Antibodies directed to angiopoietin-2 and uses thereof

The invention relates to monoclonal antibodies against Angiopoietin-2 (Ang-2) and the use of such antibodies. More particularly, the invention relates to fully human monoclonal antibodies directed against Ang-2 and the uses of these antibodies. Aspects of the invention also apply to hybridomas or other cell lines expressing such antibodies. The antibodies described are useful as diagnostic tools and in the treatment of diseases related to Ang-2 activity and / or overproduction.

BACKGROUND [0002] Angiogenesis is the process of forming new capillaries from previously existing blood vessels and is an essential component of embryogenesis, normal physiological growth, tumor repair and growth. Although a number of factors may modulate endothelial cell (EC) cell responses in vitro and in vivo vascular growth, it is believed that only members of the vascular endothelial growth factor (VEGF) family and angiopoietins only act on BCs vascular. Yancopoulos et al., Nature 407: 242-48 (2000).

[0003] Angiopoietins have been discovered as Ties ligands, a tyrosine kinase family that is selectively expressed within the vascular endothelium. Yancopoulos et al., Nature 407: 242-48 (2000). There are four certain members of the angiopoietin family present. Angiopoietin-3 and -4 (Ang-3 and Ang-4) can represent broadly variable equivalents of the same gene locus in mice and in humans. 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 cell culture experiments as respectively an agonist and antagonist. Davis et al., Cell 87: 1161-69 (1996); Maisonpierre et al., Science 277: 55-60 (1997). All known angiopoietins originally bind 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 has been shown to promote EC survival and endothelial 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 has the opposite effect and promotes destabilization of blood vessels and regression in the absence of survival factors of VEGF or simple fibroblast growth factor. Maisonpierre et al., Science 277: 55-60 (1997). However, many studies of the Ang-2 function indicated a more complex situation. Ang-2 could be a complex regulator of vascular remodeling, which plays a role in both germinating vessels and vascular regression. To support such roles 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 has the opposite effect and promotes destabilization of blood vessels and regression in the absence of survival factors of VEGF or simple fibroblast growth factor. Maisonpierre et al., Science 277: 55-60 (1997). However, many studies of the Ang-2 function indicated a more complex situation. Ang-2 could be a complex regulator of vascular remodeling, which plays a role in both germinating vessels and vascular regression. To support such roles 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 has the opposite effect and promotes destabilization of blood vessels and regression in the absence of survival factors of VEGF or simple fibroblast growth factor. Maisonpierre et al., Science 277: 55-60 (1997). However, many studies of the Ang-2 function indicated a more complex situation. Ang-2 could be a complex regulator of vascular remodeling, which plays a role in both germinating vessels and vascular regression. To support such roles whereas Ang-2 has the opposite effect and promotes destabilization of blood vessels and regression in the absence of survival factors of VEGF or simple fibroblast growth factor. Maisonpierre et al., Science 277: 55-60 (1997). However, many studies of the Ang-2 function indicated a more complex situation. Ang-2 could be a complex regulator of vascular remodeling, which plays a role in both germinating vessels and vascular regression. To support such roles whereas Ang-2 has the opposite effect and promotes destabilization of blood vessels and regression in the absence of survival factors of VEGF or simple fibroblast growth factor. Maisonpierre et al., Science 277: 55-60 (1997). However, many studies of the Ang-2 function indicated a more complex situation. Ang-2 could be a complex regulator of vascular remodeling, which plays a role in both germinating vessels and vascular regression. To support such roles as well as vessel regression. To support such roles as well as vessel regression. To support such roles

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Ang-2, expression analyzes revealed that Ang-2 is rapidly induced together with VEGF when new vasculature occurs in mature systems, whereas Ang-2 induces in the absence of VEGF in vascular regression systems. Holash et al., Science 284: 1994-98 (1999); Holash et al., Oncogene 18: 5356-62 (1999). According to the context-dependent role, Ang-2 binds to the same endothelial-specific receptor, Tie-2, which is activated by Ang-1, but has a context-dependent effect on its activation. Maisonpierre et al., Science 277: 55-60 (1997).

[0004] Corneal angiogenesis studies have shown that both Ang-1 and Ang-2 had similar effects, acting synergistically with VEGF, promoting the growth of new blood vessels. Asahara et al., Circ. Res. 83: 233-40 (1998). The possibility of a dose-dependent endothelial response has been proposed based on the observation that in high concentrations in vitro Ang-2 may 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 apoptosis resulting from plasma depletion through activation of Tie2 mediated by PI-3 kinase and the Akt pathway. Kim et al., Oncogene 19: 4549-52 (2000).

[0005] Other in vitro experiments have indicated that during prolonged exposure, the effect of Ang-2 may gradually shift from the antagonist towards the Tie2 agonist, and at later times in time may directly contribute to vascularization and the stabilization of new vessels. TeichertKuliszewska et al., Cardiovasc. Res. 49: 659-70 (2001). In addition, if the EC was grown on a fibrin gel, the activation of Tie2 by Ang-2 was also observed, perhaps indicating that the effect of Ang-2 may depend on the state of EC differentiation. Teichert-Kuliszewska et al., Cardiovasc. Res. 49: 659-70 (2001). In microwassed ECs grown in a three-dimensional collagen gel, Ang-2 can also induce Tie2 activation and promote the formation of capillary-like structures. Mochizuki et al., J. Cell. Sci. 115: 175-83 (2002). The use of spheroidal 3D co-cultures as an in vitro vascular maturation model showed that direct contact between ECs and mesenchymal cells abolished responsiveness to VeGf, while the presence of VEGF and Ang-2 induced germination. Korff et al., Faseb J. 15: 447-57 (2001). Etoh et al. demonstrated that ECs in which Tie2 expression is constitutively expressed, the expression of MMP-1, -9 and u-PA is strongly enhanced by Ang-2 in the presence of VeGf. Etoh, et al., Cancer Res. 61: 2145-53 (2001). Lobov et al. in the model of the pupil membrane Ang-2 showed that in the presence of endogenous VEGF promotes a rapid increase in capillary diameter, remodeling of the basal membrane, proliferation and migration of endothelial cells and stimulates the germination of new blood vessels. Lobov et al., Proc. Natl. Acad. Sci. USA 99: 11205-10 (2002). Ang-2, on the other hand, promotes the death of endothelial cells and vascular regression without endogenous VEGF. Lobov et al., Proc. Natl. Acad. Sci. USA 99: 11205-10 (2002). Similarly, in the in vitro tumor model Vajkoczy et al. showed that multicellular aggregates initiate

The growth of vasculature by vascular germination by simultaneous expression of VEGFR-2 and Ang-2 by the host and tumor endothelium. Vajkoczy et al., J. Clin. Invest. 109: 777-85 (2002). This model showed that the stabilized network of small blood vessels of growing tumors is characterized by continuous remodeling, presumably via the expression of VEGF and Ang-2. Vajkoczy et al., J. Clin. Invest. 109: 777-85 (2002).

[0006] Tie-2 and Angiopoietin-1 studies in knock-out mice show similar phenotypes and suggest that Angiopoietin-1-stimulated phosphorylation of Tie-2 mediates remodeling and stabilization of the developing vasculature, favoring the maturation of blood vessels during angiogenesis and maintaining adhesion. endothelial cells (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 an adult, where it is expressed in a wide range and constitutively (Hanahan, Science, 277: 48-50 (1997); Zagzag, et al., Exp Neurology, 159: 391-400 (1999)). In contrast, the expression of Angiopoietin-2 is essentially confined to vascular remodeling sites in which it is believed it blocks the constitutive function of stabilizing or maturing Angiopoietin-1, allowing vasculature to return and remain in the plastic state, which may be more reactive to germination signals (Hanahan, 1997; Holash et al., Oncogene 18: 5356-62 (1999); Maisonpierre, 1997). Studies on the expression of Angiopoietin-2 in pathological angiogenesis have shown that many types of tumors express Angiopoietin-2 (Maisonpierre et al., Science 277: 55-60 (1997)). Functional studies suggest that Angiopoietin-2 is involved in tumor angiogenesis and is involved in the overexpression of Angiopoietin-2 with increased tumor growth in the mouse xenograft model (Ahmad, et al., Cancer Res., 61: 1255-1259 (2001)). Other studies link the overexpression of Angiopoietin-2 with excessive tumor vasculature (Etoh, et al., Cancer Res. 61: 2145-53 (2001); Tanaka et al., Cancer Res.

[0007] In recent years, Angiopoietin-1, Angiopoietin-2 and / or Tie-2 have been proposed as possible targets for anti-cancer therapies. For example, US6166185, US5650490 and US5814464 disclose each antibody against a ligand and the Tie-2 receptor. It has been reported that studies using soluble Tie-2 reduced the number and size of tumors in rodents (Lin, 1997; Lin 1998). Siemester et al. (1999) produced human melanoma cell lines that expressed the extracellular domain of Tie-2, injected them into nude mice, and reported that soluble Tie-2 caused significant preservation of tumor growth and tumor angiogenesis. Considering that both Angiopoietin-1 and Angiopoietin-2 are associated with Tie-2, it is not clear in these studies whether Angiopoietin-1, Angiopoietin-2 or Tie-2 would be attractive targets for anti-cancer therapy. However, it is considered

The inhibition of this process may lead to the prevention of disease progression (Folkman, J., Nature Medicine, 1: 27-31 (1995).) In addition, some groups have reported using antibodies that bind to Angiopoietin-2. for example, U.S. Patent No. 6,166,185 and U.S. Patent Application Publication No. 2003/0124129 A1. Study of Angiopoietin-2 focal expression showed that blocking the Angiopoietin1 / Tie-2 signal weakens the vascular structure, exposing ECs to activation signals from angiogenesis inducers, e.g. VeGf (Hanahan, 1997) This pro-angiogenic effect resulting from the inhibition of Angiopoietin-1 indicates that anti-Angiopoietin-1 therapy would not be an effective anticancer treatment.

