-9A8.12
PR-1577548
5.0
1.7
97.51


9E8.4E-LS-9A8.12
PR-1577550
2.5
2.5
96.96


AB014-GS6-9E8.4 VH-VK
PR-1599234
70.0
25.6
33.8


AB014-GS10-9E8.4 VH-
PR-1599236
70.0
24.3
34.7


VK


AB014-GS15-9E8.4 VH-
PR-1599239
70.0
29.3
39.3


VK


AB014-GS10-9E8.4 VK-
PR-1599240
47.0
21.4
33.2


VH


4G8.2-GS-9E8.4
PR-1598261
29.4
10.3
98.31


4G8.4-GS-9E8.4
PR-1598262
61.0
20.4
87.65


4G8.5-GS-9E8.4
PR-1598263
31.3
11.5
98.5


4G8.12-GS-9E8.4
PR-1598264
44.0
15.1
93.12


4G8.13-GS-9E8.4
PR-1598265
6.3
2.6
83.58


4G8.14-GS-9E8.4
PR-1598266
19.3
9.9
96.52


CL-34565_GS_CL-33675
PR-1613183
101.4
27.7
88.2


CL-34565_GS_9E8.4
PR-1613184
49.3
31.3
95.9


CL-34565_GS_3E2.1
PR-1613185
109.8
82.5
96.3


4G8.5_GS_CL-33675
PR-1611291
91.1
10.4
96.9


4G8.5_GS_9E8.4
PR-1612489
39.0
23.0
97.0


4G8.5_GS_3E2.1
PR-1610560
127.0
13.9
100.0


9E10.1_GS_CL-33675
PR-1610561
136.0
19.2
92.9


9E10.1_GS_9E8.4
PR-1612491
86.0
50.1
95.0


9E10.1_GS_3E2.1
PR-1610562
44.0
10.2
96.0


9E10.6_GS_CL-33675
PR-1612492
152.0
65.7
89.0


9E10.6_GS_9E8.4
PR-1612493
96.0
50.1
93.0


9E10.6_GS_3E2.1
PR-1610563
122.0
18.0
95.0


1B10.1_GS_CL-33675
PR-1611292
233.0
22.7
75.4


1B10.1_GS_9E8.4
PR-1612494
123.0
52.1
77.0


1B10.1_GS_3E2.1
PR-1610564
142.0
23.3
93.7


1E3.4_GS_CL-33675
PR-1611293
54.0
9.3
83.7


1E3.4_GS_9E8.4
PR-1611294
67.5
11.6
72.1


1E3.4_GS_3E2.1
PR-1612495
101.0
29.6
97.0


CL-33675_GS_CL-34565
PR-1613186
73.5
17.7
87.6


CL-33675_GS_4G8.5
PR-1612496
36.0
8.6
94.0


CL-33675_GS_9E10.1
PR-1611295
148.5
2.3
95.9


CL-33675_GS_9E10.6
PR-1611296
185.3
4.9
95.8


CL-33675_GS_1B10.1
PR-1612498
19.0
7.0
65.0


CL-33675_GS_1E3.4
PR-1611297
72.8
3.5
95.9


9E8.4_GS_CL-34565
PR-1613187
67.5
53.6
79.0


9E8.4_GS_4G8.5
PR-1613188
95.2
73.6
81.7


9E8.4_GS_9E10.1
PR-1611298
237.5
21.5
73.3


9E8.4_GS_9E10.6
PR-1611299
179.0
19.1
71.9


9E8.4_GS_1B10.1
PR-1611300
93.7
12.9
71.7


9E8.4_GS_1E3.4
PR-1611301
87.9
12.2
66.4


3E2.1_GS_CL-34565
PR-1613189
76.1
65.7
93.3


3E2.1_GS_4G8.5
PR-1612499
98.0
46.9
95.0


3E2.1_GS_9E10.1
PR-1612500
126.0
59.2
85.0


3E2.1_GS_9E10.6
PR-1612501
141.0
61.0
86.5


3E2.1_GS_1B10.1
PR-1612502
141.0
61.0
97.0


3E2.1_GS_1E3.4
PR-1613190
107.8
79.9
96.5


9E10.1_SL_CL-33675
PR-1629646
7.6
1.0
98.7


1B10.1_SL_CL-33675
PR-1629647
157.0
111.7
63.3


9E10.1_LS_CL-33675
PR-1629648
64.4
36.4
92.9


1B10.1_LS_CL-33675
PR-1629649
218.4
157.7
65.4









Example 13.2: Binding Affinity of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules and CO-DVD-Ig Molecules
The binding affinity of anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules and CO-DVD-Ig molecules to VEGF-A and PDGF-BB were measured by Biacore using the method described in Example 1.1 and the data is summarized in Tables 61 and 62 below.







TABLE 61







Biacore Binding of Anti-VEGF/anti-PDGF DVD-Ig Molecules










VEGF
PDGF
















kon
koff
KD
kon
koff
KD


DVD Name
Corporate ID
(M−1 s−1)
(M−1)
(M)
(M−1 s−1)
(M−1)
(M)

















9E8.4-GS-4G8.3
PR-1563988
2.2E+05
6.3E−05
2.9E−10
1.0E+07
2.0E−04
2.0E−11


9E8.4-SS-4G8.3
PR-1563990
1.6E+05
1.2E−04
7.8E−10
1.0E+07
2.0E−04
2.0E−11


9E8.4-SL-4G8.3
PR-1563998
7.0E+05
8.0E−05
1.2E−10
1.0E+07
1.9E−04
1.9E−11


9E8.4-LS-4G8.3
PR-1564009
2.7E+05
5.5E−05
2.0E−10
1.0E+07
2.0E−04
2.0E−11


4G8.3-GS-9E8.4
PR-1564010
3.3E+06
5.7E−05
1.7E−11
1.0E+07
1.4E−04
1.3E−11


4G8.3-SS-9E8.4
PR-1564011
3.1E+06
4.1E−05
1.3E−11
7.5E+06
1.5E−04
1.9E−11


4G8.3-SL-9E8.4
PR-1564012
3.1E+06
4.1E−05
1.3E−11
1.4E+07
1.4E−04
9.9E−12


4G8.3-LS-9E8.4
PR-1564013
3.1E+06
3.9E−05
1.2E−11
1.7E+07
1.4E−04
8.6E−12


DVD3904
PR-1565031
6.1E+05
1.1E−04
1.9E−10
1.0E+07
9.0E−04
9.0E−11


DVD3905
PR-1565032
1.1E+06
1.0E−04
9.4E−11
1.0E+07
1.8E−03
1.8E−10


DVD3906
PR-1565035
9.2E+05
9.3E−05
1.0E−10
1.0E+07
7.2E−03
7.2E−10


4G8.3-GS(9)-9E8.4 (g)
PR-1572102
6.0E+06
7.6E−05
1.3E−11
1.3E+07
1.7E−04
1.3E−11


4G8.3-GS(11)-9E8.4
PR-1572103
6.3E+06
7.5E−05
1.2E−11
1.4E+07
1.7E−04
1.3E−11


(g)


4G8.3-GS(noR)-9E8.4
PR-1572104
6.1E+06
6.9E−05
1.1E−11
1.5E+07
1.4E−04
8.9E−12


(g)


4G8.3-SL-9E8.4 (g)
PR-1572105
5.6E+06
6.1E−05
1.1E−11
1.3E+07
1.7E−04
1.3E−11


4G8.3-LS-9E8.4 (g)
PR-1572106
6.3E+06
5.1E−05
8.1E−12
1.8E+07
2.0E−04
1.1E−11


4G8.3-GS-9E8.4E
PR-1575832
6.1E+06
8.0E−05
1.3E−11
1.3E+07
2.7E−04
2.0E−11


4G8.3-SL-9E8.4E
PR-1575834
6.2E+06
6.3E−05
1.0E−11
1.7E+07
2.5E−04
1.5E−11


4G8.3-LS-9E8.4E
PR-1575835
5.8E+06
5.9E−05
1.0E−11
2.0E+07
2.8E−04
1.4E−11


9A8.12-GS-9E8.4E
PR-1577165
7.7E+05
1.4E−04
1.8E−10
3.3E+07
2.6E−04
8.1E−12


9A8.12-SL-9E8.4E
PR-1577166
2.5E+05
1.2E−04
4.7E−10
2.7E+07
2.3E−04
8.3E−12


9A8.12-LS-9E8.4E
PR-1577547
2.7E+05
9.3E−05
3.5E−10
3.6E+07
2.3E−04
6.5E−12


9E8.4E-SL-9A8.12
PR-1577548
2.2E+06
3.4E−04
1.6E−10
5.0E+07
3.2E−04
6.4E−12


9E8.4E-LS-9A8.12
PR-1577550
6.4E+05
1.5E−04
2.3E−10
5.0E+07
2.5E−04
5.0E−12


9E8.4E-GS-9A8.12
PR-1578137
4.7E+05
1.8E−04
3.8E−10
5.0E+07
4.4E−04
8.8E−12


CL-34565_GS_CL-
PR-1613183
1.2E+07
2.0E−05
1.7E−12
6.0E+07
1.1E−05
1.9E−13


33675


CL-34565_GS_9E8.4
PR-1613184
1.5E+07
1.6E−05
1.1E−12
3.5E+07
1.9E−04
5.4E−12


CL-34565_GS_3E2.1
PR-1613185
1.2E+07
1.7E−05
1.4E−12
4.5E+07
5.2E−04
1.2E−11


4G8.5_GS_CL-33675
PR-1611291
4.7E+06
3.1E−05
6.6E−12
1.6E+07
1.2E−05
7.4E−13


4G8.5_GS_9E8.4
PR-1612489
5.4E+06
4.6E−05
8.5E−12
5.8E+06
1.6E−04
2.8E−11


4G8.5_GS_3E2.1
PR-1610560
4.8E+06
4.2E−05
8.7E−12
4.1E+07
5.5E−04
1.3E−11


9E10.1_GS_CL-33675
PR-1610561
9.7E+06
1.7E−05
1.8E−12
2.0E+07
9.1E−06
4.5E−13


9E10.1_GS_9E8.4
PR-1612491
1.1E+07
2.5E−05
2.2E−12
6.8E+06
1.7E−04
2.5E−11


9E10.1_GS_3E2.1
PR-1610562
9.3E+06
2.3E−05
2.4E−12
4.1E+07
8.5E−04
2.1E−11


9E10.6_GS_CL-33675
PR-1612492
1.1E+07
2.2E−05
2.0E−12
2.4E+07
2.8E−05
1.2E−12


9E10.6_GS_3E2.1
PR-1610563
8.6E+06
2.5E−05
3.0E−12
5.8E+06
2.1E−04
3.6E−11


1B10.1_GS_CL-33675
PR-1611292
2.1E+06
1.3E−04
6.2E−11
2.2E+07
1.2E−05
5.4E−13


1E3.4_GS_3E2.1
PR-1612495
5.3E+06
5.2E−05
9.8E−12
4.5E+07
5.1E−04
1.2E−11


CL-33675_GS_4G8.5
PR-1612496
2.3E+05
4.0E−05
1.8E−10
3.8E+07
9.0E−06
2.3E−13


3E2.1_GS_4G8.5
PR-1612499
2.4E+05
3.9E−05
1.7E−10
≧9.0E+07
3.4E−04
≦3.8E−12


3E2.1_GS_9E10.1
PR-1612500
6.3E+05
1.2E−05
1.9E−11
≧9.0E+07
3.9E−04
≦4.3E−12


3E2.1_GS_9E10.6
PR-1612501
5.7E+05
2.3E−05
4.1E−11
≧9.0E+07
4.5E−04
≦5.3E−12


3E2.1_GS_1B10.1
PR-1612502
3.5E+05
1.2E−04
3.2E−10
8.4E+07
1.5E−04
1.8E−12


3E2.1_GS_1E3.4
PR-1613190
3.6E+05
9.2E−05
2.6E−10
≧9.0E+07
4.8E−04
≦5.3E−12
















TABLE 62







Biacore Binding of Anti-VEGF/anti-PDGF CO-DVD-Ig Molecules










VEGF
PDGF














CO-DVD-Ig

kon
koff
KD
kon
koff
KD


Name
Corporate ID
(M−1 s−1)
(M−1)
(M)
(M−1 s−1)
(M−1)
(M)















CODV003
PR-1565044
no binding
2.3E+07
2.5E−04
1.1E−11


CODV004
PR-1565051
no binding
1.0E+07
8.7E−04
8.7E−11














CODV005
PR-1565083


3.5E−08
1.2E+07
1.3E−04
1.1E−11












CODV006
PR-1565084
no binding
2.2E+07
2.1E−04
9.7E−12














CODV007
PR-1565085


2.2E−08
2.9E+07
2.2E−04
7.3E−12












CODV008
PR-1565086
no binding
1.7E+07
1.3E−04
7.4E−12














CODV009
PR-1571821


2.6E−08
3.5E+07
2.0E−04
5.6E−12


CODV010
PR-1571823
5.7E+04
3.7E−04
6.6E−09
4.1E+07
1.6E−04
4.0E−12


CODV011
PR-1575521
1.1E+06
4.0E−05
3.8E−11
3.8E+07
6.9E−05
1.8E−12


CODV012
PR-1571824
2.7E+06
7.6E−05
2.8E−11
7.0E+07
1.0E−04
1.5E−12


CODV014
PR-1571826
2.2E+06
7.7E−05
3.6E−11
5.5E+07
1.3E−04
2.4E−12


CODV015
PR-1571827
2.7E+06
6.5E−05
2.4E−11
7.0E+07
9.1E−05
1.3E−12


CODV016
PR-1571828
2.9E+06
5.9E−05
2.0E−11
4.6E+07
1.1E−04
2.5E−12


CODV017
PR-1571830
—
—
5.7E−08
3.0E+07
2.0E−04
6.5E−12


CODV018
PR-1571831
—
—
3.1E−08
3.5E+07
1.9E−04
5.3E−12


CODV019
PR-1571832
2.9E+06
1.4E−04
5.0E−11
3.9E+07
1.7E−04
4.4E−12


CODV020
PR-1571836
3.1E+06
1.0E−04
3.3E−11
4.6E+07
1.6E−04
3.5E−12


CODV021
PR-1577053
3.8E+06
6.8E−05
1.8E−11
6.1E+07
1.2E−04
1.9E−12


CODV022
PR-1577056
4.5E+06
5.6E−05
1.3E−11
3.2E+07
1.3E−04
4.2E−12









Example 13.2.1: Binding of Anti-VEGF/anti-PDGF DVD-Ig Molecule (PR-1610561) to Various VEGF-A Isoforms and VEGF-A and PDGF-BB of Different Species
Binding of anti-VEGF/anti-PDGF DVD-Ig molecule (PR-1610561) and their parental monoclonal antibodies to various VEGF-A isoforms and VEGF-A and PDGF-BB of different species were measured by Biacore using the method described in Example 1.1 and the data is summarized in Table 63 below. Tables 63A-B summarize the high affinity for VEGF-A165 (65 pM), VEGF-A121(230 pM), VEGF-A111 (290 pM), isoforms and the high affinity for soluble PDGF-BB (5 pM), observed for PR-1610561. The data shows that PR-1610561binds to both soluble and extracellular-matrix (ECM) bound forms of PDGF-BB.







TABLE 63





Binding of Anti-VEGF/Anti-PDGF DVD-Ig Molecule (PR-1610561) and Parental mAbs to VEGF-A Isoforms and PDGF


















human VEGF 165
human PDGF-B



PR-1350437, 1925483
PR-1373790, 1926007




















Ka
Kd
KD
Ka
Kd
KD


No

PR-
lot
(M−1s−1)
(s−1)
(M)
(M−1s−1)
(s−1)
(M)





1
9E10.1-GS-33675
PR-1610561
2213329
5.2E+05
3.4E−05
6.5E−11
≧1.0E+07
5.2E−05
≦5.2E−12


2
AB014 (Avastin)
PR-1545939
2129911
5.5E+05
4.1E−05
7.6E−11


3
AB642 (9E10.1)
PR-1594047
2169800
1.6E+07
2.8E−05
1.8E−12


4
CL-33675
PR-1593725
2178826



≧1.0E+07
5.8E−06
≦5.8E−13













human VEGF 121




PR-1515941, 2069355


















Ka
Kd
KD



No

PR-
lot
(M−1s−1)
(s−1)
(M)





1
9E10.1-GS-33675
PR-1610561
2213329
1.8E+05
4.1E−05
2.3E−10


2
AB014 (Avastin)
PR-1545939
2129911
1.8E+05
5.1E−05
2.8E−10


3
AB642 (9E10.1)
PR-1594047
2169800
3.2E+06
6.8E−05
2.1E−11


4
CL-33675
PR-1593725
2178826













human VEGF 111




PR-1520687, 2074657


















Ka
Kd
KD



No

PR-
lot
(M−1s−1)
(s−1)
(M)





1
9E10.1-GS-33675
PR-1610561
2213329
1.5E+05
4.3E−05
2.9E−10


2
AB014 (Avastin)
PR-1545939
2129911
1.4E+05
5.3E−05
3.8E−10


3
AB642 (9E10.1)
PR-1594047
2169800
1.8E+06
1.0E−04
5.8E−11


4
CL-33675
PR-1593725
2178826












cyno PDGF-B



PR-1575400, 2154322


















cyno VEGF has similar
Ka
Kd
KD


No

PR-
lot
sequence as human
(M−1s−1)
(s−1)
(M)





1
9E10.1-GS-33675
PR-1610561
2213329

≧1.0E+07
8.1E−06
≦8.1E−13


2
AB014 (Avastin)
PR-1545939
2129911


3
AB642 (9E10.1)
PR-1594047
2169800


4
CL-33675
PR-1593725
2178826

≧1.0E+07
1.3E−05
≦1.3E−12













mouse VEGF
mouse PDGF-B



PR-1578904, 2150241
PR-1577160, 2147923




















Ka
Kd
KD
Ka
Kd
KD


No

PR-
lot
(M−1s−1)
(s−1)
(M)
(M−1s−1)
(s−1)
(M)





1
9E10.1-GS-33675
PR-1610561
2213329


potentially
≧1.0E+07
5.2E−05
≦5.2E−12








very weak binding


2
AB014 (Avastin)
PR-1545939
2129911


no binding


3
AB642 (9E10.1)
PR-1594047
2169800


potentially








very weak binding


4
CL-33675
PR-1593725
2178826



≧1.0E+07
5.8E−06
≦5.8E−13













rat VEGF
rat PDGF-B



PR-1645045, 2235296
PR-1645048, 2235300




















Ka
Kd
KD
Ka
Kd
KD


No

PR-
lot
(M−1s−1)
(s−1)
(M)
(M−1s−1)
(s−1)
(M)





1
9E10.1-GS-33675
PR-1610561
2213329


potentially
≧1.0E+07
5.2E−05
≦5.2E−12








very weak binding


2
AB014 (Avastin)
PR-1545939
2129911


no binding


3
AB642 (9E10.1)
PR-1594047
2169800


potentially








very weak binding


4
CL-33675
PR-1593725
2178826



≧1.0E+07
5.8E−06
≦5.8E−13













rabbit VEGF




PR-1563693, 2130027


















Ka
Kd
KD
rabbit PDGF-B has similar


No

PR-
lot
(M−1s−1)
(s−1)
(M)
sequence as rat

















1
9E10.1-GS-33675
PR-1610561
2213329
9.6E+05
4.0E−05
4.1E−11



2
AB014 (Avastin)
PR-1545939
2129911
9.4E+05
4.4E−05
4.7E−11


3
AB642 (9E10.1)
PR-1594047
2169800
1.6E+07
2.8E−05
1.8E−12


4
CL-33675
PR-1593725
2178826
















TABLE 63A







Affinity of PR-1610561 to Various Isoforms of Human VEGF-A









Human VEGF-A



Isoforms











A165
A121
A111
















Affinity KD (pM)
65
230
290

















TABLE 63B







Affinity of PR-1610561 to Human PDGF-BB











Human PDGF-BB Forms
Soluble
ECM-associated







Affinity KD (pM)
5
n/t



Cell Staining
n/t
+










Example 13.3: Neutralization Potencies of Anti-VEGF-A/anti-PDGF-BB DVD-Ig Molecules and CO-DVD-Ig Molecules
The DVD-Ig molecules and CO-DVD-Ig molecules were evaluated for their potencies to block VEGF165/VEGFR2 interaction (Example 1.4) and neutralize VEGF165 activity in HMVEC-d or VEGFR2-3T3 proliferation assays (Examples 1.10 and 1.7). The molecules were also characterized for the ability to block PDGF-BB/PDGF-Rβ interaction (Example 1.13) and inhibition of PDGF-BB induced proliferation of NIH-3T3 cells (Example 1.15). The data is summarized in Table 64 below. PR-1610561 exhibited neutralization activity against human VEGF-A (IC50 of 145 pM) and human PDGF-BB (IC50 of 34 pM), as summarized in Table 64A.







