Antibodies Directed to Angiopoietin-2 And Uses Thereof

Abstract

Antibodies directed to the antigen Ang-2 and uses of such antibodies are described. In particular, fully human monoclonal antibodies directed to the antigen Ang-2. Nucleotide sequences encoding, and amino acid sequences comprising, heavy and light chain immunoglobulin molecules, particularly sequences corresponding to contiguous heavy and light chain sequences spanning the framework regions and/or complementarity determining regions (CDR's), specifically from FR1 through FR4 or CDR1 through CDR3. Hybridomas or other cell lines expressing such immunoglobulin molecules and monoclonal antibodies.

Description

[0001] This application claims benefit to U.S. Provisional Application Ser. No. 60/638,354, filed Dec. 21, 2004, and U.S. Provisional Application Ser. No. 60/711,289, filed Aug. 25, 2005, which are incorporated herein by reference.

SEQUENCE LISTING

[0002] This application hereby incorporates by reference in its entirety the contents of the attached sequence listing on compact disk having, a file name of "ABXAZ002 SEQLIST.TXT" and being 539 kilobytes in size.

FIELD

[0003] The invention relates to monoclonal antibodies against Angiopoietin-2 (Ang-2) and uses of such antibodies. More specifically, the invention relates to fully human monoclonal antibodies directed to Ang-2. The described antibodies are useful as diagnostics and for the treatment of diseases associated with the activity and/or overproduction of Ang-2.

BACKGROUND

[0004] Angiogenesis is the process of forming new capillaries from preexisting blood vessels and is an essential component of embryogenesis, normal physiological growth, repair, and tumor expansion. Although a variety of factors can modulate endothelial cell (EC) responses in vitro and blood vessel growth in vivo, only vascular endothelial growth factor (VEGF) family members and the angiopoietins are believed to act almost exclusively on vascular ECs. Yancopoulos et al., Nature 407:242-48 (2000).

[0005] The angiopoietins were discovered as ligands for the Ties, a family of tyrosine kinases that is selectively expressed within the vascular endothelium. Yancopoulos et al., Nature 407:242-48 (2000). There are now four definitive members of the angiopoietin family. Angiopoietin-3 and -4 (Ang-3 and Ang-4) may represent widely diverged counterparts of the same gene locus in mouse and man. Kim et al., FEBS Let, 443:353-56 (1999); Kim et al., J Biol Chem 274:26523-28 (1999). Ang-1 and Ang-2 were originally identified in tissue culture experiments as agonist and antagonist, respectively. Davis et al., Cell 87:1161-69 (1996); Maisonpierre et al., Science 277:55-60 (1997). All of the known angiopoietins bind primarily to Tie2, and both Ang-1 and -2 bind to Tie2 with an affinity of 3 nM (Kd). Maisonpierre et al., Science 277:55-60 (1997). Ang-1 was shown to support EC survival and to promote endothelium integrity, Davis et al., Cell 87:1161-69 (1996); Kwak et al., FEBS Lett 448:249-53 (1999); Suri et al., Science 282:468-71 (1998); Thurston et al., Science 286: 2511-14 (1999); Thurston et al., Nat. Med. 6:460-63 (2000), whereas Ang-2 had the opposite effect and promoted blood vessel destabilization and regression in the absence of the survival factors VEGF or basic fibroblast growth factor. Maisonpierre et al., Science 277:55-60 (1997). However, many studies of Ang-2 function have suggested a more complex situation. Ang-2 might be a complex regulator of vascular remodeling that plays a role in both vessel sprouting and vessel regression. Supporting such roles for Ang-2, expression analyses reveal that Ang-2 is rapidly induced, together with VEGF, in adult settings of angiogenic sprouting, whereas Ang-2 is induced in the absence of VEGF in settings of vascular regression. Holash et al., Science 284:1994-98 (1999); Holash et al., Oncogene 18:5356-62 (1999). Consistent with a context-dependent role, Ang-2 binds to the same endothelial-specific receptor, Tie-2, which is activated by Ang-1, but has context-dependent effects on its activation. Maisonpierre et al., Science 277:55-60 (1997).

[0006] Corneal angiogenesis assays have shown that both Ang-1 and Ang-2 had similar effects, acting synergistically with VEGF to promote growth of new blood vessels. Asahara et al., Circ. Res. 83:233-40 (1998). The possibility that there was a dose-dependent endothelial response was raised by the observation that in vitro at high concentration, Ang-2 can also be pro-angiogenic. Kim et al., Oncogene 19:4549-52 (2000). At high concentration, Ang-2 acts as an apoptosis survival factor for endothelial cells during serum deprivation apoptosis through activation of Tie2 via PI-3 kinase and Akt pathway. Kim et al., Oncogene 19:4549-52 (2000).

[0007] Other in vitro experiments suggested that during sustained exposure, the effects of Ang-2 may progressively shift from that of an antagonist to an agonist of Tie2, and at later time points, it may contribute directly to vascular tube formation and neovessel stabilization. Teichert-Kuliszewska et al., Cardiovasc. Res. 49:659-70 (2001). Furthermore, if ECs were cultivated on fibrin gel, activation of Tie2 with Ang-2 was also observed, perhaps suggesting that the action of Ang-2 could depend on EC differentiation state. Teichert-Kuliszewska et al., Cardiovasc. Res. 49:659-70 (2001). In microvascular EC cultured in a three-dimensional collagen gel, Ang-2 can also induce Tie2 activation and promote formation of capillary-like structures. Mochizuki et al., J. Cell. Sci. 115:175-83 (2002). Use of a 3-D spheroidal coculture as an in vitro model of vessel maturation demonstrated that direct contact between ECs and mesenchymal cells abrogates responsiveness to VEGF, whereas the presence of VEGF and Ang-2 induced sprouting. Korff et al., Faseb J. 15:447-57 (2001). Etoh et al. demonstrated that ECs that constitutively express Tie2, the expression of MMP-1, -9 and u-PA were strongly up-regulated by Ang-2 in the presence of VEGF. Etoh, et al., Cancer Res. 61:2145-53 (2001). With an in vivo pupillary membrane model, Lobov et al. showed that Ang-2 in the presence of endogenous VEGF promotes a rapid increase in capillary diameter, remodeling of the basal lamina, proliferation and migration of endothelial cells, and stimulates sprouting of new blood vessels. Lobov et al., Proc. Natl. Acad. Sci. USA 99:11205-10 (2002). By contrast, Ang-2 promotes endothelial cell death and vessel regression without endogenous VEGF. Lobov et al., Proc. Natl. Acad. Sci. USA 99:11205-10 (2002). Similarly, with an in vivo tumor model, Vajkoczy et al. demonstrated that multicellular aggregates initiate vascular growth by angiogenic sprouting via the simultaneous expression of VEGFR-2 and Ang-2 by host and tumor endothelium. Vajkoczy et al., J. Clin. Invest. 109:777-85 (2002). This model illustrated that the established microvasculature of growing tumors is characterized by a continuous remodeling, putatively mediated by the expression of VEGF and Ang-2. Vajkoczy et al., J. Clin. Invest. 109:777-85 (2002).

[0008] Knock-out mouse studies of Tie-2 and Angiopoietin-1 show similar phenotypes and suggest that Angiopoietin-1 stimulated Tie-2 phosphorylation mediates remodeling and stabilization of developing vessel, promoting blood vessel maturation during angiogenesis and maintenance of endothelial cell-support cell adhesion (Dumont et al., Genes & Development, 8:1897-1909 (1994); Sato, Nature, 376:70-74 (1995); (Thurston, G. et al., 2000 Nature Medicine: 6, 460-463)). The role of Angiopoietin-1 is thought to be conserved in the adult, where it is expressed widely and constitutively (Hanahan, Science, 277:48-50 (1997); Zagzag, et al., Exp Neurology, 159:391-400 (1999)). In contrast, Angiopoietin-2 expression is primarily limited to sites of vascular remodeling where it is thought to block the constitutive stabilizing or maturing function of Angiopoietin-1, allowing vessels to revert to, and remain in, a plastic state which may be more responsive to sprouting signals (Hanahan, 1997; Holash et al., Oncogene 18:5356-62 (1999); Maisonpierre, 1997). Studies of Angiopoietin-2 expression in pathological angiogenesis have found many tumor types to show vascular Angiopoietin-2 expression (Maisonpierre et al., Science 277:55-60 (1997)). Functional studies suggest Angiopoietin-2 is involved in tumor angiogenesis and associate Angiopoietin-2 overexpression with increased tumor growth in a mouse xenograft model (Ahmad, et al., Cancer Res., 61:1255-1259 (2001)). Other studies have associated Angiopoietin-2 overexpression with tumor hypervascularity (Etoh, et al., Cancer Res. 61:2145-53 (2001); Tanaka et al., Cancer Res. 62:7124-29 (2002)).

[0009] In recent years Angiopoietin-1, Angiopoietin-2 and/or Tie-2 have been proposed as possible anti-cancer therapeutic targets. For example U.S. Pat. No. 6,166,185, U.S. Pat. No. 5,650,490 and U.S. Pat. No. 5,814,464 each disclose anti-Tie-2 ligand and receptor antibodies. Studies using soluble Tie-2 were reported to decrease the number and size of tumors in rodents (Lin, 1997; Lin 1998). Siemester et al. (1999) generated human melanoma cell lines expressing the extracellular domain of Tie-2, injected these into nude mice and reported soluble Tie-2 to result in significant inhibition of tumor growth and tumor angiogenesis. Given both Angiopoietin-1 and Angiopoietin-2 bind to Tie-2, it is unclear from these studies whether Angiopoietin-1, Angiopoietin-2 or Tie-2 would be an attractive target for anti-cancer therapy. However, effective anti-Angiopoietin-2 therapy is thought to be of benefit in treating diseases such as cancer, in which progression is dependant on aberrant angiogenesis where blocking the process can lead to prevention of disease advancement (Folkman, J., Nature Medicine. 1: 27-31 (1995). In addition some groups have reported the use of antibodies that bind to Angiopoietin-2, See, for example, U.S. Pat. No. 6,166,185 and U.S. Patent Application Publication No. 2003/0124129 A1. Study of the effect of focal expression of Angiopoietin-2 has shown that antagonizing the Angiopoietin-1/Tie-2 signal loosens the tight vascular structure thereby exposing ECs to activating signals from angiogenesis inducers, e.g. VEGF (Hanahan, 1997). This pro-angiogenic effect resulting from inhibition of Angiopoietin-1 indicates that anti-Angiopoietin-1 therapy would not be an effective anti-cancer treatment.

[0010] Ang-2 is expressed during development at sites where blood vessel remodeling is occurring. Maisonpierre et al., Science 277:55-60 (1997). In adult individuals, Ang-2 expression is restricted to sites of vascular remodeling as well as in highly vascularized tumors, including glioma, Osada et al., Int. J. Oncol. 18:305-09 (2001); Koga et al., Cancer Res. 61:6248-54 (2001), hepatocellular carcinoma, Tanaka et al, J. Clin. Invest. 103:341-45 (1999), gastric carcinoma, Etoh, et al., Cancer Res. 61:2145-53 (2001); Lee et al, Int. J. Oncol. 18:355-61 (2001), thyroid tumor, Bunone et al., Am J Pathol 155:1967-76 (1999), non-small cell lung cancer, Wong et al., Lung Cancer 29:11-22 (2000), and cancer of colon, Ahmad et al., Cancer 92:1138-43 (2001), and prostate Wurmbach et al., Anticancer Res. 20:5217-20 (2000). Some tumor cells are found to express Ang-2. For example, Tanaka et al., J. Clin. Invest. 103:341-45 (1999) detected Ang-2 mRNA in 10 out of 12 specimens of human hepatocellular carcinoma (HCC). Ellis' group reported that Ang-2 is expressed ubiquitously in tumor epithelium. Ahmad et al., Cancer 92:1138-43 (2001). Other investigators reported similar findings. Chen et al., J. Tongji Med. Univ. 21:228-30, 235 (2001). By detecting Ang-2 mRNA levels in archived human breast cancer specimens, Sfilogoi et al., Int. J. Cancer 103:466-74 (2003) reported that Ang-2 mRNA is significantly associated with auxiliary lymph node invasion, short disease-free time and poor overall survival. Tanaka et al., Cancer Res. 62:7124-29 (2002) reviewed a total of 236 patients of non-small cell lung cancer (NSCLC) with pathological stage-I to -IIIA, respectively. Using immunohistochemistry, they found that 16.9% of the NSCLC patients were Ang-2 positive. The microvessel density for Ang-2 positive tumor is significantly higher than that of Ang-2 negative. Such an angiogenic effect of Ang-2 was seen only when VEGF expression was high. Moreover, positive expression of Ang-2 was a significant factor to predict a poor postoperative survival. Tanaka et al., Cancer Res. 62:7124-29 (2002). However, they found no significant correlation between Ang-1 expression and the microvessel density. Tanaka et al., Cancer Res. 62:7124-29 (2002). These results suggest that Ang-2 is an indicator of poor prognosis patients with several types of cancer.

[0011] Recently, using an Ang-2 knockout mouse model, Yancopoulos' group reported that Ang-2 is required for postnatal angiogenesis. Gale et al., Dev. Cell 3:411-23 (2002). They showed that the developmentally programmed regression of the hyaloid vasculature in the eye does not occur in the Ang-2-/- mice and their retinal blood vessels fail to sprout out from the central retinal artery. Gale et al., Dev. Cell 3:411-23 (2002). They also found that deletion of Ang-2 results in profound defects in the patterning and function of the lymphatic vasculature. Gale et al., Dev. Cell 3:411-23 (2002). Genetic rescue with Ang-1 corrects the lymphatic, but not the angiogenesis defects. Gale et al., Dev. Cell 3:411-23 (2002).

[0012] Peters and his colleagues reported that soluble Tie2, when delivered either as recombinant protein or in a viral expression vector, inhibited in vivo growth of murine mammary carcinoma and melanoma in mouse models. Lin et al., Proc. Natl. Acad. Sci. USA 95:8829-34 (1998); Lin et al., J. Clin. Invest. 100:2072-78 (1997). Vascular densities in the tumor tissues so treated were greatly reduced. In addition, soluble Tie2 blocked angiogenesis in the rat corneal stimulated by tumor cell conditioned media. Lin et al., J. Clin. Invest. 100:2072-78 (1997). Furthermore, Isner and his team demonstrated that addition of Ang-2 to VEGF promoted significantly longer and more circumferential neovascularity than VEGF alone. Asahara et al., Circ. Res. 83:233-40 (1998). Excess soluble Tie2 receptor precluded modulation of VEGF-induced neovascularization by Ang-2. Asahara et al., Circ. Res. 83:233-40 (1998). Siemeister et al., Cancer Res. 59:3185-91 (1999) showed with nude mouse xenografts that overexpression of the extracellular ligand-binding domains of either Flt-1 or Tie2 in the xenografts results in significant inhibition of pathway could not be compensated by the other one, suggesting that the VEGF receptor pathway and the Tie2 pathway should be considered as two independent mediators essential for the process of in vivo angiogenesis. Siemeister et al., Cancer Res. 59:3185-91 (1999). This is proven by a more recent publication by White et al., Proc. Natl. Acad. Sci. USA 100:5028-33 (2003). In their study, it was demonstrated that a nuclease-resistant RNA aptamer that specifically binds and inhibits Ang-2 significantly inhibited neovascularization induced by bFGF in the rat corneal micropocket angiogenesis model.

SUMMARY

[0013] Embodiments of the invention relate to targeted binding agents that specifically bind to Angiopoietin-2 and therein inhibit tumor angiogenesis and reduce tumor growth. Mechanisms by which this can be achieved can include and are not limited to either inhibition of binding of Ang-2 to its receptor Tie2, inhibition of Ang-2 induced Tie2 signaling, or increased clearance of Ang-2, therein reducing the effective concentration of Ang-2.

[0014] One embodiment of the invention, the targeted binding agent is a fully human antibody that binds to Ang-2 and prevents Ang-2 binding to Tie2. Yet another embodiment of the invention is a fully human monoclonal antibody that binds to Ang-2 and Ang-1, and also inhibits Ang-2 induced Tie2 phosphorylation. The antibody may bind Ang-2 with a K.sub.d of less than 100 pM, 30 pM, 20 pM, 10 pM or 5 pM.

[0015] The antibody may comprise a heavy chain amino acid sequence having a complementarity determining region (CDR) with one of the sequences shown in Table 11. It is noted that those of ordinary skill in the art can readily accomplish CDR determinations. See for example, Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda Md. (1991), vols. 1-3.

[0016] One embodiment of the invention comprises fully human monoclonal antibodies 3.3.2 (ATCC Accession Number PTA-7258), 3.1-9.3 (ATCC Accession Number PTA-7260) and 5.88.3 (ATCC Accession Number PTA-7259) which specifically bind to Ang-2, as discussed in more detail below.

[0017] Yet another embodiment is an antibody that binds to Ang-2 and comprises a light chain amino acid sequence having a CDR comprising one of the sequences shown in Table 12. In certain embodiments the antibody is a fully human monoclonal antibody.

[0018] A further embodiment is an antibody that binds to Ang-2 and comprises a heavy chain amino acid sequence having one of the CDR sequences shown in Table 11 and a light chain amino acid sequence having one of the CDR sequences shown in Table 12. In certain embodiments the antibody is a fully human monoclonal antibody. A further embodiment of the invention is an antibody that cross-competes for binding to Ang-2 with the fully human antibodies of the invention, preferably an antibody comprising a heavy chain amino acid sequence having one of the CDR sequences shown in Table 11 and a light chain amino acid sequence having one of the CDR sequences shown in Table 12. A further embodiment of the invention is an antibody that binds to the same epitope on Ang-2 as a fully human antibodies of the invention, preferably an antibody comprising a heavy chain amino acid sequence having one of the CDR sequences shown in Table 11 and a light chain amino acid sequence having one of the CDR sequences shown in Table 12.

[0019] Further embodiments of the invention include human monoclonal antibodies that specifically bind to Angiopoietin-2, wherein the antibodies comprise a heavy chain complementarity determining region 1 (CDR1) corresponding to canonical class 1. The antibodies provided herein can also include a heavy chain complementarity determining region 2 (CDR2) corresponding to canonical class 3, a light chain complementarity determining region 1 (CDR1) corresponding to canonical class 2, a light chain complementarity determining region 2 (CDR2) corresponding to canonical class 1, and a light chain complementarity determining region 3 (CDR3) corresponding to canonical class 1.

[0020] The invention further provides methods for assaying the level of Angiopoietin-2 (Ang-2) in a patient sample, comprising contacting an anti-Ang-2 antibody with a biological sample from a patient, and detecting the level of binding between said antibody and Ang-2 in said sample. In more specific embodiments, the biological sample is blood.

[0021] In other embodiments the invention provides compositions, including an antibody or functional fragment thereof, and a pharmaceutically acceptable carrier.

[0022] Still further embodiments of the invention include methods of effectively treating an animal suffering from an angiogenesis-related disease, including selecting an animal in need of treatment for a neoplastic or non-neoplastic disease, and administering to said animal a therapeutically effective dose of a fully human monoclonal antibody that specifically binds to Angiopoietin-2 (Ang-2).

[0023] Treatable angiogenesis-related diseases can include neoplastic diseases, such as, melanoma, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, thyroid tumor, gastric (stomach) cancer, prostate cancer, breast cancer, ovarian cancer, bladder cancer, lung cancer, glioblastoma, endometrial cancer, kidney cancer, colon cancer, pancreatic cancer, esophageal carcinoma, head and neck cancers, mesothelioma, sarcomas, biliary (cholangiocarcinoma), small bowel adenocarcinoma, pediatric malignancies and epidermoid carcinoma.

[0024] Additional embodiments of the invention include methods of inhibiting Angiopoietin-2 (Ang-2) induced angiogenesis in an animal. These methods include selecting an animal in need of treatment for Ang-2 induced angiogenesis, and administering to said animal a therapeutically effective dose of a fully human monoclonal antibody wherein said antibody specifically binds to Ang-2.

[0025] Further embodiments of the invention include the use of an antibody of in the preparation of medicament for the treatment of angiogenesis-related diseases in an animal, wherein said monoclonal antibody specifically binds to Angiopoietin-2 (Ang-2). Treatable angiogenesis-related diseases can include neoplastic diseases, such as, melanoma, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, thyroid tumor, gastric (stomach) cancer, prostate cancer, breast cancer, ovarian cancer, bladder cancer, lung cancer, glioblastoma, endometrial cancer, kidney cancer, colon cancer, pancreatic cancer, esophageal carcinoma, head and neck cancers, mesothelioma, sarcomas, cholangiocarcinoma, small bowel adenocarcinoma, pediatric malignancies and epidermoid carcinoma.

[0026] In still further embodiments, the antibodies described herein can be used for the preparation of a medicament for the effective treatment of Angiopoietin-2 induced angiogenesis in an animal, wherein said monoclonal antibody specifically binds to Angiopoietin-2 (Ang-2).

[0027] Embodiments of the invention described herein relate to monoclonal antibodies that bind Ang-2 and affect Ang-2 function. Other embodiments relate to fully human anti-Ang-2 antibodies and anti-Ang-2 antibody preparations with desirable properties from a therapeutic perspective, including high binding affinity for Ang-2, the ability to neutralize Ang-2 in vitro and in vivo, and the ability to inhibit Ang-2 induced angiogenesis.

[0028] In a preferred embodiment, antibodies described herein bind to Ang-2 with very high affinities (Kd). For example a human, rabbit, mouse, chimeric or humanized antibody that is capable of binding Ang-2 with a Kd less than, but not limited to, 10.sup.-5, 10.sup.-6, 10.sup.-7, 10.sup.-8, 10.sup.-9, 10.sup.-10, 10.sup.-11, 10.sup.-12, 10.sup.-13 or 10.sup.-14 M, or any range or value therein. Affinity and/or avidity measurements can be measured by KinExA.RTM. and/or BIACORE.RTM., as described herein.

[0029] Accordingly, one embodiment described herein includes isolated antibodies, or fragments of those antibodies, that bind to Ang-2. As known in the art, the antibodies can advantageously be, for example, polyclonal, oligoclonal, monoclonal, chimeric, humanized, and/or fully human antibodies. Embodiments of the invention described herein also provide cells for producing these antibodies.

[0030] Another embodiment of the invention is a fully human antibody that binds to other Angiopoietin-2 family members including, but not limited to, Angiopoietin-1, Angiopoietin-3, and Angiopoietin-4. A further embodiment herein is an antibody that cross-competes for binding to Tie2 with Ang-2 with the fully human antibodies of the invention. In one embodiment of the invention, the antibody binds to and neutralizes Angiopoietin-2, and also binds to and neutralizes, Angiopoietin-1.

[0031] It will be appreciated that embodiments of the invention are not limited to any particular form of an antibody or method of generation or production. For example, the anti-Ang-2 antibody may be a full-length antibody (e.g., having an intact human Fc region) or an antibody fragment (e.g., a Fab, Fab' or F(ab').sub.2). In addition, the antibody may be manufactured from a hybridoma that secretes the antibody, or from a recombinantly produced cell that has been transformed or transfected with a gene or genes encoding the antibody.

[0032] Other embodiments of the invention include isolated nucleic acid molecules encoding any of the antibodies described herein, vectors having isolated nucleic acid molecules encoding anti-Ang-2 antibodies or a host cell transformed with any of such nucleic acid molecules. In addition, one embodiment of the invention is a method of producing an anti-Ang-2 antibody by culturing host cells under conditions wherein a nucleic acid molecule is expressed to produce the antibody followed by recovering the antibody. It should be realized that embodiments of the invention also include any nucleic acid molecule which encodes an antibody or fragment of an antibody of the invention including nucleic acid sequences optimized for increasing yields of antibodies or fragments thereof when transfected into host cells for antibody production.

[0033] A further embodiment herein includes a method of producing high affinity antibodies to Ang-2 by immunizing a mammal with human Ang-2, or a fragment thereof, and one or more orthologous sequences or fragments thereof.

[0034] Other embodiments are based upon the generation and identification of isolated antibodies that bind specifically to Ang-2. Ang-2 is expressed at elevated levels in angiogenesis-related diseases, such as neoplastic diseases. Inhibition of the biological activity of Ang-2 can prevent Ang-2 induced angiogenesis and other desired effects.

[0035] Another embodiment of the invention includes a method of diagnosing diseases or conditions in which an antibody prepared as described herein is utilized to detect the level of Ang-2 in a patient sample. In one embodiment, the patient sample is blood or blood serum. In further embodiments, methods for the identification of risk factors, diagnosis of disease, and staging of disease is presented which involves the identification of the overexpression of Ang-2 using anti-Ang-2 antibodies.

[0036] Another embodiment of the invention includes a method for diagnosing a condition associated with the expression of Ang-2 in a cell by contacting the serum or a cell with an anti-Ang-2 antibody, and thereafter detecting the presence of Ang-2. Preferred conditions include angiogenesis-related diseases including, but not limited to, neoplastic diseases, such as, melanoma, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, and carcinoma of the thyroid, stomach, prostate, breast, ovary, bladder, lung, uterus, kidney, colon, and pancreas, salivary gland, and colorectum.

[0037] In another embodiment, the invention includes an assay kit for detecting Angiopoietin-2 and Angiopoietin family members in mammalian tissues, cells, or body fluids to screen for angiogenesis-related diseases. The kit includes an antibody that binds to Angiopoietin-2 and a means for indicating the reaction of the antibody with Angiopoietin-2, if present. Preferably the antibody is a monoclonal antibody. In one embodiment, the antibody that binds Ang-2 is labeled. In another embodiment the antibody is an unlabeled primary antibody and the kit further includes a means for detecting the primary antibody. In one embodiment, the means includes a labeled second antibody that is an anti-immunoglobulin. Preferably the antibody is labeled with a marker selected from the group consisting of a fluorochrome, an enzyme, a radionuclide and a radiopaque material.

[0038] Yet another embodiment includes methods for treating diseases or conditions associated with the expression of Ang-2 in a patient, by administering to the patient an effective amount of an anti-Ang-2 antibody. The anti-Ang-2 antibody can be administered alone, or can be administered in combination with additional antibodies or chemotherapeutic drug or radiation therapy. For example, a monoclonal, oligoclonal or polyclonal mixture of Ang-2 antibodies that block angiogenesis can be administered in combination with a drug shown to inhibit tumor cell proliferation directly. The method can be performed in vivo and the patient is preferably a human patient. In a preferred embodiment, the method concerns the treatment of angiogenesis-related diseases including, but not limited to, neoplastic diseases, such as, melanoma, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, and carcinoma of the thyroid, stomach, prostate, breast, ovary, bladder, lung, uterus, kidney, colon, and pancreas, salivary gland, and colorectum.

[0039] In another embodiment, the invention provides an article of manufacture including a container. The container includes a composition containing an anti-Ang-2 antibody, and a package insert or label indicating that the composition can be used to treat angiogenesis-related diseases characterized by the overexpression of Ang-2.

[0040] In some embodiments, the anti-Ang-2 antibody is administered to a patient, followed by administration of a clearing agent to remove excess circulating antibody from the blood.

[0041] Yet another embodiment is the use of an anti-Ang-2 antibody in the preparation of a medicament for the treatment of diseases such as angiogenesis-related diseases. In one embodiment, the angiogenesis-related diseases include carcinoma, such as breast, ovarian, stomach, endometrial, salivary gland, lung, kidney, colon, colorectum, esophageal, thyroid, pancreatic, prostate and bladder cancer. In another embodiment, the angiogenesis-related diseases include, but are not limited to, neoplastic diseases, such as, melanoma, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, sarcoma, head and neck cancers, mesothelioma, biliary (cholangiocarcinoma), small bowel adenocarcinoma, pediatric malignancies and glioblastoma.

[0042] Ang-2 is an important "on-switch" of angiogenesis. Accordingly, antagonizing this molecule is expected to inhibit pathophysiological procedures, and thereby act as a potent therapy for various angiogenesis-dependent diseases. Besides solid tumors and their metastases, haematologic malignancies, such as leukemias, lymphomas and multiple myeloma, are also angiogenesis-dependent. Excessive vascular growth contributes to numerous non-neoplastic disorders. These non-neoplastic angiogenesis-dependent diseases include: atherosclerosis, haemangioma, haemangioendothelioma, angiofibroma, vascular malformations (e.g. Hereditary Hemorrhagic Teleangiectasia (HHT), or Osler-Weber syndrome), warts, pyogenic granulomas, excessive hair growth, Kaposis' sarcoma, scar keloids, allergic oedema, psoriasis, dysfunctional uterine bleeding, follicular cysts, ovarian hyperstimulation, endometriosis, respiratory distress, ascites, peritoneal sclerosis in dialysis patients, adhesion formation result from abdominal surgery, obesity, rheumatoid arthritis, synovitis, osteomyelitis, pannus growth, osteophyte, hemophilic joints, inflammatory and infectious processes (e.g. hepatitis, pneumonia, glomerulonephritis), asthma, nasal polyps, liver regeneration, pulmonary hypertension, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration., leukomalacia, neovascular glaucoma, corneal graft neovascularization, trachoma, thyroiditis, thyroid enlargement, and lymphoproliferative disorders.

BRIEF DESCRIPTION OF THE DRAWINGS

[0043] FIG. 1 is a Western Blot showing that Ang-2 mAbs inhibit Ang-2-induced phosphorylation of Tie2 ectopically expressed in HEK293F cells.

[0044] FIG. 2 is a line graph of the dose-response relationship of anti-Ang-2 monoclonal antibodies on the inhibition of Ang-2 induced Tie2 phosphorylation.

[0045] FIG. 3 is a line graph showing inhibition of both Ang-1 (top graph) and Ang-2 (bottom graph) binding to Tie2 in a dose-dependent manner using mAb 3.19.3 or Tie2/Fc.

[0046] FIG. 4 is a Western blot showing inhibition of Angiopoietin-1 stimulated phosphorylation of Tie-2 on Eahy 926 endothelial cells by mAb 3.19.3. Inhibition of Angiopoietin-1 induced Tie-2 phosphorylation is observed in this system. The antibody concentrations are shown in nM.

[0047] FIG. 5 is a line graph showing inhibition of Angiopoietin-1 stimulated phosphorylation of Tie-2 on Eahy 926 endothelial cells by mAb 3.19.3. The IC50=99 nM. The x axis is the concentration of mAb 3.19.3 and the y axis indicates the response.

[0048] FIG. 6 is a schematic diagram of the protein structure of human Ang-2 and Ang-2.sub.443. The upper numbers denote amino acid sequences (diagram taken from Injune et al., (2000) JBC 275: 18550).

[0049] FIG. 7 displays the amino acid sequence of a Mouse/Human chimeric molecule (SEQ ID NO: 1). The human residues (cloned as StuI-TfiI fragment) 310-400 are underlined.

[0050] FIG. 8 is an amino acid sequence comparison of human Ang-1 (SEQ ID NO: 2), human Ang-2 (SEQ ID NO: 3), and mouse Ang-2 (SEQ ID NO: 4) proteins. The fusion points of Ang-2 chimeric molecules and point mutations are noted in bold.

[0051] FIG. 9 is an amino acid sequence comparison of mouse Ang-1 (SEQ ID NO: 5), human Ang-1 (SEQ ID NO: 2), mouse Ang-2 (SEQ ID NO: 4), and human Ang-2 (SEQ ID NO: 3). The arrowhead shows the cleavage site for hydrophobic leader sequences. The arrows define the limits of the coiled-coil and fibrinogen like domains. The solid circles show the conserved cysteine residues (image taken from Maisonpierre et al., 1997, Science 277:55).

[0052] FIG. 10 is a line graph demonstrating mouse cross-reactivity in a dose-response relationship. Monoclonal antibody clones 5.2.1, 5.28.1, 3.19.3, and 3.31.2 are shown.

[0053] FIG. 11 is a line graph showing inhibition of both human (black triangles) and mouse (black squares) Ang-2 binding to human Tie2 in a dose-dependent manner using mAb 3.19.3.

[0054] FIG. 12 is a bar graph analysis of the effect of antibodies on MCF-7 cell-induced angiogenesis. FIG. 12A shows the effect of anti-Ang-2 antibodies on the number of blood vessels ends where the x axis indicates the experimental groups and the y axis indicates the mean number of vessel ends (+/-SD). FIG. 12B demonstrates the effect of anti-Ang-2 antibodies on blood vessel length where the x axis indicates the experimental groups and the y axis indicates the mean vessel length (+/-SD).

[0055] FIG. 13 is a line graph showing the anti-tumor effect of the anti-Ang-2 monoclonal antibody clone 3.19.3, as tested in a mouse xenograft model of human skin epidermoid carcinoma using the A431 cell line. The x axis indicates the number of days post tumor cell implantation and the y axis indicates the mean tumor volume+/-SEM in cm.sup.3. The Solid black triangles represent the post implantation tumor volume measurements of mice injected with anti-Ang-2 monoclonal antibody clone 3.19.3; the solid black circles represent the post implantation tumor volume measurements of mice injected with an isotype control antibody PK16.3.1.

[0056] FIG. 14A is a line graph showing prevention of tumor growth in the human colon adenocarcinoma LoVo xenograft model with tumor size indicated for mice treated with 0.5, 2, and 10 mg/kg or isotype control indicated. The x axis indicates the number of days post tumor cell implantation and the y axis indicates the mean tumor volume+/-SEM in cm.sup.3. FIG. 14B is a line graph showing tumor growth inhibitory effect of the mAb in a human colon adenocarcinoma SW480 xenograft model.

[0057] FIG. 15A is a line graph showing prevention of tumor growth in the HT29 xenograft model. The x axis indicates the number of days post tumor cell implantation, and the y axis indicates the mean tumor volume+/-SEM in cm.sup.3. FIG. 15B is a line graph showing prevention of tumor growth in the Calu-6 xenograft model with tumor size indicated for mice treated with 10 mg/kg of mAb clone 3.3.2 or 3.19.3 or with isotype control antibody. FIG. 15C is a bar graph indicating the density of CD31+ staining in tumors from MDA-MB-231 tumor-bearing mice treated with either IgG control or 10 mg/kg 3.19.3 mAb. Results from both threshold and manual grid counting methods are shown.

DETAILED DESCRIPTION

[0058] Embodiments of the invention described herein relate to monoclonal antibodies that bind to Ang-2. In some embodiments, the antibodies bind to Ang-2 and inhibit the binding of Ang-2 to its receptor, Tie2. Other embodiments of the invention include fully human anti-Ang-2 antibodies, and antibody preparations that are therapeutically useful. Such anti-Ang-2 antibody preparations preferably have desirable therapeutic properties, including strong binding affinity for Ang-2, the ability to neutralize Ang-2 in vitro, and the ability to inhibit Ang-2-induced angiogenesis in vivo.

[0059] One embodiment of the invention includes an antibody that binds to and neutralizes Ang-2, but does not bind to Ang-1. In another embodiment, the antibody binds to both Ang-2 and Ang-1, but only neutralizes Ang-2. In another embodiment, the antibody binds to both Ang-2 and Ang-1, and neutralizes binding of both Ang-1 and Ang-2 to Tie2.

[0060] Embodiments of the invention also include isolated binding fragments of anti-Ang-2 antibodies. Preferably, the binding fragments are derived from fully human anti-Ang-2 antibodies. Exemplary fragments include Fv, Fab' or other well know antibody fragments, as described in more detail below. Embodiments of the invention also include cells that express fully human antibodies against Ang-2. Examples of cells include hybridomas, or recombinantly created cells, such as Chinese hamster ovary (CHO) cells, variants of CHO cells (for example DG44) and NSO cells that produce antibodies against Ang-2. Additional information about variants of CHO cells can be found in Andersen and Reilly (2004) Current Opinion in Biotechnology 15, 456-462 which is incorporated herein in its entirety by reference.

[0061] In addition, embodiments of the invention include methods of using these antibodies for treating diseases. Anti-Ang-2 antibodies are useful for preventing Ang-2 mediated Tie2 signal transduction, thereby inhibiting angiogenesis. The mechanism of action of this inhibition may include inhibition of Ang-2 from binding to its receptor, Tie2, inhibition of Ang-2 induced Tie2 signaling, or enhanced clearance of Ang-2 therein lowering the effective concentration of Ang-2 for binding to Tie-2. Diseases that are treatable through this inhibition mechanism include, but are not limited to, neoplastic diseases, such as, melanoma, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, and cancers and tumors of the thyroid, stomach, prostate, breast, ovary, bladder, lung, uterus, kidney, colon, and pancreas, salivary gland, and colorectal.

[0062] Other embodiments of the invention include diagnostic assays for specifically determining the quantity of Ang-2 in a biological sample. The assay kit can include anti-Ang-2 antibodies along with the necessary labels for detecting such antibodies. These diagnostic assays are useful to screen for angiogenesis-related diseases including, but not limited to, neoplastic diseases, such as, melanoma, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, and carcinoma of the thyroid, stomach, prostate, breast, ovary, bladder, lung, uterus, kidney, colon, and pancreas, salivary gland, and colorectum.

[0063] According to one aspect of the invention there is provided an antagonist of the biological activity of Angiopoietin-1 and Angiopoietin-2 wherein the antagonist does not bind to the ATP-binding site of Tie-2.

[0064] According to another aspect of the invention there is provided an antagonist of the biological activity of Angiopoietin-1 and Angiopoietin-2 wherein the antagonist binds to Angiopoietin-1 and Angiopoietin-2.

[0065] According to another aspect of the invention there is provided an antagonist of the biological activity of Angiopoietin-1 and Angiopoietin-2 wherein the antagonist is not a compound.

[0066] In one embodiment there is provided an antagonist of the biological activity of Angiopoietin-1 and Angiopoietin-2 wherein the Angiopoietin-1 antagonist activity and the Angiopoietin-2 antagonist activity is comprised within one molecule. In an alternative embodiment there is provided an antagonist wherein the Angiopoietin-1 antagonist activity and the Angiopoietin-2 antagonist activity is comprised within more than one molecule.

[0067] In one embodiment there is provided an antagonist of the biological activity of Angiopoietin-1 and Angiopoietin-2 wherein the antagonist may bind to:

[0068] i) the Tie-2 receptor;

[0069] ii) Angiopoietin-1 and/or Angiopoietin-2;

[0070] iii) Tie-2 receptor-Angiopoietin-1 complex; or

[0071] iv) Tie-2 receptor-Angiopoietin-2 complex,

[0072] or any combination of these.

[0073] In one embodiment the antagonist of the biological activity of Angiopoietin-1 and Angiopoietin-2 may bind to Angiopoietin-1 and/or Angiopoietin-2 and/or Tie-2 and thereby prevent Angiopoietin-1 and Angiopoietin-2 mediated Tie-2 signal transduction, thereby inhibiting angiogenesis. The mechanism of action of this inhibition may include; [0074] i) binding of the antagonist to Angiopoietin-1 and inhibiting the binding of Angiopoietin-1 to its receptor, Tie-2, and/or [0075] ii) binding of the antagonist to Angiopoietin-2 and inhibit the binding of Angiopoietin-2 to its receptor, Tie-2, and/or [0076] iii) enhancing the clearance of Angiopoietin-1 and/or Angiopoietin-2 therein lowering the effective concentration of Angiopoietin-1 and/or Angiopoietin-2 available for binding to Tie-2,

[0077] or any combination of these, sufficient to antagonize the biological activity of Angiopoietin-1 and Angiopoietin-2.

[0078] Without wishing to be bound by theoretical considerations mechanisms by which antagonism of the biological activity of Angiopoietin-1 and Angiopoietin-2 can be achieved include, but are not limited to, inhibition of binding of Angiopoietin-1 and Angiopoietin-2 to the receptor Tie-2, inhibition of Angiopoietin-1 and Angiopoietin-2 induced Tie-2 signaling, or increased clearance of Angiopoietin-1 and Angiopoietin-2, therein reducing the effective concentration of Angiopoietin-1 and Angiopoietin-2.

[0079] In one embodiment there is provided an antagonist of the biological activity of Angiopoietin-1 and Angiopoietin-2 wherein the antagonist is an antibody. Preferably the antibody is able to antagonize the biological activity of Angiopoietin-1 and/or Angiopoietin-2 in vitro and in vivo. Preferably the antibody is a polyclonal or monoclonal antibody. More preferably the antibody is a monoclonal antibody and more preferably the antibody is a fully human monoclonal antibody. Most preferably the antibody is the fully human monoclonal antibody 3.19.3.

[0080] In one embodiment there is provided an antibody which binds to the same epitope or epitopes as fully human monoclonal antibody 3.19.3.

[0081] In one embodiment of the invention there is provided a fully human antibody that binds to Angiopoietin-1 and prevents Angiopoietin-1 binding to Tie-2. Yet another embodiment of the invention is a fully human monoclonal antibody that binds to Angiopoietin-1 and inhibits Angiopoietin-1 induced Tie-2 phosphorylation. In one embodiment, the antibody binds Angiopoietin-1 with a K.sub.d of less than 1 nanomolar (nM). More preferably, the antibody binds with a Kd less than 500 picomolar (pM). More preferably, the antibody binds with a Kd less than 100 picomolar (pM). More preferably, the antibody binds with a Kd less than 30 picomolar (pM). More preferably, the antibody binds with a K.sub.d of less than 20 pM. Even more preferably, the antibody binds with a K.sub.d of less than 10 or 5 pM.

[0082] In one embodiment of the invention there is provided a fully human antibody that binds to Angiopoietin-2 and prevents Angiopoietin-2 binding to Tie-2. Yet another embodiment of the invention is a fully human monoclonal antibody that binds to Angiopoietin-2 and inhibits Angiopoietin-2 induced Tie-2 phosphorylation. In one embodiment, the antibody binds Angiopoietin-2 with a K.sub.d of less than 1 nanomolar (nM). More preferably, the antibody binds with a Kd less than 500 picomolar (pM). More preferably, the antibody binds with a Kd less than 100 picomolar (pM). More preferably, the antibody binds with a Kd less than 30 picomolar (pM). More preferably, the antibody binds with a K.sub.d of less than 20 pM. Even more preferably, the antibody binds with a K.sub.d of less than 10 or 5 pM.

[0083] In one embodiment there is provided a hybridoma that produces the light chain and/or the heavy chain of antibody as described hereinabove. Preferably the hybridoma produces the light chain and/or the heavy chain of a fully human monoclonal antibody. More preferably the hybridoma produces the light chain and/or the heavy chain of the fully human monoclonal antibody 3.19.3, 3.3.2 or 5.88.3. Alternatively the hybridoma produces an antibody which binds to the same epitope or epitopes as fully human monoclonal antibody 3.19.3, 3.3.2 or 5.88.3.

[0084] In one embodiment there is provided a nucleic acid molecule encoding the light chain or the heavy chain of the antibody as described hereinabove. Preferably there is provided a nucleic acid molecule encoding the light chain or the heavy chain of a fully human monoclonal antibody. More preferably there is provided a nucleic acid molecule encoding the light chain or the heavy chain of the fully human monoclonal antibody 3.19.3.

[0085] In one embodiment of the invention there is provided a vector comprising a nucleic acid molecule or molecules as described hereinabove, wherein the vector encodes a light chain and/or a heavy chain of an antibody as defined hereinabove.

[0086] In one embodiment of the invention there is provided a host cell comprising a vector as described hereinabove. Alternatively the host cell may comprise more than one vector.

[0087] In addition, one embodiment of the invention is a method of producing an antibody by culturing host cells under conditions wherein a nucleic acid molecule is expressed to produce the antibody, followed by recovery of the antibody.

[0088] In one embodiment of the invention there is provided a method of making an antibody comprising transfecting at least one host cell with at least one nucleic acid molecule encoding the antibody as described hereinabove, expressing the nucleic acid molecule in said host cell and isolating said antibody.

[0089] According to another aspect of the invention there is provided a method of antagonising the biological activity of Angiopoietin-1 and Angiopoietin-2 comprising administering an antagonist as described hereinabove. The method may include selecting an animal in need of treatment for disease-related angiogenesis, and administering to said animal a therapeutically effective dose of an antagonist of the biological activity of Angiopoietin-1 and Angiopoietin-2.

[0090] According to another aspect of the invention there is provided a method of antagonising the biological activity of Angiopoietin-1 and Angiopoietin-2 comprising administering an antibody as described hereinabove. The method may include selecting an animal in need of treatment for disease-related angiogenesis, and administering to said animal a therapeutically effective dose of an antibody which antagonises the biological activity of Angiopoietin-1 and Angiopoietin-2.

[0091] According to another aspect there is provided a method of treating disease-related angiogenesis in a mammal comprising administering a therapeutically effective amount of an antagonist of the biological activity of Angiopoietin-1 and Angiopoietin-2. The method may include selecting an animal in need of treatment for disease-related angiogenesis, and administering to said animal a therapeutically effective dose of an antagonist of the biological activity of Angiopoietin-1 and Angiopoietin-2.

[0092] According to another aspect there is provided a method of treating disease-related angiogenesis in a mammal comprising administering a therapeutically effective amount of an antibody which antagonizes the biological activity of Angiopoietin-1 and Angiopoietin-2. The method may include selecting an animal in need of treatment for disease-related angiogenesis, and administering to said animal a therapeutically effective dose of an antibody which antagonises the biological activity of Angiopoietin-1 and Angiopoietin-2. The antibody can be administered alone, or can be administered in combination with additional antibodies or chemotherapeutic drug or radiation therapy.

[0093] According to another aspect there is provided a method of treating cancer in a mammal comprising administering a therapeutically effective amount of an antagonist of the biological activity of Angiopoietin-1 and Angiopoietin-2. The method may include selecting an animal in need of treatment for cancer, and administering to said animal a therapeutically effective dose of an antagonist which antagonises the biological activity of Angiopoietin-1 and Angiopoietin-2. The antagonist can be administered alone, or can be administered in combination with additional antibodies or chemotherapeutic drug or radiation therapy.

[0094] According to another aspect there is provided a method of treating cancer in a mammal comprising administering a therapeutically effective amount of an antibody which antagonizes the biological activity of Angiopoietin-1 and Angiopoietin-2. The method may include selecting an animal in need of treatment for cancer, and administering to said animal a therapeutically effective dose of an antibody which antagonises the biological activity of Angiopoietin-1 and Angiopoietin-2. The antibody can be administered alone, or can be administered in combination with additional antibodies or chemotherapeutic drug or radiation therapy.

[0095] According to another aspect of the invention there is provided the use of an antagonist of the biological activity of Angiopoietin-1 and Angiopoietin-2 for the manufacture of a medicament for the treatment of disease-related angiogenesis.

[0096] According to another aspect of the invention there is provided the use of an antibody which antagonizes the biological activity of Angiopoietin-1 and Angiopoietin-2 for the manufacture of a medicament for the treatment of disease-related angiogenesis.

[0097] In a preferred embodiment the present invention is particularly suitable for use in antagonizing Angiopoietin-1 or Angiopoietin-2, in patients with a tumour which is dependent alone, or in part, on a Tie-2 receptor.

[0098] Another embodiment of the invention includes an assay kit for detecting Angiopoietin-1 and/or Angiopoietin-2 in mammalian tissues, cells, or body fluids to screen for angiogenesis-related diseases. The kit includes an antibody that binds to Angiopoietin-1 and/or Angiopoietin-1 and a means for indicating the reaction of the antibody with Angiopoietin-1 and/or Angiopoietin-2, if present. The antibody may be a monoclonal antibody. In one embodiment, the antibody that binds Angiopoietin-2 is labeled. In another embodiment the antibody is an unlabeled primary antibody and the kit further includes a means for detecting the primary antibody. In one embodiment, the means includes a labeled second antibody that is an anti-immunoglobulin. Preferably the antibody is labeled with a marker selected from the group consisting of a fluorochrome, an enzyme, a radionuclide and a radio-opaque material.

[0099] Further embodiments, features, and the like regarding anti-Ang-2 antibodies are provided in additional detail below.

Sequence Listing

[0100] Embodiments of the invention include the specific anti-Ang-2 antibodies listed below in Table 1. This table reports the identification number of each anti-Ang-2 antibody, along with the SEQ ID number of the corresponding heavy chain and light chain genes.

[0101] Each antibody has been given an identification number that includes either two or three numbers separated by one or two decimal points. For most of the antibodies, only two identification numbers, separated by one decimal point, are listed.

[0102] However, in some cases, several clones of one antibody were prepared. Although the clones have the identical nucleic acid and amino acid sequences as the parent sequence, they may also be listed separately, with the clone number indicated by the number to the right of a second decimal point. Thus, for example, the nucleic acid and amino acid sequences of antibody 5.35 are identical to the sequences of antibody 5.35.1, 5.35.2, and 5.35.3.