[0008] Ang-2 is expressed during development at sites where blood vessel remodeling occurs. Maisonpierre et al., Science 277: 55-60 (1997). In adult subjects, Ang-2 expression is restricted to vascular remodeling sites as well as 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 cancer, 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 Patho / 155: 1967-76 (1999), non-small cell lung cancer, Wong et al., Lung Cancer 29: 11-22 (2000) and colon cancer, Ahmad et al., Cancer 92: 1138-43 (2001) and prostate Wurmbach et al., Anticancer Res. 20: 5217-20 (2000). It was found that Ang-2 expression is expressed in some tumor cells. For example, Tanaka et al., J. Clin. Invest. 103: 341-45 (1999) found Ang-2 mRNA in 10 of 12 human hepatocellular carcinoma (HCC). Ellis's team reported that Ang-2 is ubiquitously expressed in the endothelium of the tumor. Ahmad et al., Cancer 92: 1138-43 (2001). Other researchers have reported similar discoveries. Chen et al., J. Tongji Med. Univ. 21: 228-30, 235 (2001). Detecting Ang-2 mRNA levels in archival samples of human breast cancer, Sfilogoi et al., Int. J. Cancer 103: 466-74 (2003) reported that Ang2 mRNA is significantly associated with invasion of the lymph node, a short time free of disease and generally a little experience. Tanaka et al., Cancer Res. 62: 7124-29 (2002) examined 236 patients with non-small cell lung cancer (NSCLC) with the pathological condition -I to -IIIA, respectively. Using immunochemistry, they found that 16.9% of NSCLC patients were positive for Ang-2. The density of the microvessels in the Ang-2 positive tumor is much higher than in the Ang-2 negative tumor. This Ang-2 angiogenic effect was observed only when the expression of VEGF was high. In addition, the positive expression of Ang-2 was a significant factor in predicting a small post-operative survival. Tanaka et al., Cancer Res. 62: 712-429 (2002). However, they did not find a significant correlation between Ang-1 expression and microvascular density. Tanaka et al., Cancer Res. 62: 7124-29 The density of the microvessels in the Ang-2 positive tumor is much higher than in the Ang-2 negative tumor. This Ang-2 angiogenic effect was observed only when the expression of VEGF was high. In addition, the positive expression of Ang-2 was a significant factor in predicting a small post-operative survival. Tanaka et al., Cancer Res. 62: 712-429 (2002). However, they did not find a significant correlation between Ang-1 expression and microvascular density. Tanaka et al., Cancer Res. 62: 7124-29 The density of the microvessels in the Ang-2 positive tumor is much higher than in the Ang-2 negative tumor. This Ang-2 angiogenic effect was observed only when the expression of VEGF was high. In addition, the positive expression of Ang-2 was a significant factor in predicting a small post-operative survival. Tanaka et al., Cancer Res. 62: 712-429 (2002). However, they did not find a significant correlation between Ang-1 expression and microvascular density. Tanaka et al., Cancer Res. 62: 7124-29 However, they did not find a significant correlation between Ang-1 expression and microvascular density. Tanaka et al., Cancer Res. 62: 7124-29 However, they did not find a significant correlation between Ang-1 expression and microvascular density. Tanaka et al., Cancer Res. 62: 7124-29

EP 1 838 733B1 (2002). These results suggest that Ang-2 is an indicator of patients with poor prognosis with various types of cancer.

[0009] Recently, using the Ang-2 knock-out mouse model, the Yancopoulos syndrome 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 hyalinic vascularization does not occur in Ang-2 - / - mice, and their retinal blood vessels do not germinate from the main retinal artery. Gale et al., Dev. Cell 3: 411-23 (2002). They also found that the deletion of Ang-2 results in profound defects in the education and function of the lymphatic vasculature. Gale et al., Dev. Cell 3: 411-23 (2002).

Genetic support Ang-1 corrects defects of absorbent but not angiogenic angiogenesis. Gale et al., Dev. Cell 3: 411-23 (2002).

[0010] Peters et al. Reported that soluble Tie2, administered either as a recombinant protein or in a viral expression vector, inhibited the in vitro increase in mouse mammary and melanoma tumors 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). The vessel densities in such treated tumor tissues have significantly decreased. In addition, soluble Tie2 blocked angiogenesis in the rat cornea stimulated by conditioned medium of the tumor cell. Lin et al., J. Clin. Invest. 100: 207278 (1997). In addition, Isner and his team demonstrated that the addition of Ang-2 to VEGF promoted significantly longer and more peripheral vascular rebuild than VEGF alone. Asahara et al ,, Circ. Res. 83: 233-40 (1998). The excess soluble Tie2 receptor precluded modulation of Ang39-induced vascular rebuilding. Asahara et al., Circ, Res. 83: 333-40 (1998). Siemeister et al., Cancer Res. 59: 3185-91 (1999) showed that overexpression of extracellular ligand-binding domains of either Flt-1 or Tie2 in intercellular transplants resulted in significant inhibition of the pathway that could not be compensated for by another, suggesting that the VEGF receptor pathway and pathway Tie2 should be considered as two independent mediators that are crucial for the in vivo angiogenesis process. Siemeister et al., Cancer Res. 59: 3185-91 (1999). This is demonstrated in the newer publication White et al., Proc. Natl. Acad. Sci. USA 100: 5028-33 (2003). Their study showed that a nuclease-resistant RNA aptamer that specifically binds and inhibits Ang-2,

SUMMARY [0011] Embodiments of the invention relate to targeted binding: agents that specifically bind to Angiopoietin-2 and there inhibit tumor angiogenesis and limit tumor growth. The mechanisms by which this can be achieved may include and are not limited

For the purpose of inhibiting Ang-2 binding to its Tie2 receptor, inhibiting Ang-2 induced Tie2 signaling or increased Ang-2 clearance, also reducing the effective concentration of Ang-2.

[0012] According to one aspect of the invention, an antibody or antigen-binding fragment according to the present claim 1 is provided.

[0013] According to one aspect of the invention, an isolated antibody or antigen-binding fragment according to the present claim 3 is provided.

[0014] According to one aspect of the invention, an antibody or antigen-binding fragment according to the present claim 4 is provided.

[0015] According to one aspect of the invention, an antibody or antigen-binding fragment according to the present claim 5 is provided.

[0016] According to one aspect of the invention, an antibody or antigen-binding fragment according to the present claim 6 is provided.

[0017] According to another aspect of the present invention, the use of an antibody or antigen-binding fragment of the invention in the preparation of a medicament for treating a malignant tumor is provided.

[0018] According to another aspect of the present invention, the use of an antibody or antigen-binding fragment of the invention is provided for the treatment of a malignant tumor.

[0019] The antibody may be a fully human antibody that binds Ang-2 and presents the binding of Ang-2 to Tie2. The antibody may be 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 Kd of less than 100 pM, 30 pM, 20 pM, 10 pM or 5 pM.

[0020] The antibody may comprise a heavy chain amino acid sequence having a complementarity determining region (CDR), wherein one of the sequences is shown in Table 11. It is worth noting that experts can easily make CDR determinations. See. for example, Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIB Publication 91-3242, Bethesda MD (1991), Volumes 1-3. In certain embodiments, the antibody is a fully human monoclonal antibody. [0021] A malignant tumor may be selected from the group consisting of: melanoma, small cell lung cancer, non-small cell lung cancer, hepatocellular carcinoma of the liver, thyroid cancer, gastric (stomach) cancer, prostate cancer, breast cancer, ovarian cancer, cancer bladder cancer, lung cancer, glioblastoma multiforme, endorrion, kidney cancer, colon cancer,

[0022] Embodiments of the invention described herein refer to monoclonal antibodies that bind to Ang-2 and affect the function of Ang-2. Other embodiments refer to fully human anti-Ang-2 antibodies and anti-Ang-2 antibody preparations with characteristics desirable from a therapeutic perspective, including high affinity binding to Ang2, Ang-2 in vitro and in vivo neutralization, and the ability to inhibit Ang-2-induced angiogenesis.

[0023] In a preferred embodiment, the antibodies described herein bind to Ang-2 with very high affinity (Kd). For example, a human, rabbit, murine chimeric or humanized antibody that is capable of binding Ang-2 to Kd with less but not limited to 10 '⁵, 10 '⁶10 '7, 10-8, 10-9, 10-10, 10-11, 10-12, 13-13 or 10-'⁴_M or in any range or value included in it. Affinity and / or binding strength can be measured using KinExA® and / or BIACORE® as described herein.

[0024] Accordingly, one embodiment described herein includes isolated antibodies or fragments of these antibodies that bind to Ang-2. According to the prior art, the antibodies may preferably be, for example, polyclonal oligoclonal, monoclonal, chimeric humanized and / or fully human antibodies.

[0025] In one embodiment, the antibody binds to and neutralizes Angiopoietin-2, and also binds to and neutralizes Angiopoietin-1. [0026] It will be appreciated that the embodiments of the invention are not limited to any particular form of the antibody or production or production method. For example, anti-Ang-2 antibodies can be full-length antibodies (e.g., having an intact human Fc region) or antibody fragments (e.g., Fab, Fab 'or F (ab') 2). In addition, the antibody can be made from a hybridoma that secretes the antibody, or from a recombinantly produced cell that has been transformed or transfected with the gene or genes encoding the antibody.

[0027] Inhibition of the biological activity of Ang-2 may represent Ang-2 induced angiogenesis and other desired effects.

[0028] Ang-2 is an important "switch" of angiogenesis. Correspondingly, blocking of this molecule is expected to inhibit pathophysiological processes and thus act as a potential therapy for various angiogenesis dependent diseases. In addition, solid tumors and metastases, hematopoietic proliferative diseases such as leukemia, lymphoma and multiple myeloma are also dependent on angiogenesis. Excessive vascular growth contributes to numerous non-neoplastic disorders. These non -oplastic angiogenesis-dependent diseases include: atherosclerosis, angioma, endothelial sarcoma, angiofibroma, vascular deformity (e.g., congenital haemorrhagic hemangiomatosis or Osler-Weber's syndrome), warts, pyogenic pyogenic granuloma, excessive hair growth, Kaposi's sarcoma, post-traumatic keloid, allergic edema,

The white matter brain softening, neovascular glaucoma, corneal neovascularization, trachoma, thyroiditis, thyroid hyperplasia and lymphoproliferative disorders are also observed.

BRIEF DESCRIPTION OF THE DRAWINGS [0029] Figure 1 is a Western blot illustrating that Ang-2 mAbs inhibit Ang-2-induced phosphorylation of Tie2 expressed ectopically in HEK293F cells.

[0030] Figure 2 is a linear graph of the dose-response relationship of anti-Ang-2 monoclonal antibodies to Ang-2 induced Tie2 phosphorylation.

[0031] Figure 3 is a line graph showing the inhibition of both Ang-1 (upper graph) and Ang-2 (bottom graph) binding in a dose-dependent manner using mAb 3.19.3 or Tie2 / Fc.