TABLE 64







Human VEGF-A and Human PDGF-BB Neutralization Potency of


Anti-VEGF-A/anti-PDGF-BB DVD-Ig and CO-DVD-Ig Proteins









Potency IC50 (nM)


















hVEGFR2
hPDGF β





VEGFR2-

Competition
Competition




HMVEC-d
3T3
NIH-3T3
ELISA
ELISA


DVD-Ig
Corporate ID
hVEGF165
hVEGF165
hPDGF-BB
IC50 nM
IC50 nM
















9E8.4-GS-4G8.3
PR-1563988
2.643
>5
0.076
NT
NT


9E8.4-SS-4G8.3
PR-1563990
NT
>5
0.094
NT
NT


9E8.4-SL-4G8.3
PR-1563998
NT
>5
0.091
NT
NT


9E8.4-LS-4G8.3
PR-1564009
NT
>5
0.104
NT
NT


4G8.3-GS-9E8.4
PR-1564010
0.096
NT
NT
0.126
NT


4G8.3-GS-9E8.4E
PR-1575832
NT
2.953
>5
NT
NT


4G8.3-SS-9E8.4
PR-1564011
NT
0.747
5.511
NT
NT


4G8.3-SL-9E8.4
PR-1564012
NT
NT
0.365
0.086
NT


4G8.3-SL-9E8.4E
PR-1575834
NT
3.090
0.572
NT
NT


4G8.3-LS-9E8.4
PR-1564013
0.060
NT
0.152
0.092
NT


CODV009
PR-1571821
NT
>5
>5
NT
NT


CODV010
PR-1571823
NT
>5
2.139
NT
NT


CODV011
PR-1575521
NT
2.553
0.043
NT
NT


CODV012
PR-1571824
NT
1.424
0.182
NT
NT


CODV013
PR-1571825
NT
0.785
0.11
NT
NT


CODV014
PR-1571826
NT
3.768
0.469
NT
NT


CODV015
PR-1571827
0.104
0.407
0.075
NT
NT


CODV021
PR-1577053
NT
>5
0.056
NT
NT


CODV016
PR-1571828
0.115
0.503
0.096
NT
NT


CODV022
PR-1577056
NT
1.462
0.059
NT
NT


CODV017
PR-1571830
NT
>5
>5
NT
NT


CODV018
PR-1571831
NT
>5
>5
NT
NT


DVD3904
PR-1565031
NT
>5
>5
NT
NT


DVD3905
PR-1565032
NT
>5
>5
NT
NT


DVD3906
PR-1565035
NT
>5
>5
NT
NT


CODV003
PR-1565044
NT
>5
>5
NT
NT


CODV004
PR-1565051
NT
>5
>5
NT
NT


CODV005
PR-1565083
NT
>5
>5
NT
NT


CODV006
PR-1565084
NT
>5
>5
NT
NT


CODV007
PR-1565085
NT
>5
>5
NT
NT


CODV008
PR-1565086
NT
>5
>5
NT
NT


4G8.3-GS(9)-9E8.4 (g)
PR-1572102
0.417
0.986
.528
0.157
>5


4G8.3-GS(11)-9E8.4 (g)
PR-1572103
NT
0.318
0.298
NT
NT


4G8.3-GS(noR)-9E8.4 (g)
PR-1572104
NT
0.217
0.095
NT
NT


4G8.3-SL-9E8.4 (g)
PR-1572105
0.347
1.603
0.290
0.111
>5


4G8.3-LS-9E8.4 (g)
PR-1572106
NT
0.203
0.109
NT
NT


4G8.3-LS-9E8.4E
PR-1575835
NT
2.852
0.176
NT
NT


9A8.12-GS-9E8.4E
PR-1577165
NT
2.992
0.204
NT
NT


9A8.12-SL-9E8.4E
PR-1577166
NT
5.536
0.148
NT
NT


9A8.12-LS-9E8.4E
PR-1577547
NT
4.13
0.133
NT
NT


9E8.4E−SL-9A8.12
PR-1577548
NT
>5
0.147
NT
NT


9E8.4E−LS-9A8.12
PR-1577550
NT
>5
0.066
NT
NT


9E8.4E−GS-9A8.12
PR-1578137
NT
>5
0.327
NT
NT


hVEGF 4G8.3-GS-hPDGF
PR-1569574
0.341
1.02
0.630
0.137
>5


9E8.4 [hu IgG1/k]


mut(234, 235) H435A


hVEGF 4G8.3-SL-hPDGF
PR-1569579
0.36 
1.178
0.427
0.133
>5


9E8.4 [hu IgG1/k]


mut(234, 235) H435A


hVEGF 4G8.3-LS-hPDGF
PR-1575573
NT
NT
NT
0.131
>5


9E8.4 [hu IgG1/k]


mut(234, 235) H435A


AB014-GS6-9E8.4
PR-1599234
0.124
NT
0.222
NT
NT


VH-VK


AB014-GS10-9E8.4
PR-1599236
0.095
NT
0.063
NT
NT


VH-VK


AB014-GS15-9E8.4
PR-1599239
0.13 
NT
0.066
NT
NT


VH-VK


AB014-GS10-9E8.4
PR-1599240
0.086
NT
0.074
NT
NT


VK-VH


4G8.2-GS10-9E8.4
PR-1598261
0.221
NT
>5
NT
NT


4G8.4-GS10-9E8.4
PR-1598262
0.281
NT
1.327
NT
NT


4G8.5-GS10-9E8.4
PR-1598263
0.079
NT
>5
NT
NT


4G8.12-GS10-9E8.4
PR-1598264
0.079
NT
0.227
NT
NT


4G8.13-GS10-9E8.4
PR-1598265
0.907
NT
0.255
NT
NT


4G8.14-GS10-9E8.4
PR-1598266
0.113
NT
0.459
NT
NT


4G8.5_GS_CL-33675
PR-1611291
0.076
NT
0.05
NT
NT


4G8.5_GS_3E2.1
PR-1610562
0.072
NT
1.398
NT
NT


9E10.1_GS_CL-33675
PR-1610561
0.145
0.433
0.034
0.045
   0.09


9E10.1_GS_3E2.1
PR-1610562
0.054
NT
5.724
NT
NT


9E10.6_GS_3E2.1
PR-1610563
0.06 
NT
1.317
NT
NT


1B10.1_GS_CL-33675
PR-1611292
0.05 
NT
0.037
NT
NT


1B10.1_GS_3E2.1
PR-1610564
0.084
NT
1.545
NT
NT


1E3.4_GS_CL-33675
PR-1611293
0.067
NT
0.037
NT
NT


1E3.4_GS_9E8.4
PR-1611294
0.092
NT
0.329
NT
NT


CL-33675_GS_9E10.1
PR-1611295
0.064
NT
0.031
NT
NT


CL-33675_GS_9E10.6
PR-1611296
0.082
NT
0.037
NT
NT


CL-33675_GS_1E3.4
PR-1611297
0.372
NT
0.039
NT
NT


9E8.4_GS_9E10.1
PR-1611298
0.073
NT
0.317
NT
NT


9E8.4_GS_9E10.6
PR-1611299
0.132
NT
0.213
NT
NT


9E8.4_GS_1B10.1
PR-1611300
0.391
NT
0.109
NT
NT


9E8.4_GS_1E3.4
PR-1611301
0.897
NT
0.131
NT
NT


4G8.5_GS_9E8.4
PR-1612489
0.069
NT
4.829
NT
NT


9E10.1_GS_9E8.4
PR-1612491
0.059
NT
1.913
NT
NT


9E10.6_GS_CL-33675
PR-1612492
0.05 
NT
0.037
NT
NT


9E10.6_GS_9E8.4
PR-1612493
0.049
NT
1.14
NT
NT


1B10.1_GS_9E8.4
PR-1612494
0.127
NT
0.678
NT
NT


1E3.4_GS_3E2.1
PR-1612495
0.043
NT
6.253
NT
NT


CL-33675_GS_4G8.5
PR-1612496
0.219
NT
0.035
NT
NT


CL-33675_GS_1B10.1
PR-1612498
0.265
NT
0.11
NT
NT


3E2.1_GS_4G8.5
PR-1612499
0.743
NT
0.38
NT
NT


3E2.1_GS_9E10.1
PR-1612500
0.133
NT
0.394
NT
NT


3E2.1_GS_9E10.6
PR-1612501
0.188
NT
0.377
NT
NT


3E2.1_GS_1B10.1
PR-1612502
1.78 
NT
0.187
NT
NT


CL-34565_GS_CL-33675
PR-1613183
0.059
NT
0.052
NT
NT


CL-34565_GS_9E8.4
PR-1613184
0.065
NT
0.323
NT
NT


CL-34565_GS_3E2.1
PR-1613185
0.053
NT
6.005
NT
NT


CL-33675_GS_CL-34565
PR-1613186
0.05 
NT
0.043
NT
NT


9E8.4_GS_CL-34565
PR-1613187
0.058
NT
0.134
NT
NT


9E8.4_GS_4G8.5
PR-1613188
0.354
NT
0.108
NT
NT


3E2.1_GS_CL-34565
PR-1613189
0.063
NT
1.157
NT
NT


3E2.1_GS_1E3.4
PR-1613190
0.709
NT
0.896
NT
NT





NT—Not tested













TABLE 64A







Neutralization Activities in Cellular Assays











Protein
Human VEGF-A
Human PDGF-BB







Potency IC50 (pM)
145
34










Selected DVD-Ig molecules were further characterized for the ability to neutralize human VEGF111 and human VEGF121, isoforms of human VEGF-A. The molecules were tested for inhibition of VEGF111 and human VEGF121 induced proliferation of VEGFR2-3T3 cells (Example 1.8). Neutralization of non-human VEGF-A species was also evaluated. Molecules were tested for inhibition of rabbit VEGF165 induced proliferation of VEGFR2-3T3 cells (Example 1.9). The data is summarized in Table 65 below. As noted, the amino acid sequence of cynomolgus monkey VEGF-A is identical to human VEGF-A. Parental antibodies had previously been examined for mouse VEGF164 cross-reactivity in a competition ELISA and no blocking was observed (Example 1.5).







TABLE 65







Neutralization of Different VEGF-A Isoforms by Anti-VEGF-A/


Anti-PDGF-BB DVD-Ig Molecules









Potency IC50 (nM)













human
human
rabbit


DVD-Ig and Controls
Corporate ID
VEGF111
VEGF121
VEGF165





4G8.3-GS(9)-9E8.4
PR-1572102
0.771
0.182
0.869


(g)


4G8.3-SL-9E8.4 (g)
PR-1572105
0.654
0.139
1.194


4G8.3-LS-9E8.4 (g)
PR-1572106
0.431
0.148
0.601


4G8.3-LS-9E8.4E
PR-1575835
NT
NT
1.534


hVEGF 4G8.3-GS-
PR-1569574
0.674
0.124
0.841


hPDGF 9E8.4


[hu IgG1/k]


mut(234, 235) H435A


hVEGF 4G8.3-SL-
PR-1569579
0.576
0.154
1.213


hPDGF 9E8.4


[hu IgG1/k]


mut(234, 235) H435A


9E10.1_GS_CL-
PR-1610561
0.213
0.097
0.520


33675





NT—Not tested






Selected DVD-Ig molecules were further evaluated for their potencies to neutralize PDGF-BB of different species using the assay described in Examples 1.15-1.18. The data is summarized in Table 66 below. As noted, the amino acid sequence of rabbit PDGF-BB is identical to rat PDGF-BB.







TABLE 66







Neutralization of Different PDGF-BB Species by Anti-VEGF-


A/Anti-PDGF-BB DVD-Ig Molecules









Potency IC50 (nM)











DVD-Ig and
Corporate
cynoPDGF-
mPDGF-
ratPDGF-


Controls
ID
BB
BB
BB





4G8.3-GS-9E8.4
PR-1564010
NT
0.440
1.359


4G8.3-SL-9E8.4
PR-1564012
NT
0.290
0.650


4G8.3-SL-9E8.4E
PR-1575834
NT
0.772
NT


4G8.3-LS-9E8.4
PR-1564013
NT
0.110
0.210


4G8.3-GS(9)-9E8.4
PR-1572102
0.139
0.174
2.202


(g)


4G8.3-SL-9E8.4 (g)
PR-1572105
0.142
0.096
1.296


4G8.3-LS-9E8.4 (g)
PR-1572106
0.094
0.14
NT


hVEGF 4G8.3-GS-
PR-1569574
0.139
0.134
1.514


hPDGF 9E8.4


[hu IgG1/k]


mut(234, 235)


H435A


hVEGF 4G8.3-SL-
PR-1569579
0.144
0.150
0.994


hPDGF 9E8.4


[hu IgG1/k]


mut(234, 235)


H435A


9E10.1_GS_CL-
PR-1610561
0.035
0.032
0.038


33675





NT—Not tested






Selected DVD-Ig molecules were evaluated for their ability to neutralize in the presence of a second ligand. To evaluate hPDGF-BB potency, the DVD-Ig molecules were pre-incubated with an excess of human VEGF165 prior to testing in the NIH-3T3 proliferation assay (Example 1.21). To evaluate hVEGF165 potency, the DVD-Ig molecules were pre-incubated with an excess of human hPDGF-BB prior to testing in the VEGFR2-3T3 (KDR/Flk-1) phosphorylation assay (Example 1.20). The data is summarized in Table 67 below.







TABLE 67







Simultaneous binding to VEGF and PDGF









Co-incubation Potency



IC50 (nM)










DVD-Ig
Corporate ID
hPDGF-BB
hVEGF165





9E8.4-GS-4G8.3
PR-1563988
NT
NT


9E8.4-SS-4G8.3
PR-1563990
NT
NT


9E8.4-SL-4G8.3
PR-1563998
NT
NT


9E8.4-LS-4G8.3
PR-1563009
NT
NT


4G8.3-GS-9E8.4
PR-1564010
NT
NT


4G8.3-SS-9E8.4
PR-1564011
NT
NT


4G8.3-SL-9E8.4
PR-1564012
NT
NT


4G8.3-LS-9E8.4
PR-1564013
NT
NT


4G8.3-GS(9)-9E8.4 (g)
PR-1572102
0.051
0.701


4G8.3-SL-9E8.4 (g)
PR-1572105
0.047
0.773


hVEGF 4G8.3-GS-
PR-1569574
0.032
0.594


hPDGF 9E8.4 [hu


IgG1/k] mut(234, 235)


H435A


hVEGF 4G8.3-SL-
PR-1569579
0.038
0.789


hPDGF 9E8.4 [hu


IgG1/k] mut(234, 235)


H435A


9E10.1_GS_CL-33675
PR-1610561
0.04
0.464





NT—Not tested






Selected DVD-Ig molecules were further evaluated for their ability to bind naturally derived human VEGF165 (Example 1.11) and naturally derived human PDGF-BB (Example 1.19). The data is summarized in Table 68 below.







TABLE 68







Binding of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to


hVEGF165 and hPDGF-BB by ELISA









Binding












Platelet derived
Y-79 derived


DVD-Ig
Corporate ID
hPDGF-BB
hVEGF165





4G8.3-GS(9)-9E8.4 (g)
PR-1572102
Yes
NT


4G8.3-SL-9E8.4 (g)
PR-1572105
Yes
NT


hVEGF 4G8.3-GS-
PR-1569574
Yes
NT


hPDGF 9E8.4 [hu


IgG1/k] mut(234, 235)


H435A


hVEGF 4G8.3-SL-
PR-1569579
Yes
NT


hPDGF 9E8.4 [hu


IgG1/k] mut(234, 235)


H435A


9E10.1_GS_CL-33675
PR-1610561
Yes
Yes





NT—Not tested






Example 13.4: Species Cross-Reactivity of an Anti-VEGF/Anti-PDGF DVD-Ig Molecule (PR-1610561)
PR-1610561 was further evaluated for its ability to cross-react with cynomolgus monkey, mouse, rat, and rabbit using cell-based proliferation assays (Examples 1.6, 1.17, 1.18, and 1.25). The data is summarized in Table 69 below.