TABLE-US-00001 TABLE 1 mAb ID No.: Sequence SEQ ID NO: 3.1 Nucleotide sequence encoding the variable region of the heavy chain 6 Amino acid sequence encoding the variable region of the heavy chain 7 Nucleotide sequence encoding the variable region of the light chain 8 Amino acid sequence encoding the variable region of the light chain 9 3.2 Nucleotide sequence encoding the variable region of the heavy chain 10 Amino acid sequence encoding the variable region of the heavy chain 11 Nucleotide sequence encoding the variable region of the light chain 12 Amino acid sequence encoding the variable region of the light chain 13 3.3 Nucleotide sequence encoding the variable region of the heavy chain 14 Amino acid sequence encoding the variable region of the heavy chain 15 Nucleotide sequence encoding the variable region of the light chain 16 Amino acid sequence encoding the variable region of the light chain 17 3.3.1 Nucleotide sequence encoding the variable region of the heavy chain 18 Amino acid sequence encoding the variable region of the heavy chain 19 Nucleotide sequence encoding the variable region of the light chain 20 Amino acid sequence encoding the variable region of the light chain 21 3.3.2 Nucleotide sequence encoding the variable region of the heavy chain 22 Amino acid sequence encoding the variable region of the heavy chain 23 Nucleotide sequence encoding the variable region of the light chain 24 Amino acid sequence encoding the variable region of the light chain 25 3.6 Nucleotide sequence encoding the variable region of the heavy chain 26 Amino acid sequence encoding the variable region of the heavy chain 27 Nucleotide sequence encoding the variable region of the light chain 28 Amino acid sequence encoding the variable region of the light chain 29 3.7 Nucleotide sequence encoding the variable region of the heavy chain 30 Amino acid sequence encoding the variable region of the heavy chain 31 Nucleotide sequence encoding the variable region of the light chain 32 Amino acid sequence encoding the variable region of the light chain 33 3.8 Nucleotide sequence encoding the variable region of the heavy chain 34 Amino acid sequence encoding the variable region of the heavy chain 35 Nucleotide sequence encoding the variable region of the light chain 36 Amino acid sequence encoding the variable region of the light chain 37 3.9 Nucleotide sequence encoding the variable region of the heavy chain 38 Amino acid sequence encoding the variable region of the heavy chain 39 Nucleotide sequence encoding the variable region of the light chain 40 Amino acid sequence encoding the variable region of the light chain 41 3.10 Nucleotide sequence encoding the variable region of the heavy chain 42 Amino acid sequence encoding the variable region of the heavy chain 43 Nucleotide sequence encoding the variable region of the light chain 44 Amino acid sequence encoding the variable region of the light chain 45 3.11 Nucleotide sequence encoding the variable region of the heavy chain 46 Amino acid sequence encoding the variable region of the heavy chain 47 Nucleotide sequence encoding the variable region of the light chain 48 Amino acid sequence encoding the variable region of the light chain 49 3.12 Nucleotide sequence encoding the variable region of the heavy chain 50 Amino acid sequence encoding the variable region of the heavy chain 51 Nucleotide sequence encoding the variable region of the light chain 52 Amino acid sequence encoding the variable region of the light chain 53 3.13 Nucleotide sequence encoding the variable region of the heavy chain 54 Amino acid sequence encoding the variable region of the heavy chain 55 Nucleotide sequence encoding the variable region of the light chain 56 Amino acid sequence encoding the variable region of the light chain 57 3.14 Nucleotide sequence encoding the variable region of the heavy chain 58 Amino acid sequence encoding the variable region of the heavy chain 59 Nucleotide sequence encoding the variable region of the light chain 60 Amino acid sequence encoding the variable region of the light chain 61 3.15 Nucleotide sequence encoding the variable region of the light chain 62 Amino acid sequence encoding the variable region of the light chain 63 3.16 Nucleotide sequence encoding the variable region of the light chain 64 Amino acid sequence encoding the variable region of the light chain 65 3.17 Nucleotide sequence encoding the variable region of the heavy chain 66 Amino acid sequence encoding the variable region of the heavy chain 67 Nucleotide sequence encoding the variable region of the light chain 68 Amino acid sequence encoding the variable region of the light chain 69 3.18 Nucleotide sequence encoding the variable region of the heavy chain 70 Amino acid sequence encoding the variable region of the heavy chain 71 Nucleotide sequence encoding the variable region of the light chain 72 Amino acid sequence encoding the variable region of the light chain 73 3.19.1 Nucleotide sequence encoding the variable region of the heavy chain 74 Amino acid sequence encoding the variable region of the heavy chain 75 Nucleotide sequence encoding the variable region of the light chain 76 Amino acid sequence encoding the variable region of the light chain 77 3.19.3 Nucleotide sequence encoding the variable region of the heavy chain 78 Amino acid sequence encoding the variable region of the heavy chain 79 Nucleotide sequence encoding the variable region of the light chain 80 Amino acid sequence encoding the variable region of the light chain 81 3.20 Nucleotide sequence encoding the variable region of the light chain 82 Amino acid sequence encoding the variable region of the light chain 83 3.21 Nucleotide sequence encoding the variable region of the heavy chain 84 Amino acid sequence encoding the variable region of the heavy chain 85 Nucleotide sequence encoding the variable region of the light chain 86 Amino acid sequence encoding the variable region of the light chain 87 3.22 Nucleotide sequence encoding the variable region of the heavy chain 88 Amino acid sequence encoding the variable region of the heavy chain 89 Nucleotide sequence encoding the variable region of the light chain 90 Amino acid sequence encoding the variable region of the light chain 91 3.26 Nucleotide sequence encoding the variable region of the heavy chain 92 Amino acid sequence encoding the variable region of the heavy chain 93 Nucleotide sequence encoding the variable region of the light chain 94 Amino acid sequence encoding the variable region of the light chain 95 3.28.1 Nucleotide sequence encoding the variable region of the heavy chain 96 Amino acid sequence encoding the variable region of the heavy chain 97 3.31.1 Nucleotide sequence encoding the variable region of the heavy chain 98 Amino acid sequence encoding the variable region of the heavy chain 99 Nucleotide sequence encoding the variable region of the light chain 100 Amino acid sequence encoding the variable region of the light chain 101 3.31.2 Nucleotide sequence encoding the variable region of the heavy chain 102 Amino acid sequence encoding the variable region of the heavy chain 103 Nucleotide sequence encoding the variable region of the light chain 104 Amino acid sequence encoding the variable region of the light chain 105 3.32 Nucleotide sequence encoding the variable region of the heavy chain 106 Amino acid sequence encoding the variable region of the heavy chain 107 Nucleotide sequence encoding the variable region of the light chain 108 Amino acid sequence encoding the variable region of the light chain 109 3.33 Nucleotide sequence encoding the variable region of the heavy chain 110 Amino acid sequence encoding the variable region of the heavy chain 111 Nucleotide sequence encoding the variable region of the light chain 112 Amino acid sequence encoding the variable region of the light chain 113 3.34 Nucleotide sequence encoding the variable region of the heavy chain 114 Amino acid sequence encoding the variable region of the heavy chain 115 Nucleotide sequence encoding the variable region of the light chain 116 Amino acid sequence encoding the variable region of the light chain 117 3.35 Nucleotide sequence encoding the variable region of the heavy chain 118 Amino acid sequence encoding the variable region of the heavy chain 119 3.37 Nucleotide sequence encoding the variable region of the heavy chain 120 Amino acid sequence encoding the variable region of the heavy chain 121 Nucleotide sequence encoding the variable region of the light chain 122 Amino acid sequence encoding the variable region of the light chain 123 3.39 Nucleotide sequence encoding the variable region of the heavy chain 124 Amino acid sequence encoding the variable region of the heavy chain 125 Nucleotide sequence encoding the variable region of the light chain 126 Amino acid sequence encoding the variable region of the light chain 127 3.40 Nucleotide sequence encoding the variable region of the heavy chain 128 Amino acid sequence encoding the variable region of the heavy chain 129 Nucleotide sequence encoding the variable region of the light chain 130 Amino acid sequence encoding the variable region of the light chain 131 3.41 Nucleotide sequence encoding the variable region of the heavy chain 132 Amino acid sequence encoding the variable region of the heavy chain 133 Nucleotide sequence encoding the variable region of the light chain 134 Amino acid sequence encoding the variable region of the light chain 135 3.42 Nucleotide sequence encoding the variable region of the heavy chain 136 Amino acid sequence encoding the variable region of the heavy chain 137 Nucleotide sequence encoding the variable region of the light chain 138 Amino acid sequence encoding the variable region of the light chain 139 4.2 Nucleotide sequence encoding the variable region of the heavy chain 140 Amino acid sequence encoding the variable region of the heavy chain 141 Nucleotide sequence encoding the variable region of the light chain 142 Amino acid sequence encoding the variable region of the light chain 143 4.3 Nucleotide sequence encoding the variable region of the heavy chain 144 Amino acid sequence encoding the variable region of the heavy chain 145 Nucleotide sequence encoding the variable region of the light chain 146 Amino acid sequence encoding the variable region of the light chain 147 4.4 Nucleotide sequence encoding the variable region of the light chain 148 Amino acid sequence encoding the variable region of the light chain 149 4.5 Nucleotide sequence encoding the variable region of the heavy chain 150 Amino acid sequence encoding the variable region of the heavy chain 151 Nucleotide sequence encoding the variable region of the light chain 152 Amino acid sequence encoding the variable region of the light chain 153 4.6 Nucleotide sequence encoding the variable region of the heavy chain 154 Amino acid sequence encoding the variable region of the heavy chain 155 4.7 Nucleotide sequence encoding the variable region of the heavy chain 156 Amino acid sequence encoding the variable region of the heavy chain 157 4.8 Nucleotide sequence encoding the variable region of the heavy chain 158 Amino acid sequence encoding the variable region of the heavy chain 159 Nucleotide sequence encoding the variable region of the light chain 160 Amino acid sequence encoding the variable region of the light chain 161 4.9 Nucleotide sequence encoding the variable region of the heavy chain 162 Amino acid sequence encoding the variable region of the heavy chain 163 Nucleotide sequence encoding the variable region of the light chain 164 Amino acid sequence encoding the variable region of the light chain 165 4.11 Nucleotide sequence encoding the variable region of the heavy chain 166 Amino acid sequence encoding the variable region of the heavy chain 167 Nucleotide sequence encoding the variable region of the light chain 168 Amino acid sequence encoding the variable region of the light chain 169 4.13 Nucleotide sequence encoding the variable region of the heavy chain 170 Amino acid sequence encoding the variable region of the heavy chain 171 Nucleotide sequence encoding the variable region of the light chain 172 Amino acid sequence encoding the variable region of the light chain 173 4.14 Nucleotide sequence encoding the variable region of the heavy chain 174 Amino acid sequence encoding the variable region of the heavy chain 175 Nucleotide sequence encoding the variable region of the light chain 176 Amino acid sequence encoding the variable region of the light chain 177 4.15 Nucleotide sequence encoding the variable region of the heavy chain 178 Amino acid sequence encoding the variable region of the heavy chain 179 Nucleotide sequence encoding the variable region of the light chain 180 Amino acid sequence encoding the variable region of the light chain 181 4.16 Nucleotide sequence encoding the variable region of the heavy chain 182 Amino acid sequence encoding the variable region of the heavy chain 183 Nucleotide sequence encoding the variable region of the light chain 184 Amino acid sequence encoding the variable region of the light chain 185 4.18 Nucleotide sequence encoding the variable region of the heavy chain 186 Amino acid sequence encoding the variable region of the heavy chain 187 Nucleotide sequence encoding the variable region of the light chain 188 Amino acid sequence encoding the variable region of the light chain 189 5.1 Nucleotide sequence encoding the variable region of the heavy chain 190 Amino acid sequence encoding the variable region of the heavy chain 191 Nucleotide sequence encoding the variable region of the light chain 192 Amino acid sequence encoding the variable region of the light chain 193 5.2 Nucleotide sequence encoding the variable region of the heavy chain 194 Amino acid sequence encoding the variable region of the heavy chain 195 5.2.1 Nucleotide sequence encoding the variable region of the heavy chain 196 Amino acid sequence encoding the variable region of the heavy chain 197 5.3 Nucleotide sequence encoding the variable region of the light chain

198 Amino acid sequence encoding the variable region of the light chain 199 5.4 Nucleotide sequence encoding the variable region of the heavy chain 200 Amino acid sequence encoding the variable region of the heavy chain 201 5.5 Nucleotide sequence encoding the variable region of the heavy chain 202 Amino acid sequence encoding the variable region of the heavy chain 203 5.6 Nucleotide sequence encoding the variable region of the heavy chain 204 Amino acid sequence encoding the variable region of the heavy chain 205 Nucleotide sequence encoding the variable region of the light chain 206 Amino acid sequence encoding the variable region of the light chain 207 5.7 Nucleotide sequence encoding the variable region of the heavy chain 208 Amino acid sequence encoding the variable region of the heavy chain 209 5.8 Nucleotide sequence encoding the variable region of the heavy chain 210 Amino acid sequence encoding the variable region of the heavy chain 211 Nucleotide sequence encoding the variable region of the light chain 212 Amino acid sequence encoding the variable region of the light chain 213 5.9 Nucleotide sequence encoding the variable region of the heavy chain 214 Amino acid sequence encoding the variable region of the heavy chain 215 5.10 Nucleotide sequence encoding the variable region of the heavy chain 216 Amino acid sequence encoding the variable region of the heavy chain 217 Nucleotide sequence encoding the variable region of the light chain 218 Amino acid sequence encoding the variable region of the light chain 219 5.11 Nucleotide sequence encoding the variable region of the heavy chain 220 Amino acid sequence encoding the variable region of the heavy chain 221 Nucleotide sequence encoding the variable region of the light chain 222 Amino acid sequence encoding the variable region of the light chain 223 5.12 Nucleotide sequence encoding the variable region of the heavy chain 224 Amino acid sequence encoding the variable region of the heavy chain 225 Nucleotide sequence encoding the variable region of the light chain 226 Amino acid sequence encoding the variable region of the light chain 227 5.13.1 Nucleotide sequence encoding the variable region of the heavy chain 228 Amino acid sequence encoding the variable region of the heavy chain 229 Nucleotide sequence encoding the variable region of the light chain 230 Amino acid sequence encoding the variable region of the light chain 231 5.14.1 Nucleotide sequence encoding the variable region of the heavy chain 232 Amino acid sequence encoding the variable region of the heavy chain 233 5.15 Nucleotide sequence encoding the variable region of the heavy chain 234 Amino acid sequence encoding the variable region of the heavy chain 235 Nucleotide sequence encoding the variable region of the light chain 236 Amino acid sequence encoding the variable region of the light chain 237 5.16.1 Nucleotide sequence encoding the variable region of the heavy chain 238 Amino acid sequence encoding the variable region of the heavy chain 239 Nucleotide sequence encoding the variable region of the light chain 240 Amino acid sequence encoding the variable region of the light chain 241 5.17 Nucleotide sequence encoding the variable region of the heavy chain 242 Amino acid sequence encoding the variable region of the heavy chain 243 Nucleotide sequence encoding the variable region of the light chain 244 Amino acid sequence encoding the variable region of the light chain 245 5.18 Nucleotide sequence encoding the variable region of the heavy chain 246 Amino acid sequence encoding the variable region of the heavy chain 247 Nucleotide sequence encoding the variable region of the light chain 248 Amino acid sequence encoding the variable region of the light chain 249 5.19 Nucleotide sequence encoding the variable region of the heavy chain 250 Amino acid sequence encoding the variable region of the heavy chain 251 5.20 Nucleotide sequence encoding the variable region of the heavy chain 252 Amino acid sequence encoding the variable region of the heavy chain 253 5.21 Nucleotide sequence encoding the variable region of the heavy chain 254 Amino acid sequence encoding the variable region of the heavy chain 255 Nucleotide sequence encoding the variable region of the light chain 256 Amino acid sequence encoding the variable region of the light chain 257 5.22 Nucleotide sequence encoding the variable region of the heavy chain 258 Amino acid sequence encoding the variable region of the heavy chain 259 Nucleotide sequence encoding the variable region of the light chain 260 Amino acid sequence encoding the variable region of the light chain 261 5.23 Nucleotide sequence encoding the variable region of the heavy chain 262 Amino acid sequence encoding the variable region of the heavy chain 263 Nucleotide sequence encoding the variable region of the light chain 264 Amino acid sequence encoding the variable region of the light chain 265 5.24 Nucleotide sequence encoding the variable region of the heavy chain 266 Amino acid sequence encoding the variable region of the heavy chain 267 Nucleotide sequence encoding the variable region of the light chain 268 Amino acid sequence encoding the variable region of the light chain 269 5.25 Nucleotide sequence encoding the variable region of the light chain 270 Amino acid sequence encoding the variable region of the light chain 271 5.26 Nucleotide sequence encoding the variable region of the heavy chain 272 Amino acid sequence encoding the variable region of the heavy chain 273 5.27 Nucleotide sequence encoding the variable region of the light chain 274 Amino acid sequence encoding the variable region of the light chain 275 5.28.1 Nucleotide sequence encoding the variable region of the heavy chain 276 Amino acid sequence encoding the variable region of the heavy chain 277 Nucleotide sequence encoding the variable region of the light chain 278 Amino acid sequence encoding the variable region of the light chain 279 5.29 Nucleotide sequence encoding the variable region of the heavy chain 280 Amino acid sequence encoding the variable region of the heavy chain 281 Nucleotide sequence encoding the variable region of the light chain 282 Amino acid sequence encoding the variable region of the light chain 283 5.30 Nucleotide sequence encoding the variable region of the heavy chain 284 Amino acid sequence encoding the variable region of the heavy chain 285 Nucleotide sequence encoding the variable region of the light chain 286 Amino acid sequence encoding the variable region of the light chain 287 5.31 Nucleotide sequence encoding the variable region of the heavy chain 288 Amino acid sequence encoding the variable region of the heavy chain 289 Nucleotide sequence encoding the variable region of the light chain 290 Amino acid sequence encoding the variable region of the light chain 291 5.33 Nucleotide sequence encoding the variable region of the heavy chain 292 Amino acid sequence encoding the variable region of the heavy chain 293 5.34 Nucleotide sequence encoding the variable region of the light chain 294 Amino acid sequence encoding the variable region of the light chain 295 5.35.1 Nucleotide sequence encoding the variable region of the heavy chain 296 Amino acid sequence encoding the variable region of the heavy chain 297 Nucleotide sequence encoding the variable region of the light chain 298 Amino acid sequence encoding the variable region of the light chain 299 5.36 Nucleotide sequence encoding the variable region of the heavy chain 300 Amino acid sequence encoding the variable region of the heavy chain 301 Nucleotide sequence encoding the variable region of the light chain 302 Amino acid sequence encoding the variable region of the light chain 303 5.37 Nucleotide sequence encoding the variable region of the heavy chain 304 Amino acid sequence encoding the variable region of the heavy chain 305 Nucleotide sequence encoding the variable region of the light chain 306 Amino acid sequence encoding the variable region of the light chain 307 5.38 Nucleotide sequence encoding the variable region of the heavy chain 308 Amino acid sequence encoding the variable region of the heavy chain 309 Nucleotide sequence encoding the variable region of the light chain 310 Amino acid sequence encoding the variable region of the light chain 311 5.39.1 Nucleotide sequence encoding the variable region of the heavy chain 312 Amino acid sequence encoding the variable region of the heavy chain 313 Nucleotide sequence encoding the variable region of the light chain 314 Amino acid sequence encoding the variable region of the light chain 315 5.40.2 Nucleotide sequence encoding the variable region of the heavy chain 316 Amino acid sequence encoding the variable region of the heavy chain 317 Nucleotide sequence encoding the variable region of the light chain 318 Amino acid sequence encoding the variable region of the light chain 319 5.41.1 Nucleotide sequence encoding the variable region of the heavy chain 320 Amino acid sequence encoding the variable region of the heavy chain 321 Nucleotide sequence encoding the variable region of the light chain 322 Amino acid sequence encoding the variable region of the light chain 323 5.43 Nucleotide sequence encoding the variable region of the heavy chain 324 Amino acid sequence encoding the variable region of the heavy chain 325 Nucleotide sequence encoding the variable region of the light chain 326 Amino acid sequence encoding the variable region of the light chain 327 5.44 Nucleotide sequence encoding the variable region of the heavy chain 328 Amino acid sequence encoding the variable region of the heavy chain 329 Nucleotide sequence encoding the variable region of the light chain 330 Amino acid sequence encoding the variable region of the light chain 331 5.45 Nucleotide sequence encoding the variable region of the heavy chain 332 Amino acid sequence encoding the variable region of the heavy chain 333 Nucleotide sequence encoding the variable region of the light chain 334 Amino acid sequence encoding the variable region of the light chain 335 5.46 Nucleotide sequence encoding the variable region of the heavy chain 336 Amino acid sequence encoding the variable region of the heavy chain 337 5.47 Nucleotide sequence encoding the variable region of the heavy chain 338 Amino acid sequence encoding the variable region of the heavy chain 339 5.48 Nucleotide sequence encoding the variable region of the heavy chain 340 Amino acid sequence encoding the variable region of the heavy chain 341 Nucleotide sequence encoding the variable region of the light chain 342 Amino acid sequence encoding the variable region of the light chain 343 5.51 Nucleotide sequence encoding the variable region of the heavy chain 344 Amino acid sequence encoding the variable region of the heavy chain 345 5.52 Nucleotide sequence encoding the variable region of the heavy chain 346 Amino acid sequence encoding the variable region of the heavy chain 347 Nucleotide sequence encoding the variable region of the light chain 348 Amino acid sequence encoding the variable region of the light chain 349 5.52.1 Nucleotide sequence encoding the variable region of the heavy chain 350 Amino acid sequence encoding the variable region of the heavy chain 351 Nucleotide sequence encoding the variable region of the light chain 352 Amino acid sequence encoding the variable region of the light chain 353 5.53 Nucleotide sequence encoding the variable region of the heavy chain 354 Amino acid sequence encoding the variable region of the heavy chain 355 5.54.1 Nucleotide sequence encoding the variable region of the heavy chain 356 Amino acid sequence encoding the variable region of the heavy chain 357 Nucleotide sequence encoding the variable region of the light chain 358 Amino acid sequence encoding the variable region of the light chain 359 5.55 Nucleotide sequence encoding the variable region of the heavy chain 360 Amino acid sequence encoding the variable region of the heavy chain 361 5.56.1 Nucleotide sequence encoding the variable region of the heavy chain 362 Amino acid sequence encoding the variable region of the heavy chain 363 Nucleotide sequence encoding the variable region of the light chain 364 Amino acid sequence encoding the variable region of the light chain 365 5.58 Nucleotide sequence encoding the variable region of the heavy chain 366 Amino acid sequence encoding the variable region of the heavy chain 367 Nucleotide sequence encoding the variable region of the light chain 368 Amino acid sequence encoding the variable region of the light chain 369 5.59 Nucleotide sequence encoding the variable region of the heavy chain 370 Amino acid sequence encoding the variable region of the heavy chain 371 5.60 Nucleotide sequence encoding the variable region of the heavy chain 372 Amino acid sequence encoding the variable region of the heavy chain 373 Nucleotide sequence encoding the variable region of the light chain 374 Amino acid sequence encoding the variable region of the light chain 375 5.61 Nucleotide sequence encoding the variable region of the heavy chain 376 Amino acid sequence encoding the variable region of the heavy chain 377 Nucleotide sequence encoding the variable region of the light chain 378 Amino acid sequence encoding the variable region of the light chain 379 5.62.1 Nucleotide sequence encoding the variable region of the heavy chain 380 Amino acid sequence encoding the variable region of the heavy chain 381 Nucleotide sequence encoding the variable region of the light chain 382 Amino acid sequence encoding the variable region of the light chain 383 5.64 Nucleotide sequence encoding the variable region of the heavy chain 384 Amino acid sequence encoding the variable region of the heavy chain 385 Nucleotide sequence encoding the variable region of the light chain 386 Amino acid sequence encoding the variable region of the light chain 387 5.66 Nucleotide sequence encoding the variable region of the heavy chain 388 Amino acid sequence encoding the variable region of the heavy chain 389 Nucleotide sequence encoding the variable region of the light chain 390 Amino acid sequence encoding the variable region of the light chain 391

5.67 Nucleotide sequence encoding the variable region of the heavy chain 392 Amino acid sequence encoding the variable region of the heavy chain 393 Nucleotide sequence encoding the variable region of the light chain 394 Amino acid sequence encoding the variable region of the light chain 395 5.68 Nucleotide sequence encoding the variable region of the heavy chain 396 Amino acid sequence encoding the variable region of the heavy chain 397 5.70 Nucleotide sequence encoding the variable region of the heavy chain 398 Amino acid sequence encoding the variable region of the heavy chain 399 5.71 Nucleotide sequence encoding the variable region of the heavy chain 400 Amino acid sequence encoding the variable region of the heavy chain 401 Nucleotide sequence encoding the variable region of the light chain 402 Amino acid sequence encoding the variable region of the light chain 403 5.72 Nucleotide sequence encoding the variable region of the heavy chain 404 Amino acid sequence encoding the variable region of the heavy chain 405 Nucleotide sequence encoding the variable region of the light chain 406 Amino acid sequence encoding the variable region of the light chain 407 5.73 Nucleotide sequence encoding the variable region of the heavy chain 408 Amino acid sequence encoding the variable region of the heavy chain 409 Nucleotide sequence encoding the variable region of the light chain 410 Amino acid sequence encoding the variable region of the light chain 411 5.74 Nucleotide sequence encoding the variable region of the heavy chain 412 Amino acid sequence encoding the variable region of the heavy chain 413 Nucleotide sequence encoding the variable region of the light chain 414 Amino acid sequence encoding the variable region of the light chain 415 5.75 Nucleotide sequence encoding the variable region of the heavy chain 416 Amino acid sequence encoding the variable region of the heavy chain 417 5.76 Nucleotide sequence encoding the variable region of the heavy chain 418 Amino acid sequence encoding the variable region of the heavy chain 419 Nucleotide sequence encoding the variable region of the light chain 420 Amino acid sequence encoding the variable region of the light chain 421 5.77 Nucleotide sequence encoding the variable region of the light chain 422 Amino acid sequence encoding the variable region of the light chain 423 5.78 Nucleotide sequence encoding the variable region of the heavy chain 424 Amino acid sequence encoding the variable region of the heavy chain 425 Nucleotide sequence encoding the variable region of the light chain 426 Amino acid sequence encoding the variable region of the light chain 427 5.78.1 Nucleotide sequence encoding the variable region of the heavy chain 428 Amino acid sequence encoding the variable region of the heavy chain 429 Nucleotide sequence encoding the variable region of the light chain 430 Amino acid sequence encoding the variable region of the light chain 431 5.79 Nucleotide sequence encoding the variable region of the heavy chain 432 Amino acid sequence encoding the variable region of the heavy chain 433 5.80 Nucleotide sequence encoding the variable region of the heavy chain 434 Amino acid sequence encoding the variable region of the heavy chain 435 Nucleotide sequence encoding the variable region of the light chain 436 Amino acid sequence encoding the variable region of the light chain 437 5.81 Nucleotide sequence encoding the variable region of the heavy chain 438 Amino acid sequence encoding the variable region of the heavy chain 439 Nucleotide sequence encoding the variable region of the light chain 440 Amino acid sequence encoding the variable region of the light chain 441 5.82 Nucleotide sequence encoding the variable region of the heavy chain 442 Amino acid sequence encoding the variable region of the heavy chain 443 Nucleotide sequence encoding the variable region of the light chain 444 Amino acid sequence encoding the variable region of the light chain 445 5.83 Nucleotide sequence encoding the variable region of the heavy chain 446 Amino acid sequence encoding the variable region of the heavy chain 447 5.83.1 Nucleotide sequence encoding the variable region of the heavy chain 448 Amino acid sequence encoding the variable region of the heavy chain 449 Nucleotide sequence encoding the variable region of the light chain 450 Amino acid sequence encoding the variable region of the light chain 451 5.86.1 Nucleotide sequence encoding the variable region of the heavy chain 452 Amino acid sequence encoding the variable region of the heavy chain 453 Nucleotide sequence encoding the variable region of the light chain 454 Amino acid sequence encoding the variable region of the light chain 455 5.87 Nucleotide sequence encoding the variable region of the heavy chain 456 Amino acid sequence encoding the variable region of the heavy chain 457 Nucleotide sequence encoding the variable region of the light chain 458 Amino acid sequence encoding the variable region of the light chain 459 5.88 Nucleotide sequence encoding the variable region of the heavy chain 460 Amino acid sequence encoding the variable region of the heavy chain 461 Nucleotide sequence encoding the variable region of the light chain 462 Amino acid sequence encoding the variable region of the light chain 463 5.88.1 Nucleotide sequence encoding the variable region of the heavy chain 464 Amino acid sequence encoding the variable region of the heavy chain 465 Nucleotide sequence encoding the variable region of the light chain 466 Amino acid sequence encoding the variable region of the light chain 467 5.88.3 Nucleotide sequence encoding the variable region of the heavy chain 468 Amino acid sequence encoding the variable region of the heavy chain 469 Nucleotide sequence encoding the variable region of the light chain 470 Amino acid sequence encoding the variable region of the light chain 471 5.89 Nucleotide sequence encoding the variable region of the heavy chain 472 Amino acid sequence encoding the variable region of the heavy chain 473 5.90 Nucleotide sequence encoding the variable region of the heavy chain 474 Amino acid sequence encoding the variable region of the heavy chain 475 Nucleotide sequence encoding the variable region of the light chain 476 Amino acid sequence encoding the variable region of the light chain 477 5.91 Nucleotide sequence encoding the variable region of the heavy chain 478 Amino acid sequence encoding the variable region of the heavy chain 479 5.92 Nucleotide sequence encoding the variable region of the heavy chain 480 Amino acid sequence encoding the variable region of the heavy chain 481 Nucleotide sequence encoding the variable region of the light chain 482 Amino acid sequence encoding the variable region of the light chain 483 5.93 Nucleotide sequence encoding the variable region of the light chain 484 Amino acid sequence encoding the variable region of the light chain 485 5.94 Nucleotide sequence encoding the variable region of the heavy chain 486 Amino acid sequence encoding the variable region of the heavy chain 487 5.95 Nucleotide sequence encoding the variable region of the light chain 488 Amino acid sequence encoding the variable region of the light chain 489 5.97 Nucleotide sequence encoding the variable region of the heavy chain 490 Amino acid sequence encoding the variable region of the heavy chain 491 Nucleotide sequence encoding the variable region of the light chain 492 Amino acid sequence encoding the variable region of the light chain 493 5.99 Nucleotide sequence encoding the variable region of the light chain 494 Amino acid sequence encoding the variable region of the light chain 495 5.101.1 Nucleotide sequence encoding the variable region of the heavy chain 496 Amino acid sequence encoding the variable region of the heavy chain 497 Nucleotide sequence encoding the variable region of the light chain 498 Amino acid sequence encoding the variable region of the light chain 499 5.102 Nucleotide sequence encoding the variable region of the heavy chain 500 Amino acid sequence encoding the variable region of the heavy chain 501 5.103.1 Nucleotide sequence encoding the variable region of the heavy chain 502 Amino acid sequence encoding the variable region of the heavy chain 503 Nucleotide sequence encoding the variable region of the light chain 504 Amino acid sequence encoding the variable region of the light chain 505 5.104 Nucleotide sequence encoding the variable region of the heavy chain 506 Amino acid sequence encoding the variable region of the heavy chain 507 5.106 Nucleotide sequence encoding the variable region of the heavy chain 508 Amino acid sequence encoding the variable region of the heavy chain 509 5.107 Nucleotide sequence encoding the variable region of the heavy chain 510 Amino acid sequence encoding the variable region of the heavy chain 511 5.108.1 Nucleotide sequence encoding the variable region of the heavy chain 512 Amino acid sequence encoding the variable region of the heavy chain 513 Nucleotide sequence encoding the variable region of the light chain 514 Amino acid sequence encoding the variable region of the light chain 515 5.109 Nucleotide sequence encoding the variable region of the heavy chain 516 Amino acid sequence encoding the variable region of the heavy chain 517 Nucleotide sequence encoding the variable region of the light chain 518 Amino acid sequence encoding the variable region of the light chain 519 5.111 Nucleotide sequence encoding the variable region of the heavy chain 520 Amino acid sequence encoding the variable region of the heavy chain 521 Nucleotide sequence encoding the variable region of the light chain 522 Amino acid sequence encoding the variable region of the light chain 523 5.112 Nucleotide sequence encoding the variable region of the heavy chain 524 Amino acid sequence encoding the variable region of the heavy chain 525 5.114 Nucleotide sequence encoding the variable region of the light chain 526 Amino acid sequence encoding the variable region of the light chain 527 5.115 Nucleotide sequence encoding the variable region of the heavy chain 528 Amino acid sequence encoding the variable region of the heavy chain 529 Nucleotide sequence encoding the variable region of the light chain 530 Amino acid sequence encoding the variable region of the light chain 531 6.1 Nucleotide sequence encoding the variable region of the heavy chain 532 Amino acid sequence encoding the variable region of the heavy chain 533 6.2 Nucleotide sequence encoding the variable region of the heavy chain 534 Amino acid sequence encoding the variable region of the heavy chain 535 Nucleotide sequence encoding the variable region of the light chain 536 Amino acid sequence encoding the variable region of the light chain 537 6.3.1 Nucleotide sequence encoding the variable region of the heavy chain 538 Amino acid sequence encoding the variable region of the heavy chain 539 Nucleotide sequence encoding the variable region of the light chain 540 Amino acid sequence encoding the variable region of the light chain 541 6.4 Nucleotide sequence encoding the variable region of the light chain 542 Amino acid sequence encoding the variable region of the light chain 543 6.5 Nucleotide sequence encoding the variable region of the heavy chain 544 Amino acid sequence encoding the variable region of the heavy chain 545 6.6 Nucleotide sequence encoding the variable region of the heavy chain 546 Amino acid sequence encoding the variable region of the heavy chain 547 Nucleotide sequence encoding the variable region of the light chain 548 Amino acid sequence encoding the variable region of the light chain 549 6.7 Nucleotide sequence encoding the variable region of the heavy chain 550 Amino acid sequence encoding the variable region of the heavy chain 551 6.8 Nucleotide sequence encoding the variable region of the heavy chain 552 Amino acid sequence encoding the variable region of the heavy chain 553 6.9 Nucleotide sequence encoding the variable region of the heavy chain 554 Amino acid sequence encoding the variable region of the heavy chain 555 6.10 Nucleotide sequence encoding the variable region of the light chain 556 Amino acid sequence encoding the variable region of the light chain 557

DEFINITIONS

[0103] Unless otherwise defined, scientific and technical terms used herein shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, nomenclatures utilized in connection with, and techniques of, cell and tissue culture, molecular biology, and protein and oligo- or polynucleotide chemistry and hybridization described herein are those well known and commonly used in the art.

[0104] Standard techniques are used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Enzymatic reactions and purification techniques are performed according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures 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. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2001)), which is incorporated herein by reference. The nomenclatures utilized 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.

[0105] As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0106] An antagonist may be a polypeptide, nucleic acid, carbohydrate, lipid, small molecular weight compound, an oligonucleotide, an oligopeptide, RNA interference (RNAi), antisense, a recombinant protein, an antibody, or conjugates or fusion proteins thereof. For a review of RNAi see Milhavet O, Gary D S, Mattson M P. (Pharmacol Rev. 2003 December; 55(4):629-48. Review.) and antisense see Opalinska J B, Gewirtz A M. (Sci STKE. 2003 Oct. 28; 2003(206):pe47.)

[0107] Disease-related angiogenesis may be any abnormal, undesirable or pathological angiogenesis, for example tumor-related angiogenesis. Angiogenesis-related diseases include, but are not limited to, non-solid tumors such as leukaemia, multiple myeloma or lymphoma, and also solid tumors such as melanoma, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, carcinoma of the thyroid, bile duct, bone, gastric, brain/CNS, head and neck, hepatic, stomach, prostate, breast, renal, testicular, ovarian, skin, cervical, lung, muscle, neuronal, oesophageal, bladder, lung, uterine, vulval, endometrial, kidney, colorectal, pancreatic, pleural/peritoneal membranes, salivary gland, and epidermoid tumors.

[0108] A compound refers to any small molecular weight compound with a molecular weight of less than about 2000 Daltons.

[0109] The term "Ang-2" refers to the molecule Angiopoietin-2.

[0110] The term "neutralizing" when referring to an antibody relates to the ability of an antibody to eliminate, or significantly reduce, the activity of a target antigen. Accordingly, a "neutralizing" anti-Ang-2 antibody is capable of eliminating or significantly reducing the activity of Ang-2. A neutralizing Ang-2 antibody may, for example, act by blocking the binding of Ang-2 to its receptor Tie2. By blocking this binding, the Tie2 mediated signal transduction is significantly, or completely, eliminated. Ideally, a neutralizing antibody against Ang-2 inhibits angiogenesis.

[0111] The term "isolated polynucleotide" as used herein shall mean a polynucleotide that has been isolated from its naturally occurring environment. Such polynucleotides may be genomic, cDNA, or synthetic. Isolated polynucleotides preferably are not associated with all or a portion of the polynucleotides they associate with in nature. The isolated polynucleotides may be operably linked to another polynucleotide that it is not linked to in nature. In addition, isolated polynucleotides preferably do not occur in nature as part of a larger sequence.

[0112] The term "isolated protein" referred to herein means a protein that has been isolated from its naturally occurring environment. Such proteins may be derived from genomic DNA, cDNA, recombinant DNA, recombinant RNA, or synthetic origin or some combination thereof, which by virtue of its origin, or source of derivation, the "isolated protein" (1) is not associated with proteins found in nature, (2) is free of other proteins from the same source, e.g. free of murine proteins, (3) is expressed by a cell from a different species, or (4) does not occur in nature.

[0113] The term "polypeptide" is used herein as a generic term to refer to native protein, fragments, or analogs of a polypeptide sequence. Hence, native protein, fragments, and analogs are species of the polypeptide genus. Preferred polypeptides in accordance with the invention comprise the human heavy chain immunoglobulin molecules and the human kappa light chain immunoglobulin molecules, as well as antibody molecules formed by combinations comprising the heavy chain immunoglobulin molecules with light chain immunoglobulin molecules, such as the kappa or lambda light chain immunoglobulin molecules, and vice versa, as well as fragments and analogs thereof. Preferred polypeptides in accordance with the invention may also comprise solely the human heavy chain immunoglobulin molecules or fragments thereof.

[0114] The term "naturally-occurring" as used herein as applied to an object refers to the fact that an object can be found in nature. For example, a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory or otherwise is naturally-occurring.

[0115] The term "operably linked" as used herein refers to positions of components so described that are in a relationship permitting them to function in their intended manner. For example, a control sequence "operably linked" to a coding sequence is connected in such a way that expression of the coding sequence is achieved under conditions compatible with the control sequences.

[0116] The term "control sequence" as used herein refers to polynucleotide sequences that are necessary either to effect or to affect the expression and processing of coding sequences to which they are connected. The nature of such control sequences differs depending upon the host organism; in prokaryotes, such control sequences generally include promoter, ribosomal binding site, and transcription termination sequence; in eukaryotes, generally, such control sequences may include promoters, enhancers, introns, transcription termination sequences, polyadenylation signal sequences, and 5' and 3' untranslated regions. The term "control sequences" is intended to include, at a minimum, all components whose presence is essential for expression and processing, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences.

[0117] The term "polynucleotide" as referred to herein means a polymeric form of nucleotides of at least 10 bases in length, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide, or RNA-DNA hetero-duplexes. The term includes single and double stranded forms of DNA.

[0118] The term "oligonucleotide" referred to herein includes naturally occurring, and modified nucleotides linked together by naturally occurring, and non-naturally occurring linkages. Oligonucleotides are a polynucleotide subset generally comprising a length of 200 bases or fewer. Preferably, oligonucleotides are 10 to 60 bases in length and most preferably 12, 13, 14, 15, 16, 17, 18, 19, or 20 to 40 bases in length. Oligonucleotides are usually single stranded, e.g. for probes; although oligonucleotides may be double stranded, e.g. for use in the construction of a gene mutant. Oligonucleotides can be either sense or antisense oligonucleotides.

[0119] The term "naturally occurring nucleotides" referred to herein includes deoxyribonucleotides and ribonucleotides. The term "modified nucleotides" referred to herein includes nucleotides with modified or substituted sugar groups and the like. The term "oligonucleotide linkages" referred to herein includes oligonucleotides linkages such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phosphoraniladate, phosphoroamidate, and the like. See e.g., LaPlanche et al. Nucl. Acids Res. 14:9081 (1986); Stec et al. J. Am. Chem. Soc. 106:6077 (1984); Stein et al. Nucl. Acids Res. 16:3209 (1988); Zon et al. Anti-Cancer Drug Design 6:539 (1991); Zon et al. Oligonucleotides and Analogues: A Practical Approach, pp. 87-108 (F. Eckstein, Ed., Oxford University Press, Oxford England (1991)); Stec et al. U.S. Pat. No. 5,151,510; Uhlmann and Peyman Chemical Reviews 90:543 (1990), the disclosures of which are hereby incorporated by reference. An oligonucleotide can include a label for detection, if desired.

[0120] The term "selectively hybridize" referred to herein means to detectably and specifically bind. Polynucleotides, oligonucleotides and fragments thereof selectively hybridize to nucleic acid strands under hybridization and wash conditions that minimize appreciable amounts of detectable binding to nonspecific nucleic acids. High stringency conditions can be used to achieve selective hybridization conditions as known in the art and discussed herein. Generally, the nucleic acid sequence homology between the polynucleotides, oligonucleotides, or antibody fragments and a nucleic acid sequence of interest will be at least 80%, and more typically with preferably increasing homologies of at least 85%, 90%, 95%, 99%, and 100%.

[0121] Two amino acid sequences are "homologous" if there is a partial or complete identity between their sequences. For example, 85% homology means that 85% of the amino acids are identical when the two sequences are aligned for maximum matching. Gaps (in either of the two sequences being matched) are allowed in maximizing matching; gap lengths of 5 or less are preferred with 2 or less being more preferred. Alternatively and preferably, two protein sequences (or polypeptide sequences derived from them of at least about 30 amino acids in length) are homologous, as this term is used herein, if they have an alignment score of at more than 5 (in standard deviation units) using the program ALIGN with the mutation data matrix and a gap penalty of 6 or greater. See Dayhoff, M. O., in Atlas of Protein Sequence and Structure, pp. 101-110 (Volume 5, National Biomedical Research Foundation (1972)) and Supplement 2 to this volume, pp. 1-10. The two sequences or parts thereof are more preferably homologous if their amino acids are greater than or equal to 50% identical when optimally aligned using the ALIGN program. It should be appreciated that there can be differing regions of homology within two orthologous sequences. For example, the functional sites of mouse and human orthologues may have a higher degree of homology than non-functional regions.

[0122] The term "corresponds to" is used herein to mean that a polynucleotide sequence is homologous (i.e., is identical, not strictly evolutionarily related) to all or a portion of a reference polynucleotide sequence, or that a polypeptide sequence is identical to a reference polypeptide sequence.

[0123] In contradistinction, the term "complementary to" is used herein to mean that the complementary sequence is homologous to all or a portion of a reference polynucleotide sequence. For illustration, the nucleotide sequence "TATAC" corresponds to a reference sequence "TATAC" and is complementary to a reference sequence "GTATA".

[0124] The following terms are used to describe the sequence relationships between two or more polynucleotide or amino acid sequences: "reference sequence", "comparison window", "sequence identity", "percentage of sequence identity", and "substantial identity". A "reference sequence" is a defined sequence used as a basis for a sequence comparison. A reference sequence may be a subset of a larger sequence, for example, as a segment of a full-length cDNA or gene sequence given in a sequence listing or may comprise a complete cDNA or gene sequence. Generally, a reference sequence is at least 18 nucleotides or 6 amino acids in length, frequently at least 24 nucleotides or 8 amino acids in length, and often at least 48 nucleotides or 16 amino acids in length. Since two polynucleotides or amino acid sequences may each (1) comprise a sequence (i.e., a portion of the complete polynucleotide or amino acid sequence) that is similar between the two molecules, and (2) may further comprise a sequence that is divergent between the two polynucleotides or amino acid sequences, sequence comparisons between two (or more) molecules are typically performed by comparing sequences of the two molecules over a "comparison window" to identify and compare local regions of sequence similarity. A "comparison window", as used herein, refers to a conceptual segment of at least about 18 contiguous nucleotide positions or about 6 amino acids wherein the polynucleotide sequence or amino acid sequence is compared to a reference sequence of at least 18 contiguous nucleotides or 6 amino acid sequences and wherein the portion of the polynucleotide sequence in the comparison window may include additions, deletions, substitutions, and the like (i.e., gaps) of 20 percent or less as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. Optimal alignment of sequences for aligning a comparison window may be conducted by the local homology algorithm of Smith and Waterman Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman and Wunsch J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson and Lipman Proc. Natl. Acad. Sci. (U.S.A.) 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, (Genetics Computer Group, 575 Science Dr., Madison, Wis.), GENEWORKS.TM., or MACVECTOR.RTM. software packages), or by inspection, and the best alignment (i.e., resulting in the highest percentage of homology over the comparison window) generated by the various methods is selected.

[0125] The term "sequence identity" means that two polynucleotide or amino acid sequences are identical (i.e., on a nucleotide-by-nucleotide or residue-by-residue basis) over the comparison window. The term "percentage of sequence identity" is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I) or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The terms "substantial identity" as used herein denotes a characteristic of a polynucleotide or amino acid sequence, wherein the polynucleotide or amino acid comprises a sequence that has at least 85 percent sequence identity, preferably at least 90 to 95 percent sequence identity, more preferably at least 99 percent sequence identity, as compared to a reference sequence over a comparison window of at least 18 nucleotide (6 amino acid) positions, frequently over a window of at least 24-48 nucleotide (8-16 amino acid) positions, wherein the percentage of sequence identity is calculated by comparing the reference sequence to the sequence which may include deletions or additions which total 20 percent or less of the reference sequence over the comparison window. The reference sequence may be a subset of a larger sequence.

[0126] As used herein, the twenty conventional amino acids and their abbreviations follow conventional usage. See Immunology--A Synthesis (2.sup.nd Edition, E. S. Golub and D. R. Gren, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference. Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids, unnatural amino acids such as .alpha.-, .alpha.-disubstituted amino acids, N-alkyl amino acids, lactic acid, and other unconventional amino acids may also be suitable components for polypeptides of the present invention. Examples of unconventional amino acids include: 4-hydroxyproline, .gamma.-carboxyglutamate, .epsilon.-N,N,N-trimethyllysine, .epsilon.-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, .sigma.-N-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the left-hand direction is the amino terminal direction and the right-hand direction is the carboxy-terminal direction, in accordance with standard usage and convention.

[0127] Similarly, unless specified otherwise, the left-hand end of single-stranded polynucleotide sequences is the 5' end; the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5' direction. The direction of 5' to 3' addition of nascent RNA transcripts is referred to as the transcription direction; sequence regions on the DNA strand having the same sequence as the RNA and which are 5' to the 5' end of the RNA transcript are referred to as "upstream sequences"; sequence regions on the DNA strand having the same sequence as the RNA and which are 3' to the 3' end of the RNA transcript are referred to as "downstream sequences".

[0128] As applied to polypeptides, the term "substantial identity" means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 80 percent sequence identity, preferably at least 90 percent sequence identity, more preferably at least 95 percent sequence identity, and most preferably at least 99 percent sequence identity. Preferably, residue positions that are not identical differ by conservative amino acid substitutions. Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains. For example, a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur-containing side chains is cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic-aspartic, and asparagine-glutamine.

[0129] As discussed herein, minor variations in the amino acid sequences of antibodies or immunoglobulin molecules are contemplated as being encompassed by the present invention, providing that the variations in the amino acid sequence maintain at least 75%, more preferably at least 80%, 90%, 95%, and most preferably 99% sequence identity to the antibodies or immunoglobulin molecules described herein. In particular, conservative amino acid replacements are contemplated. Conservative replacements are those that take place within a family of amino acids that have related side chains. Genetically encoded amino acids are generally divided into families: (1) acidic=aspartate, glutamate; (2) basic=lysine, arginine, histidine; (3) non-polar=alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan; and (4) uncharged polar=glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine. More preferred families are: serine and threonine are an aliphatic-hydroxy family; asparagine and glutamine are an amide-containing family; alanine, valine, leucine and isoleucine are an aliphatic family; and phenylalanine, tryptophan, and tyrosine are an aromatic family. For example, it is reasonable to expect that an isolated replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, a threonine with a serine, or a similar replacement of an amino acid with a structurally related amino acid will not have a major effect on the binding function or properties of the resulting molecule, especially if the replacement does not involve an amino acid within a framework site. Whether an amino acid change results in a functional peptide can readily be determined by assaying the specific activity of the polypeptide derivative. Assays are described in detail herein. Fragments or analogs of antibodies or immunoglobulin molecules can be readily prepared by those of ordinary skill in the art. Preferred amino- and carboxy-termini of fragments or analogs occur near boundaries of functional domains. Structural and functional domains can be identified by comparison of the nucleotide and/or amino acid sequence data to public or proprietary sequence databases. Preferably, computerized comparison methods are used to identify sequence motifs or predicted protein conformation domains that occur in other proteins of known structure and/or function. Methods to identify protein sequences that fold into a known three-dimensional structure are known. Bowie et al. Science 253:164 (1991). Thus, the foregoing examples demonstrate that those of skill in the art can recognize sequence motifs and structural conformations that may be used to define structural and functional domains in accordance with the antibodies described herein.

[0130] Preferred amino acid substitutions are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinities, and (4) confer or modify other physicochemical or functional properties of such analogs. Analogs can include various muteins of a sequence other than the naturally-occurring peptide sequence. For example, single or multiple amino acid substitutions (preferably conservative amino acid substitutions) may be made in the naturally-occurring sequence (preferably in the portion of the polypeptide outside the domain(s) forming intermolecular contacts. A conservative amino acid substitution should not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence). Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W.H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, N.Y. (1991)); and Thornton et al. Nature 354:105 (1991), which are each incorporated herein by reference.

[0131] The term "polypeptide fragment" as used herein refers to a polypeptide that has an amino-terminal and/or carboxy-terminal deletion, but where the remaining amino acid sequence is identical to the corresponding positions in the naturally-occurring sequence deduced, for example, from a full-length cDNA sequence. Fragments typically are at least 5, 6, 8 or 10 amino acids long, preferably at least 14 amino acids long, more preferably at least 20 amino acids long, usually at least 50 amino acids long, and even more preferably at least 70 amino acids long. The term "analog" as used herein refers to polypeptides which are comprised of a segment of at least 25 amino acids that has substantial identity to a portion of a deduced amino acid sequence and which has at least one of the following properties: (1) specific binding to a Ang-2, under suitable binding conditions, (2) ability to block appropriate Ang-2 binding, or (3) ability to inhibit Ang-2 activity. Typically, polypeptide analogs comprise a conservative amino acid substitution (or addition or deletion) with respect to the naturally-occurring sequence. Analogs typically are at least 20 amino acids long, preferably at least 50 amino acids long or longer, and can often be as long as a full-length naturally-occurring polypeptide.

[0132] Peptide analogs are commonly used in the pharmaceutical industry as non-peptide drugs with properties analogous to those of the template peptide. These types of non-peptide compound are termed "peptide mimetics" or "peptidomimetics". Fauchere, J. Adv. Drug Res. 15:29 (1986); Veber and Freidinger TINS p. 392 (1985); and Evans et al. J. Med. Chem. 30:1229 (1987), which are incorporated herein by reference. Such compounds are often developed with the aid of computerized molecular modeling. Peptide mimetics that are structurally similar to therapeutically useful peptides may be used to produce an equivalent therapeutic or prophylactic effect. Generally, peptidomimetics are structurally similar to a paradigm polypeptide (i.e., a polypeptide that has a biochemical property or pharmacological activity), such as human antibody, but have one or more peptide linkages optionally replaced by a linkage selected from the group consisting of: --CH.sub.2NH--, --CH.sub.2S--, --CH.sub.2--CH.sub.2--, --CH.dbd.CH-(cis and trans), --COCH.sub.2--, --CH(OH)CH.sub.2--, and --CH.sub.2SO--, by methods well known in the art. Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) may be used to generate more stable peptides. In addition, constrained peptides comprising a consensus sequence or a substantially identical consensus sequence variation may be generated by methods known in the art (Rizo and Gierasch Ann. Rev. Biochem. 61:387 (1992), incorporated herein by reference); for example, by adding internal cysteine residues capable of forming intramolecular disulfide bridges which cyclize the peptide.

[0133] As used herein, the term "antibody" refers to a polypeptide or group of polypeptides that are comprised of at least one binding domain that is formed from the folding of polypeptide chains having three-dimensional binding spaces with internal surface shapes and charge distributions complementary to the features of an antigenic determinant of an antigen. An antibody typically has a tetrameric form, comprising two identical pairs of polypeptide chains, each pair having one "light" and one "heavy" chain. The variable regions of each light/heavy chain pair form an antibody binding site.

[0134] As used herein, a "targeted binding agent" is an antibody, or binding fragment thereof, that preferentially binds to a target site. In one embodiment, the targeted binding agent is specific for only one target site. In other embodiments, the targeted binding agent is specific for more than one target site. In one embodiment, the targeted binding agent may be a monoclonal antibody and the target site may be an epitope.

[0135] "Binding fragments" of an antibody are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab').sub.2, Fv, and single-chain antibodies. An antibody other than a "bispecific" or "bifunctional" antibody is understood to have each of its binding sites identical. An antibody substantially inhibits adhesion of a receptor to a counter-receptor when an excess of antibody reduces the quantity of receptor bound to counter-receptor by at least about 20%, 40%, 60% or 80%, and more usually greater than about 85% (as measured in an in vitro competitive binding assay).

[0136] An antibody may be oligoclonal, a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a multi-specific antibody, a bi-specific antibody, a catalytic antibody, a chimeric antibody, a humanized antibody, a fully human antibody, an anti-idiotypic antibody and antibodies that can be labeled in soluble or bound form as well as fragments, variants or derivatives thereof, either alone or in combination with other amino acid sequences provided by known techniques. An antibody may be from any species. The term antibody also includes binding fragments of the antibodies of the invention; exemplary fragments include Fv, Fab, Fab', single stranded antibody (svFC), dimeric variable region (Diabody) and disulphide stabilized variable region (dsFv).

[0137] The term "epitope" includes any protein determinant capable of specific binding to an immunoglobulin or T-cell receptor. Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and may, but not always, have specific three-dimensional structural characteristics, as well as specific charge characteristics. An antibody is said to specifically bind an antigen when the dissociation constant is .ltoreq.1 .mu.M, preferably .ltoreq.100 nM and most preferably .ltoreq.10 nM.

[0138] The term "agent" is used herein to denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials.

[0139] "Active" or "activity" in regard to an Ang-2 polypeptide refers to a portion of an Ang-2 polypeptide that has a biological or an immunological activity of a native Ang-2 polypeptide. "Biological" when used herein refers to a biological function that results from the activity of the native Ang-2 polypeptide. A preferred Ang-2 biological activity includes, for example, Ang-2 induced angiogenesis.

[0140] "Mammal" when used herein refers to any animal that is considered a mammal. Preferably, the mammal is human.

[0141] Digestion of antibodies with the enzyme, papain, results in two identical antigen-binding fragments, known also as "Fab" fragments, and a "Fc" fragment, having no antigen-binding activity but having the ability to crystallize. Digestion of antibodies with the enzyme, pepsin, results in the a F(ab').sub.2 fragment in which the two arms of the antibody molecule remain linked and comprise two-antigen binding sites. The F(ab').sub.2 fragment has the ability to crosslink antigen.

[0142] "Fv" when used herein refers to the minimum fragment of an antibody that retains both antigen-recognition and antigen-binding sites.

[0143] "Fab" when used herein refers to a fragment of an antibody that comprises the constant domain of the light chain and the CH1 domain of the heavy chain.

[0144] The term "mAb" refers to monoclonal antibody.

[0145] "Liposome" when used herein refers to a small vesicle that may be useful for delivery of drugs that may include the Ang-2 polypeptide of the invention or antibodies to such an Ang-2 polypeptide to a mammal.

[0146] "Label" or "labeled" as used herein refers to the addition of a detectable moiety to a polypeptide, for example, a radiolabel, fluorescent label, enzymatic label chemiluminescent labeled or a biotinyl group. Radioisotopes or radionuclides may include .sup.3H, .sup.14C, .sup.15N, .sup.35S, .sup.90Y, .sup.99Tc, .sup.111In, .sup.125I, .sup.131I, fluorescent labels may include rhodamine, lanthanide phosphors or FITC and enzymatic labels may include horseradish peroxidase, .beta.-galactosidase, luciferase, alkaline phosphatase.

[0147] The term "pharmaceutical agent or drug" as used herein refers to a chemical compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient. Other chemistry terms herein are used according to conventional usage in the art, as exemplified by The McGraw-Hill Dictionary of Chemical Terms (Parker, S., Ed., McGraw-Hill, San Francisco (1985)), (incorporated herein by reference).

[0148] As used herein, "substantially pure" means an object species is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition), and preferably a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all macromolecular species present. Generally, a substantially pure composition will comprise more than about 80 percent of all macromolecular species present in the composition, more preferably more than about 85%, 90%, 95%, and 99%. Most preferably, the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species.

[0149] The term "patient" includes human and veterinary subjects.

Human Antibodies and Humanization of Antibodies

[0150] Human antibodies avoid some of the problems associated with antibodies that possess murine or rat variable and/or constant regions. The presence of such murine or rat derived proteins can lead to the rapid clearance of the antibodies or can lead to the generation of an immune response against the antibody by a patient. In order to avoid the utilization of murine or rat derived antibodies, fully human antibodies can be generated through the introduction of functional human antibody loci into a rodent, other mammal or animal so that the rodent, other mammal or animal produces fully human antibodies.

[0151] One method for generating fully human antibodies is through the use of XenoMouse.RTM. strains of mice that have been engineered to contain up to but less than 1000 kb-sized germline configured fragments of the human heavy chain locus and kappa light chain locus. See Mendez et al. Nature Genetics 15:146-156 (1997) and Green and Jakobovits J. Exp. Med. 188:483-495 (1998). The XenoMouse.RTM. strains are available from Abgenix, Inc. (Fremont, Calif.).

[0152] The production of the XenoMouse.RTM. strains of mice is further discussed and delineated in U.S. patent application Ser. Nos. 07/466,008, filed Jan. 12, 1990, 07/610,515, filed Nov. 8, 1990, 07/919,297, filed Jul. 24, 1992, 07/922,649, filed Jul. 30, 1992, 08/031,801, filed Mar. 15, 1993, 08/112,848, filed Aug. 27, 1993, 08/234,145, filed Apr. 28, 1994, 08/376,279, filed Jan. 20, 1995, 08/430, 938, filed Apr. 27, 1995, 08/464,584, filed Jun. 5, 1995, 08/464,582, filed Jun. 5, 1995, 08/463,191, filed Jun. 5, 1995, 08/462,837, filed Jun. 5, 1995, 08/486,853, filed Jun. 5, 1995, 08/486,857, filed Jun. 5, 1995, 08/486,859, filed Jun. 5, 1995, 08/462,513, filed Jun. 5, 1995, 08/724,752, filed Oct. 2, 1996, 08/759,620, filed Dec. 3, 1996, U.S. Publication 2003/0093820, filed Nov. 30, 2001 and U.S. Pat. Nos. 6,162,963, 6,150,584, 6,114,598, 6,075,181, and 5,939,598 and Japanese Patent Nos. 3 068 180 B2, 3 068 506 B2, and 3 068 507 B2. See also European Patent No., EP 0 463 151 B1, grant published Jun. 12, 1996, International Patent Application No., WO 94/02602, published Feb. 3, 1994, International Patent Application No., WO 96/34096, published Oct. 31, 1996, WO 98/24893, published Jun. 11, 1998, WO 00/76310, published Dec. 21, 2000. The disclosures of each of the above-cited patents, applications, and references are hereby incorporated by reference in their entirety.

[0153] In an alternative approach, others, including GenPharm International, Inc., have utilized a "minilocus" approach. In the minilocus approach, an exogenous Ig locus is mimicked through the inclusion of pieces (individual genes) from the Ig locus. Thus, one or more V.sub.H genes, one or more D.sub.H genes, one or more J.sub.H genes, a mu constant region, and usually a second constant region (preferably a gamma constant region) are formed into a construct for insertion into an animal. This approach is described in U.S. Pat. No. 5,545,807 to Surani et al. and U.S. Pat. Nos. 5,545,806, 5,625,825, 5,625,126, 5,633,425, 5,661,016, 5,770,429, 5,789,650, 5,814,318, 5,877,397, 5,874,299, and 6,255,458 each to Lonberg and Kay, U.S. Pat. Nos. 5,591,669 and 6,023.010 to Krimpenfort and Berns, U.S. Pat. Nos. 5,612,205, 5,721,367, and 5,789,215 to Berns et al., and U.S. Pat. No. 5,643,763 to Choi and Dunn, and GenPharm International U.S. patent application Ser. No. 07/574,748, filed Aug. 29, 1990, 07/575,962, filed Aug. 31, 1990, 07/810,279, filed Dec. 17, 1991, 07/853,408, filed Mar. 18, 1992, 07/904,068, filed Jun. 23, 1992, 07/990,860, filed Dec. 16, 1992, 08/053,131, filed Apr. 26, 1993, 08/096,762, filed Jul. 22, 1993, 08/155,301, filed Nov. 18, 1993, 08/161,739, filed Dec. 3, 1993, 08/165,699, filed Dec. 10, 1993, 08/209,741, filed Mar. 9, 1994, the disclosures of which are hereby incorporated by reference. See also European Patent No. 0 546 073 B1, International Patent Application Nos. WO 92/03918, WO 92/22645, WO 92/22647, WO 92/22670, WO 93/12227, WO 94/00569, WO 94/25585, WO 96/14436, WO 97/13852, and WO 98/24884 and U.S. Pat. No. 5,981,175, the disclosures of which are hereby incorporated by reference in their entirety. See further Taylor et al., 1992, Chen et al., 1993, Tuaillon et al., 1993, Choi et al., 1993, Lonberg et al., (1994), Taylor et al., (1994), and Tuaillon et al., (1995), Fishwild et al., (1996), the disclosures of which are hereby incorporated by reference in their entirety.

[0154] Kirin has also demonstrated the generation of human antibodies from mice in which, through microcell fusion, large pieces of chromosomes, or entire chromosomes, have been introduced. See European Patent Application Nos. 773 288 and 843 961, the disclosures of which are hereby incorporated by reference. Additionally, KM.TM.-mice, which are the result of cross-breeding of Kirin's Tc mice with Medarex's minilocus (Humab) mice have been generated. These mice possess the human IgH transchromosome of the Kirin mice and the kappa chain transgene of the Genpharm mice (Ishida et al., Cloning Stem Cells, (2002) 4:91-102).

[0155] Human antibodies can also be derived by in vitro methods. Suitable examples include but are not limited to phage display (CAT, Morphosys, Dyax, Biosite/Medarex, Xoma, Symphogen, Alexion (formerly Proliferon), Affimed) ribosome display (CAT), yeast display, and the like.

Preparation of Antibodies

[0156] Antibodies, as described herein, were prepared through the utilization of the XenoMouse.RTM. technology, as described below. Such mice, then, are capable of producing human immunoglobulin molecules and antibodies and are deficient in the production of murine immunoglobulin molecules and antibodies. Technologies utilized for achieving the same are disclosed in the patents, applications, and references disclosed in the background section herein. In particular, however, a preferred embodiment of transgenic production of mice and antibodies therefrom is disclosed in U.S. patent application Ser. No. 08/759,620, filed Dec. 3, 1996 and International Patent Application Nos. WO 98/24893, published Jun. 11, 1998 and WO 00/76310, published Dec. 21, 2000, the disclosures of which are hereby incorporated by reference. See also Mendez et al. Nature Genetics 15:146-156 (1997), the disclosure of which is hereby incorporated by reference.

[0157] Through the use of such technology, fully human monoclonal antibodies to a variety of antigens have been produced. Essentially, XenoMouse.RTM. lines of mice are immunized with an antigen of interest (e.g. Ang-2), lymphatic cells (such as B-cells) are recovered from the hyper-immunized mice, and the recovered lymphocytes are fused with a myeloid-type cell line to prepare immortal hybridoma cell lines. These hybridoma cell lines are screened and selected to identify hybridoma cell lines that produced antibodies specific to the antigen of interest. Provided herein are methods for the production of multiple hybridoma cell lines that produce antibodies specific to Ang-1 and Ang-2. Further, provided herein are characterization of the antibodies produced by such cell lines, including nucleotide and amino acid sequence analyses of the heavy and light chains of such antibodies.