[0032] Figure 4 is a Western blot demonstrating the inhibition of Angiopoietin-1 stimulated phosphorylation of Tie-2 on Eahy 926 endothelial cells by mAb 3.19.3. In this system, inhibition of Angiopoietin-1 induced Tie-2 phosphorylation is observed. Antibody concentrations are shown in nM.

[0033] Figure 5 is a line graph showing the inhibition of Angiopoietin-1 stimulated phosphorylation of Tie-2 on Eahy 926 endothelial cells by mAb 3.19.3. IC 50 = 99nM. The x-axis is the concentration of mAb 3.19.3 and the y-axis indicates the response.

[0034] Figure 6 is a schematic diagram of the protein structure of human Ang-2 and Ang-2443. The upper numbers represent the amino acid sequences (diagram drawn from Injune et al., (2000) JBC 275: 18550).

[0035] Figure 7 shows the amino acid sequence of a chimeric mouse / human molecule (SEQ ID No. 1). Human residuals (cloned as StuI-Tfil fragment) 310-400 are underlined.

[0036] Figure 8 is a comparison of the amino acid sequence of human Ang1 proteins (SEQ ID No. 2), human Ang-2 (SEQ ID No. 3) and mouse Ang-2 (SEQ ID No. 4). The fusion points of the Ang-2 chimeric particles and the point mutations are highlighted in bold.

[0037] Figure 9 is a comparison of the amino acid sequence of mouse Ang-1 (SEQ ID NO: 5), human Ang-1 (SEQ ID NO: 2) of mouse Ang-2 (SEQ ID No. 4) and human Ang-2 (SEQ ID No. ID No: 3). The arrowhead indicates the cutting point for the hydrophobic lead sequences. Arrows define the boundaries of coiled-coil and fibrinogen-like domains. The filled circles show conserved cysteine ​​residues (image taken from Maisonpierre et al., 1997, Science 277: 55).

[0038] Figure 10 is a line graph showing mouse cross reactivity versus dose-response. Clone monoclonal antibodies 5.2.1, 5.28.1.3.19.3 and 3.31.2 are shown.

[0039] Figure 11 is a line graph showing the 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.

[0040] Figure 12 is an analysis using a bar graph of antibody activity on MCF-7-induced angiogenesis. Figure 12A shows the effect of anti-Ang-2 antibodies on the number of vascular endings, where the x-axis indicates the experimental groups, and the y-axis indicates the average number of blood vessel endings (+/- SD). Figure 12A shows the effect of anti-Ang-2 antibodies on the length of blood vessels, where the x-axis indicates the experimental groups, and the y-axis indicates the mean length of the blood vessels (+/- SD).

[0041] Figure 13 is a line graph showing the anti-tumor effect of an anti-Ang-2 monoclonal antibody clone 3.19.3 tested in a murine model of human skin epidermoid carcinoma transplant using the A431 cell line. The x-axis indicates the number of days after implantation of the tumor cell, and the y-axis indicates the mean volume of +/- SEM in cm³. Filled black triangles show measurements of tumor volume after transplantation in mice injected with the anti-Ang-2 monoclonal antibody clone 3.19.3; filled black circles represent the volume of tumor after transplantation in mice injected with the isotype control antibody PK1631.

[0042] Figure 14A is a line graph showing the prevention of tumor growth in a hepatic colon adenocarcinoma model of LoVo, with the tumor size indicated for mice, obtained with 0.5, 2 and 10 mg / kg or the isotype control indicated. The x-axis indicates the number of days after implantation of the tumor cell, and the y-axis indicates the mean tumor volume +/- SEM in cm3. Figure 14B is a line graph showing the effect of mAbs on tumor growth in a human xenograft adenocarcinoma SW480.

[0043] Figure 15A is a line graph showing the prevention of tumor growth in a HT29 xenograft model. The x-axis indicates the number of days after implantation of the tumor cell, and the y-axis indicates the mean tumor volume +/- SEM in cm3. Figure 15B is a line graph showing the prevention of tumor growth in a Calu-6 xenograft model with the tumor size indicated for mice treated with 10 mg / kg of mAb clone 3.3.2 or 3.193 or with an isotype control antibody. Figure 15C is a bar graph indicating the CD31 + staining density in tumors in mice bearing MDA-MB-231 tumor treated with either control IgG or 10mg / kg mAb 3.19.3. The results obtained both by the method of threshold measurements and manual counting on the grid are shown.

DETAILED DESCRIPTION [0044] Embodiments of the invention described herein refer to monoclonal antibodies that bind to Ang-2. In certain embodiments, the antibodies bind to Ang-2 and inhibit the binding of Ang-2 to its receptor, Tie2. Other embodiments include fully human anti-Ang-2 antibodies and antibody preparations that are

Therapeutically useful. Such anti-Ang-2 antibody preparations preferably have the desired therapeutic features, including a strong binding affinity to Ang-2, the in-vitro neutralization of Ang-2, and the ability to inhibit Ang-2 induced angiogenesis in vivo.

[0045] 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-known antibody fragments, as described in more detail below.

[0046] The cells may express fully human anti-Ang-2 antibodies. Examples of cells include hybridomas or recombinantly produced cells, such as Chinese hamster ovary (CHO) cells, CHO cell variants (e.g. DG44), and NS0 cells that produce anti-Ang2 antibodies. Additional information on CHO cell variants can be found in Andersen and Reilly (2004) Current Opinion in Biotechnology 15, 456-462, [0047] Anti-Ang-2 antibodies are useful in the prevention of Ang-2 mediated signal transduction through Tie2, inhibiting thus, angiogenesis. The mechanism of action of this inhibition may include inhibition of Ang-2 binding to its receptor, Tie2, inhibition of Ang-2 induced Tie2 signaling or increased Ang-2 clearance, and thus lowering the effective concentration of Ang-2 to bind to Tie-2. Diseases that can be treated via this mechanism of inhibition include, but are not limited to, neoplastic diseases such as melanoma, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular carcinoma (liver), glial cell cancer, and thyroid cancer and tumors, stomach , prostaggies, breasts, ovaries, bladders, lungs, uterus, kidneys, colon and pancreas, salivary glands and large intestine.

[0048] In a preferred embodiment, the present invention is particularly suitable for use in blocking Angiopoietin-1 or Angiopoietin-2 in a patient with a tumor that is partially or wholly dependent on the Tie-2 receptor.

[0049] Further embodiments, features and the like regarding anti-Ang-2 antibodies are provided in additional details below.

List of Sequences [0050] Specific anti-Ang-2 antibodies are listed below in Table 1. This table gives the identification number of each anti-Ang-2 antibody along with the SEQ ID of the corresponding heavy and light chain genes. [0051] Each antibody has been assigned an identification number that includes either two or three numbers separated by one or two decimal points. For the majority of antibodies, only two identification numbers are listed separated by one decimal point.

[0052] However, in some cases several clones of one antibody have been prepared. Although the clones have identical sequences

The nucleotide and amino acid sequences with the parent sequence may also be listed separately, with the number of the clone indicated by the number to the right of the decimal point. Thus, for example, the nucleotide and amino acid sequences of antibody 5.35 are identical to the sequences of antibodies 5.35.1, 5.35.2 and 5.35.3.

Table 1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="4">3.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>6</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>7</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>8</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>9</td>

<td rowspan="4">3.2</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>10</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>11</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>12</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>13</td>

<td rowspan="4">3.3</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>14</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>15</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>16</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>17</td>

<td rowspan="4">3.3.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>18</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>19</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>20</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>21</td>

<td>3.3.2</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>22</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="3"></td><td>The amino acid sequence coding for the heavy chain variable region</td><td>23</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>24</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>25</td>

<td rowspan="4">3.6</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>26</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>27</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>28</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>29</td>

<td rowspan="4">3.7</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>thirty</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>31</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>32</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>33</td>

<td rowspan="4">3.8</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>34</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>35</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>36</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>37</td>

<td rowspan="4">3.9</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>38</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>39</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>40</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>41</td>

<td>3.10</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>42</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td></td><td>The amino acid sequence coding for the heavy chain variable region</td><td>43</td>

<td></td><td>Nucleotide sequence coding for the light chain variable region</td><td>44</td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>45</td>

<td></td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>46</td>

<td rowspan="2">3.11</td><td>The amino acid sequence coding for the heavy chain variable region</td><td>47</td>

<td rowspan="2">Nucleotide sequence coding for the light chain variable region</td><td rowspan="2">48</td>

<td></td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>49</td>

<td></td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>50</td>

<td rowspan="2">3.12</td><td>The amino acid sequence coding for the heavy chain variable region</td><td>51</td>

<td rowspan="2">Nucleotide sequence coding for the light chain variable region</td><td rowspan="2">52</td>

<td></td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>53</td>

<td></td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>54</td>

<td rowspan="2">3.13</td><td>The amino acid sequence coding for the heavy chain variable region</td><td>55</td>

<td rowspan="2">Nucleotide sequence coding for the light chain variable region</td><td rowspan="2">56</td>

<td></td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>57</td>

<td></td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>58</td>

<td rowspan="2">3.14</td><td>The amino acid sequence coding for the heavy chain variable region</td><td>59</td>

<td rowspan="2">Nucleotide sequence coding for the light chain variable region</td><td rowspan="2">60</td>

<td></td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>61</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="2">3.15</td><td>Nucleotide sequence coding for the light chain variable region</td><td>62</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>63</td>

<td rowspan="2">3.16</td><td>Nucleotide sequence coding for the light chain variable region</td><td>64</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>65</td>

<td rowspan="4">3.17</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>66</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>67</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>68</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>69</td>

<td rowspan="4">3.18</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>70</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>71</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>72</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>73</td>

<td rowspan="4">3.19.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>74</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>75</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>76</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>77</td>

<td rowspan="3">3.19.3</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>78</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>79</td>

<td>A nucleotide sequence encoding a variable chain region</td><td>80</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="2"></td><td>light</td><td></td>

<td>The amino acid sequence coding for the light chain variable region</td><td>81</td>

<td rowspan="2">3.20</td><td>Nucleotide sequence coding for the light chain variable region</td><td>82</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>83</td>

<td rowspan="4">3.21</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>84</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>85</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>86</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>87</td>

<td rowspan="4">3.22</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>88</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>89</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>90</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>91</td>

<td rowspan="4">3.26</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>92</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>93</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>94</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>95</td>

<td rowspan="2">3.28.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>96</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>97</td>