TABLE 69







Species Cross-Reactivity of Anti-VEGF/anti-


PDGF DVD-Ig Molecule (PR-1610561)










VEGF
PDGF















Protein
cyno
mo
rat
rab
cyno
mo
rat
rab





Affinity
65
—
—
41
0.8
0.3
3
3


KD (pM)









Example 13.5: Reactivity of Anti-PDGF-BB Antibodies and Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to ECM-Associated PDGF-BB
As described in Example 1.27, first recombinant cell line HEK293 cells over-expressing PDGFBB-RM and then HUVEC naturally expressing ECM-associated PDGF-BB cells were used for staining:
HEK293 Cell Staining:
PDGFB-RM transient transfected HEK 293 cells and parental HEK293 cells were re-suspended at 1E6 cells/mL in PBS and fixed in 4% paraformaldehyde at RT for 10 minutes, washed with PBS and 2E5 cells/tube were incubated in blocking buffer (10% goat serum in PBS) for one hour on ice. Cells were washed with PBS and incubated with primary antibody or DVD at 33 nM in antibody dilution buffer (5% goat serum in PBS) for one hour on ice. Cells were washed three times with PBS and incubated with Alexa Fluo 488 conjugated Goat anti-Human IgG (Jackson Immune, code: 109-546-098; lot: 108427) 1:400 dilution in antibody dilution buffer, incubate on ice for 45 minutes. Cells were washed three times with PBS and cytospin onto glass slides and mounted with mounting media with DAPI. Pictures were taken by fluorescent microscopy. Anti-PDGF-BB parental and affinity matured mAbs and three DVD-Ig molecules all showed positive staining on PDGFB-RM transient transfected 293 cells (FIG. 2A) and no staining on parental HEK 293 cells except for the slightly positive staining of affinity matured anti-PDGF-BB mAb. It is unclear if parental HEK 293 cells express low level of PDGF-BB endogenously
HUVEC Staining:
HUVEC cells secrete PDGF-BB, and low level of PDGF-BB may be captured on the cell surface as ECM-associated PDGF-BB. Affinity matured anti-PDGF-BB mAb and anti-VEGF/anti-PDGF DVD-Ig built with affinity-matured anti-PDGF-BB mAb was further assessed for its staining on naturally derived ECM-associated PDGF-BB on HUVEC cells. HUVECs (Lonza, cat#: C2519A lot: 181607) were trypsinized, resuspended at 2E4 cells/mL in culture media (Lonza, EGM2 MV Bulletkit: CC-3202). Cells were plated at 10,000 cells/500 μl/well in 8-chamber glass slide and incubated for 16 hours at 37° C., 5% CO2. After incubation, cells were fixed with 200 μl 4% paraformaldehyde at RT for 10 minutes, washed with PBS and incubated in blocking buffer (10% goat serum in PBS) for one hour on ice. Cells were washed with PBS 3× and incubated with primary antibodies or DVD-Ig molecules at 33 nM in antibody dilution buffer (5% goat serum in PBS) for one hour on ice. Cells were washed three times with PBS and incubated with Alexa Fluo 488 conjugated Goat anti-Human IgG (JacksonImmune, code: 109-546-098; lot: 108427) 1:400 dilution in antibody dilution buffer, incubate on ice for 45 minutes. Cells were washed three times with PBS and mounted with mounting media with DAPI. Pictures were taken by fluorescent microscopy. As shown in FIG. 2B, affinity matured anti-PDGF-BB mAb showed positive staining on HUVEC cells while the staining of parental anti-PDGF-BB mAb on HUVEC cells is not evident (FIG. 2B). Anti-VEGF/anti-PDGF DVD-Ig (PR-1610561) built with affinity-matured anti-PDGF-BB mAb showed positive staining on HUVEC cells but control anti-tetanus toxoid DVD-Ig molecule also showed some weak staining which may be due to the background issue.
Example 13.6: Inhibition of Sprouting in HUVEC/MSC Co-culture Sprouting Assay by Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules
As described in Example 1.28, in early therapeutic treatment mode, Cytodex-3 beads (Sigma-Aldrich, cat# C3275) were coated with HUVEC cells (Lonza) overnight, and then embedded (100 beads/well) with human mesenchymal stem cells (Lonza, 20,000 cells/well) in fibrin gel in 24-well tissue culture plates. A 1:1 mixture of fresh EGM-2 complete media (Lonza) and fibroblast (Lonza) conditioned EGM-2 media were added on top of the fibrin gel along with 2 ng/mL of recombinant human HGF. Medium was replaced every 2-3 days till the end of the experiment. After EC sprouts and pericyte coverings were formed, usually on day 4, anti-VEGF-A (4G8.4), anti-PDGFBB (9E8.) or anti-PDGFBB/VEGF-A DVD-Ig were added to the culture medium at 10 nM. 10 days later cells were fixed in 4% PFA overnight at 4° C. Endothelial cells were stained with anti-PECAM (Abcam, ab32457), followed by fluorescence-conjugated secondary antibody, and pericytes were labeled with anti-aSMA-Cy3 (Sigma, C6198). Cells were then viewed by an inverted fluorescence microscope and 5× images were captured (FIG. 3). As seen in the pictures, DVD-Ig molecules as well as the combination of anti-VEGF and anti-PDGF mAbs are able to prevent sprouting formation greater than that of anti-VEGF mAb alone. Neither anti-PDGF mAb or anti-PDGF aptamer alone appear to have any significant inhibition of sprouting formation (FIG. 3). Similar experiments were also conducted in prophylactic and later therapeutic treatment modes and the results clearly demonstrated that anti-VEGF/anti-PDGF DVD-Ig (PR-1610561) strongly inhibited sprouting formation in this 3D co-culture assay.
Example 13.7: Characterization of FcRn and FcγRs Binding
Anti-VEGF/anti-PDGF DVD-Ig molecules, including 4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, 4G8.3-GS-9E8.4(g), 4G8.3-SL-9E8.4(g), 9E10.1GS_CL-33675, are human IgG1/κ isotype with L234A, L235A mutations to attenuate FcγRs binding and H435A mutation to eliminate FcRn binding. The binding of DVD-Ig molecules to FcRn from various species and the binding of DVD-Ig molecules to various FcγRs were characterized by Biacore using the method described in Example 1.2. The data is summarized in Tables 70 and 71 below.







TABLE 70







Binding of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules


to FcRn from Different Species, Measured by Biacore










Steady State
1:1 Binding fit













huFcRn
cynoFcRn
rabbitFcRn
ratFcRn
muFcRn

















KD
KD
KD
ka
kd
KD
ka
kd
KD


Immobilized
(M)
(M)
(M)
(1/Ms)
(1/s)
(M)
(1/Ms)
(1/s)
(M)





4G8.3-GS-9E8.4(g)
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB


PR-1572102


4G8.3-SL-9E8.4(g)
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB


PR-1572105


9E10.1_GS_C
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB


L-33675 PR-1610561


4G8.3-GS-9E8.4
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB


PR-1569574


4G8.3-SL-9E8.4
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB


PR-1569579





* NSB = No significant binding at the concentration tested;


n/a = not available













TABLE 71







Binding of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to Various Human FcγRs, Measured by Biacore















huFcRIIa
huFcRIIa
huFcRIIIa
huFcRIIIa




huFcRIIb
131H
131R
158F
158V
















KD
KD
KD
KD
ka
kd
KD



Sample
(M)
(M)
(M)
(M)
(1/Ms)
(1/s)
(M)
Fit





4G8.3-GS-9E8.4(g)
NSB
NSB
NSB
NSB
n/a
n/a
7.40E−06 
steady state


PR-1572102


4G8.3-SL-9E8.4(g)
NSB
NSB
NSB
NSB
n/a
n/a
6.20E−06 
steady state


PR-1572105


9E10.1_GS_CL-33675
NSB
NSB
NSB
NSB
n/a
n/a
1.1E−05*
steady state


PR-1610561


4G8.3-GS-9E8.4
NSB
NSB
NSB
NSB
n/a
n/a
1.6E−05*
steady state


PR-1569574


4G8.3-SL-9E8.4
NSB
NSB
NSB
NSB
n/a
n/a
1.2E−05*
steady state


PR-1569579





*NSB = No significant binding at the concentration tested;


n/a = not available






Example 14: Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules
Example 14.1: Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules
Twenty one DVD-Ig molecules were selected for a screen of their solubility and stability profiles. Samples were prepped and evaluated according to Example 2.4. The DVD-Ig proteins were prepared in a formulation buffer and stored at 40° C. and 5° C. for up to 21 days. Samples were pulled and analyzed by SEC to determine changes in aggregation (Table 72). The molecules were evaluated at the listed concentrations. SEC was used to quantitate the aggregation percentage.







TABLE 72







Aggregation and Solubility Screening Of Selected DVD-Ig


Molecules Stored At 40° C. and 5° C. for 21 Days


in a Formulation Buffer











% Aggregation



Concentration
Change from T0










DVD-Ig Molecule
(mg/ml)
T21 d 5° C.
T21 d 40° C.













4G8.3-GS-9E8.4
100
0.24
*


4G8.3-SL-9E8.4
100
0.27
*


CL-34565_GS_CL-33675
48.7
0.20
0.25


CL-34565_GS_9E8.4
4.3
−0.30
0.05


CL-34565_GS_3E2.1
10.9
−1.12
−0.89


4G8.5_GS_CL-33675
50
−0.09
*


4G8.5_GS_9E8.4
50
−0.09
12.50


4G8.5_GS_3E2.1
50
0.53
14.63


9E10.1_GS_CL-33675
50
−2.08
−3.09


9E10.1_GS_9E8.4
50.7
2.95
−0.39


9E10.1_GS_3E2.1
43.2
−6.16
−9.05


9E10.6_GS_CL-33675
50
3.17
1.87


9E10.6_GS_3E2.1
34.9
−0.63
−0.65


1B10.1_GS_CL-33675
50
0.72
1.10


1E3.4_GS_3E2.1
50
0.17
*


CL-33675_GS_4G8.5
38.7
0.15
2.34


3E2.1_GS_4G8.5
50
16.15
*


3E2.1_GS_9E10.1
30.4
*
*


3E2.1_GS_9E10.6
50
0.17
5.55


3E2.1_GS_1B10.1
38.6
−6.33
*


3E2.1_GS_1E3.4
50
10.12
*





* Samples were too degraded or compromised to evaluate with SEC (e.g. gelled, precipitated).






Example 14.2: Further Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules (Stability During Storage at 40° C., 25° C., and 5° C.)
Based on the physicochemical screen discussed above (Example 14.1), three anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules (4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, and 9E10.1-GS-33675) were selected for further characterization. Sample prep and analysis was performed according to Example 2.4.
Briefly, the molecules were prepared in a formulation buffer at 100±10 mg/ml and stored at 40° C., 25° C., and 5° C. for 84 days. Samples were periodically pulled for characterization (Tables 73-75 below).
As mentioned in Example 2.4, both 25° C. (room temperature) and 5° C. (storage temperature) are typical temperatures at which the samples would be subjected either during preparation and storage for manufacture or as part of the final drug product presentation. Also, storage at 40° C. is considered an accelerated stability condition which provides an indication of long-term stability prospects.







TABLE 73







Stability of 4G8.3-GS-9E8.4 During Storage. Aggregate, Monomer,


And Fragment Percentages Were Quantitated By SEC















Area Under SEC



%
%
%
Chromatogram Signal



Aggregate
Monomer
Fragment
Relative to T0















T0
1.8
97.3
0.9
1.00


T7 d 40° C.
*
*
*
*


T7 d 25° C.
2.2
97.0
0.9
0.91


T7 d 5° C.
1.9
97.2
0.9
0.92


T21 d 40° C.
*
*
*
*


T21 d 25° C.
3.0
96.4
0.6
0.84


T21 d 5° C.
1.8
97.8
0.5
0.90


T42 d 40° C.
*
*
*
*


T42 d 25° C.
3.4
95.6
1.0
0.88


T42 d 5° C.
2.0
97.3
0.7
1.00


T63 d 40° C.
*
*
*
*


T63 d 25° C.
4.2
94.7
1.0
0.85


T63 d 5° C.
2.1
97.4
0.5
0.92


T84 d 40° C.
*
*
*
*


T84 d 25° C.
5.0
93.7
1.3
0.79


T84 d 5° C.
2.2
97.3
0.6
0.85





* Samples were too degraded or compromised to evaluate with SEC (e.g. gelled, precipitated).













TABLE 74







Stability of 4G8.3-SL-9E8.4 During Storage. Aggregate, Monomer,


And Fragment Percentages Were Quantitated by SEC















Area Under SEC



%
%
%
Chromatogram Signal



Aggregate
Monomer
Fragment
Relative to T0















T0
4.2
94.7
1.1
1.00


T7 d 40° C.
*
*
*
*


T7 d 25° C.
6.6
92.2
1.3
0.86


T7 d 5° C.
4.3
94.7
1.0
0.82


T21 d 40° C.
*
*
*
*


T21 d 25° C.
8.5
90.5
1.1
0.77


T21 d 5° C.
3.9
95.3
0.8
0.87


T42 d 40° C.
*
*
*
*


T42 d 25° C.
13.2 
85.6
1.3
0.80


T42 d 5° C.
4.5
94.4
1.1
0.97


T63 d 40° C.
*
*
*
*


T63 d 25° C.
13.2 
85.3
1.5
0.73


T63 d 5° C.
4.3
95.0
0.7
0.87


T84 d 40° C.
*
*
*
*


T84 d 25° C.
10.3 
88.1
1.6
0.62


T84 d 5° C.
4.5
94.7
0.7
0.80





* Samples were too degraded or compromised to evaluate with SEC (e.g. gelled, precipitated).













TABLE 75







Stability of 9E10.1-GS-33675 During Storage. Aggregate, Monomer,


And Fragment Percentages Were Quantitated by SEC.















Area Under SEC



%
%
%
Chromatogram Signal



Aggregate
Monomer
Fragment
Relative to T0















T0
0.8
98.4
0.7
1.00


T7 d 40° C.
5.3
93.8
0.8
0.84


T7 d 25° C.
4.8
94.6
0.6
0.89


T7 d 5° C.
3.7
95.5
0.8
0.92


T21 d 40° C.
6.1
92.5
1.4
0.77


T21 d 25° C.
4.4
95.0
0.6
0.82


T21 d 5° C.
6.7
92.8
0.5
0.89


T42 d 40° C.
13.8
83.9
2.3
0.76


T42 d 25° C.
4.7
94.6
0.8
0.85


T42 d 5° C.
7.7
91.7
0.5
0.92


T63 d 40° C.
19.8
77.0
3.2
0.77


T63 d 25° C.
4.8
94.4
0.8
0.84


T63 d 5° C.
8.4
91.2
0.4
0.94


T84 d 40° C.
22.8
73.2
4.0
0.68


T84 d 25° C.
5.3
93.7
1.0
0.80


T84 d 5° C.
8.1
91.5
0.4
0.88









Both 4G8.3-GS-9E8.4 and 4G8.3-SL-9E8.4 formed a white precipitate when stored at 40° C. after 7 days and thus could not be analyzed by SEC. The samples are assumed to be completely aggregated. At 25° C., there was an observable increase in aggregation for both molecules. The aggregation was less rapid for 4G8.3-GS-9E8.4 than for 4G8.3-SL-9E8.4. Aggregation of the former increased from 1.8% to 5.0% after 84 days while that of the latter started at 4.2% and reached as high as 13.2% over the course of 84 days. At 5° C., there is no noticeable aggregate increase for the two molecules.
For 9E10.1-GS-33675, aggregation at 5° C. increased from 0.8% to 6.7% by 21 days and levelled off at  ̃8% from 42 to 84 days. At 25° C., aggregation increased from 0.8% to 4.7% by 7 days and levelled off at that value up to 84 days. Finally, aggregation at 40° C. increased from 0.8% to 22.8% in an apparently linear fashion over the course of 84 days. The aggregation at 40° C. for 9E10.1-GS-33675 is much less that that observed for the other two DVD-Ig molecules. This may be the result of the universal formulation buffer used.
There was no apparent change in fragmentation for all three DVD-Ig molecules at 25° C. or 5° C. At 40° C., an apparent and expected increase in fragmentation was observed for 9E10.1-GS-33675 after 21 days.
Example 14.3: Further Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules (Stability to Freeze-Thaw Stress)
Based on the earlier physicochemical screen (Example 14.1), three anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules (4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, and 9E10.1-GS-33675) were selected for further characterization. Sample prep, stress, and analysis were performed according to Example 2.5. Briefly, the molecules were prepared in a formulation buffer at concentrations of 100±10 mg/ml or 1 mg/ml and subjected to four cycles of freezing ( ̃80° C.) and thawing (30° C.). Samples were characterized after the second and fourth thaw (Tables 76-81 below).
As mentioned in Example 2.5, protein samples are typically frozen at −80° C. for long term storage as well as shipping to remote manufacturing sites. The samples are then thawed in order to complete the drug product manufacturing process.







TABLE 76







Stability of 4G8.3-GS-9E8.4 at 100 ± 10 mg/ml When Subjected


To Freeze-Thaw Stress (−80° C./30° C.). Aggregate,


Monomer, And Fragment Percentages Were Quantitated by SEC.















Area Under SEC



%
%
%
Chromatogram Signal



Aggregate
Monomer
Fragment
Relative to T0















F/T 0
1.8
97.3
0.9
1.00


F/T 2
1.8
97.4
0.8
0.90


F/T 4
2.2
96.9
0.9
0.92
















TABLE 77







Stability of 4G8.3-SL-9E8.4 at 100 ± 10 mg/ml


When Subjected To Freeze-Thaw stress (−80°


C./30° C.). Aggregate, Monomer, And Fragment


Percentages Were Quantitated by SEC















Area Under SEC



%
%
%
Chromatogram Signal



Aggregate
Monomer
Fragment
Relative to T0















F/T 0
4.2
94.7
1.1
1.00


F/T 2
4.1
95.2
0.7
0.83


F/T 4
4.3
94.4
1.3
0.82
















TABLE 78







Stability of 9E10.1-GS-33675 at 100 ± 10 mg/ml


when Subjected To Freeze-Thaw Stress (−80°


C./30° C.). Aggregate, Monomer, And Fragment


Percentages Were Quantitated by SEC.















Area Under SEC



%
%
%
Chromatogram Signal



Aggregate
Monomer
Fragment
Relative to T0















F/T 0
0.8
98.4
0.7
1.00


F/T 2
1.1
98.5
0.4
0.91


F/T 4
1.8
97.6
0.6
0.88
















TABLE 79







Stability of 4G8.3-GS-9E8.4 at 1 mg/ml When


Subjected To Freeze-Thaw Stress (−80°


C./30° C.). Aggregate, Monomer, And Fragment


Percentages Were Quantitated by SEC.















Area Under SEC



%
%
%
Chromatogram Signal



Aggregate
Monomer
Fragment
Relative to T0















F/T 0
1.8
97.3
0.9
1.00


F/T 2
1.9
97.5
0.6
0.95


F/T 4
2.0
97.1
0.9
0.96
















TABLE 80







Stability of 4G8.3-SL-9E8.4 at 1 mg/When Subjected To


Freeze-Thaw Stress (−80° C./30° C.). Aggregate,


Monomer, And Fragment Percentages Were Quantitated by SEC.















Area Under SEC



%
%
%
Chromatogram Signal



Aggregate
Monomer
Fragment
Relative to T0















F/T 0
4.2
94.7
1.1
1.00


F/T 2
3.9
95.4
0.7
0.94


F/T 4
4.1
94.9
1.0
0.94
















TABLE 81







Stability of 9E10.1-GS-33675 at 1 mg/ml When Subjected


To Freeze-Thaw Stress (−80° C./30° C.). Aggregate,


Monomer, And Fragment Percentages Were Quantitated by SEC.