[0158] Alternatively, instead of being fused to myeloma cells to generate hybridomas, B cells can be directly assayed. For example, CD19+ B cells can be isolated from hyperimmune XenoMouse.RTM. mice and allowed to proliferate and differentiate into antibody-secreting plasma cells. Antibodies from the cell supernatants are then screened by ELISA for reactivity against the Ang-2 immunogen. The supernatants might also be screened for immunoreactivity against fragments of Ang-2 to further map the different antibodies for binding to domains of functional interest on Ang-2. The antibodies may also be screened against Ang-1, Ang-3 or Ang-4, other related human chemokines and against the rat, the mouse, and non-human primate, such as Cynomolgus monkey, orthologues of Ang-2, the last to determine species cross-reactivity. B cells from wells containing antibodies of interest may be immortalized by various methods including fusion to make hybridomas either from individual or from pooled wells, or by infection with EBV or transfection by known immortalizing genes and then plating in suitable medium. Alternatively, single plasma cells secreting antibodies with the desired specificities are then isolated using an Ang-1 or Ang-2-specific hemolytic plaque assay (see for example Babcook et al., Proc. Natl. Acad. Sci. USA 93:7843-48 (1996)). Cells targeted for lysis are preferably sheep red blood cells (SRBCs) coated with the Ang-2 antigen. In screening for an antibody also able to antagonize Angiopoietin-1 the above methods can equally be used substituting Angiopoietin-2 with Angiopoietin-1.

[0159] In the presence of a B-cell culture containing plasma cells secreting the immunoglobulin of interest and complement, the formation of a plaque indicates specific Ang-1/Ang-2-mediated lysis of the sheep red blood cells surrounding the plasma cell of interest. The single antigen-specific plasma cell in the center of the plaque can be isolated and the genetic information that encodes the specificity of the antibody is isolated from the single plasma cell. Using reverse-transcription followed by PCR (RT-PCR), the DNA encoding the heavy and light chain variable regions of the antibody can be cloned. Such cloned DNA can then be further inserted into a suitable expression vector, preferably a vector cassette such as a pcDNA, more preferably such a pcDNA vector containing the constant domains of immunglobulin heavy and light chain. The generated vector can then be transfected into host cells, e.g., HEK293 cells, CHO cells, and cultured in conventional nutrient media modified as appropriate for inducing transcription, selecting transformants, or amplifying the genes encoding the desired sequences.

[0160] In general, antibodies produced by the fused hybridomas were human IgG2 heavy chains with fully human kappa or lambda light chains. Antibodies described herein possess human IgG4 heavy chains as well as IgG2 heavy chains. Antibodies can also be of other human isotypes, including IgG1. The antibodies possessed high affinities, typically possessing a Kd of from about 10.sup.-6 through about 10.sup.-12 M or below, when measured by solid phase and solution phase techniques. Antibodies possessing a KD of at least 10.sup.-11 M are preferred to inhibit the activity of Ang-1 and/or Ang-2.

[0161] As will be appreciated, antibodies can be expressed in cell lines other than hybridoma cell lines. Sequences encoding particular antibodies can be used to transform a suitable mammalian host cell. Transformation can be by any known method for introducing polynucleotides into a host cell, including, for example packaging the polynucleotide in a virus (or into a viral vector) and transducing a host cell with the virus (or vector) or by transfection procedures known in the art, as exemplified by U.S. Pat. Nos. 4,399,216, 4,912,040, 4,740,461, and 4,959,455 (which patents are hereby incorporated herein by reference). The transformation procedure used depends upon the host to be transformed. Methods for introducing heterologous polynucleotides into mammalian cells are well known in the art and include dextran-mediated transfection, calcium phosphate precipitation, polybrene mediated transfection, protoplast fusion, electroporation, encapsulation of the polynucleotide(s) in liposomes, and direct microinjection of the DNA into nuclei.

[0162] Mammalian cell lines available as hosts for expression are well known in the art and include many immortalized cell lines available from the American Type Culture Collection (ATCC), including but not limited to Chinese hamster ovary (CHO) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), human epithelial kidney 293 cells, and a number of other cell lines. Cell lines of particular preference are selected through determining which cell lines have high expression levels and produce antibodies with constitutive Ang-2 binding properties.

[0163] Based on the ability of mAbs to significantly neutralize Angiopoietin-1 and Angiopoietin-2 activity (as demonstrated in the Examples below), these antibodies will have therapeutic effects in treating symptoms and conditions resulting from Angiopoietin-1 and/or Angiopoietin-2 expression. In specific embodiments, the antibodies and methods herein relate to the treatment of symptoms resulting from Angiopoietin-1 and/or Angiopoietin-2 induced angiogenesis.

[0164] According to another aspect of the invention there is provided a pharmaceutical composition comprising an antagonist of the biological activity of Angiopoietin-1 and Angiopoietin-2, and a pharmaceutically acceptable carrier. In one embodiment the antagonist comprises an antibody. According to another aspect of the invention there is provided a pharmaceutical composition comprising an antagonist of the biological activity of Angiopoietin-2, and a pharmaceutically acceptable carrier. In one embodiment the antagonist comprises an antibody.

[0165] Anti-Ang-2 antibodies are useful in the detection of Ang-2 in patient samples and accordingly are useful as diagnostics for disease states as described herein. In addition, based on their ability to significantly neutralize Ang-2 activity (as demonstrated in the Examples below), anti-Ang-2 antibodies have therapeutic effects in treating symptoms and conditions resulting from Ang-2 expression. In specific embodiments, the antibodies and methods herein relate to the treatment of symptoms resulting from Ang-2 induced angiogenesis. Further embodiments involve using the antibodies and methods described herein to treat angiogenesis-related diseases including neoplastic diseases, such as, melanoma, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, thyroid tumor, gastric (stomach) cancer, prostate cancer, breast cancer, ovarian cancer, bladder cancer, lung cancer, glioblastoma, endometrial cancer, kidney cancer, colon cancer, and pancreatic cancer.

Therapeutic Administration and Formulations

[0166] Embodiments of the invention include sterile pharmaceutical formulations of anti-Ang-2 antibodies or antibodies which bind to both Ang-1 and Ang-2 that are useful as treatments for diseases. Such formulations would inhibit the binding of Ang-2 or Ang-1 and Ang-2 to its receptor Tie2, thereby effectively treating pathological conditions where, for example, serum or tissue Ang-1 and/or Ang-2 is abnormally elevated. Anti-Ang-2 antibodies preferably possess adequate affinity to potently neutralize Ang-2, and preferably have an adequate duration of action to allow for infrequent dosing in humans. Anti-Ang-1/Ang-2 antibodies preferably possess adequate affinity to potently neutralize Ang-1 and Ang-2, and preferably have an adequate duration of action to allow for infrequent dosing in humans. A prolonged duration of action will allow for less frequent and more convenient dosing schedules by alternate parenteral routes such as subcutaneous or intramuscular injection.

[0167] Sterile formulations can be created, for example, by filtration through sterile filtration membranes, prior to or following lyophilization and reconstitution of the antibody. The antibody ordinarily will be stored in lyophilized form or in solution. Therapeutic antibody compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having an adapter that allows retrieval of the formulation, such as a stopper pierceable by a hypodermic injection needle.

[0168] The route of antibody administration is in accord with known methods, e.g., injection or infusion by intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial, intrathecal, inhalation or intralesional routes, or by sustained release systems as noted below. The antibody is preferably administered continuously by infusion or by bolus injection.

[0169] An effective amount of antibody to be employed therapeutically will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the patient. Accordingly, it is preferred that the therapist titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. Typically, the clinician will administer antibody until a dosage is reached that achieves the desired effect. The progress of this therapy is easily monitored by conventional assays or by the assays described herein.

[0170] Antibodies, as described herein, can be prepared in a mixture with a pharmaceutically acceptable carrier. This therapeutic composition can be administered intravenously or through the nose or lung, preferably as a liquid or powder aerosol (lyophilized). The composition may also be administered parenterally or subcutaneously as desired. When administered systemically, the therapeutic composition should be sterile, pyrogen-free and in a parenterally acceptable solution having due regard for pH, isotonicity, and stability. These conditions are known to those skilled in the art. Briefly, dosage formulations of the compounds described herein are prepared for storage or administration by mixing the compound having the desired degree of purity with physiologically acceptable carriers, excipients, or stabilizers. Such materials are non-toxic to the recipients at the dosages and concentrations employed, and include buffers such as TRIS HCl, phosphate, citrate, acetate and other organic acid salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidinone; amino acids such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium and/or nonionic surfactants such as TWEEN, PLURONICS or polyethyleneglycol.

[0171] Sterile compositions for injection can be formulated according to conventional pharmaceutical practice as described in Remington: The Science and Practice of Pharmacy (20.sup.th ed, Lippincott Williams & Wilkens Publishers (2003)). For example, dissolution or suspension of the active compound in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired. Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.

[0172] Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the polypeptide, which matrices are in the form of shaped articles, films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) as described by Langer et al., J. Biomed Mater. Res., (1981) 15:167-277 and Langer, Chem. Tech., (1982) 12:98-105, or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al., Biopolymers, (1983) 22:547-556), non-degradable ethylene-vinyl acetate (Langer et al., supra), degradable lactic acid-glycolic acid copolymers such as the LUPRON Depot.TM. (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid (EP 133,988).

[0173] While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated proteins remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37.degree. C., resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for protein stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S--S bond formation through disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.

[0174] Sustained-released compositions also include preparations of crystals of the antibody suspended in suitable formulations capable of maintaining crystals in suspension. These preparations when injected subcutaneously or intraperitonealy can produce a sustained release effect. Other compositions also include liposomally entrapped antibodies. Liposomes containing such antibodies are prepared by methods known per se: U.S. Pat. No. DE 3,218,121; Epstein et al., Proc. Natl. Acad. Sci. USA, (1985) 82:3688-3692; Hwang et al., Proc. Natl. Acad. Sci. USA, (1980) 77:4030-4034; EP 52,322; EP 36,676; EP 88,046; EP 143,949; 142,641; Japanese patent application 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324.

[0175] The dosage of the antibody formulation for a given patient will be determined by the attending physician taking into consideration various factors known to modify the action of drugs including severity and type of disease, body weight, sex, diet, time and route of administration, other medications and other relevant clinical factors. Therapeutically effective dosages may be determined by either in vitro or in vivo methods.

[0176] An effective amount of the antibodies, described herein, to be employed therapeutically will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the patient. Accordingly, it is preferred for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. A typical daily dosage might range from about 0.001 mg/kg to up to 100 mg/kg or more, depending on the factors mentioned above. Typically, the clinician will administer the therapeutic antibody until a dosage is reached that achieves the desired effect. The progress of this therapy is easily monitored by conventional assays or as described herein.

[0177] It will be appreciated that administration of therapeutic entities in accordance with the compositions and methods herein will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as Lipofectin.TM.), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. Any of the foregoing mixtures may be appropriate in treatments and therapies in accordance with the present invention, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration. See also Baldrick P. "Pharmaceutical excipient development: the need for preclinical guidance." Regul. Toxicol. Pharmacol. 32(2):210-8 (2000), Wang W. "Lyophilization and development of solid protein pharmaceuticals." Int. J. Pharm. 203(1-2):1-60 (2000), Charman W N "Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts." J Pharm Sci. 89(8):967-78 (2000), Powell et al. "Compendium of excipients for parenteral formulations" PDA J Pharm Sci Technol. 52:238-311 (1998) and the citations therein for additional information related to formulations, excipients and carriers well known to pharmaceutical chemists.

Combinations

[0178] The anti-angiogenic treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti tumor agents:

[0179] (i) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5* reductase such as finasteride;

[0180] (ii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);

[0181] (iii) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti erbb2 antibody trastuzumab [Herceptin.TM.] and the anti erbb1 antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N (3 chloro 4 fluorophenyl) 7 methoxy 6 (3 morpholinopropoxy)quinazolin 4 amine (gefitinib, AZD1839), N (3 ethynylphenyl) 6,7 bis (2 methoxyethoxy)quinazolin 4 amine (erlotinib, OSI 774) and 6 acrylamido N (3 chloro 4 fluorophenyl) 7 (3 morpholinopropoxy)quinazolin 4 amine (CI 1033)), for example inhibitors of the platelet derived growth factor family and for example inhibitors of the hepatocyte growth factor family;

[0182] (iv) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti vascular endothelial cell growth factor antibody bevacizumab [Avastin.TM.], anti-vascular endothelial growth factor receptor antibodies such anti-KDR antibodies and anti-flt1 antibodies, compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/3285, WO 98/13354, WO00/47212 and WO01/32651) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin avb3 function and angiostatin);

[0183] (v) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

[0184] (vi) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti ras antisense;

[0185] (vii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene directed enzyme pro drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi drug resistance gene therapy; and

[0186] (viii) immunotherapy approaches, including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy, approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using anti idiotypic antibodies.

[0187] In one embodiment of the invention the anti-angiogenic treatments of the invention are combined with agents which inhibit the effects of vascular endothelial growth factor (VEGF), (for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin.RTM.), anti-vascular endothelial growth factor receptor antibodies such anti-KDR antibodies and anti-flt1 antibodies, compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/3285, WO 98/13354, WO00/47212 and WO01/32651) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin avb3 function and angiostatin); In another embodiment of the invention the anti-angiogenic treatments of the invention are combined agents which inhibit the tyrosine kinase activity of the vascular endothelial growth factor receptor, KDR (for example AZD2171 or AZD6474). Additional details on AZD2171 may be found in Wedge et al (2005) Cancer Research. 65(10):4389-400. Additional details on AZD6474 may be found in Ryan & Wedge (2005) British Journal of Cancer. 92 Suppl 1:S6-13. Both publications are herein incorporated by reference in their entireties. In another embodiment of the invention the fully human antibodies 3.19.3, 3.3.2 or 5.88.3 are combined alone or in combination with Avastin.TM., AZD2171 or AZD6474.

[0188] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically active agent within its approved dosage range.

EXAMPLES

[0189] The following examples, including the experiments conducted and results achieved are provided for illustrative purposes only and are not to be construed as limiting upon the teachings herein.

Example 1

Immunization and Titering

Immunization

[0190] Recombinant human Ang-2 obtained from R&D Systems, Inc. (Minneapolis, Minn. Cat. No. 623-AM/CF) was used as an antigen. Monoclonal antibodies against Ang-2 were developed by sequentially immunizing XenoMouse.RTM. mice (XenoMouse strains XMG2 and XMG4 (3C-1 strain), Abgenix, Inc. Fremont, Calif.). XenoMouse animals were immunized via footpad route for all injections. The total volume of each injection was 50 .mu.l per mouse, 25 .mu.l per footpad. The first injection was with 2.35 .mu.g recombinant human Ang-2 (rhAng-2, cat#623-AM/CF; lot #BN023202A) in pyrogen-free Dulbecco's PBS (DPBS) and admixed 1:1 v/v with 10 .mu.g CpG (15 .mu.l of ImmunEasy Mouse Adjuvant, catalog #303101; lot #11553042; Qiagen) per mouse. The next 6 boosts were with 2.35 .mu.g rhANG-2 in pyrogen-free DPBS, admixed with 25 .mu.g of Adju-Phos (aluminum phosphate gel, Catalog #1452-250, batch #8937, HCl Biosector) and 10 .mu.g CpG per mouse, followed by a final boost of 2.35 .mu.g rhAng-2 in pyrogen-free DPBS, without adjuvant. The XenoMouse mice were immunized on days 0, 3, 6, 10, 13, 17, 20, and 24 for this protocol and fusions were performed on day 29.

Selection of Animals for Harvest by Titer

[0191] Anti-Ang-2 antibody titers in the serum from immunized XenoMouse mice were determined by ELISA. Briefly, recombinant Ang-2 (1 .mu.g/ml) was coated onto Costar Labcoat Universal Binding Polystyrene 96-well plates (Corning, Acton, Mass.) overnight at four degrees in Antigen Coating Buffer (0.1 M Carbonate Buffer, pH 9.6 NaHCO.sub.3 8.4 g/L). The next day, the plates were washed 3 times with washing buffer (0.05% Tween 20 in 1.times.PBS) using a Biotek plate washer. The plates were then blocked with 200 .mu.l/well blocking buffer (0.5% BSA, 0.1% Tween 20, 0.01% Thimerosal in 1.times.PBS) and incubated at room temperature for 1 h. After the one-hour blocking, the plates were washed 3 times with washing buffer using a Biotek plate washer. Sera from either Ang-2 immunized XenoMouse mice or naive XenoMouse animals were titrated in 0.5% BSA/PBS buffer at 1:3 dilutions in duplicate from a 1:100 initial dilution. The last well was left blank. These plates were incubated at room temperature for 2 hr, and the plates were then washed 3 times with washing buffer using a Biotek plate washer. A goat anti-human IgG Fc-specific horseradish peroxidase (HRP, Pierce, Rockford, Ill.) conjugated antibody was added at a final concentration of 1 .mu.g/ml and incubated for 1 hour at room temperature. Then the plates were washed 3 times with washing buffer using a Biotek plate washer.

[0192] After washing, the plates were developed with the addition of TMB chromogenic substrate (BioFx BSTP-0100-01) for 10-20 min or until negative control wells start to show color. Then the ELISA was stopped by the addition of Stop Solution (650 nM Stop reagent for TMB (BioFx BSTP-0100-01), reconstituted with 100 ml H.sub.2O per bottle). The specific titer of each XenoMouse animal was determined from the optical density at 650 nm and is shown in Tables 2 and 3 below. The titer value is the reciprocal of the greatest dilution of sera with an OD reading two-fold that of background. Therefore, the higher the number, the greater was the humoral immune response to Ang-2.

TABLE-US-00002 TABLE 2 Group 1: 10 mice (XMG2 strain) After 4 injections After 6 injections Reactivity to rhAng-2 Mouse ID Titers via hIgG O825-1 92,000 231,000 O825-2 56,000 212,000 O825-3 73,000 331,000 O825-4 16,000 175,000 O825-5 95,000 236,000 O825-6 27,000 119,000 O825-7 100,000 239,000 O825-8 25,000 165,000 O825-9 68,000 136,000 O825-10 120,000 264,000 NC 35 65 PC Sensitivity: 10 ng/ml Sensitivity: 9 ng/ml * NC = xmg2 strain, ova gp2, fp * PC = goat AB, anti-huAng-2 (R&D Systems, Catalog No. AF623) 1 mg/ml

TABLE-US-00003 TABLE 3 Group 2: 10 mice (XMG4 strain) After 4 injections After 6 injections Reactivity to rhAng-2 Mouse ID Titers via hIgG O824-1 750 4,600 O824-2 200 5,800 O824-3 500 7,400 O824-4 225 4,700 O824-5 300 5,800 O824-6 550 7,400 O824-7 1,600 11,000 O824-8 45 2,400 O824-9 600 6,900 O824-10 225 2,300 NC <100 35 PC Sensitivity: 12 ng/ml Sensitivity: 8 ng/ml * NC = 3c-1 N128-3 * PC = goat AB, anti-huAng-2 (R&D Systems, Catalog No. AF623) 1 mg/ml

Example 2

Recovery of Lymphocytes, B-Cell Isolations, Fusions and Generation of Hybridomas

[0193] Immunized mice were sacrificed by cervical dislocation, and the draining lymph nodes harvested and pooled from each cohort. The lymphoid cells were dissociated by grinding in DMEM to release the cells from the tissues and the cells were suspended in DMEM. The cells were counted, and 0.9 ml DMEM per 100 million lymphocytes added to the cell pellet to resuspend the cells gently but completely. Using 100 .mu.l of CD90+ magnetic beads per 100 million cells, the cells were labeled by incubating the cells with the magnetic beads at 4.degree. C. for 15 minutes. The magnetically labeled cell suspension containing up to 10.sup.8 positive cells (or up to 2.times.10.sup.9 total cells) was loaded onto a LS+ column and the column washed with DMEM. The total effluent was collected as the CD90-negative fraction (most of these cells were expected to be B cells).

[0194] The fusion was performed by mixing washed enriched B cells from above and nonsecretory myeloma P3X63Ag8.653 cells purchased from ATCC, cat. # CRL 1580 (Kearney et al, J. Immunol. 123, 1979, 1548-1550) at a ratio of 1:1. The cell mixture was gently pelleted by centrifugation at 800.times.g. After complete removal of the supernatant, the cells were treated with 2-4 mL of Pronase solution (CalBiochem, cat. #53702; 0.5 mg/ml in PBS) for no more than 2 minutes. Then 3-5 ml of FBS was added to stop the enzyme activity and the suspension was adjusted to 40 ml total volume using electro cell fusion solution, (ECFS, 0.3M Sucrose, Sigma, Cat# S7903, 0.1 mM Magnesium Acetate, Sigma, Cat# M2545, 0.1 mM Calcium Acetate, Sigma, Cat# C4705). The supernatant was removed after centrifugation and the cells were resuspended in 40 ml ECFS. This wash step was repeated and the cells again were resuspended in ECFS to a concentration of 2.times.10.sup.6 cells/ml.

[0195] Electro-cell fusion was performed using a fusion generator(model ECM2001, Genetronic, Inc., San Diego, Calif.). The fusion chamber size used was 2.0 ml, using the following instrument settings:

[0196] Alignment condition: voltage: 50 V, time: 50 sec.

[0197] Membrane breaking at: voltage: 3000 V, time: 30 .mu.sec

[0198] Post-fusion holding time: 3 sec

[0199] After ECF, the cell suspensions were carefully removed from the fusion chamber under sterile conditions and transferred into a sterile tube containing the same volume of Hybridoma Culture Medium (DMEM, JRH Biosciences), 15% FBS (Hyclone), supplemented with L-glutamine, pen/strep, OPI (oxaloacetate, pyruvate, bovine insulin) (all from Sigma) and IL-6 (Boehringer Mannheim). The cells were incubated for 15-30 minutes at 37.degree. C., and then centrifuged at 400.times.g (1000 rpm) for five minutes. The cells were gently resuspended in a small volume of Hybridoma Selection Medium (Hybridoma Culture Medium supplemented with 0.5.times.HA (Sigma, cat. # A9666)), and the volume adjusted appropriately with more Hybridoma Selection Medium, based on a final plating of 5.times.10.sup.6 B cells total per 96-well plate and 200 .mu.l per well. The cells were mixed gently and pipetted into 96-well plates and allowed to grow. On day 7 or 10, one-half the medium was removed, and the cells re-fed with Hybridoma Selection Medium.

Example 3

Selection of Candidate Antibodies by ELISA

[0200] After 14 days of culture, hybridoma supernatants were screened for Ang-2-specific monoclonal antibodies. The ELISA plates (Fisher, Cat. No. 12-565-136) were coated with 50 .mu.l/well of human Ang-2 (2 .mu.g/ml) in Coating Buffer (0.1 M Carbonate Buffer, pH 9.6, NaHCO.sub.3 8.4 g/L), then incubated at 4.degree. C. overnight. After incubation, the plates were washed with Washing Buffer (0.05% Tween 20 in PBS) 3 times. 200 .mu.l/well Blocking Buffer (0.5% BSA, 0.1% Tween 20, 0.01% Thimerosal in 1.times.PBS) were added and the plates incubated at room temperature for 1 hour. After incubation, the plates were washed with Washing Buffer three times. 50 .mu.l/well of hybridoma supernatants, and positive and negative controls were added and the plates incubated at room temperature for 2 hours. The positive control used throughout was serum from the Ang-2 immunized XenoMouse mouse, XMG2 Ang-2 Group 1, footpad (fp) N160-7, and the negative control was serum from the KLH-immunized XenoMouse mouse, XMG2 KLH Group 1, footpad (fp) L627-6.

[0201] After incubation, the plates were washed three times with Washing Buffer. 100 .mu.l/well of detection antibody goat anti-huIgGFc-HRP (Caltag, Cat. No. H10507), was added and the plates incubated at room temperature for 1 hour. In the secondary screen, the positives in first screening were screened in two sets, one for hIgG detection and the other for human Ig kappa light chain detection (goat anti-hIg kappa-HRP (Southern Biotechnology, Cat. No. 2060-05) in order to demonstrate fully human composition for both IgG and Ig kappa. After incubation, the plates were washed three times with Washing Buffer. 100 .mu.l/well of TMB (BioFX Lab. Cat. No. TMSK-0100-01) were added and the plates allowed to develop for about 10 minutes (until negative control wells barely started to show color). 50 .mu.l/well stop solution (TMB Stop Solution, (BioFX Lab. Cat. No. STPR-0100-01) was then added and the plates read on an ELISA plate reader at 450 nm. There were 185 fully human IgG kappa antibodies against Ang-2.

[0202] All antibodies that bound in the ELISA assay were counter screened for binding to Ang-1 by ELISA in order to exclude those that cross-reacted with Ang-1. The ELISA plates (Fisher, Cat. No. 12-565-136) were coated with 50 .mu.l/well of recombinant Ang-1 (2 .mu.g/ml, obtained from R&D Systems, Cat. #293-AN-025/CF) in Coating Buffer (0.1 M Carbonate Buffer, pH 9.6, NaHCO.sub.3 8.4 g/L), then incubated at 4.degree. C. overnight. Under the experimental conditions described here, when the recombinant Ang-1 molecule was immobilized on the ELISA plate, no antibodies were found to bind to Ang-1. However, the counter screening described here has technical limitations. First, the antibodies derive from line materials, but not a cloned hybridoma. Binding signals from a particular clone, which only account for a minor percentage of the line, may fall below the detection sensitivity threshold. Second, certain epitopes in the antigen may be concealed from the antibodies in this experiment due to slight conformational changes induced by immobilization of the antigen. For all of these reasons, the cross-reactivity of each antibody to Ang-1 was further examined using cloned antibodies and a Biacore system (see Example 8). As described in Example 8, one clone (mAb 3.19.3) was in fact found to have strong cross-reactivity to human recombinant Ang-1 (Examples 8, 9 and 12).

Example 4

Inhibition of ANG-2 Binding to Tie2

[0203] As discussed above, Ang-2 exerts its biological effect by binding to the Tie2 receptor. Monoclonal antibodies that inhibited Ang-2/Tie2 binding were identified by a competitive binding assay using a modified ELISA. The mAbs used were products of micro-purification from 50 ml of exhaustive supernatants of the hybridoma pools that were specific for Ang-2 (see Example 3). 96-well Nunc Immplates.TM. were coated with 100 .mu.l of recombinant human Tie2/Fc fusion protein (R&D Systems, Inc., Cat. No. 313-TI-100) at 4 .mu.g/ml by incubating overnight at 4.degree. C. The plates were washed four times using Phosphate Buffer Saline (PBS) with a Skan.TM. Washer 300 station (SKATRON). The wells were blocked by 100 .mu.l of ABX-blocking buffer (0.5% BSA, 0.1% Tween, 0.01% Thimerosal in PBS) for 1 hour.

[0204] Biotinylated recombinant human Ang-2 (R&D Systems, Inc. Cat. No. BT623) at 100 ng/ml was added in each well with or without the anti Ang-2 mAbs at 100 .mu.g/ml. The plates were incubated at room temperature for two hours before the unbound molecules were washed off. Bound biotinylated Ang-2 was then detected using 100 .mu.l/well of Streptavidin-HRP conjugate at 1:200 by incubating at room temperature for half an hour. After washing twice, the bound Streptavidin was detected by HRP substrate (R&D Systems, Cat. No. DY998). The plates were incubated for 30 minutes before 450 stop solution (100 .mu.l/well, BioFX, Cat# BSTP-0100-01) was added to terminate the reaction. The light absorbance at 450 nm was determined by a Spectramax Plus reader.

[0205] Soluble recombinant Tie2/Fc fusion protein at 10-fold molar excess to Ang-2 was used as a positive control. At this concentration, Tie2/Fc inhibited binding of Ang-2 to immobilized Tie2 by 80%. With this as an arbitrary criterion, 74 out of 175 Ang-2 binding mAbs showed inhibitory activity. For the convenience of operation, the top 27 neutralizers were selected for subsequent hybridoma cloning.

[0206] Each hybridoma was cloned using a limited dilution method by following standard procedures. Three sister clones were collected from each hybridoma. For each clone, the supernatant was tested using ELISA binding to human Ang-2 and counter binding to Ang-1, as described above, to ensure that each antibody was only specific for Ang-2. Concentrations of IgG in the exhaustive supernatants were determined, and one clone with the highest yield among the three sister clones from each hybridoma was selected for IgG purification. 0.5 to 1 mg of IgG was purified from each supernatant for further characterization.

[0207] To quantitate the inhibitory activities of the mAbs on Ang-2 binding to Tie2, the titer was determined for purified mAbs from the top 27 candidates using a competitive binding assay. Each concentration of the mAb was tested in duplicate. The concentration-response relationship was found by curve fitting using Graphpad Prism.TM. graphic software (non-linear, Sigmoid curve). The maximal inhibition (efficacy) and IC.sub.50 (potency) were calculated by the software. Ten monoclonal antibodies that exhibited both relative high efficacy and potency were selected for further investigation. The efficacy and potency of these 10 mAbs are listed in Table 4.

TABLE-US-00004 TABLE 4 Efficacy and potency of top 10 mAbs Clone Efficacy* EC50 (.mu.g/ml) 3.31.2 0.3751 0.04169 5.16.3 0.3279 0.08532 5.86.1 0.3844 0.1331 5.88.3 0.4032 0.1557 3.3.2 0.3881 0.1684 5.103.1 0.2317 0.3643 5.101.1 0.3639 0.3762 3.19.3 0.3945 0.7976 5.28.1 0.3892 2.698 5.78.3 0.2621 5.969 *Efficacy is expressed as the ratio of bound Ang-2 with mAbs (30 .mu.g/ml) versus without mAbs.

Example 5

Binning of Antibodies

[0208] Epitope binning was performed to determine which of the anti-Ang-2 antibodies would cross compete with one another, and thus were likely to bind to the same epitope on Ang-2. The binning process is described in U.S. Patent Application 20030175760, also described in Jia et al., J. Immunol. Methods, (2004) 288:91-98, both of which are incorporated by reference in entirety. Briefly, Luminex beads were coupled with mouse anti-huIgG (Pharmingen#555784) following the protein coupling protocol provided on the Luminex website. Pre-coupled beads were prepared for coupling to primary unknown antibody using the following procedure, protecting the beads from light. Individual tubes were used for each unknown supernatant. The volume of supernatant needed was calculated using the following formula: (nX2+10).times.50 .mu.l (where n=total number of samples). A concentration of 0.1 .mu.g/ml was used in this assay. The bead stock Was gently vortexed, and diluted in supernatant to a concentration of 2500 of each bead in 50 .mu.l per well or 0.5.times.10.sup.5 beads/ml.

[0209] Samples were incubated on a shaker in the dark at room temperature overnight.

[0210] The filter plate was pre-wetted by adding 200 .mu.l wash buffer per well, which was then aspirated. 50 .mu.l of each bead was added to each well of the filter plate. Samples were washed once by adding 100 .mu.l/well wash buffer and aspirating. Antigen and controls were added to the filter plate at 50 .mu.l/well. The plate was covered, incubated in the dark for 1 hour on a shaker, and then samples were washed 3 times. A secondary unknown antibody was then added at 50 .mu.l/well. A concentration of 0.1 .mu.g/ml was used for the primary antibody. The plate was then incubated in the dark for 2 hours at room temperature on a shaker, and then samples were washed 3 times. 50 .mu.l/well of biotinylated mouse anti-human IgG (Pharmingen #555785) diluted at 1:500 was added, and samples were incubated in the dark for 1 hour with shaking at room temperature.

[0211] Samples were washed 3 times. 50 .mu.l/well Streptavidin-PE at a 1:1000 dilution was added, and samples were incubated in the dark for 15 minutes with shaking at room temperature. After running two wash cycles on the Luminex100, samples were washed 3 times. Contents in each well were resuspended in 80 .mu.l blocking buffer. Samples were carefully mixed with pipetting several times to resuspend the beads. Samples were then analyzed on the Luminex100. Results are presented below in Table 5.

TABLE-US-00005 TABLE 5 Bins for top 24 of Ang-2 antibodies positive in functional assay Bin 1 Bin 2 Bin 3 Bin 4 Bin 5 Bin 6 Bin 7 Bin 8 3.3 3.38 5.56* 5.28 5.78 3.19 6.3 5.35 3.28 5.103 5.40 3.31 5.14 5.2 5.16 5.39 5.41 5.49 5.54 5.62 5.83 5.86 5.88 5.101 5.108 *Note: mAb 5.56 had a similar binding pattern as that of 3.38 and 5.103 with minor differences and much lower signal.

Example 6

Determination of Anti-Ang-2 Antibody Affinity Using Biacore Analysis

Low Resolution Screen of 27 Purified Monoclonal Antibodies

[0212] The label-free surface plasmon resonance (SPR), or Biacore, was utilized to measure the antibody affinity to the antigen. For this purpose, a high-density goat anti-human antibody surface over a CM5 Biacore chip was prepared using routine amine coupling. All the purified mAbs were diluted to approximately 8 .mu.g/ml in HBS-P running buffer containing 100 .mu.g/ml BSA and 10 mg/mL carboxymethyldextran. Each mAb was captured on a separate surface using a 42-second contact time, and a 5-minute wash for stabilization of the mAb baseline.

[0213] Ang-2 was injected at 90.9 nM over all surfaces for one minute, followed by a 10-minute dissociation. Double-referenced binding data was prepared by subtracting the signal from a control flow cell and subtracting the baseline drift of a buffer injected just prior to the Ang-2 injection. Ang-2 binding data for each mAb were normalized for the amount of mAb captured on each surface, and the normalized, drift-corrected responses for the 27 mAbs were determined. Data were fit globally to a 1:1 interaction model to determine the binding kinetics. The kinetic analysis results of Ang-2 binding at 25.degree. C. are listed in the table below. The mAbs are ranked from highest to lowest affinity.

TABLE-US-00006 TABLE 6 Ang-2 low resolution Biacore screen of 27 purified monoclonal antibodies Amt. Captured Sample (RU) k.sub.a (M.sup.-1s.sup.-1) k.sub.d (s.sup.-1) K.sub.d (pM) 5.16 157 3.6 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 27 5.41 152 3.6 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 28 5.35 138 3.4 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 29 3.38 143 3.4 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 30 5.108 66 3.2 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 31 3.3 125 3.0 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 33 5.49 260 3.0 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 33 3.28 280 2.7 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 37 5.88 65 2.7 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 37 5.28 136 2.5 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 40 5.78 222 2.4 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 42 5.39 166 2.3 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 43 5.103 127 2.2 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 45 5.13 78 2.1 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 47 5.14 471 2.0 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 49 3.31 196 1.9 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 51 5.56 144 1.9 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 52 5.2 111 1.6 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 62 5.62 126 1.5 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 65 5.54 131 1.5 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 66 6.3 221 1.4 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 73 3.19 252 9.0 .times. 10.sup.4 1.0 .times. 10.sup.-5 * 111 5.40 130 7.8 .times. 10.sup.4 1.0 .times. 10.sup.-5 * 129 5.83 157 6.8 .times. 10.sup.4 1.0 .times. 10.sup.-5 * 147 5.101 217 1.5 .times. 10.sup.5 8.7 .times. 10.sup.-5 581 5.86 126 1.5 .times. 10.sup.5 1.1 .times. 10.sup.-4 744 5.52 114 1.3 .times. 10.sup.5 1.0 .times. 10.sup.-5 * 750

[0214] The asterisks next to the k.sub.d results for all mAbs except for mAbs 5.101 and 5.86 indicate that these k.sub.d's were held constant as a best estimate for the order of magnitude characteristic of slow off-rate data. The fitting model for these samples detected no measurable change in the off-rate over the relatively brief dissociation time and therefore required the k.sub.d to be constant in order to fit the on-rate data. The data for those indicated k.sub.d's also fit well in a simulation with the k.sub.d on the order of 10.sup.-6 s.sup.-1, therefore the interactions may be 10-fold or more stronger than reported above.

[0215] Dissociation data is normally measured 4-6 hours for high-resolution kinetic experiments with mAbs having sub-100 pM affinities. The maximum dissociation time that can be measured without drift artifacts from a captured mAb surface is 20 minutes. Almost negligible signal decay is measured over such a relatively short time with high affinity mAbs so the k.sub.d estimate may vary by as much as two orders of magnitude.

Example 7

Determination of Anti-Ang-2 Antibody Affinity Using Biacore Analysis

[0216] Ang-2 Medium/High Resolution Screen with Three Purified Monoclonal Antibodies

[0217] Purified mAbs 5.16, 5.35, and 5.41 were diluted to approximately 8 .mu.g/ml in 10 mM sodium acetate, pH 5.0. Each diluted mAB was then immobilized on a different flow cell surface (CM5 Biacore chip) using routine amine coupling.

[0218] For on-rate data acquisition, eight concentrations (2-fold dilutions) ranging from 90.9-0.71 nM of Ang-2 were randomly injected for 90 seconds in triplicate with several buffer injections interspersed for double referencing, followed by a four minute dissociation. The antibody surfaces were regenerated with two 9-second pulses of 10 mM glycine-HCl, pH 1.5 after each injection cycle.

[0219] For off-rate data acquisition, three 90.9 nM Ang-2 samples in HBS-P running buffer containing 100 .mu.g/ml BSA were injected as described above and dissociation data was recorded over eight hours. The sample injections alternated with three blank injection cycles. Regeneration was performed as described above.

[0220] The data were globally fit to a 1:1 interaction model with mass transport using CLAMP (David G. Myszka and Thomas Morton (1998) "CLAMP.COPYRGT.: a biosensor kinetic data analysis program," TIBS 23, 149-150). The resulting binding constants are shown in Table 7 below.

TABLE-US-00007 TABLE 7 Ang-2 medium resolution Biacore screen of 3 purified monoclonal antibodies Sample R.sub.max k.sub.a (M.sup.-1s.sup.-1) k.sub.d (s.sup.-1) K.sub.d (pM) 5.16 36 3.41 .times. 10.sup.5 2.77 .times. 10.sup.-6 8.13 5.35 54 5.64 .times. 10.sup.5 1.87 .times. 10.sup.-6 3.31 5.41 44 4.69 .times. 10.sup.5 8.31 .times. 10.sup.-6* 17.7*

[0221] Significant signal decay was measured over the 8-hour dissociation time. With the eight hour dissociation data, CLAMP was able to more reasonably estimate the k.sub.d for each mAb. Here the k.sub.d's for both 5.16 and 5.35 are on the order of 10.sup.-6 s.sup.-1.

[0222] The cross-reactivity of antibodies to Ang-1 was then investigated by measuring the affinity of the mAbs to Ang-1, as described below in Example 8.

Example 8

Determination of Anti-Ang-1 Antibody Affinity Using Biacore Analysis

[0223] The cross-reactivity of antibodies to Ang-1 was further investigated by measuring the affinity of the mAbs to Ang-1. Instead of immobilizing Ang-1, as described in ELISA-based counter-binding (Example 3), Ang-2 mAbs were immobilized to the CMS Biacore chips, and Ang-1 in solution was injected for the determination of the on-rate and off-rate. Six mAbs, including 3.3.2, 3.31.2, 5.16.3, 5.86.1, 5.88.3, and 3.19.3, were tested in this experiment as described below to determine how strongly they cross-reacted with Ang-1.

Medium Resolution Screen of Six Purified Monoclonal Antibodies

[0224] Label-free surface plasmon resonance (SPR), or a Biacore 2000 instrumentation, was utilized to measure antibody affinity to Ang-1. For this purpose, a high-density goat .alpha.-human antibody surface over a CM5 Biacore chip was prepared using routine amine coupling. For developmental experiments, purified mAbs (clones 3.19.3, 3.3.2, 5.88.3, 5.86.1, 3.31.2, 5.16.3) were diluted to approximately 2.5-3.5 .mu.g/ml in HBS-P running buffer containing 100 .mu.g/ml BSA. The capture level for each mAb was approximately 150 RU. A 5-minute wash followed each capture cycle to stabilize the mAb baseline.

[0225] A single Ang-1 sample diluted to 87.4 nM in the running buffer was injected for one minute over all capture surfaces. No binding was evident for five mAbs, although Ang-1 was found to bind to mAb 3.19.3. This experiment was repeated by increasing the mAb capture levels to well over 500-600 RU and injecting 380 nM Ang-1 for one minute. The mAb 3.19.3 was again found to bind Ang-1.

[0226] Because Ang-1 only showed binding activity towards mAb 3.19.3, the affinity of this mAb to both Ang-1 and Ang-2 was determined. Since Ang-1 displayed a slow off-rate during the above developmental experiments, a medium resolution capture experiment would not have recorded sufficient off-rate data to accurately estimate kd. As a result, the binding of Ang-1 and Ang-2 to mAb 3.19.3 was measured under high-resolution Biacore conditions.

Example 9

Determination of mAb 3.19.3 Affinity for Ang-1 and Ang-2 Using High Resolution Biacore Analysis

[0227] Purified mAb 3.19.3 was diluted to 12.5 .mu.g/ml in 10 mM sodium acetate, pH 4.0. The mAb was then immobilized on flow cells 1-3 (CM5 Biacore chip) using routine amine coupling, leaving flow cell 4 as the reference flow cell.

[0228] For on-rate data acquisition, eight concentrations (2-fold dilutions) ranging from 39.8-0.31 nM of Ang-1 (in HBS-P running buffer containing 100 .mu.g/ml BSA) were randomly injected for 90 seconds (100 .mu.L/min. flow rate) in triplicate with several buffer injections interspersed for double referencing, followed by a four minute dissociation. The antibody surfaces were regenerated with a 6-second pulse of 10 mM NaOH after each injection cycle.

[0229] For off-rate data acquisition, three 19.9 nM Ang-1 samples were injected as described above and dissociation data was recorded over six hours. The sample injections alternated with three blank injection cycles. Regeneration was performed as described above.

[0230] The data were globally fit to a 1:1 interaction model with a term for mass transport included using CLAMP (David G. Myszka and Thomas Morton (1998) "CLAMP.COPYRGT.: a biosensor kinetic data analysis program," TIBS 23, 149-150).

ANG-2 High Resolution Biacore Study with Purified MAb 3.19.3

[0231] Purified mAb 3.19.3 was diluted to 12.5 .mu.g/ml in 10 mM sodium acetate, pH 4.0. The mAb was then immobilized on flow cells 1-3 (CM5 Biacore chip) using routine amine coupling, leaving flow cell 4 as the reference flow cell.

[0232] For on-rate data acquisition, eight concentrations (2-fold dilutions) ranging from 30.0-0.23 nM of Ang-2 (in HBS-P running buffer containing 100 .mu.g/ml BSA) were randomly injected for 90 seconds (100 .mu.L/min. flow rate) in triplicate with several buffer injections interspersed for double referencing, followed by a four minute dissociation. The antibody surfaces were regenerated with a 6-second pulse of 15 mM NaOH after each injection cycle.

[0233] For off-rate data acquisition, three 15.0 nM Ang-2 samples were injected as described above and dissociation data were recorded over six hours. The sample injections alternated with three blank injection cycles. Each surface was regenerated with a 6-second pulse of 15 mM NaOH after each long off-rate injection cycle.

[0234] The data were globally fit to a 1:1 interaction model with a term for mass transport included using CLAMP (David G. Myszka and Thomas Morton (1998) "CLAMP.COPYRGT.: a biosensor kinetic data analysis program," TIBS 23, 149-150).

Results And Discussion: ANG-1 and ANG-2 High Resolution Biacore Study with mAb 3.19.3

[0235] Two independent experiments were run with each antigen. The results are shown in Table 8 below:

TABLE-US-00008 TABLE 8 High resolution Biacore results of Ang-1 and Ang-2 binding to purified mAb 3.19.3 Antigen k.sub.a (M.sup.-1s.sup.-1) k.sub.d (s.sup.-1) K.sub.D (pM) Ang-1 (1.sup.st) 1.33 .times. 10.sup.5 4.05 .times. 10.sup.-6 30.4 Ang-1 (2.sup.nd) 1.82 .times. 10.sup.5 5.51 .times. 10.sup.-6 30.2 Ang-2 (1.sup.st) 1.89 .times. 10.sup.5 1.00 .times. 10.sup.-6* 5.3 Ang-2 (2.sup.nd) 1.78 .times. 10.sup.5 1.00 .times. 10.sup.-6* 5.6

[0236] The k.sub.d's for Ang-2 in the above table are asterisked because these values were held constant during the 1:1 interaction model fit in CLAMP software. There was no significant dissociation signal recorded for the Ang-2 experiments, so the best off-rate estimate was to hold k.sub.d constant at 1.times.10.sup.-6 sec.sup.-1. The long off-rate data for Ang-2 actually displayed an upward trend over the six hours of data acquisition. This trend was repeated on two different sensor chips with two different instruments after both instruments had been subjected to a "super clean" maintenance protocol. In order to more precisely measure the binding affinity of mAb 3.19.3 for Ang-1 and Ang-2, a further experiment (see Example 10) was run to determine the Kd of mAb 3.19.3 towards these antigens.

[0237] Interestingly, mAb 3.19.3 did not bind to Ang-1 in the ELISA-based binding assay (Example 3), when Ang-1 was immobilized on the ELISA plate. The likely explanation for this discrepancy is that when Ang-1 was immobilized on the surface of plastics, a subtle epitope critical for the binding of mAb 3.19.3 was not exposed appropriately. However, when Ang-1 was in the liquid phase, such as in the Biacore experimental conditions, this epitope became accessible to mAb 3.19.3 and binding occurred.

Example 10

Determination of Affinity of mAb 3.19.3 to Human Ang-2 Using High Resolution Kinexa (Kinetic Exclusion Assay)

[0238] When affinity of mAb 3.19.3 to human Ang-2 was measured using high resolution Biacore (Example 9), it was found that there was no significant dissociation signal. The long off-rate data for Ang-2 shows an upward trend over the six-hour data acquisition. Because of this, the K.sub.D of mAb 3.19.3 binding to human Ang-2 was determined using KinExA technology, with the goal of obtaining a more reliable Kd value. For this purpose, a KinExA 3000 instrument was utilized. Firstly, 1 mL (.about.271 .mu.g) of stock Ang-2 (R&D Systems, Inc., Lot# BNO32510A) was buffer exchanged into 1.times.PBS, pH 7.0 using a 10 mL desalting column (Pierce D-Salt.TM. polyacrylamide column, 6000 molecular weight cut-off, Lot# GF97965). The concentration of the pooled fractions was determined to be 1.7 .mu.M using the protein concentration determination method described by C. Nick Pace (Pace, et al., Protein Science, Vol. 4: 2411-2423, 1995). Secondly, 200 mg of polymethyl methacrylate (PMMA, Lot#206-01) beads were coupled with 450 .mu.L (.about.122 .mu.g) of stock Ang-2 overnight at 24.degree. C. The beads were then centrifuged and washed once with blocking buffer (1.times.PBS, 10 mg/ml BSA), centrifuged again, and then incubated in blocking buffer for one hour at 24.degree. C. After blocking, the beads were diluted in approximately 30 mL of HBS buffer (0.01 M Hepes, 0.15 M NaCl, pH 7.4) in a standard KinExA bead reservoir vial and placed on the instrument.

K.sub.D-Controlled Titration

[0239] Twelve solutions containing a mAb 3.19.3 binding site concentration of 25.3 pM were titrated with increasing concentrations of Ang-2. The buffer-exchanged Ang-2 was used for the sample preparations. Each solution had a total volume of 25 mL and was allowed to equilibrate for 5 days at .about.24.degree. C. The titration solutions were prepared using volumetric glassware and the Ang-2 concentrations varied from 5.09 nM to 99.3 fM. The KinExA instrument method used for the analysis of these solutions consisted of a bead packing step in which the PMMA beads were packed into a glass capillary, and the equilibrated solutions were flowed through the bead column at 0.25 mL/min for 6 min (1.5 mL) in duplicate. Subsequently, a fluorescently labeled Cy-5 goat anti-human (Fc specific) polyclonal antibody at 3.4 nM was flowed through the bead pack for 1 min at 0.5 mL/min to label the mAb with free binding sites captured on the beads. The fluorescence emission from the bead pack was measured at 670 nm with excitation at 620 nm. The resulting fluorescence measurements were converted into "% free mAb binding site" versus total antigen concentration using the accompanying KinExA software package (version 1.0.3, Sapidyne, Inc.). The resulting K.sub.D-controlled titration curve was fit with the KinExA software to a 1:1 equilibrium isotherm with a drift correction factor included. The value of the K.sub.D that fit the data optimally was 86.4 pM with low and high 95% confidence limits at 64.3 pM and 98.7 pM, respectively. A mAb-controlled titration curve was not performed.

Example 11

Blockage of Ang-2-Induced Tie2 Phosphorylation Ectopically Expressed in HEK293 Cells

[0240] As discussed above, Tie2 is an endothelial cell specific receptor tyrosine kinase. In vitro experiments with vascular endothelial cells show that Ang-1 induces Tie2 phosphorylation, whereas, Ang-2 inhibits the receptor phosphorylation induced by Ang-1. However, when Tie2 is expressed ectopically, such as in fibroblasts, Ang-2 is also able to induce Tie2 phosphorylation under certain conditions, including but not limited to, prolonged exposure to Angiopoietin-2 or exposure to high concentrations of Angiopoietin-2.

[0241] Ang-2 induced Tie2 phosphorylation also occurs when the receptor is expressed in HEK293F cells. The ability of anti-Ang-2 mAbs to block Ang-2 induced Tie2 phosphorylation was examined using HEK293F cells transfected with human Tie2 receptor. Plasmid vector pORK/pBS-SK having a Tie2 cDNA was obtained from the ATCC (Cat. No. 69003, Genbank sequence BC033514). The accuracy of the cDNA was confirmed by nucleotide sequencing. A 3.9 kb fragment containing a 3375 by cDNA that encodes human Tie2 was removed from the vector by EcoRI digestion. This fragment was subcloned in the proper orientation into a pCR3.1 vector digested with EcoRI following standard procedures. The selected plasmid was amplified and purified by standard protocols.

[0242] The Tie2 containing construct obtained by the above procedures was transfected into HEK293F cells by the calcium phosphate transfection method. 1.times.10.sup.6 HEK293F cells were grown in 100 mm tissue culture dishes coated with 1% gelatin at 37.degree. C. with 5% CO.sub.2. The cells were fed with fresh media for 2-3 hours before transfection. 10 .mu.g of the plasmid DNA was dissolved in 248 mM calcium phosphate solution. Transfection was performed using standard procedures. Stable transfectants were selected by incubation in 0.5 mg/ml G418. Stable transfectants expressing Tie2 were identified by FACS analysis using mouse anti-Tie2 mAb (R&D Cat. No. MAB313) and a goat anti-mouse IgG-PE conjugate antibody (Caltag, Cat. No. M30004-4) for detection.

[0243] To perform the Tie2 phosphorylation assay, HEK 293F/Tie-2 transfectants were grown in 60 mm cell culture dishes at a density of 2.times.10.sup.6 cells/plate with complete medium at 37.degree. C. with 5% CO.sub.2 until they reached sub-confluency. The complete medium in each plate was replaced with 2 ml of serum free medium. The cells were incubated for an additional 16 hours. Subsequently, the medium was replaced again with 2 ml of serum-free medium. After an additional 2-hr incubation, the cells were treated with 0.1 mM sodium orthovanadate (Sigma, Cat. No. S 6508) for 20 minutes. The cells were treated with Ang-2 (2 .mu.g/ml) in the presence or absence of mAbs at 100 .mu.g/ml. Treatments were performed in duplicate. A negative control without Ang-2 treatment was included. Cells were rinsed with ice-cold TBS containing vanadate and lysed with 300 .mu.l/plate of cooled NP-40 lysis buffer (50 mM Hepes, pH7.2, supplemented with 0.15M NaCl, 10% glycerol, 10 mM pyrophosphate, 50 mM NaF, 1% NP40, 100 U/ml aprotinin, 1 mM PMSF, 0.1 mM orthovanadate, 10 .mu.M leupeptin and 10 .mu.M pepstatin A), while putting the plates on ice for 10 minutes. The treated cells were scraped from the plates into a microtube pre-chilled on ice.

[0244] The cell lysates were sonicated briefly and centrifuged at 12,000.times.g for 10 minutes at 4.degree. C. in a tabletop microfuge. Supernatants were collected into fresh microtubes, and 1-5 .mu.g of anti-Tie2 mAb (R&D Systems, Inc.) were added to the supernatant, followed by gentle rocking for 2 hours at 4.degree. C. 50 .mu.A of ImmunoPure Immobilized Protein A (PIERCE Cat. No. 20333) was added to the mixture, and incubated for at least 3 hours at 4.degree. C. on a rocking platform. Complexes were collected by centrifugation at 12,000.times.g for 10 minutes. After carefully removing the supernatant, the complexes were washed twice with the lysis buffer by centrifuging (12,000.times.g, 4.degree. C.) for 4 minutes. The pellets were re-suspended in 50 .mu.l of 2.times. electrophoresis sample buffer (Invitrogen, Cat. No. LC-2676) with 1 mM of .beta.-mercaptoethanol or DTT, and boiled for 5 minutes before being centrifuged (12,000.times.g, 4.degree. C.) for 5 minutes. The supernatants were transferred to fresh tubes.

[0245] The samples were loaded into the wells of an SDS-PAGE gel (e.g., 4-20% Tris-Glycine gel, Invitrogen, Cat. No. EC 6025). Electrophoreses was performed in Tris-Glycine buffer system. After electrophoresis, the gel was blotted onto a PVDF membrane (Invitrogen, Cat. No. LC 2005) following a standard protocol. Tyrosine phosphorylation was probed with 4G10 anti-phosphotyrosine antibody at 1 .mu.g/ml (Upstate, Cat. No. 05-321) by incubation for 1 hour at room temperature with shaking, and followed by washing with 1.times.TBST (TBS with 0.1% of Tween-20) three times. The bound antibodies were detected by incubation with horseradish peroxidase-conjugated goat anti-mouse IgG (Santa Cruz, Cat. No. sc-2302) at 1:10,000 dilution for 1 hour at room temperature, followed by the enhance chemiluminescence reaction using SuperSignal West Dura Extended Duration Substrate system (PIERCE Cat. No. 34075). Subsequently, the blot was stripped with Restore Western Blot Stripping Buffer (PIERCE, Cat. No. 21059) and re-probed with specific antibodies against RTK to verify the quality of sample loading.

[0246] It was discovered that when human Tie2 was ectopically expressed in HEK293F cells, autophosphorylation of Tie2 was not detectable. In response to Ang-2 (2 .mu.g/ml) treatment, a significant level of tyrosine phosphorylation was detected by a mAb to phosphorylated tyrosine (4G10) from Tie2 immunoprecipitated by the specific mAb. At a concentration of 100 .mu.g/ml, all the anti-Ang-2 mAbs tested showed obvious inhibition of Tie2 phosphorylation, whereas, the isotype control mAb did not have inhibitory effect (FIG. 1). Monoclonal antibody 5.103.1, which is not shown in FIG. 1, had a similar inhibitory effect.

[0247] To rank the potency of the Ang-2 mAbs to inhibit Ang-2-induced Tie2 phosphorylation in vitro, an ELISA-based quantifiable method to detect Tie2 phosphorylation was established. Briefly, cell lysates were made from HEK293F/Tie2 transfectants that were treated with Ang-2 with the mAbs at various concentrations. Total Tie2 from the lysate was captured in the 96-well ELISA plate that was coated with mouse anti-hTie-2 mAb. The phosphorylated Tie2 was detected using primary antibody 4G10-HRP (purchased from Upstate) and HRP substrate solution. OD at 650 nm was determined by a SpectraMax reader. The concentration-response relationship was found by curve fitting using Graphpad Prism.TM. graphic software (non-linear, Sigmoid curve). The maximal inhibition (efficacy) and IC.sub.50 (potency) were calculated as shown in FIG. 2. The EC50 was calculated as shown in below in Table 9.

TABLE-US-00009 TABLE 9 mAb EC50 (.mu.g/ml) 95% CI 3.19.3 0.006 0.004 to 0.009 5.86.1 0.008 0.007 to 0.011 5.88.3 0.016 0.011 to 0.024 3.31.2 0.043 0.029 to 0.064 3.3.2 0.046 0.020 to 0.105 5.16.3 0.089 0.046 to 0.174 5.103.3 0.095 0.046 to 0.199 5.101.1 0.733 0.487 to 1.105

[0248] As reported above, it was found that mAb 3.19.3 cross-reacted with Ang-1. However, the results of initial experiments did not find inhibition of Angiopoietin-1 induced Tie-2 phosphorylation by mAb 3.19.3. It is worthwhile to note that ectopic expression of Tie2 may affect its susceptibility to activation by different ligands, as evidenced by the fact that Ang-2 does not induce Tie2 phosphorylation in HUVECs, whereas, it does induce robust Tie2 phosphorylation when the receptor is ecotopically expressed in HEK293 cells.

[0249] In view of these results further experiments were performed to more fully investigate whether mAb 3.19.3 was capable of inhibiting binding of both Ang-1 and Ang-2 to cell-bound Tie2. In addition, inhibition of Angiopoietin-1 induced Tie-2 phosphorylation by mAb 3.19.3 was investigated in more detail as described in Example 12 below.