<td>3.31.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>98</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="3"></td><td>The amino acid sequence coding for the heavy chain variable region</td><td>99</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>100</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>101</td>

<td rowspan="4">3.31.2</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>102</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>103</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>104</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>105</td>

<td rowspan="4">3.32</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>106</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>107</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>108</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>109</td>

<td rowspan="4">3.33</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>110</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>111</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>112</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>113</td>

<td rowspan="4">3.34</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>114</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>115</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>116</td>

<td>The amino acid sequence coding for the variable region of the chain</td><td>117</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td></td><td>light</td><td></td>

<td rowspan="2">3.35</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>118</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>119</td>

<td rowspan="4">3.37</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>120</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>121</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>122</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>123</td>

<td rowspan="4">3.39</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>124</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>125</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>126</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>127</td>

<td rowspan="4">340</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>128</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>129</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>130</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>131</td>

<td rowspan="4">3.41</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>132</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>133</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>134</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>135</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="4">3.42</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>136</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>137</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>138</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>139</td>

<td rowspan="4">4.2</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>140</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>141</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>142</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>143</td>

<td rowspan="4">4.3</td><td>&gt; Nucleotide sequence encoding the heavy chain variable region</td><td>144</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>145</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>146</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>147</td>

<td rowspan="2">4.4</td><td>Nucleotide sequence coding for the light chain variable region</td><td>148</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>149</td>

<td rowspan="4">4.5</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>150</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>151</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>152</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>153</td>

<td>4.6</td><td>A nucleotide sequence encoding a variable chain region</td><td>154</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="2"></td><td>heavy</td><td></td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>155</td>

<td rowspan="2">4.7</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>156</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>157</td>

<td rowspan="4">4.8</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>158</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>159</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>160</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>161</td>

<td rowspan="4">4.9</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>162</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>163</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>164</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>165</td>

<td rowspan="4">4.11</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>166</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>167</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>168</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>169</td>

<td rowspan="3">4.13</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>170</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>171</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>172</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>173</td>

<td rowspan="4">4.14</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>174</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>175</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>176</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>177</td>

<td rowspan="4">4.15</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>178</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>179</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>180</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>181</td>

<td rowspan="4">4.16</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>182</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>183</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>184</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>185</td>

<td rowspan="4">4.18</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>186</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>187</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>188</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>189</td>

<td rowspan="2">5.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>190</td>

<td>The amino acid sequence coding for the variable region of the chain</td><td>191</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="3"></td><td>heavy</td><td></td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>192</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>193</td>

<td rowspan="2">5.2</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>194</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>195</td>

<td rowspan="2">5.2.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>196</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>197</td>

<td rowspan="2">5.3</td><td>Nucleotide sequence coding for the light chain variable region</td><td>198</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>199</td>

<td rowspan="2">5.4</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>200</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>201</td>

<td rowspan="2">5.5</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>202</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>203</td>

<td rowspan="4">5.6</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>204</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>205</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>206</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>207</td>

<td rowspan="2">5.7</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>208</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>209</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="4">5.8</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>210</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>211</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>212</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>213</td>

<td rowspan="2">5.9</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>214</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>215</td>

<td rowspan="4">5.10</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>216</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>217</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>218</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>219</td>

<td rowspan="4">5.11</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>220</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>221</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>222</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>223</td>

<td rowspan="4">5.12</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>224</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>225</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>226</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>227</td>

<td>5.13.1</td><td>A nucleotide sequence encoding a variable chain region</td><td>228</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="4"></td><td>heavy</td><td></td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>229</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>230</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>231</td>

<td rowspan="2">5.14.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>232</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>233</td>

<td rowspan="4">5.15</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>234</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>235</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>236</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>237</td>

<td rowspan="4">5.16.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>238</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>239</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>240</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>241</td>

<td rowspan="4">5.17</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>242</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>243</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>244</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>245</td>

<td>5.18</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>246</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="3"></td><td>The amino acid sequence coding for the heavy chain variable region</td><td>247</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>248</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>249</td>

<td rowspan="2">5.19</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>250</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>251</td>

<td rowspan="2">5.20</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>252</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>253</td>

<td rowspan="4">5.21</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>254</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>255</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>256</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>257</td>

<td rowspan="4">5.22</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>258</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>259</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>260</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>261</td>

<td rowspan="4">5.23</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>262</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>263</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>264</td>

<td>The amino acid sequence coding for the variable region of the chain</td><td>265</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td></td><td>light</td><td></td>

<td rowspan="4">5.24</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>266</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>267</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>268</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>269</td>

<td rowspan="2">5.25</td><td>Nucleotide sequence coding for the light chain variable region</td><td>270</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>271</td>

<td rowspan="2">5.26</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>272</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>273</td>

<td rowspan="2">5.27</td><td>Nucleotide sequence coding for the light chain variable region</td><td>274</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>275</td>

<td rowspan="4">5.28.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>276</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>277</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>278</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>279</td>

<td rowspan="4">5.29</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>280</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>281</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>282</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>283</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="4">5.30</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>284</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>285</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>286</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>287</td>

<td rowspan="4">5.31</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>288</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>289</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>290</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>291</td>

<td rowspan="2">5.33</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>292</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>293</td>

<td rowspan="2">5.34</td><td>Nucleotide sequence coding for the light chain variable region</td><td>294</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>295</td>

<td rowspan="4">5.35.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>296</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>297</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>298</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>299</td>

<td rowspan="3">5.36</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>300</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>301</td>

<td>A nucleotide sequence encoding a variable chain region</td><td>302</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td></td><td>light</td><td></td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>303</td>

<td></td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>304</td>

<td rowspan="2">5.37</td><td>The amino acid sequence coding for the heavy chain variable region</td><td>305</td>

<td rowspan="2">Nucleotide sequence coding for the light chain variable region</td><td rowspan="2">306</td>

<td></td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>307</td>

<td></td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>308</td>

<td rowspan="2">5.38</td><td>The amino acid sequence coding for the heavy chain variable region</td><td>309</td>

<td rowspan="2">Nucleotide sequence coding for the light chain variable region</td><td rowspan="2">310</td>

<td></td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>311</td>

<td></td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>312</td>

<td rowspan="2">5.39.1</td><td>The amino acid sequence coding for the heavy chain variable region</td><td>313</td>

<td rowspan="2">Nucleotide sequence coding for the light chain variable region</td><td rowspan="2">314</td>

<td></td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>315</td>

<td></td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>316</td>

<td rowspan="2">5.40.2</td><td>The amino acid sequence coding for the heavy chain variable region</td><td>317</td>

<td rowspan="2">Nucleotide sequence coding for the light chain variable region</td><td rowspan="2">318</td>

<td></td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>319</td>

<td>5.41.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>320</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="3"></td><td>The amino acid sequence coding for the heavy chain variable region</td><td>321</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>322</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>323</td>

<td rowspan="4">5.43</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>324</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>325</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>326</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>327</td>

<td rowspan="4">5.44</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>328</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>329</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>330</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>331</td>

<td rowspan="4">5.45</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>332</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>333</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>334</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>335</td>

<td rowspan="2">5.46</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>336</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>337</td>

<td rowspan="2">5.47</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>338</td>

<td>The amino acid sequence coding for the variable region of the chain</td><td>339</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td></td><td>heavy</td><td></td>

<td rowspan="4">5.48</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>340</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>341</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>342</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>343</td>

<td rowspan="2">5.51</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>344</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>345</td>

<td rowspan="4">5.52</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>346</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>347</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>348</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>349</td>

<td rowspan="4">5.52.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>350</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>351</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>352</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>353</td>

<td rowspan="2">5.53</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>354</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>355</td>

<td rowspan="2">5.54.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>356</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>357</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="2"></td><td>Nucleotide sequence coding for the light chain variable region</td><td>358</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>359</td>

<td rowspan="2">5.55</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>360</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>361</td>

<td rowspan="4">5.56.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>362</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>363</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>364</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>365</td>

<td rowspan="4">5.58</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>366</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>367</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>368</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>369</td>

<td rowspan="2">5.59</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>370</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>371</td>

<td rowspan="4">5.60</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>372</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>373</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>374</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>375</td>

<td>5.61</td><td>A nucleotide sequence encoding a variable chain region</td><td>376</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="4"></td><td>heavy</td><td></td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>377</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>378</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>379</td>

<td rowspan="4">5.62.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>380</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>381</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>382</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>383</td>

<td rowspan="4">5.64</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>384</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>385</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>386</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>387</td>

<td rowspan="4">5.66</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>388</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>389</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>390</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>391</td>

<td rowspan="3">5.67</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>392</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>393</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>394</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>395</td>

<td rowspan="2">5.68</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>396</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>397</td>

<td rowspan="2">5.70</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>398</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>399</td>

<td rowspan="4">5.71</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>400</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>401</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>402</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>403</td>

<td rowspan="4">5.72</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>404</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>405</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>406</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>407</td>

<td rowspan="4">5.73</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>408</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>409</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>410</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>411</td>

<td rowspan="2">5.74</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>412</td>

<td>The amino acid sequence coding for the variable region of the chain</td><td>413</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="3"></td><td>heavy</td><td></td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>414</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>415</td>

<td rowspan="2">5.75</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>416</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>417</td>

<td rowspan="4">576</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>418</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>419</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>420</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>421</td>

<td rowspan="2">5.77</td><td>Nucleotide sequence coding for the light chain variable region</td><td>422</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>423</td>

<td rowspan="4">5.78</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>424</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>425</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>426</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>427</td>

<td rowspan="4">5.78.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>428</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>429</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>430</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>431</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="2">5.79</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>432</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>433</td>

<td rowspan="4">5.80</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>434</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>435</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>436</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>437</td>

<td rowspan="4">5.81</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>438</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>439</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>440</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>441</td>

<td rowspan="4">5.82</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>442</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>443</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>444</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>445</td>

<td rowspan="2">5.83</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>446</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>447</td>

<td rowspan="3">5.83.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>448</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>449</td>

<td>A nucleotide sequence encoding a variable chain region</td><td>450</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td></td><td>light</td><td></td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>451</td>

<td></td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>452</td>

<td rowspan="2">5.86.1</td><td>The amino acid sequence coding for the heavy chain variable region</td><td>453</td>

<td rowspan="2">Nucleotide sequence coding for the light chain variable region</td><td rowspan="2">454</td>

<td></td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>455</td>

<td></td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>456</td>

<td rowspan="2">5.87</td><td>The amino acid sequence coding for the heavy chain variable region</td><td>457</td>