Area Under SEC



%
%
%
Chromatogram Signal



Aggregate
Monomer
Fragment
Relative to T0















F/T 0
0.8
98.4
0.7
1.00


F/T 2
1.0
98.6
0.5
0.98


F/T 4
1.2
98.2
0.6
0.98









For all three DVD-Igs, at either 100±10 mg/ml or 1 mg/ml, no apparent increase in aggregation was observed due to freeze-thaw stress after two cycles.
Example 14.4: Further Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules (Viscosity Determination)
Based on the earlier physicochemical screen (Example 14.1), three anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules (4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, and 9E10.1-GS-33675) were selected for further characterization. The molecules were prepared in a formulation buffer at 100±10 mg/ml and the viscosities were measured at room temperature (Example 2.6). The viscosities were 5.1, 7.2, and 7.2 centipoise, respectively. The values are within the range that enables ease of administration via a small diameter needle attached to a syringe.
Example 14.5: Further Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules (Thermal Stability Assessment)
Based on the earlier physicochemical screen (Example 14.1), three anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules (4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, and 9E10.1-GS-33675) were selected for further characterization. The molecules were prepared in a formulation buffer at 1 mg/ml according to Example 2.3 and the thermal stabilities were determined according to Example 2.2. The midpoint temperatures of the first transition of unfolding are 52° C., 51° C., and 62° C., respectively. The temperatures at which the first transitions began to appear are 44° C., 42° C., and 62° C., respectively. The data indicate that 9E10.1-GS-33675 has a significantly greater thermal stability than the other two DVD-Ig molecules.
Example 14.6: Physicochemical Properties of an Anti-VEGF/anti-PDGF DVD-Ig Molecule (PR-1610561)
Testing of PR-1610561 revealed high thermostability (Tonset=62° C.), solubility at least at 76 mg/ml, and a viscosity at 100 mg/ml at room temperature of 7.2 centipoise, which is within the range that enables ease of administration via a small diameter needle attached to a syringe. PR-1610561 has appropriate storage stability in a universal buffer and freeze-thaw stability.
Example 14.76: Intact and Reduced Molecular Weight Determination
Q-TOF LC-MS can detect mass differences between proteins that can result from mis-sense mutations, post-translational modifications, truncations, and other covalent changes that affect protein molecular weight. Table 82 shows the intact molecular weight and deglycosylated intact molecular weight of all three DVD-Ig molecules. Table 83 shows the molecular weights of light chain, heavy chain and deglycosylated heavy chain. The observed molecular weights of the three DVD-Ig molecules match well with the theoretical values with difference of less than 3 Dalton, which is well within the expected range of the error for the instrument.







TABLE 82







Intact molecular weight










Intact MW
Deglycosylated Intact MW












Theoretical
Observed
Theoretical
Observed















PR-1572102
203220
203219
200330
200330


PR-1572105
204350
204348
201460
201460


PR-1610561
202452
202450
199562
199562
















TABLE 83







Reduced molecular weight











Light Chain
Heavy Chain
Deglycosylated



MW
MW
HC MW














Theo-
Ob-
Theo-
Ob-
Theo-
Ob-



retical
served
retical
served
retical
served

















PR-1572102
36080
36080
65533
65533
64088
64091


PR-1572105
36735
36734
65444
65444
63999
64002


PR-1610561
36006
36005
65224
65224
63779
63780









Example 14.8: Oligosaccharide Profiles by Fc Molecular Weight
DVD-Ig molecules contain N-linked oligosaccharides in the Fc region of the heavy chain Fc molecular weight measurement can provide a semi-quantitative analysis of the oligosaccharide profiles. Table 84 shows the results of oligosaccharide profiles by Fc molecular weight. The oligosaccharide profiles of all three DVD-Ig molecules were similar to what is normally observed for mAbs, with 70-73% Gal 0F and 21-24% Gal 1F. The level of high mannose species was very low in all three samples. No significant level of aglycosylated species was detected.







TABLE 84







Oligosaccharide Profiles By Fc Molecular Weight










Species
PR-1572102
PR-1572105
PR-1610561













Man 5
1.0
1.1
0.4


Gal 0F-GlcNAc
0.5
0.4
0.0


Gal 0
0.5
0.2
0.7


Gal 0F
73.4
73.4
70.8


Lys-1
0.8
0.3
0.8


Gal 1F
21.0
21.2
23.8


Gal 2F
2.8
3.3
3.6









Example 14.9: Charge Heterogeneity by Weak Cation Exchange Chromatography and Imaged Isoelectric Focusing
Weak cation exchange (WCX) chromatography separates molecules on the basis of the differences in their net surface charge. Variation in the extent of C terminal processing and certain post-translational modifications can lead to different species of an antibody with different charge distributions. Molecules that vary in their charge properties will exhibit different degrees of interaction with ion exchange resins, thus different elution profiles. Each chromatogram is characterized by a predominant peak (“main”) and species eluting before (“acidic”) or after (“basic”). The relative abundances of these species types are shown in Table 85.







TABLE 85







Results of Weak Cation Exchange Chromatography Analysis











Acidic (%)
Main (%)
Basic (%)
















PR-1572102
9.2
63.9
26.9



PR-1572105
14.9
52.4
32.7



PR-1610561
17.7
56.5
25.8










Imaged capillary isoelectric focusing (icIEF) is a technique that separates proteins on the basis of their isoelectric points or pI values. Different proteins have different pI and peak profiles, which makes icIEF an ideal identity assay. In icIEF, proteins with different pI values focus into distinctive bands in a linear pH gradient formed by ampholytes after applying high voltage. Table 86 shows the theoretical pI (calculated based on amino acid sequence) and the observed pI values measured by imaged icIEF. Also shown in Table 86 are the relative abundances of different charge species detected by imaged icIEF.







TABLE 86







Results of Imaged Isoelectric Focusing














pI by






Thoe. pI
icIEF
Acidic (%)
Main (%)
Basic (%)
















PR- 1572102
6.13
6.78
14.3
71.6
14.1


PR-1572105
6.13
6.74
25.3
60.2
14.4


PR-1610561
6.67
7.27
27.2
63.2
9.6









Example 15: Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules
Example 15.1: Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Intravenously Administered in huFcRN Transgenic Mice
Studies were conducted in accordance with the AbbVie IACUC guidelines. Anti-VEGF/anti-PDGF DVD-Ig molecules PR-1572102 (lot 2211502), PR-1572105 (lot 2211597), or PR-1610561 (lot 2213329) were administered to huFcRn B6.Cg transgenic mice (5/group) at 5 mg/kg by slow intravenous bolus dose injection. Blood samples were collected from each mouse at 1, 24 and 96 hours and 7, 10, 14 and 21 days post dose. All samples were stored at −80° C. until analysis. DVD-Ig serum concentrations were measured using a Meso Scale Discovery (MSD) electrochemiluminescence (ECL) Ligand Binding Assay. Biotinylated VEGF ligand was coated onto streptavidin MSD plates for capture of anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules from blood samples, and detection was achieved with a sulfo-tag goat anti-human IgG antibody. Concentrations were calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).
All three anti-VEGF/PDGF DVD-Ig molecules carrying the H435A substitution had serum concentrations rapidly clear, with measurable concentrations only to 24 hours. These results are in agreement with the rapid clearance observed with other H435A modified antibody and DVD-Ig molecules in human FcRn transgenic mice.
Example 15.2: Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Intravitreously Administered in Rabbit
Studies were conducted in accordance with the Abbott IACUC guidelines. Female New Zealand White rabbits were used for the ocular pharmacokinetic characterization of Anti-VEGF-A/anti-PDGF-BB DVD-Igs: PR-1572102, PR-1572105 and PR-1610561. Animals (4 animals) were split into two cohorts of two for determination of ocular pharmacokinetics. Samples of aqueous humour were taken at 4, 24, 48, 72, 120, 168, 336 and 504 hours post dosing. With cohort 1 providing samples at 4, 48, 120 and 168 hours, and cohort 2 providing samples at 24, 72, 336 and 504 hours, post dosing. Drug levels in the eye were determined from concentrations in aqueous humour as a surrogate for the vitreous concentrations. Vitreous was harvested from each animal as a terminal sample after their last aqueous humour sample. The proportion of aqueous to vitreous concentration was determined from these terminal time points. Blood samples for the harvest of serum used to estimate systemic exposure after vitreous dosing were also collected at 4, 24, 48, 72, 120, and 168 hours post dosing from all animals, and at 336 and 504 hours from the animals in cohort 2. Test articles were dosed into the vitreous compartment at a range of 0.25 to 0.50 mg per eye with a dose volume of no more than 0.050 mL. Only the right eye of each animal was dosed. Prior to dosing, animals were anesthetized with xylazine/ketamine. The eye was prepared by first applying topical analgesic drops (procaine HCl Ophthalmic solution, 0.5%), then the injections site was swabbed with a saturated povidone-iodine swabstick (10% solution equivalent to 1% available iodine) prior to injection. The intravitreal dose was administered with a 26 gauge needle. The point of entry for the injection was 1-2 mm from the limbus through the sclera. After injection, a sterile cotton eye spear was placed on the injection site and held for 30 seconds to prevent leakage Animals were anesthetized for aqueous fluid collection. At the selected time points after dosing, the aqueous fluid was collected using a 30 gauge needle inserted through the cornea. The needle was advanced just past the bevel and fluid was collected. The samples provided approximately 0.05-0.1 mL of aqueous humour per sampling period. At the selected time points after dosing, blood samples were obtained from an ear vein or artery. Hemostasis following collection was achieved by the application of manual pressure and topical clotting factor or tissue glue as needed. The samples were from 0.5-1 ml in volume, and were allowed to clot for harvest of serum. Aqueous, vitreous and serum samples were stored at −80° C., and submitted for drug level determinations.
All DVD-Ig serum concentrations were measured using a GYROS method employing biotinylated VEGF ligand for capture, and Alexa Flour 647 goat anti-human IgG detection. Concentrations were calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).







TABLE 87







Ocular Half Lives in Rabbit from Analysis of Aqueous Humor










Experiment
Test Article
Corporate ID
Half life (hours)





#1
9E10.1_GS_CL-33675
PR-1610561
111


#2
9E10.1_GS_CL-33675
PR-1610561
Pending









Example 15.3: Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Intravenously Administered in Cynomolgus Monkey
Studies are conducted in accordance with the AbbVie IACUC guidelines. Female cynomolgus are used for the systemic pharmacokinetic characterization of Anti-VEGF-A/anti-PDGF-BB DVD-Igs, including PR-1572102, PR-1572105 and PR-1610561 after intravenous dosing. Monkeys are dosed intravenously at 5 mg/kg by slow bolus into the saphenous vein over approximately 2 minutes with a volume of 0.5 mL/kg. Samples are taken for determination of the pharmacokinetics of the test compounds at 0, 0.08, 4, 8, 24, 72, 168, 240, 336, 504 and 672 hours post dosing. At the selected time points after dosing, blood samples are obtained from a femoral vein. Hemostasis following collection is achieved by the application of manual pressure and topical clotting factor or tissue glue as needed. The samples may be approximately 1 ml in volume, and are allowed to clot for harvest of serum. Serum samples are stored at −80° C., and submitted for drug level determinations.
DVD-Ig serum concentrations are measured using either a GYROS or a MSD method. GYROS employs biotinylated VEGF ligand for capture, and Alexa Flour 647 goat anti-human IgG detection. MSD employs biotinylated VEGF ligand for capture, and Sulfo-tag goat anti-human IgG or sulfo-tag VEGF for detection. Concentrations are calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters are calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).
Example 15.4: Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Intravitreously Administered in Cynomolgus Monkey
Studies are conducted in accordance with the AbbVie IACUC guidelines. Female cynomolgus are used for the ocular pharmacokinetic characterization of Anti-VEGF-A/anti-PDGF-BB DVD-Igs, including PR-1572102, PR-1572105 and PR-1610561. Animals (4 animals) are split into two cohorts of two for determination of ocular pharmacokinetics. Samples of aqueous humour are taken at 4, 24, 48, 72, 120, 168, 336 and 504 hours post dosing. With cohort 1 providing samples at 4, 48, 120 and 168 hours, and cohort 2 providing samples at 24, 72, 336 and 504 hours, post dosing. Drug levels in the eye are determined from concentrations in aqueous humour as a surrogate for the vitreous concentrations. Blood samples for the harvest of serum used to estimate systemic exposure after vitreous dosing are also collected at 4, 24, 48, 72, 120, and 168 hours post dosing from all animals, and at 336 and 504 hours from the animals in cohort 2. Test articles are dosed into the vitreous compartment at a range of 0.25 to 0.50 mg per eye with a dose volume of no more than 0.050 mL. Only the right eye of each animal is dosed. Prior to dosing, animals are anesthetized with xylazine/ketamine. The eye is prepared by first applying topical analgesic drops (procaine HCl Ophthalmic solution, 0.5%), then the injections site is swabbed with a saturated povidone-iodine swabstick (10% solution equivalent to 1% available iodine) prior to injection. The intravitreal dose is administered with a 26 gauge needle. The point of entry for the injection is 1-2 mm from the limbus through the sclera. After injection, a sterile cotton eye spear is placed on the injection site and held for 30 seconds to prevent leakage. Animals are anesthetized for aqueous fluid collection. At the selected time points after dosing, the aqueous fluid is collected using a 30 gauge needle inserted through the cornea. The needle is advanced just past the bevel and fluid was collected. The samples provide approximately 0.05-0.1 mL of aqueous humour per sampling period. At the selected time points after dosing, blood samples are obtained from an ear vein or artery. Hemostasis following collection is achieved by the application of manual pressure and topical clotting factor or tissue glue as needed. The samples are approximately 1 ml in volume, and are allowed to clot for harvest of serum. Aqueous, vitreous and serum samples are stored at −80° C., and submitted for drug level determinations.
DVD-Ig serum concentrations are measured using either a GYROS or a MSD method. GYROS employs biotinylated VEGF ligand for capture, and Alexa Flour 647 goat anti-human IgG detection. MSD employs biotinylated VEGF ligand for capture, and Sulfo-tag goat anti-human IgG or sulfo-tag VEGF for detection. Concentrations are calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters are calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).
Example 16: Efficacy of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Human VEGF Transgenic Mice
Example 16.1: Efficacy of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to Inhibit Subretinal Neovascularization in Rho/huVEGF Transgenic Mice
Transgenic mice in which the rhodopsin promoter drives expression of human VEGF165 in photoreceptors (Rho-VEGF mice) have onset of VEGF expression at P7 and starting at P10, develop sprouts of NV from the deep capillary bed of the retina that grow through the photoreceptor layer and form an extensive network of new vessels in the subretinal space. Since the new vessels originate from retinal capillaries and not choroidal vessels, it is technically a model of retinal angiomatous proliferation (RAP) which occurs in roughly 30% of patients with neovascular AMD, but in general it mimics critical features of wet AMD. At P14, hemizygous Rho-VEGF mice were given an intraocular injection of test reagents. At P21, the mice were euthanized, and eyes were fixed in 10% phosphate-buffered formalin for 2 hours. Retinas were dissected, blocked with 5% normal swine serum in PBS for 1 hour, stained with FITC-conjugated GSA, a vascular stain, for 2 hours to stain vascular cells, flat mounted with the photoreceptor side up, and examined by fluorescence microscopy. The area of subretinal NV was measured with image analysis by an investigator blinded with respect to treatment group. The other eye will provide information regarding systemic effect of an intraocular injection.
In the study below, nine treatment groups were evaluated: DVD-Ig Control (DVD 889), Eylea, Anti VEGF mAb, Anti PDGF mAb, Anti VEGF+Anti PDGF (combination Ab treatment), Anti-VEGF/anti-PDGF DVD-Ig. Only eye measurements in the experimental eye were analyzed and reported here using one way ANOVA analysis. Posthoc comparison of treatment vs the DVD control groups was analysed by Dunnett's test. Results are shown in See FIG. 4 and in Table 88 below. Further, differences in PDGF neutralization potencies and the molecular size of the DVD-Ig versus IgG did not have an effect in this model.
An overall ANOVA F-test for significance was used and the data was shown to be significant (p<0.0001). Comparison of the test groups to the DVD-Ig control group shows that the difference from all the groups was significant (Dunnet test p<0.0001). PR-1610561 was significantly more effective at inhibiting subretinal neovascularization in Rho/huVEGF transgenic mice than Eylea (Tukey HSD test pvalue=0.0031). PR-1610561 was more effective, but not significantly different from, the anti-VEGF and anti-PDGF (potency matched mAbs) combination group.







TABLE 88







Inhibition Efficacy of Anti-VEGF-A, Anti-PDGF-


BB, Anti-VEGF-A + Anti-PDGF-BB, and Anti-


VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to Subretinal


Neovascularization in Rho/huVEGF Transgenic Mice














Cor-
N (# of







porate
ani-

Std
Std
CV


Groups
ID#
mals)
Mean
Dev
Err
(%)
















DVD negative
PR-
8
0.0892
0.0665
0.0235
74


control
1250499


Eylea
—
19
0.0198
0.0224
0.0051
113


Anti VEGF
—
7
0.0164
0.0088
0.0033
54


Anti PDGF
—
16
0.0297
0.0265
0.0066
89


Anti VEGF +
—
10
0.0119
0.0182
0.0058
153


Anti PDGF


Anti-VEGF/
PR-
9
0.0033
0.0038
0.0013
115


anti-PDGF
1610561


DVD-Ig









Example 16.2: Efficacy of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules in Tet-Opsin-Human VEGF165 Double-Transgenic Mice
When given injections of doxycycline, Tet-opsin-VEGF double-transgenic mice with Dox-inducible expression of VEGF express 10-fold higher levels of human VEGF165 than Rho-VEGF-transgenic mice and develop severe NV and exudative retinal detachments within 3 to 5 days. Tet-opsin-VEGF mice provide a severe model where mice develop exudative retinal detachments and only the most effective agents have a significant impact. Double-hemizygous Tet-opsin-VEGF mice were given intraocular injections of test reagent in the right eyes. For the next 3 days, the mice were also administered a daily subcutaneous injection of 50 mg/kg doxycycline. At the 4th day, mice were euthanized and fundus photographs taken with Micron III retinal imaging microscope (Phoenix Research Laboratories, Pleasanton, Calif.). Also, OCT images were taken by Bioptigen Image-guided OCT (Envisu R4110, Bioptigen Inc. Morrisville, N.C.). Then eyes were frozen in optimal cutting temperature embedding solution. Ten-micron ocular serial sections were cut through the entire eye, stained with H&E stain and examined by light microscopy. After that mean length of the retinal detachment per section was measured with image analysis by an investigator blinded with respect to treatment group. The percentage of the detached retina was computed. Retinal detachment was graded as no detachment (0); partial retinal detachment (1); or total retinal detachment (2).
Anti-VEGF-A, anti-PDGF-BB, and the combination of anti-VEGF-A and anti-PDGF-BB were tested for their ability to suppress retinal detachment (RD) in tet-opsin-VEGF double transgenic mice. Results showed differences among the 3 test groups (P=0.01, Kruskal-Wallis test). Based on the RD number, the combination of anti-VEGF-A and anti-PDGF-BB (7 NRD, 1 PRD, 0 TRD), and the anti-VEGF-A alone (5 NRD, 0 PRD, 0 TRD) groups were more effective than anti-PDGF-BB alone (2 NRD, 2 PRD, 2 TRD) in preventing RD in Tet-opsin-VEGF double transgenic mice.
The differences in efficacy between PR-1610561, Eylea, and control IgG were compared next in tet-opsin-VEGF mice. Differences were also found among the 3 groups (P=0.01, Kruskal-Wallis test). PR-1610561 (10 NRD, 0 PRD, 1 TRD) and Eylea (4 NRD, 3 PRD, 1 TRD) were more effective than IgG control (2 NRD, 2 PRD, 2 TRD) in preventing RD in Tet-opsin-VEGF double transgenic mice. The data is summarized in Table 89 below.