Example 12

mAb 3.19.3 Inhibits Angiopoietin-1 Binding to Tie-2 and Ang-1 Induced Tie2 Phosphorylation

[0250] The mAb 3.19.3 cross-reacts with human Ang-1 (Examples 8 and 9). However, initial experiments indicated that mAb 3.19.3 did not inhibit Tie2 phosphorylation induced by Ang-1. The discrepancy may be explained by the following: (1) high concentration of Ang-1, which is far above physiological concentration, may be required to generate robust Tie2 phosphorylation signal; or (2) Ecotopic expression of Tie2 in HEK293 may alter the conformation of Tie2, and thus change its susceptibility to different ligands. To test there hypotheses mAb 3.19.3 was tested in a binding assay where low concentration of Ang-1 or Ang-2 (3 nM) bound to cell surface Tie2. It was found that mAb 3.19.3 inhibited binding of both Ang-1 and Ang-2 in this experiment. Secondly, immortalized endothelial cells (EA.hy926/B3) were used to investigate Ang-1 induced Tie2 phosphorylation. The results of this experiment, as described in more detail below, demonstrate that mAb 3.19.3 inhibits Ang-1 induced Tie2 phosphorylation in a dose-dependent manner.

[0251] HEK293F/Tie2 transfectants were allowed to grow until 95% confluent in culture flasks before being harvested. Cell suspension of 4 million cells/mL in FACS Buffer were prepared, and then aliquoted to a 96-well polypropylene plate with 50 ul per well. The mAb 3.19.3 with indicated concentrations were added into the cell suspension. Subsequently, solutions of recombinant human Ang-1 and Ang-2 were added into the cell suspension, followed by incubation at room temperature for 2 hours. Cells were washed by centrifuging the plate at 1,200 rpm for 5 minutes, removing the supernatant by aspirating, and resuspending the cells with 200 ul per well of FACS Buffer. Washing procedures were repeated twice. The cells were then suspended with 100 ul of mouse Anti-6.times.-Histidine antibody diluted to 2 ug/ml in FACS Buffer, and incubated at room temperature for 30 minutes. After washing, the cells were suspended in 100 ul of PE-conjugated goat anti-mouse-IgG, which was diluted 1:100 in FACS Buffer, for incubation at room temperature for 30 minutes. The volume of the samples were brought to 300 ul with FACS Buffer, and measured with FACS Calibur.

[0252] The results are illustrated in FIG. 3 and summarized in Table 10. As shown, soluble Tie2/Fc dose-dependently inhibited binding of both Ang-1 and Ang-2 by blocking the ligands, whereas, the isotype control mAb, PK16.3.1 had no effect in the binding of either ligand. The mAb 3.19.3 showed concentration dependent inhibition of both Ang-1 and Ang-2. Interestingly, with the potency of Tie2/Fc as a reference, the potency of mAb 3.19.3 to the binding of Ang-2 was higher than that to Ang-1.

TABLE-US-00010 TABLE 10 Inhibition of Ang-1 and Ang-2 binding to Tie2 EC50 (nM) Ang-1 Ang-2 Tie2/Fc 18.73 25.70 3.19.3 218.5 0.7310

[0253] These results indicated that mAb 3.19.3 not only bound to human Ang-1, but also blocked its binding to the receptor Tie2. This was further confirmed by the inhibition of Ang-1 induced Tie2 phosphorylation in immortalized endothelial cells as described below.

[0254] The inhibitory activity of the mAb 3.19.3 on Ang-1 induced Tie2 phosphorylation was quantified as follows. The mAb showed an obvious increasing inhibition of Tie-2 phosphorylation with increasing antibody concentration, as shown in FIGS. 4 and 5. A plot of the dose response curve led to the calculation of an IC50 of 99 nM.

Angiopoietin-1 Ligand Stimulated Tie-2 Receptor Phosphorylation Assay

[0255] EA.hy926/B3 cells were seeded into 6 well plates using 2.5.times.105 EA.hy 926 cells/well in 2 ml volume DMEM; HAT; 10% FCS and incubated for 3 days under standard mammalian cell growth conditions.

[0256] The growth medium was replaced with 2 mls of DMEM (with no FCS) and the cells serum-starved for a total of 2 hours. Test compounds were diluted in DMEM; 1% FCS to twice the desired final concentration. After 1 hour 40 minutes of the serum starvation, the medium was removed from the cells and replaced with 1 ml of test compound dilutions. Similarly, non-compound treated controls were also progressed to provide samples that represent 100% ligand stimulation standards.

[0257] Incubation was continued for a further 10 minutes after which 100 .mu.l of an 10 mM orthovanadate in DMEM solution was added to each well to obtain a final concentration of 1 mM orthovanadate in each well. The cells were then incubated for the last 10 minutes of the 2 hour serum starvation period.

[0258] Once the 2 hour serum starvation period was complete, 1 ml of Angiopoietin-1 (diluted to the appropriate concentration in DMEM and containing 1 mM orthovanadate) was added to each well and incubated at 37.degree. C. for a further 10 minutes.

[0259] The 6 well plate(s) were then cooled by placing on an ice cold metal plate (itself kept on ice). The cell medium was removed and the cell layer washed with 5 ml of cold PBS; 1 mM orthovanadate. One ml of ice cold lysis buffer (20 mM Tris pH 7.6, 150 mM NaCl, 50 mM NaF, 0.1% SDS, 1% NP40, 0.5% DOC, 1 mM orthovanadate, 1 mM EDTA, 1 mM PMSF, 30 .mu.l/ml Aprotinin, 10 .mu.g/ml Pepstatin, 10 .mu.g/ml Leupeptin) was added to each well and left on ice for 10-20 minutes. The cells were scraped off the plate using a cell lifter and the whole lysate solution transfer to a 1.5 ml Eppendorf tube and kept on ice. The samples were then spun for 3 minutes at 13000 rpm at 4.degree. C. and all subsequent steps carried out at 4.degree. C.

[0260] 50 .mu.l of each lysate were kept for the BCA Protein assay (Pierce, Cat. No. 23225) (in low protein binding polypropylene microtiter plates from Greiner). The protein concentration was determined using the standard assay conditions supplied with the kit. A further 800 .mu.l of each sample lysate was transferred to a fresh 2 ml Eppendorf tube in preparation for the immunoprecipitation (IP). 15 .mu.l (3 mg) of anti P-Y (Santa Cruz Cat. No. E2203) were added to the lysates and left to incubate for 2 hours at 4.degree. C. before adding 600 .mu.l of the Magnabind beads (goat anti mouse IgG, Pierce Cat. No. 21354). The Magnabind beads were prepared as follows: The required volume was transferred into 15 ml conical tubes. Tubes were then placed in the presence of a magnetic field and the liquid was removed. Fresh PBS was added using the original volume, and the beads were re-suspended. This process was repeated twice. The lysate-containing solution was then mixed with the beads and the tubes left to rotate overnight at 4.degree. C. on a rotor mixer.

[0261] The samples were exposed for about 1 min to the magnet and the liquid carefully removed. 1 ml lysis buffer was added and the tubes rotated for 5 min to wash. The wash steps were repeated twice. The liquid was completely removed and the beads re-suspended in 12 .mu.l of hot (94.degree. C.) 2.times. Laemmli loading buffer+bME, then left to stand for 15 min at room temperature. The tubes were exposed for 1 min in the magnet, and the liquid which separated from the beads was analyzed on PAGE/SDS gels.

[0262] The samples were analyzed using PAGE/SDS gels using 4-12% BisTris NuPAGE/MOPS gels with 15 wells (Novex). The total 12 .mu.l of each immunoprecipitate was loaded per slot. The gels were run at 200 V/120 mA/25 Watts for 55 minutes and then the samples western blotted onto nitrocellulose membrane for 1 hr 30 min at 50 V/250 mA. All blots were then treated with 5% Marvel in PBS-Tween for 1 hour at room temperature and then washed with PBS-Tween

[0263] Rabbit anti Tie-2 antibody (Santa Cruz Cat. No. C1303) was diluted 1:500 in 0.5% Marvel/PBS-Tween and 12.5 mls added to each blot and left at 4.degree. C. overnight. The blots were then washed with PBS-Tween and goat anti rabbit-POD (Dako Cat. No. P 0448) (1:5000 dilution in 0.5% Marvel/PBS-Tween) added to each blot and left for 1 hour at room temperature. The blots were washed with PBS-Tween and each blot developed for 10 minutes using 12.5 mLs (equal volumes of solution A and B) of Supersignal (PIERCE Cat. No. 34080). The blots were transfer to X-Ray cassette and expose to film (5 sec/15 sec/30 sec/60 sec/150 second exposures). FIG. 4 is a Western blot showing the results of this assay. In this system, inhibition of Angiopoietin-1 stimulated phosphorylation of Tie-2 by mAb 3.19.3 was observed.

[0264] The images seen on the film for each sample were then evaluated using the Fluor S BioRad image analyzer system. The pixel density was measured as OD/mm.sup.2 and expressed in percentage volume. The percentage volume results were normalized to 1 mg protein/immunoprecipitation using the protein concentration determined using the BCA assay and the lysate volume of each sample used in the immunoprecipitation. The percentage phosphorylation of each sample was calculated against the 100% phosphorylation value of the untreated control sample on each gel with percentage inhibition of each sample being calculated against the 100% phosphorylation value, which itself represents 0% inhibition). FIG. 5 is a graphical representation of these values, and shows that the IC50 for inhibition of Angiopoietin-1 stimulated Tie-2 phosphorylation is 99 nM.

[0265] Taken together, these data show that, in this system, the mAb inhibits Angiopoietin-1 induced phosphorylation of Tie-2.

Example 13

Structural Analysis of Ang-2 Antibodies

[0266] The variable heavy chains and the variable light chains of the antibodies were sequenced to determine their DNA sequences. The complete sequence information for the anti-Ang-2 antibodies is provided in the sequence listing with nucleotide and amino acid sequences for each gamma and kappa chain combination. The variable heavy sequences were analyzed to determine the VH family, the D-region sequence and the J-region sequence. The sequences were then translated to determine the primary amino acid sequence and compared to the germline VH, D and J-region sequences to assess somatic hypermutations.

[0267] Table 11 is a table comparing the antibody heavy chain regions to their cognate germ line heavy chain region. Table 12 is a table comparing the antibody kappa light chain regions to their cognate germ line light chain region.

[0268] The variable (V) regions of immunoglobulin chains are encoded by multiple germ line DNA segments, which are joined into functional variable regions (V.sub.HDJ.sub.H or V.sub.KJ.sub.K) during B-cell ontogeny. The molecular and genetic diversity of the antibody response to Ang-2 was studied in detail. These assays revealed several points specific to anti-Ang-2 antibodies.

[0269] Analysis of 152 individual antibodies specific to Ang-2 resulted in the determination that the antibodies were derived from 21 different germline VH genes, 112 of them from the VH3 family, with 46 antibodies being derived from the VH3-33 gene segment. Tables 11 and 12 show the results of this analysis.

[0270] It should be appreciated that amino acid sequences among the sister clones collected from each hybridoma are identical. For example, the heavy chain and light chain sequences for mAb 3.19.3 are identical to the sequences shown in Tables 11 and 12 for mAbs 3.19 and 3.19.1.

TABLE-US-00011 TABLE 11 Heavy chain analysis SEQ Chain ID Name NO: V D J FR1 CDR1 FR2 CDR2 FR3 CDR3 J 558 Germline EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLYLQM DYGDYGM WGQGTT PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCTT DV VTVSSA 4.2 141 VH3-15 D4-17 JH6B EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTVGGT RFTISRDDSKNTLYLQM DYGDYYN WGQGTT PGGSLRLSCAAS NAWMT KGLEWVG TDYAAPVKG NSLKTEDTAVYYCTT SGYGMDV VTVSSA 559 Germline QVQLVQSGAEVKK GYTFT WVRQAPG WINPNSGGTN RVTMTRDTSISTAYMEL IAVAGFDY WGQGTL PGASVKVSCKAS GYYMH QGLEWMG YAQKFQG SRLRSDDTAVYYCAR VTVSSA 5.103.1 503 VH1-2 D6-19 JH4A QVQLVQSGAEVKK GYTFT WVpQAPG WIsPNSGGTN RVTMTRDTSISTAYMEL DQVIAVA WAQGTL PGASVKVSCKAS GYYLY QGLEWMG YAQKFQG SRLRSDDTAVYYCAR GPFDY VTVSSA 560 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM DYGGNFDY WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR VTVSSA 3.42 137 VH3-33 D4-23 JH4B QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSSKY RFTISRDNSKNTLYLQM ANDYGGN WGQGTL PGRSLRLSCAAS SYGIH KGLEWVA YADSVKG NSLRAEDTAVYYCAR GLFDY VTVSSA 561 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM AFDI WGQGTM PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR VTVSSA 5.11 221 VH3-33 -NA- JH3B QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM DKALAFDI WGQGTM PGRSLRLPCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR VTVSSA 562 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM EL WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR VTVSSA 5.108 513 VH3-33 D1-7 JH5B QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM ELAL WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAMYYCAR VTVSSA 5.108.1 513 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM ELAL WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAMYYCAR VTVSSA 563 Germline EVQLVESGGGVVR GFTFD WVRQAPG GINWNGGSTG RFTISRDNAKNSLYLQM QWLWYFDL WGRGTL PGGSLRLSCAAS DYGMS KGLEWVS YADSVKG NSLRAEDTALYHCAR VTVSSA 5.19 251 VH3-20 D6-19 JH2 EVQLVESGGGVVR GFSFD WVRQAPG GINWNGGRTV RFTISRDSAKNSLYLQM NKQWLWY WGRGTL PGGSLRLSCAAS DYGMS KGLEWVS YADSVKG NSLRAEDTALYHCAR FDL VTVSSA 5.6 205 '' '' '' EVQLVESGGGVVR GFSFD WVRQAPG GINWNGGRTV RFTISRDSAKNSLYLQM NKQWLWY WGRGTL PGGSLRLSCAAS DYGMS KGLEWVS YADSVKG NSLRAEDTALYHCAR FDL VTVSSA 5.8 211 '' '' '' EVQLVESGGGVVR GFTFD WVRQAPG GINWNGGGTG RFTISRDDAKNSLYLQM NKQWLWY WGRGTL PGGSLRLSCAAS DYGMS KGLEWVS YADSMKG NSLRAEDTALYHCAR FDL VTVSSA 5.35 297 '' '' '' EVQLVESGGGVVR GFTFD WVRQAPG GINWNGGSTV RFTISRDSAKNSLYLQM NKQWLWY WGRGTL PGGSLRLSCTTS DYGMS KGLEWVS YADSVKG NSLRAEDTALYHCAR FDL VTVSSA 5.38 309 '' '' '' EVKLVESGGGMVR GFTFD WVRQAPG GINWNGGGTA RFTISRDNAKNSLYLQL NKQWLWY WGRGTL PGGSLRLSCAAS DYGMS KGLEWVS YADSVKG NSLRAEDTALYHCAR FDL VTVSSA 5.44 329 '' '' '' EVQLVESGGGVVR GFSFD WVRQAPG GINWNGGRTV RFTISRDSAKNSLYLQM NKQWLWY WGRGTL TGGSLRLSCAAS DYGMS KGLEWVS YADSVKG NSLRAEDTALYHCAR FDL VTVSSA 5.35.1 297 '' '' '' EVQLVESGGGVVR GFTFD WVRQAPG GINWNGGSTV RFTISRDSAKNSLYLQM NKQWLWY WGRGTL PGGSLRLSCTTS DYGMS KGLEWVS YADSVKG NSLRAEDTALYHCAR FDL VTVSSA 564 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM YGGNSYY WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCA YYYGMDV VTVSSA 3.1 7 VH3-33 D4-23 JH6B QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM DYGEYFY WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAG YGMDV VTVSSA 3.18 71 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWFDGSNKY RFTISRDNSKNTLYLQM DYGDYFY WGQGTT PGRSLRLSCAAS SFGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAS YGMDV VTVSSA 3.39 125 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM DRSYGGN WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCA SFYYYYY VTVSSA GMDV 3.11 47 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM DYGDYFY WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAG YGMDV VTVSSA 3.26 93 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM DYGEYFY WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAG YGMDV VTVSSA 565 Germline EVQLVESGGVVVQ GFTFD WVRQAPG LISWDGGSTY RFTISRDNSKNSLYLQM DIAVAGF WGQGTL PGGSLRLSCAAS DYTMH KGLEWVS YADSVKG NSLRTEDTALYYCAK DY VTVSSA 5.28 277 VH3-43 D6-19 JH4B EVQLVESGGIVVQ GFTFD WVRQTPG LISWDGGSTY RFTISRDNSKNSLYLQM DIDIAVA WGQGTL PGGSLRLSCAAS DYTMH KGLEWVS YADSVKG NSLRTEDTALYYCAK GTGFDH VTVSSA 5.28.1 277 '' '' '' EVQLVESGGIVVQ GFTFD WVRQTPG LISWDGGSTY RFTISRDNSKNSLYLQM DIDIAVA WGQGTL PGGSLRLSCAAS DYTMH KGLEWVS YADSVKG NSLRTEDTALYYCAK GTGFDH VTVSSA 566 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM NWNYFDY WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR VTVSSA 5.56.1 363 VH3-33 D1-7 JH4B QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM EDNWNFY WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR FDY VTVSSA 5.56 363 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM EDNWNFY WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR FDY VTVSSA 567 Germline QVQLQQWGAGLLK GGSFS WIRQPPG EINHSGSTNY RVTISVDTSKNQFSLKL DYGDFDY WGQGTL PSETLSLTCAVY GYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 3.37 121 VH4-34 D4-17 JH4B QVQLQQWGAGLLK GGSFS WIRQPPG EIYHSGSTNY RVTISVDTSKNQFSLKL NDYGDHE WGQGTL PSETLSLTCAVY GYYWS KGLEWIG NPSLKS SSVTAADTAVYSCAR GFDY VTVSSA 568 Germline QVQLQESGPGLVK GGSVS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL GYSYGYY WGQGTL PSETLSLTCTVS SGGYY KGLEWIG NPSLKS SSVTAADTAVYYCAR FDY VTVSSA WS 5.36 301 VH4-61 D5-5 JH4B QVQLQESGPGLVK GGSVS WIRQPPG YINYSRSTNH RVTISVDTSKNQFSLKL EGRGDSY WGQGTL PSETLSLTCTVS SGGYY KGLEWIG NPSLKS SSVTAADTAVYYCAR GYYFDY VTVSSA WS 6.7 551 '' '' '' QVQLQESGPGLVK GGSVS WIRQPPG YIYYSRSTNY RVTISVDTSKNQFSLKL EGRGYSY WGQGTL PSETLSLTCTVS SGGYY KGLEWIG NPSLKS SSVTAADTAVYYCAR GYYFDY VTVSSA WS 5.107 511 '' '' '' QVQLQESGPGLVK GGSVS WIRQPPG YIYYSRSTNY RVTISVDTSKNQFSLKL EGRGNSY WGQGTL PSETLSLTCTVS SGGYY KGLEWIG NPSLKS SSVTAADTAVYYCAR GYYFDY VTVSSA WS 569 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VISYDGSNKY RFTISRDNSKNTLYLQM WLRYYYY WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR GMDV VTVSSA 5.111 521 VH3-30 D5-12 JH6B QVQLVESGGDVVQ GFTFS WVRQAPG VISYDGSNKY RFTISRDNSKNTLYLQM DGGWLRL WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG HLRAEDTAVYYCAR DYYYYGM VTVSSA DV 570 Germline EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLYLQM YSSGWYW WGRGTL PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCTT YFDL VTVSSA 5.45 333 VH3-15 D6-19 JH2 EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLYLQM SYSSGWF WGRGTP PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCTT YWYFDI VTVSSA 571 Germline EVQLVESGGGLVQ GFTFS WVRQAPG YISSSSSTIY RFTISRDNAKNSLYLQM AAAGFDY WGQGTL PGGSLRLSCAAS SYSMN KGLEWVS YADSVKG NSLRDEDTAVYYCAR VTVSSA 5.43 325 VH3-48 D6-13 JH4B EVQLVESGGGLVQ GFTFS WVRQAPG YISRSSRTIN RFTVSRDNAKNSLYLQM KAAAGPF WGQGTL PGGSLRLSCAAS TYSMN KGLEWIS HADSVKG ISLRDEDTAVYYCAR DY VTVASA 572 Germline EVQLLESGGGLVQ GFTFS WVRQAPG AISGSGGSTY RFTISRDNSKNTLYLQM DYGGNFDY WGQGTL PGGSLRLSCAAS SYAMS KGLEWVS YADSVKG NSLRAEDTAVYYCAK VTVSSA 5.97 491 VH3-23 D4-23 JH4B EVQLLESGGGLVQ GFTFS WVRQAPG GISGSGGNTY RFTISRDNSKNTLYLQM DEDYGGN WGQGTL PGGSLRLSCAAS SYAMS KGLEWVS HADSVKG NSLRAEDTAVYYCAK YSDFDY VTVSSA 6.8 553 '' '' '' EVQLLESGGGLVQ GFTFS WVRQAPG AISGSGGSTY RFTISRDNSKNTLYLQM DEDYGGN WGQGTL PGGSLRLSCAAS SYAMS KGLEWVS YADSVKG NSLRAEDTAVYYCAK SDFDY VTVSSA 573 Germline QVQLQQSGPGLVK GDSVS WIRQSPS RTYYRSKWYN RITINPDTSKNQFSLQL WFYWYFDL WGRGTL PSQTLSLTCAIS SNSAA RGLEWLG DYAVSVKS NSVTPEDTAVYYCA VTVSSA WN 5.61 377 VH6-1 D3-9 JH2 QVQLQQSGPGLVK GDSVS WIRQSPS MTYYRSKWSN RITINPDTSKNQFSLQL GNWFYWY WGRGTL PSQTLSLTCAIS SNSAA RGLEWLG DYAVSLKS NSVTPEDTAVYYCAR FDL VTVSSA WN 574 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM TGDY WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR VTVSSA 5.52 347 VH3-33 D1-1 JH4B QVQLVESGGGVVQ GFTFS WVRQAPG VRWYDESNKY RFTISRDNSKNTLYLQM DPFETGT WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR TFDY VTVSSA 5.52.1 351 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VRWYDESNKY RFTISRDNSKNTLYLQM DPFETGT WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR TFDY VTVSSA 5.53 355 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VLWYDESNKY RFTISRDSSKNTLYLQM DPFETGT WGQGTL PGRSLRLSCAAS DYGMH KGLEWMA YADSVKG NSLRAEDTAVYYCAR TFDY VTVSSA 5.26 273 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDESNKY RFTISRDNSKNTLYLQM DPFETGT WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR TFDY VTVSSA 575 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VISYDGSNKY RFTISRDNSKNTLYLQM GYSSGWF WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR DY VTVSSA 5.20 253 VH3-30 D6-19 JH4B QVQLVESGGGVVQ GFTFS WVRQAPG VISYDGSKKY RFTISRDNSKNTLYLQM GGYSTGW WGQGTL PGRSLRLSCAAS TYGMH KGLEWVA YADSVKG NSLRAEDTALYYCAR GPDFDY VTVSSA 576 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM CGGDCYY WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR YYYGMDV VTVSSA 3.22 89 VH3-33 D2-21 JH6B QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSRNTLYLQM EGGYCGG WGQGTT PGRSLRLSCAAS NYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR DCWVYGM VTVSSA DV 5.51 345 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM ENCGGDC WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR YQLNYYY VTVSSA YYGMDV 5.47 339 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM

ENCGGDC WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR YQLNYYY VTVSSA YYGMDV 577 Germline QVQLQESGPGLVK GGSIS WIRQHPG YIYYSGSTYY RVTISVDTSKNQFSLKL WDFDY WGQGTL PSQTLSLTCTVS SGGYY KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA WS 3.21 85 VH4-31 D7-27 JH4B QVQLQESGPGLVK GGSIS WIRQHPG YIYYSGRTYY RVTISVDASKNQFSLKL EGSYWDF WGQGTL PSQTLSLTCTVS SGGYF KGLEWIG NPSLKS SSVTAADTAVYHCAR DY VTVSSA WS 578 Germline QVQLQESGPGLVK GGSIS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL P WGQGTL PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 5.66 389 VH4-59 -NA- JH5B QVQLQESGPGLVK GGSIS WIRQPPG FIYYSGTTNY RVTISVDTSKNQFSLKL AYDP WGQGTL PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 579 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM NWNYYYY WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR GMDV VTVSSA 5.73 409 VH3-33 D1-20 JH6B QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM GDNWNYE WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR GDGMDV VTVSSA 5.29 281 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM APYDWNS WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR YYGLDV VTVSSA 5.104 507 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM APYDWNS WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKD NSLRAEDTAVYYCAR YYGLDV VTVSSA 580 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VISYDGSNKY RFTISRDNSKNTLYLQM YYGSGSY WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR GMDV VTVSSA 5.21 255 VH3-30 D3-10 JH6B QVQLVESAGGVVQ GFTFS WVRQAPG VISYDGSNKY RFTISRDDSKNTLYLQM NYYGSGS WGQGTT PGRSLRLSCAAS IYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR PYGMDV VTVSSA 581 Germline QVQLQESGPGLVK GGSVS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL YYGSGYY WGQGTT PSETLSLTCTVS SGGYY KGLEWIG NPSLKS SSVTAADTAVYYCAR YYGMDV VTVSSA WS 3.2 11 VH4-61 D3-10 JH6B QVQLQESGPGLVK GGSVS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL DQDYYGS WGQGTT PSETLSLTCTVS SGGYY KGLEWIG NPSLKS SSVTAADTAVYYCAR GRGYYYY VTVSS WN GMDV 582 Germline QVQLVQSGAEVKK GYTFT WVRQAPG WINPNSGGTN RVTMTRDTSISTAYMEL NWNYFDY WGQGTL PGASVKVSCKAS GYYMH QGLEWMG YAQKFQG SRLRSDDTAVYYCAR VTVSSA 6.3.1 539 VH1-2 D1-7 JH4B QVQLVQSGAEVKK GYTFT WVPQAPG WINPNSGGTN RVTMTRDTSISTAYMEL DPWQNWN WGQGTL PGASVKVSCKAS GYFMH QGLEWMG YAQNFQG SRLRSDDTPVYYCAR SYFDY VTVSSA 583 Germline EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLYLQM YGWYFDL WGRGTL PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCT VTVSSA 5.46 337 VH3-15 D4-17 JH2 EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTMSRDDSKNTLYLQM LYGDFWY WGRGTL PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCTI FDL VTVSSA 3.9 39 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLYLQM EYGDFWY WGRGTL PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCTT FDF VTVSSA 584 Germline QVQLQESGPGLVK GGSIS WIRQPAG RIYTSGSTNY RVTMSVDTSKNQFSLKL WWYFDL WGRGTL PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 5.68 397 VH4-4 D2-21 JH2 QVQLQESGPGLVK GGSIS WIRQPAG RIYSSGSTNY RVTMSGDTSKNQFSLKL GRWGSWY WGRGTL PSETLSLTCTVS SHYWI KGLEWIG NPSLKS SSVTAADTAVYYCAR FDL VTVSSA 585 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM Y WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR VTVSSA 5.67 393 VH3-33 -NA- JH4B QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM ELAY WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR VTVSSA 586 Germline QVQLVQSGAEVKK GYTFT WVRQAPG WINPNSGGTN RVTMTRDTSISTAYMEL WYYYYYY WGQGTT PGASVKVSCKAS GYYMH QGLEWMG YAQKFQG SRLRSDDTAVYYCAR GMDV VTVSSA 5.78.1 429 VH1-2 D2-2 JH6B QVQLVQSGAEVKK GYTFT WVRQAPG WINPNSGGTN RVTMTRDTSISTAYMEL DRGWNYA WGQGTT PGASVKVSCKAS GYYMH QGLEWMG YAQKFQG SRLRSDDTAVYYCAR DYYYYGM VTVSSA DV 587 Germline EVQLVESGGGLVK GFTFS WVRQAPG SISSSSSYIY RFTISRDNAKNSLYLQM VGAFDY WGQGTL PGGSLRLSCAAS SYSMN KGLEWVS YADSVKG NSLRAEDTAVYYCAR VTVSSA 4.18 187 VH3-21 D1-26 JH4B EVQLVESGGGLVK GFTFS WVRQAPG SISSSSSHIY RFTISRDNAKNSLYLQM DRGVGAP WGQGTL PGGSLRLSCAAS SYRMN KGLEWVS YVDSVKG NSLRAEDTAVYYCAR FDY VTVSSA 3.40 129 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG SISSSSSHIY RFTISRDNAKNSLYLQM DRGVGAP WGQGTL PGGSLRLSCAAS SYRMN KGLEWVS YVDSVKG NSLRAEDTAVYYCAR FDY VTVSSA 5.80 435 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG SISSSGSYIY RFTISRDNAKNSLYLQM DRGVGAA WGQGTL PGGSLRLSCAAS SYRMN KGLEWVS YADSVKG NSLARAEDTAVYYFAR FDY VTVSSA 3.41 133 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG SISSSSSHIY RFTISRDNAKNSLYLQM DRGVGAP WGQGTL PGGSLRLSCAAS SYRMN KGLEWVS YVDSVKG NSLRAEDTAVYYCAR FDY VTVSSA 588 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM YSYFDY WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR VTVSSA 5.22 259 VH3-33 D6-6 JH4B QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM GGPLYSN WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR SFYYFDY VTVSSA 5.31 289 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG IIWFDGSNEY RFTISRDNSKNTLYLQM GGPLYSN WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYFCAR SFYYFDY VTVSSA 5.37 305 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSHKY RFTISRDNSKNSLYLQM GGPLYSN WGQGTL PGRSLRLSCAAS NYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR SFYYFDY VTVSSA 5.112 525 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG ILWYDGSNKY RFTISRDNSKNTLYLQM GGPLYTN WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR SFYYFDY VTVSSA 5.10 217 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPD VIWYDGSYKY RFTISRDNSKNTLYLQM GGPLYSN WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR SFYYFDY VTVSSA 5.76 419 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM GGPLYSN WGQGTL PGRSLRLSCVAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR SFYYFDY VTVSSA 5.17 243 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDSSKNTLYLQM GGPLYSN WGQGTL PGRSLRLSCAAS SYGMH KGLEWVT YADSVKG NSLRAEDTAVYYCAR SFYYFDY VTVSSA 589 Germline QVQLQESGPGLVK GGSIS WIRQPAG RIYTSGSTNY RVTMSVDTSKNQFSLKL DDYSYYY WGQGTT PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR YYGMDV VTVSSA 5.81 439 VH4-4 D4-11 JH6B QVQLQESGPGLVK GGSIS WIRQPAG RIYTSGSTNY RVTMSVDTSKNQFSLKL DDYSHSY WGQGTT PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR YYYGMDV VTVSSA 590 Germline EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLYLQM YGGNSYG WGQGTT PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCTT MDV VTVSSA 4.5 151 VH3-15 D4-23 JH6B EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLYLQM AYGGNSD WGQGTT PGGSLRLSCAAS NAWMN KGLEWVG TDYAAPVKG NSLKTEDTAVYYCTT QEDYGMDV VTVSSA 591 Germline EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSEKY RFTISRDNAKNSLYLQM GIAVAFDY WGQGTL PGGSLRLSCAAS SYWMS KGLEWVA YVDSVKG NSLRAEDTAVYYCAR VTVSSA 3.31.1 99 VH3-7 D6-19 JH4B EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSDKY RFTISRDNAKNSLYLRM DMGSGWF WGQGTL PGGSLRLSCAAS SYWMS KGLEWVA YVDSVKG NSLRAEDTAVFYCAR DYFDY VTVSSA 5.13.1 229 '' '' '' EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSEKY RFTISRDNAKNSLYLQM DPGIAVA WGQGTL PGGSLRLSCAAS SYWMS KGLEWVA YVDSVKG NSLRAEDTAVYYCAR GPFDY VTVSSA 5.13 229 '' '' '' EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSEKY RFTISRDNAKNSLYLQM DPGIAVA WGQGTL PGGSLRLSCAAS SYWMS KGLEWVA YVDSVKG NSLRAEDTAVYYCAR GPFDY VTVSSA 5.62 381 '' '' '' EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSEKY RFTISRDNAKNSLYLQM DPGIAVA WGQGTL PGGSLRLSCAAS SYWMS KGLEWVA YVDSVKG NSLRAEDTAVYYCAR GPFDY VTVSSA 3.28.1 97 '' '' '' EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSDKY RFTISRDNAKNSLYLQM DKGSGWF WGQGTL PGGSLRLSCAAS SSWMS KGLEWVA YVDSVKG NSLRAEDTAVYYCVR DY VTVSSA 5.41 321 '' '' '' EVQLVESGGGLVQ GFTFS WVRQAPG NIKEDGSEKY RFTISRDNAKNSLYLQM DRSSGFF WGQGTL PGGSLRLSCAAS SYWMS KGLEWVA YVDSVKG NSLRAEDTAVFYCAR DY VTVSSA 5.109 517 '' '' '' EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSEQY RFTISRDNAKNSLYLQM DPGIEVA WGQGTL PGGSLRLSCAAS SYWMS KGLEWVA SVDSVKG NTLRAEDTAVYYCVR GPFDY VTVSSA 3.3 15 '' '' '' EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSEKY RFTISRDNAKNSLYLQM DQGIAVA WGQGTL PGGSLRLSCAVS SYWMS KGLEWVA YVDSVKG NSLRAEDTAVYYCAR GPFDY VTVSSA 3.3.1 19 '' '' '' EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSEKY RFTISRDNAKNSLYLQM DQGIAVA WGQGTL PGGSLRLSCAVS SYWMS KGLEWVA YVDSVKG NSLRAEDTAVYYCAR GPFDY VTVSSA 5.41.1 321 '' '' '' EVQLVESGGGLVQ GFTFS WVRQAPG NIKEDGSEKY RFTISRDNAKNSLYLQM DRSSGFF WGQGTL PGGSLRLSCAAS SYWMS KGLEWVA YVDSVKG NSLRAEDTAVFYCAR DY VTVSSA 5.62.1 381 '' '' '' EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSEKY RFTISRDNAKNSLYLQM DPGIAVA WGQGTL PGGSLRLSCAAS SYWMS KGLEWVA YVDSVKG NSLRAEDTAVYYCAR GPFDY VTVSSA 5.83 447 '' '' '' EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSEKY RFTISRDNAKNSLYLQM DAGMEVA WGQGTL PGGSLRLSCEAS TYWMT KGLEWVA YVDSVKG NSLRAEDTAVYYCAR GPFDY VTVSSA 592 Germline EVQLLESGGGLVQ GFTFS WVRQAPG AISGSGGSTY RFTISRDNSKNTLYLQM QWLVFDY WGQGTL PGGSLRLSCAAS SYAMS KGLEWVS YADSVKG NSLRAEDTAVYYCAK VTVSSA 5.40.2 317 VH3-23 D6-19 JH4B EVQLLESGGGLVQ GFTFS WVRQAPG AISGSGYSTY RFTISRDNSKNTLYLQM DLQQWLV WGQGTL PGGSLRLSCAAS SYAMS KGLEWVS YADSVKG NSLRAEDTAVYYCAK PTVFDY VTVSSA 593 Germline QVQLQESGPGLVK GGSIS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL QWLDY WGQGTL PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 5.15 235 VH4-59 D6-19 JH4B QVQLQESGPGLVK GGSIS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL DRQWLDY WGQGTL PSETLSLTCTVS GYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 594 Germline QVQLQESGPGLVK GGSIS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL AFDI WGQGTM PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 3.13 55 VH4-59 -NA- JH3B QVQLQESGPGLVK GGSIS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL DRADAFDI WGQGTM PSETLSLTCTVS NYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 3.7 31 '' '' '' QVQLQESGPGLVK GGSIS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL DRADAFDI WGQGTM PSETLSLTCTVS NYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 3.12 51 '' '' '' QVQLQESGPGLVK GGSIS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL DRADAFDI WGQGTM

PSETLSLTCTVS NYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 3.33 111 '' '' '' QVQLQESGPGLVK GDSIS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL ERGDAFDI WGQGRV PSETLSLTCTVS NYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 4.16 183 '' '' '' QVQLQESGPGLVK GGSIS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL DRADAFDI WGQGTM PSETLSLTCTVS NYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 3.35 119 '' '' '' QVQLQESGPGLVK GDSIS WIRQPPG YIYYSGSTNY RVTISVDTSKNQLSLKL ERGDAFDI WGQGRV PSETLSLTCTVS NYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 3.32 107 '' '' '' QVQLQESGPGLVK GGSIS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL DRADAFDI WGQGTM PSETLSLTCTVS NYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 595 Germline QVQLVESGGGLVK GFTFS WIRQAPG YISSSGSTIY RFTISRDNAKNSLYLQM GAFDI WGQGTM PGGSLRLSCAAS DYYMS KGLEWVS YADSVKG NSLRAEDTAVYYCAR VTVSSA 5.90 475 VH3-11 D3-16 JH3B QVQLVESGGGLVK GFTFS WIRQAPG YISSSGSSKN RITISRDNAKNSLYLQM ERGDAFDI WGQGTM PGGSLRLSCAAS DYYMS KGLEWVS YADSVKG NSLRAEDTAVYYCAR VTVSSA 596 Germline QVQLQESGPGLVK GGSIS WIRQPAG RIYTSGSTNY RVTMSVDTSKNQFSLKL YNWNYWY WGRGTL PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR FDL VTVSSA 5.18 247 VH4-4 D1-20 JH2 QVQLQESGPGLVK GGSIS WIRQPAG RIYTSGFTNY RVTMSVDTSKNQFSLKL YNWNYWY WGRGIL PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR FDL VTVSSA 597 Germline QVQLVQSGAEVKK GYTFT WVRQAPG WINPNSGGTN RVTMTRDTSISTAYMEL IAVAGFDY WGQGTL PGASVKVSCKAS GYYMH QGLEWMG YAQKFQG SRLRSDDTAVYYCAR VTVSSA 5.54.1 357 VH1-2 D6-19 JH4B QVQLVQSGAEVKK GYTFT WVRQAPG WINPNSGGTN RVTMTRDTSISTAYMEL DGGSIAV WGQGTL PGASVKVSCKAS GYYMH QGLEWMG YAQKFQG SRLRSDDTAVYYCAR AGHFEY VTVSSA 5.14.1 233 '' '' '' QVQLVQSGAEVKK GYTFT WVRQAPG WINPNSGGTN RVTMTRDTSISTAYMEL DQGITVA WGQGSL PGASVKVSCKAS GYYMY QGLEWMG YAQKFQG SRLRSDDTAVYYCAR GPFDY VTVSSA 5.101.1 497 '' '' '' QVQLVQSGAEVKK GYTFT WVPQAPG WINPNSGGTN RVTMTRDTSISTAYMEL DGGSIPV WGQGTL PGASVKVSCKAS GYYMH QGLEWMG YAQKFQG RLRSDDTAVYYCAR SGHFDY VTVSSA 5.83.1 449 '' '' '' QVQLVQSGAEVKK GYTFT WVRQAPG WINPNSGGTN RVTMTRDTSISTAYMEL DGGSIAV WGQGTL PGASVKVSCKAS GYYMH QGLEWMG YAQKFQG SRLRSDDTAVYYCAR AGHFDY VTVSSA 598 Germline EVQLVESGGGLIQ GFTVS WVRQAPG VIYSGGSTYY RFTISRDNSKNTLYLQM YSSGWYY WGQGTT PGGSLRLSCAAS SNYMS KGLEWVS ADSVKG NSLRAEDTAVYYCA GMDV VTVSSA 6.9 555 VH3-53 D6-19 JH6B EVQLVESGGGLIQ GFTVS WVRQAPG VIYSGGFTYY RFTVSRDNSKNTLYLQM YSSGWHY WGQGTT SGGSLRLSCAAS SKYMS KGLEWVS ADSVKG NSLGAEDTAVYYCAT YGMDV VTVSSA 599 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM GDLLLRY GPRDHG PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR GRL HRLLS 3.10 43 VH3-33 D4-17 JH6B QVQLVESGGGVVQ GFTFS WVRQAPG VIRYDGSNKY RFTISRDNSKNTLNLQM DRDGDYP WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR LLLGMDV VTVSSA 4.13 171 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM DYGDSDY WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAA YYYGMDV VTVSSA 600 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM DIVATIN WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR YYYGMDV VTVSSA 5.2 195 VH3-33 D5-12 JH6B QVQLVESGGGVVQ GFTFS WVRQAPG VIWFDGFNKY RFTISRDNSKNTLYLQM DRGYSGY WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYHCAR DHYYGMDV VTVSSA 5.12 225 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGGNKY RFTISRDNSKNTLYLQM DEDIVAT WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YTDSVKG NSLRAEDTAVYYCAR INYYYGM VTVSSA DV 601 Germline EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSEKY RFTISRDNAKNSLYLQM DIWYFDL WGRGTL PGGSLRLSCAAS SYWMS KGLEWVA YVDSVKG NSLRAEDTAVYYCAR VTVSSA 5.4 201 VH3-7 D3-22 JH2 EVQLVESGGDLVQ GFTFS WVRQAPG NIKQDGSEKY RFTISRDNAKNSLYLQM DIRWYFDL WGRGTL PGGSLRLSCAAS SYWMS KGLEWVA FDSVKG NSLRAEDTAVYYCAR VTVSSA 602 Germline EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSEKY RFTISRDNAKNSLYLQM WYFDL WGRGTL PGGSLRLSCAAS SYWMS KGLEWVA YVDSVKG NSLRAEDTAVYYCAR VTVSSA 5.91 479 VH3-7 -NA- JH2 EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSEKY RFTISRDNAKNSLYLQM DSWWYFDL WGRGTL PGGSLRLSCAAS SYWMS KGLEWVA YVDSVKG NSLRAEDTAVYYCAR VTVSSA 603 Germline EVQLVESGGGLVQ GFTFS WVRQAPG NIKQDGSEKY RFTISRDNAKNSLYLQM AAAFDY WGQGTL PGGSLRLSCAAS SYWMS KGLEWVA YVDSVKG NSLRAEDTAVYYCAR VTVSSA 5.88 461 VH3-7 D6-13 JH4B EVQMVESGGGLVQ GFTLR WVRQAPG NIKEDGSEKY RFTISRDNAENSLFLQM DMEASAG WGQGTL PGGSLRLSCAAS SYWMS KGLEWVA HVDSVKG SSLRAEDTAVYYCAR LFDY VTVSSA 5.88.1 465 '' '' '' EVQMVESGGGLVQ GFTLR WVRQAPG NIKEDGSEKY RFTISRDNAENSLFLQM DMEASAG WGQGTL PGGSLRLSCAAS SYWMS KGLEWVA HVDSVKG SSLRAEDTAVYYCAR LFDY VTVSSA 604 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM YSNYYFDY WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCA VTVSSA 5.89 473 VH3-33 D4-11 JH4B QVQLVESGGGVVQ GFTFR WVRQAPG VIWYDGSYKN RFTISRDNSKNTLYLQM DYSNYEE WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YGDSVKG NSLRAEDTAVYYCAR YFDY VTVSSA 605 Germline QITLKESGPTLVK GFSLS WIRQPPG LIYWNDDKRY RLTITKDTSKNQVVLTM RSSSWFDY WGQGTL PTQTLTLTCTFS TSGVG KALEWLA SPSLKS TNMDPVDTATYYCAH VTVSSA VG 5.115 529 VH2-5 D6-13 JH4B QITLKESGPTLVK GFSLS WIRQPPG FIYWNDDKRY RLTITKDTSKNQVVLTM RPDSSSW WGQGTL PTQTLTLTCTLS ISGVG KALEWLA SPSLKS TNMDPVDTATYYCAH DFDY VTVSSA VG 606 Germline EVQLVESGGGLVK GFTFS WVRQAPG SISSSSSYIY RFTISRDNAKNSLYLQM GIAFDY WGQGTL PGGSLRLSCAAS SYSMN KGLEWVS YADSVKG NSLRAEDTAVYYCAR VTVSSA 5.64 385 VH3-21 D2-2 JH4B EVQLVESGGGLVK GFTFN WVRQAPG SITSSSHYIY RFTISRDNAKNSLYLQM DRGIAAP WGQGTL PGGSLRLSCAAS SYRMN KGLEWVS YADSVKG NSLRAEDTAVYYCAR FDY VTVSSA 607 Germline QVQLVQSGAEVKK GYTFT WVRQAPG WINPNSGGTN RVTMTRDTSISTAYMEL GIAAAGF WGQGTL PGASVKVSCKAS GYYMH QGLEWMG YAQKFQG SRLRSDDTAVYYCAR DY VTVSSA 5.39.1 313 VH1-2 D6-13 JH4B QVQLVQSGAEVTK GYTFT WVRQAPG WINPNSGGTN RVTMTRDTSISTAYMEL DQGIAAA WGQGTL PGASVKVSCKAS AYHMY QGLEWMG YAQKFQG SRLRSDDSPVYYCAR GPFDY VTVSSA 5.16.1 239 '' '' '' QVQLVQSGAEVKK GYTFT WVRQAPG WINPNSSGTN RVTMTRDTSISTAYMEL DQDIATA WGQGTL PGASVKVSCKAS GFYMY QGLEWMG HAQKFQG SRLRSDDTAVYYCAR GPFDY VTVSSA 5.86.1 453 '' '' '' QVQLVQSGAEVKK GYTFT WVRQAPG WINPNSGGTN RVTMTRDTSISTAYMEL DQGIAAA WCQGTL PGASVKVSCKAS GYHMY QGLEWLG YAQKFQG SRLRSDDTAVYYCVR GPFDY VTVSSA 608 Germline QVQLQESGPGLVK GGSIS WIRQPAG RIYTSGSTNY RVTMSVDTSKNQFSLKL GITFDP WGQGTL PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 5.79 433 VH4-4 D1-20 JH5B QVQLQESGPGLVK GGSIS WIRQPAG RIYTSGSTNY RVTMSVDTSKNQFSLKL GITGYGG WGQGTL PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR FDP VTVSSA 5.23 263 '' '' '' QVQLQESGPGLVK GDSIN WIRQPAG RIYTSGSTNY RVTMSVDTSKNQFSLKL GITGYGG WGQGTL PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR FDP VTVSSA 609 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM GMDV WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCG VTVSSA 5.87 457 VH3-33 D3-16 JH6B QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM GATAMDV CGQGST PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAG GTVSSA 610 Germline EVQLVQSGAEVKK GYSFT WVRQMPG IIYPGDSDTR QVTISADKSISTAYLQW NWNFDI WGQGTM PGESLKISCKGS SYWIG KGLEWMG YSPSFQG SSLKASDTAMYYCAR VTVSSA 3.6 27 VH5-51 D1-7 JH3B EVQLVQSGAEVKK GYSFS WVRQMPG IIYPGDSDTR QVTISADKSISTAYLQW HENWN WGQGTM PGESLKISCKGS NYWIA KGLEWMG YSPSFQG SSLKASDTAMYYCAR FFDTFDI VTVSSA 611 Germline EVQLVESGGGLVK GFTFS WVRQAPG SISSSSSYIY RFTISRDNAKNSLYLQM IFGVVNW WGRGTL PGGSLRLSCAAS SYSMN KGLEWVS YADSVKG NSLRAEDTAVYYCAR YFDL VTVSSA 4.6 155 VH3-21 D3-3 JH2 EVQLVESGGGLVK GFTFS WVRQAPG SISSSSSYIY RFTISRDNAKNSLYLQM DGAIFGV WGRGTL PGGSLRLSCAAS SYSMN KGLEWVS YADSVKG NSLRAEDTAVYYCAR VNWYFDL VTVSSA 5.94 487 '' '' '' EVQLVESGGGLFK GFTFS WVRQAPG SISSSSSYIY RFTISRDNAKNSLYLQM DGAIFGV WGRGTL PGGSLRLSCAAS SYSMN KGLEWVS YADSVKG NSLRAEDTAVYYCAR VNWYFDL VTVSSA 5.58 367 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG SISSSSSYIY RFTISRDNAKNSLYLQM DGAIFGV WGRGTL PGGSLRLSCAAS SYSMN KGLEWVS YADSVKG NSLRAEDTAVYYCAR VNWYFDL VTVSSA 4.9 163 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG SISSSSSYIY RFTISRDNAKNSLYLQM DGAIFGV WGRGTL PGGSLRLSCAAS SYSMN KGLEWVS YADSVKG NSLRAEDTAVYYCAR VNWYFDL VTVSSA 5.70 399 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG SISSSSSYIY RFTISRDNAKNSLYLQM DGAIFGV WGRGTL PGGSLRLSCAAS SYSMN KGLEWVS YADSVKG NSLRAEDTAVYYCAR VNWYFDL VTVSSA 4.15 179 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG SISSSSSYIY RFTISRDNAKNSLYLQM DGAIFGV WGRGTL PGGSLRLSCAAS SYSMN KGLEWVS YADSVKG NSLRAEDTAVYYCAR VNWYFDL VTVSSA 4.8 159 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG SISSSSSYIY RFTISRDNAKNSLYLQM DGAIFGV WGRGTL PGGSLRLSCAAS SYSMN KGLEWVS YADSVKG NSLRAEDTAVYYCAR VNWYFDL VTVSSA 4.7 157 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG SISSSSSYIY RFTISRDNAKNSLYLQM DGAIFGV WGRGTL PGGSLRLSCAAS SYSMN KGLEWVS YADSVKG NSLRAEDTAVYYCAR VNWYFDL VTVSSA 612 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM QNYDFWS WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR GYGMDV VTVSSA 4.11 167 VH3-33 D3-3- JH6B QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM DFFQNYD WGQGTT D3-3 PGRSLRLSCAAS SYGMY KGLEWVA YADSVKG NSLRAEDTAVYYCAR FWSGSPV VTVSSA GYGMDV 613 Germline QVQLVQSGAEVKK GYTFT WVRQAPG WISAYNGNTN RVTMTTDTSTSTAYMEL VGADY WGQGTL PGASVKVSCKAS SYGIS QGLEWMG YAQKLQG RSLRSDDTAVYYCAR VTVSSA 6.6 547 VH1-18 D1-26 JH4B LVQSGAEVKKPGA GYTFT WVRQAPG WISAYNGNTN RVTMTTDTSTSTAYMEL GVGAKDY WGQGTL SVKVSCKAS SYGIS QGLEWMG YAQKLQD RSLRSDDTAVYYCAR VTVSSA 3.34 115 '' '' '' QVQLVQSGAEVKK GYTFT WVRQAPG WISTYNDNTN RVTMTTDTSTSTAYMEL GVGATDY WGQGTL PGASVKVSCKAS SYGIS QGLEWMG YAQKLQG RSLRSDDTAVYYCAR VTVSSA 5.30 285 '' '' '' QVQLVQSGAEVKK GYTFT WVRQAPG WISAHNGNTN RVTMTTDTSTSTAYMEL GVGSKDY WGQGTL PGASVKVSCKAS SYGIS QGLEWMG YAQKLQG RSLRSDDTAVYYCAR VTVSSA 614 Germline EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLYLQM SSGWYYY WGQGTT PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCT YYGMDV VTVSSA

5.55 361 VH3-15 D6-19 JH6B EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLYLQM GSSGWYE WGQGTT PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCTI AYYYYGM VTVSSA DV 5.7 209 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKYTLYLQM GSSGWYE WGQGTT PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCTI AYYYYGM VTVSSA DV 5.5 203 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKYTLYLQM GSSGWYE WGQGTT PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCTI AYYYYGM VTVSSA DV 615 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VISYDGSNKY RFTISRDNSKNTLYLQM DFWSNWF WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR DP VTVSSA 3.19 75 VH3-30 D3-3 JH5B QVQLVESGGGVVQ GFTFT WGRQAPG VISHDGNNKY RFTISRDNSKNTLYLQM EGIDFWS WGQGTL PGRSLRLSCAAS NYGMH KGLEWVA YVDSVKG NSLRAEDTAVYYCAR GLNWFDP VTVSSA 3.19.1 75 '' '' '' QVQLVESGGGVVQ GFTFT WGRQAPG VISHDGNNKY RFTISRDNSKNTLYLQM EGIDFWS WGQGTL PGRSLRLSCAAS NYGMH KGLEWVA YVDSVKG NSLRAEDTAVYYCAR GLNWFDP VTVSSA 616 Germline EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLYLQM YGDAFDI WGQGTM PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCT VTVSSA 5.72 405 VH3-15 D4-17 JH3B EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLYLQM YYGDFYA WGQGTM PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCTN FDI VTVSSA 3.14 59 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLYLQM FYGDFDA WGQGTM PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCII FDI- VTVSSA 3.17 67 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSENTLYLQM DYGDFYA WGQGTM PGGSLRLSCAAS NAWMH KGLDWVG ADYAAPVKG NSLKTEDTAVYYCTN FDI VTVSSA 617 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM GYCSGGY WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR GMDV VTVSSA 5.82 443 VH3-33 D2-15 JH6B QVQLVESGGGVVQ GFTFS WVRQAPG IIWFDGSNKY RFTISRDNSKNTLYLQM KGYCSGG WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG VSLRAEDTAVYYCAR RCVYGMDV VTVSSA 5.59 371 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG IIWYDGSNKY RFTISRDNSKNTLHLQM KGYCSGG WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR SCVYGMDV VTVSSA 5.92 481 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM KGYCSGG WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR RCVYGMDV VTVSSA 618 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM RYFDWDY WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR VTVSSA 6.5 545 VH3-33 D3-9 JH4B QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM GPLRYFD WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR WPSDY VTVSSA 6.2 535 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG LIWYAGSNKY RFTISRDNSKNTLYLQM GPLRYFD WGQGTL PGRSLRLSCAAS SYGMH KGLEWVS YADSVKG NSLRAEDTAVYYCAR WPSDY VTVSSA 3.8 35 '' '' '' QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM GPLRYFD WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR WPPDY VTVSSA 619 Germline QVQLVQSGAEVKK GYTFT WVRQAPG WISAYNGNTN RVTMTTDTSTSTAYMEL YSSFDY WGQGTL PGASVKVSCKAS SYGIS QGLEWMG YAQKLQG RSLRSDDTAVYYCAR VTVSSA 5.74 413 VH1-18 D6-19 JH4B QVQLVQSGAEVKK GYTFT WVRQAPG WICSYNGNTN RVTMTTDTSTTTAYMEL ESLYSSG WGQGTL PGASVKVSCKAS SYCIS RGLEWMG CAQKLQG RGLRSDDTAVYYCAR WFDY VTVSSA 620 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM DFWSNWF WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR DP VTVSSA 5.71 401 VH3-33 D3-3 JH5B QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM EGLDFWS WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR DFYNWFDP VTVSSA 621 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR VTVSSA 4.14 175 VH3-33 -NA- JH5B QVQLVESGGGVVQ GFTFS WVRQAPG VIWYDGSNKY RFTISRDNSKNTLYLQM ELAS WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR VTVSSA 6.1 533 '' '' '' QVLLVESGGGVVQ GFTFS WVRQAPG VIWFDGSKKY RFTISRDNSKNSLYLQM ELEL WGLGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR VTVSSA 622 Germline QVQLQESGPGLVK GGSIS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL TGDY WGQGTL PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCA VTVSSA 5.106 509 VH4-59 D7-27 JH4B QVQLQESGPGLVK GGSIS WIRQPPG YIYYSGSTNF RVTTSVDTSKNQFSLNL GTGASDY WGQGTL PSETLSLTCTVS SYYWS KGLEWIG NPSLKS RSVTAADTAVYYCAR VTVSSA 5.48 341 '' '' '' QVQLQESAPGLVK GGSIS WIRQPPG YISYSGSTNY RVTTSVDTSKNQFSLKL GTGASDY WGQGTL PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCTR VTVSSA 623 Germline QVQLVESGGGLVK GFTFS WIRQAPG YISSSGSTIY RFTISRDNAKNSLYLQM AFDI WGQGTM PGGSLRLSCAAS DYYMS KGLEWVS YADSVKG NSLRAEDTAVYYCAR VTVSSA 5.102 501 VH3-11 -NA- JH3B QVQLVESGGGLVK GFTFS WIRQAPG YISSSGSTIY RFTISRDNAKNSLYLQM ERGDAFDI WGQGTM PGGSLRLSCAAS DYYMS KGLEWVS YADSVKG NSLRAEDTAVYYCAR VTVSSA 5.24 267 '' '' '' QVRLVESGGGLVK GFTFS WIRQAPG YISSSGYSIY RFTISRDNAKNSLYLQM ERGDAFDI WGQGTM PGGSLRLSCAAS DYYMS KGLEWAS YADSVKG NSLRAEDTAVYYCAR VTVSSA 624 Germline EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLYLQM YGDYYFDY WGQGTL PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCT VTVSSA 5.1 191 VH3-15 D4-17 JH4B EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLYLQM TYGDYPY WGQGTL PGGSLRLSCAAS NAWMS KGLEWVG TDYAAPVKG NSLKIEDTAVYYCTI FDC VTVSSA 5.33 293 '' '' '' EVQLVESGGGLVK GFTFS WVRQAPG RIKSKTDGGT RFTISRDDSKNTLCLQL GYGDYPY WGQGTL PGGSLRLSCAAS NTWMS KGLEWVG TDYAAPVKG NSLKTEDTAVYYCSA FDF VTVSSA 625 Germline QVQLQESGPGLVK GGSIS WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL FDY WGQGTL PSETLSLTCTVS SYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 4.3 145 VH4-59 -NA- JH4B QVQLQESGPGLVK GGSIN WIRQPPG YIYYSGSTNY RVTISVDTSKNQFSLKL ERGDSFDY WGQGTL PSETLSLTCTVS NYYWS KGLEWIG NPSLKS SSVTAADTAVYYCAR VTVSSA 626 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VISYDGSNKY RFTISRDNSKNTLYLQM QLWDY WGQGTL PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR VTVSSA 5.60 373 VH3-30 D5-5 JH4B QVQLVESGGGVVQ GFTFS WVRQAPG VISYDGSNKY RFTISRDNSKNTLYLQM ERQLWLI WGQGTL PGRSLRLSCAAS GYDIH KGLEWVA YADSVKG NSLRAEDTAVYYCAR DY VTVSSA 627 Germline QVQLVESGGGVVQ GFTFS WVRQAPG VISYDGSNKY RFTISRDNSKNTLYLQM GIAVAYG WGQGTT PGRSLRLSCAAS SYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR MDV VTVSSA 5.75 417 VH3-30 D6-19 JH6B QVQLVESGGGVVQ GFTFS WVRQAPG VISYDGSNKY RFTISRDNSKNTLYLQM DRGIAVA WGQGNT PGRSLRLSCAAS GYGMH KGLEWVA YADSVKG NSLRAEDTAVYYCAR GYYGMDV VTVSSA