<td rowspan="2">Nucleotide sequence coding for the light chain variable region</td><td rowspan="2">458</td>

<td></td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>459</td>

<td></td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>460</td>

<td rowspan="2">5.88</td><td>The amino acid sequence coding for the heavy chain variable region</td><td>461</td>

<td rowspan="2">Nucleotide sequence coding for the light chain variable region</td><td rowspan="2">462</td>

<td></td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>463</td>

<td></td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>464</td>

<td rowspan="2">5.88.1</td><td>The amino acid sequence coding for the heavy chain variable region</td><td>465</td>

<td rowspan="2">Nucleotide sequence coding for the light chain variable region</td><td rowspan="2">466</td>

<td></td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>467</td>

<td>5.88.3</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>468</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="3"></td><td>The amino acid sequence coding for the heavy chain variable region</td><td>469</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>470</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>471</td>

<td rowspan="2">5.89</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>472</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>473</td>

<td rowspan="4">5.90</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>474</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>475</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>476</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>477</td>

<td rowspan="2">5.91</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>478</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>479</td>

<td rowspan="4">5.92</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>480</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>481</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>482</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>483</td>

<td rowspan="2">5.93</td><td>Nucleotide sequence coding for the light chain variable region</td><td>484</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>485</td>

<td rowspan="2">5.94</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>486</td>

<td>The amino acid sequence coding for the variable region of the chain</td><td>487</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td></td><td>heavy</td><td></td>

<td rowspan="2">5.95</td><td>Nucleotide sequence coding for the light chain variable region</td><td>488</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>489</td>

<td rowspan="4">5.97</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>490</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>491</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>492</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>493</td>

<td rowspan="2">5.99</td><td>Nucleotide sequence coding for the light chain variable region</td><td>494</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>495</td>

<td rowspan="4">5.101.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>496</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>497</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>498</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>499</td>

<td rowspan="2">5.102</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>500</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>501</td>

<td rowspan="4">5.103.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>502</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>503</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>504</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>505</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="2">5.104</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>506</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>507</td>

<td rowspan="2">5.106</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>508</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>509</td>

<td rowspan="2">5.107</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>510</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>511</td>

<td rowspan="4">5.108.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>512</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>513</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>514</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>515</td>

<td rowspan="4">5.109</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>516</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>517</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>518</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>519</td>

<td rowspan="4">5.111</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>520</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>521</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>522</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>523</td>

<td>5.112</td><td>A nucleotide sequence encoding a variable chain region</td><td>524</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td rowspan="2"></td><td>heavy</td><td></td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>525</td>

<td rowspan="2">5.114</td><td>Nucleotide sequence coding for the light chain variable region</td><td>526</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>527</td>

<td rowspan="4">5.115</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>528</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>529</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>530</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>531</td>

<td rowspan="2">6.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>532</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>533</td>

<td rowspan="4">6.2</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>534</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>535</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>536</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>537</td>

<td rowspan="4">6.3.1</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>538</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>539</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>540</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>541</td>

<td>6.4</td><td>Nucleotide sequence coding for the light chain variable region</td><td>542</td>

EP 1 838 733B1

<td>ID mAb Nr:</td><td>Sequence</td><td>SEQ ID No:</td>

<td></td><td>The amino acid sequence coding for the light chain variable region</td><td>543</td>

<td rowspan="2">6.5</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>544</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>545</td>

<td rowspan="4">6.6</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>546</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>547</td>

<td>Nucleotide sequence coding for the light chain variable region</td><td>548</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>549</td>

<td rowspan="2">6.7</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>550</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>551</td>

<td rowspan="2">6.8</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>552</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>553</td>

<td rowspan="2">6.9</td><td>Nucleotide sequence encoding the heavy chain variable region</td><td>554</td>

<td>The amino acid sequence coding for the heavy chain variable region</td><td>555</td>

<td rowspan="2">6.10</td><td>Nucleotide sequence coding for the light chain variable region</td><td>556</td>

<td>The amino acid sequence coding for the light chain variable region</td><td>557</td>

Definitions [0053] Unless defined otherwise, all technical and scientific terms used in the present description have the same meanings as commonly understood by experts. Furthermore, unless the context requires otherwise, the concepts in the singular shall include the plural and the plural shall be singular. In general, terminology used in connection with, and techniques of cell and tissue culture, molecular biology and chemistry

EP 1 838 733 B1 protein and oligo- or polynucleotides and the hybridization described herein are well known and commonly used in the art.

[0054] Standard techniques are used in recombinant DNA methods, oligonucleotide synthesis and tissue culture and transformation (e.g., electroporation, lipofection). Enzymatic reactions and purification techniques are performed according to the manufacturer's requirements or as is usual in the art or as described herein. The following techniques and procedures are generally carried out in accordance with conventional methods well known in the art and as described in the various general and more detailed references cited and discussed in the present specification. See. e.g. Sarnbrook et al. Molecular Cloning: A Laboratory Manual (3rd edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor NY (2001)).

[0055] The nomenclature used in connection with, and the laboratory and analytical chemistry, synthetic organic chemistry and medical and pharmaceutical chemistry techniques described herein are well known and commonly used in the art. Standard techniques are used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients.

[0056] As used in accordance with the present disclosure, the following terms, unless otherwise indicated, are to be understood as having the following meanings:

[0057] The antagonist may be a polypeptide, a nucleic acid, a hydrocarbon, a fat, a low molecular weight compound, oligonucleotide, oligopeptide, interference RNA (RNAi), antisense, recombinant protein, antibody or conjugated or fusion proteins thereof. To learn about RNAi, see Milhavet O, Gary DS, Mattson MP. (Pharmacol Rev. 2003 Dec; 55 (4): 629-48. Review.), And with antisense see Opalinska JB, Gewirtz AM. (Sci STKE. 2003 Oct 28; 2003 (206): pe47.) [0058] The disease-related angiogenesis may be abnormal, undesirable or pathological angiogenesis, for example angiogenesis associated with a tumor. The diseases associated with angiogenesis include, but are not limited to, non-solid tumors such as leukemia, multiple myeloma or lymphoma, and solid tumors such as melanoma, small cell lung cancer, non-small cell lung cancer, glioma,

[0059] The compound refers to any low molecular weight compound having a molecular weight less than about 2,000 Daltons. [0060] The term "Ang-2" refers to the molecule Angiopoietin-2.

[006] The term "neutralizing" with respect to an antibody refers to the ability of an antibody to eliminate or significantly reduce the activity of a target antigen. Accordingly, a "neutralizing" anti-Ang-2 antibody

EP 1 838 733 B1 is able to eliminate or significantly reduce Ang-2 activity. A neutralizing Ang-2 antibody can, for example, act by blocking the binding of Ang-2 to its Tie2 receptor. By blocking this binding, Tie2 mediated signal transduction can be completely or substantially eliminated. Ideally, a neutralizing anti-Ang2 antibody inhibits angiogenesis.

[0062] The term "isolated polynucleotide" as used herein is intended to mean a polynucleotide that has been isolated from its naturally occurring environment. Such polynucleotides may be genomic, cDNA or synthetic. The isolated polynucleotides are preferably not associated with all or part of the polynucleotides with which they bind in nature. Isolated polynucleotides may be operably linked to another polynucleotide with which they are not linked in nature. In addition, isolated polynucleotides preferably do not occur in nature as part of a larger sequence.

[0063] The term "isolated protein" as used 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, artificial source or a combination thereof, and which "isolated protein" due to its origin, source or derivation (1) is not associated with proteins found in nature, (2 ) is free of other proteins from the same source, e.g. free from mouse proteins, (3) is expressed in a cell of another species or (4) is not found in nature. [0064] The term "polypeptide" is used herein as a generic term to refer to native protein, fragments or analogs of a polypeptide sequence. Thus, the native protein, fragments and analogs are species of the polypeptide type. Preferred polypeptides of the invention include human immunoglobulin heavy chain molecules and human kappa light chain immunoglobulin molecules, as well as antibody molecules formed by combinations comprising immunoglobulin heavy chain molecules with immunoglobulin light chain molecules, such as immunoglobulin kappa or lambda light chain molecules, and vice versa, as well also their fragments and analogs. Preferred polypeptides of the invention may also comprise only immunoglobulin heavy chain human molecules or fragments thereof. as well as antibody molecules formed by combinations comprising immunoglobulin heavy chain molecules with immunoglobulin light chain molecules, such as immunoglobulin kappa or lambda light chain molecules and vice versa, as well as fragments and analogs thereof. Preferred polypeptides of the invention may also comprise only immunoglobulin heavy chain human molecules or fragments thereof. as well as antibody molecules formed by combinations comprising immunoglobulin heavy chain molecules with immunoglobulin light chain molecules, such as immunoglobulin kappa or lambda light chain molecules and vice versa, as well as fragments and analogs thereof. Preferred polypeptides of the invention may also comprise only immunoglobulin heavy chain human molecules or fragments thereof.

[0065] The term "naturally occurring" as used herein to an object refers to the fact that an object can be found in nature. For example, a polypeptide and polynucleotide sequence present in an organism (including a virus) that can be isolated from a source in nature and which has not been deliberately modified by a human in a laboratory or otherwise naturally occurring.

[0066] The term "operably linked", as used herein, refers to the position of components described in the following which are in a relationship that enables them to function in the intended manner. For example, a control sequence "operably linked" to a coding sequence is linked in such a way,

It is believed that the expression of the coding sequence is achieved under conditions comparable to the control sequences.

[0067] The term "control sequence," as used herein, refers to polynucleotide sequences that are necessary either to perform or to affect the expression and processing of the coding sequences to which they are associated. The nature of such control sequences varies depending on the host organism; in prokaryotes, such control sequences generally include a promoter, a ribosome binding site and a transcription termination sequence; in eukaryotes, such control sequences may generally include promoters, enhancers, introns, transcription termination sequences, polyadenylation signaling sequences, and 5 'and 3' untranslated regions. The term "control sequences" is intended to include at least all components,

The term &amp; quot; polynucleotide, &amp; quot; as used herein, means a polymeric form of at least 10 bases in length, or ribonucleotides, or deoxynucleotides or modified forms of any type of nucleotide, or RNA-DNA heteroduplexes. The term includes single- and double-stranded DNA forms.