TABLE 89







The efficacy of test articles in tet-


opsin-VEGF double transgenic mice















Anti-
Anti-
Anti-





IgG
VEGF
PDGF
VEGF +
PR-


Grade
control
mAb
mAb
Anti-PDGF
1610561
Eylea
















0
2
5
2
7
10
4


(NRD)


1
1
0
2
1
0
3


(PRD)


2
6
0
3
0
1
1


(TRD)








Total
9
5
7
8
11
8


eyes









The effects of PR-1610561 in a tet/opsin/huVEGF double transgenic mouse retinal detachment model were also analyzed by another grading system (Table 89A). 1 μl of reagent was injected into one eye, followed by subcutaneous injection of doxycycline at 500 mg/kg once a day for three days, and then fundus images and OCTs were done at day 4. Retinal detachment was graded as no detachment (0); no retinal detachment but at least one sign selected from dilated retinal vessels, retinal edema, or hemorrhage (1); one or less than one quadrant of retinal detachment (2); two or three quandrants of retinal detachment or shallow pan retinal detachment (3); or severe bullous retinal detachment (4).







TABLE 89A







Efficacy of Anti-VEGF, Anti-PDGF, Anti-VEGF + Anti-PDGF, and Anti-


VEGF/Anti-PDGF DVD-Ig Molecules in Tet/Opsin/huVEGF Double Transgenic Mice













Grade
DVD889
Anti-VEGF
Anti-PDGF
Combo
PR-1610561
Aflibercept
















0
1
4
1
4
3
1


1
1
1
1
2
7
3


2
1
0
2
0
0
1


3
0
0
0
1
1
1


4
6
0
3
0
0
1


Total eyes
9
5
7
8
11
7


evaluated









The results in the tables above show that PR-1610561 has similar efficacy to a combination of anti-VEGF-A and anti-PDGF-BB, and is superior to Aflibercept alone in suppressing subretinal neovascularization in Rho/huVEGF transgenic mice. PR-1610561 is also superior to the combination of Aflibercept and anti-PDGF-BB in the prevention of vascular leakage in Rho/huVEGF transgenic mice.
Example 16.3: Effects of Anti-VEGF/Anti-PDGF on Ocular Neovascularization and Vascular Permeability/Perfusion
This study compared the effects of intraocular injections of anti-VEGF/anti-PDGF DVD-Ig molecules, anti-VEGF mAb alone, anti-PDGF alone, and a combination of antibodies.
DVD-Ig molecules and DVD-Ig Fab fragments were selected for evaluation, first in Rho/VEGF mice and then in Tet/opsin/VEGF double transgenic mice.
Studies used rho/VEGF and Tet/opsin/VEGF mouse models as described in Example 16.1. The compounds evaluated are shown in Table 90 below. About 20 mice were included per experiment, where one eye was injected with agent and the other eye was not injected.







TABLE 90





Study Agents

















4G8.3-GS-9E8.4 (PR-1572102; DVD-Ig-1)



4G8.3-LS-9E8.4 (PR-PR-1575573; DVD-Ig-2)



4G8.3-SL-9E8.4 (PR-1572105; DVD-Ig-3)



DVD 889(IgG control)



Anti-VEGF IgG 4G83



Anti-PDGF-BB IgG 9E8.4



Anti-VEGF IgG 24 μg + Anti-PDGF-BB IgG



Avastin 24 μg



Anti-PDGF-BB aptamer E10030.1



Avastin 24 μg + Anti-PDGF-BB aptamer










Transgenic mice in which the rhodopsin promoter drives expression of VEGF in photoreceptors (rho/VEGF mice) develop retinal angiomatous proliferation (RAP) which originates from the deep capillary bed of the retina and grows through the photoreceptor layer to reach the subretinal spaces. The transgenic mice were utilized to determine the effects of DVD-Ig molecules on subretinal neovascularization. The rho/VEGF mice have an onset of VEGF expression at P7 and, starting at P10, develop sprouts of NV from the deep capillary bed of the retina that grow through the photoreceptor layer and form an extensive network of new vessels in the subretinal space. At P14, hemizygous Rho-VEGF mice were given an intraocular injection of test reagents. At P21, the mice were euthanized, and eyes were fixed in 10% phosphate-buffered formalin for 2 hours. Retinas were dissected, blocked with 5% normal swine serum in PBS for 1 hour, stained with FITC-conjugated GSA for 2 hours to stain vascular cells, flat mounted with the photoreceptor side up, and examined by fluorescence microscopy. The area of subretinal NV was measured with image analysis by an investigator blinded with respect to treatment group.
Compared with the control DVD-Ig molecule, DVD-Ig-1 and DVD-Ig-3 significantly decreased choroidal neovascularization (CNV) (p=0.02, 0.04), whereas DVD-Ig-2 did not show much effect. Compared with the IgG control, the combined administration of anti-VEGF IgG and anti-PDGF-BB IgG significantly decreased CNV (p=0.045), while administration of anti-VEGF IgG or anti-PDGF IgG alone did not significantly reduce subretinal NV. No other difference was observed in eyes injected with Avastin, anti-PDGF-BB aptamer, or a mixture of Avastin and anti-PDGF-BB aptamer. Significantly decreased subretinal NV was found after administration of DVD-Ig-1 and DVD-Ig-3, when compared to the mixture of Avastin and the anti-PDGF-BB aptamer. No other difference was found between DVD-Ig reagents and the combined administration of anti-VEGF-IgG and anti-PDGF IgG. FIG. 5.
No difference was found in the untreated eyes of mice injected with anti-VEGF/anti-PDGF DVD-Ig molecules, control DVD-Ig, anti-VEGF mAb alone, anti-PDGF alone, and a combination of antibodies (ANOVA, P>0.05), indicating there was no clear systemic effect of intraocular injection. FIG. 6.
Tet/opsin/VEGF mice express higher levels of VEGF in photoreceptors than rho/VEGF mice, resulting in severe NV and vascular leakage with exudative retinal detachment. The efficacy of intraocular injections of anti-VEGF/anti-PDGF DVD-Ig molecules in this transgenic mouse was also evaluated. Mice were given intraocular injections of test reagent in the right eye. For the next 3 days, the mice were also administered a daily subcutaneous injection of 50 mg/kg doxycycline. At the 4th days, mice were euthanized and fundus photographs were taken with Micron III retinal imaging microscope (Phoenix Research Laboratories, Pleasanton, Calif.). OCT images were taken by Bioptigen Image-guided OCT (Envisu R4110, Bioptigen Inc. Morrisville, N.C.). Then eyes were frozen in optimal cutting temperature embedding solution. Ten-micron ocular serial sections were cut through the entire eye, stained with H&E stain and examined by light microscopy. Mean length of the retinal detachment per section was measured with image analysis by an investigator blinded with respect to treatment group. The percentage of the retina that was detached was computed.
Five mice in each test group were injected with DVD-Ig reagents separately. In DVD-Ig-1 injected eyes, two were not detached and three were partially detached, while three eyes were totally detached and two partially detached in the uninjected eye. In DVD-Ig-3 injected eyes, one was not detached, two were partially detached, and two were totally detached, while all the uninjected eyes were totally detached. In the DVD-Ig-2 injected eyes, one was not detached and four were totally detached, while one eye was partially detached and four eyes were totally detached in the uninjected eye. In the IgG control group, one injected eye was not detached, one eye was partially detached, and three eyes were totally detached, while all eyes were totally detached in the uninjected eye. FIG. 7.
Thus, DVD-Ig-1 and DVD-Ig-3 appeared to perform at least as well as a combination of anti-VEGF mAb and anti-PDGF mAb for the measured parameters, while requiring the administration of only one compound.
Example 17: Generation and Identification of Various Molecular Formats Optimal for Applications in Ocular Diseases
Several attributes were considered in the design of a therapeutic biologic for the treatment of wet AMD:
PK, Efficacy and Frequency of Administration:
Longer ocular duration may support less frequent intravitreous injection. The size of the administered molecule may play a role in determining ocular half-life. This is supported by consistently longer ocular half-life for the current anti-VEGF agents with larger molecular size in humans and in experimental animals. Bevacizumab, which has a larger molecular size (150 kDa) than ranibizumab (49 kDa), also seems to have more robust duration of efficacy in both Rho/huVEGF and tet/huVEGF transgenic mice, the two models used for preclinical efficacy.
FcRn and FcγR Binding and Safety:
Fc neonatal receptor (FcRn), which plays a role for long circulating half-life of IgG molecules in serum, may or may not play an important role in determining ocular half-life. The molecules with wild type FcRn binding, however, will have long systemic half-life and may increase safety risk due to unnecessary systemic exposure of intravitreously injected molecules. FcRn is also perceived to play a role in active efflux of IgGs across blood-retina barrier. This may lead to shortened ocular retention time for the intravitreously inject molecules. Effector functions are not needed for the efficacy of anti-wet AMD agents. But both VEGF-A and PDGF-BB may be associated with extracellular matrix when they are initially synthesized and secreted. The ECM-associated VEGF-A and PDGF-BB therefore may potentially mediate effector functions.
Affinity, Valency and Potency:
Both VEGF-A and PDGF-BB are homodimeric molecules. If a monovalent molecular format similar to that of ranibizumab (Fab) is used for bispecific molecules targeting VEGF and PDGF for the treatment of wet AMD, high affinity may be needed to maintain binding and potent neutralization of both VEGF-A and PDGF-BB.
Manufacturability:
Any viable format needs to have acceptable expression, purification, formulation properties to accommodate DS and DP manufacturing.
Various binding protein formats disclosed herein may satisfy these characteristics:
(1) Full length DVD-Ig [L234A, L235A] (200 kDa, lacks binding to FcgRs)
(2) Full length DVD-Ig [L234A, L235A, H435A] (200 kDa, lacks binding to FcgRs and FcRn)
(3) Half DVD-Ig (100 kDa, lacks binding to FcgRs and FcRn)
(4) DVD-Fab (75 kDa, no Fc)
Example 17.1: Generation of Various Molecular Formats Including DVD-Ig [L234A, L235A], DVD-Ig [L234A, L235A and H435A], DVD-Ig [L234A, L235A and H435R], Half DVD-Ig and DVD-Fab
This example evaluates the impact of Fc mutations on the PK properties of DVD-Ig binding proteins. DVD-038 was used a tool molecule to study various DVD-Ig formats, including a half-DVD-Ig (DVD038 [L234A, L235A] Half-DVD), full DVD-Ig binding proteins having three constant domain mutations (DVD038 [L234A, L235A and H435A] and DVD038 [L234A, L235A and H435R]), and a full DVD-Ig binding protein having two constant domain mutations (DVD038 [L234A, L235A]). The data below was used to evaluate options for producing a VEGF/PDGF binding protein structure with good drug-like properties and exhibiting high ocular duration but low systemic circulation. DVD038 is a dual variable domain binding protein that binds HER2 and VEGF.
To prepare mutants of DVD038, overlapping PCR was used with primers designed to include the desired mutations. PCR products were digested and ligated into the cloning vector. Bacterial transformation was performed to identify positive clones and constructs were harvested and purified for use in mammalian transfection using standard protocols known in the art.
All variants were transiently transfected into 10 L of HEK 293 6E suspension cell cultures in a Wave-bag with a ratio of 60% to 40% light to heavy chain construct. 0.5 mg/mL PEI was used to transfect the cells. Supernatants were harvested after 11 days by centrifugation at 16000 g for 20 minutes followed by filtration using Pall Serum Capsule and Pall AcroPak 1000. All except DVD-Fab were purified on MabSelectSuRe resin (GE Healthcare, 17-5438-04). Following equilibration with PBS pH 7.4, the supernatant was loaded on the resin and washed with PBS pH 7.4. DVD-Ig protein was eluted with 50 mM Glycine, 50 mM NaCl pH 3.5. DVD-Fab was purified using Protein G Sepharose 4 FF resin (GE Healthcare, 17-0618-04). Elution was performed with Immunopure IgG elution buffer (Pierce, 185 1520). Fractions containing DVD-Ig were pooled and dialyzed in 30 mM Histidine pH 6, 8% sucrose overnight at 4° C.
Example 17.2: Binding of Various Formats to FcRns from Different Species
As described in Example 1.2, all variants of DVD038, except for DVD038 Fab which does not have an Fc region, were analyzed for their binding to FcRns from different species. The data is summarized in Table 91 below.







TABLE 91







Binding of Various Formats to FcRns from Different Species














Hu
Cyno
Rabbit




Corporate
FcRn
FcRn
FcRn
Rat FcRn














Test Articles
ID
KD (M)
KD (M)
KD (M)
ka (1/Ms)
kd (1/s)
KD (M)





DVD038 (L234A,
PR-1578399
6.26E−06
3.13E−06
6.76E−07
3.06E+04
2.57E−02
8.40E−07


L235A) Half DVD-Ig


DVD038 (L234A,
PR-1564681
7.96E−06
2.57E−06
3.98E−07
5.15E+04
5.53E−02
1.07E−06


L235A, H435R)


DVD038 (L234A,
PR-1565009
4.90E−06
1.74E−06
2.75E−07
3.66E+04
1.94E−02
5.31E−07


L235A)












DVD038 (L234A,
PR-1565689
NSB
NSB
NSB
NSB


L235A, H435A)














HERCEPTIN
—
4.53E−06
2.62E−06
4.69E−07
3.27E+04
1.81E−02
5.55E−07





* NSB = no significant binding






Example 17.3: Pharmacokinetic Properties of Different Formats in huFcRn Transgenic Mice Administered Intravenously
Studies were conducted in accordance with the Abbott IACUC guidelines. DVD038 (L234A, L235A) (PR-1565009), DVD038 (L234A, L235A, H435R) (PR-1564681), and DVD038 (L234A, L235A, H435A) (PR-1565689) were administered to huFcRn transgenic mice (5/group) at 6.7 mg/kg by slow intravenous bolus dose injection. Blood samples were collected from each mouse at 1, 24 and 96 hours and 7, 10, 14 and 21 days post dose. All samples were stored at −80° C. until analysis. DVD-Ig serum concentrations were measured using a Meso Scale Discovery (MSD) electrochemiluminescence (ECL) Ligand Binding Assay. Biotinylated VEGF ligand was coated onto streptavidin MSD plates for capture of anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules from blood samples, and detection was achieved with a sulfo-tag goat anti-human IgG antibody. Concentrations were calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).







TABLE 92







PK in huFcRn Transgenic Mice













CL


Test Articles
Corporate ID
T1⁄2 (d)
(mL/h/kg)





DVD038 (L234A, L235A)
PR-1565009
2.8
0.81


DVD038 (L234A, L235A, H435R)
PR-1564681
1.8
1.25


DVD038 (L234A, L235A, H435A)
PR-1565689
0.6
1.58









The results demonstrate a trend for increased clearance and shorter half-life for DVD constructs with reduced or lack of Fc binding in huFcRn transgenic mice.
Example 17.4: Pharmacokinetic Properties of Different Formats in CD-1 Mice Administered Intravenously
Studies were conducted in accordance with the Abbott IACUC guidelines. DVD038 (L234A, L235A) (PR-1565009), DVD038 (L234A, L235A, H435R) (PR-1564681), DVD038 (L234A, L235A, H435A) (PR-1565689), DVD038 half DVD-Ig (L234A, L235A) (PR-1578399) and DVD-Fab (PR-1574215) were administered to CD-1 mice (5/group) at 6.7 mg/kg by slow intravenous bolus dose injection. Blood samples were collected from each mouse at 1, 24 and 96 hours and 7, 10, 14 and 21 days post dose. All samples were stored at −80° C. until analysis. DVD-Ig serum concentrations were measured using a Meso Scale Discovery (MSD) electrochemiluminescence (ECL) Ligand Binding Assay. Biotinylated VEGF ligand was coated onto streptavidin MSD plates for capture of anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules from blood samples, and detection was achieved with a sulfo-tag goat anti-human IgG antibody. Concentrations were calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).







TABLE 93







PK in CD-1 Mice













CL


Test Articles
Corporate ID
T1⁄2 (d)
(mL/h/kg)













DVD038 (L234A, L235A)
PR-1565009
7.6
0.46


DVD038 (L234A, L235A, H435R)
PR-1564681
6.4
0.29


DVD038 (L234A, L235A, H435A)
PR-1565689
2.7
0.73


DVD038 Half DVD-Ig (L234A,
PR-1578399
0.4
8.86


L235A)


DVD038 DVD-Fab
PR-1574215
0.2
20.76









Results demonstrate a trend for increased clearance and shorter half-life for DVD constructs with reduced or lack of Fc binding in CD-1 mice. Molecules composed of a fragment of immunoglobulin structure are cleared fastest.
Example 17.5: Pharmacokinetic Properties of Different Formats in Rabbits Administered Intravitreously
Studies were conducted in accordance with the AbbVie IACUC guidelines. Female New Zealand White rabbits were used for the ocular pharmacokinetic characterization of formats DVD038 (PR-1565009, lot 2131983), DVD038 H435A (PR-1565689, lot 2131481), DVD038 Dhab (PR-1578399, lot 2149586) and DVDFab (PR-1574215, lot 2143755). Animals (4 animals) were split into two cohorts of two for determination of ocular pharmacokinetics. Samples of aqueous humour were taken at 48, 168, 336 and 504 hours post dosing. With cohort 1 providing samples at 48 and 168 hours, and cohort 2 providing samples at 336 and 504 hours, post dosing. Drug levels in the eye were determined from concentrations in aqueous humour. Blood samples for the harvest of serum used to estimate systemic exposure after vitreous dosing were also collected at 4, 24, 48, 72, 120, 168 hours post dosing from all animals, and at 336 and 504 hours from the animals in cohort 2. Test articles were dosed into the vitreous compartment at 0.50 mg per eye with a volume of no more than 0.050 mL. Only the right eye of each animal was dosed. Prior to dosing, animals were anesthetized with xylazine/ketamine. The eye was prepared by first applying topical analgesic drops (procaine HCl Ophthalmic solution, 0.5%), then the injections site was swabbed with a saturated povidone-iodine swab stick (10% solution equivalent to 1% available iodine) prior to injection. The intravitreal dose was administered with a 26 gauge needle. The point of entry for the injection was 1-2 mm from the limbus through the sclera. After injection, a sterile cotton eye spear was placed on the injection site and held for 30 seconds to prevent leakage. Animals were anesthetized for aqueous fluid collection. At the selected time points after dosing, the aqueous fluid was collected using a 30 gauge needle inserted through the cornea. The needle was advanced just past the bevel and fluid was collected. The samples provided approximately 0.05-0.1 mL of aqueous humour per sampling period. At the selected time points after dosing, blood samples were obtained from an ear vein or artery. Hemostasis following collection was achieved by the application of manual pressure and topical clotting factor or tissue glue as needed. The samples were from 0.5-1 ml in volume, and were allowed to clot for harvest of serum. Aqueous, vitreous and serum samples were stored at −80° C., and submitted for drug level determinations.
The serum, and aqueous humour concentrations for these molecules were measured using either a GYROS or a MSD method. GYROS employs a biotinylated VEGF ligand for capture, and Alexa Flour 647 goat anti-human IgG detection. MSD employs biotinylated VEGF ligand for capture, and Sulfo-tag goat anti-human IgG or sulfo-tag VEGF for detection. Results were comparable between the two methods. Concentrations were calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie). Results from the experiment are shown in Table 94.