TABLE-US-00012 TABLE 12 Light chain analysis SEQ Chain ID Name NO: V J FR1 CDR1 FR2 CDR2 FR3 CDR3 J 628 Germline EIVLTQSPGTLS RASQSVSSSYLA WYQQKPGQ GASSRAT GIPDRFSGSGSGTDFT QQYGSSPWT FGQGTKVEIKR LSPGERATLSC APRLLIY LTISRLEPEDFAVYYC 5.77 423 A27 JK1 EVVLTQSPGTLS RASQSVSSSYLA WYNQKPGQ GASSRAT GIPDRFSGSGSGTDFT LQYGSSPWT FGQGTKVEIKR LSPGDRATLSC APRLLIF LTISRLEPEDFAVYYC 629 Germline DIQMTQSPSSLS QASQDISNYLN WYQQKPGK DASNLET GVPSRFSGSGSGTDFT QQYDN FGQGTKLEIKR ASVGDRVTITC APKLLIY FTISSLQPEDIATYYC 5.61 379 O18 JK2 DIQMTQSPSSLS QASQDISNYLN WYQQKPGK DASNLET GVPSRFSGSGSGTDFT QQYDNLCS FGQGTKLEIKR ASVGDRVTITC APKLLIY FTISRLQPEDIATYYC 630 Germline DIQMTQSPSSVS RASQGISSWLA WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQANSFPWT FGQGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 5.3 199 L5 JK1 DIQMTQSPSSVS RASQGIRSWLA WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQANSFPWT FGQGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 3.2 13 L5 JK1 DIQMTQSPSSVS RASQGISSWLA WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQAYSFRT FGQGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 5.34 295 L5 JK1 DIQMTQSPSSVS RASQGISSWLA WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQANSFPWT FGQGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 3.22 91 L5 JK1 DIQMTQSPFSVS RASQGISNWLA WYQQKPGK TASSLQN GVPSRFSGSGSGTDFT QQINSFPWT FGQGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 5.73 411 L5 JK1 DIQMTQSPSSVS RASQGISRWLA WYQQKPGK VASSLQS GVPSRFSGSGSGTDFT QQANSFPRT FGQGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 5.1 193 L5 JK1 DIQMTQSPSSVS RASQGIRSWLA WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQANSFPWT FGQGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 3.9 41 L5 JK1 DIQMTQSPSSVS RASQGISSWLA WYQQKPGK AASSLQS GVPSRFSGSGSGTDFI QQSNSFPRT FGQGTKVEIKR ASVGDRVTITC APNLLIY LTISSLQPEDFATYYC 5.81 441 L5 JK1 DIQMTQSPSSVS RASQGISSWLA WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQANSFPRT FGQGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 631 Germline ETTLTQSPAFMS KASQDIDDDMN WYQQKPGE EATTLVP GIPPRFSGSGYGTDFT LQHDNFPLT FGGGTKVEIKR ATPGDKVNISC AAIFIIQ LTINNIESEDAAYYFC 5.24 269 B2 JK4 ETTLTQSPAFMS KASQDIDDDMN WYQQKPGE EATTLVP GIPPRFSGSGYGTDFT LQHDNFPLT FGGGTKVEIKR ATPGDKVNISC VAIFIIQ LTINNIESEDAAYYFC 632 Germline DIQMTQSPSSLS RASQGISNYLA WYQQKPGK AASTLQS GVPSRFSGSGSGTDFT QKYNSAPFT FGPGTKVDIKR ASVGDRVTITC VPKLLIY LTISSLQPEDVATYYC 5.56.1 365 A20 JK3 DIQMTQSPSSLS RASQGISYYLA WYQQKPGK AASTLQS GVPSRFSGSGSGTDFT QKYNSAPFT FGPGTKVDIKR ASVGDRVTITC VPKLLIY LTISSLQPEDVATYYC 633 Germline EIVMTQSPATLS RASQSVSSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNNWPLT FGGGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 5.6 207 L2 JK4 EIVMTQSPATLS RASQSVSSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTELT QQYNNWPLT FGGGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 5.44 331 L2 JK4 EIVMTQSPATLS RASQSISSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNNWPLT FGRGTKVEIKR VSPGERATLSC APRLLIY LTISSLQPEDFAVYYC 5.38 311 L2 JK4 EIVMTQSPATLS RASQSVSGNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QHYNNWPLT FGGGTKVEIKR VSPGERVTLSC APRLLIY LTISSLQSEDFAVYYC 5.35 299 L2 JK4 EIVMTQSPATLS RASQSVSSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT EQYNNWPLT FGGGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 5.8 213 L2 JK4 EIVMTQSPATLS RASQSVRSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTELT HQYNNWPLT FGGGTKVEIKR VSLGERATLSC APRLLIY LTISSLQSEDFAVYYC 5.35.1 299 L2 JK4 EIVMTQSPATLS RASQSVSSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT EQYNNWPLT FGGGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 634 Germline DIQMTQSPSSLS RASQGIRNDLG WYQQKPGK AASSLQS GVPSRFSGSGSGTEFT LQHNSYPFT FGPGTKVDIKR ASVGDRVTITC APKRLIY LTISSLQPEDFATYYC 4.13 173 A30 JK3 DIQMTQSPSSLS RASQGIRDDLG WYQQKPGK AASSLQS GVPSRFSGSGSGTEFT LQYNSYPFT FGPGTKVDIKR ASVGDRVTITC APKRLTY LTISSLQPEDFATYYC 635 Germline EIVMTQSPATLS RASQSVSSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNNWPFT FGPGTKVDIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 5.28.1 279 L2 JK3 EIVMTQSPATLS RASQSVTSNLA WYQQKPGQ GALIRAT GIPARFSGSGSGTEFT QQYNNWPFT FGPGTKVDIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 5.28 279 L2 JK3 EIVMTQSPATLS RASQSVTSNLA WYQQKPGQ GALIRAT GIPARFSGSGSGTEFT QQYNNWPFT FGPGTKVDIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 636 Germline DIQMTQSPSSLS RASQGIRNDLG WYQQKPGK AASSLQS GVPSRFSGSGSGTEFT LQHNSYP FGQGTKLEIKR ASVGDRVTITC APKRLIY LTISSLQPEDFATYYC 4.4 149 A30 JK2 DIQMTQSPSSLS RASQGIRNDLG WYQQKPGK AASSLQS GVPSRFSGSRSGTEFT LQHNSYPPS FGQGTKLEIKR ASVGDRVTITC APKRLIY LTISSLQPEDFATYYC 3.33 113 A30 JK2 DIQMTQSPSSLS RASQGIRNDLG WYQQKPGK AASSLQS GVPSRFSGSRSGTEFT LQHNSYPPS FGQGTKLEIKR ASVGDRVTITC APKRLIY LTISSLQPEDFATYYC 3.39 127 A30 JK2 DIQMTQSPSSLS RASQGIRNDLG WYQQKPGK AASSLQS GVPSRFSGSRSGTEFT LQHNSYPPS FGQGTKLEIKR ASVGDRVTITC APKRLIY LTISSLQPEDFATYYC 637 Germline DIQMTQSPSSLS RASQGIRNDLG WYQQKPGK AASSLQS GVPSRFSGSGSGTEFT LQHNSYPRT FGQGTKVEIKR ASVGDRVTITC APKRLIY LTISSLQPEDFATYYC 3.26 95 A30 JK1 DIQMTQSPSSLS RASQGIRNDLG WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT LQHNNYPRT FGQGTKVEIKR ASVGDRVTITC APKRLIY LTISSLQPEDFATYYC 3.11 49 A30 JK1 DIQMTQSPSSLS RASQGIRNDLG WYQQKPGK AASSLQS GVPSRFSGSGSGTEFT LQLNSYPRT FGQGTKVEIKR TSVGDRVTITC APKRLIY LTISSLRPEDFATYYC 3.1 9 A30 JK1 DIQMTQSPSSLS RASQGIRNDLG WYQQKPGK AASSLQS GVPSRFSGSGSGTEFT LQHNSYPRT FGQGTKVEIKR ASVGDRVTITC APKRLIY LTISSLQPEDFATYYC 4.15 181 A30 JK1 DIQMTQSPSSLS RASQGIRNDLG WYQQKPGK AASSLQS GVPSRFSGSGSGTEFT LQHNSYPPT FGQGTKVEIKR ASVGDRVTITC APKRLIY LTISSLQPEDFATYYC 3.18 73 A30 JK1 DIQMTQSPSSLS RASQGIRNDLG WYQQKPGK AASSLQS GVPSRFSGSGSGTEFT LQYNSYPRT FGQGTKVEIKR ASVGDRVTITC APKRLIY LTISSLQPEDFATYYC 638 Germline EIVMTQSPATLS RASQSVSSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNNWPRT FGQGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 5.16.1 241 L2 JK1 EIVMTQSPATLS RASQSVSSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNNWWT FGRGTKVEIKR VSPGERATLSC APRLLIF LTISSLQSEDFAVYYC 5.40.2 319 L2 JK1 EIVMTQSPATLS RASQSVSSNLV WYQQKPGQ DSSTRAT GIPVRFSGSGSGTEFT QQYNHWWT FGQGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 5.41.1 323 L2 JK1 EIVMTQSPATLS RASQSVSSNLV WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNHWWT FGQGTKVEIKR VSPGERATLSC APRFLIY LTISSLQSEDFAVYYC 6.4 543 L2 JK1 EIVMTQSPATLS RASQSLISNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT HQYNNWWT FGQGTKVEIKR VSPGERATLSC APRQLLF LTISSLQSEDFAVYYC 5.103.1 505 L2 JK1 ETVMTQSPATLS RASQSVISSLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNNWWT FGQGTKVEIKR VSPGERVTLSC APRLLIY LTISSLQSEDFAVYYC 5.54.1 359 L2 JK1 EIVMTQSPATLS RASQSLISNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT HQYNNWWT FGQGTKVEIKR VSPGERATLSC APRLLIF LTISSLQSEDFAVYYC 5.13 231 L2 JK1 EIVMTQSPATLS RASQSVSSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNHWWT FGQGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 3.31.1 101 L2 JK1 EVVMTQSPATLS RASQSVGSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNHWWT FGQGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYCC 5.88.1 467 L2 JK1 EIVMTQSPATLS RASQSISSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNYWWT FGQGTKVEIKR VSPGERAILSC APRLLIY LTISSLQSEDFAVYYC 3.3 17 L2 JK1 EIVMTQSPATLS RASQTVSSDLA WYQQKPGQ GASIRAT GIPARFSGSGSGTEFT QQYYNWWT FGQGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYSC 5.62 383 L2 JK1 EIVMTQSPATLS RASQSVSSNLA WYQQKPGQ GAFTRAT GIPARFSGSGSGTEFT QQYNHWWT FGQGTKVGIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 5.101 499 L2 JK1 EIVMTQSPATLS RASQSLISNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT HQYNNWWT FGQGTKVEIKR VSPGERATLSC APRLLIF LTISSLQSEDFAVYYC 5.52 349 L2 JK1 EIVMTQSPATLA RARQSVSSNLA WYQQKPGQ GASTMAT GFPARFSGRGSGTEFT QQYNNWWT FGQGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 5.16 241 L2 JK1 EIVMTQSPATLS RASQSVSSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNNWWT FGRGTKVEIKR VSPGERATLSC APRLLIF LTISSLQSEDFAVYYC 5.39 315 L2 JK1 EIVMTQSPATLS RASQSVSSNFA WYQQKPGQ GSSTRAT GIPARFSGSGSGTEFT QQYHYWWT FGQGTKVEFKR VSPGDRATLSC APRLLIY LTISSLQSEDFAVYYC 3.6 29 L2 JK1 EIVMTQSPATLS RASQSISSNLA WFQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNNWPRT FGQGTTVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 5.39.1 315 L2 JK1 EIVMTQSPATLS RASQSVSSNFA WYQQKPGQ GSSTRAT GIPARFSGSGSGTEFT QQYHYWWT FGQGTKVEFKR VSPGDRATLSC APRLLIY LTISSLQSEDFAVYYC 5.15 237 L2 JK1 EIVMTQSPATLS RASQTVISNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNNWWT FGQGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFALYYC 5.83.1 451 L2 JK1 EIVMTQSPATLS RASQSLISNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT HQYNNWWT FGQGTKVEIKR VSPGERATLSC APRLLIF LTISSLQSEDFAVYYC 5.41 323 L2 JK1 EIVMTQSPATLS RASQSVSSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNHWWT FGQGTKVEIKR VSPGERATLSC APRFLIY LTISSLQSEDFAVYYC 5.62.1 383 L2 JK1 EIVMTQSPATLS RASQSVSSNLA WYQQKPGQ GAFTRAT GIPARFSGSGSGTEFT QQYNHWWT FGQGTKVGIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC

5.64 387 L2 JK1 EIVMTQSPATLS RASQSVSSNLA WYQQKPGQ GASTRAT GFPARFSGSGSGTEFT QQYNNWWT FGQGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 5.101.1 499 L2 JK1 EIVMTQSPATLS RASQSLISNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT HQYNNWWT FGQGTKVEIKR VSPGERATLSC APRLLIF LTISSLQSEDFAVYYC 5.103 505 L2 JK1 ETVMTQSPATLS RASQSVISSLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNNWWT FGQGTKVEIKR VSPGERVTLSC APRLLIY LTISSLQSEDFAVYYC 5.54 359 L2 JK1 EIVMTQSPATLS RASQSLISNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT HQYNNWWT FGQGTKVEIKR VSPGERATLSC APRLLIF LTISSLQSEDFAIYYC 5.13.1 231 L2 JK1 EIVMTQSPATLS RASQSVSSNLA WYQQKPGQ GASTRAT GIPARFSGSGSGTEFT QQYNHWWT FGQGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 5.109 519 L2 JK1 EIVMTQSPATLS RASQSVSSYLA WYQQKPGQ GAFTRAT GIPARFRGSGSGPEFT QQYSHWWT FGQGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 5.108.1 515 L2 JK1 EIVMTQSPATLS RASQSVSSYLA WYQQKPGQ GAFTRAT GIPARFRGSGSGPEFT QQYSHWWT FGQGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYYC 3.3.1 21 L2 JK1 EIVMTQSPATLS RASQTVSSDLA WYQQKPGQ GASIRAT GIPARFSGSGSGTEFT QQYYNWWT FGQGTKVEIKR VSPGERATLSC APRLLIY LTISSLQSEDFAVYSC 639 Germline DIVMTQSPLSLP RSSQSLLHSNG WYLQKPGQ LGSNRAS GVPDRFSGSGSGTDFT MQALQTPIT FGQGTRLEIKR VTPGEPASISC YNYLD SPQLLIY LKISRVEAEDVGVYYC 5.92 483 A3 JK5 DIVMTQSPLSLP RSSQSLLYSNG WYLQKPGQ LGSNRAS GVPDRFSGSGSGTDFT MQALQTPIT FGQGTRLEIKR VTPGEPASISC YNYLD SPQVLIY LKISRVEAEDVGVYYC 5.82 445 A3 JK5 DIVMTQSPLSLP RSSQSLLHSNG WYLQKPGQ LGSNRAS GVPDRFGGSGSGTDFT MQALQTPIT FGQGTRLEIKR VTPGEPASISC YNYLD SPQLLIY LKISRVEAEDVGVYYC 640 Germline DVVMTQSPLSLP RSSQSLVYSDG WFQQRPGQ KVSNWDS GVPDRFSGSGSGTDFT MQGTHWPPLT FGGGTKVEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAEDVGVYYC 3.41 135 A1 JK4 DVVMTQSPLSLP RSSQSLVYSDG WFQQRPGQ KVSNWDS GVPDRFSGSGSGTDFT MQGTHWPLT FGGGTNVEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAEDVGVYYC 3.40 131 A1 JK4 DVVMTQSPLSLP RSSQSLVYSDG WFQQRPGQ KDSNWDS GVPDRFSGSGSGTDFT MQGTHWPLT FGGGTNVEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAEDVGVYYC 3.13 57 A1 JK4 DVVMTQSPLSLP RSSQSLVYSDG WFQQRPGQ KVSNWDS GVPDRFSGSGSGTDFT MQGTHWPPLT FGGGTKVEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAEDVGVYYC 3.12 53 A1 JK4 DVVMTQSPLSLP RSSQSLVYSDG WFQQRPGQ KVSNWDS GVPDRFSGSGSGTDFT MQGTHWPPLT FGGGTKVEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAEDVGVYYC 3.32 109 A1 JK4 DVVMTQSPLSLP RSSQSLVYSDG WFQQRPGQ KVSNWDS GVPDRFSGSGSGTDFT MQGTHWPPLT FGGGTKVEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAEDVGVYYC 4.18 189 A1 JK4 DVVMTQSPLSLP RSSQSLVYSDG WFQQRPGQ KVSNWDS GVPDRFSGSGSGTDFT MQGTHWPLT FGGGTNVEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAEDVGVYYC 4.16 185 A1 JK4 DVVMTQSPLSLP RSSQSLVYSDG WFQQRPGQ KVSNWDS GVPDRFSGSGSGTDFT MQGTHWPPLT FGGGTKVEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAEDVGVYYC 3.7 33 A1 JK4 DVVMTQSPLSLP RSSQSLVYSDG WFQQRPGQ KVSNWDS GVPDRFSGSGSGTDFT MQGTHWPPLT FGGGTKVEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAEDVGVYYC 4.14 177 A1 JK4 DVVMTQSPLSLP RSSQSLVYSDG WFQQRPGQ KVSNWDS GVPDRFSGSGSGTDFT MQGTHWPPLT FGGGTKVEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAEDVGVYYC 3.15 63 A1 JK4 DVVMTQSPLSLP RSSQSLVYSDG WFQQRPGQ KVSNWDS GVPDRFSGSGSGTDFT MQGTHWPPLT FGGGTKVEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAEDVGVYYC 641 Germline DIVMTQSPLSLP RSSQSLLHSNG WYLQKPGQ LGSNRAS GVPDRFSGSGSGTDFT MQALQTPLT FGGGTKVEIKR VTPGEPASISC YNYLD SPQLLIY LKISRVEAEDVGVYYC 3.10 45 A3 JK4 DIVMTQSPLSLP RSSQSLLHSNG WYLQKPGQ LGSNRAS GVPDRFSGSGSGTDST MQALQTPLT FGGGTKVEIKR VTPGEPASISC YNYLD SPQLLIY LKISRVEAEDVGVYYC 3.37 123 A3 JK4 DIVMTQSPLSLP RSSQSLLHSDG WYLQKPGQ LGSNRAS GVPDRFSGSGSCTDFT MQALQTPHF FGGGTKVEIKR VTPGEPASISC YNYLD SPQLLIY LKISRVEAEDVGIYYC 642 Germline DIVMTQSPDSLA KSSQSVLYSSN WYQQKPGQ WASTRES GVPDRFSGSGSGTDFT QQYYSTPIT FGQGTRLEIKR VSLGERATINC NKNYLA PPKLLIY LTISSLQAEDVAVYYC 5.78 427 B3 JK5 DIVMTQSPDSLA KSSQSVLYSSN WYQQKPGQ WASTRES GVPDRFSGSGSGTDFT HQYYSTPIT FGQGTRLEIKR VSLGERATINC NQNFLA PPKLLIY LTISSLQAEDVAVYYC 5.90 477 B3 JK5 DIVMTQSPDSLA KSSQSVIYSSN WYQHKPGQ WASTRES GVPDRFSGSGSGTDFT HQYYSTPIT FGQGTRLEIKR VSLGEKATINC NQNFLA PPKLLIY LTISSLQAEDVAVYYC 5.78.1 431 B3 JK5 DIVMTQSPDSLA KSSQSVLYSSN WYQQKPGQ WASTRES GVPDRFSGSGSGTDFT HQYYSTPIT FGQGTRLEIKR VSLGERATINC NQNFLA PPKLLIY LTISSLQAEDVAVYYC 643 Germline DVVMTQSPLSLP RSSQSLVYSDG WFQQRPGQ KVSNWDS GVPDRFSGSGSGTDFT MQGTHW FGQGTKLEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAEDVGVYYC 4.3 147 A1 JK2 DVVMTQSPLSLP RSSRSLVYSDG WFQQRPGQ KVSNWDS GVPDRFSGSGSGTDFT MQGTHWPCS FGQGTKLEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAADVGVYYC 644 Germline DIVMTQSPDSLA KSSQSVLYSSN WYQQKPGQ WASTRES GVPDRFSGSGSGTDFT QQYYSTT FGGGTKVEIKR VSLGERATINC NKNYLA PPKLLIY LTISSLQAEDVAVYYC 5.43 327 B3 JK4 DIVMTQSPDSLA KSSQSVLYSSN WYQQKPGQ WSSTRES GVPDRFSGSGSGTDFT QQYYSTPLT FGGGTKVEIKR VSLGERATINC NKNYLA PPKLLIY LTISSLQAEDVAVYYC 645 Germline DVVMTQSPLSLP RSSQSLVYSDG WFQQRPGQ KVSNWDS GVPDRFSGSGSGTDFT MQGTHWPPT FGQGTKVEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAEDVGVYYC 3.20 83 A1 JK1 DVVMTQSPLSLP RSSQSLVYSDG WFQQRPGQ KVSKWDS GVPDRFSGSGSGTDFT MQGTHWPPT FGQGTKVEIKR VTLGQPASISC NTYLN SPRRLIY LKISRVEAEDVGVYYC 646 Germline DIVMTQSPLSLP RSSQSLLHSNG WYLQKPGQ LGSNRAS GVPDRFSGSGSGTDFT MQALQWT FGQGTKVEIKR VTPGEPASISC YNYLD SPQLLIY LKISRVEAEDVGVYYC 5.9 647 A3 JK1 DIVMTQSPLSLP RSSQSLLHSNG WYLQKPGQ LGSNRAS GVPDRFSGSGSGTDFT MQALQTPWT FGQGTKVEIKR VTPGEPASISC YNYLD SPQLLIY LKISRVEAEDVGVYYC 4.11 169 A3 JK1 DIVMTQSPLSLP RSSQSLLYSNG WYLQKPGQ LGSNRAS GVPDRFGGSGSGTDFT MQALQTPWT FGQGTKVEIKR VTPGEPASISC YNYLD SPQLLIY LKISRVEAEDVGVYYC 648 Germline DIQMTQSPSSLS RASQSISSYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSTT FGGGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 5.115 531 O12 JK4 DIEMTQSPSSLS RASQNISSYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSSPLT FGGGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 5.66 391 O12 JK4 DIQMTQSPSSLS RASQSISSYFN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSTPLT FGGGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 5.72 407 O12 JK4 DIQMTQSPSSLS RASQTISSYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQTYSKSLT FGGGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 5.114 527 O12 JK4 DIEMTQSPSSLS RASQNISSYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSSPLT FGGGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 4.5 153 O12 JK4 DIQMTQSPSSLS RASQSISIYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSTPLT FGGGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 649 Germline DIVMTQSPDSLA KSSQSVLYSSN WYQQKPGQ WASTRES GVPDRFSGSGSGTDFT QQYYST FGQGTKLEIKR VSLGERATINC NKNYLA PPKLLIY LTISSLQAEDVAVYYC 3.42 139 B3 JK2 DIVMTQSPDSLA RSSQSILFSSN WYQQKPGQ WASTRES GVPARFSGSGSGTDFT QQYYSTPCS FGQGTRLEIKR VSLGERATINC NKNYLA PPKLLLY LTISSLQAEDVAVYYC 5.60 375 B3 JK2 DIVMTQSPDSLA KSSQSVLYSSN WYQQKPGQ WASTRES GVPDRFSGSGSGTDFT QQYYNTPCS FGQGTKLEIKR VSLGERATINC NKNYLV PPKLLIY LTISSLQAEDVAVYYC 650 Germline EIVLTQSPGTLS RASQSVSSSYLA WYQQKPGQ GASSRAT GIPDRFSGSGSGTDFT QQYGIT FGQGTRLEIKR LSPGERATLSC APRLLIY LTISRLEPEDFAVYYC 5.58 369 A27 JK5 EIVLTQSPGTLS RASQSVSSSYLA WYQQKAGQ GASSRAT GIPDRFSGSGSGTDFT QQYGWSSIT FGQGTRLEIKR LSPGERATLSC APRLLIY LTISRLEPEDFAVYYC 3.19.1 77 A27 JK5 EIVLTQSPGTLS RASQSITGSYLA WYQQKPGQ GASSWAT GIPDRFSGSGSGTDFT QQYSSSPIT FGQGTRLEIKR LSPGERATLSC APRLLIC LTISRLEPEDFAVYYC 651 Germline DIQMTQSPSSLS RASQGISNYLA WFQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQYNSYPLT FGGGTKVEIKR ASVGDRVTITC APKSLIY LTISSLQPEDFATYYC 3.16 65 L1 JK4 DIQMTQSPSSLS RASQGISSYLA WFQQKPGK AASSLQS GVPSKFSGSGSGTDFT QQYNSYPLT FGGGTKVEIKR ASVGDRVTITC APKSLIY LTISSLQPEDFATYYC 5.67 395 L1 JK4 DIQMTQSPSSLS RASQGISNYLA WFQQKPGK AASSLQT GVPSKFSGNGSGTDFT QQYNSYPLT FGGGTKVEIKR ASVGDRVTITC APESLIY LTISSLQPEDFATYYC 652 Germline DIQMTQSPSSLS RASQSISSYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSTPFT FGPGTKVDIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 5.86 455 O12 JK3 DIRMTQSPSSLS RASQRISTYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYTTPFT FGPGTKVDIKR ASVGDRVTITC APKFLIY LTISSLQPEDFATYYC 5.71 403 O12 JK3 DIQMTQSPSSLS RASQSISNYLN WYQQKPGK TASSLQS GVPSRFSGSGSGTDFT QQSYSTPFT FGPGTKVGIKR ASVGDRVTITC APKLLIF LTISSLQPEDFATYFC 5.25 271 O12 JK3 DIRMTQSPSSLS RASQRISSYLN WFQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSTPFT FGPGTKVDIKR ASVGDRVTITC APKFLIY LTISSLQPEDFATYYC 5.74 415 O12 JK3 DIRMTQSPSSLS RASQRISTYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYTTPFT FGPGTKVDIKR ASVGDRVTITC APKFLIY LTISSLQPEDFATYYC 3.14 61 O12 JK3 DIQMTQSPSSLS RASQSISSYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSLT FGPGTKVDIKR ASVGDRVTITC APKLLIY LTISSLQAEDFATYYC 5.111 523 O12 JK3 DIQMTQSPSSLS RASQSIITFLN WFQHKPGK GASSLES GVPSRFSGSGSGTNFT QQSYSDPFT FGPGTKVDIKR ASVGDRVTFTC APKLLFY LTISSLQPEDFATYYC 5.87 459 O12 JK3 DIRMTQSPSSLS RASQGIRTYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQNYTTPFT FGPGTKVDIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 4.2 143 O12 JK3 DIQMTQSPSSLS RASQSISFYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSSPFT FGPGTKVDIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 5.86.1 455 O12 JK3 DIRMTQSPSSLS RASQRISTYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYTTPFT FGPGTKVDIKR

ASVGDRVTITC APKFLIY LTISSLQPEDFATYYC 3.17 69 O12 JK3 DIQMTQSPSSLS RARQSISSYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSTPFT FGPGAKVDIKR ASVGDRITITC APKLLIY LTISSLQPEDFATYFC 5.11 223 O12 JK3 DIQMTQSPSSLS RASQSISNYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSIPFT FGPGTKVDIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 5.45 335 O12 JK3 DIQMTQSPSSLS RASQSISSYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYINPFT FGPGTKVDIKR ASVGDRVTITC APELLIY LTISSLQPEDFATYYC 5.12 227 O12 JK3 DIQMTQSPSSLS RASQSISNYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSIPFT FGPGTKVDIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 653 Germline EIVLTQSPGTLS RASQSVSSSYLA WYQQKPGQ GASSRAT GIPDRFSGSGSGTDFT QQYGSST FGGGTKVEIKR LSPGERATLSC APKLLIY LTISRLEPEDFAVYYC 6.2 537 A27 JK4 EIVLTQSPGTLS RASQSFSSSYLA WFQQKPGQ GASNRAT GIPDRFSGSGSGTDFT HHFGTSPLT FGGGTKVEIKR LSPGERATLSC APRLLIY LTISRLEPEDFAVYYC 654 Germline DIQMTQSPSSLS QASQDISNYLN WYQQKPGK DASNLET GVPSRFSGSGSGTDFT QQYDNLPIT FGQGTRLEIKR ASVGDRVTITC APKLLIY FTITSLQPEDIATYYC 5.23 265 O18 JK5 DIQMTQSPSSLS QASQDISNYLN WYQQKPGK DASNLET GVPSRFSGSGSGTDFT QQYYNLPIT FGQGTRLEIKR ASVGDRVTITC APNLLIY FTITSLQPEDIATYYC 5.17 245 O18 JK5 DIQMTQSPSSLS QASQDIRNYLN WYQQKPGK DASNLET GVPSRFSGSGSGTDFT QQYANLPIT FGQGTRLEIKR TSVGDRVTITC APKLLIH FTITSLQPEDIATYYC 5.29 283 O18 JK5 DIQMTQSPSSLS QASQDIRNYLN WYQQKPGK DASNLET GVPSRFSGSGSGTDFT QQYDNLPIT FGQGTRLEIKR ASVGDRVTITC APKLLIY FTISSLQPEDIATYYC 5.76 421 O18 JK5 DIQMTQSPSSLS QASQDIRNYLN WYQQKPGT DASNLET GVPSRFSGSGSGTDFT QQYDNLPIT FGQGTRLEIKR ASVGDRVTITC APKLLIY FTISSLQPEDIATYYC 5.10 219 O18 JK5 DIQMTQSPSSLS QASQDIRNYLN WYQQKPGK DASNLET GVPSRFSGSGSGTDFT QQYDNLPIT FGQGARLEIKR ASVGDRVTITC APKLLIY FTISSLQPEDIATYYC 5.22 261 O18 JK5 DIRMTQSPSSLS QASQDIRNYLN WYQQKPGK DASNLET GVPSRFSGSGSGTDFT QQYDNLPIT FGQGTRLEIKR ASVGDSVTITC APKLLIY FTISSLQPEDIATYYC 5.37 307 O18 JK5 DIQMTQSPSSLS QASQDIRNYLN WYQQKPGK DASNLET GVPSRFSGSGSGTDFT QQYDNLPIT FGQGTRLEIKR ASVGDRVTITC APKLLIY FTISSLQPEDIATYYC 5.31 291 O18 JK5 DIQMTQSPSSLS QASQDIRNYLN WYQQKPGK DASNLET GVPSRFSGSGSGTDFT QQYDNLPIT FGQGTRLEIKR ASVGDRVTITC APKLLIY FTISSLQPEDIATYYC 655 Germline DIQMTQSPSSLS RASQGISNYLA WFQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQYNSYT FGPGTKVDIKR ASVGDRVTITC APKSLIY LTISSLQPEDFATYYC 3.34 117 L1 JK3 DIQMTQSPSSLS RASQGISNYLA WFQQKPGK AASSLQS GVPSKFSGSGSGTDFT QQYNSYPST FGPGTKVDIKR ASVGDRVSIIC APKSLIY LTISSLQPEDFATYYC 5.99 495 L1 JK3 DIQMTQSPSSLS RASQDISNYLA WFQQKPGK AASSLQS GVPSQFSGSGSGTDFT QQYNNYPFT FGPGTKVDVKR ASVGDRVTITC APKSLIY LTISSLQPEDFATYYC 656 Germline DIQMTQSPSSLS RASQSISSYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSTP FGQGTKLEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 6.3.1 541 O12 JK2 DIQMTQSPSSLS RASQSIRSYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSTLCS FGQGTKLEIKR ASVGDRVTITC APKVLIY LTISSLQPEDFATYYC 5.97 493 O12 JK2 DIQMTQSPSSLS RASQSIRSYLN WYQQKPGK AASSLQR GVPSRFSGSGSGTDFT QQSYTTPLCS FGQGTRLEIKR ASVGTRVTITC APKLLIY LTISSLQAEDFATYYC 5.27 275 O12 JK2 DIQMTQSPSSLS RASQSISSYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSCSTPPE FGQGTKLEIKR ASVGDRVTITC APKILIY LTISSLQPEDFATYYC CS 5.21 257 O12 JK2 DIQMTQSPSSLS RASQSISSYLN WYQQKPGK AASSLQS GVPSRFSGSRSGTDFT QQSYSVPCS FGQGTKLEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 6.3 657 O12 JK2 DIQMTQSPSSLS RASQSIRSYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSTLCS FGQGTKLEIKR ASVGDRVTITC APKVLIY LTISSLQPEDFATYYC 5.93 485 O12 JK2 DIQMTQSPSSLS RASQSISSYLN WYQQKPGK GASSLQS GVPSRFSGSGSGTDFT QQSYSTLCS FGQGTKLEIKR ASVGDRVTITC APKVLIY LTISSLQPEDFATYYC 658 Germline DIQMTQSPSSVS RASQGISSWLA WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQANSFPLT FGGGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 5.95 489 L5 JK4 DIQMTQSPSSVS RASQGISSWLA WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQANSFPLT FGGGTKVEIKR ASVGDRVTITC APKLLIF LTISSLQPEDFATYYC 5.52.1 353 L5 JK4 DIQMTQSPSSVS RASQGISSWLA WYQQKPGK AVSSLES GVPSRFSGSGSGTDFT QQALT FGGGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 659 Germline EIVLTQSPGTLS RASQSVSSSYLA WYQQKPGQ GASSRAT GIPDRFSGSGSGTDFT QQYGSSPFT FGPGTKVDIKR LSPGERATLSC APRLLIY LTISRLEPEDFAVYYC 3.8 37 A27 JK3 EIVLTQSPGTLS RASQSVSSSYLA WYQQKPGQ GASNRAT GIPDRFSASGSGTDFT QQFGTSPFT FGPGTKVDIKR LSPGERATLSC APRLLIY LTISRLEPEDFAVYYC 3.21 87 A27 JK3 EIVLTQSPGTLS RASQSVSSSYLA WYQQKPGQ GTSSRAT GIPDRFSGSGSGTDFT QQYGSSLFT FGPGTKVDIKR LSPGERATLSC APRLLIY LTISRLEPEDFAVYYC 660 Germline DIQMTQSPSSLS QASQDISNYLN WYQQKPGK DASNLET GVPSRFSGSGSGTDFT QQYDNLT FGGGTKVEIKR ASVGDRVTITC APKLLIY FTISSLQPEDIATYYC 5.18 249 O18 JK4 DIQMTQSPSSLS QASQDITNYLN WYQKKPGK DASNLET GVPSRFSGSGSGTGFT QQYDHIPLT FGGGTKVEIKR ASVGDRVTITC APKVLIY FTISSLQPEDIATYYC 5.48 343 O18 JK4 DIQMTQSPSSLS QASQDITNYLN WYQQKPGK DASNLET GVPSRFSGSGSGTDFT QQYDNLPLT FGGGTKVEIKR ASVGDRVTITC APKLLIY FTISSLQPEDIATYFC 661 Germline DIQMTQSPSSLS RASQSISSYLN WYQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQSYSTPT FGQGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 5.36 303 O12 JK1 DIQMTQSPSSLS RASQSISSYLN WYQQKPGK GASSLQS GVPSRFSGSGSGTDFT QQSYSIPRT FGQGTKVEIKR ASVGDRVTITC APKLLIY LTISSLQPEDFATYYC 662 Germline DIQMTQSPSSLS RASQGISNYLA WFQQKPGK AASSLQS GVPSRFSGSGSGTDFT QQYNSYPRT FGQGTKVEIKR ASVGDRVTITC APKSLIY LTISSLQPEDFATYYC 5.80 437 L1 JK1 DIQMTQSPSSLS RASQDISNYLA WFQQKPGK AASSLQS GVPSKFSGSGSGTDFT QQYNSYPRT FGQGTKVEIKR ASVGDRVTITC APKSLIY LTISSLQPEDFATYYC 6.10 557 L1 JK1 DIQMTQSPSSLS RASQDISNYLA WFQQKPGK AVSSLQS GVPSKFSGSGSGTDFT QQYNSYPRT FGQGTKVEIKR ASVGDRVTITC APKSLIY LTISSLQPEDFATYYC 4.9 165 L1 JK1 DIQMTQSPSSLS RASQGISNYLA WFQQKPGK AASSLQS GVPSKFSGSGSGTDFT QQYNSYPST FGQGTKVEIKR ASVGDRVTITC APKSLIY LTISSLQPEDFATYYC 4.8 161 L1 JK1 DIQMTQSPSSLS RASQGISNYLA WFQQKPGK AASSLQS GVPSKFSGSGSGTDFT QQYNSYPST FGQGTKVEIKR ASVGDRVTITC APKSLIY LTISSLQPEDFATYYC 5.30 287 L1 JK1 DIQMTQSPSSLS RASQDISNYLA WFQQKPGK AASSLQS GVPSKFSGSGSGTDFT QQYNSYPRT FGQGTKVEIKR ASVGDRVTITC APKSLIY LTISSLQPEDFATYYC 6.6 549 L1 JK1 DIQMTQSPSSLS RASQGISNYLA WFQQKPGK AASSLES GVPSKFSGSGSGTDFN QQYNSYPRT FGQGTKVESKR ASVGDRVTITC APKSLIY LTISSLQPEDFATYYC

Example 14

Determination of Canonical Classes of Antibodies

[0271] Chothia, et al. have described antibody structure in terms of "canonical classes" for the hypervariable regions of each immunoglobulin chain (J Mol Biol. 1987 Aug. 20; 196(4):901-17). The atomic structures of the Fab and VL fragments of a variety of immunoglobulins were analyzed to determine the relationship between their amino acid sequences and the three-dimensional structures of their antigen binding sites. Chothia, et al. found that there were relatively few residues that, through their packing, hydrogen bonding or the ability to assume unusual phi, psi or omega conformations, were primarily responsible for the main-chain conformations of the hypervariable regions. These residues were found to occur at sites within the hypervariable regions and in the conserved beta-sheet framework. By examining sequences of immunoglobulins having unknown structure, Chothia, et al. show that many immunoglobuins have hypervariable regions that are similar in size to one of the known structures and additionally contained identical residues at the sites responsible for the observed conformation.

[0272] Their discovery implied that these hypervariable regions have conformations close to those in the known structures. For five of the hypervariable regions, the repertoire of conformations appeared to be limited to a relatively small number of discrete structural classes. These commonly occurring main-chain conformations of the hypervariable regions were termed "canonical structures." Further work by Chothia, et al. (Nature 1989 Dec. 21-28; 342(6252):877-83) and others (Martin, et al. J Mol Biol. 1996 Nov. 15; 263(5):800-15) confirmed that there is a small repertoire of main-chain conformations for at least five of the six hypervariable regions of antibodies.

[0273] The CDRs of each antibody described above were analyzed to determine their canonical class. As is known, canonical classes have only been assigned for CDR1 and CDR2 of the antibody heavy chain, along with CDR1, CDR2 and CDR3 of the antibody light chain. The table below (Table 13) summarizes the results of the analysis. The Canonical Class data is in the form of *HCDR1-HCDR2-LCDR1-LCDR2-LCDR3, wherein "HCDR" refers to the heavy chain CDR and "LCDR" refers to the light chain CDR. Thus, for example, a canonical class of 1-3-2-1-5 refers to an antibody that has a HCDR1 that falls into canonical class 1, a HCDR2 that falls into canonical class 3, a LCDR1 that falls into canonical class 2, a LCDR2 that falls into canonical class 1, and a LCDR3 that falls into canonical class 5.

[0274] Assignments were made to a particular canonical class where there was 70% or greater identity of the amino acids in the antibody with the amino acids defined for each canonical class. Where there was less than 70% identity, the canonical class assignment is marked with an asterisk ("*") to indicate that the best estimate of the proper canonical class was made, based on the length of each CDR and the totality of the data. Where there was no matching canonical class with the same CDR length, the canonical class assignment is marked with a "Y." The amino acids defined for each antibody can be found, for example, in the articles by Chothia, et al. referred to above. Table 13 reports the canonical class data for each of the Ang-2 antibodies.

TABLE-US-00013 TABLE 13 Canonical classes of antibodies against Ang-2 Antibody Canonical Class 5.18 1-1-2-1-1 5.81 1-1-2-1-1 5.66 1-1-2-1-1 5.48 1-1-2-1-1 5.23 1-1-2-1-1 3.33 1-1-2-1-1 5.15 1-1-2-1-3* 4.3 1-1-4-1-1 3.12 1-1-4-1-5* 4.16 1-1-4-1-5* 3.13 1-1-4-1-5* 3.7 1-1-4-1-5* 3.32 1-1-4-1-5* 3.37 1-1-4-1-Y 5.30 1-2-2-1-1 3.6 1-2-2-1-1 6.6 1-2-2-1-1 3.34 1-2*-2-1-1 5.74 1-2*-2-1-1 5.38 1-3-2-1-1 5.28.1 1-3-2-1-1 5.6 1-3-2-1-1 5.44 1-3-2-1-1 5.28 1-3-2-1-1 5.86.1 1-3-2-1-1 5.35.1 1-3-2-1-1 5.35 1-3-2-1-1 5.8 1-3-2-1-1 5.22 1-3-2-1-1 4.15 1-3-2-1-1 5.67 1-3-2-1-1 5.87 1-3-2-1-1 5.10 1-3-2-1-1 5.71 1-3-2-1-1 5.21 1-3-2-1-1 5.80 1-3-2-1-1 3.18 1-3-2-1-1 3.11 1-3-2-1-1 3.26 1-3-2-1-1 5.31 1-3-2-1-1 5.76 1-3-2-1-1 4.9 1-3-2-1-1 5.17 1-3-2-1-1 3.39 1-3-2-1-1 5.37 1-3-2-1-1 3.22 1-3-2-1-1 5.29 1-3-2-1-1 5.73 1-3-2-1-1 5.12 1-3-2-1-1 3.1 1-3-2-1-1 5.11 1-3-2-1-1 4.8 1-3-2-1-1 5.24 1-3-2-1-1 6.3.1 1-3-2-1-1* 5.56.1 1-3-2-1-1* 5.111 1-3-2-1*-1 4.13 1-3-2-1*-1 5.52 1-3*-2-1-3* 5.16.1 1-3-2-1-3* 5.39.1 1-3-2-1-3* 5.103.1 1-3-2-1-3* 5.101.1 1-3-2-1-3* 5.54.1 1-3-2-1-3* 5.83.1 1-3-2-1-3* 5.62 1-3-2-1-3* 5.88.1 1-3-2-1-3* 5.40.2 1-3-2-1-3* 5.109 1-3-2-1-3* 5.64 1-3-2-1-3* 5.13 1-3-2-1-3* 3.3 1-3-2-1-3* 5.41 1-3-2-1-3* 3.3.1 1-3-2-1-3* 3.31.1 1-3-2-1-3* 5.41.1 1-3-2-1-3* 5.62.1 1-3-2-1-3* 5.108.1 1-3-2-1-3* 5.13.1 1-3-2-1-3* 5.97 1-3-2-1-5* 5.52.1 1-3-2-1-Y 5.78.1 1-3-3-1-1 5.60 1-3-3-1-1 5.43 1-3-3-1-1 5.90 1-3-3-1*-1 3.42 1-3-3-1*-1 4.11 1-3-4-1-1 3.40 1-3-4-1-1 5.82 1-3-4-1-1 4.18 1-3-4-1-1 3.41 1-3-4-1-1 5.92 1-3-4-1-1 3.10 1-3-4*-1-1 4.14 1-3-4-1-5* 3.19.1 1-3-8*-1-1 6.2 1-3-8*-1-1 3.8 1-3-8*-1-1 5.58 1-3-8-1-1* 4.5 1-4*-2-1-1 5.1 1-4*-2-1-1 4.2 1-4*-2-1-1 3.9 1-4*-2-1-1 5.45 1-4*-2-1-1 3.17 1-4*-2-1-1 5.72 1-4*-2-1-1* 3.14 1-4*-2-1-Y 5.115 3-1-2-1-1 5.36 3-1*-2-1-1 3.2 3-1-2-1-3* 3.21 3-1-8-1-1* 5.61 3-Y-2-1-3*

[0275] Table 14 is an analysis of the number of antibodies per class. The number of antibodies having the particular canonical class designated in the left column is shown in the right column.

TABLE-US-00014 TABLE 14 Number of anti-Ang-2 antibodies in each canonical class H1-H2-L1-L2-L3 Number of mAbs 1-1-2-1-1 6 1-1-2-1-3* 1 1-1-4-1-1 1 1-1-4-1-5* 5 1-1-4-1-Y 1 1-2-2-1-1 5 1-3-2-1-1 38 1-3-2-1-3* 21 1-3-2-1-5* 1 1-3-2-1-Y 1 1-3-3-1-1 5 1-3-4-1-1 7 1-3-4-1-5* 1 1-3-8*-1-1 4 1-4*-2-1-1 7 1-4*-2-1-Y 1 3-1-2-1-1 2 3-1-2-1-3* 1 3-1-8-1-1* 1 3-Y-2-1-3* 1 Notes: 1. Those with * means assignment has been given to the best matching class, although there are some violations at the defining positions. 2. Y means there is no matching canonical class with the same CDR length.

Example 15

Epitope Mapping of Ang-2 Antibodies

[0276] The binding domain of 27 antibodies neutralizing the activity of Ang-2 was analyzed.

[0277] Recombinant Human Ang-2 was purchased from R&D systems (623-AN). Goat anti-human Ang-2 polyclonal antibodies (R&D systems AF623) were selected for their ability to recognize rhAng-2 in direct ELISA and Western blots. The polyclonal antibodies were biotinylated for detection with HRP conjugated--Streptavidin

[0278] All restriction enzymes were supplied by New England Biolabs and were used according to the manufacture's instructions. All plasmids DNA were purified using spin mini columns (Invitrogen, Carlsbad, Calif.). Oligonucleotide primers used for cloning and site directed mutagenesis were synthesized by Qiagen Operon.

[0279] Antibodies: 27 hybridoma derived human anti Ang-2 antibodies were selected based on their ability to inhibit binding of rhAng-2 to its receptor. The antibodies are listed below in Table 15.

TABLE-US-00015 TABLE 15 Hybridoma code OD650 in inibition assay 1 x5.56 0.0863 2 x3.38 0.0792 3 x3.19 0.0633 4 x3.28* 0.0588 5 x3.3 0.0558 6 x3.31* 0.0516 7 x5.88* 0.0874 8 x5.49* 0.0856 9 x5.101 0.0824 10 x5.41* 0.0776 11 x5.108* 0.0688 12 x5.62 0.0650 13 x5.39 0.0519 14 x5.16* 0.0500 15 x5.83 0.0484 16 x5.54 0.0440 17 x5.14 0.0430 18 x5.86 0.0419 19 x5.78 0.0984 20 x5.103* 0.1013 21 x5.28 0.0821 22 x5.40 0.0691 23 x5.35* 0.0663 24 x6.3 0.0617 25 x5.13 0.0744 26 x5.2 0.0690 27 x5.52 0.0627

Epitope Characterization of the 27 Neutralizing Anti-Ang-2 Antibodies

Dot Blots

[0280] RhAng-2 (R&D systems) was spotted on nitrocellulose membrane in its native or reduced form, using Bio-Dot Microfiltration unit. All human monoclonal antibodies (MAbs) raised against human Ang-2 had bound to non-reduced Ang-2, but not to reduced form, indicating that all mAbs recognize conformational epitopes, which are apparently destroyed upon reduction of the protein.

Cloning and Expression of Ang1 and Ang-2 Proteins

[0281] To better understand the structural basis for interaction of mAbs with Ang-2, a set of chimeric Ang1/Ang-2 molecules were used. This approach takes advantage of the fact that members of the angiogenic family are structurally related. Although Ang-2 and Ang1 show only 60% homology in their protein sequence, both share the same modular structure composed of an amino terminal coiled-coil domain and a carboxyl terminal fibrinogen like-domain.

Cloning of human Ang-1 and Ang-2

[0282] Two alternatively spliced forms of human Ang-2 cDNAs were amplified from human umbilical vein endothelial cell line (HUVEC). PCR amplification of HUVEC cDNA using Ang-2 specific primers reveled both the full length Ang-2 (1491 bp) and a 1330 base pain variant Ang-2.sub.443 (Injune et al., (2000) JBC 275: 18550). Ang-2.sub.443 is a variant generated by alternative splicing of exon B and missing part of the coiled-coil domain (amino-acids 96-148). Both Ang-2 cDNAs were cloned into pCR3.1 expression vector and expressed in 293F cells as shown in FIG. 6. Human Ang-1 cDNA was obtained by RT-PCR using total RNA extracted from human breast cell line MDA-MB-231. A 1.5 Kb cDNA was cloned into pCR3.1 expression vector and expression was detected in the supernatant of transiently transfected 293F cells.

Elisa

[0283] Binding of the 27 mAbs to supernatants generated from transient transfection of Ang-2 and Ang1 cDNAs was tested using antibody capture ELISA. Ang-2, Ang-2.sub.443 and Ang-1 were bound to an ELISA plate coated with goat polyclonal antibodies against human Ang-2 or Ang-1 (respectively). The binding of the top 27 human monoclonal antibodies was detected with a HRP-conjugated goat anti-human antibody, followed by colorimetric horseradish peroxidase substrate (Enhanced K-Blue TMB substrate Neogen Corporation). The absorbance of each well of the ELISA plates was measured at 450 nm on a microplate autoreader.

Transfection of 293F Cells

[0284] 293F human embryonic kidney cells were maintained in 10% fetal bovine serum in Dulbecco's modified eagles medium supplemented with penicillin and streptomycin. 293F cells were transiently transfected using Calcium phosphate. At 72 hours, the medium was harvested and filtered for ELISA and Western Blot analysis.

[0285] All 27 antibodies were shown to bind specifically Ang-2/Ang-2.sub.443 antigens. No cross reactivity was detected with human Ang-1. Amino acids 96-148 in the coiled-coil domain of Ang-2, which are missing in the Ang-2.sub.443 protein sequence, were excluded as the binding domain for each of the 27 antibodies.

Construction of Ang-1/Ang-2 Chimeric Molecules

[0286] Restriction cleavage sites common in human Ang-1 and Ang-2 genes were used for construction of In-frame fusion Angiopoietin chimeric proteins.

[0287] Four constructs were made: Human Ang-1/2 BsmI, Ang-2/1BsmI, Ang-1/2SspI and Ang-2/1 SspI. All proteins were expressed and secreted in detectable levels measured by ELISA assay using polyclonal antibodies against human Ang-1 and Ang-2.

[0288] The Amino acid joining points are at the following positions:

[0289] BsmI-117(Ang-2)/119(Ang-1)

[0290] SspI-353(Ang-2)/354(Ang-1)

[0291] The difference of one amino acid is due to the presence of 497 residues in the human Ang-1 compared to 496 residues in the human Ang-2. All constructs were expressed in 293F cells, and detected by goat anti-human polyclonal antibodies against Ang-1 and Ang-2. The top 27 antibodies were tested for their ability to bind chimeric Ang-1/2 molecules. All 27 antibodies showed a similar pattern of binding to the Ang-1/2BsmI construct only. The results of these experiments indicate that the binding domain for all antibodies is between residues 117-496, most likely in the fibrinogen binding domain, where the epitope is disrupted in the SspI fusion Ang proteins around amino acid 353.

Construction of Mouse/Human Ang-2 Chimeric Molecules

[0292] Since Ang-2 shares .about.55% amino acid identity with Ang-1, it was difficult to find a common restriction site to be used for cloning of chimeric molecules. Mouse and human Ang-2 are more similar, having about 85% sequence homology. Mouse Ang-2 cDNA cloned in the pCMCsport expression vector was purchased from Invitrogen. The 27 selected antibodies were tested for their immunoreactivity with recombinant mouse Ang-2. Six out of the 27 cross reacted with mouse Ang-2 with 100% of their immunoreactivity on human Ang-2, indicating that the murine antigen retains most of the immunoreactivity of human Ang-2 (Data are summarized in Table 16).

[0293] The human-Mouse chimeric system was chosen for epitope mapping based on the findings that most antibodies bind specifically to the human Ang-2 antigen and do not cross react with mouse Ang-2. Various cDNA constructs of Ang-2 were generated and cloned into a mammalian expression vector.

[0294] Constructs of Mouse/human Ang-2 were made using the common Stul restriction site, located in the fibrinogen-binding domain, with the amino acid joining point at residue 311. All mAbs specific to the human Ang-2 were able to bind to the Mouse/Human Ang-2 StuI, indicating that the binding domain is in the fibrinogen-binding domain between residues 311-496. In order to narrow down the binding domain, a new construct was prepared in which the human fragment StuI/TfiI replaced the mouse sequence in the mouse Ang-2 cDNA. (FIG. 9).

[0295] All antibodies specific to human Ang-2 showed a positive ELISA signal, with 15-100% of their immunoreactivity on human Ang-2. The binding domain of two antibodies with a unique VH gene usage 5.35.1 (VH3-20) and 5.28.1 (VH3-43) as shown in Table 17, was mapped to a region between amino-acids 310-400.

[0296] Antibodies that cross reacted with mouse Ang-2 were expected to show 100% reactivity and could not be mapped using Mouse/human chimeric constructs.

Site Directed Mutagenesis

[0297] In order to define the important residues involved in the binding site of different antibodies, a few residues of Human Ang-2 were mutated, and screened against the entire panel of antibodies for binding by ELISA assay.

[0298] Because direct binding detected by ELISA is insensitive to small and moderate differences in affinity, large changes in binding observed after substitution of single amino acid probably identify key sites that interact with the antibody. In addition, polyclonal antibodies against human Ang-2 maintain 100% reactivity with each construct, indicating that the mutagenesis procedure did not introduce any broad structural changes across the Ang-2 molecule. Two independent changes of Val to Met in position 345 (V345M) and His to Gln at position 375 (H375Q) were ignored by all 27 antibodies, indicating that these residues are not reactive, or that the changes in the conformational epitopes require more than single amino acid substitution. Changing of two residues at positions 365 and 367 dramatically changed the binding of single antibody, Mab 5.35.1. Sequence analysis of 5.35.1 showed the unique usage of VH3-20 and unique CDR3 on both the heavy and light chains. All fusion points of Ang-2 chimeric molecules and point mutations are highlighted in FIG. 8. FIG. 9 is an amino acid sequence comparison of mouse Ang-1 (SEQ ID NO: 5), human Ang-1 (SEQ ID NO: 2), mouse Ang-2 (SEQ ID NO: 4), and human Ang-2 (SEQ ID NO: 3). The arrowhead shows the cleavage site for hydrophobic leader sequences. The arrows define the limits of the coiled-coil and fibrinogen like domains. The solid circles show the conserved cysteine residues (image taken from Maisonpierre et al., 1997, Science 277:55).