[0069] The term "oligonucleotide" as used herein includes naturally occurring and modified nucleotides joined together by naturally occurring and non-naturally occurring bonds. Oligonucleotides are a subset of polynucleotides generally including a length of 200 bases or less. The oligonucleotides are preferably 10 to 50 bases long, and most preferably 12, 13, 14, 15, 16, 17, 18, 19 or 20 to 40 bases long. Oligonucleotides are generally single-stranded, e.g. for probes; although oligonucleotides may be double-stranded, e.g. for use in the construction of a gene mutant. Oligonucleotides may be sense or antisense oligonucleotides.

[0070] The term "naturally occurring nucleotides" as used herein includes deoxyribonucleotides and ribonucleotides. The term "modified nucleotides" as used herein includes nucleotides with modified or substituted sugar groups and the like. The term "oligonucleotide linkages" as used herein includes oligonucleotide linkages such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoranilinothioate, phosphoranilidate, phosphoramidate 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. Patent No. 5,151,510; Uhlmann and Peyman Chemical Reviews 90: 543 (1990). includes a detection label if desired.

[0071] The term "selectively hybridize" as used herein means to bind detectably and selectively. Polynucleotides, oligonucleotides and fragments thereof selectively hybridize to nucleic acid strands under hybridization and washing conditions that minimize significant amounts of detectable binding to nonspecific nucleic acids. To obtain the conditions for selective hybridization, very stringent conditions can be used because it is known that polynucleotides, oligonucleotides or antibody fragments and the nucleotide sequence of interest will have at least 80%, and more typically a higher degree of homology of at least 85%, 90%, 95 %, 99% and 100%.

[0072] Two amino acid sequences are "homologous" if there is partial or complete identity between their sequences. For example, 85% homology means that 85% of amino acids are identical when two sequences are aligned to match each other as closely as possible. When maximizing the match, breaks are allowed (in one of two matching sequences); breaks of 5 or less are preferred, and more preferably 2 or less. Alternatively and preferably, two protein sequences (or polypeptide sequences derived therefrom at least 30 amino acids long) are homologous, in the sense that the term is used herein, if they have an alignment score equal to or greater than 5 (in standard deviation units) using the ALIGN program with a mutational data matrix and a break penalty of 6 or more. See. Dayhoff, MO, at Atlas of Protein Sequence and Structure, pp. 101-110 (Volume 5, National Biomedical Research Foundation (1972)) and Appendix 2 to this volume, pp. 1-10. The two sequences or parts thereof are more preferably homologous if their amino acids are more than or equal to 50% identical with optimal alignment using the ALIGN program. It will be appreciated that there may be different regions of homology between the two orthologous sequences. For example, functional sites in mouse and human orthologs may have a higher degree of homology than non-functional regions. 101-110 (Volume 5, National Biomedical Research Foundation (1972)) and Appendix 2 to this volume, pp. 1-10. The two sequences or parts thereof are more preferably homologous if their amino acids are more than or equal to 50% identical with optimal alignment using the ALIGN program. It will be appreciated that there may be different regions of homology between the two orthologous sequences. For example, functional sites in mouse and human orthologs may have a higher degree of homology than non-functional regions. 101-110 (Volume 5, National Biomedical Research Foundation (1972)) and Appendix 2 to this volume, pp. 1-10. The two sequences or parts thereof are more preferably homologous if their amino acids are more than or equal to 50% identical with optimal alignment using the ALIGN program. It will be appreciated that there may be different regions of homology between the two orthologous sequences. For example, functional sites in mouse and human orthologs may have a higher degree of homology than non-functional regions. that there may be different regions of homology between two orthologous sequences. For example, functional sites in mouse and human orthologs may have a higher degree of homology than non-functional regions. that there may be different regions of homology between two orthologous sequences. For example, functional sites in mouse and human orthologs may have a higher degree of homology than non-functional regions.

[0073] The term "refers to" is used herein in the sense that the polynucleotide sequence is homologous (i.e., is identical, not closely related evolutionarily) to all or part of the polynucleotide reference sequence, or that the polypeptide sequence is identical to the polypeptide reference sequence.

[0074] In distinction, the term "complementary to" is used herein to mean that the complementary sequence is homologous to all or part of the polynucleotide reference sequence. For purposes of illustration, the nucleotide sequence "TAtAC" corresponds to the reference sequence "TATAC" and is complementary to the reference sequence "GTATA".

[0075] The following terms are used to describe the relationship between two or more polynucleotide or amino acid sequences: "reference sequence", "comparison frame", "sequence match", "percent sequence match", and "substantial similarity". "Sequence

Sequence comparisons between two (or more) molecules are usually performed by comparing the sequence of two molecules in a "comparison frame" to identify and compare local regions of sequence similarity. A "comparison frame" as used herein refers to a conceptual segment of at least about 18 contiguous nucleotide positions or 6 amino acids, wherein the polynucleotide sequence or amino acid sequence is compared to a reference sequence comprising at least 18 contiguous nucleotides or 6 amino acids, and wherein the polynucleotide sequence in the comparison frame may contain additions, deletions, substitutions and the like (i.e. gaps) representing 20 percent or less relative to the reference sequence (which contains no addition or deletion) for optimal alignment of the two sequences. Optimal alignment of the sequences to align the comparison frame can be performed 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), a way of looking for similarities between Pearson and Lipman, Proc. Natl. Acad. Sci. (USA) 85: 2444 (1988), computer implementations of these algorithms (GaP, BESTFIT, FASTA and TfAsTA in Wisconsin Genetics Software Package Release 7.0, (Genetics Computer Group, 575 Science Dr., Madison, Wis.), Geneworks or MACVECTOR®) or by testing and selecting the best alignment (i.e.

[0076] The term "sequence identity" means that two polynucleotides or amino acid sequences are identical (i.e., on a nucleotide-isotope-nucleotide or residue-with-a-residue basis) throughout the comparison frame. The term "percent sequence identity" is calculated by comparing two optimally aligned sequences in the comparison frame, determining the number of positions in which identical nucleic acid bases (e.g., A, T, C, G, U or I) or amino acid residues occur in both sequences to obtain the number of matching items, dividing the number of matching items by the total number of positions in the comparison frame (i.e., frame size) and multiplying the result by 100 to obtain a percent identity

EP 1 838 733B1 sequence. The terms "substantial identity" as used herein means a trait of a nucleotide 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 identity sequences compared to the reference sequence in a comparison frame of at least 18 nucleotide positions (6 amino acids), often in a frame of at least 24-48 nucleotide positions (8-16 amino acids) in which the percent sequence identity is calculated by comparing the reference sequence with a sequence that can include deletions or additions that add up to 20 percent or less of the reference sequence in the comparison frame.

[0077] As used herein, twenty typical amino acids and their abbreviations are consistent with the customary use. See. Immunology - A Synthesis (2nd Edition, ES Golub and DR Gren, Eds., Sinauer Associates, Sunderland, Mass. (1991)). Stereoisomers (e.g., D-amino acids) of twenty typical amino acids, unnatural amino acids such as α, α disubstituted amino acids, N-alkylamino acids, lactic acid and other atypical amino acids can also be suitable components of the polypeptides of the present invention. Examples of unconventional amino acids include: 4-hydroxyproline, γ-carboxyglutamate, ε-Ν, Ν, Νtrimylolizine, ε-N-acetyl lysine, O-phosphoserine, N-acetylserine, Nformylmethionine, 3-methylhistidine, 5-hydroxylysine, σ-N-methylarginine and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the Way direction is the amino acid end direction, and the right direction is the carboxyl terminus direction, according to standard use and convention.

[0078] 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 5 'to 3' direction of the addition of nascent RNA transcripts is defined as the direction of transcription; sequence regions on DNA strands with the same sequence as RNA, and which are 5 'to the 5' end of the RNA transcript are referred to as "upstream" sequences, sequence regions on DNA strands having the same sequence as RNA, and which are 3 ' up to the 3 'end of the RNA transcript are referred to as "downstream" sequences.

[0079] With respect to polypeptides, the term "substantial identity" means that two peptide sequences, when optimally aligned, such as by using GAP or BESTFIT programs using the 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, the positions of residues that are not identical differ by conservative amino acid substitutions. Conservative amino acid substitutions refer to the interchangeability of residues

EP 1 838 733 B1 having similar side chains. For example, a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine and isoleucine; the group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having side chains containing amides is asparagine and glutamine; the group of amino acids having aromatic side chains is phenylalanine, tyrosine and tryptophan; the group of amino acids having basic side chains is lysine, arginine and histidine; a group of amino acids having sulfur-containing side chains is cysteine ​​and methionine. Preferred groups of conservative amino acid substitutions are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid - aspartic acid and asparagine-glutamine.

[0080] As discussed herein, small changes in the amino acid sequences of the antibody or immunoglobulin molecules fall within the scope of the present invention, provided that the changes in the amino acid sequence maintain at least 75%, more preferably at least 80%, 90%, 95%, and most preferably 99% sequence identity with the antibody or immunoglobulin molecules described herein. In particular, conservative amino acid substitutions are considered. Conservative replacements are those that occur within the family of amino acids that have associated side chains. Genetically encoded amino acids are generally divided into families: (1) acidic = aspartic acid glutamic acid; (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, which are an aliphatic-hydroxyl family; asparagine and glutamine, which are an amide containing family; alanine, valine, leucine and isoleucine, which constitute an aliphatic family; and phenylalanine, tryptophan and tyrosine, which are an aromatic family. For example, it is reasonable to expect that a single conversion of leucine to isoleucine or valine, aspartic acid to glutamine, threonine to serine, or similar amino acid exchange with a structurally similar amino acid will not have a major impact on the binding function or traits of the resulting molecule, especially if the replacement does not include the amino acid in the skeleton. By examining the specific activity of a polypeptide derivative, it is easy to see if an amino acid change results in a functional peptide. The tests are described in detail. Fragments or analogs of antibody or immunoglobulin molecules can be readily prepared by those skilled in the art. Preferred amino-terminal or carboxyl-terminal fragments or analogs occur near boundaries or functional domains. Structural and functional domains can be identified by comparing the nucleotide and amino acid sequence data with public or proprietary sequence databases. Preferably, it is used Preferred amino-terminal or carboxyl-terminal fragments or analogs occur near boundaries or functional domains. Structural and functional domains can be identified by comparing the nucleotide and amino acid sequence data with public or proprietary sequence databases. Preferably, it is used Preferred amino-terminal or carboxyl-terminal fragments or analogs occur near boundaries or functional domains. Structural and functional domains can be identified by comparing the nucleotide and amino acid sequence data with public or proprietary sequence databases. Preferably, it is used

Computer comparison methods to identify sequence motifs or predicted protein conformation domains that exist in another protein of known structure and / or function. There are known methods for identifying protein sequences that fold to a known three-dimensional structure. Bowie et al. Science 253: 164 (1991). Thus, the following examples show that those skilled in the art can easily recognize sequence motifs and structural conformations that can be used to define structural and functional domains compatible with the antibodies described herein.