TABLE 94







Ocular Half Lives in Rabbit from Analysis of Aqueous Humor









Test Articles
Corporate ID
Half life












DVD038 (L234A, L235A)
PR-1565009
151


DVD038 (L234A, L235A, H435A)
PR-1565689
157


DVD038 Half DVD-Ig (L234A, L235A)
PR-1578399
90


DVD038 DVD-Fab
PR-1574215
110









Population analysis of the pooled data sets was performed on the composite profile from multiple animals at each dose level. The analysis provided parameter estimates with reasonable variability (CV<30%). The larger molecular weight constructs show a weak trend towards a longer ocular half-life.







TABLE 95







Exemplary DVD-Ig Binding Proteins And Component Subunits











SEQ






ID NO
DVD-Ig
Outer VD name
Linker
Inner VD name














45
PR-1563988H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBDB-4G8.3 VH (VEGF)




(SEQ ID NO: 1)

(SEQ ID NO: 17)


46
PR-1563988L
hBDI-9E8.4 VL (PDGF)
GS-L10
hBDB-4G8.3 VL (VEGF)




(SEQ ID NO: 2)

(SEQ ID NO: 18)


47
PR-1563990H
hBDI-9E8.4 VH (PDGF)
HG-short
hBDB-4G8.3 VH (VEGF)




(SEQ ID NO: 1)

(SEQ ID NO: 17)


48
PR-1563990L
hBDI-9E8.4 VL (PDGF)
LK-short
hBDB-4G8.3 VL (VEGF)




(SEQ ID NO: 2)

(SEQ ID NO: 18)


49
PR-1563998H
hBDI-9E8.4 VH (PDGF)
HG-short
hBDB-4G8.3 VH (VEGF)




(SEQ ID NO: 1)

(SEQ ID NO: 17)


50
PR-1563998L
hBDI-9E8.4 VL (PDGF)
LK-long
hBDB-4G8.3 VL (VEGF)




(SEQ ID NO: 2)

(SEQ ID NO: 18)


51
PR-1564009H
hBDI-9E8.4 VH (PDGF)
HG-long
hBDB-4G8.3 VH (VEGF)




(SEQ ID NO: 1)

(SEQ ID NO: 17)


51
PR-1564009L
hBDI-9E8.4 VL (PDGF)
LK-short
hBDB-4G8.3 VL (VEGF)




(SEQ ID NO: 2)

(SEQ ID NO: 18)


53
PR-1564010H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 17)

(SEQ ID NO: 1)


54
PR-1564010L
hBDB-4G8.3 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 18)

(SEQ ID NO: 2)


55
PR-1564011H
hBDB-4G8.3 VH (VEGF)
HG-short
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 17)

(SEQ ID NO: 1)


56
PR-1564011L
hBDB-4G8.3 VL (VEGF)
LK-short
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 18)

(SEQ ID NO: 2)


57
PR-1564012H
hBDB-4G8.3 VH (VEGF)
HG-short
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 17)

(SEQ ID NO: 1)


58
PR-1564012L
hBDB-4G8.3 VL (VEGF)
LK-long
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 18)

(SEQ ID NO: 2)


59
PR-1564013H
hBDB-4G8.3 VH (VEGF)
HG-long
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 17)

(SEQ ID NO: 1)


60
PR-1564013L
hBDB-4G8.3 VL (VEGF)
LK-short
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 18)

(SEQ ID NO: 2)


61
PR-1564883H
hBDI-5H1.9 VH (PDGF)
HG-short
hBDB-4G8.13 VH (VEGF)



(DVD3896H)a
(SEQ ID NO: 3)

(SEQ ID NO: 19)


62
PR-1564883L
hBDI-5H1.9 VL (PDGF)
LK-long
hBDB-4G8.13 VL (VEGF)



(DVD3896L)a
(SEQ ID NO: 4)

(SEQ ID NO: 20)


63
PR-1564893H
hBDI-5H1.9 VH (PDGF)
HG-short
hBDB-4G8.14 VH (VEGF)



(DVD3897H)a
(SEQ ID NO: 3)

(SEQ ID NO: 21)


64
PR-1564893L
hBDI-5H1.9 VL (PDGF)
LK-long
hBDB-4G8.14 VL (VEGF)



(DVD3897L)a
(SEQ ID NO: 4)

(SEQ ID NO: 22)


209
PR-1564896H
hBDI-5H1.9 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)



(DVD3898H)a
(SEQ ID NO: 3)

(SEQ ID NO: 23)


65
PR-1564896L
hBDI-5H1.9 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)



(DVD3898L)a
(SEQ ID NO: 4)

(SEQ ID NO: 24)


66
PR-1564898H
hBDI-5H1.12 VH (PDGF)
HG-short
hBDB-4G8.14 VH (VEGF)



(DVD3899H)a
(SEQ ID NO: 211)

(SEQ ID NO: 21)


67
PR-1564898L
hBDI-5H1.12 VL (PDGF)
LK-long
hBDB-4G8.14 VL (VEGF)



(DVD3899L)a
(SEQ ID NO: 212)

(SEQ ID NO: 22)


68
PR-1564899H
hBDI-5H1.12 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)



(DVD3900H)a
(SEQ ID NO: 211)

(SEQ ID NO: 23)


69
PR-1564899L
hBDI-5H1.12 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)



(DVD3900L)a
(SEQ ID NO: 212)

(SEQ ID NO: 24)


70
PR-1565023H
hBDI-9E8.9 VH (PDGF)
HG-short
hBDB-4G8.13 VH (VEGF)



(DVD3901H)a
(SEQ ID NO: 7)

(SEQ ID NO: 19)


71
PR-1565023L
hBDI-9E8.9 VL (PDGF)
LK-long
hBDB-4G8.13 VL (VEGF)



(DVD3901L)a
(SEQ ID NO: 8)

(SEQ ID NO: 20)


72
PR-1565029H
hBDI-9E8.9 VH (PDGF)
HG-short
hBDB-4G8.14 VH (VEGF)



(DVD3902H)a
(SEQ ID NO: 7)

(SEQ ID NO: 21)


73
PR-1565029L
hBDI-9E8.9 VL (PDGF)
LK-long
hBDB-4G8.14 VL (VEGF)



(DVD3902L)a
(SEQ ID NO: 8)

(SEQ ID NO: 22)


74
PR-1565030H
hBDI-9E8.9 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)



(DVD3903H)a
(SEQ ID NO: 7)

(SEQ ID NO: 23)


75
PR-1565030L
hBDI-9E8.9 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)



(DVD3903L)a
(SEQ ID NO: 8)

(SEQ ID NO: 24)


76
PR-1565031H
hBDI-9E8.12 VH (PDGF)
HG-short
hBDB-4G8.14 VH (VEGF)



(DVD3904H)a
(SEQ ID NO: 9)

(SEQ ID NO: 21)


77
PR-1565031L
hBDI-9E8.12 VL (PDGF)
LK-long
hBDB-4G8.14 VL (VEGF)



(DVD3904L)a
(SEQ ID NO: 10)

(SEQ ID NO: 22)


78
PR-1565032H
hBDI-9E8.12 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)



(DVD3905H)a
(SEQ ID NO: 5)

(SEQ ID NO: 23)


79
PR-1565032L
hBDI-9E8.12 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)



(DVD3905L)a
(SEQ ID NO: 6)

(SEQ ID NO: 24)


80
PR-1565035H
hBDI-5H1.10 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)



(DVD3906H)a
(SEQ ID NO: 9)

(SEQ ID NO: 23)


81
PR-1565035L
hBDI-5H1.10 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)



(DVD3906L)a
(SEQ ID NO: 10)

(SEQ ID NO: 24)


82
PR-1565033H
hBDI-9E8.10 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)



(DVD3907H)a
(SEQ ID NO: 9)

(SEQ ID NO: 23)


83
PR-1565033L
hBDI-9E8.10 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)



(DVD3907L)a
(SEQ ID NO: 10)

(SEQ ID NO: 24)


84
PR-1569574H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBDB-4G8.3 VH (VEGF)




(SEQ ID NO: 1)

(SEQ ID NO: 17)


85
PR-1569574L
hBDI-9E8.4 VL (PDGF)
GS-L10
hBDB-4G8.3 VL (VEGF)




(SEQ ID NO: 2)

(SEQ ID NO: 18)


86
PR-1569579H
hBDI-9E8.4 VH (PDGF)
HG-short
hBDB-4G8.3 VH (VEGF)




(SEQ ID NO: 1)

(SEQ ID NO: 17)


87
PR-1569579L
hBDI-9E8.4 VL (PDGF)
LK-long
hBDB-4G8.3 VL (VEGF)




(SEQ ID NO: 2)

(SEQ ID NO: 18)


88
PR-1572102H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 17)

(SEQ ID NO: 1)


89
PR-1572102L
hBDB-4G8.3 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 18)

(SEQ ID NO: 2)


90
PR-1572103H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 17)

(SEQ ID NO: 1)


91
PR-1572103L
hBDB-4G8.3 VL (VEGF)
GS-L11
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 18)

(SEQ ID NO: 2)


92
PR-1572104H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 17)

(SEQ ID NO: 1)


93
PR-1572104L
hBDB-4G8.3 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 18)

(SEQ ID NO: 2)


94
PR-1572105H
hBDB-4G8.3 VH (VEGF)
HG-short
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 17)

(SEQ ID NO: 1)


95
PR-1572105L
hBDB-4G8.3 VL (VEGF)
LK-long
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 18)

(SEQ ID NO: 2)


96
PR-1572106H
hBDB-4G8.3 VH (VEGF)
HG-long
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 17)

(SEQ ID NO: 1)


97
PR-1572106L
hBDB-4G8.3 VL (VEGF)
LK-short
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 18)

(SEQ ID NO: 2)


210
PR-1575573H
hBDI-9E8.4 VH (PDGF)
HG-long
hBDB-4G8.3 VH (VEGF)




(SEQ ID NO: 1)

(SEQ ID NO: 17)


98
PR-1575573L
hBDI-9E8.4 VL (PDGF)
LK-short
hBDB-4G8.3 VL (VEGF)




(SEQ ID NO: 2)

(SEQ ID NO: 18)


99
PR-1575832H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4E VH (PDGF)




(SEQ ID NO: 17)

(SEQ ID NO: 11)


100
PR-1575832L
hBDB-4G8.3 VL (VEGF)
GS-L10
hBDI-9E8.4E VL (PDGF)




(SEQ ID NO: 18)

(SEQ ID NO: 12)


101
PR-1575834H
hBDB-4G8.3 VH (VEGF)
HG-short
hBDI-9E8.4E VH (PDGF)




(SEQ ID NO: 17)

(SEQ ID NO: 11)


102
PR-1575834L
hBDB-4G8.3 VL (VEGF)
LK-long
hBDI-9E8.4E VL (PDGF)




(SEQ ID NO: 18)

(SEQ ID NO: 12)


103
PR-1575835H
hBDB-4G8.3 VH (VEGF)
HG-long
hBDI-9E8.4E VH (PDGF)




(SEQ ID NO: 17)

(SEQ ID NO: 11)


104
PR-1575835L
hBDB-4G8.3 VL (VEGF)
LK-short
hBDI-9E8.4E VL (PDGF)




(SEQ ID NO: 18)

(SEQ ID NO: 12)


105
PR-1577165H
hBEW-9A8.12 VH (VEGF)
GS-H10
hBDI-9E8.4E VH (PDGF)




(SEQ ID NO: 25)

(SEQ ID NO: 11)


106
PR-1577165L
hBEW-9A8.12 VL (VEGF)
GS-L10
hBDI-9E8.4E VL (PDGF)




(SEQ ID NO: 26)

(SEQ ID NO: 12)


107
PR-1577166H
hBEW-9A8.12 VH (VEGF)
HG-short
hBDI-9E8.4E VH (PDGF)




(SEQ ID NO: 25)

(SEQ ID NO: 11)


108
PR-1577166L
hBEW-9A8.12 VL (VEGF)
LK-long
hBDI-9E8.4E VL (PDGF)




(SEQ ID NO: 26)

(SEQ ID NO: 12)


109
PR-1577547H
hBEW-9A8.12 VH (VEGF)
HG-long
hBDI-9E8.4E VH (PDGF)




(SEQ ID NO: 25)

(SEQ ID NO: 11)


110
PR-1577547L
hBEW-9A8.12 VL (VEGF)
LK-short
hBDI-9E8.4E VL (PDGF)




(SEQ ID NO: 26)

(SEQ ID NO: 12)


111
PR-1577548H
hBDI-9E8.4E VH (PDGF)
HG-short
hBEW-9A8.12 VH (VEGF)




(SEQ ID NO: 11)

(SEQ ID NO: 25)


112
PR-1577548L
hBDI-9E8.4E VL (PDGF)
LK-long
hBEW-9A8.12 VL (VEGF)




(SEQ ID NO: 12)

(SEQ ID NO: 26)


113
PR-1577550H
hBDI-9E8.4E VH (PDGF)
HG-long
hBEW-9A8.12 VH (VEGF)




(SEQ ID NO: 11)

(SEQ ID NO: 25)


114
PR-1577550L
hBDI-9E8.4E VL (PDGF)
LK-short
hBEW-9A8.12 VL (VEGF)




(SEQ ID NO: 12)

(SEQ ID NO: 26)


115
PR-1578137H
hBDI-9E8.4E VH (PDGF)
GS-H10
hBEW-9A8.12 VH (VEGF)




(SEQ ID NO: 11)

(SEQ ID NO: 25)


116
PR-1578137L
hBDI-9E8.4E VL (PDGF)
GS-L10
hBEW-9A8.12 VL (VEGF)




(SEQ ID NO: 12)

(SEQ ID NO: 26)


117
PR-1598261H
hBDB-4G8.2 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 27)

(SEQ ID NO: 1)


118
PR-1598261L
hBDB-4G8.2 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 28)

(SEQ ID NO: 2)


119
PR-1598262H
hBDB-4G8.4 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 29)

(SEQ ID NO: 1)


120
PR-1598262L
hBDB-4G8.4 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 30)

(SEQ ID NO: 2)


121
PR-1598263H
hBDB-4G8.5 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 31)

(SEQ ID NO: 1)


122
PR-1598263L
hBDB-4G8.5 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 32)

(SEQ ID NO: 2)


123
PR-1598264H
hBDB-4G8.12 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 33)

(SEQ ID NO: 1)


124
PR-1598264L
hBDB-4G8.12 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 34)

(SEQ ID NO: 2)


125
PR-1598265H
hBDB-4G8.13 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 19)

(SEQ ID NO: 1)


126
PR-1598265L
hBDB-4G8.13 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 20)

(SEQ ID NO: 2)


127
PR-1598266H
hBDB-4G8.14 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 21)

(SEQ ID NO: 1)


128
PR-1598266L
hBDB-4G8.14 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 22)

(SEQ ID NO: 2)


129
PR-1610560H
hBDB-4G8.5 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)




(SEQ ID NO: 31)

(SEQ ID NO: 13)


130
PR-1610560L
hBDB-4G8.5 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)




(SEQ ID NO: 32)

(SEQ ID NO: 14)


131
PR-1610561H
hBEW-9E10.1 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)




(SEQ ID NO: 35)

(SEQ ID NO: 15)


132
PR-1610561L
hBEW-9E10.1 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)




(SEQ ID NO: 36)

(SEQ ID NO: 16)


133
PR-1610562H
hBEW-9E10.1 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)




(SEQ ID NO: 35)

(SEQ ID NO: 13)


134
PR-1610562L
hBEW-9E10.1 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)




(SEQ ID NO: 36)

(SEQ ID NO: 14)


135
PR-1610563H
hBEW-9E10.6 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)




(SEQ ID NO: 37)

(SEQ ID NO: 13)


136
PR-1610563L
hBEW-9E10.6 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)




(SEQ ID NO: 38)

(SEQ ID NO: 14)


137
PR-1610564H
hBEW-1B10.1 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)




(SEQ ID NO: 39)

(SEQ ID NO: 13)


138
PR-1610564L
hBEW-1B10.1 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)




(SEQ ID NO: 40)

(SEQ ID NO: 14)


139
PR-1611291H
hBDB-4G8.5 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)




(SEQ ID NO: 31)

(SEQ ID NO: 15)


140
PR-1611291L
hBDB-4G8.5 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)




(SEQ ID NO: 32)

(SEQ ID NO: 16)


141
PR-1611292H
hBEW-1B10.1 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)




(SEQ ID NO: 39)

(SEQ ID NO: 15)


142
PR-1611292L
hBEW-1B10.1 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)




(SEQ ID NO: 40)

(SEQ ID NO: 16)


143
PR-1611293H
hBEW-1E3.4 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)




(SEQ ID NO: 41)

(SEQ ID NO: 15)


144
PR-1611293L
hBEW-1E3.4 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)




(SEQ ID NO: 42)

(SEQ ID NO: 16)


145
PR-1611294H
hBEW-1E3.4 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 41)

(SEQ ID NO: 1)


146
PR-1611294L
hBEW-1E3.4 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 42)

(SEQ ID NO: 2)


147
PR-1611295H
CL-33675 VH (PDGF)
GS-H10
hBEW-9E10.1 VH (VEGF)




(SEQ ID NO: 15)

(SEQ ID NO: 35)


148
PR-1611295L
CL-33675 VL (PDGF)
GS-L10(dR)
hBEW-9E10.1 VL (VEGF)




(SEQ ID NO: 16)