[0299] Binding data to all Ang-2 molecules is summarized below in Table 16:

TABLE-US-00016 TABLE 16 Human Ang-2- Mouse M/H M/H StuI Stu-TfiI Clone Bin binding domain 443 CX BsmI 310-496 310-400 V345M N365Q367 H375Q 5.39.1 1 Fib.Like Domain 100% No 100% 100% 25% 100% 100% 100% 5.16.1* 1 Fib.Like Domain 100% No 100% 100% 30% 100% 100% 100% 5.86.1 1 Fib.Like Domain 100% No 100% 100% 23% 100% 100% 100% 5.54.1 1 Fib.Like Domain 100% No 100% 100% 77% 100% 100% 100% 5.14.1 1 Fib.Like Domain 100% No 100% 100% 31% 100% 100% 100% 5.83.1 1 Fib.Like Domain 100% No 100% 100% 86% 100% 100% 100% 5.101.1 1 Fib.Like Domain 100% No 100% 100% 28% 100% 100% 100% 6.3.1 7 Fib.Like Domain 100% No 100% 100% 27% 100% 100% 100% 5.103.1* 2 Fib.Like Domain 100% No 100% 100% 40% 100% 100% 100% 5.78.1 5 Fib.Like Domain 100% Yes 100% 100% 100% 100% 100% 100% 5.35.1* 8 Fib.Like Domain 100% No 100% 100% 100% 100% 15% 100% 5.40.2* 8 Fib.Like Domain 100% No 100% 100% 65% 100% 100% 100% 3.19.1 6 Fib.Like Domain 100% Yes 100% 100% 100% 100% 100% 100% 5.108.1* 1 Fib.Like Domain 100% No 100% 100% 36% 100% 100% 100% 5.52.1 Fib.Like Domain 100% Yes 100% 100% 100% 100% 100% 100% 5.56.1 3 Fib.Like Domain 100% Yes 100% 100% 100% 100% 100% 100% 5.2 Fib.Like Domain 100% Yes 100% 100% 100% 100% 100% 100% 5.28.1 4 Fib.Like Domain 100% No 100% 100% 100% 100% 100% 100% 5.41.1* 1 Fib.Like Domain 100% No 100% 100% 30% 100% 100% 100% 5.13.1 Fib.Like Domain 100% No 100% 100% 27% 100% 100% 100% 3.3.1 1 Fib.Like Domain 100% No 100% 100% 15% 100% 100% 100% 3.31.1* 1 Fib.Like Domain 100% No 100% 100% 15% 100% 100% 100% 5.62.1 1 Fib.Like Domain 100% No 100% 100% 30% 100% 100% 100% 3.28.1* 1 Fib.Like Domain 100% No 100% 100% 31% 100% 100% 100% 5.88.1* 1 Fib.Like Domain 100% No 100% 100% 20% 100% 100% 100% 3.38 Fib.Like Domain 100% Yes 100% 100% ND 100% 100% 100% 5.49* Fib.Like Domain 100% No 100% 100% 35% 100% 100% 100% Data are presented as percent binding compared to human Ang-2.

TABLE-US-00017 TABLE 17 Sequence analysis and cross reactivity with mouse Ang-2. Hybridoma OD650 in inibition Mouse Ang-2 code assay XR Bin VH DH JH VK JK x5.56 0.0863 Yes 3 VH3-33 D1-7 JH4b A20 JK3 x3.38 0.0792 Yes 2 x3.19 0.0633 Yes 6 VH3-30 D3-3 JH5b A27 JK5 x3.28* 0.0588 No 1 VH3-7 D6-19 JH4b L2 JK1 x3.3 0.0558 No 1 VH3-7 D6-19 JH4b L2 JK1 x3.31* 0.0516 No 1 VH3-7 D6-19 JH4b L2 JK1 x5.88* 0.0874 No 1 VH3-7 D6-19 JH4b L2 JK1 x5.49* 0.0856 No 1 x5.101 0.0824 No 1 VH1-2 D6-19 JH4b L2 JK1 x5.41* 0.0776 No 1 VH3-7 D6-19 JH4b L2 JK1 x5.108* 0.0688 No 1 VH3-33 D1-7 JH5b L2 JK1 x5.62 0.0650 No 1 VH3-7 D6-19 JH4b L2 JK1 x5.39 0.0519 No 1 VH1-2 D6-13 JH4b L2 JK1 x5.16* 0.0500 No 1 VH1-2 D6-13 JH4b L2 JK1 x5.83 0.0484 No 1 VH1-2 D6-19 JH4b L2 JK1 x5.54 0.0440 No 1 VH1-2 D6-19 JH4b L2 JK1 x5.14 0.0430 No 1 VH1-2 D6-19 JH4b x5.86 0.0419 No 1 VH1-2 D6-13 JH4b O12 JK3 x5.78 0.0984 Yes 5 VH1-2 D2-2 JH6b B3 JK5 x5.103* 0.1013 No 2 VH1-2 D6-19 JH4a L2 JK1 x5.28 0.0821 No 4 VH3-43 D6-19 JH4b L2 JK3 x5.40 0.0691 No 8 VH3-23 D6-19 JH4B L2 JK1 x5.35* 0.0663 No 8 VH3-20 D6-19 JH2 L2 JK4 x6.3 0.0617 No 7 VH1-2 D1-7 JH4b O12 JK2 x5.13 0.0744 No VH3-7 D6-19 JH4b L2 JK1 x5.2 0.0690 Yes VH3-33 D5-12 JH6b x5.52 0.0627 Yes VH3-33 D1-1 JH4b L5 JK4

[0300] The sequence analysis of IgH and IgL sequences was accomplished using sequence analysis software tools, and by alignment of VH genes to a germ line database. The software also evaluates D elements, reading frame, N region insertion, P nucleotide addition, nucleotide loss and CDR3 length. Analysis of 27 individual antibodies specific to CR64 yielded only 7 germline VH genes, 10 of them from the same VH1 family. Selection of neutralizing antibodies showed that antibodies expressing same Ig V.sub.H and in some cases same V.sub.HDJ.sub.H rearrangements and that pairs of H and L chain were conserved. This finding suggests that, for any given epitope, only a few members of the germ line repertoire are used to form the corresponding paratope, and for each antigenic epitope a limited number of L- and H-chain genes can pair to form a specific paratope.

[0301] Recurrent usage of similar V.sub.H, V.sub.K and complementary determining region (CDR) structures by different monoclonal antibodies is linked to the fact that all Ang-2 neutralizing activity is restricted to the fibrinogen like domain, and is in agreement with work published by Procopio et al (1999, JBC 274: 30196), showing that the effect of Ang-2 on Tie2 is linked to the Fibrinogen-like domain. The epitope mapping data indicates that the monoclonal antibodies bind Ang-2 through a broad interface that includes most of the fibrinogen like domain.

Example 16

Determination of Cross-Reactivity with Mouse Ang-2

[0302] The cross-reactivity of the anti-human Ang-2 mAbs to mouse Ang-2 was tested by ELISA. For this purpose, a mouse Ang-2 expression vector was constructed, and eukaryotic cells were transfected transiently to produce mouse Ang-2.

[0303] The mouse Angiopoietin-2 (mAng-2) expression construct was obtained from Research Genetics, a distributor of the I.M.A.G.E consortium (see world wide web at image.llnl.gov). Mouse Ang-2 cDNA (GenBank Accession No. BC027216, IMAGE:3494566) was derived from the library NCI_CGAP_Lu29, which is a lung tumor library. The cDNA was cloned into the pCMV-SPORT6 expression vector (Invitrogen Carlsbad, Calif.) through SalI(5') and NotI(3') sites and contained the full length mouse Ang-2 (mAng-2) open reading frame of 496 amino acids, as well as the 5' and 3' untranslated flanking regions for a total of 2471 base pairs.

[0304] Ten .mu.g of the above mAng-2 plasmid was transfected into HEK293F cells using the calcium phosphate method. Approximately, 1.times.10.sup.6 HEK293F cells were seeded on a 10 cm tissue culture plate on the previous day. The medium was changed after 5 hours or overnight transfection and the cells were grown for another 2-3 days before the supernatants containing the secreted mAng-2 protein were collected. The expression of mAng-2 was confirmed by ELISA using a polyclonal antibody obtained from R&D Systems (catalog No. AF623).

[0305] 96-well Nunc Immplates were coated with conditioned-medium collected from HEK293F/mouse Ang-2 transfectants, 100 .mu.l in each well. The plates were incubated at 4.degree. C. overnight, followed by washing four times using Phosphate Buffer Saline with a Skan Washer 300 station (SKATRON). The wells were blocked by 100 .mu.l of ABX-block buffer (0.5% BSA, 0.1% Tween, 0.01% Thimerosal in PBS) for 1 hour. Anti-Ang-2 mAbs with appropriate concentrations and diluted in the blocking buffer were added into the wells with a volume of 100 .mu.l/well, and incubated at room temperature for at least 1 hour. The mAbs and each of their dilutes were tested in duplicate. After washing twice, the bound mAbs were detected by goat anti-human Fc-HPPO-conjugated antibody (Caltag, Code H10507) at 1/1,000 dilution at room temperature for an hour. To set up the detecting chromagenic reaction, 100 .mu.l of TMB substrate (TMB-microwell, BioFX, Cat. No. TMSK-1000-01) was added after washing the wells three times using PBS. The plates were incubated for 30 minutes before 650 stop solution (100 .mu.l/well, BioFX, Cat. No. BSTP-0100-01) was added to terminate the reaction. The light absorbance at 650 nm was determined by a Spectramax Plus reader.

[0306] The top 27 neutralizing mAbs were tested in this assay. The light absorbance demonstrated that monoclonal antibodies 3.19.3, 3.38, 5.2.1, 5.52.1, 5.56.1, and 5.78.1 were capable of binding to mouse Ang-2 under the experimental conditions. For confirmation, each binding antibody was titered by ELISA. The mean OD 650 nm (.+-.S.D.) values were plotted against Log concentration of mAbs (.mu.g/ml) is shown in FIG. 10. The clones 5.2.1, 5.28.1, 3.19.3 and 3.31.2 are shown in the figure. Monoclonal antibodies 5.2.1 and 3.19.3 bound mouse Ang-2 in a dose-dependent manner, reaching saturation at about 10 .mu.g/ml (FIG. 10). The binding curves of these two mAbs were typical Sigmoidal dose-response relationship curves. Dose-dependency and saturation was not observed in the antibody concentration range tested, except for clones 5.2.1 and 3.19.3. Based on this result, it appears that only mAbs 5.2.1 and 3.19.3 have cross-reactivity to mouse Ang-2.

Example 17

Inhibition of Murine Ang-2 Binding to Human Tie2

[0307] The monoclonal antibody 3.19.3 was selected for further testing of its ability to inhibit the binding of mouse Ang-2 to human Tie2. For this purpose, an ELISA plate was coated with 4 .mu.g/ml of hTie2/Fc (R&D Systems, Inc.) at 100 .mu.l/well, and the wells were blocked as routine at 4.degree. C. overnight. The recombinant mouse Ang-2 (mAng-2) in the culture supernatant of the 293T/mAng-2 transfectants described above was employed. 100 .mu.l of mAng-2 containing supernatant with mAb 3.19.3 at various concentrations was added into the pre-coated wells, and incubated at room temperature for 1 hr.

[0308] As a control, recombinant human Ang-2 (R&D Systems, Inc.) mixed with the antibody was also included. Each concentration of the mAb was tested in triplicate. The bound mouse and human Ang-2 were detected using a goat anti-human Ang-2 polyclonal antibody (Santa Cruz Biotechnology, Santa Cruz, Calif.) that cross-react with mouse Ang-2, coupled with a secondary rabbit anti-goat IgG-HRP. OD650 was determined 30 min after the HRP substrate was added. It was discovered that mAb 3.19.3 inhibited binding of both human and mouse Ang-2 to human Tie2 in a dose-dependent manner (FIG. 11).

Example 18

Determination of Cross-Reactivity with Monkey Vasculature

[0309] Because Ang-2 is specifically expressed in angiogenic endothelial cells, these cells from monkeys were immunohistochemically stained with anti-Ang-2 antibodies as a way to indirectly determine whether each antibody cross-reacted with monkey Ang-2.

[0310] The top 10 neutralizing mAbs selected as described in Example 4 (Table 4) were examined in this experiment using endothelial cell-rich ovarian tissue from monkeys. Completely dried 6 .mu.m frozen monkey (Cynomolgus macaque) ovary tissue sections were fixed with 4.degree. C. acetone for 5 minutes. After washing the slides three times with PBS, the endogenous peroxidase of the tissues was blocked with 0.3% of H.sub.2O.sub.2 for 10 minutes. Subsequently, the tissues were washed with PBS and blocked with 10 pg/ml goat anti-human IgG Fab for 15 minutes. The tissue sections were washed again with PBS followed by treatment with 10% normal goat serum for 10 minutes. After draining the serum, each of the 10 anti-Ang-2 mAbs (10 .mu.g/ml) were applied to the sections and incubated for 2 hours. The bound Ang-2 mAbs were detected with 10 .mu.g/ml mouse anti-human IgG for 15 minutes followed by incubation with peroxidase conjugated goat anti-mouse IgG for 30 minutes. Staining was performed using AEC-substrate system (DAKO, Cat. No. 3464) under microscopic observation for optimal result.

[0311] All 10 mAbs were found to stain the angiogenic vascular endothelial cells among the ovary tissue; whereas, the isotype control mAbs did not stain. This demonstrated that the 10 mAbs from Table 4 would cross react with monkey Ang-2.

Example 19

mAb 3.19.3 Inhibits In Vivo Angiogenesis in Matrigel Plug Assay

[0312] To evaluate the in vivo anti-angiogenic potential of anti-Ang-2 monoclonal antibodies, a Matrigel plug angiogenesis assay was conducted. MCF-7 cells were found to produce Ang-2 when cultured in vitro, or implanted in an immunodeficient mouse as a xenograft. When MCF-7 was incorporated into Matrigel and implanted subcutaneously into nude mice, robust vascular in growth into the gel was found. To establish the Matrigel plug model, 6-8 week old female BALB/c/nu/nu mice, with body weights ranging from 18 to 20 g (Charles River Laboratories, Wilmington, Mass.) were employed. A total of 0.5 mL of Matrigel containing 2.times.10.sup.6 MCF-7 cells, with or without Ang-2 antibodies, or control agents (including Matrigel alone, Tie2/Fc, IgG2 and IgG4 isotype controls, and anti-VEGF mAb), were subcutaneously injected into the right flank of the nude mice. Five mice were used for each test group. All the mAbs tested were adjusted to a concentration of 100 .mu.g/ml.

[0313] After seven days, Matrigel plugs were harvested and scored for blood vessel density. For this purpose, cervical dislocation of mice under deep anesthesia was performed. The Matrigel plugs were exposed through removal of the covering skin flap. The Matrigel plugs were then removed and digital images were then recorded. The Matrigel plugs were resected carefully and cut into two parts. One part was snap frozen in TissueTek and the other fixed in buffered formalin. Both parts were then embedded in paraffin for sectioning. Three 5 to 7 .mu.m thick sections from each mouse were cut and stained with hematoxylin and eosin. The sections were then examined under a phase contrast microscope. Representative photomicrographs were recorded [two frames (100.times. and 400.times.)] and endothelial cell and blood vessel infiltration was recorded.

[0314] The frozen Matrigel plugs were sectioned (10 .mu.m sections) in a Cryocut microtome. Two independent sections per mouse were made and used for staining. Sections were blocked with BSA (0.1%) and then treated with monoclonal antibody reactive to mouse. CD31 conjugated to Phycoerythin (dilutions as recommended by the manufacturer). After thorough washings, sections were mounted under anti-fading reagent (Vecta Shield) and observed under a UV microscope using a red filter. Representative Digital images were captured (two images at 100.times. and 200.times. magnification). Nuclei were counterstained with DAPI. Immunofluorescence images of CD31 staining were analyzed by a Skeletinization program. Data were processed to provide mean vessel density, node and length for each group. The results can be found in FIGS. 12A and 12B, which show the effect of anti-Ang-2 antibodies on the number of blood vessels ends (FIG. 12A) and blood vessel length (FIG. 12B).

[0315] This experiment demonstrated that, in comparison with Matrigel alone, MCF-7 cells that were incorporated in the Matrigel were able to induce a significant level of angiogenesis. The induced angiogenesis could be inhibited by a positive control anti-VEGF antibody. The angiogenesis was also significantly inhibited by soluble recombinant Tie2/Fc protein, suggesting that Ang-2 produced by MCF-7 cells plays a role in the angiogenesis in this model. By binding to any Ang-2, the Tie2/Fc would effectively reduce the level of Ang-2 that is exposed to the MCF-7 cells.

[0316] It is not clear how the IgG2 isotype negative control antibody, PK16.1.3, impacted angiogenesis, although this antibody was also found to occasionally interfere with tumor growth in some xenograft models (data not shown). The IgG4 isotype control antibody did not have any effect on the angiogenesis in this model. As seen in FIGS. 12A and 12B, clones 5.88.3, 3.3.2, 3.19.3 and 5.28.1 significantly inhibited angiogenesis (P<0.05, t-test performed by VasculoGen), while others had lesser effects.

[0317] It is well established that Ang-2 is expressed by endothelial cells in the tumor, and thus has been considered as a autocrine angiogenic factor. However, Ang-2 has also been found to be expressed by many types of tumor cells in vitro and in vivo. Except 3.19.3, the mAbs tested here do not cross-react with mouse Ang-2. In this in vivo model, the mAbs only neutralized human Ang-2 produced by the MCF-7 cell, but not the mouse Ang-2. The inhibitory effect of these mAbs suggests that tumor expressed Ang-2 can be a paracrine angiogenesis factor. The overall anti-angiogenic activity of the mAb was partially attributable to the neutralization of the tumor Ang-2, in addition to neutralization of vascular endothelium expressed Ang-2.

Example 20

Determination of the Therapeutic Efficacy of mAb 3.19.3 in A431 Preventional Xenograft Model

[0318] Anti-Ang-2 mAb clone 3.19.3 not only bound to mouse Ang-2, but also inhibited binding of mouse Ang-2 to human Tie2. The anti-tumor activity of this monoclonal antibody was tested in a mouse xenograft model of human skin epidermoid carcinoma by using the A431 cell line.

[0319] A431 cells were cultured in flasks as routine until the cells reached sub-confluence. Immunodeficient 6-8 week old female mice (Balb/c/nu/nu) were employed for model development. The A431 cells were harvested and suspended in Matrigel. A cell suspension containing 5.times.10.sup.6 cells was injected intradermally into the flank of the mice. The mice were randomized into different groups, each containing 11 mice. On the same day, the mice were injected intraperitoneally with 0.5 mg of mAb 3.19.3, or isotype control antibody, and twice per week thereafter. The dimensions of each tumor were measured twice per week. The volume of the tumor was calculated as: Volume=Length.times.(Width).sup.2.times.0.5 (cm.sup.3).

[0320] As illustrated in FIG. 13, mAb 3.19.3 significantly delayed A431 xenograft tumor growth. The average tumor volume of the isotype control group reached about 1.5 cm.sup.3 at the end of the experiment, whereas the growth rate of the treated group significantly slowed after Day 10, and was about 0.5 cm.sup.3 at the end. At Day 23, the volume ration of T/C (Treatment/Control) is 1/3, indicating a 66% inhibition of the growth.

[0321] The results suggest that at the dosage used in this experiment, by binding to mouse Ang-2 and blocking the binding of this ligand to its receptor Tie2, mAb 3.16.3 was able to significantly delay the growth of A431 xenograft in nude mice. It is likely that the anti-tumor effect of the monoclonal antibody is due to inhibiting angiogenesis in the host, as demonstrated by the Matrigel plug assays. Using the Microvessel Density (MVD) in the tumor as a pharmacodynamic marker, the mechanism of action with respect to anti-angiogenesis is further demonstrated in Example 22.

[0322] The mechanism of action of mAb 3.19.3 may not be limited to its blockage of Ang-2/Tie2 association and consequent signaling. As indicated in Example 7, this mAb is also found to bind to Ang-1 and block binding of Ang-1 to Tie2. Interestingly, the mAb also blocks Ang-1-induced Tie2 phosphorylation. It is known that Ang-1 is involved in vessel maturation. When comparing the potency of mAb 3.19.3 for its inhibition in the binding of Ang-1 versus Ang-2 to Tie2 (Example 12), it is apparent that mAb 3.19.3 is predominantly an Ang-2 antagonist. Without being bound to any particular theory, it is possible that dual blockage of signaling from Ang-2 and Ang-1 impairs angiogenesis and consequently tumor growth.

Example 21

mAb 3.19.3 Inhibits Tumor Growth in Established Xenograft Models

[0323] Ang-2 is upregulated by angiogenic endothelial cells, and is correlated to progression of many types of tumor. It is reasonable to postulate that a monoclonal antibody that blocks binding of Ang-2/Tie2 association will be able to inhibit angiogenesis, and therefore, inhibit the tumor growth. In this experiment, the therapeutic efficacy of an anti-Ang-2 mAb was demonstrated. Since mAb 3.19.3 cross-reacts and neutralizes mouse Ang-2/Tie2 signaling, this mAb was chosen to demonstrate the in vivo efficacy of inhibiting tumor growth.

[0324] To test whether anti-Ang-2 mAb 3.19.3 also inhibits established tumor, and tumors other than A-431, the human colon adenocarcinoma LoVo xenograft model was employed. Doses of Mab 3.19.3 at 0.5, 2, and 10 mg/kg were administered twice per week intraperitoneally. The treatments did not start until the tumors were established with an average volume of 0.2 cm.sup.3. On these established tumors, mAb 3.19.3 also demonstrated an inhibitory effect in comparison with the isotype control. FIG. 14A shows that 79% inhibition at 0.5 and 2 mg/kg (p values are 0.022 and 0.027, respectively) was achieved, and 75% inhibition on tumor growth were found (p=0.006) at 10 mg/kg.

[0325] The tumor growth inhibitory effect was reproduced in an additional xenograft model, human colon adenocarcinoma SW480, which was allowed to grow to an average volume of 0.2 cm.sup.3. Although at 0.5 mg/kg the mAb 3.19.3 was not found to have a significant effect, at both 2 and 10 mg/kg, the mAb inhibited tumor growth by 60% (p=0.003 and 0.006 respectively) at Day 53 after tumor implantation (FIG. 14B).

[0326] In summary of the above results, anti-Ang-2 mAb 3.19.3 significantly inhibited tumor growth in the three models tested. Interestingly, both LoVo and SW480 express human Ang-2. However, two other mAbs that have no mouse Ang-2 cross-reactivity did not show significant inhibitory activity on tumor growth (data not shown), despite the fact that human Ang-2 was expressed by the tumor cells. These results imply that an antagonist of the host Ang-2 is required to block angiogenesis and tumor growth.

[0327] As discussed above, Mab 3.19.3 cross-reacts with Ang-1. However, the potency of mAb 3.19.3 on Ang-1/Tie2 association was far lower than that on Ang-2/Tie2 association (Example 12). For this reason, it is reasonable to conclude that the therapeutic efficacy seen in these models is predominantly due to Ang-2 antagonism. However, blockage of Ang-1 in vivo in the models could not be completely excluded. During the entire course of the experiments, no obvious toxicity effect, such as weight loss or bleeding, was observed.

Example 22

In Vivo Efficacy of mAb 3.19.3 in Additional Tumor Xenograft Models

[0328] The anti-tumor activity of the 3.19.3 monoclonal antibody was tested in mouse xenograft models of human cancer by using 9 different tumor cell lines.

[0329] Colon adenocarcinoma (Lovo, SW480, Colo205, HT29, HCT116), epidermoid carcinoma (A431), lung carcinoma (Calu-6) and breast adenocarcinoma (MCF7, MDA-MB-231) cells were cultured in flasks as routine until the cells reached sub-confluence. Immunodeficient 7-10 week old female mice were employed for model development. The cells were harvested, suspended in Matrigel, and then injected subcutaneously into each mouse. The mice were then randomized into cohorts containing 10-12 mice. The mice were injected intraperitoneally with 0.5 mg of mAb 3.19.3, or isotype control antibody, and twice per week thereafter. For all experiments, isotype control antibody treatment was included. The dimensions of each tumor were measured twice per week. The volume of the tumor was calculated as: Volume=Length.times.(Width).sup.2.times.0.5 (cm.sup.3). Graphical comparisons of tumor growth inhibition is shown for HT29 (FIG. 15A) and Calu6 (FIG. 15B) xenografts.

[0330] As seen in Table 16, mAb 3.19.3 showed significant activity in all 7 xenograft subcutaneous models tested and both orthotopic models with non-optimized dose and schedule.

TABLE-US-00018 TABLE 18 Summary of in vivo efficacy of mAb 3.19.3 % Inhibition % Inhibition 2 mg/kg 10 mg/kg SubQ Xenografts twice weekly twice weekly Tumor models Colo205 35 46 A431 43 66 HT29 N.D. 54 Calu6 N.D 38 HCT116 N.D 33 Orthotopic models MCF7 35* 74 MDA-MB-231 50 58 P < 0.05 in all cases *Growth inhibition not statistically significant. N.D.--not determined

[0331] The MDA-MB-231 tumor tissue was analyzed via CD31+ vessel staining density. CD31 staining density was measured by threshold and by manual grid counting methods. Eleven tumors per group and at least 20 images per tumor were analyzed. As seen in FIG. 15C, treatment of mice with 3.19.3 antibody decreased the density of CD31 staining by 40% compared to a control IgG antibody. This was statistically significant with both counting methods, threshold (p<0.015) and manual grid counting (p<0.00004) by 1-tailed T-test. Similar CD31+ vessel counts were made on ex-vivo tissue for the Co10205 and HCT116 xenografts. These samples also exhibited a similar significant reduction in CD31+ vessels.

Example 23

Uses of Anti-Ang-2 Antibodies for the Treatment of Angiogenesis Related Diseases

[0332] To determine the in vivo effects of anti-Ang-1 and anti-Ang-2 antibody treatment in human patients with various solid tumors, human patients are dosed periodically with an effective amount of anti-Ang-1 and anti-Ang-2 antibody. At periodic times during the treatment, the human patients are monitored to determine whether tumor growth is inhibited. Following treatment, it is found that patients undergoing treatment with the anti-Ang-1 and anti-Ang-2 antibody in comparison to patients that are not treated have relative improvements in one or more of the following including but not limited to smaller tumors, delayed time to progression or longer time of survival.

Example 24

Use of Anti-Ang-2 Antibodies as a Diagnostic Agent

Detection of Ang-2 Antigen in a Sample

[0333] An Enzyme-Linked Immunosorbent Assay (ELISA) for the detection of Ang-1 or Ang-2 antigen in a sample may be developed. In the assay, wells of a microtiter plate, such as a 96-well microtiter plate or a 384-well microtiter plate, are adsorbed for several hours with a first fully human monoclonal antibody directed against Ang-1 and Ang-2. The immobilized antibody serves as a capture antibody for any of the antigen that may be present in a test sample. The wells are rinsed and treated with a blocking agent such as milk protein or albumin to prevent nonspecific adsorption of the analyte.

[0334] Subsequently the wells are treated with a test sample suspected of containing the antigen, or with a solution containing a standard amount of the antigen. Such a sample may be, for example, a serum sample from a subject suspected of having levels of circulating antigen considered to be diagnostic of a pathology.

[0335] After rinsing away the test sample or standard, the wells are treated with a second fully human monoclonal anti-Ang-1 and anti-Ang-2 antibody that is labeled by conjugation with biotin. A monoclonal or mouse or other species origin might also be used. The labeled anti-Ang-1 and anti-Ang-2 antibody serves as a detecting antibody. After rinsing away excess second antibody, the wells are treated with avidin-conjugated horseradish peroxidase (HRP) and a suitable chromogenic substrate. The concentration of the antigen in the test samples is determined by comparison with a standard curve developed from the standard samples.

[0336] This ELISA assay provides a highly specific and very sensitive assay for the detection of the Ang-1 and Ang-2 antigen in a test sample.

Determination of Ang-2 Antigen Concentration in Patients

[0337] A sandwich ELISA is developed to quantify Ang-1 and Ang-2 levels in human serum. The two fully human monoclonal anti-Ang-2 antibodies from the sandwich ELISA, recognizes different epitopes on the Ang-2 molecule. Alternatively, monoclonal antibodies of mouse or other species origin may be used. The ELISA could be but is not necessarily performed as follows: 50 .mu.L of capture anti-Ang-2 antibody in coating buffer (0.1 M NaHCO.sub.3, pH 9.6) at a concentration of 2 .mu.g/mL is coated on ELISA plates (Fisher). After incubation at 4.degree. C. overnight, the plates are treated with 2004 of blocking buffer (0.5% BSA, 0.1% Tween 20, 0.01% Thimerosal in PBS) for 1 hour at 25.degree. C. The plates are washed (3.times.) using 0.05% Tween 20 in PBS (washing buffer, WB). Normal or patient sera (Clinomics, Bioreclaimation) are diluted in blocking buffer containing 50% human serum. The plates are incubated with serum samples overnight at 4.degree. C., washed with WB, and then incubated with 100 .mu.L/well of biotinylated detection anti-Ang-2 antibody for 1 hour at 25.degree. C. After washing, the plates are incubated with HRP-Streptavidin for 15 minutes, washed as before, and then treated with 100 .mu.L/well of o-phenylenediamine in H.sub.2O.sub.2 (Sigma developing solution) for color generation. The reaction is stopped with 50 .mu.L/well of H.sub.2SO.sub.4 (2M) and analyzed using an ELISA plate reader at 492 nm. Concentration of Ang-2 antigen in serum samples is calculated by comparison to dilutions of purified Ang-2 antigen using a four parameter curve fitting program.

INCORPORATION BY REFERENCE

[0338] All references cited herein, including patents, patent applications, papers, text books, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated herein by reference in their entirety.

EQUIVALENTS

[0339] The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. The foregoing description and Examples detail certain preferred embodiments of the invention and describes the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the invention may be practiced in many ways and the invention should be construed in accordance with the appended claims and any equivalents thereof.

Sequence CWU 1

1

6621496PRTArtificial SequenceArtificially created chimeric human/mouse polypeptide sequence 1Met Trp Gln Ile Ile Phe Leu Thr Phe Gly Trp Asp Leu Val Leu Ala1 5 10 15Ser Ala Tyr Ser Asn Phe Arg Lys Ser Val Asp Ser Thr Gly Arg Arg 20 25 30Gln Tyr Gln Val Gln Asn Gly Pro Cys Ser Tyr Thr Phe Leu Leu Pro 35 40 45Glu Thr Asp Ser Cys Arg Ser Ser Ser Ser Pro Tyr Met Ser Asn Ala 50 55 60Val Gln Arg Asp Ala Pro Leu Asp Tyr Asp Asp Ser Val Gln Arg Leu65 70 75 80Gln Val Leu Glu Asn Ile Leu Glu Asn Asn Thr Gln Trp Leu Met Lys 85 90 95Leu Glu Asn Tyr Ile Gln Asp Asn Met Lys Lys Glu Met Val Glu Ile 100 105 110Gln Gln Asn Val Val Gln Asn Gln Thr Ala Val Met Ile Glu Ile Gly 115 120 125Thr Ser Leu Leu Asn Gln Thr Ala Ala Gln Thr Arg Lys Leu Thr Asp 130 135 140Val Glu Ala Gln Val Leu Asn Gln Thr Thr Arg Leu Glu Leu Gln Leu145 150 155 160Leu Gln His Ser Ile Ser Thr Asn Lys Leu Glu Lys Gln Ile Leu Asp 165 170 175Gln Thr Ser Glu Ile Asn Lys Leu Gln Asn Lys Asn Ser Phe Leu Glu 180 185 190Gln Lys Val Leu Asp Met Glu Gly Lys His Ser Glu Gln Leu Gln Ser 195 200 205Met Lys Glu Gln Lys Asp Glu Leu Gln Val Leu Val Ser Lys Gln Ser 210 215 220Ser Val Ile Asp Glu Leu Glu Lys Lys Leu Val Thr Ala Thr Val Asn225 230 235 240Asn Ser Leu Leu Gln Lys Gln Gln His Asp Leu Met Glu Thr Val Asn 245 250 255Ser Leu Leu Thr Met Met Ser Ser Pro Asn Ser Lys Ser Ser Val Ala 260 265 270Ile Arg Lys Glu Glu Gln Thr Thr Phe Arg Asp Cys Ala Glu Ile Phe 275 280 285Lys Ser Gly Leu Thr Thr Ser Gly Ile Tyr Thr Leu Thr Phe Pro Asn 290 295 300Ser Thr Glu Glu Ile Lys Ala Tyr Cys Asp Met Glu Ala Gly Gly Gly305 310 315 320Gly Trp Thr Ile Ile Gln Arg Arg Glu Asp Gly Ser Val Asp Phe Gln 325 330 335Arg Thr Trp Lys Glu Tyr Lys Val Gly Phe Gly Asn Pro Ser Gly Glu 340 345 350Tyr Trp Leu Gly Asn Glu Phe Val Ser Gln Leu Thr Asn Gln Gln Arg 355 360 365Tyr Val Leu Lys Ile His Leu Lys Asp Trp Glu Gly Asn Glu Ala Tyr 370 375 380Ser Leu Tyr Glu His Phe Tyr Leu Ser Ser Glu Glu Leu Asn Tyr Arg385 390 395 400Ile His Leu Thr Gly Leu Thr Gly Thr Ala Ala Lys Ile Ser Ser Ile 405 410 415Ser Gln Pro Gly Ser Asp Phe Ser Thr Lys Asp Ser Asp Asn Asp Lys 420 425 430Cys Ile Cys Lys Cys Ser Gln Met Leu Ser Gly Gly Trp Trp Phe Asp 435 440 445Ala Cys Gly Pro Ser Asn Leu Asn Gly Gln Tyr Tyr Pro Gln Lys Gln 450 455 460Asn Thr Asn Lys Phe Asn Gly Ile Lys Trp Tyr Tyr Trp Lys Gly Ser465 470 475 480Gly Tyr Ser Leu Lys Ala Thr Thr Met Met Ile Arg Pro Ala Asp Phe 485 490 4952497PRTHomo sapiens 2Met Thr Val Phe Leu Ser Phe Ala Phe Leu Ala Ala Ile Leu Thr His1 5 10 15Ile Gly Cys Ser Asn Gln Arg Arg Ser Pro Glu Asn Ser Gly Arg Arg 20 25 30Tyr Asn Arg Ile Gln His Gly Gln Cys Ala Tyr Thr Phe Ile Leu Pro 35 40 45Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gln Tyr Asn Thr 50 55 60Asn Ala Leu Gln Arg Asp Ala Pro His Val Glu Pro Asp Phe Ser Ser65 70 75 80Gln Lys Leu Gln His Leu Glu His Val Met Glu Asn Tyr Thr Gln Trp 85 90 95Leu Gln Lys Leu Glu Asn Tyr Ile Val Glu Asn Met Lys Ser Glu Met 100 105 110Ala Gln Ile Gln Gln Asn Ala Val Gln Asn His Thr Ala Thr Met Leu 115 120 125Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Arg Lys 130 135 140Leu Thr Asp Val Glu Thr Gln Val Leu Asn Gln Thr Ser Arg Leu Glu145 150 155 160Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu Lys Gln 165 170 175Leu Leu Gln Gln Thr Asn Glu Ile Leu Lys Ile His Glu Lys Asn Ser 180 185 190Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys Glu Glu 195 200 205Leu Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu Val Thr 210 215 220Arg Gln Thr Tyr Ile Ile Gln Glu Leu Glu Lys Gln Leu Asn Arg Ala225 230 235 240Thr Thr Asn Asn Ser Val Leu Gln Lys Gln Gln Leu Glu Leu Met Asp 245 250 255Thr Val His Asn Leu Val Asn Leu Cys Thr Lys Glu Val Leu Leu Lys 260 265 270Gly Gly Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys Ala Asp Val 275 280 285Tyr Gln Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Ile Asn 290 295 300Asn Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn Gly305 310 315 320Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp Phe 325 330 335Gln Arg Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Ser Gly 340 345 350Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln Arg 355 360 365Gln Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg Ala 370 375 380Tyr Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gln Asn Tyr385 390 395 400Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys Gln Ser Ser 405 410 415Leu Ile Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala Asp Asn Asp 420 425 430Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp Phe 435 440 445Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala Gly 450 455 460Gln Asn His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr Phe Lys Gly465 470 475 480Pro Ser Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg Pro Leu Asp 485 490 495Phe3496PRTHomo sapiens 3Met Trp Gln Ile Val Phe Phe Thr Leu Ser Cys Asp Leu Val Leu Ala1 5 10 15Ala Ala Tyr Asn Asn Phe Arg Lys Ser Met Asp Ser Ile Gly Lys Lys 20 25 30Gln Tyr Gln Val Gln His Gly Ser Cys Ser Tyr Thr Phe Leu Leu Pro 35 40 45Glu Met Asp Asn Cys Arg Ser Ser Ser Ser Pro Tyr Val Ser Asn Ala 50 55 60Val Gln Arg Asp Ala Pro Leu Glu Tyr Asp Asp Ser Val Gln Arg Leu65 70 75 80Gln Val Leu Glu Asn Ile Met Glu Asn Asn Thr Gln Trp Leu Met Lys 85 90 95Leu Glu Asn Tyr Ile Gln Asp Asn Met Lys Lys Glu Met Val Glu Ile 100 105 110Gln Gln Asn Ala Val Gln Asn Gln Thr Ala Val Met Ile Glu Ile Gly 115 120 125Thr Asn Leu Leu Asn Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp 130 135 140Val Glu Ala Gln Val Leu Asn Gln Thr Thr Arg Leu Glu Leu Gln Leu145 150 155 160Leu Glu His Ser Leu Ser Thr Asn Lys Leu Glu Lys Gln Ile Leu Asp 165 170 175Gln Thr Ser Glu Ile Asn Lys Leu Gln Asp Lys Asn Ser Phe Leu Glu 180 185 190Lys Lys Val Leu Ala Met Glu Asp Lys His Ile Ile Gln Leu Gln Ser 195 200 205Ile Lys Glu Glu Lys Asp Gln Leu Gln Val Leu Val Ser Lys Gln Asn 210 215 220Ser Ile Ile Glu Glu Leu Glu Lys Lys Ile Val Thr Ala Thr Val Asn225 230 235 240Asn Ser Val Leu Gln Lys Gln Gln His Asp Leu Met Glu Thr Val Asn 245 250 255Asn Leu Leu Thr Met Met Ser Thr Ser Asn Ser Ala Lys Asp Pro Thr 260 265 270Val Ala Lys Glu Glu Gln Ile Ser Phe Arg Asp Cys Ala Glu Val Phe 275 280 285Lys Ser Gly His Thr Thr Asn Gly Ile Tyr Thr Leu Thr Phe Pro Asn 290 295 300Ser Thr Glu Glu Ile Lys Ala Tyr Cys Asp Met Glu Ala Gly Gly Gly305 310 315 320Gly Trp Thr Ile Ile Gln Arg Arg Glu Asp Gly Ser Val Asp Phe Gln 325 330 335Arg Thr Trp Lys Glu Tyr Lys Val Gly Phe Gly Asn Pro Ser Gly Glu 340 345 350Tyr Trp Leu Gly Asn Glu Phe Val Ser Gln Leu Thr Asn Gln Gln Arg 355 360 365Tyr Val Leu Lys Ile His Leu Lys Asp Trp Glu Gly Asn Glu Ala Tyr 370 375 380Ser Leu Tyr Glu His Phe Tyr Leu Ser Ser Glu Glu Leu Asn Tyr Arg385 390 395 400Ile His Leu Lys Gly Leu Thr Gly Thr Ala Gly Lys Ile Ser Ser Ile 405 410 415Ser Gln Pro Gly Asn Asp Phe Ser Thr Lys Asp Gly Asp Asn Asp Lys 420 425 430Cys Ile Cys Lys Cys Ser Gln Met Leu Thr Gly Gly Trp Trp Phe Asp 435 440 445Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Tyr Tyr Pro Gln Arg Gln 450 455 460Asn Thr Asn Lys Phe Asn Gly Ile Lys Trp Tyr Tyr Trp Lys Gly Ser465 470 475 480Gly Tyr Ser Leu Lys Ala Thr Thr Met Met Ile Arg Pro Ala Asp Phe 485 490 4954496PRTMus musculus 4Met Trp Gln Ile Ile Phe Leu Thr Phe Gly Trp Asp Leu Val Leu Ala1 5 10 15Ser Ala Tyr Ser Asn Phe Arg Lys Ser Val Asp Ser Thr Gly Arg Arg 20 25 30Gln Tyr Gln Val Gln Asn Gly Pro Cys Ser Tyr Thr Phe Leu Leu Pro 35 40 45Glu Thr Asp Ser Cys Arg Ser Ser Ser Ser Pro Tyr Met Ser Asn Ala 50 55 60Val Gln Arg Asp Ala Pro Leu Asp Tyr Asp Asp Ser Val Gln Arg Leu65 70 75 80Gln Val Leu Glu Asn Ile Leu Glu Asn Asn Thr Gln Trp Leu Met Lys 85 90 95Leu Glu Asn Tyr Ile Gln Asp Asn Met Lys Lys Glu Met Val Glu Ile 100 105 110Gln Gln Asn Val Val Gln Asn Gln Thr Ala Val Met Ile Glu Ile Gly 115 120 125Thr Ser Leu Leu Asn Gln Thr Ala Ala Gln Thr Arg Lys Leu Thr Asp 130 135 140Val Glu Ala Gln Val Leu Asn Gln Thr Thr Arg Leu Glu Leu Gln Leu145 150 155 160Leu Gln His Ser Ile Ser Thr Asn Lys Leu Glu Lys Gln Ile Leu Asp 165 170 175Gln Thr Ser Glu Ile Asn Lys Leu Gln Asn Lys Asn Ser Phe Leu Glu 180 185 190Gln Lys Val Leu Asp Met Glu Gly Lys His Ser Glu Gln Leu Gln Ser 195 200 205Met Lys Glu Gln Lys Asp Glu Leu Gln Val Leu Val Ser Lys Gln Ser 210 215 220Ser Val Ile Asp Glu Leu Glu Lys Lys Leu Val Thr Ala Thr Val Asn225 230 235 240Asn Ser Leu Leu Gln Lys Gln Gln His Asp Leu Met Glu Thr Val Asn 245 250 255Ser Leu Leu Thr Met Met Ser Ser Pro Asn Ser Lys Ser Ser Val Ala 260 265 270Ile Arg Lys Glu Glu Gln Thr Thr Phe Arg Asp Cys Ala Glu Ile Phe 275 280 285Lys Ser Gly Leu Thr Thr Ser Gly Ile Tyr Thr Leu Thr Phe Pro Asn 290 295 300Ser Thr Glu Glu Ile Lys Ala Tyr Cys Asp Met Asp Val Gly Gly Gly305 310 315 320Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Val Asp Phe Gln 325 330 335Arg Thr Trp Lys Glu Tyr Lys Glu Gly Phe Gly Asn Pro Leu Gly Glu 340 345 350Tyr Trp Leu Gly Asn Glu Phe Val Ser Gln Leu Thr Gly Gln His Arg 355 360 365Tyr Val Leu Lys Ile Gln Leu Lys Asp Trp Glu Gly Asn Glu Ala His 370 375 380Ser Leu Tyr Asp His Phe Tyr Leu Ala Gly Glu Glu Ser Asn Tyr Arg385 390 395 400Ile His Leu Thr Gly Leu Thr Gly Thr Ala Ala Lys Ile Ser Ser Ile 405 410 415Ser Gln Pro Gly Ser Asp Phe Ser Thr Lys Asp Ser Asp Asn Asp Lys 420 425 430Cys Ile Cys Lys Cys Ser Gln Met Leu Ser Gly Gly Trp Trp Phe Asp 435 440 445Ala Cys Gly Pro Ser Asn Leu Asn Gly Gln Tyr Tyr Pro Gln Lys Gln 450 455 460Asn Thr Asn Lys Phe Asn Gly Ile Lys Trp Tyr Tyr Trp Lys Gly Ser465 470 475 480Gly Tyr Ser Leu Lys Ala Thr Thr Met Met Ile Arg Pro Ala Asp Phe 485 490 4955498PRTMus musculus 5Met Thr Val Phe Leu Ser Phe Ala Phe Phe Ala Ala Ile Leu Thr His1 5 10 15Ile Gly Cys Ser Asn Gln Arg Arg Asn Pro Glu Asn Gly Gly Arg Arg 20 25 30Tyr Asn Arg Ile Gln His Gly Gln Cys Ala Tyr Thr Phe Ile Leu Pro 35 40 45Glu His Asp Gly Asn Cys Arg Glu Ser Ala Thr Glu Gln Tyr Asn Thr 50 55 60Asn Ala Leu Gln Arg Asp Ala Pro His Val Glu Pro Asp Phe Ser Val65 70 75 80Gln Lys Leu Gln His Leu Glu His Val Met Glu Asn Tyr Thr Gln Trp 85 90 95Leu Gln Lys Leu Glu Asn Tyr Ile Val Glu Asn Met Lys Ser Glu Met 100 105 110Ala Gln Ile Gln Gln Asn Ala Val Gln Asn His Thr Ala Thr Met Leu 115 120 125Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Arg Lys 130 135 140Leu Thr Asp Val Glu Thr Gln Val Leu Asn Gln Thr Ser Arg Leu Glu145 150 155 160Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu Lys Gln 165 170 175Leu Leu Gln Gln Thr Asn Glu Ile Leu Lys Ile His Glu Lys Asn Ser 180 185 190Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys Glu Glu 195 200 205Leu Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu Val Ser 210 215 220Arg Gln Thr Phe Ile Ile Gln Glu Leu Glu Lys Gln Leu Ser Arg Ala225 230 235 240Thr Asn Asn Asn Ser Ile Leu Gln Lys Gln Gln Leu Glu Leu Met Asp 245 250 255Thr Val His Asn Leu Val Ser Leu Cys Thr Lys Glu Gly Val Leu Leu 260 265 270Lys Gly Gly Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys Ala Asp 275 280 285Val Tyr Gln Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Phe 290 295 300Asn Asn Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn305 310 315 320Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp 325 330 335Phe Gln Arg Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Ser 340 345 350Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln 355 360 365Arg Gln Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg 370 375 380Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gln Asn385 390 395 400Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys Gln Ser 405 410 415Ser Leu Ile Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala Asp Asn 420 425 430Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp 435 440 445Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala 450 455 460Gly Gln Asn

His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr Phe Lys465 470 475 480Gly Pro Ser Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg Pro Leu 485 490 495Asp Phe6366DNAHomo sapiens 6caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gggggactac 300ggtgagtact tctactacgg tatggacgtc tggggccaag ggaccacggt caccgtctcc 360tcagcc 3667122PRTHomo sapiens 7Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Gly Asp Tyr Gly Glu Tyr Phe Tyr Tyr Gly Met Asp Val Trp Gly 100 105 110Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 1208324DNAHomo sapiens 8gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtctacag cataatagtt accctcggac gttcggccaa 300gggaccaagg tggaaatcaa acga 3249108PRTHomo sapiens 9Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 10510386DNAHomo sapiens 10caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccgtcagc agtggtggtt actactggaa ctggatccgg 120cagcccccag ggaagggact ggagtggatt ggatatatct attacagtgg gagcaccaac 180tacaacccct ccctcaagag tcgagtcacc atatcagtag acacgtccaa gaaccagttc 240tccctgaagc tgagctctgt gaccgctgcg gacacggccg tgtattactg tgcgagagat 300caggattact atggttcggg gaggggctac tactactacg gtatggacgt ctggggccaa 360gggaccacgg tcaccgtctc ctcagc 38611128PRTHomo sapiens 11Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30Gly Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95Cys Ala Arg Asp Gln Asp Tyr Tyr Gly Ser Gly Arg Gly Tyr Tyr Tyr 100 105 110Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 12512322DNAHomo sapiens 12gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtcaacag gcttacagtt tccggacgtt cggccaaggg 300accaaggtgg aaatcaaacg aa 32213107PRTHomo sapiens 13Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Tyr Ser Phe Arg Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 10514366DNAHomo sapiens 14gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gaaatactat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcaa 300ggtatagcag tggctgggcc ctttgactac tggggccagg gaaccctggt caccgtctcc 360tcagcc 36615122PRTHomo sapiens 15Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gln Gly Ile Ala Val Ala Gly Pro Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 12016322DNAHomo sapiens 16gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gactgttagc agcgacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatgga gcatccatta gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttattc ctgtcagcag tattataact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg aa 32217107PRTHomo sapiens 17Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Val Ser Ser Asp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Ser Cys Gln Gln Tyr Tyr Asn Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 10518366DNAHomo sapiens 18gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gaaatactat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcaa 300ggtatagcag tggctgggcc ctttgactac tggggccagg gaaccctggt caccgtctcc 360tcagcc 36619122PRTHomo sapiens 19Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gln Gly Ile Ala Val Ala Gly Pro Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 12020322DNAHomo sapiens 20gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gactgttagc agcgacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatgga gcatccatta gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttattc ctgtcagcag tattataact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg aa 32221107PRTHomo sapiens 21Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Val Ser Ser Asp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Ser Cys Gln Gln Tyr Tyr Asn Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 10522366DNAHomo sapiens 22gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gaaatactat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcaa 300ggtatagcag tggctgggcc ctttgactac tggggccagg gaaccctggt caccgtctcc 360tcagcc 36623122PRTHomo sapiens 23Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gln Gly Ile Ala Val Ala Gly Pro Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 12024322DNAHomo sapiens 24gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gactgttagc agcgacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatgga gcatccatta gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttattc ctgtcagcag tattataact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg aa 32225107PRTHomo sapiens 25Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Val Ser Ser Asp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Ser Cys Gln Gln Tyr Tyr Asn Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 10526366DNAHomo sapiens 26gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggggagtc tctgaagatc 60tcctgtaagg gttctggata cagcttttcc aactactgga tcgcctgggt gcgccagatg 120cccgggaaag gcctggagtg gatggggatc atctatcctg gtgactctga taccagatac 180agcccgtcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag taccgcctac 240ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgc gagacatgag 300aactggaact tttttgatac ttttgatatc tggggccaag ggacaatggt caccgtctct 360tcagcc 36627122PRTHomo sapiens 27Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser Asn Tyr 20 25 30Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Glu Asn Trp Asn Phe Phe Asp Thr Phe Asp Ile Trp Gly 100 105 110Gln Gly Thr Met Val Thr Val Ser Ser Ala 115 12028324DNAHomo sapiens 28gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtattagc agcaacttag cctggttcca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tataataact ggcctcggac gttcggccaa 300gggaccacgg tggagatcaa acga 32429108PRTHomo sapiens 29Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Asn 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Thr Val Glu Ile Lys Arg 100 10530351DNAHomo sapiens 30caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagt aattactact ggagctggat ccggcagccc 120ccagggaagg gactggagtg gattggatat atctattaca gtgggagcac caactacaac 180ccctccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240aaactgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agaccgggct 300gatgcttttg atatctgggg ccaagggaca atggtcaccg tctcttcagc c 35131117PRTHomo sapiens 31Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asn Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Ala Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val 100 105 110Thr Val Ser Ser Ala 11532342DNAHomo sapiens 32gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgtt tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca

ctgatttcac actgaaaatc 240agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300ccgctcactt tcggcggagg gaccaaggtg gagatcaaac ga 34233114PRTHomo sapiens 33Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110Lys Arg34366DNAHomo sapiens 34caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctaag agccgaggac acggctgtgt attactgtgc gagaggggga 300ttacgatatt ttgactggcc ccctgactac tggggccagg gaaccctggt caccgtctcc 360tcagcc 36635122PRTHomo sapiens 35Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Leu Arg Tyr Phe Asp Trp Pro Pro Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 12036327DNAHomo sapiens 36gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca acagggccac tggcatccca 180gacaggttca gtgccagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtttggta cctcaccatt cactttcggc 300cctgggacca aagtggatat caaacga 32737109PRTHomo sapiens 37Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Ala Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe Gly Thr Ser Pro 85 90 95Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 10538366DNAHomo sapiens 38gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60tcctgtgcag cctctggatt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaaaacacg 240ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtaccacg 300gaatacggtg acttttggta cttcgatttc tggggccgtg gcaccctggt cactgtctcc 360tcagcc 36639122PRTHomo sapiens 39Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Thr Glu Tyr Gly Asp Phe Trp Tyr Phe Asp Phe Trp Gly 100 105 110Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 12040324DNAHomo sapiens 40gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120gggaaagccc ctaacctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcattctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtcaacag tctaacagtt tccctcggac gttcggccaa 300gggaccaagg tggaaatcaa acga 32441108PRTHomo sapiens 41Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Ile Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Ser Phe Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 10542374DNAHomo sapiens 42caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt ataaggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgaat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcgg 300gacggtgact atcctctgct actactgggt atggacgtct ggggccaagg gaccacggtc 360accgtctcct cagc 37443125PRTHomo sapiens 43Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Asn65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Asp Gly Asp Tyr Pro Leu Leu Leu Leu Gly Met Asp 100 105 110Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 12544339DNAHomo sapiens 44gatattgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca gagcctcctg catagtaatg gatacaacta tttggattgg 120tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc 180tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattctac actgaaaatc 240agcagagtgg aggctgagga tgttggggtt tattactgca tgcaagctct acaaactcct 300ctcactttcg gcggagggac caaggtggag atcaaacga 33945113PRTHomo sapiens 45Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Ser Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg46366DNAHomo sapiens 46gtcaggtgca gctggtggag tctgggggag gcgtggtcca gcctgggagg tccctgagac 60tctcctgtgc agcgtctgga ttcaccttca gtagctatgg catgcactgg gtccgccagg 120ctccaggcaa ggggctggag tgggtggcag ttatatggta tgatggaagt aataaatact 180atgcagactc cgtgaagggc cgattcacca tctccagaga caattccaag aacacgctgt 240atctgcaaat gaacagcctg agagccgagg acacggctgt gtattactgt gcgggggact 300acggtgacta cttctactac ggtatggacg tctggggcca agggaccacg gtcaccgtct 360cctcag 36647122PRTHomo sapiens 47Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Gly Asp Tyr Gly Asp Tyr Phe Tyr Tyr Gly Met Asp Val Trp Gly 100 105 110Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 12048324DNAHomo sapiens 48gacatccaga tgacccagtc tccatcctcc ctgtctacat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcggcct 240gaagattttg caacttatta ctgtctacag cttaatagtt accctcggac gttcggccaa 300gggaccaagg tggaaatcaa acga 32449108PRTHomo sapiens 49Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Arg Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Leu Asn Ser Tyr Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 10550351DNAHomo sapiens 50caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagt aattactact ggagctggat ccggcagccc 120ccagggaagg gactggagtg gattggatat atctattaca gtgggagcac caactacaac 180ccctccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240aaactgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agaccgggct 300gatgcttttg atatctgggg ccaagggaca atggtcaccg tctcttcagc c 35151117PRTHomo sapiens 51Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asn Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Ala Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val 100 105 110Thr Val Ser Ser Ala 11552342DNAHomo sapiens 52gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgtt tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300ccgctcactt tcggcggagg gaccaaggtg gagatcaaac ga 34253114PRTHomo sapiens 53Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110Lys Arg54351DNAHomo sapiens 54caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagt aattactact ggagctggat ccggcagccc 120ccagggaagg gactggagtg gattggatat atctattaca gtgggagcac caactacaac 180ccctccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240aaactgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agaccgggct 300gatgcttttg atatctgggg ccaagggaca atggtcaccg tctcttcagc c 35155117PRTHomo sapiens 55Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asn Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Ala Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val 100 105 110Thr Val Ser Ser Ala 11556342DNAHomo sapiens 56gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgtt tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300ccgctcactt tcggcggagg gaccaaggtg gagatcaaac ga 34257114PRTHomo sapiens 57Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110Lys Arg58366DNAHomo sapiens 58gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60tcctgtgcag cctctggatt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaaaacacg 240ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ttgtatcatt 300ttctacggtg actttgatgc ttttgatatc tggggccaag ggacaatggt caccgtctct 360tcagcc 36659122PRTHomo sapiens 59Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr

Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ile Ile Phe Tyr Gly Asp Phe Asp Ala Phe Asp Ile Trp Gly 100 105 110Gln Gly Thr Met Val Thr Val Ser Ser Ala 115 12060313DNAHomo sapiens 60gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaagct 240gaagattttg caacttacta ctgtcaacag agtttaactt tcggccctgg gaccaaagtg 300gatatcaaac gaa 31361104PRTHomo sapiens 61Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Leu Thr Phe Gly Pro 85 90 95Gly Thr Lys Val Asp Ile Lys Arg 10062342DNAHomo sapiens 62gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgtt tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300ccgctcactt tcggcggagg gaccaaggtg gagatcaaac ga 34263114PRTHomo sapiens 63Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110Lys Arg64324DNAHomo sapiens 64gacatccaaa tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggcattagc agttatttag cctggtttca gcagaaacca 120gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aagttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgccaacag tataatagtt accctctcac tttcggcgga 300gggaccaagg tggagatcaa acga 32465108PRTHomo sapiens 65Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 10566366DNAHomo sapiens 66gaggtgcaac tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60tcctgtgcag cctctggatt cactttcagt aacgcctgga tgcactgggt ccgccaggct 120ccagggaagg ggctggactg ggttggccgt attaaaagca aaactgatgg tgggacagca 180gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc agaaaacacg 240ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtaccaat 300gactacggtg acttctatgc ttttgatatc tggggccaag ggacaatggt caccgtctct 360tcagcc 36667122PRTHomo sapiens 67Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Ala Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Glu Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Asn Asp Tyr Gly Asp Phe Tyr Ala Phe Asp Ile Trp Gly 100 105 110Gln Gly Thr Met Val Thr Val Ser Ser Ala 115 12068324DNAHomo sapiens 68gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagaatcacc 60atcacttgcc gggcaaggca gagcattagc agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttactt ctgtcaacag agttacagta ccccattcac tttcggccct 300ggggccaaag tggatatcaa acga 32469108PRTHomo sapiens 69Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Ile Thr Ile Thr Cys Arg Ala Arg Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Ser Tyr Ser Thr Pro Phe 85 90 95Thr Phe Gly Pro Gly Ala Lys Val Asp Ile Lys Arg 100 10570366DNAHomo sapiens 70caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctttggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtttg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagtgactac 300ggtgactact tctactacgg tatggacgtc tggggccaag ggaccacggt caccgtctcc 360tcagcc 36671122PRTHomo sapiens 71Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Ser Asp Tyr Gly Asp Tyr Phe Tyr Tyr Gly Met Asp Val Trp Gly 100 105 110Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 12072324DNAHomo sapiens 72gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180agattcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtctacag tataatagtt accctcggac gttcggccaa 300gggaccaagg tggaaatcaa acga 32473108PRTHomo sapiens 73Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Ser Tyr Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 10574372DNAHomo sapiens 74caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcact aactatggca tgcactgggg ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcacatg atggaaataa taagtattat 180gtagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagaggga 300atcgattttt ggagtggcct caactggttc gacccctggg gccagggaac cctggtcacc 360gtctcctcag cc 37275124PRTHomo sapiens 75Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asn Tyr 20 25 30Gly Met His Trp Gly Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser His Asp Gly Asn Asn Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Ile Asp Phe Trp Ser Gly Leu Asn Trp Phe Asp Pro 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 12076327DNAHomo sapiens 76gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccact 60ctctcctgca gggccagtca gagtattacc ggcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccagact cctcatctgt ggtgcatcca gctgggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag tagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatagta gttcaccgat caccttcggc 300caagggacac gactggagat taaacga 32777109PRTHomo sapiens 77Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Thr Gly Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Cys Gly Ala Ser Ser Trp Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ser Ser Pro 85 90 95Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 10578372DNAHomo sapiens 78caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcact aactatggca tgcactgggg ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcacatg atggaaataa taagtattat 180gtagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagaggga 300atcgattttt ggagtggcct caactggttc gacccctggg gccagggaac cctggtcacc 360gtctcctcag cc 37279124PRTHomo sapiens 79Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asn Tyr 20 25 30Gly Met His Trp Gly Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser His Asp Gly Asn Asn Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Ile Asp Phe Trp Ser Gly Leu Asn Trp Phe Asp Pro 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 12080327DNAHomo sapiens 80gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccact 60ctctcctgca gggccagtca gagtattacc ggcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccagact cctcatctgt ggtgcatcca gctgggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag tagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatagta gttcaccgat caccttcggc 300caagggacac gactggagat taaacga 32781109PRTHomo sapiens 81Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Thr Gly Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Cys Gly Ala Ser Ser Trp Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ser Ser Pro 85 90 95Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 10582339DNAHomo sapiens 82gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taagtgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300ccgacgttcg gccaagggac caaggtggaa atcaaacga 33983113PRTHomo sapiens 83Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Lys Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110Arg84360DNAHomo sapiens 84caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagt agtggtggtt acttctggag ctggatccgc 120cagcacccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagaacctac 180tacaacccgt ccctcaagag tcgagttacc atatcagtag acgcgtctaa gaaccagttc 240tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtatcactg tgcgagagag 300gggtcgtact gggactttga ctactggggc cagggaaccc tggtcaccgt ctcctcagcc 36085120PRTHomo sapiens 85Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30Gly Tyr Phe Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Arg Thr Tyr Tyr Asn Pro Ser 50 55 60Leu Lys Ser Arg Val Thr Ile Ser Val Asp Ala Ser Lys Asn Gln Phe65 70 75 80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr His 85 90 95Cys Ala Arg Glu Gly Ser Tyr Trp Asp Phe Asp Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 12086327DNAHomo sapiens 86gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtacatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt

ttgcagtgta ttactgtcag cagtatggta gctcactatt cactttcggc 300cctgggacca aagtggatat caaacga 32787109PRTHomo sapiens 87Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Thr Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Leu 85 90 95Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 10588378DNAHomo sapiens 88caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt aactatggca tgcactgggt ccgtcaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaggaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagagggg 300gggtattgtg gtggtgactg ctgggtttac ggtatggacg tctggggcca agggaccacg 360gtcaccgtct cctcagcc 37889126PRTHomo sapiens 89Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Gly Tyr Cys Gly Gly Asp Cys Trp Val Tyr Gly Met 100 105 110Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 12590324DNAHomo sapiens 90gacatccaga tgacccagtc tccattttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattagc aactggttag cctggtatca gcagaaacca 120gggaaagccc ctaaactcct gatctatact gcatccagtt tgcaaaatgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtcaacag attaacagtt tcccgtggac gttcggccaa 300gggaccaagg tggaaatcaa acga 32491108PRTHomo sapiens 91Asp Ile Gln Met Thr Gln Ser Pro Phe Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Thr Ala Ser Ser Leu Gln Asn Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ile Asn Ser Phe Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 10592366DNAHomo sapiens 92caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gggggactac 300ggtgagtact tctactacgg tatggacgtc tggggccaag ggaccacggt caccgtctcc 360tcagcc 36693122PRTHomo sapiens 93Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Gly Asp Tyr Gly Glu Tyr Phe Tyr Tyr Gly Met Asp Val Trp Gly 100 105 110Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 12094324DNAHomo sapiens 94gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtttacag cataataatt accctcggac gttcggccaa 300gggaccaagg tggaaatcaa acga 32495108PRTHomo sapiens 95Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Asn Tyr Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 10596357DNAHomo sapiens 96gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagt agctcttgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga caaatactat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgt gagagataag 300ggcagtggct ggtttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagcc 35797119PRTHomo sapiens 97Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Asp Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Val Arg Asp Lys Gly Ser Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 11598357DNAHomo sapiens 98gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga caaatactat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcgaatga acagcctgag agccgaggac acggctgtgt tttactgtgc gagagatatg 300ggcagtggct ggtttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagcc 35799119PRTHomo sapiens 99Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Asp Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Arg Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Phe Tyr Cys 85 90 95Ala Arg Asp Met Gly Ser Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115100321DNAHomo sapiens 100gaagtagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttggc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttattg ctgtcagcag tataatcact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg a 321101107PRTHomo sapiens 101Glu Val Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Cys Cys Gln Gln Tyr Asn His Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105102357DNAHomo sapiens 102gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga caaatactat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcgaatga acagcctgag agccgaggac acggctgtgt tttactgtgc gagagatatg 300ggcagtggct ggtttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagcc 357103119PRTHomo sapiens 103Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Asp Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Arg Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Phe Tyr Cys 85 90 95Ala Arg Asp Met Gly Ser Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115104321DNAHomo sapiens 104gaagtagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttggc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttattg ctgtcagcag tataatcact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg a 321105107PRTHomo sapiens 105Glu Val Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Cys Cys Gln Gln Tyr Asn His Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105106351DNAHomo sapiens 106caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagt aattactact ggagctggat ccggcagccc 120ccagggaagg gactggagtg gattggatat atctattaca gtgggagcac caactacaac 180ccctccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240aaactgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agaccgggct 300gatgcttttg atatctgggg ccaagggaca atggtcaccg tctcttcagc c 351107117PRTHomo sapiens 107Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asn Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Ala Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val 100 105 110Thr Val Ser Ser Ala 115108342DNAHomo sapiens 108gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgtt tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300ccgctcactt tcggcggagg gaccaaggtg gagatcaaac ga 342109114PRTHomo sapiens 109Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110Lys Arg110351DNAHomo sapiens 110caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggaaac cctgtccctc 60acctgcactg tctctggtga ctccatcagt aattactact ggagctggat ccggcagccc 120ccagggaagg gactggagtg gattgggtat atctattaca gtgggagcac caactacaat 180ccctccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240aagctgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agagaggggt 300gatgcttttg atatctgggg ccaagggaga gtggtcaccg tctcttcagc c 351111117PRTHomo sapiens 111Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Ser Asn Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Arg Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly Arg Val Val 100 105 110Thr Val Ser Ser Ala 115112324DNAHomo sapiens 112gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcatcaga aatgatttag gctggtatca gcagaaacca 120gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtagatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtctccag cataatagtt accctcccag ttttggccag 300gggaccaagc tggagatcaa acga 324113108PRTHomo sapiens 113Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Pro 85 90

95Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105114351DNAHomo sapiens 114caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta cacctttacc agctatggta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcagcactt acaatgataa cacaaactat 180gcacagaagc tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gaggggagtg 300ggagctacgg actactgggg ccagggaacc ctggtcaccg tctcctcagc c 351115117PRTHomo sapiens 115Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Ser Thr Tyr Asn Asp Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Val Gly Ala Thr Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala 115116324DNAHomo sapiens 116gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtctcc 60atcatttgtc gggcgagtca gggcattagc aattatttag cctggtttca gcagaaacca 120gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aagttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgccaacag tataatagtt acccatcaac tttcggccct 300gggaccaaag tggatatcaa acga 324117108PRTHomo sapiens 117Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Ser Ile Ile Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Ser 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105118351DNAHomo sapiens 118caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggaaac cctgtccctc 60acctgcactg tctctggtga ctccatcagt aattactact ggagctggat ccggcagccc 120ccagggaagg gactggagtg gattgggtat atctattaca gtgggagcac caactacaat 180ccctccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gctctccctg 240aagctgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agagaggggt 300gatgcttttg atatctgggg ccaagggaga gtggtcaccg tctcttcagc c 351119117PRTHomo sapiens 119Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Ser Asn Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Leu Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Arg Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly Arg Val Val 100 105 110Thr Val Ser Ser Ala 115120360DNAHomo sapiens 120caggtgcagc tacagcagtg gggcgcagga ctgttgaagc cttcggagac cctgtccctc 60acctgcgctg tctatggtgg gtccttcagt ggttactact ggagctggat ccgccagccc 120ccagggaagg ggctggagtg gattggggaa atctatcata gtggaagcac caactacaac 180ccgtccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240aagctgagct ctgtgaccgc cgcggacacg gctgtgtatt cctgtgcgag aaatgactac 300ggtgaccacg aaggctttga ctactggggc cagggaaccc tggtcaccgt ctcctcagcc 360121120PRTHomo sapiens 121Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Ser Cys Ala 85 90 95Arg Asn Asp Tyr Gly Asp His Glu Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 120122337DNAHomo sapiens 122gatattgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca gagcctcctg catagtgatg gatacaacta tttggattgg 120tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc 180tccggggtcc ctgacaggtt cagtggcagt ggatcatgca cagattttac actgaaaatc 240agcagagtgg aggctgagga tgttgggatt tattactgca tgcaagctct acaaactcct 300cactttcggc ggagggacca aggtggagat caaacga 337123112PRTHomo sapiens 123Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30Asp Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Cys Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Ala 85 90 95Leu Gln Thr Pro His Phe Arg Arg Arg Asp Gln Gly Gly Asp Gln Thr 100 105 110124383DNAHomo sapiens 124caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcgg 300agctacggtg gtaactcctt ctactactac tactacggta tggacgtctg gggccaaggg 360accacggtca ccgtctcctc agc 383125128PRTHomo sapiens 125Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Ser Tyr Gly Gly Asn Ser Phe Tyr Tyr Tyr Tyr Tyr 100 105 110Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125126324DNAHomo sapiens 126gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcatcaga aatgatttag gctggtatca gcagaaacca 120gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtagatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtctccag cataatagtt accctcccag ttttggccag 300gggaccaagc tggagatcaa acga 324127108PRTHomo sapiens 127Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Pro 85 90 95Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105128360DNAHomo sapiens 128gaggtgcaac tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatagaa tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attagtagta gtagtagtca catatactac 180gtagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ttcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcga 300ggagtgggag ctccctttga ctactggggc cagggaaccc tggtcaccgt ctcctcagcc 360129120PRTHomo sapiens 129Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Arg Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ser Ser Ser Ser His Ile Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Gly Val Gly Ala Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 120130339DNAHomo sapiens 130gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggattc taactgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300ctcactttcg gcggagggac caacgtggag atcaaacga 339131113PRTHomo sapiens 131Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Asp Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Leu Thr Phe Gly Gly Gly Thr Asn Val Glu Ile Lys 100 105 110Arg132360DNAHomo sapiens 132gaggtgcaac tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatagaa tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attagtagta gtagtagtca catatactac 180gtagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ttcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcga 300ggagtgggag ctccctttga ctactggggc cagggaaccc tggtcaccgt ctcctcagcc 360133120PRTHomo sapiens 133Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Arg Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ser Ser Ser Ser His Ile Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Gly Val Gly Ala Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 120134339DNAHomo sapiens 134gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300ctcactttcg gcggagggac caacgtggag atcaaacga 339135113PRTHomo sapiens 135Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Leu Thr Phe Gly Gly Gly Thr Asn Val Glu Ile Lys 100 105 110Arg136366DNAHomo sapiens 136caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tacactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atttggtatg atggaagtag taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagcgaat 300gactacggtg gtaacgggct ttttgactac tggggccagg gaaccctggt caccgtctcc 360tcagcc 366137122PRTHomo sapiens 137Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Ser Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Ala Asn Asp Tyr Gly Gly Asn Gly Leu Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120138342DNAHomo sapiens 138gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60atcaactgca ggtccagcca gagtatttta ttcagctcca acaataagaa ctacttagct 120tggtaccagc agaaaccagg gcagcctcct aagttgctcc tttactgggc atctacccgg 180gaatccgggg tccctgcccg attcagtggc agcgggtctg ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtact 300ccgtgcagtt ttggccaggg gaccaggctg gagatcaaac ga 342139114PRTHomo sapiens 139Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Ile Leu Phe Ser 20 25 30Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45Pro Pro Lys Leu Leu Leu Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95Tyr Tyr Ser Thr Pro Cys Ser Phe Gly Gln Gly Thr Arg Leu Glu Ile 100 105 110Lys Arg140377DNAHomo sapiens 140gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60tcctgtgcag cctctggatt cactttcagt aacgcctgga tgacctgggt ccgccaggct 120ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgttgg tgggacaaca 180gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaaaacacg 240ctgtatctgc aaatgaacag tctgaaaacc gaggacacag ccgtgtatta ctgtaccaca 300gactacggtg actactataa ctccggctac ggtatggacg tctggggcca agggaccacg 360gtcaccgtct cctcagc 377141126PRTHomo sapiens 141Glu Val Gln Leu Val Glu Ser Gly

Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Val Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Thr Asp Tyr Gly Asp Tyr Tyr Asn Ser Gly Tyr Gly Met 100 105 110Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125142325DNAHomo sapiens 142gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc ttctatttaa attggtatca gcagaaacca 120gggaaagccc ctaaactcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacagtt ccccattcac tttcggccct 300gggaccaaag tggatatcaa acgaa 325143108PRTHomo sapiens 143Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Phe Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ser Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105144351DNAHomo sapiens 144caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcaat aattactact ggagctggat ccggcagccc 120ccagggaagg gactggagtg gattggttat atctattaca gtgggagcac caactacaac 180ccctccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240aagctgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agagaggggt 300gactcctttg actactgggg ccagggaacc ctggtcaccg tctcctcagc c 351145117PRTHomo sapiens 145Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Asn Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Arg Gly Asp Ser Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala 115146339DNAHomo sapiens 146gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtcg aagcctcgta tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240agcagggtgg aggctgcgga tgttggggtt tattactgca tgcaaggtac acactggccg 300tgcagttttg gccaggggac caagctggag atcaaacga 339147113PRTHomo sapiens 147Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Arg Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Ala Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Cys Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110Arg148324DNAHomo sapiens 148gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcatcaga aatgatttag gctggtatca gcagaaacca 120gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtagatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtctccag cataatagtt accctcccag ttttggccag 300gggaccaagc tggagatcaa acga 324149108PRTHomo sapiens 149Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Pro 85 90 95Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105150381DNAHomo sapiens 150gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60tcctgtgcag cctctggatt cactttcagt aacgcctgga tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaaaacacg 240ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtaccaca 300gcctacggtg gtaactccga tcaggaggac tacggtatgg acgtctgggg ccaagggacc 360acggtcaccg tctcctcagc c 381151127PRTHomo sapiens 151Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Thr Ala Tyr Gly Gly Asn Ser Asp Gln Glu Asp Tyr Gly 100 105 110Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125152325DNAHomo sapiens 152gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc atctatttaa attggtatca gcagagacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagac ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacagta ccccgctcac tttcggcgga 300gggaccaagg tggagatcaa acgaa 325153108PRTHomo sapiens 153Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ile Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105154372DNAHomo sapiens 154gaggtgcagt tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatagca tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attagtagta gtagtagtta tatatattac 180gcagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatggg 300gcgatttttg gagtggttaa ctggtacttc gatctctggg gccgtggcac cctggtcact 360gtctcctcag cc 372155124PRTHomo sapiens 155Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Ala Ile Phe Gly Val Val Asn Trp Tyr Phe Asp Leu 100 105 110Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120156372DNAHomo sapiens 156gaggtgcagt tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatagca tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attagtagta gtagtagtta tatatattac 180gcagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatggg 300gcgatttttg gagtggttaa ctggtacttc gatctctggg gccgtggcac cctggtcact 360gtctcctcag cc 372157124PRTHomo sapiens 157Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Ala Ile Phe Gly Val Val Asn Trp Tyr Phe Asp Leu 100 105 110Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120158372DNAHomo sapiens 158gaggtgcagt tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatagca tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attagtagta gtagtagtta tatatattac 180gcagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatggg 300gcgatttttg gagtggttaa ctggtacttc gatctctggg gccgtggcac cctggtcact 360gtctcctcag cc 372159124PRTHomo sapiens 159Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Ala Ile Phe Gly Val Val Asn Trp Tyr Phe Asp Leu 100 105 110Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120160324DNAHomo sapiens 160gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggcattagc aattatttag cctggtttca gcagaaacca 120gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aagttcagcg gcagtggatc tgggacagac ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgccaacag tataatagtt acccttcgac gttcggccaa 300gggaccaagg tggaaatcaa acga 324161108PRTHomo sapiens 161Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Ser 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105162372DNAHomo sapiens 162gaggtgcagt tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatagca tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attagtagta gtagtagtta tatatattac 180gcagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatggg 300gcgatttttg gagtggttaa ctggtacttc gatctctggg gccgtggcac cctggtcact 360gtctcctcag cc 372163124PRTHomo sapiens 163Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Ala Ile Phe Gly Val Val Asn Trp Tyr Phe Asp Leu 100 105 110Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120164324DNAHomo sapiens 164gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggcattagc aattatttag cctggtttca gcagaaacca 120gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aagttcagcg gcagtggatc tgggacagac ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgccaacag tataatagtt acccttcgac gttcggccaa 300gggaccaagg tggaaatcaa acga 324165108PRTHomo sapiens 165Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Ser 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105166389DNAHomo sapiens 166caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgtactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatttc 300ttccaaaatt acgatttttg gagtggttcc cccgttgggt acggtatgga cgtctggggc 360caagggacca cggtcaccgt ctcctcagc 389167130PRTHomo sapiens 167Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50

55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Phe Phe Gln Asn Tyr Asp Phe Trp Ser Gly Ser Pro Val 100 105 110Gly Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 115 120 125Ser Ala 130168339DNAHomo sapiens 168gatattgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca gagcctcctg tatagtaatg gatacaacta tttggattgg 120tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc 180tccggggtcc ctgacaggtt cggtggcagt ggatcaggca cagattttac actgaaaatc 240agcagagtgg aggctgagga tgttggggtt tattactgca tgcaagctct acaaactccg 300tggacgttcg gccaagggac caaggtggaa atcaaacga 339169113PRTHomo sapiens 169Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Leu Gln Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110Arg170375DNAHomo sapiens 170caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc ggccgactac 300ggtgactctg attactacta ctactacggt atggacgtct ggggccaagg gaccacggtc 360accgtctcct cagcc 375171125PRTHomo sapiens 171Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Ala Asp Tyr Gly Asp Ser Asp Tyr Tyr Tyr Tyr Tyr Gly Met Asp 100 105 110Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125172324DNAHomo sapiens 172gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga gatgatttag gctggtttca gcagaaacca 120gggaaagccc ctaagcgcct gacctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtctacag tataatagtt acccattcac tttcggccct 300gggaccaaag tggatatcaa acga 324173108PRTHomo sapiens 173Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asp Asp 20 25 30Leu Gly Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Thr 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Ser Tyr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105174342DNAHomo sapiens 174caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagaattg 300gcctcgtggg gccagggaac cctggtcacc gtctcctcag cc 342175114PRTHomo sapiens 175Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Leu Ala Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110Ser Ala176343DNAHomo sapiens 176gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgtt tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300ccgctcactt tcggcggagg gaccaaggtg gagatcaaac gaa 343177114PRTHomo sapiens 177Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110Lys Arg 178372DNAHomo sapiens 178gaggtgcagt tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatagca tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attagtagta gtagtagtta tatatattac 180gcagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatggg 300gcgatttttg gagtggttaa ctggtacttc gatctctggg gccgtggcac cctggtcact 360gtctcctcag cc 372179124PRTHomo sapiens 179Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Ala Ile Phe Gly Val Val Asn Trp Tyr Phe Asp Leu 100 105 110Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120180324DNAHomo sapiens 180gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtctacag cataatagtt accctccgac gttcggccaa 300gggaccaagg tggaaatcaa acga 324181108PRTHomo sapiens 181Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Pro 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105182351DNAHomo sapiens 182caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagt aattactact ggagctggat ccggcagccc 120ccagggaagg gactggagtg gattggatat atctattaca gtgggagcac caactacaac 180ccctccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240aaactgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agaccgggct 300gatgcttttg atatctgggg ccaagggaca atggtcaccg tctcttcagc c 351183117PRTHomo sapiens 183Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asn Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Ala Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val 100 105 110Thr Val Ser Ser Ala 115184342DNAHomo sapiens 184gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgtt tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300ccgctcactt tcggcggagg gaccaaggtg gagatcaaac ga 342185114PRTHomo sapiens 185Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110Lys Arg186360DNAHomo sapiens 186gaggtgcaac tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatagaa tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attagtagta gtagtagtca catatactac 180gtagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ttcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcga 300ggagtgggag ctccctttga ctactggggc cagggaaccc tggtcaccgt ctcctcagcc 360187120PRTHomo sapiens 187Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Arg Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ser Ser Ser Ser His Ile Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Gly Val Gly Ala Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 120188339DNAHomo sapiens 188gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300ctcactttcg gcggagggac caacgtggag atcaaacga 339189113PRTHomo sapiens 189Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Leu Thr Phe Gly Gly Gly Thr Asn Val Glu Ile Lys 100 105 110Arg190365DNAHomo sapiens 190gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60tcctgtgcag cctctggatt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaaaacacg 240ctgtatctgc aaatgaacag cctgaaaatc gaggacacag ccgtgtatta ctgtaccata 300acctacggtg actaccccta ctttgactgc tggggccagg gaaccctggt caccgtctcc 360tcagc 365191122PRTHomo sapiens 191Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Ile Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Ile Thr Tyr Gly Asp Tyr Pro Tyr Phe Asp Cys Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120192324DNAHomo sapiens 192gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattcgc agctggttag cctggtatca gcagaaacca 120gggaaagccc ctaaactcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtcaacag gctaacagtt tcccgtggac gttcggccaa 300gggaccaagg tggaaatcaa acga 324193108PRTHomo sapiens 193Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105194375DNAHomo sapiens 194caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg

ggctggagtg ggtggcagtt atatggtttg atggatttaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt atcactgtgc gagagatcgg 300ggatatagtg gctacgatca ctactacggt atggacgtct ggggccaagg gaccacggtc 360accgtctcct cagct 375195125PRTHomo sapiens 195Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Phe Asp Gly Phe Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys 85 90 95Ala Arg Asp Arg Gly Tyr Ser Gly Tyr Asp His Tyr Tyr Gly Met Asp 100 105 110Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125196375DNAHomo sapiens 196caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtttg atggatttaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt atcactgtgc gagagatcgg 300ggatatagtg gctacgatca ctactacggt atggacgtct ggggccaagg gaccacggtc 360accgtctcct cagct 375197125PRTHomo sapiens 197Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Phe Asp Gly Phe Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys 85 90 95Ala Arg Asp Arg Gly Tyr Ser Gly Tyr Asp His Tyr Tyr Gly Met Asp 100 105 110Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125198324DNAHomo sapiens 198gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattcgc agctggttag cctggtatca gcagaaacca 120gggaaagccc ctaaactcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtcaacag gctaacagtt tcccgtggac gttcggccaa 300gggaccaagg tggaaatcaa acga 324199108PRTHomo sapiens 199Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105200354DNAHomo sapiens 200gaggtgcagc tggtggagtc tgggggagac ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gaaattctat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatatc 300aggtggtact tcgatctctg gggccgtggc accctggtca ctgtctcctc agct 354201118PRTHomo sapiens 201Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Phe Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Ile Arg Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110Val Thr Val Ser Ser Ala 115202383DNAHomo sapiens 202gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60tcctgtgcag cctctggatt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120ccagggaagg gactagaatg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaatacacg 240ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtaccata 300ggtagcagtg gctggtacga ggcctactac tattacggta tggacgtctg gggccaaggg 360accacggtca ccgtctcctc agc 383203128PRTHomo sapiens 203Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Tyr Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Ile Gly Ser Ser Gly Trp Tyr Glu Ala Tyr Tyr Tyr Tyr 100 105 110Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125204360DNAHomo sapiens 204gaggtgcagc tggtggagtc tgggggaggt gtggtacggc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cagctttgat gattatggca tgagctgggt ccgccaagct 120ccagggaagg ggctggagtg ggtctctggt attaattgga atggtggtag gacagtttat 180gcagactctg tgaagggccg attcaccatc tccagagaca gcgccaagaa ctccctgtat 240ctgcaaatga acagtctgag agccgaggac acggccttgt atcactgtgc gagaaataag 300cagtggctct ggtacttcga tctctggggc cgtggcaccc tggtcactgt ctcctcagct 360205120PRTHomo sapiens 205Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Asp Asp Tyr 20 25 30Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Asn Trp Asn Gly Gly Arg Thr Val Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr His Cys 85 90 95Ala Arg Asn Lys Gln Trp Leu Trp Tyr Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 120206325DNAHomo sapiens 206gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ctcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tataataact ggcctctcac tttcggcggt 300gggaccaagg tggagatcaa acgaa 325207108PRTHomo sapiens 207Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Leu Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105208383DNAHomo sapiens 208gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60tcctgtgcag cctctggatt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120ccagggaagg gactagaatg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaatacacg 240ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtaccata 300ggtagcagtg gctggtacga ggcctactac tattacggta tggacgtctg gggccaaggg 360accacggtca ccgtctcctc agc 383209128PRTHomo sapiens 209Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Tyr Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Ile Gly Ser Ser Gly Trp Tyr Glu Ala Tyr Tyr Tyr Tyr 100 105 110Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125210360DNAHomo sapiens 210gaggtgcaac tggtggagtc tgggggaggt gtggtacggc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatggca tgagctgggt ccgccaagct 120ccagggaagg ggctggagtg ggtctctggt attaattgga atggtggtgg cacaggttat 180gcagactcta tgaagggccg attcaccatc tccagagacg acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag agccgaggac acggccttgt atcactgtgc gagaaataag 300cagtggctct ggtacttcga tctctggggc cgtggcaccc tggtcactgt ctcctcagct 360211120PRTHomo sapiens 211Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Asn Trp Asn Gly Gly Gly Thr Gly Tyr Ala Asp Ser Met 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr His Cys 85 90 95Ala Arg Asn Lys Gln Trp Leu Trp Tyr Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 120212324DNAHomo sapiens 212gaaatcgtga tgacgcagtc tccagccacc ctgtctgtgt ctctagggga aagagccacc 60ctctcctgca gggccagtca gagtgttcgc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ctcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcaccag tacaataact ggcctctcac tttcggcggt 300gggaccaagg tggagatcaa acga 324213108PRTHomo sapiens 213Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Leu Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Leu Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr Asn Asn Trp Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105214339DNAHomo sapiens 214gatattgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca gagcctcctg catagtaatg gatacaacta tttggattgg 120tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc 180tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240agcagagtgg aggctgagga tgttggggtt tattactgca tgcaagctct acaaaccccg 300tggacgttcg gccaagggac caaggtggaa atcaaacga 339215113PRTHomo sapiens 215Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Leu Gln Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110Arg216372DNAHomo sapiens 216caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccagacaagg ggctggagtg ggtggcagtt atatggtatg atggaagtta taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggaggc 300cctctgtata gcaactcctt ttactacttt gactactggg gccagggaac cctggtcacc 360gtctcctcag ct 372217124PRTHomo sapiens 217Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Asp Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Pro Leu Tyr Ser Asn Ser Phe Tyr Tyr Phe Asp Tyr 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120218324DNAHomo sapiens 218gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc aggcgagtca ggacattaga aactatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccgtca 180aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240gaagatattg caacatatta ctgtcaacag tatgataatc tcccgatcac cttcggccaa 300ggggcacgac tggagattaa acga 324219108PRTHomo sapiens 219Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Ile 85 90 95Thr Phe Gly Gln Gly Ala Arg Leu Glu Ile Lys Arg 100 105220354DNAHomo sapiens 220caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60ccctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagataag 300gccttggctt ttgatatctg gggccaaggg acaatggtca ccgtctcttc agct 354221118PRTHomo sapiens

221Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Pro Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Lys Ala Leu Ala Phe Asp Ile Trp Gly Gln Gly Thr Met 100 105 110Val Thr Val Ser Ser Ala 115222324DNAHomo sapiens 222gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc aactatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacagta tcccattcac tttcggccct 300gggaccaaag tggatatcaa acga 324223108PRTHomo sapiens 223Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ile Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105224377DNAHomo sapiens 224caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaggtaa taaatactat 180acagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatgag 300gatatagtgg ctacgattaa ctactactac ggtatggacg tctggggcca agggaccacg 360gtcaccgtct cctcagc 377225126PRTHomo sapiens 225Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Gly Asn Lys Tyr Tyr Thr Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Glu Asp Ile Val Ala Thr Ile Asn Tyr Tyr Tyr Gly Met 100 105 110Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125226324DNAHomo sapiens 226gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc aactatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacagta tcccattcac tttcggccct 300gggaccaaag tggatatcaa acga 324227108PRTHomo sapiens 227Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ile Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105228366DNAHomo sapiens 228gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gaaatactat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatccg 300ggtatagcag tggctggccc ctttgactac tggggccagg gaaccctggt caccgtctcc 360tcagct 366229122PRTHomo sapiens 229Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Pro Gly Ile Ala Val Ala Gly Pro Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120230321DNAHomo sapiens 230gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tataatcact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg a 321231107PRTHomo sapiens 231Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn His Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105232365DNAHomo sapiens 232caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc ggctattata tgtactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagatcag 300ggtataacag tggctggccc ctttgactac tggggccagg gaagcctggt caccgtctcc 360tcagc 365233122PRTHomo sapiens 233Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gln Gly Ile Thr Val Ala Gly Pro Phe Asp Tyr Trp Gly 100 105 110Gln Gly Ser Leu Val Thr Val Ser Ser Ala 115 120234348DNAHomo sapiens 234caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagt ggttactact ggagctggat ccggcagccc 120ccagggaagg gactggagtg gattgggtat atctattaca gtgggagcac caactacaac 180ccctccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240aagctgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agatcggcag 300tggcttgact actggggcca gggaaccctg gtcaccgtct cctcagct 348235116PRTHomo sapiens 235Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Gly Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Gln Trp Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser Ala 115236322DNAHomo sapiens 236gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gactgttatc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagaa ttcactctca ccatcagcag cctgcagtct 240gaagattttg cactttatta ctgtcagcag tataataact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg aa 322237107PRTHomo sapiens 237Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Val Ile Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Leu Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105238365DNAHomo sapiens 238caggtacagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc ggcttctata tgtactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtagtgg cacaaaccat 180gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagatcag 300gatatagcaa cagctggtcc ctttgactac tggggccagg gaaccctggt caccgtctcc 360tcagc 365239122PRTHomo sapiens 239Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Phe 20 25 30Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Ser Gly Thr Asn His Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gln Asp Ile Ala Thr Ala Gly Pro Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120240322DNAHomo sapiens 240gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctttggt gcatccaccc gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tataataact ggtggacgtt cggccgaggg 300accaaggtgg aaatcaaacg aa 322241107PRTHomo sapiens 241Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Phe Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Trp Thr 85 90 95Phe Gly Arg Gly Thr Lys Val Glu Ile Lys Arg 100 105242370DNAHomo sapiens 242caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtgacagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca gttccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggaggc 300cctctgtata gcaactcctt ttactacttt gactactggg gccagggaac cctggtcacc 360gtctcctcag 370243124PRTHomo sapiens 243Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Thr Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Pro Leu Tyr Ser Asn Ser Phe Tyr Tyr Phe Asp Tyr 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120244324DNAHomo sapiens 244gacatccaga tgacccagtc tccatcctcc ctgtctacat ctgtaggaga cagagtcacc 60atcacttgcc aggcgagtca ggacattaga aactatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatccacgat gcatccaatt tggaaacagg ggtcccatca 180agattcagtg gaaatggatc tgggacagat ttttctttca ccatcaccag cctgcagcct 240gaagatattg caacctatta ctgtcaacag tatgctaatc tcccgatcac cttcggccaa 300gggacacgac tggagattaa acga 324245108PRTHomo sapiens 245Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45His Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Asn Gly Ser Gly Thr Asp Phe Ser Phe Thr Ile Thr Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ala Asn Leu Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105246357DNAHomo sapiens 246caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagt agttactact ggagctggat ccggcagccc 120gccgggaagg gactggagtg gattgggcgt atctatacca gtgggttcac caactacaac 180ccctccctca agagtcgagt caccatgtca gtagacacgt ccaagaacca gttctccctg 240aagctgagct ctgtgaccgc cgcggacacg gccgtgtatt actgtgcgag gtataactgg 300aactactggt acttcgatct ctggggccgt ggcatcctgg tcactgtctc ctcagct 357247119PRTHomo sapiens 247Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Arg Ile Tyr Thr Ser Gly Phe Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys

Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Tyr Asn Trp Asn Tyr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Ile 100 105 110Leu Val Thr Val Ser Ser Ala 115248324DNAHomo sapiens 248gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc aggcgagtca ggacattacc aactatttaa attggtatca gaagaaacca 120gggaaagccc ctaaggtcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180aggttcagtg gaagtggatc tgggacaggt tttactttca ccatcagcag cctgcagcct 240gaagatattg caacatatta ctgtcaacag tatgatcata tcccgctcac tttcggcgga 300gggaccaagg tggagatcaa acga 324249108PRTHomo sapiens 249Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Thr Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Lys Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Gly Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp His Ile Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105250360DNAHomo sapiens 250gaggtgcagc tggtggagtc tgggggaggt gtggtacggc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cagctttgat gattatggca tgagctgggt ccgccaagct 120ccagggaagg ggctggagtg ggtctctggt attaattgga atggtggtag gacagtttat 180gcagactctg tgaagggccg attcaccatc tccagagaca gcgccaagaa ctccctgtat 240ctgcaaatga acagtctgag agccgaggac acggccttgt atcactgtgc gagaaataag 300cagtggctct ggtacttcga tctctggggc cgtggcaccc tggtcactgt ctcctcagct 360251120PRTHomo sapiens 251Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Asp Asp Tyr 20 25 30Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Asn Trp Asn Gly Gly Arg Thr Val Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr His Cys 85 90 95Ala Arg Asn Lys Gln Trp Leu Trp Tyr Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 120252369DNAHomo sapiens 252caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt acctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa aaaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctctgt attactgtgc gagaggaggg 300tatagcactg gctggggccc cgactttgac tactggggcc agggaaccct ggtcaccgtc 360tcctcagct 369253123PRTHomo sapiens 253Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ser Lys Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Tyr Ser Thr Gly Trp Gly Pro Asp Phe Asp Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120254369DNAHomo sapiens 254caggtgcagc tggtggagtc tgcgggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt atctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagacg attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaaattac 300tatggttcgg ggagtcccta cggtatggac gtctggggcc aagggaccac ggtcaccgtc 360tcctcagct 369255123PRTHomo sapiens 255Gln Val Gln Leu Val Glu Ser Ala Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ile Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asn Tyr Tyr Gly Ser Gly Ser Pro Tyr Gly Met Asp Val Trp 100 105 110Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120256324DNAHomo sapiens 256gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtagatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacagtg tcccctgcag ttttggccag 300gggaccaagc tggagatcaa acga 324257108PRTHomo sapiens 257Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Val Pro Cys 85 90 95Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105258372DNAHomo sapiens 258caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggaggc 300cctctgtata gcaactcctt ttactacttt gactactggg gccagggaac cctggtcacc 360gtctcctcag ct 372259124PRTHomo sapiens 259Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Pro Leu Tyr Ser Asn Ser Phe Tyr Tyr Phe Asp Tyr 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120260324DNAHomo sapiens 260gacatccgga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagcgtcacc 60atcacttgcc aggcgagtca ggacattaga aactatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240gaagatattg caacatatta ctgtcaacag tatgataatc tcccgatcac cttcggccaa 300gggacacgac tggagattaa acga 324261108PRTHomo sapiens 261Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Ser Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105262357DNAHomo sapiens 262caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtga ctccatcaat agttactact ggagctggat ccggcagccc 120gccgggaagg gactggagtg gattgggcgt atctatacca gtgggagcac caactacaac 180ccctccctca agagtcgagt caccatgtca gtagacacgt ccaagaacca gttctccctg 240aagctgagct ctgtgaccgc cgcggacacg gccgtgtatt actgtgcgag aggtataact 300ggttacgggg ggttcgaccc ctggggccag ggaaccctgg tcaccgtctc ctcagct 357263119PRTHomo sapiens 263Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Asn Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Arg Ile Tyr Thr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Gly Ile Thr Gly Tyr Gly Gly Phe Asp Pro Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115264324DNAHomo sapiens 264gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc aggcgagtca ggacattagc aactatttaa attggtatca gcagaaacca 120gggaaagccc ctaacctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240gaagatattg caacatatta ctgtcaacag tattataatc tcccgatcac cttcggccaa 300gggacacgac tggagattaa acga 324265108PRTHomo sapiens 265Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Asn Leu Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105266354DNAHomo sapiens 266caggtgcgcc tggtggagtc tgggggaggc ctggtcaagc ctggagggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt gactactaca tgagctggat ccgccaggct 120ccagggaagg ggctggagtg ggcttcatac attagtagta gtggttatag catatactac 180gcagactctg tgaagggccg attcaccatc tccagggaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagagaaaga 300ggggatgctt ttgatatctg gggccaaggg acaatggtca ccgtctcttc agct 354267118PRTHomo sapiens 267Gln Val Arg Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ala 35 40 45Ser Tyr Ile Ser Ser Ser Gly Tyr Ser Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Arg Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met 100 105 110Val Thr Val Ser Ser Ala 115268325DNAHomo sapiens 268gaaacgacac tcacgcagtc tccagcattc atgtcagcga ctccaggaga caaagtcaac 60atctcctgca aagccagcca agacattgat gatgatatga actggtacca acagaaacca 120ggagaagttg ctattttcat tattcaagaa gctactactc tcgttcctgg aatcccacct 180cgattcagtg gcagcgggta tggaacagat tttaccctca caattaataa catagaatct 240gaggatgctg catattactt ctgtctacaa catgataatt tccctctcac tttcggcgga 300gggaccaagg tggagatcaa acgaa 325269108PRTHomo sapiens 269Glu Thr Thr Leu Thr Gln Ser Pro Ala Phe Met Ser Ala Thr Pro Gly1 5 10 15Asp Lys Val Asn Ile Ser Cys Lys Ala Ser Gln Asp Ile Asp Asp Asp 20 25 30Met Asn Trp Tyr Gln Gln Lys Pro Gly Glu Val Ala Ile Phe Ile Ile 35 40 45Gln Glu Ala Thr Thr Leu Val Pro Gly Ile Pro Pro Arg Phe Ser Gly 50 55 60Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu Ser65 70 75 80Glu Asp Ala Ala Tyr Tyr Phe Cys Leu Gln His Asp Asn Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105270324DNAHomo sapiens 270gacatccgga tgacccagtc tccatcctcc ctgtctgcat ctgttggaga cagagtcacc 60atcacttgcc gggcaagtca gcgcattagc agctatttaa attggtttca gcagaaacca 120gggaaagccc ctaagttcct gatctatgct gcatctagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacagta ccccattcac tttcggccct 300gggaccaaag tggatatcaa acga 324271108PRTHomo sapiens 271Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Ser Tyr 20 25 30Leu Asn Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Phe Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105272363DNAHomo sapiens 272caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atgaaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatccc 300tttgaaactg gaactacttt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360gct 363273121PRTHomo sapiens 273Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Glu Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Pro Phe Glu Thr Gly Thr Thr Phe Asp Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser Ala 115 120274330DNAHomo sapiens 274gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaaaatcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg cgacttacta ctgtcaacag agttgcagta cccctccgga gtgcagtttt 300ggccagggga ccaagctgga gatcaaacga

330275110PRTHomo sapiens 275Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ile Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Cys Ser Thr Pro Pro 85 90 95Glu Cys Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110276369DNAHomo sapiens 276gaagtgcagc tggtggagtc tgggggaatc gtggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccgtcaaact 120ccggggaagg gtctggagtg ggtctctctt attagttggg atggtggtag cacatactat 180gcagactctg tgaagggccg attcaccatc tccagagaca acagcaaaaa ctccctgtat 240ctgcaaatga acagtctgag aactgaggac accgccttgt attactgtgc aaaagatata 300gatatagcag tggctggtac aggatttgac cactggggcc agggaaccct ggtcaccgtc 360tcctcagct 369277123PRTHomo sapiens 277Glu Val Gln Leu Val Glu Ser Gly Gly Ile Val Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Thr Met His Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Leu Ile Ser Trp Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Lys Asp Ile Asp Ile Ala Val Ala Gly Thr Gly Phe Asp His Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120278324DNAHomo sapiens 278gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttacc agcaacctag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcattaatta gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcaa tataataact ggccattcac tttcggccct 300gggaccaaag tggatatcaa acga 324279108PRTHomo sapiens 279Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Leu Ile Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105280369DNAHomo sapiens 280gtcaggtgca gctggtggag tctgggggag gcgtggtcca gcctgggagg tccctgagac 60tctcctgtgc agcgtctgga ttcaccttca gtagctatgg catgcactgg gtccgccagg 120ctccaggcaa ggggctggaa tgggtggcag ttatatggta tgatggaagt aataaatact 180atgcagactc cgtgaagggc cgattcacca tctccagaga caattccaag aacacgctgt 240atctgcaaat gaacagcctg agagccgagg acacggctgt gtattactgt gcgagagctc 300cgtatgactg gaactcatac tacggtttgg acgtctgggg ccaagggacc acggtcaccg 360tctcctcag 369281123PRTHomo sapiens 281Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Ala Pro Tyr Asp Trp Asn Ser Tyr Tyr Gly Leu Asp Val Trp 100 105 110Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120282324DNAHomo sapiens 282gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc aggcgagtca ggacattagg aactatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240gaagatattg caacatatta ctgtcaacag tatgataatc tcccgatcac cttcggccaa 300gggacacgac tggagattaa acga 324283108PRTHomo sapiens 283Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105284351DNAHomo sapiens 284caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta cacctttacc agctatggta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcagcgctc acaatggtaa cacaaactat 180gcacagaagc tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240atggagctga ggagcctgag atctgacgac acggccgtgt attattgtgc gagaggcgtg 300ggatctaagg attactgggg ccagggaacc ctggtcaccg tctcctcagc t 351285117PRTHomo sapiens 285Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Ser Ala His Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Val Gly Ser Lys Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala 115286324DNAHomo sapiens 286gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca ggacattagc aattatttag cctggtttca gcagaaacca 120gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aagttcagcg gcagtggatc tgggaccgat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgccaacag tataatagtt accctcggac gttcggccaa 300gggaccaagg tggaaatcaa acga 324287108PRTHomo sapiens 287Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105288372DNAHomo sapiens 288caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcaatt atttggtttg atggaagtaa tgaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt atttctgtgc gagaggaggc 300cctctgtata gcaactcctt ttactacttt gactactggg gccagggaac cctggtcacc 360gtctcctcag ct 372289124PRTHomo sapiens 289Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ile Ile Trp Phe Asp Gly Ser Asn Glu Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95Ala Arg Gly Gly Pro Leu Tyr Ser Asn Ser Phe Tyr Tyr Phe Asp Tyr 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120290324DNAHomo sapiens 290gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc aggcgagtca ggacattaga aactatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240gaagatattg caacatatta ctgtcaacag tatgataatc tcccgatcac cttcggccaa 300gggacacgac tggagattaa acga 324291108PRTHomo sapiens 291Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105292365DNAHomo sapiens 292gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60tcctgtgcag cctctggatt cactttcagt aacacctgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180gactacgctg cacccgtgaa gggcagattc accatctcaa gagatgattc aaaaaacacg 240ctgtgtctgc aactgaacag cctgaaaacc gaggacacag ccgtgtatta ctgttccgca 300ggctacggtg actaccccta ctttgacttc tggggccagg gaaccctggt caccgtctcc 360tcagc 365293122PRTHomo sapiens 293Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Thr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Cys Leu Gln Leu Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ser Ala Gly Tyr Gly Asp Tyr Pro Tyr Phe Asp Phe Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120294324DNAHomo sapiens 294gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtcaacag gctaacagtt tcccgtggac gttcggccaa 300gggaccaagg tggaaatcaa acga 324295108PRTHomo sapiens 295Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105296360DNAHomo sapiens 296gaggtgcagc tggtggagtc tgggggaggt gtggtacggc ctggggggtc cctgagactc 60tcctgtacaa cctctggatt cacctttgat gattatggca tgagctgggt ccgccaagct 120ccagggaagg ggctggagtg ggtctctggt attaattgga atggtggtag cacagtttat 180gcagactctg tgaagggccg attcaccatc tccagagaca gcgccaagaa ctccctgtat 240ctgcaaatga acagtctgag agccgaggac acggccttgt atcactgtgc gagaaataag 300cagtggctct ggtacttcga tctctggggc cgtggcaccc tggtcactgt ctcctcagct 360297120PRTHomo sapiens 297Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Thr Thr Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Val Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr His Cys 85 90 95Ala Arg Asn Lys Gln Trp Leu Trp Tyr Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 120298324DNAHomo sapiens 298gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg gattccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtgagcag tataataact ggcctctcac tttcggcggt 300gggaccaagg tggagatcaa acga 324299108PRTHomo sapiens 299Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Glu Gln Tyr Asn Asn Trp Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105300372DNAHomo sapiens 300caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccgtcagc agtggtggtt actactggag ctggatccgg 120cagcccccag ggaagggact ggagtggatt ggatatatca attacagtcg gagcaccaac 180cacaacccct ccctcaagag tcgagtcacc atatcagtag acacgtccaa gaatcagttc 240tccctgaagc tgagctctgt gaccgctgcg gacacggccg tgtattactg tgcgagagag 300ggacgtggag acagctatgg ttactacttt gactattggg gccagggaac cctggtcacc 360gtctcctcag ct 372301124PRTHomo sapiens 301Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45Trp Ile Gly Tyr Ile Asn Tyr Ser Arg Ser Thr Asn His Asn Pro Ser 50 55 60Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp

Thr Ala Val Tyr Tyr 85 90 95Cys Ala Arg Glu Gly Arg Gly Asp Ser Tyr Gly Tyr Tyr Phe Asp Tyr 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120302324DNAHomo sapiens 302gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatggt gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcagcct 240gaagattttg caacttacta ctgtcagcag agttacagta tccctcgcac gttcggccaa 300gggaccaagg tggaaatcaa acga 324303108PRTHomo sapiens 303Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ile Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105304371DNAHomo sapiens 304caggtgcaac tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt aactatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atctggtatg atggaagtca taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa ctcgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggaggc 300cctctgtata gcaactcctt ttactacttt gactactggg gccagggaac cctggtcacc 360gtctcctcag c 371305124PRTHomo sapiens 305Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser His Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Pro Leu Tyr Ser Asn Ser Phe Tyr Tyr Phe Asp Tyr 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120306324DNAHomo sapiens 306gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc aggcgagtca ggacattaga aactatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240gaagatattg caacatatta ctgtcaacag tatgataatc tcccgatcac cttcggccaa 300gggacacgac tggagattaa acga 324307108PRTHomo sapiens 307Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105308360DNAHomo sapiens 308gaggtgaagc tggtggagtc tgggggagga atggtccggc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattacggca tgagctgggt ccgccaagct 120ccagggaagg ggctggagtg ggtctctggt attaattgga atggtggtgg cacagcttat 180gcagactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaattga acagtctgag agccgaggac acggccttgt atcactgtgc gagaaataag 300cagtggctct ggtacttcga tctctggggc cgtggcaccc tggtcactgt ctcctcagct 360309120PRTHomo sapiens 309Glu Val Lys Leu Val Glu Ser Gly Gly Gly Met Val Arg Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Asn Trp Asn Gly Gly Gly Thr Ala Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Leu Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr His Cys 85 90 95Ala Arg Asn Lys Gln Trp Leu Trp Tyr Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 120310324DNAHomo sapiens 310gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagtcacc 60ctctcctgca gggccagtca gagtgttagc ggcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcac tataataact ggcctctcac tttcggcggt 300gggaccaagg tggagatcaa acga 324311108PRTHomo sapiens 311Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Asn Trp Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105312366DNAHomo sapiens 312caggtgcagc tggtgcagtc tggggctgag gtgacgaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc gcctaccata tgtactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggaactga gcaggctgag atctgacgac tcgcccgtgt attactgtgc gagagatcag 300ggtatagcag cagctggtcc ctttgactac tggggccagg gaaccctggt caccgtctcc 360tcagct 366313122PRTHomo sapiens 313Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Thr Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ala Tyr 20 25 30His Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Ser Pro Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gln Gly Ile Ala Ala Ala Gly Pro Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120314321DNAHomo sapiens 314gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga tagagccacc 60ctctcctgca gggccagtca gagtgttagc agcaactttg cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt tcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tatcattact ggtggacgtt cggccaaggg 300accaaggtgg aattcaaacg a 321315107PRTHomo sapiens 315Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ser Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr His Tyr Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Phe Lys Arg 100 105316369DNAHomo sapiens 316gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagct attagtggta gtggttatag cacatactac 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatctg 300cagcagtggc tggtaccgac cgtctttgac tactggggcc agggaaccct ggtcaccgtc 360tcctcagct 369317123PRTHomo sapiens 317Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Tyr Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Leu Gln Gln Trp Leu Val Pro Thr Val Phe Asp Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120318322DNAHomo sapiens 318gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcaacttag tctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatgat tcatccacca gggccactgg tatcccagtc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtgtatta ctgtcagcag tataatcact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg aa 322319107PRTHomo sapiens 319Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ser Ser Thr Arg Ala Thr Gly Ile Pro Val Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn His Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105320357DNAHomo sapiens 320gaggtgcagt tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaaggaag atggaagtga gaaatactat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt tttactgtgc gagagatcgg 300agcagtggct tttttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagct 357321119PRTHomo sapiens 321Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Glu Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Phe Tyr Cys 85 90 95Ala Arg Asp Arg Ser Ser Gly Phe Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115322321DNAHomo sapiens 322gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggttcct catctatggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tataatcact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg a 321323107PRTHomo sapiens 323Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Phe Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn His Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105324357DNAHomo sapiens 324gtgaggtgca gctggtggag tctgggggag gcttggtaca gcctgggggg tccctgagac 60tctcctgtgc agcctctgga ttcaccttca gtacctatag catgaactgg gtccgccagg 120ctccagggaa ggggctggag tggatttcat acattagtcg tagtagtaga accataaacc 180acgcagactc tgtgaagggc cgattcaccg tctccagaga caatgccaag aactcactgt 240atctgcaaat gatcagcctg agagacgagg acacggctgt gtattactgt gcgagaaagg 300cagcagctgg tccctttgac tactggggcc agggaaccct ggtcaccgtc gcctcag 357325119PRTHomo sapiens 325Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Ser Tyr Ile Ser Arg Ser Ser Arg Thr Ile Asn His Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Ile Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Lys Ala Ala Ala Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ala Ser Ala 115326342DNAHomo sapiens 326gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60atcaactgca agtccagcca gagtgtttta tacagctcca acaataagaa ctacttagct 120tggtaccagc agaaaccagg acagcctcct aagctgctca ttcactggtc atctacccgg 180gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtact 300ccgctcactt tcggcggagg gaccaaggtg gagatcaaac ga 342327114PRTHomo sapiens 327Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45Pro Pro Lys Leu Leu Ile His Trp Ser Ser Thr Arg Glu Ser Gly Val 50 55 60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95Tyr Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110Lys Arg328360DNAHomo sapiens 328gaggtgcagc tggtggagtc tgggggaggt gtggtacgga ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cagctttgat gattatggca tgagctgggt ccgccaagct 120ccagggaagg ggctggagtg ggtctctggt attaattgga atggtggtag gacagtttat 180gcagactctg tgaagggccg attcaccatc tccagagaca gcgccaagaa ctccctgtat 240ctgcaaatga acagtctgag agccgaggac acggccttgt atcactgtgc gagaaataag 300cagtggctct ggtacttcga tctctggggc cgtggcaccc tggtcactgt ctcctcagct 360329120PRTHomo sapiens 329Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Thr Gly Gly1

5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Asp Asp Tyr 20 25 30Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Asn Trp Asn Gly Gly Arg Thr Val Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr His Cys 85 90 95Ala Arg Asn Lys Gln Trp Leu Trp Tyr Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 120330324DNAHomo sapiens 330gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtattagc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagcct 240gaagattttg cagtttatta ctgtcagcag tataataact ggcctctcac tttcggccgt 300gggaccaagg tggagatcaa acga 324331108PRTHomo sapiens 331Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu 85 90 95Thr Phe Gly Arg Gly Thr Lys Val Glu Ile Lys Arg 100 105332375DNAHomo sapiens 332gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60tcctgtgcag cctctggatt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaaaacacg 240ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtaccaca 300tcgtatagca gtggctggtt ctactggtac ttcgatatct ggggccgtgg caccccggtc 360actgtctcct cagct 375333125PRTHomo sapiens 333Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Thr Ser Tyr Ser Ser Gly Trp Phe Tyr Trp Tyr Phe Asp 100 105 110Ile Trp Gly Arg Gly Thr Pro Val Thr Val Ser Ser Ala 115 120 125334324DNAHomo sapiens 334gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120gggaaagccc ctgagctcct gatctatgct gcatccagtt tgcaaagtgg agtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacatta acccattcac tttcggccct 300gggaccaaag tggatatcaa acga 324335108PRTHomo sapiens 335Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Glu Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Asn Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105336366DNAHomo sapiens 336gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60tcctgtgcag cctctggatt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180gactacgctg cacccgtgaa aggcagattc accatgtcaa gagatgattc aaaaaacacg 240ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ttgtaccatc 300ctctacggtg acttctggta cttcgatctc tggggccgtg gcaccctggt cactgtctcc 360tcagct 366337122PRTHomo sapiens 337Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Met Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Ile Leu Tyr Gly Asp Phe Trp Tyr Phe Asp Leu Trp Gly 100 105 110Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120338389DNAHomo sapiens 338caggtgcagc tggtggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagaaaat 300tgtggtggtg actgctatca gctaaattac tactactact acggtatgga cgtctggggc 360caagggacca cggtcaccgt ctcctcagc 389339130PRTHomo sapiens 339Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Cys Gly Gly Asp Cys Tyr Gln Leu Asn Tyr Tyr Tyr 100 105 110Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 115 120 125Ser Ala 130340348DNAHomo sapiens 340caggtgcagc tgcaggagtc ggccccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagt agttactact ggagctggat ccggcagccc 120ccagggaagg gactggagtg gattgggtat atctcttaca gtgggagcac caactacaac 180ccctccctca agagtcgagt caccacatca gtagacacgt ccaagaacca gttctccctg 240aagctgagct ctgtgaccgc cgcggacacg gccgtgtatt actgtacgag gggaactggg 300gcctctgact actggggcca gggaaccctg gtcaccgtct cctcagct 348341116PRTHomo sapiens 341Gln Val Gln Leu Gln Glu Ser Ala Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Thr Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Thr 85 90 95Arg Gly Thr Gly Ala Ser Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser Ala 115342324DNAHomo sapiens 342gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc aggcgagtca ggacattacc aactatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240gaagatattg caacatattt ctgtcaacag tatgataatc tcccgctcac tttcggcgga 300gggaccaagg tggagatcaa acga 324343108PRTHomo sapiens 343Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Thr Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Tyr Asp Asn Leu Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105344390DNAHomo sapiens 344tcaggtgcag ctggtggagt cggggggagg cgtggtccag cctgggaggt ccctgagact 60ctcctgtgca gcgtctggat tcaccttcag tagctatggc atgcactggg tccgccaggc 120tccaggcaag gggctggagt gggtggcagt tatatggtat gatggaagta ataaatacta 180tgcagactcc gtgaagggcc gattcaccat ctccagagac aattccaaga acacgctgta 240tctgcaaatg aacagcctga gagccgagga cacggctgtg tattactgtg cgagagaaaa 300ttgtggtggt gactgctatc agctaaatta ctactactac tacggtatgg acgtctgggg 360ccaagggacc acggtcaccg tctcctcagc 390345130PRTHomo sapiens 345Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Cys Gly Gly Asp Cys Tyr Gln Leu Asn Tyr Tyr Tyr 100 105 110Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 115 120 125Ser Ala 130346362DNAHomo sapiens 346caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt agatggtatg atgaaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatccc 300tttgaaactg gaactacttt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360gc 362347121PRTHomo sapiens 347Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Arg Trp Tyr Asp Glu Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Pro Phe Glu Thr Gly Thr Thr Phe Asp Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser Ala 115 120348322DNAHomo sapiens 348gaaatagtga tgacgcagtc tccagccacc ctggctgtgt ctccagggga aagagccacc 60ctctcctgca gggccaggca gagtgttagc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca tggccactgg tttcccagcc 180aggttcagtg gcagagggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcaacag tataataact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg aa 322349107PRTHomo sapiens 349Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ala Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Arg Gln Ser Val Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Met Ala Thr Gly Phe Pro Ala Arg Phe Ser Gly 50 55 60Arg Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105350362DNAHomo sapiens 350caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt agatggtatg atgaaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatccc 300tttgaaactg gaactacttt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360gc 362351121PRTHomo sapiens 351Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Arg Trp Tyr Asp Glu Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Pro Phe Glu Thr Gly Thr Thr Phe Asp Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser Ala 115 120352313DNAHomo sapiens 352gacatccaga tgacccagtc tccttcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gtatccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtcaacag gctctcactt tcggcggagg gaccaaggtg 300gagatcaaac gaa 313353104PRTHomo sapiens 353Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Val Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Leu Thr Phe Gly Gly 85 90 95Gly Thr Lys Val Glu Ile Lys Arg 100354363DNAHomo sapiens 354caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt gactatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg gatggcagtt ttatggtatg atgaaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca gttccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatccc 300tttgaaactg gaactacttt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360gct 363355121PRTHomo sapiens 355Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35