[0081] Preferred amino acid substitutions are those that (1) reduce susceptibility to proteolysis, (2) limit susceptibility to oxidation, (3) alter binding affinity in protein complex formation, (4) alter binding affinity and (4) impart or modify other physicochemical or functional properties of such analogs. Analogs may include various sequence mutations other than the naturally occurring peptide sequence. For example, a single or more amino acid substitution (preferably a conservative amino acid substitution) may be introduced in the natural sequence, preferably in the polypeptide fragment outside the domain (s) forming intermolecular linkages. Conservative amino acid substitution should not significantly alter the structural characteristics of the parent sequence (e.g. a replacement amino acid should not be able to break a helix that occurs in the parent sequence or destroy other types of secondary structure that characterizes the parent sequence). Examples of secondary and tertiary polypeptide structures known in the art are described in Proteins, structures and Molecular principles (Creighton, Red., W, H. Freeman and Company, New York (1934)); Introduction to protein structure (C. Branden and J. Tooze, ed., Garland Publishing, New York, N, Y. (1991)); and Thornton et al. Nature 354: 105 1991). The term "polypeptide fragment," as used herein, refers to a polypeptide that has an amino-terminal deletion and / or a carboxyl-terminal deletion, but in which the remaining amino acid sequence is identical to the corresponding position in a naturally occurring sequence derived, for example, from the full-length cDNA sequence. Fragments typically have at least 5, 6, 8 or 10 amino acids in length, preferably at least 14 amino acids in length, more preferably at least 20 amino acids in length, usually at least 50 amino acids in length, and even more preferably at least 70 amino acids in length. The term "analog", as used herein, refers to polypeptides that contain a segment of at least 25 amino acids that has substantial identity with a fragment of the deduced amino acid sequence and which has at least one of the following features: (1) specific binding to Ang. 2 under the appropriate binding conditions, (2) the ability to block the proper Ang-2 binding or (3) the ability to inhibit Ang-2 activity. Typically, polypeptide analogs contain a conservative amino acid substitution (or addition or deletion) with respect to the natural

EP 1 838 733 B1 of the existing sequence. Analogs typically have at least 20 amino acids in length, preferably at least 50 amino acids in length or more, and can often be as long as a naturally occurring full length polypeptide. [0083] Peptide analogs are commonly used in the pharmaceutical industry as non-peptide drugs with properties analogous to the properties of a standard peptide. These types of non-peptide compounds are referred to as "peptide mimetics" or "peptidomimetics" Fauchere, J. Adv. Drug Res. 15:29 (1986); Veber and Freidinger TINS ​​p.393 (1985) and Evans et al. J. Chem. 30: 1229 (1987).

Such compounds are often developed using computerized molecular modeling. Peptide mimetics that are structurally similar to therapeutically useful peptides can be used to provide an equivalent therapeutic or prophylactic effect. In general, peptidomimetics are structurally similar to a model polypeptide (i.e., a polypeptide that has a biochemical or pharmacological activity), such as a human antibody, but have one or more peptide bonds replaced optionally with a bond selected from the group consisting of: --CH2NH-- , --CH2S--, --CH2-CH2--, -CH = CH- (cis and trans), - COCH2-, -CH (OH) CH2-, and -CH2SO--, by methods well known in the art . The systematic substitution of one or more amino acids of the consensus sequence 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, restricted peptides comprising a consensus sequence or a substantially identical variation of the consensus sequence may be prepared by methods known in the art (Rizo and Glerasch Ann, Rev. Biochem. 61:87 (1992), e.g. by adding internal cysteine ​​residues capable of forming intramolecular disulfide bridges, which cyclize the peptide.

[0084] As used herein, the term "antibody" refers to a polypeptide or group of polypeptides that consist of at least one binding domain that is formed by folding polypeptide chains having three-dimensional binding spaces with internal surface shapes and charge distributions complementary to the properties antigenic determinants of the antigen. The antibody is usually in the form of a tetramer containing two identical pairs of polypeptide chains, each pair having one "light" chain and one "heavy" chain. The variable regions of each pair of light / heavy chains form the antibody binding site.

[0085] As used herein, a "targeting binding agent" is an antibody or a binding fragment thereof that preferably binds to the target site. In one embodiment, the targeted binding agent is specific for only one binding site. In other embodiments, the targeted binding agent is specific for more than one binding site. In one of

For example, the targeted binding agent may be a monoclonal antibody and the target site may be an epitope.

[0086] "Antibody fragments" of antibodies are produced by recombinant DNA techniques or by enzymatic or chemical cleansing of intact antibodies. Binding fragments include Fab, Fab ', F (ab') 2, Fv and single chain antibodies. An antibody other than the "bispecific" or "bifunctional" antibody is understood to have identical each of its binding sites. The antibody significantly inhibits receptor adhesion to the antireceptor if the excess antibody limits the amount of receptor associated with the antireceptor by at least about 20%, 40%, 60% or 80%, and more usually by more than about 85% (measured in a competitive binding assay in vitro) ).

[0087] The antibody may be an oligoclonal antibody, a monoclonal antibody, a chimeric antibody, a cDr grafted antibody, a multispecific antibody, a bispecific antibody, a catalytic antibody, a chimeric antibody, a humanized antibody, a fully human antibody, an anti-idiotype antibody, and antibodies that can be labeled in the form of soluble or bound, as well as fragments, variants or derivatives thereof, either alone or in combination with other amino acid sequences provided by known techniques. The antibody can be from any species. The term antibody also includes binding antibody fragments of the invention; exemplary fragments include Fv, Fab, Fab ', single-stranded antibody (svFC),

[0088] The term "epitope" includes any protein determinant capable of specifically binding to an immunoglobulin or T-cell receptor. Epitope determinants usually consist of chemically active surface species of molecules such as amino acids or sugar side chains and may or may not have specific three-dimensional properties. structural feature as well as specific charge characteristics. The antibody is believed to specifically bind to the antigen if the dissociation constant is &amp; lt; 1 μ, preferably &amp; lt; 100 nM, and most preferably &amp; lt; 10 nM.

[0089] The term "agent" is used herein to mean a chemical compound, a mixture of chemical compounds, a biological macromolecule or an extract made from biological materials.

[0090] "Active" or "activity" with respect to the Ang-2 polypeptide refers to a part of the Ang-2 polypeptide that has the biological or immunological activity of the native Ang-2 polypeptide. "Biological", as used herein, means a biological function that results from the activity of the native Ang-2 polypeptide. The preferred biological activity of Ang-2 includes, for example, Ang2-induced angiogenesis.

[0091] A "mammal", as used herein, refers to any animal that is considered to be a mammal. Preferably, the mammal is a human. [0092] Pickling the antibodies with an enzyme, papain, gives two identical antigen-binding fragments, known as "Fab" fragments, and an "Fc" fragment,

EP 1 838 733 B1, not having antigen-binding activity but having the ability to crystallize. Digesting antibodies with an enzyme, pepsin, results in an F (ab ') 2 fragment in which the two arms of the antibody molecule remain joined and include two antigen binding sites. The F (ab ') 2 fragment has the ability to cross-link antigen.

[0093] "Fv", when used herein, refers to a minimal antibody fragment that retains both antigen recognition sites and antigen binding sites.

[0094] "Fab", when used herein, refers to an antibody fragment that has a light chain constant domain and a heavy chain CH1 domain.

[0095] The term "mAb" refers to a monoclonal antibody.

[0096] A "liposome" when used herein refers to a small vesicle that may be useful for delivering to a mammal a drug that may comprise an Ang-2 polypeptide of the invention or an antibody to such an Ang-2 polypeptide.

[0097] A "label" or "labeled" as used herein refers to the addition of a detectable moiety to a polypeptide, for example a radioactive label, a fluorescent label, an enzyme label, a chemiluminescent label or a biotinyl group. Radioactive isotopes or radioactive nuclides may include³H ¹⁴C ¹⁵N ³⁵S ⁹⁰Y, "Tc, ¹¹¹In, 1²⁵I 13¹And, fluorescent labels may include rhodamine, lanthanide phosphors or FITC, and enzyme labels may include β-galactosidase, luciferase, alkaline phosphatase.

[0098] The term "pharmaceutical agent or drug" as used herein refers to a chemical compound or composition capable of eliciting the desired therapeutic effect when administered to a patient. Other chemical terms are used herein according to conventional usage in the art, as can be seen in the examples in The McGraw-hill Dictionary of Chemical Terms (Parker, S., Ed., McGraw-Hill, San Francisco (1985)). (1985)).

[0099] As used herein, "substantially pure" means that the substance of interest is the dominant substance present (i.e., with respect to moles it is more abundant (than any separate substance in the composition) and preferably the substantially purified fraction is a composition in of which the substance of interest comprises at least about 50 percent, based on moles) of all macromolecular substances present. In general, the substantially pure composition will comprise more than about 80 percent of all macromolecular substances present in the composition, more preferably more than about 85%, 90%, 95% and 99%. More preferably an object,

[0100] The term "patient" includes human and veterinary subjects.

EP 1 838 733B1

Human Antibodies and Humanization of Antibodies [0101] Human antibodies bypass some of the problems associated with antibodies that have murine or rat constant and / or variable regions. The presence of such proteins derived from a mouse or rat can lead to rapid clearance of the antibodies or can lead to the patient's production of an immune response against the antibody. To avoid the use of antibodies derived from a mouse or rat, human antibodies can be made by introducing functional human antibody loci into the rodent, other mammal, or animal, such that the rodent, other mammal, or other animal produces fully human antibodies.

[0102] One way to make fully human antibodies is by using strains of XenoMouse® mice that have been modified to contain configured germline fragments up to but less than 1000pz from the human heavy chain locus and the 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). XenoMouse® strains are available from Abgenix, Inc. (Fremont, CA).