(SEQ ID NO: 36)


149
PR-1611296H
CL-33675 VH (PDGF)
GS-H10
hBEW-9E10.6 VH (VEGF)




(SEQ ID NO: 15)

(SEQ ID NO: 37)


150
PR-1611296L
CL-33675 VL (PDGF)
GS-L10(dR)
hBEW-9E10.6 VL (VEGF)




(SEQ ID NO: 16)

(SEQ ID NO: 38)


151
PR-1611297H
CL-33675 VH (PDGF)
GS-H10
hBEW-1E3.4 VH (VEGF)




(SEQ ID NO: 15)

(SEQ ID NO: 41)


152
PR-1611297L
CL-33675 VL (PDGF)
GS-L10(dR)
hBEW-1E3.4 VL (VEGF)




(SEQ ID NO: 16)

(SEQ ID NO: 42)


153
PR-1611298H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBEW-9E10.1 VH (VEGF)




(SEQ ID NO: 1)

(SEQ ID NO: 35)


154
PR-1611298L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBEW-9E10.1 VL (VEGF)




(SEQ ID NO: 2)

(SEQ ID NO: 36)


155
PR-1611299H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBEW-9E10.6 VH (VEGF)




(SEQ ID NO: 1)

(SEQ ID NO: 37)


156
PR-1611299L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBEW-9E10.6 VL (VEGF)




(SEQ ID NO: 2)

(SEQ ID NO: 38)


157
PR-1611300H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBEW-1B10.1 VH (VEGF)




(SEQ ID NO: 1)

(SEQ ID NO: 39)


158
PR-1611300L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBEW-1B10.1 VL (VEGF)




(SEQ ID NO: 2)

(SEQ ID NO: 40)


159
PR-1611301H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBEW-1E3.4 VH (VEGF)




(SEQ ID NO: 1)

(SEQ ID NO: 41)


160
PR-1611301L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBEW-1E3.4 VH (VEGF)




(SEQ ID NO: 2)

(SEQ ID NO: 42)


161
PR-1612489H
hBDB-4G8.5 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 31)

(SEQ ID NO: 1)


162
PR-1612489L
hBDB-4G8.5 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 32)

(SEQ ID NO: 2)


163
PR-1612491H
hBEW-9E10.1 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 35)

(SEQ ID NO: 1)


164
PR-1612491L
hBEW-9E10.1 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 36)

(SEQ ID NO: 2)


165
PR-1612492H
hBEW-9E10.6 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)




(SEQ ID NO: 37)

(SEQ ID NO: 15)


166
PR-1612492L
hBEW-9E10.6 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)




(SEQ ID NO: 38)

(SEQ ID NO: 16)


167
PR-1612493H
hBEW-9E10.6 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 37)

(SEQ ID NO: 1)


168
PR-1612493L
hBEW-9E10.6 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 38)

(SEQ ID NO: 2)


169
PR-1612494H
hBEW-1B10.1 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 39)

(SEQ ID NO: 1)


170
PR-1612494L
BEW-1B10.1 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 40)

(SEQ ID NO: 2)


171
PR-1612495H
hBEW-1E3.4 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)




(SEQ ID NO: 41)

(SEQ ID NO: 13)


172
PR-1612495L
hBEW-1E3.4 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)




(SEQ ID NO: 42)

(SEQ ID NO: 14)


173
PR-1612496H
CL-33675 VH (PDGF)
GS-H10
hBDB-4G8.5 VH (VEGF)




(SEQ ID NO: 15)

(SEQ ID NO: 31)


174
PR-1612496L
CL-33675 VL (PDGF)
GS-L10(dR)
hBDB-4G8.5 VL (VEGF)




(SEQ ID NO: 16)

(SEQ ID NO: 32)


175
PR-1612498H
CL-33675 VH (PDGF)
GS-H10
hBEW-1B10.1 VH (VEGF)




(SEQ ID NO: 15)

(SEQ ID NO: 39)


176
PR-1612498L
CL-33675 VL (PDGF)
GS-L10(dR)
hBEW-1B10.1 VL (VEGF)




(SEQ ID NO: 16)

(SEQ ID NO: 40)


177
PR-1612499H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBDB-4G8.5 VH (VEGF)




(SEQ ID NO: 13)

(SEQ ID NO: 31)


178
PR-1612499L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBDB-4G8.5 VL (VEGF)




(SEQ ID NO: 14)

(SEQ ID NO: 32)


179
PR-1612500H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBEW-9E10.1 VH (VEGF)




(SEQ ID NO: 13)

(SEQ ID NO: 35)


180
PR-1612500L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBEW-9E10.1 VL (VEGF)




(SEQ ID NO: 14)

(SEQ ID NO: 36)


181
PR-1612501H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBEW-9E10.6 VH (VEGF)




(SEQ ID NO: 13)

(SEQ ID NO: 37)


182
PR-1612501L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBEW-9E10.6 VL (VEGF)




(SEQ ID NO: 14)

(SEQ ID NO: 38)


183
PR-1612502H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBEW-1B10.1 VH (VEGF)




(SEQ ID NO: 13)

(SEQ ID NO: 39)


184
PR-1612502L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBEW-1B10.1 VL (VEGF)




(SEQ ID NO: 14)

(SEQ ID NO: 40)


185
PR-1613183H
CL-34565 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)




(SEQ ID NO: 43)

(SEQ ID NO: 15)


186
PR-1613183L
CL-34565 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)




(SEQ ID NO: 44)

(SEQ ID NO: 16)


187
PR-1613184H
CL-34565 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)




(SEQ ID NO: 43)

(SEQ ID NO: 1)


188
PR-1613184L
CL-34565 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)




(SEQ ID NO: 44)

(SEQ ID NO: 2)


189
PR-1613185H
CL-34565 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)




(SEQ ID NO: 43)

(SEQ ID NO: 13)


190
PR-1613185L
CL-34565 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)




(SEQ ID NO: 44)

(SEQ ID NO: 14)


191
PR-1613186H
CL-33675 VH (PDGF)
GS-H10
CL-34565 VH (VEGF)




(SEQ ID NO: 15)

(SEQ ID NO: 43)


192
PR-1613186L
CL-33675 VL (PDGF)
GS-L10(dR)
CL-34565 VL (VEGF)




(SEQ ID NO: 16)

(SEQ ID NO: 44)


193
PR-1613187H
hBDI-9E8.4 VH (PDGF)
GS-H10
CL-34565 VH (VEGF)




(SEQ ID NO: 1)

(SEQ ID NO: 43)


194
PR-1613187L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
CL-34565 VL (VEGF)




(SEQ ID NO: 2)

(SEQ ID NO: 44)


195
PR-1613188H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBDB-4G8.5 VH (VEGF)




(SEQ ID NO: 1)

(SEQ ID NO: 31)


196
PR-1613188L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBDB-4G8.5 VL (VEGF)




(SEQ ID NO: 2)

(SEQ ID NO: 32)


197
PR-1613189H
hBFU-3E2.1 VH (PDGF)
GS-H10
CL-34565 VH (VEGF)




(SEQ ID NO: 13)

(SEQ ID NO: 43)


198
PR-1613189L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
CL-34565 VL (VEGF)




(SEQ ID NO: 14)

(SEQ ID NO: 44)


199
PR-1613190H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBEW-1E3.4 VH (VEGF)




(SEQ ID NO: 13)

(SEQ ID NO: 41)


200
PR-1613190L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBEW-1E3.4 VL (VEGF)




(SEQ ID NO: 14)

(SEQ ID NO: 42)


201
PR-1629646H
hBEW-9E10.1 VH (VEGF)
HG-short
CL-33675 VH (PDGF)




(SEQ ID NO: 35)

(SEQ ID NO: 15)


202
PR-1629646L
hBEW-9E10.1 VL (VEGF)
LK-long
CL-33675 VL (PDGF)




(SEQ ID NO: 36)

(SEQ ID NO: 16)


203
PR-1629647H
hBEW-1B10.1 VH (VEGF)
HG-short
CL-33675 VH (PDGF)




(SEQ ID NO: 39)

(SEQ ID NO: 15)


204
PR-1629647L
hBEW-1B10.1 VL (VEGF)
LK-long
CL-33675 VL (PDGF)




(SEQ ID NO: 40)

(SEQ ID NO: 16)


205
PR-1629648H
hBEW-9E10.1 VH (VEGF)
HG-long
CL-33675 VH (PDGF)




(SEQ ID NO: 35)

(SEQ ID NO: 15)


206
PR-1629648L
hBEW-9E10.1 VL (VEGF)
LK-short
CL-33675 VL (PDGF)




(SEQ ID NO: 36)

(SEQ ID NO: 16)


207
PR-1629649H
hBEW-1B10.1 VH (VEGF)
HG-long
CL-33675 VH (PDGF)




(SEQ ID NO: 39)

(SEQ ID NO: 15)


208
PR-1629649L
hBEW-1B10.1 VL (VEGF)
LK-short
CL-33675 VL (PDGF)




(SEQ ID NO: 40)

(SEQ ID NO: 16)
















TABLE 96







Sequences of Exemplary DVD-Ig Binding Proteins









SEQ




ID NO
DVD-Ig
Sequence












45
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1563988H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW




GQGTMVTVSSGGGGSGGGGSEVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY




WVRQAPGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT




AVYYCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAA




LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI




CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP




EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNHYTQKSLSLSPGK


 


46
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS



1563988L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGGSGGG




GSGDTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNL




ESGVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


47
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1563990H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW




GQGTMVTVSSASTKGPEVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQ




APGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYY




CARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV




KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH




KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV




VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG




KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP




SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE




ALHNHYTQKSLSLSPGK


 


48
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS



1563990L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPDT




VLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESGVP




ARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVFIF




PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS




LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


49
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1563998H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW




GQGTMVTVSSASTKGPEVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQ




APGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYY




CARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV




KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH




KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV




VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG




KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP




SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE




ALHNHYTQKSLSLSPGK


 


50
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS



1563998L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPSV




FIFPPDTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASN




LESGVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVA




APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS




KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


51
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1564009H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW




GQGTMVTVSSASTKGPSVFPLAPEVQLVQSGSELKKPGASVKVSCKASGYTFTNYG




MYWVRQAPGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAE




DTAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGT




AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ




TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS




RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL




HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT




CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV




FSCSVMHEALHNHYTQKSLSLSPGK


 


51
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS



1564009L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPDT




VLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESGVP




ARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVFIF




PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS




LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


53
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1564010H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM




GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP




VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNHYTQKSLSLSPGK


 


54
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1564010L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG




SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR




PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


55
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1564011H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI




RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT




YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV




KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH




KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV




VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG




KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP




SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE




ALHNHYTQKSLSLSPGK


 


56
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1564011L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF




VLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGI




PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPSVFI




FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY




SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


57
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1564012H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI




RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT




YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV




KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH




KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV




VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG




KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP




SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE




ALHNHYTQKSLSLSPGK


 


58
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1564012L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVF




IFPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ




RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


59
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1564013H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG




MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM




DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA




ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT




YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR




TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH




QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS




CSVMHEALHNHYTQKSLSLSPGK


 


60
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1564013L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF




VLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGI




PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPSVFI




FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY




SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


61
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIRQPPGKALEWLANIWWDD



1564883H
DKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWG



(DVD3896H)a
QGTTVTVSSASTKGPEIQLVQSGTEVKKPGESLKISCKASGYTFTNYGMYWVKQMP




GKGLEYMGWINTETGKPTYADDFKGRFTFSLDKSFNTAFLQWSSLKASDTAMYFCA




RTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP




SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV




DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE




YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD




IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL




HNHYTQKSLSLSPGK


 


62
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVSWYQQKPGQPPKNVIYGNDQRP



1564883L
SGVPDRFSGSGSGNSATLTISSLQAEDVAVYFCQSYDSDIDIVFGGGTKVEIKGTVAA



(DVD3896L)a
PSVFIFPPETVLTQSPATLSVSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYG




ASNLESGVPARFSGSGSGTDFTLTISSLQSEDFAVYFCQQSWNDPFTFGQGTRLEIKRT




VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ




DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


63
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIRQPPGKALEWLANIWWDD



1564893H
DKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWG



(DVD3897H)a
QGTTVTVSSASTKGPEIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQAP




GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFCA




RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP




SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV




DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE




YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD




IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL




HNHYTQKSLSLSPGK


 


64
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVSWYQQKPGQPPKNVIYGNDQRP



1564893L
SGVPDRFSGSGSGNSATLTISSLQAEDVAVYFCQSYDSDIDIVFGGGTKVEIKGTVAA



(DVD3897L)a
PSVFIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGA




SNLESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTV




AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD




SKDSTYSLSSTLTLSKADYEK


 


209
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIRQPPGKALEWLANIWWDD



1564896H
DKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWG



(DVD3898H)a
QGTTVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQAP




GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYFCA




RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP




SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV




DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE




YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD




IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL




HNHYTQKSLSLSPGK


 


65
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVSWYQQKPGQPPKNVIYGNDQRP



1564896L
SGVPDRFSGSGSGNSATLTISSLQAEDVAVYFCQSYDSDIDIVFGGGTKVEIKGTVAA



(DVD3898L)a
PSVFIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYG




ASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRT




VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ




DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


66
PR-
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTFGMGVGWIRQAPGKGLEWLANIWWD



1564898H
DDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCARISTGISSYYVMDAW



(DVD3899H)a
GQGTLVTVSSASTKGPEIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQA




PGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFC




ARTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK




DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK




PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV




VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK




EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS




DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA




LHNHYTQKSLSLSPGK


 


67
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAPKNVIYGNDQRP



1564898L
SGVPSRFSGSGSGNSATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVEIKGTVAAP



(DVD3899L)a
SVFIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGAS




NLESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTV




AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD




SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


68
PR-
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTFGMGVGWIRQAPGKGLEWLANIWWD



1564899H
DDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCARISTGISSYYVMDAW



(DVD3900H)a
GQGTLVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQ




APGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYF




CARTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV




KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH




KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV




VVDVSHEDPEVKTNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG




KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP




SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE




ALHNHYTQKSLSLSPGK


 


69
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAPKNVIYGNDQRP



1564899L
SGVPSRFSGSGSGNSATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVEIKGTVAAP



(DVD3900L)a
SVFIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYGA




SNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRTV




AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD




SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


70
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1565023H
DDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWG



(DVD3901H)a
QGTTVTVSSASTKGPEIQLVQSGTEVKKPGESLKISCKASGYTFTNYGMYWVKQMP




GKGLEYMGWINTETGKPTYADDFKGRFTFSLDKSFNTAFLQWSSLKASDTAMYFCA




RTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP




SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV




DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE




YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD




IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL




HNHYTQKSLSLSPGK


 


71
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVSWYQQKPGQPPKNVIYADDQRP



1565023L
SGVPDRFSGSGSGNSASLTISSLQAEDVAVYFCQSYDINIDIVFGGGTKVEIKGTVAAP



(DVD3901L)a
SVFIFPPETVLTQSPATLSVSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGA




SNLESGVPARFSGSGSGTDFTLTISSLQSEDFAVYFCQQSWNDPFTFGQGTRLEIKRTV




AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD




SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


72
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1565029H
DDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWG



(DVD3902H)a
QGTTVTVSSASTKGPEIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQAP




GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFCA




RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP




SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV




DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE




YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD




IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL




HNHYTQKSLSLSPGK


 


73
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVSWYQQKPGQPPKNVIYADDQRP



1565029L
SGVPDRFSGSGSGNSASLTISSLQAEDVAVYFCQSYDINIDIVFGGGTKVEIKGTVAAP



(DVD3902L)a
SVFIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGAS




NLESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTV




AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD




SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


74
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1565030H
DDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWG



(DVD3903H)a
QGTTVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQAP




GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYFCA




RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP




SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV




DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE




YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD




IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL




HNHYTQKSLSLSPGK


 


75
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVSWYQQKPGQPPKNVIYADDQRP



1565030L
SGVPDRFSGSGSGNSASLTISSLQAEDVAVYFCQSYDINIDIVFGGGTKVEIKGTVAAP



(DVD3903L)a
SVFIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYGA




SNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRTV




AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD




SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


76
PR-
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTYGMGVGWIRQAPGKGLEWLANIWW



1565031H
DDDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCARIESIGTTYSFDYW



(DVD3904H)a
GQGTLVTVSSASTKGPEIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQA




PGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFC




ARTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK




DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK




PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV




VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK




EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS




DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA




LHNHYTQKSLSLSPGK


 


77
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAPKNVIYADDQRPS



1565031L
GVPSRFSGSGSGNSASLTISSLQPEDFATYFCQSYDINIDIVFGQGTKVEIKGTVAAPSV



(DVD3904L)a
FIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGASNL




ESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


78
PR-
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTYGMGVGWIRQAPGKGLEWLANIWW



1565032H
DDDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCARIESIGTTYSFDYW



(DVD3905H)a
GQGTLVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQ




APGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYF




CARTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV




KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH




KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV




VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG




KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP




SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE




ALHNHYTQKSLSLSPGK


 


79
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAPKNVIYADDQRPS



1565032L
GVPSRFSGSGSGNSASLTISSLQPEDFATYFCQSYDINIDIVFGQGTKVEIKGTVAAPSV



(DVD3905L)a
FIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYGASN




LESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRTVA




APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS




KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


80
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIRQPPGKALEWLANIWWDD



1565035H
DKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWG



(DVD3906H)a
QGTTVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQAP




GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYFCA




RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP




SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV




DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE




YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD




IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL




HNHYTQKSLSLSPGK


 


81
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAPKNVIYGNDQRP



1565035L
SGVPSRFSGSGSGNSATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVEIKGTVAAP



(DVD3906L)a
SVFIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYGA




SNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRTV




AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD




SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


82
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1565033H
DDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWG



(DVD3907H)a
QGTTVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQAP




GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYFCA




RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP




SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV




DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE




YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD




IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL




HNHYTQKSLSLSPGK


 


83
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAPKNVIYADDQRPS



1565033L
GVPSRFSGSGSGNSASLTISSLQPEDFATYFCQSYDINIDIVFGQGTKVEIKGTVAAPSV



(DVD3907L)a
FIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGASNL




ESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


84
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1569574H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM




GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP




VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


85
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1569574L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG




SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR




PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


86
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1569579H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI




RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT




YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV




KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH




KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV




VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG




KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP




SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE




ALHNAYTQKSLSLSPGK


 


87
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1569579L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVF




IFPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ




RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


88
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1572102H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM




GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP




VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


89
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1572102L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG




SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR




PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


90
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1572103H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM




GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP




VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


91
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1572103L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG




SGGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ




RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


92
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1572104H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM




GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP




VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


93
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1572104L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGSGGGGS




GGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ




RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


94
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1572105H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI




RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT




YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV




KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH




KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV




VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG




KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP




SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE




ALHNAYTQKSLSLSPGK


 


95
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1572105L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVF




IFPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ




RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


96
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1572106H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG




MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM




DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA




ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT




YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR




TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH




QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS




CSVMHEALHNAYTQKSLSLSPGK


 


97
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1572106L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF




VLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGI




PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPSVFI




FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY




SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


210
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1575573H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG




MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM




DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA




ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT




YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR




TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH




QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS




CSVMHEALHNAYTQKSLSLSPGK


 


98
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1575573L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF




VLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGI




PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPSVFI




FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY




SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


99
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1575832H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM




GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP




VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


100
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1575832L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG




SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQR




PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


101
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1575834H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI




RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT




YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV




KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH




KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV




VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG




KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP




SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE




ALHNAYTQKSLSLSPGK


 


102
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1575834L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVF




IFPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQ




RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


103
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1575835H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG




MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM




DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA




ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT




YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR




TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH




QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS




CSVMHEALHNAYTQKSLSLSPGK


 


104
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1575835L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF




VLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPSGI




PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPSVFI




FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY




SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


105
PR-
EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1577165H
TGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARVDYDGSFWFAY




WGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV




GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD




TATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC




LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV




NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT




CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL




NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG




FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNAYTQKSLSLSPGK


 


106
PR-
DTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLESGV



1577165L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRGGSGGGGS




GEFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRP




SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


107
PR-
EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1577166H
TGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARVDYDGSFWFAY




WGQGTLVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR




QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATY




YCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK




DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK




PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV




VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK




EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS




DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA




LHNAYTQKSLSLSPGK


 


108
PR-
DTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLESGV



1577166L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAAPSVFI




FPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQ




RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


109
PR-
EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1577547H
TGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARVDYDGSFWFAY




WGQGTLVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM




GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP




VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


110
PR-
DTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLESGV



1577547L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAAPEFVL




TQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPSGIPD




RFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPSVFIFP




PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL




SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


111
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1577548H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW




GQGTMVTVSSASTKGPEVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQ




APGQGLEWMGWINTETGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYY




CARVDYDGSFWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP




SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV




DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE




YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD




IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL




HNAYTQKSLSLSPGK


 


112
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPS



1577548L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPSV




FIFPPDTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNL




ESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


113
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1577550H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW




GQGTMVTVSSASTKGPSVFPLAPEVQLVQSGAEVKKPGASVKVSCKASGYTFTNYG




MYWVRQAPGQGLEWMGWINTETGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRS




DDTAVYYCARVDYDGSFWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA




LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI




CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP




EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


114
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPS



1577550L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPDT




QLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLESGVPS




RFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAAPSVFIFP




PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL




SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


115
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1578137H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW




GQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMY




WVRQAPGQGLEWMGWINTETGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDD




TAVYYCARVDYDGSFWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG




CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN




VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV




TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW




LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK




GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNAYTQKSLSLSPGK


 


116
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPS



1578137L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRGGSGGG




GSGDTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLE




SGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


117
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE



1598261H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD




YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM




GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP




VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNHYTQKSLSLSPGK


 


118
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV



1598261L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRGGSGGGGS




GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP




SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


119
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET



1598262H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY




WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG




VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG




CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN




VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV




TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW




LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK




GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNHYTQKSLSLSPGK


 


120
PR-
AIQLTQSPSSLSASVGDRVTITCRASESVSTHMHWYQQKPGKAPKLLIYGASNLESGV



1598262L
PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSWNDPFTFGQGTKLEIKRGGSGGGGS




GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP




SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


121
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET



1598263H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY




WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG




VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG




CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN




VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV




TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW




LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK




GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNHYTQKSLSLSPGK


 


122
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV



1598263L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRGGSGGGGS




GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP




SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


123
PR-
EIQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET



1598264H
GKPTYADDFKGRFTFTLDTSTSTAYMELRSLRSDDTAVYFCARTNYYYRSYIFYFDY




WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG




VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG




CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN




VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV




TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW




LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK




GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNHYTQKSLSLSPGK


 


124
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1598264L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG




SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR




PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


125
PR-
EIQLVQSGTEVKKPGESLKISCKASGYTFTNYGMYWVKQMPGKGLEYMGWINTETG



1598265H
KPTYADDFKGRFTFSLDKSFNTAFLQWSSLKASDTAMYFCARTNYYYRSYIFYFDY




WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG




VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG




CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN




VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV




TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW




LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK




GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNHYTQKSLSLSPGK


 


126
PR-
ETVLTQSPATLSVSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG



1598265L
VPARFSGSGSGTDFTLTISSLQSEDFAVYFCQQSWNDPFTFGQGTRLEIKRGGSGGGG




SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR




PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


127
PR-
EIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQAPGKGLEYMGWINTET



1598266H
GKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFCARTNYYYRSYIFYFDY




WGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV




GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD




TATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC




LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV




NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT




CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL




NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG




FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNHYTQKSLSLSPGK


 


128
PR-
DTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGASNLESGV



1598266L
PSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRGGSGGGGS




GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP




SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


129
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET



1610560H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY




WGQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYM




YWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSEDT




AVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALG




CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN




VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV




TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW




LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK




GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNAYTQKSLSLSPGK


 


130
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV



1610560L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKGGSGGGGSG




GETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESG




VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPSV




FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST




YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


131
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET



1610561H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA




YWGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG




VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


132
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV



1610561L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG




GEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRA




SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


133
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET



1610562H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA




YWGQGTLVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESY




MYWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSE




DTAVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


134
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV



1610562L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG




GETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESG




VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPSV




FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST




YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


135
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWIDTE



1610563H
TGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDTAVYYCARWSGDTTGIRGPWF




AYWGQGTLVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESY




MYWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSE




DTAVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


136
PR-
DIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV



1610563L
PSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG




GETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESG




VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPSV




FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST




YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


137
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV



1610564H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT




TVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQ




APGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFC




ARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP




SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV




DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE




YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD




IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL




HNAYTQKSLSLSPGK


 


138
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG



1610564L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKGGSGGGGS




GGETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLES




GVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


139
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET



1611291H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY




WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG




VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


140
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV



1611291L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKGGSGGGGSG




GEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRA




SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


141
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV



1611292H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT




TVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQ




PPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYY




CARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP




SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV




DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE




YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD




IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL




HNAYTQKSLSLSPGK


 


142
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG



1611292L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKGGSGGGGS




GGEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQR




ASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


143
PR-
EIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMYWVKQAPGQGLEYMGWINTEA



1611293H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWGYISDNSYGWFDY




WGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV




GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD




TATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG




CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN




VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV




TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW




LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK




GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNAYTQKSLSLSPGK


 


144
PR-
ATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNLASG



1611293L
VPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKGGSGGGGS




GGEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQR




ASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


145
PR-
EIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMYWVKQAPGQGLEYMGWINTEA



1611294H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWGYISDNSYGWFDY




WGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV




GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD




TATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC




LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV




NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT




CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL




NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG




FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNAYTQKSLSLSPGK


 


146
PR-
ATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNLASG



1611294L
VPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKGGSGGGGS




GGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ




RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


147
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1611295H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW




GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY




WVKQAPGQGLEYMGWIDTETGRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT




AVYFCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA




ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT




YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR




TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH




QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS




CSVMHEALHNAYTQKSLSLSPGK


 


148
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS



1611295L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG




SGGDIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQ




NGVPSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


149
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1611296H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW




GQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMY




WVRQAPGQGLEWMGWIDTETGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDT




AVYYCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA




ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT




YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR




TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH




QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS




CSVMHEALHNAYTQKSLSLSPGK


 


150
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS



1611296L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG




SGGDIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQ




NGVPSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


151
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1611297H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW




GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMY




WVKQAPGQGLEYMGWINTEAGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT




AVYFCARWGYISDNSYGWFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA




LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI




CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP




EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


152
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS



1611297L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG




SGGATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNL




ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


153
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1611298H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW




GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY




WVKQAPGQGLEYMGWIDTETGRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT




AVYFCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA




ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT




YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR




TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH




QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS




CSVMHEALHNAYTQKSLSLSPGK


 


154
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS



1611298L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG




SGGDIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQ




NGVPSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


155
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1611299H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW




GQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMY




WVRQAPGQGLEWMGWIDTETGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDT




AVYYCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA




ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT




YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR




TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH




QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS




CSVMHEALHNAYTQKSLSLSPGK


 


156
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS



1611299L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG




SGGDIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQ




NGVPSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


157
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1611300H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW




GQGTMVTVSSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMA




WFRQAPGKGLEWVASITTSGVGTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDT




AVYYCARGYGAMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK




DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK




PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV




VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK




EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS




DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA




LHNAYTQKSLSLSPGK


 


158
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS



1611300L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG




SGGDIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRL




ADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


159
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1611301H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW




GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMY




WVKQAPGQGLEYMGWINTEAGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT




AVYFCARWGYISDNSYGWFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA




LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI




CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP




EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


160
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS



1611301L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG




SGGATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNL




ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


161
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET



1612489H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY




WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG




VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG




CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN




VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV




TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW




LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK




GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNAYTQKSLSLSPGK


 


162
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV



1612489L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKGGSGGGGSG




GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP




SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


163
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET



1612491H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA




YWGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG




VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV




DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG




CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN




VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV




TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW




LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK




GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNAYTQKSLSLSPGK


 


164
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV



1612491L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG




GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP




SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


165
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWIDTE



1612492H
TGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDTAVYYCARWSGDTTGIRGPWF




AYWGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM




GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP




VDTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAA




LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI




CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP




EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


166
PR-
DIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV



1612492L
PSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG




GEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRA




SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


167
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWIDTE



1612493H
TGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDTAVYYCARWSGDTTGIRGPWF




AYWGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM




GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP




VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


168
PR-
DIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV



1612493L
PSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG




GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP




SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


169
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV



1612494H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT




TVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQ




PPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYY




CARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD




YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP




SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV




DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE




YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD




IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL




HNAYTQKSLSLSPGK


 


170
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG



1612494L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKGGSGGGGS




GGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ




RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


171
PR-
EIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMYWVKQAPGQGLEYMGWINTEA



1612495H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWGYISDNSYGWFDY




WGQGTLVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYM




YWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSEDT




AVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALG




CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN




VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV




TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW




LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK




GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNAYTQKSLSLSPGK


 


172
PR-
ATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNLASG



1612495L
VPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKGGSGGGGS




GGETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLES




GVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


173
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1612496H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW




GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY




WVRQAPGQGLEYMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT




AVYFCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


174
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS



1612496L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG




SGGATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLE




SGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


175
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1612498H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW




GQGTMVTVSSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMA




WFRQAPGKGLEWVASITTSGVGTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDT




AVYYCARGYGAMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK




DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK




PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV




VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK




EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS




DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA




LHNAYTQKSLSLSPGK


 


176
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS



1612498L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG




SGGDIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRL




ADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


177
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG



1612499H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG




QGTTVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWV




RQAPGQGLEYMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVY




FCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL




VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN




HKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC




VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN




GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF




YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM




HEALHNAYTQKSLSLSPGK


 


178
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV



1612499L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS




GGATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLES




GVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRTVAAPSV




FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST




YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


179
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG



1612500H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG




QGTTVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWV




KQAPGQGLEYMGWIDTETGRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVY




FCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC




LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV




NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT




CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL




NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG




FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNAYTQKSLSLSPGK


 


180
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV



1612500L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS




GGDIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLTYNANGLQN




GVPSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


181
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG



1612501H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG




QGTTVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMYW




VRQAPGQGLEWMGWIDTETGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDTA




VYYCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA




LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI




CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP




EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


182
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV



1612501L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS




GGDIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLTYNANGLQN




GVPSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


183
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG



1612502H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG




QGTTVTVSSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWF




RQAPGKGLEWVASITTSGVGTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAV




YYCARGYGAMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF




PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN




TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVD




VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY




KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI




AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH




NAYTQKSLSLSPGK


 


184
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV



1612502L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS




GGDIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLA




DGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


185
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGLEWMGWIDTE



1613183H
TGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRNYMFYF




DYWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG




MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM




DPVDTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGT




AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ




TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS




RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL




HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT




CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV




FSCSVMHEALHNAYTQKSLSLSPGK


 


186
PR-
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILESGV



1613183L
PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKGGSGGGGSG




GEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRA




SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


187
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGLEWMGWIDTE



1613184H
TGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRNYMFYF




DYWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG




MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM




DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA




ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT




YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR




TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH




QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS




CSVMHEALHNAYTQKSLSLSPGK


 


188
PR-
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILESGV



1613184L
PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKGGSGGGGSG




GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP




SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


189
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGLEWMGWIDTE



1613185H
TGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRNYMFYF




DYWGQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTES




YMYWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRS




EDTAVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAA




LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI




CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP




EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


190
PR-
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILESGV



1613185L
PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKGGSGGGGSG




GETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESG




VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPSV




FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST




YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


191
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1613186H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW




GQGTMVTVSSGGGGSGGGGSEVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMY




WVRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT




AVYYCARTNYYYRNYMFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA




ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT




YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR




TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH




QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS




CSVMHEALHNAYTQKSLSLSPGK


 


192
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS



1613186L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG




SGGEIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILE




SGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


193
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1613187H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW




GQGTMVTVSSGGGGSGGGGSEVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMY




WVRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT




AVYYCARTNYYYRNYMFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA




ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT




YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR




TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH




QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS




CSVMHEALHNAYTQKSLSLSPGK


 


194
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS



1613187L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG




SGGEIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILE




SGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


195
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD



1613188H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW




GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY




WVRQAPGQGLEYMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT




AVYFCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL




GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC




NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE




VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


196
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS



1613188L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG




SGGATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLE




SGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


197
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG



1613189H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG




QGTTVTVSSGGGGSGGGGSEVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW




VRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTA




VYYCARTNYYYRNYMFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAA




LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI




CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP




EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD




WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV




KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS




VMHEALHNAYTQKSLSLSPGK


 


198
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV



1613189L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS




GGEIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILES




GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKRTVAAPS




VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS




TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


199
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG



1613190H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG




QGTTVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMYWV




KQAPGQGLEYMGWINTEAGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAV




YFCARWGYISDNSYGWFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG




CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN




VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV




TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW




LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK




GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV




MHEALHNAYTQKSLSLSPGK


 


200
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV



1613190L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS




GGATQLTQSPSSLSASVGDRQVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNLA




SGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKRTVAAP




SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD




STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


201
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET



1629646H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA




YWGQGTLVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI




RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT




YYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV




KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH




KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV




VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG




KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP




SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE




ALHNAYTQKSLSLSPGK


 


202
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV



1629646L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAPSVFI




FPPEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQR




ASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAA




PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK




DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


203
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV



1629647H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT




TVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKA




LEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIE




SSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP




VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK




VDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS




HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC




KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV




EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNA




YTQKSLSLSPGK


 


204
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG



1629647L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAAPSVF




IFPPEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQ




RASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVA




APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS




KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


205
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET



1629648H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA




YWGQGTLVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG




MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM




DPVDTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGT




AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ




TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS




RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL




HQDWLNGKEYKCKVSNKALPAPIEKTIMISKAKGQPREPQVYTLPPSREEMTKNQVSLT




CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV




FSCSVMHEALHNAYTQKSLSLSPGK


 


206
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV



1629648L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAPEIVL




TQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRASGIPD




RFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAPSVFIFP




PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL




SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


 


207
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV



1629649H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT




TVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI




RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT




YYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV




KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH




KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV




VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG




KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP




SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE




ALHNAYTQKSLSLSPGK


 


208
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG



1629649L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAAPEIV




LTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRASGIP




DRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAPSVFI




FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY




SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC









Example 18: PR-1610561 Cell Lines
Chimeric, humanized, and affinity matured antibodies, and DVD-Ig binding proteins were expressed using pHybE vectors. Transient expression of PR-1610561 in HEK cells was also achieved using a vector similar to pHybE-hCg1,z,non-a,mut(234,235) V2. See U.S. Pat. No. 8,187,836.
CHO cell lines producing PR-1610561 have been generated. The growth and productivity of the CHO cell lines were similar to those of other DVD-Ig molecules. All cell lines passed a screening for acceptable product quality by MS, SEC, and CIEX. CHO cell lines were produced using pBJ and pCD plasmid vectors encoding the amino acid sequences of PR-1610561. See US 2014/0295497.
Example 19: Epitope Binning
Antibodies and binding proteins disclosed herein are tested in a label-free cell-based competition assay in order to determine which antibodies and binding proteins are capable of binding to the same antigen (e.g., VEGF, PDGF, or one of their receptors) simultaneously. If antibodies or binding proteins are not able to bind simultaneously (therefore possibly competing for the same or similar epitope), those antibodies or binding proteins are assigned to the same “epitope bin.” If antibodies or binding proteins are capable of binding simultaneously and therefore do not compete for antigen binding, those antibodies or binding proteins are assigned to different epitope bins.
INCORPORATION BY REFERENCE
The contents of all cited references (including literature references, patents, patent applications, and websites) that maybe cited throughout this application are hereby expressly incorporated by reference in their entirety for any purpose, as are the references cited therein. To the extent those references contradict or are inconsistent with any statements in this application, the text of the application will control. The disclosure will employ, unless otherwise indicated, conventional techniques of immunology, molecular biology and cell biology, and pathology, which are well known in the art.
EQUIVALENTS
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting of the inventions described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced herein.

## Claims

1. An antibody or antigen binding fragment thereof capable of binding platelet-derived growth factor (PDGF), wherein the antibody or antigen binding fragment comprises
CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16.

2. The antibody or antigen binding fragment of claim 1, wherein the antibody or antigen binding fragment comprises
SEQ ID NO: 15 and SEQ ID NO: 16.

3. The antibody or antigen binding fragment of claim 1, further comprising heavy and light chain constant domains selected from Table 3.

4. The antibody or antigen binding fragment of claim 1, further comprising:
a) a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by substitution of leucines at positions 234 and 235 with alanines, and optionally also comprises a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and
(b) a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence.

5. An antibody or antigen binding fragment that competes with the antibody or antigen binding fragment of claim 1 for binding to PDGF.

6. An antibody or antigen binding fragment that binds to the same epitope of PDGF as the antibody or antigen binding fragment of claim 1.

7. An antibody conjugate comprising the antibody or antigen binding fragment of claim 1, the antibody conjugate further comprising an immunoadhesion molecule, an imaging agent, a therapeutic agent, or a cytotoxic agent, wherein the imaging agent is a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, or biotin, wherein the radiolabel is 3H, 14C, 35S, 90Y, 99Tc, 111In, 125I, 131I, 177Lu, 166Ho, or 153Sm, and wherein the therapeutic or cytotoxic agent is an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, toxin, or an apoptotic agent.

8. A pharmaceutical composition comprising the antibody or antigen binding fragment of claim 1, and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8, further comprising at least one additional therapeutic agent.