40 45Ala Val Leu Trp Tyr Asp Glu Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Pro Phe Glu Thr Gly Thr Thr Phe Asp Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser Ala 115 120356368DNAHomo sapiens 356caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagatggg 300ggcagtatag cagtggctgg tcactttgag tactggggcc agggaaccct ggtcaccgtc 360tcctcagc 368357123PRTHomo sapiens 357Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Gly Ser Ile Ala Val Ala Gly His Phe Glu Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120358322DNAHomo sapiens 358gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtcttatc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctttggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg caatttatta ctgtcatcag tataataact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg aa 322359107PRTHomo sapiens 359Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Ile Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Phe Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Ile Tyr Tyr Cys His Gln Tyr Asn Asn Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105360383DNAHomo sapiens 360gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60tcctgtgcag cctctggatt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaaaacacg 240ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtaccata 300ggtagcagtg gctggtacga ggcctactat tactacggta tggacgtctg gggccaaggg 360accacggtca ccgtctcctc agc 383361128PRTHomo sapiens 361Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Ile Gly Ser Ser Gly Trp Tyr Glu Ala Tyr Tyr Tyr Tyr 100 105 110Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125362360DNAHomo sapiens 362caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagaggat 300aactggaact tctactttga ctactggggc cagggaaccc tggtcaccgt ctcctcagct 360363120PRTHomo sapiens 363Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asp Asn Trp Asn Phe Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 120364324DNAHomo sapiens 364gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcgagtca gggcattagc tattatttag cctggtatca gcagaaacca 120gggaaagttc ctaagctcct gatctatgct gcatccactt tgcaatcagg ggtcccatct 180cggttcagtg gaagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagatgttg caacttatta ctgtcaaaag tataacagtg ccccattcac tttcggccct 300gggaccaaag tggatatcaa acga 324365108PRTHomo sapiens 365Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Tyr Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105366372DNAHomo sapiens 366gaggtgcagt tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatagca tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attagtagta gtagtagtta tatatattac 180gcagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatggg 300gcgatttttg gagtggttaa ctggtacttc gatctctggg gccgtggcac cctggtcact 360gtctcctcag cc 372367124PRTHomo sapiens 367Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Ala Ile Phe Gly Val Val Asn Trp Tyr Phe Asp Leu 100 105 110Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120368328DNAHomo sapiens 368gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgta gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120gctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggtt ggtcatcgat caccttcggc 300caagggacac gactggagat caaacgaa 328369109PRTHomo sapiens 369Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Ala Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Trp Ser Ser 85 90 95Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105370374DNAHomo sapiens 370caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcaatt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatt tccagagaca attccaagaa cacgctgcat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaaaggga 300tattgtagtg gtggtagctg tgtctacggt atggacgtct ggggccaagg gaccacggtc 360accgtctcct cagc 374371125PRTHomo sapiens 371Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ile Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu His65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Lys Gly Tyr Cys Ser Gly Gly Ser Cys Val Tyr Gly Met Asp 100 105 110Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125372357DNAHomo sapiens 372caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt ggctatgaca tccactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagagaga 300cagctatggt tgattgacta ctggggccag ggaaccctgg tcaccgtctc ctcagct 357373119PRTHomo sapiens 373Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30Asp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Arg Gln Leu Trp Leu Ile Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115374342DNAHomo sapiens 374gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60atcaactgca agtccagcca gagtgtttta tacagctcca acaataagaa ctacttagtt 120tggtaccagc agaaaccagg gcagcctcct aagctgctca tttactgggc atctacccgg 180gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttataatact 300ccgtgcagtt ttggccaggg gaccaagctg gagatcaaac ga 342375114PRTHomo sapiens 375Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30Ser Asn Asn Lys Asn Tyr Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95Tyr Tyr Asn Thr Pro Cys Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg376369DNAHomo sapiens 376caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60acctgtgcca tctccgggga cagtgtctct agcaacagtg ctgcttggaa ctggatcagg 120cagtccccat cgagaggcct tgagtggctg ggaatgacat actacaggtc caagtggtct 180aatgattatg cagtatctct gaaaagtcga ataaccatca acccagacac atccaagaac 240cagttctccc tgcagctgaa ctctgtgact cccgaggaca cggctgtgta ttactgtgca 300aggggtaact ggttctactg gtacttcgat ctctggggcc gtggcaccct ggtcactgtc 360tcctcagct 369377123PRTHomo sapiens 377Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn 20 25 30Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45Trp Leu Gly Met Thr Tyr Tyr Arg Ser Lys Trp Ser Asn Asp Tyr Ala 50 55 60Val Ser Leu Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn65 70 75 80Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val 85 90 95Tyr Tyr Cys Ala Arg Gly Asn Trp Phe Tyr Trp Tyr Phe Asp Leu Trp 100 105 110Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120378322DNAHomo sapiens 378gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc aggcgagtca ggacattagc aactatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag gctgcagcct 240gaagatattg caacatatta ctgtcaacag tatgataatc tgtgcagttt tggccagggg 300accaagttgg agatcaaacg aa 322379107PRTHomo sapiens 379Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Arg Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Cys Ser 85 90 95Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105380364DNAHomo sapiens 380gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gaaatactat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatccg 300ggtatagcag tggctggccc ctttgactac tggggccagg gaaccctggt caccgtctcc 360tcag 364381122PRTHomo sapiens 381Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75

80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Pro Gly Ile Ala Val Ala Gly Pro Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120382321DNAHomo sapiens 382gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcattcacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cggtttatta ctgtcagcag tataatcact ggtggacgtt cggccaaggg 300accaaggtgg gaatcaaacg a 321383107PRTHomo sapiens 383Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Phe Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn His Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Gly Ile Lys Arg 100 105384360DNAHomo sapiens 384gaggtgcagc tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcaat agctatagaa tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attactagta gtagtcatta catatactat 180gcagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcgc 300ggtatagcag ccccctttga ctactggggc cagggaaccc tggtcaccgt ctcctcagct 360385120PRTHomo sapiens 385Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ser Tyr 20 25 30Arg Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Thr Ser Ser Ser His Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Gly Ile Ala Ala Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 120386321DNAHomo sapiens 386gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tttcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tataataact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg a 321387107PRTHomo sapiens 387Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Phe Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105388337DNAHomo sapiens 388caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagt agttactact ggagctggat ccggcagccc 120ccagggaagg gactggagtg gattgggttt atctattaca gtgggaccac caactacaac 180ccctccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240aagctgagtt ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agcgtacgat 300ccctggggcc agggaaccct ggtcaccgtc tcctcag 337389113PRTHomo sapiens 389Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Phe Ile Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Ala Tyr Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100 105 110Ala390324DNAHomo sapiens 390gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagtataagc agctatttta attggtatca gcagaaacca 120gggaaagccc ctaaactcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacagta ccccgctcac tttcggcgga 300gggaccaagg tggagatcaa acga 324391108PRTHomo sapiens 391Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Phe Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105392342DNAHomo sapiens 392caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagagctt 300gcctactggg gccagggaac cctggtcacc gtctcctcag ct 342393114PRTHomo sapiens 393Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Leu Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110Ser Ala394324DNAHomo sapiens 394gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggcattagc aattatttag cctggtttca gcagaaacca 120gggaaagccc ctgagtccct gatctatgct gcatccagtt tgcaaactgg ggtcccatca 180aagttcagcg gcaatggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacctatta ttgccaacag tataatagtt acccgctcac tttcggcgga 300gggaccaagg tggagatcaa acga 324395108PRTHomo sapiens 395Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Glu Ser Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Thr Gly Val Pro Ser Lys Phe Ser Gly 50 55 60Asn Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105396357DNAHomo sapiens 396caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagt agtcactact ggatctggat ccggcagccc 120gccgggaagg gactggagtg gattgggcgt atctatagca gtgggagtac caactacaac 180ccctccctca agagtcgagt caccatgtca ggagacacgt ccaagaacca gttctccctg 240aagctgagct ctgtgaccgc cgcggacacg gccgtgtatt actgtgcgag agggaggtgg 300ggatcctggt acttcgatct ctggggccgt ggcaccctgg tcactgtctc ctcagct 357397119PRTHomo sapiens 397Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser His 20 25 30Tyr Trp Ile Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Arg Ile Tyr Ser Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Met Ser Gly Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Gly Arg Trp Gly Ser Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115398372DNAHomo sapiens 398gaggtgcagt tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatagca tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attagtagta gtagtagtta tatatattac 180gcagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatggg 300gcgatttttg gagtggttaa ctggtacttc gatctctggg gccgtggcac cctggtcact 360gtctcctcag cc 372399124PRTHomo sapiens 399Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Ala Ile Phe Gly Val Val Asn Trp Tyr Phe Asp Leu 100 105 110Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120400375DNAHomo sapiens 400caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctggaaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagagggc 300ctggattttt ggagtgattt ttacaactgg ttcgacccct ggggccaggg aaccctggtc 360accgtctcct cagct 375401125PRTHomo sapiens 401Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Leu Asp Phe Trp Ser Asp Phe Tyr Asn Trp Phe Asp 100 105 110Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120 125402324DNAHomo sapiens 402gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc aactatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctttact gcatccagtt tacaaagtgg ggtcccatca 180agattcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttactt ctgtcaacag agttacagta ccccattcac tttcggccct 300gggaccaaag tgggtatcaa acga 324403108PRTHomo sapiens 403Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Phe Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Ser Tyr Ser Thr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Gly Ile Lys Arg 100 105404365DNAHomo sapiens 404gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60tcctgtgcag cctctggatt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaaaacacg 240ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtaccaac 300tactacggtg acttttatgc ttttgatatc tggggccaag ggacaatggt caccgtctct 360tcagc 365405122PRTHomo sapiens 405Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Asn Tyr Tyr Gly Asp Phe Tyr Ala Phe Asp Ile Trp Gly 100 105 110Gln Gly Thr Met Val Thr Val Ser Ser Ala 115 120406324DNAHomo sapiens 406gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gaccattagc agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tacaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag acttacagta aatcgctcac tttcggcgga 300gggaccaagg tggagatcaa acga 324407108PRTHomo sapiens 407Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Tyr Ser Lys Ser Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105408368DNAHomo sapiens 408caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggggat 300aactggaact acgaggggga cggtatggac gtctggggcc aagggaccac ggtcaccgtc 360tcctcagc

368409123PRTHomo sapiens 409Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Asp Asn Trp Asn Tyr Glu Gly Asp Gly Met Asp Val Trp 100 105 110Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120410324DNAHomo sapiens 410gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattagc aggtggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgtt gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtcaacag gctaacagtt tccctcggac gttcggccaa 300gggaccaagg tggaaatcaa acga 324411108PRTHomo sapiens 411Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Arg Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Val Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105412362DNAHomo sapiens 412caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta cacctttacc agctattgta tcagctgggt gcgacaggcc 120cctggacgag ggcttgagtg gatgggttgg atctgctctt acaatggtaa cacaaactgt 180gcacagaagc tccagggcag agtcaccatg accacagaca catccacgac tacagcctac 240atggagctga ggggcctgag atctgacgac acggccgtgt attactgtgc gagagagtcc 300ctttatagca gtggctggtt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360gc 362413121PRTHomo sapiens 413Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30Cys Ile Ser Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Cys Ser Tyr Asn Gly Asn Thr Asn Cys Ala Gln Lys Leu 50 55 60Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Thr Thr Ala Tyr65 70 75 80Met Glu Leu Arg Gly Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Ser Leu Tyr Ser Ser Gly Trp Phe Asp Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser Ala 115 120414324DNAHomo sapiens 414gacatccgga tgacccagtc tccatcctcc ctgtctgcat ctgttggaga cagagtcacc 60atcacttgcc gggcaagtca gcgcattagc acctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagttcct gatctatgct gcatctagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacacta ccccattcac tttcggccct 300gggaccaaag tggatatcaa acga 324415108PRTHomo sapiens 415Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Thr Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Phe Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105416372DNAHomo sapiens 416caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt ggctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatagg 300ggtatagcag tggctgggta ttacggtatg gacgtctggg gccaagggaa cacggtcacc 360gtctcctcag ct 372417124PRTHomo sapiens 417Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Gly Ile Ala Val Ala Gly Tyr Tyr Gly Met Asp Val 100 105 110Trp Gly Gln Gly Asn Thr Val Thr Val Ser Ser Ala 115 120418372DNAHomo sapiens 418caggtacaac tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgtag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggaggt 300cctctgtata gcaactcctt ttactacttt gactactggg gccagggaac cctggtcacc 360gtctcctcag ct 372419124PRTHomo sapiens 419Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Pro Leu Tyr Ser Asn Ser Phe Tyr Tyr Phe Asp Tyr 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120420324DNAHomo sapiens 420gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc aggcgagtca ggacattaga aactatttaa attggtatca gcagaaacca 120gggacagccc ctaaactcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240gaagatattg caacatatta ctgtcaacag tatgataatc tcccgatcac cttcggccaa 300gggacacgac tggagattaa acga 324421108PRTHomo sapiens 421Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Thr Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105422327DNAHomo sapiens 422gaagttgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga tagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta caaccagaaa 120cctggccagg ctcccaggct cctcatcttt ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcta cagtatggta gctcaccgtg gacgttcggc 300caagggacca aggtggaaat caaacga 327423109PRTHomo sapiens 423Glu Val Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Asn Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Tyr Gly Ser Ser Pro 85 90 95Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105424378DNAHomo sapiens 424caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagatagg 300ggctggaact acgcagacta ctactactac ggtatggacg tctggggcca agggaccacg 360gtcaccgtct cctcagct 378425126PRTHomo sapiens 425Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Gly Trp Asn Tyr Ala Asp Tyr Tyr Tyr Tyr Gly Met 100 105 110Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125426342DNAHomo sapiens 426gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60atcaactgca agtccagcca gagtgtttta tacagttcca acaatcagaa cttcttagct 120tggtatcagc agaaaccagg acagcctcct aaactgctca tttactgggc atctacccgg 180gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca gtttattact gtcaccaata ttatagtact 300ccgatcacct tcggccaagg gacacgactg gagattaaac ga 342427114PRTHomo sapiens 427Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30Ser Asn Asn Gln Asn Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys His Gln 85 90 95Tyr Tyr Ser Thr Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile 100 105 110Lys Arg428378DNAHomo sapiens 428caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagatagg 300ggctggaact acgcagacta ctactactac ggtatggacg tctggggcca agggaccacg 360gtcaccgtct cctcagct 378429126PRTHomo sapiens 429Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Gly Trp Asn Tyr Ala Asp Tyr Tyr Tyr Tyr Gly Met 100 105 110Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125430342DNAHomo sapiens 430gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60atcaactgca agtccagcca gagtgtttta tacagttcca acaatcagaa cttcttagct 120tggtatcagc agaaaccagg acagcctcct aaactgctca tttactgggc atctacccgg 180gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca gtttattact gtcaccaata ttatagtact 300ccgatcacct tcggccaagg gacacgactg gagattaaac ga 342431114PRTHomo sapiens 431Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30Ser Asn Asn Gln Asn Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys His Gln 85 90 95Tyr Tyr Ser Thr Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile 100 105 110Lys Arg432357DNAHomo sapiens 432caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagt agttactact ggagctggat ccggcagccc 120gccgggaagg gactggagtg gattgggcgt atctacacca gtgggagcac caactacaac 180ccctccctca agagtcgagt caccatgtcc gtagacacgt ccaagaacca gttctccctg 240aagctgagct ctgtgaccgc cgcggacacg gccgtgtatt actgtgcgag aggtataact 300ggttacgggg ggttcgaccc ctggggccag ggaaccctgg tcaccgtctc ctcagct 357433119PRTHomo sapiens 433Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Arg Ile Tyr Thr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Gly Ile Thr Gly Tyr Gly Gly Phe Asp Pro Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115434360DNAHomo sapiens 434gaggtgcagc tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatcgca tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attagcagta gtggtagcta catatactac 180gcagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgttt attactttgc gagagatcgg 300ggagtgggag ctgcctttga ctactggggc cagggaaccc tggtcaccgt ctcctcagct 360435120PRTHomo sapiens 435Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Arg Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

Val 35 40 45Ser Ser Ile Ser Ser Ser Gly Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Phe 85 90 95Ala Arg Asp Arg Gly Val Gly Ala Ala Phe Asp Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 120436324DNAHomo sapiens 436gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca ggacattagc aattatttag cctggtttca gcagaaacca 120gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aaattcagcg gcagtggatc tgggaccgat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgccaacag tataatagtt accctcggac gttcggccaa 300gggaccaagg tggaaatcaa acga 324437108PRTHomo sapiens 437Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105438372DNAHomo sapiens 438caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagt agttactact ggagctggat ccggcagccc 120gccgggaagg gactggagtg gattgggcgt atctatacca gtgggagcac caactacaac 180ccctccctca agagtcgagt caccatgtca gtagacacgt ccaagaacca gttctccctg 240aagctgagct ctgtgaccgc cgcggacacg gccgtgtatt actgtgcgag agatgactac 300agtcactctt actactacta ctacggtatg gacgtctggg gccaagggac cacggtcacc 360gtctcctcag ct 372439124PRTHomo sapiens 439Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Arg Ile Tyr Thr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Asp Tyr Ser His Ser Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val 100 105 110Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120440324DNAHomo sapiens 440gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtcaacag gctaacagtt tccctcggac gttcggccaa 300gggaccaagg tggaaatcaa acga 324441108PRTHomo sapiens 441Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105442375DNAHomo sapiens 442caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggctatt atatggtttg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaagtga acagcctgcg agccgaggac acggctgtgt attactgtgc gagaaaggga 300tattgtagtg gtggtagatg tgtctacggt atggacgtct ggggccaagg gaccacggtc 360accgtctcct cagct 375443125PRTHomo sapiens 443Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ile Ile Trp Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Val Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Lys Gly Tyr Cys Ser Gly Gly Arg Cys Val Tyr Gly Met Asp 100 105 110Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125444339DNAHomo sapiens 444gatattgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca gagcctcctg catagtaatg gatacaacta tttggattgg 120tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc 180tccggggtcc ctgacagatt cggtggcagt ggatcaggca cagattttac actgaaaatc 240agcagagtgg aggctgagga tgttggggtt tattactgca tgcaagctct acaaactcct 300atcaccttcg gccaagggac acgactggag attaaacga 339445113PRTHomo sapiens 445Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Leu Gln Thr Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110Arg446366DNAHomo sapiens 446gaggtgcagc tggtggtgtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgaag cctctggatt cacctttagt aactattgga tgacctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gaaatactat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatgcc 300ggtatggaag tggctggccc ttttgactac tggggccagg gaaccctggt caccgtctcc 360tcagct 366447122PRTHomo sapiens 447Glu Val Gln Leu Val Val Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Ala Gly Met Glu Val Ala Gly Pro Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120448368DNAHomo sapiens 448caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagatggg 300ggcagtatag cagtggctgg tcactttgac tactggggcc agggaaccct ggtcaccgtc 360tcctcagc 368449123PRTHomo sapiens 449Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Gly Ser Ile Ala Val Ala Gly His Phe Asp Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120450321DNAHomo sapiens 450gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtcttatc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctttggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcatcag tataataact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg a 321451107PRTHomo sapiens 451Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Ile Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Phe Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr Asn Asn Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105452366DNAHomo sapiens 452caggtgcagc tggtgcagtc cggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc ggctaccata tgtactgggt gcgacaggcc 120cctggacaag ggcttgagtg gctgggatgg atcaacccta acagtggtgg cacaaactat 180gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgt gagagatcag 300ggtatagcag cagctggtcc ctttgactac tggtgccagg gaaccctggt caccgtctcc 360tcagct 366453122PRTHomo sapiens 453Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30His Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Leu 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Val Arg Asp Gln Gly Ile Ala Ala Ala Gly Pro Phe Asp Tyr Trp Cys 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120454324DNAHomo sapiens 454gacatccgga tgacccagtc tccatcctcc ctgtctgcat ctgttggaga cagagtcacc 60atcacttgcc gggcaagtca gcgcattagc acctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagttcct gatctatgct gcatctagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacacta ccccattcac tttcggccct 300gggaccaaag tggatatcaa acga 324455108PRTHomo sapiens 455Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Thr Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Phe Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105456352DNAHomo sapiens 456caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc cgggggagct 300acggccatgg acgtctgcgg ccaagggagc acgggcaccg tctcctcagc ct 352457117PRTHomo sapiens 457Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Gly Gly Ala Thr Ala Met Asp Val Cys Gly Gln Gly Ser Thr Gly 100 105 110Thr Val Ser Ser Ala 115458324DNAHomo sapiens 458gacatccgga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga acctatttaa actggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatctagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcagcct 240gaagattttg caacttacta ctgtcaacag aattacacta ccccattcac tttcggccct 300gggaccaaag tggatatcaa acga 324459108PRTHomo sapiens 459Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Thr Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Tyr Thr Thr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105460363DNAHomo sapiens 460gaggtgcaga tggtggagtc tgggggaggc ttggtccagc cgggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttaaga agctactgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaaggaag acggaagtga gaaataccat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccgagaa ctcactgttt 240ctgcaaatga gcagcctgcg agccgaggac acggctgtgt attactgtgc gagagatatg 300gaagcatcag ctggcctctt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360gct 363461121PRTHomo sapiens 461Glu Val Gln Met Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Arg Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Glu Asp Gly Ser Glu Lys Tyr His Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser Leu Phe65 70 75 80Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Met Glu Ala Ser Ala Gly Leu

Phe Asp Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser Ala 115 120462321DNAHomo sapiens 462gaaatagtga tgacgcagtc cccagccacc ctgtctgtgt ctccagggga aagagccatc 60ctctcctgca gggccagtca gagtattagc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tataattact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg a 321463107PRTHomo sapiens 463Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Ile Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Tyr Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105464363DNAHomo sapiens 464gaggtgcaga tggtggagtc tgggggaggc ttggtccagc cgggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttaaga agctactgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaaggaag acggaagtga gaaataccat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccgagaa ctcactgttt 240ctgcaaatga gcagcctgcg agccgaggac acggctgtgt attactgtgc gagagatatg 300gaagcatcag ctggcctctt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360gct 363465121PRTHomo sapiens 465Glu Val Gln Met Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Arg Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Glu Asp Gly Ser Glu Lys Tyr His Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser Leu Phe65 70 75 80Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Met Glu Ala Ser Ala Gly Leu Phe Asp Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser Ala 115 120466321DNAHomo sapiens 466gaaatagtga tgacgcagtc cccagccacc ctgtctgtgt ctccagggga aagagccatc 60ctctcctgca gggccagtca gagtattagc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tataattact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg a 321467107PRTHomo sapiens 467Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Ile Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Tyr Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105468363DNAHomo sapiens 468gaggtgcaga tggtggagtc tgggggaggc ttggtccagc cgggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttaaga agctactgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaaggaag acggaagtga gaaataccat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccgagaa ctcactgttt 240ctgcaaatga gcagcctgcg agccgaggac acggctgtgt attactgtgc gagagatatg 300gaagcatcag ctggcctctt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360gct 363469121PRTHomo sapiens 469Glu Val Gln Met Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Arg Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Glu Asp Gly Ser Glu Lys Tyr His Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser Leu Phe65 70 75 80Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Met Glu Ala Ser Ala Gly Leu Phe Asp Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser Ala 115 120470321DNAHomo sapiens 470gaaatagtga tgacgcagtc cccagccacc ctgtctgtgt ctccagggga aagagccatc 60ctctcctgca gggccagtca gagtattagc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tataattact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg a 321471107PRTHomo sapiens 471Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Ile Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Tyr Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105472363DNAHomo sapiens 472caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagg agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtta taaaaactat 180ggagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagggactac 300agtaactacg aggagtactt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360gct 363473121PRTHomo sapiens 473Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Tyr Lys Asn Tyr Gly Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Tyr Ser Asn Tyr Glu Glu Tyr Phe Asp Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser Ala 115 120474354DNAHomo sapiens 474caggtgcagc tggtggagtc tgggggaggc ttggtcaagc ctggagggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt gactactaca tgagctggat ccgccaggct 120ccagggaagg ggctggagtg ggtttcatac attagtagta gtggtagttc caaaaactac 180gcagactctg tgaagggccg aatcaccatc tccagggaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagagagagg 300ggggatgctt ttgatatctg gggccaaggg acaatggtca ccgtctcttc agct 354475118PRTHomo sapiens 475Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Tyr Ile Ser Ser Ser Gly Ser Ser Lys Asn Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Ile Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Arg Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met 100 105 110Val Thr Val Ser Ser Ala 115476342DNAHomo sapiens 476gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gaaggccacc 60atcaactgca agtccagcca gagtgttata tacagttcca acaatcagaa cttcttagct 120tggtatcagc ataaaccagg acagcctcct aaactgctca tttactgggc atctacccgg 180gaatccgggg tccctgaccg attcagtgac agcgggtctg ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca gtttattact gtcaccaata ttatagtact 300ccgatcacct tcggccaagg gacacgactg gagattaaac ga 342477114PRTHomo sapiens 477Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15Glu Lys Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Ile Tyr Ser 20 25 30Ser Asn Asn Gln Asn Phe Leu Ala Trp Tyr Gln His Lys Pro Gly Gln 35 40 45Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60Pro Asp Arg Phe Ser Asp Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys His Gln 85 90 95Tyr Tyr Ser Thr Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile 100 105 110Lys Arg478354DNAHomo sapiens 478gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gaaatactat 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtat attactgtgc gagagatagc 300tggtggtact tcgatctctg gggccgtggc accctggtca ctgtctcctc agct 354479118PRTHomo sapiens 479Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Ser Trp Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110Val Thr Val Ser Ser Ala 115480375DNAHomo sapiens 480caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaaaggga 300tattgtagtg gtggtaggtg tgtctacggt atggacgtct ggggccaagg gaccacggtc 360accgtctcct cagct 375481125PRTHomo sapiens 481Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Lys Gly Tyr Cys Ser Gly Gly Arg Cys Val Tyr Gly Met Asp 100 105 110Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125482339DNAHomo sapiens 482gatattgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca gagcctcctg tatagtaatg gatacaacta tttggattgg 120tacctgcaga agccagggca gtctccacag gtcctgatct atttgggttc taatcgggcc 180tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240agcagagtgg aggctgagga tgttggggtt tattactgca tgcaagctct acaaactcct 300atcaccttcg gccaagggac acgactggag attaaacga 339483113PRTHomo sapiens 483Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Val Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Leu Gln Thr Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110Arg484324DNAHomo sapiens 484gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaaggtcct gatctatggt gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacagta ccctgtgcag ttttggccag 300gggaccaagc tggagatcaa acga 324485108PRTHomo sapiens 485Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Cys 85 90 95Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105486372DNAHomo sapiens 486gaggtgcagt tggtggagtc tgggggaggc ctgttcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatagca tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attagtagta gtagtagtta tatatattac 180gcagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatggg 300gcgatttttg gagtggttaa ctggtacttc gatctctggg gccgtggcac cctggtcact 360gtctcctcag cc 372487124PRTHomo sapiens 487Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Phe Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Ala Ile Phe Gly Val Val Asn Trp Tyr Phe Asp Leu 100 105 110Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120488324DNAHomo sapiens 488gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctttgct gcatccagtt tgcaaagtgg ggtcccatcc 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtcaacag gctaacagtt

tccctctcac tttcggcgga 300gggaccaagg tggagatcaa acga 324489108PRTHomo sapiens 489Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Phe Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105490366DNAHomo sapiens 490gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgctg cctctggatt caccttcagc agctatgcca tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcaggt attagtggta gtggtggtaa cacataccac 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatgaa 300gactacggtg gctactccga ctttgactac tggggccagg gaaccctggt caccgtctcc 360tcagct 366491122PRTHomo sapiens 491Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Ser Gly Ser Gly Gly Asn Thr Tyr His Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Glu Asp Tyr Gly Gly Tyr Ser Asp Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120492327DNAHomo sapiens 492gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaac cagagtcacc 60atcacttgcc gggcaagtca gagcattcgc agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tacaaagagg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaagct 240gaagattttg caacttacta ctgtcaacag agttacacta cccccctgtg cagttttggc 300caggggacca ggctggagat caaacga 327493109PRTHomo sapiens 493Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Thr Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Arg Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Arg Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Leu 85 90 95Cys Ser Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105494324DNAHomo sapiens 494gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca ggacattagc aattatttag cctggtttca gcagaaacca 120gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180cagttcagcg gcagtggctc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgccaacaa tataataatt acccattcac tttcggccct 300gggaccaaag tggatgtcaa acga 324495108PRTHomo sapiens 495Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Gln Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Asn Tyr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Val Lys Arg 100 105496369DNAHomo sapiens 496caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gccacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcttac 240atggagctga ggaggctgag atctgacgac acggccgtgt attactgtgc gagagatggg 300ggtagtatac cagtgtctgg tcactttgac tactgggggc agggaaccct ggtcaccgtc 360tcctcagct 369497123PRTHomo sapiens 497Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Pro Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Arg Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Gly Ser Ile Pro Val Ser Gly His Phe Asp Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120498321DNAHomo sapiens 498gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtcttatc agcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctttggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcatcag tataataact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg a 321499107PRTHomo sapiens 499Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Ile Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Phe Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr Asn Asn Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105500354DNAHomo sapiens 500caggtgcagc tggtggagtc tgggggaggc ttggtcaagc ctggagggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt gactactaca tgagctggat ccgccaggct 120ccagggaagg ggctggagtg ggtttcatac attagtagta gtggtagtac catatactac 180gcagactctg tgaagggccg attcaccatc tccagggaca acgccaagaa ctcactgtat 240ctgcaaatga atagcctgag agccgaggac acggccgtgt attactgtgc gagagaaaga 300ggggatgctt ttgatatctg gggccaaggg acaatggtca ccgtctcttc agct 354501118PRTHomo sapiens 501Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Arg Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met 100 105 110Val Thr Val Ser Ser Ala 115502366DNAHomo sapiens 502caggtgcagc tggtgcagtc tggggctgag gtgaaaaagc ctggggcctc agtcaaggtc 60tcctgcaagg cttctggata caccttcacc ggctactatt tgtactgggt gccacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcagcccta acagtggtgg cacaaactat 180gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagatcag 300gtcatagcag tagctggtcc ctttgactac tgggcccaag gaaccctggt caccgtctcc 360tcagct 366503122PRTHomo sapiens 503Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Leu Tyr Trp Val Pro Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Ser Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gln Val Ile Ala Val Ala Gly Pro Phe Asp Tyr Trp Ala 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120504321DNAHomo sapiens 504gaaacagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagtcacc 60ctctcctgca gggccagtca gagtgttatc agcagcttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tataataatt ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg a 321505107PRTHomo sapiens 505Glu Thr Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ile Ser Ser 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105506369DNAHomo sapiens 506caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggaatg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaaggaccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagctccg 300tatgactgga actcatacta cggtttggac gtctggggcc aagggaccac ggtcaccgtc 360tcctcagct 369507123PRTHomo sapiens 507Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Ala Pro Tyr Asp Trp Asn Ser Tyr Tyr Gly Leu Asp Val Trp 100 105 110Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120508348DNAHomo sapiens 508caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagt agttactact ggagctggat ccggcagccc 120ccagggaagg gactggagtg gattgggtat atctattaca gtgggagcac caacttcaac 180ccctccctca agagtcgagt caccacatca gtagacacgt ccaagaacca gttctccctg 240aacctgaggt ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag gggaactggg 300gcctctgact actggggcca gggaaccctg gtcaccgtct cctcagct 348509116PRTHomo sapiens 509Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Phe Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Thr Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Asn Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Gly Thr Gly Ala Ser Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser Ala 115510371DNAHomo sapiens 510caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccgtcagc agtggtggtt actactggag ctggatccgg 120cagcccccag ggaagggact ggagtggatt ggatatatct attacagtcg gagcaccaac 180tacaacccct ccctcaagag tcgagtcacc atatcagtag acacgtccaa gaaccagttc 240tccctgaagc tgagctctgt gaccgctgcg gacacggccg tgtattactg tgcgagagag 300ggacgtggaa acagttatgg ttactacttt gactactggg gccagggaac cctggtcacc 360gtctcctcag c 371511124PRTHomo sapiens 511Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45Trp Ile Gly Tyr Ile Tyr Tyr Ser Arg Ser Thr Asn Tyr Asn Pro Ser 50 55 60Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95Cys Ala Arg Glu Gly Arg Gly Asn Ser Tyr Gly Tyr Tyr Phe Asp Tyr 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120512342DNAHomo sapiens 512caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa caaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctatat 240ctgcaaatga acagcctgag agccgaggac acagctatgt attactgtgc gagagaactg 300gcactgtggg gccagggaac cctggtcacc gtctcctcag ct 342513114PRTHomo sapiens 513Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg Glu Leu Ala Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110Ser Ala514321DNAHomo sapiens 514gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catttatggt gcattcacca gggccactgg aattccagcc 180aggttcagag gcagtgggtc tgggccagaa ttcacgctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tatagtcact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg a 321515107PRTHomo sapiens 515Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Phe Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Arg Gly 50 55 60Ser Gly

Ser Gly Pro Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser His Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105516366DNAHomo sapiens 516gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagt agttattgga tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gcaatactct 180gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acaccctgag agccgaggac acggctgtgt attactgtgt gagagatccg 300ggtatagaag tggctggccc ctttgactac tggggccagg gaaccctggt caccgtctcc 360tcagct 366517122PRTHomo sapiens 517Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Glu Gln Tyr Ser Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Val Arg Asp Pro Gly Ile Glu Val Ala Gly Pro Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120518321DNAHomo sapiens 518gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catttatggt gcattcacca gggccactgg aattccagcc 180aggttcagag gcagtgggtc tgggccagaa ttcacgctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tatagtcact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg a 321519107PRTHomo sapiens 519Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Phe Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Arg Gly 50 55 60Ser Gly Ser Gly Pro Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser His Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105520378DNAHomo sapiens 520caggtgcagc tggtggagtc tgggggagac gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatgc acagcctgag agctgaggac acggctgtgt attactgtgc gagagacggg 300gggtggctac gattggacta ctactactac ggtatggacg tctggggcca ggggaccacg 360gtcaccgtct cctcagct 378521126PRTHomo sapiens 521Gln Val Gln Leu Val Glu Ser Gly Gly Asp Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met His Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Gly Trp Leu Arg Leu Asp Tyr Tyr Tyr Tyr Gly Met 100 105 110Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125522324DNAHomo sapiens 522gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60ttcacttgcc gggcaagtca gagcattatc acctttttaa attggtttca gcataaacca 120gggaaagccc ctaagctcct gttctatggt gcatccagtt tggagagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacaaat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacagtg acccattcac tttcggccct 300gggaccaaag tggatatcaa acga 324523108PRTHomo sapiens 523Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Phe Thr Cys Arg Ala Ser Gln Ser Ile Ile Thr Phe 20 25 30Leu Asn Trp Phe Gln His Lys Pro Gly Lys Ala Pro Lys Leu Leu Phe 35 40 45Tyr Gly Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asn Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Asp Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105524372DNAHomo sapiens 524caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcaatt ctatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggaggc 300cctctgtata ccaactcctt ttactacttt gactactggg gccagggaac cctggtcacc 360gtctcctcag ct 372525124PRTHomo sapiens 525Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ile Leu Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Pro Leu Tyr Thr Asn Ser Phe Tyr Tyr Phe Asp Tyr 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120526324DNAHomo sapiens 526gacatcgaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gaacattagc agctatttaa attggtatca gcagaagcca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacagtt ccccgctcac tttcggcgga 300gggaccaagg tggagatcaa acga 324527108PRTHomo sapiens 527Asp Ile Glu Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ser Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105528365DNAHomo sapiens 528cagatcacct tgaaggagtc tggtcctacg ctggtgaaac ccacacagac cctcacgctg 60acctgtaccc tctctgggtt ctcactcagt attagtggag tgggtgtggg ctggatccgt 120cagcccccag gaaaggccct ggagtggctt gcattcattt attggaatga tgataagcgc 180tacagcccat ctctgaagag caggctcacc atcaccaagg acacctccaa aaaccaggtg 240gtccttacaa tgaccaacat ggaccctgtg gacacagcca catattactg tgcacacaga 300ccggatagca gcagctggga ctttgactac tggggccagg gaaccctggt caccgtctcc 360tcagc 365529122PRTHomo sapiens 529Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln1 5 10 15Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Ser Ile Ser 20 25 30Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45Trp Leu Ala Phe Ile Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val65 70 75 80Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95Cys Ala His Arg Pro Asp Ser Ser Ser Trp Asp Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120530324DNAHomo sapiens 530gacatcgaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gaacattagc agctatttaa attggtatca gcagaagcca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacagtt ccccgctcac tttcggcgga 300gggaccaagg tggagatcaa acga 324531108PRTHomo sapiens 531Asp Ile Glu Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ser Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105532343DNAHomo sapiens 532caggtgctac tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtttg atggaagtaa aaaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa ctcgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtat attactgtgc gagagaactg 300gaactgtggg gcctgggaac cctggtcacc gtctcctcag ctt 343533114PRTHomo sapiens 533Gln Val Leu Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Phe Asp Gly Ser Lys Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Leu Glu Leu Trp Gly Leu Gly Thr Leu Val Thr Val Ser 100 105 110Ser Ala534366DNAHomo sapiens 534caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtgtcactt atatggtatg ctggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggacct 300ctacgatatt ttgactggcc cagtgactac tggggccagg gaaccctggt caccgtctcc 360tcagct 366535122PRTHomo sapiens 535Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Leu Ile Trp Tyr Ala Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Pro Leu Arg Tyr Phe Asp Trp Pro Ser Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120536327DNAHomo sapiens 536gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctcctgggga aagagccacc 60ctctcctgca gggccagtca gagttttagc agcagctact tagcctggtt ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca acagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcat cattttggta cctcaccgct cactttcggc 300ggagggacca aggtggagat caaacga 327537109PRTHomo sapiens 537Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Phe Ser Ser Ser 20 25 30Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys His His Phe Gly Thr Ser Pro 85 90 95Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105538366DNAHomo sapiens 538caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc ggctacttta tgcactgggt gccacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180gcacagaatt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga gcaggctgag atctgacgac acgcccgtgt attactgtgc gagagatccc 300tggcaaaact ggaactctta ctttgactac tggggccagg gaaccctggt caccgtctcc 360tcagct 366539122PRTHomo sapiens 539Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Phe Met His Trp Val Pro Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Asn Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Pro Val Tyr Tyr Cys 85 90 95Ala Arg Asp Pro Trp Gln Asn Trp Asn Ser Tyr Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120540324DNAHomo sapiens 540gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattaga agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaaggtcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacagta ccctgtgcag ttttggccag 300gggaccaagc tggagatcaa acga 324541108PRTHomo sapiens 541Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Arg Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Cys 85 90 95Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105542321DNAHomo sapiens 542gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtcttatc agcaacttag cctggtacca gcagaaacct 120ggccaggctc

ccaggctcct catctttggt gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcatcag tataataact ggtggacgtt cggccaaggg 300accaaggtgg aaatcaaacg a 321543107PRTHomo sapiens 543Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Ile Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Phe Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr Asn Asn Trp Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105544366DNAHomo sapiens 544caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggacct 300ctacgatatt ttgactggcc cagtgactac tggggccagg gaaccctggt caccgtctcc 360tcagct 366545122PRTHomo sapiens 545Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Pro Leu Arg Tyr Phe Asp Trp Pro Ser Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120546343DNAHomo sapiens 546ctggtgcagt ctggagctga ggtgaagaag cctggggcct cagtgaaggt ctcctgcaag 60gcttctggtt acacctttac cagctatggt atcagctggg tgcgacaggc ccctggacaa 120gggcttgagt ggatgggatg gatcagcgct tacaatggta acacaaacta tgcacagaag 180ctccaggaca gagtcaccat gaccacagac acatccacga gcacagccta catggagctg 240aggagcctga gatctgacga cacggccgtg tattactgtg cgagaggcgt gggagctaag 300gactactggg gccagggaac cctggtcacc gtctcctcag ctt 343547114PRTHomo sapiens 547Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys1 5 10 15Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Gly Ile Ser 20 25 30Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Trp Ile 35 40 45Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu Gln Asp Arg 50 55 60Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu Leu65 70 75 80Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly 85 90 95Val Gly Ala Lys Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110Ser Ala548324DNAHomo sapiens 548gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggcattagc aattatttag cctggtttca gcagaaacca 120gggaaagccc ctaagtccct gatctatgct gcatccagtt tggaaagtgg agtcccatca 180aagttcagcg gcagtggatc tgggacagat ttcaatctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgccaacag tataatagtt atcctcggac gttcggccaa 300gggaccaagg tggaaagcaa acga 324549108PRTHomo sapiens 549Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Asn Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ser Lys Arg 100 105550372DNAHomo sapiens 550caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccgtcagc agtggtggtt actactggag ctggatccgg 120cagcccccag ggaagggact ggagtggatt ggatatatct attacagtcg gagcaccaac 180tacaacccct ccctcaagag tcgagtcacc atatcagtag acacgtccaa gaaccagttc 240tccctgaaac tgagctctgt gaccgctgcg gacacggccg tgtattactg tgcgagagag 300ggacgtggat acagctatgg ttactacttt gactactggg gccagggaac cctggtcacc 360gtctcctcag ct 372551124PRTHomo sapiens 551Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45Trp Ile Gly Tyr Ile Tyr Tyr Ser Arg Ser Thr Asn Tyr Asn Pro Ser 50 55 60Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95Cys Ala Arg Glu Gly Arg Gly Tyr Ser Tyr Gly Tyr Tyr Phe Asp Tyr 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120552366DNAHomo sapiens 552gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag tacatactac 180gcagactccg taaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatgaa 300gactacggtg gtaactccga ctttgactac tggggccagg gaaccctggt caccgtctcc 360tcagct 366553122PRTHomo sapiens 553Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Glu Asp Tyr Gly Gly Asn Ser Asp Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120554363DNAHomo sapiens 554gaggtgcagc tggtggaatc tggaggaggc ttgatccagt ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caccgtcagt agcaaataca tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagtt atttatagcg gaggtttcac atactacgca 180gactccgtga agggccgatt caccgtctcc agagacaatt ccaagaacac gctgtatctt 240caaatgaaca gcctgggagc cgaggacacg gccgtgtatt actgtgcgac ctatagcagt 300ggctggcact actacggtat ggacgtctgg ggccaaggga ccacggtcac cgtctcctca 360gct 363555121PRTHomo sapiens 555Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Ser Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Lys 20 25 30Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Val Ile Tyr Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Gly Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Thr Tyr Ser Ser Gly Trp His Tyr Tyr Gly Met Asp Val Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser Ala 115 120556324DNAHomo sapiens 556gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca ggacattagc aattatttag cctggtttca gcagaaacca 120gggaaagccc ctaagtccct gatctatgct gtatccagtt tgcaaagtgg ggtcccatca 180aagttcagcg gcagtggatc tgggaccgat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgccaacag tataatagtt accctcggac gttcggccaa 300gggaccaagg tggaaatcaa acga 324557108PRTHomo sapiens 557Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45Tyr Ala Val Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105558121PRTHomo sapiens 558Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Thr Asp Tyr Gly Asp Tyr Gly Met Asp Val Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser Ala 115 120559118PRTHomo sapiens 559Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Ile Ala Val Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ser Ala 115560118PRTHomo sapiens 560Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Tyr Gly Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ser Ala 115561114PRTHomo sapiens 561Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser 100 105 110Ser Ala562112PRTHomo sapiens 562Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110563118PRTHomo sapiens 563Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr His Cys 85 90 95Ala Arg Gln Trp Leu Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110Val Thr Val Ser Ser Ala 115564123PRTHomo sapiens 564Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Tyr Gly Gly Asn Ser Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp 100 105 110Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120565119PRTHomo sapiens 565Glu Val Gln Leu Val Glu Ser Gly Gly Val Val Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Leu Ile Ser Trp Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Lys Asp Ile Ala Val Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115566117PRTHomo sapiens 566Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40

45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asn Trp Asn Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala 115567116PRTHomo sapiens 567Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Tyr Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser Ala 115568121PRTHomo sapiens 568Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95Cys Ala Arg Gly Tyr Ser Tyr Gly Tyr Tyr Phe Asp Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser Ala 115 120569121PRTHomo sapiens 569Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Trp Leu Arg Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser Ala 115 120570123PRTHomo sapiens 570Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Thr Tyr Ser Ser Gly Trp Tyr Trp Tyr Phe Asp Leu Trp 100 105 110Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120571117PRTHomo sapiens 571Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Tyr Ile Ser Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Ala Ala Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala 115572118PRTHomo sapiens 572Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Tyr Gly Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ser Ala 115573120PRTHomo sapiens 573Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn 20 25 30Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala 50 55 60Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn65 70 75 80Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val 85 90 95Tyr Tyr Cys Ala Trp Phe Tyr Trp Tyr Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala 115 120574114PRTHomo sapiens 574Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Thr Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110Ser Ala575119PRTHomo sapiens 575Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Tyr Ser Ser Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115576125PRTHomo sapiens 576Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Cys Gly Gly Asp Cys Tyr Tyr Tyr Tyr Tyr Tyr Gly Met Asp 100 105 110Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125577116PRTHomo sapiens 577Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95Cys Ala Arg Trp Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser Ala 115578110PRTHomo sapiens 578Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110579121PRTHomo sapiens 579Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asn Trp Asn Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser Ala 115 120580121PRTHomo sapiens 580Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Tyr Tyr Gly Ser Gly Ser Tyr Gly Met Asp Val Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser Ala 115 120581124PRTHomo sapiens 581Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95Cys Ala Arg Tyr Tyr Gly Ser Gly Tyr Tyr Tyr Tyr Gly Met Asp Val 100 105 110Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120582117PRTHomo sapiens 582Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asn Trp Asn Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala 115583118PRTHomo sapiens 583Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Tyr Gly Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110Val Thr Val Ser Ser Ala 115584115PRTHomo sapiens 584Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Arg Ile Tyr Thr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Trp Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val 100 105 110Ser Ser Ala 115585111PRTHomo sapiens 585Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110586121PRTHomo sapiens 586Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Trp Tyr Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln

100 105 110Gly Thr Thr Val Thr Val Ser Ser Ala 115 120587116PRTHomo sapiens 587Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Val Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser Ala 115588116PRTHomo sapiens 588Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Tyr Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser Ala 115589122PRTHomo sapiens 589Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Arg Ile Tyr Thr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Asp Tyr Ser Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly 100 105 110Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120590122PRTHomo sapiens 590Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Thr Tyr Gly Gly Asn Ser Tyr Gly Met Asp Val Trp Gly 100 105 110Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120591118PRTHomo sapiens 591Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Ile Ala Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ser Ala 115592117PRTHomo sapiens 592Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gln Trp Leu Val Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala 115593114PRTHomo sapiens 593Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Gln Trp Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110Ser Ala594113PRTHomo sapiens 594Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 100 105 110Ala595115PRTHomo sapiens 595Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val 100 105 110Ser Ser Ala 115596119PRTHomo sapiens 596Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Arg Ile Tyr Thr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Tyr Asn Trp Asn Tyr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115597118PRTHomo sapiens 597Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Ile Ala Val Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ser Ala 115598119PRTHomo sapiens 598Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn 20 25 30Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Tyr Ser Ser Gly Trp Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr 100 105 110Thr Val Thr Val Ser Ser Ala 115599119PRTHomo sapiens 599Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Asp Leu Leu Leu Arg Tyr Gly Arg Leu Gly Pro Arg Asp 100 105 110His Gly His Arg Leu Leu Ser 115600124PRTHomo sapiens 600Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Ile Val Ala Thr Ile Asn Tyr Tyr Tyr Gly Met Asp Val 100 105 110Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120601117PRTHomo sapiens 601Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Ile Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala 115602115PRTHomo sapiens 602Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val 100 105 110Ser Ser Ala 115603116PRTHomo sapiens 603Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Ala Ala Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser Ala 115604117PRTHomo sapiens 604Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Tyr Ser Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala 115605119PRTHomo sapiens 605Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln1 5 10 15Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45Trp Leu Ala Leu Ile Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val65 70 75 80Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95Cys Ala His Arg Ser Ser Ser Trp Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115606116PRTHomo sapiens 606Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Ile Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser Ala 115607119PRTHomo sapiens 607Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln

Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Ile Ala Ala Ala Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115608115PRTHomo sapiens 608Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Arg Ile Tyr Thr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Gly Ile Thr Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110Ser Ser Ala 115609113PRTHomo sapiens 609Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Gly Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 100 105 110Ala610116PRTHomo sapiens 610Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg Asn Trp Asn Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr 100 105 110Val Ser Ser Ala 115611121PRTHomo sapiens 611Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Ile Phe Gly Val Val Asn Trp Tyr Phe Asp Leu Trp Gly Arg 100 105 110Gly Thr Leu Val Thr Val Ser Ser Ala 115 120612123PRTHomo sapiens 612Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gln Asn Tyr Asp Phe Trp Ser Gly Tyr Gly Met Asp Val Trp 100 105 110Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120613115PRTHomo sapiens 613Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Val Gly Ala Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110Ser Ser Ala 115614124PRTHomo sapiens 614Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Ser Ser Gly Trp Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val 100 105 110Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120615119PRTHomo sapiens 615Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Phe Trp Ser Asn Trp Phe Asp Pro Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115616118PRTHomo sapiens 616Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Tyr Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met 100 105 110Val Thr Val Ser Ser Ala 115617121PRTHomo sapiens 617Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Tyr Cys Ser Gly Gly Tyr Gly Met Asp Val Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser Ala 115 120618117PRTHomo sapiens 618Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Arg Tyr Phe Asp Trp Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala 115619116PRTHomo sapiens 619Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Tyr Ser Ser Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser Ala 115620119PRTHomo sapiens 620Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Phe Trp Ser Asn Trp Phe Asp Pro Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115621110PRTHomo sapiens 621Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110622112PRTHomo sapiens 622Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Thr Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110623114PRTHomo sapiens 623Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser 100 105 110Ser Ala624119PRTHomo sapiens 624Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Thr Tyr Gly Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala 115625112PRTHomo sapiens 625Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110626115PRTHomo sapiens 626Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gln Leu Trp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110Ser Ser Ala 115627120PRTHomo sapiens 627Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Ile Ala Val Ala Tyr Gly Met Asp Val Trp Gly Gln Gly 100 105 110Thr Thr Val Thr Val Ser Ser Ala 115 120628109PRTHomo sapiens 628Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25

30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105629104PRTHomo sapiens 629Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Phe Gly Gln 85 90 95Gly Thr Lys Leu Glu Ile Lys Arg 100630108PRTHomo sapiens 630Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105631108PRTHomo sapiens 631Glu Thr Thr Leu Thr Gln Ser Pro Ala Phe Met Ser Ala Thr Pro Gly1 5 10 15Asp Lys Val Asn Ile Ser Cys Lys Ala Ser Gln Asp Ile Asp Asp Asp 20 25 30Met Asn Trp Tyr Gln Gln Lys Pro Gly Glu Ala Ala Ile Phe Ile Ile 35 40 45Gln Glu Ala Thr Thr Leu Val Pro Gly Ile Pro Pro Arg Phe Ser Gly 50 55 60Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu Ser65 70 75 80Glu Asp Ala Ala Tyr Tyr Phe Cys Leu Gln His Asp Asn Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105632108PRTHomo sapiens 632Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105633108PRTHomo sapiens 633Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105634108PRTHomo sapiens 634Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105635108PRTHomo sapiens 635Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105636106PRTHomo sapiens 636Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Phe 85 90 95Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105637108PRTHomo sapiens 637Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105638108PRTHomo sapiens 638Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105639113PRTHomo sapiens 639Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Leu Gln Thr Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110Arg640114PRTHomo sapiens 640Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110Lys Arg641113PRTHomo sapiens 641Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg642114PRTHomo sapiens 642Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95Tyr Tyr Ser Thr Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile 100 105 110Lys Arg643110PRTHomo sapiens 643Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110644112PRTHomo sapiens 644Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95Tyr Tyr Ser Thr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 110645113PRTHomo sapiens 645Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110Arg646111PRTHomo sapiens 646Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Leu Gln Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 110647113PRTHomo sapiens 647Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Leu Gln Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110Arg648106PRTHomo sapiens 648Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Thr Phe 85 90 95Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105649111PRTHomo sapiens 649Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95Tyr Tyr Ser Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110650106PRTHomo sapiens 650Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala

Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ile Thr Phe 85 90 95Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105651108PRTHomo sapiens 651Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105652108PRTHomo sapiens 652Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105653107PRTHomo sapiens 653Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105654108PRTHomo sapiens 654Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105655106PRTHomo sapiens 655Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Thr Phe 85 90 95Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105656106PRTHomo sapiens 656Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe 85 90 95Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105657108PRTHomo sapiens 657Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Arg Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Cys 85 90 95Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105658108PRTHomo sapiens 658Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105659109PRTHomo sapiens 659Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105660106PRTHomo sapiens 660Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Thr Phe 85 90 95Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105661107PRTHomo sapiens 661Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105662108PRTHomo sapiens 662Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105

Claims

1. A targeted binding agent that binds to Angiopoietin-2 with a Kd of less than 100 picomolar (pM), wherein said targeted binding agent is a fully human monoclonal antibody selected from the group consisting of: a. mAb 3.19.3 (ATCC Accession Number PTA-7260); b. mAb 3.3.2 (ATCC Accession Number PTA-7258); and c. mAb 5.88.3 (ATCC Accession Number PTA-7259).

2-13. (canceled)

14. The targeted binding agent of claim 0, in association with a pharmaceutically acceptable carrier.

15. A nucleic acid molecule encoding the targeted binding agent of claim 1.

16. A vector comprising the nucleic acid molecule of claim 15.

17. A host cell comprising the vector of claim 16.

18. A method of treating a malignant tumor in an animal, comprising administering to said animal in need thereof a therapeutically effective dose of the targeted binding agent of claim 1.

19. The method of claim 18, wherein said animal is human.

20. (canceled)

21. The method of claim 18, wherein said malignant tumor is selected from the group consisting of: melanoma, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, thyroid tumor, gastric (stomach) cancer, prostate cancer, breast cancer, ovarian cancer, bladder cancer, lung cancer, glioblastoma, endometrial cancer, kidney cancer, colon cancer, pancreatic cancer, and epidermoid carcinoma.

22. A method of treating Angiopoietin-2 induced angiogenesis, comprising administering to an animal in need thereof a therapeutically effective dose of the targeted binding agent of claim 1.

23. The method of claim 22, wherein said animal is human.

24-25. (canceled)

26. An antagonist of the biological activity of Angiopoietin-2, wherein the antagonist does not bind to the ATP-binding site of Tie-2.

27-28. (canceled)

29. The antagonist of claim 26, wherein the antagonist binds to the Tie-2 receptor.

30. (canceled)

31. The antagonist of claim 26, wherein the antagonist is an antibody.

32. The antagonist of claim 31, wherein the antagonist is a monoclonal antibody.

33. The antagonist of claim 32, wherein the monoclonal antibody is a fully human monoclonal antibody.

34. The antagonist of claim 33, wherein the fully human monoclonal antibody is antibody 3.19.3 (ATCC Accession Number PTA-7260) or 3.3.2 (ATCC Accession Number PTA-7258) or 5.88.3 (ATCC Accession Number PTA-7259).

35. The antagonist of claim 26, wherein the antagonist is an antibody that binds to the same epitope as the fully human monoclonal antibody 3.19.3 (ATCC Accession Number PTA-7260) or 3.3.2 (ATCC Accession Number PTA-7258) or 5.88.3 (ATCC Accession Number PTA-7259).