[0103] The production of strains of XenoMouse® mice is further discussed and outlined in US Patent Publication US 19970923138, US 6162963, US 6075181, US 6673986, US 6158584, US 5939598, US 6657103, WO 9622380, U S6075181 US 6114598, US2005076395, US 6075181 US 6162693, US6150584, US200370185 of US publication 2003/0093820, field November 30, 2001 and U.S. Patent 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, 3068 506 B2 and 3068507 B2. See. also European Patent No. EP 0463 151 B1, grant published on June 12, 1996, International Patent Application No. WO 94/02602, published February 3, 1994, International Patent Application No. WO 96/34096, published October 31, 1996, WO 98/24393, published 11 June 1998, WO 00/76310, published December 21, 2000.

[0104] In an alternative approach, others, including GenPharm International, Inc. used a "minilocus" approach. In the minilocus approach, the exogenous Ig locus is imitated by incorporating a portion (individual genes) from the Ig locus. Thus, from one or more Vh genes, one or more Dh genes or one or more Jh genes, a mu constant region, and usually a second constant region (preferably a gamma constant region) a construct is formed to insert into the animal. This approach is described in U.S. Patent No. 5,545,807 to Surani et al., And U.S. Patent 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 for Lomberg and Kay, US 5,591,669 and 6,023.010 for Krimpenfort and Berns, U.S. Patent Nos. 5,612,205, 5,721,367 and 5,789,215 to Berns et al. and U.S. Patent No. 5,643,763 to Choi and Dunn and GenPharm International for U.S. Patent Publication No. US

EP 1 838 733B1

5569825, WO 9203919, US 5569825 US 5789650, US 5545806, US 5545806 US 5814318, WO 9425285, US 5770429.

[0105] See also European Patent No. 0 546 073 B1, International Patent Application No. 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. Patent No. 5,981,175.

[0106] See furthermore, 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).

[0107] Kirin also demonstrated the production of human antibodies from mice injected with large parts of chromosomes or whole chromosomes by microcellular fusion. See. European Patent Applications No. 773 288 and 843 961, the disclosures of which are hereby incorporated by reference. Additionally, KM mice were generated that are the result of cross-breeding of Kirin Tc mice with minarelex mice from Medarex (Humab). These mice have human IgH transchromosome of Kirin mice and the genospig kappa transgene of Genpharm mice (Ishida et al., Cloning Stern Cells, (2002) 4: 91-102). [0108] 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), ribosomal demonstration (CAT),

Preparation of Antibodies [0109] Antibodies as described herein have been prepared using XenoMouse® technology as described below. Such mice are then capable of producing human immunoglobulin molecules and antibodies and are incapable of producing mouse immunoglobulin molecules and antibodies. Technologies used to achieve this are disclosed in patents, applications and references disclosed herein in the background section. In particular, however, a preferred embodiment of the transgenic production of mice and antibodies therefrom is disclosed in US Patent Publication 2003070185 and International Patent Application No. WO 98/24893, published June 11, 1998 and WO 00/76310, published December 21, 2000. See FIG. also Mendez et al, Nature Genetics 15: 146-156 (1997), [0110] By using such technology, fully human monoclonal antibodies have been made for a number of antigens. In general, XenoMouse® mouse lines are immunized with the antigen of interest (e.g., Ang-2); hyper-immunized mice are recovered from lymphoid cells (such as B cells) and the recovered lymphocytes are fused to the myeloid cell line to prepare immortal hybridoma cell lines. These hybridoma cell lines are screened and selected to identify the hybridoma cell lines that produce antibodies to the antigen of interest. Provided herein are methods for the production of many lines hyper-immunized mice are recovered from lymphoid cells (such as B cells) and the recovered lymphocytes are fused to the myeloid cell line to prepare immortal hybridoma cell lines. These hybridoma cell lines are screened and selected to identify the hybridoma cell lines that produce antibodies to the antigen of interest. Provided herein are methods for the production of many lines hyper-immunized mice are recovered from lymphoid cells (such as B cells) and the recovered lymphocytes are fused to the myeloid cell line to prepare immortal hybridoma cell lines. These hybridoma cell lines are screened and selected to identify the hybridoma cell lines that produce antibodies to the antigen of interest. Provided herein are methods for the production of many lines which produce antibodies for the antigen of interest. Provided herein are methods for the production of many lines which produce antibodies for the antigen of interest. Provided herein are methods for the production of many lines

The hybridoma cells that produce antibodies specific for Ang-1 and Ang-2. In addition, the present invention provides the characterization of antibodies produced by such cell lines, including nucleotide and amino acid sequences of the heavy and light chains of such antibodies.

[0111] Alternatively, B cells can be tested directly instead of fused to myeloid cells to generate hybridomas. For example, CD19 + cells can be isolated from hyperimmunized XenoMouse® mice and allow them to multiply and differentiate into plasma secreting cells. Antibodies from the cell supernatant are then screened for ELISA with immunogen Ang-2. Supernatants can also be screened for immunoreactivity against Ang-2 fragments to further mimic different antibodies due to binding to domains of interest in Ang-2. Antibodies can also be screened against Ang-1, Ang-3 or Ang-4, other related human chemokines and against Ang-2 orthologs in rat, mouse and non-human primates such as the cynomolgus monkeys, to determine interspecific reactivity. B cells from Ang-2 wells to determine interspecific reactivity. B cells from wells containing antibodies of interest can be made immortal by a variety of methods, including fusion to generate hybridomas, either from the individual or from connected wells, or BEV infection or transfection with known immortality genes, and then placed in appropriate medium. Alternatively, individual antibody secreting cells with the desired specificity are then isolated using the Ang-1 or Ang-2 plate hemolysis test (see, e.g., Babcook et al., Proc. Natl Acad. Sci., 93: 784348 (1996)) . The cells directed to lysis are preferably sheep red blood cells (SRBCs) coated with the Ang-2 antigen.

[0112] In the presence of a B cell culture containing plasma cells secreting the immunoglobulin of interest and complement, platelet formation indicates the specific lysis of sheep's blood cells surrounding the plasma cell of interest via Ang-1 / Ang-2. Single antigen-specific plasma cells can be isolated from the center of the plate, and the genetic information encoding the specificity of the antibody is isolated from a single plasma cell. By using reverse transcription followed by PCR (RT-PCR), the dNAs encoding the variable regions of the antibody heavy and light chains can be cloned. Such cloned DNA may then be inserted into a suitable expression vector, preferably a vector cassette such as pcDNA, more preferably, such as an pcDNA vector comprising heavy and light chain immunoglobulin constant domains. Created with a vector

The host cells may be transfected, e.g. HEK293 cells, CHO cells, and grown in a conventional nutrient medium modified appropriately to induce transcription, select transformants, or amplify genes encoding the desired sequences.

[0113] In general, the antibodies produced by the hybridomas fused were human IgG2 heavy chains with fully human kappa or lambda light chains. The antibodies described herein have human IgG4 heavy chains as well as IgG2 heavy chains. Antibodies may also be other human isotypes, including IgG1. Antibodies had high affinities, typically having a Kd of about 10 '⁶ up to about 10 '¹² M or less, when measured by solid phase and dissolved phase techniques. Antibodies having a K D of at least 10 '' M are preferred for inhibiting Ang-1 and / or Ang-2 activity.

[0114] As will be appreciated, antibodies may be expressed in cell lines other than hybridoma cell lines. Sequences encoding individual antibodies can be used to transform a suitable mammalian host cell. Transformation may be effected by any known method of introducing polynucleotides into a host cell, e.g. by packaging polynucleotides into a virus (or viral vector) and transducing the host cell with a virus (or vector) or transfection procedures known in the art as shown in the examples in US Patent Nos. 4,399,216 , 4,912,040, 4,740,461 and 4,959,455.

[0115] The transformation procedure used depends on 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, "polybrane" mediated transfection, protoplast fusion, electroporation, encapsulation of polynucleotide (s) in liposomes and direct DNA microinjection into the nucleus.

[0116] Mammalian cell lines available as hosts for expression are well known in the art and include many immortal cell lines available from the American Type Culture Collection (ATCC), including, but not limited to, Chinese hamster ovary (CHO) cells, HeLa cells, infant hamster kidney (BHK) cells, monkey kidney (COS) cells, human hepatocellular carcinoma cells (e.g., Hep G2), human 293 kidney epithelial cells and a number of other cell lines. Particularly preferred cell lines are selected by determining which cell lines have high expression levels and producing antibodies with constitutive Ang-2 binding properties. [0117] Based on the ability of mAbs to significantly neutralize the activity of Angiopoietin-1 and Angiopoietin-2 (as shown in the Examples below), these antibodies will have therapeutic effects in the treatment of symptoms and conditions resulting from the expression of Angiopoietin-1 and / or Angiopoietin-2. In certain embodiments, the antibodies and methods herein relate to the treatment of symptoms caused by Angiopoietin-1 and / or Angiopoietin-2 angiogenesis.

[0118] Anti-Ang-2 antibodies are useful in detecting Ang-2 in patient samples and, respectively, are useful as a diagnostic tool for disease states as described herein. In addition, based on their ability to significantly neutralize Ang-2 activity (as shown in the Examples below), anti-Ang-2 antibodies have therapeutic effects in the treatment of symptoms and conditions resulting from Ang-2 expression.

Therapeutic Administration and Formulations [0119] Sterile pharmaceutical formulations of anti-Ang-2 antibodies or antibodies that bind to both Ang-1 and Ang-2 are useful for the treatment of diseases. Such formulations would inhibit the binding of Ang-2 or Ang-1 and Ang-2 to their Tie2 receptor, thereby effectively treating pathological conditions in which Ang-1 and / or Ang-2 in the plasma or tissue is abnormally elevated. Anti-Ang-2 antibodies preferably have an appropriate affinity to neutralize Ang-2 with high potency, and preferably have an adequate period of action to allow uncommon dosing to humans. The anti-Ang-1 / Ang-2 antibodies preferably have an appropriate affinity to strongly neutralize Ang-1 and Ang-2, and preferably have an adequate period of action to allow uncommon dosing to humans.

[0120] For example, sterile formulations can be formed by filtration through sterile filtering membranes before or after lyophilisation and reconstitution of the antibody. The antibody will typically be stored in lyophilized form or in solution. Therapeutic antibody compositions are generally placed in a container having a sterile access location, for example an intravenous solution bag or vial having a cap, that allows a formulation such as a plug to be pierced with a hypodermic injection needle.

[0121] The route of administration of the antibody is in accordance with known methods, e.g. by injection or infusion via intravenous, intraperitoneal, brain, intramuscular, intraocular, intra-articular, sacicular, inhalation routes or through openings in the skin or by a sustained release system as indicated below. The antibody is preferably administered continuously as a brew or a bolus injection.

[0122] The effective amount of antibody to be used therapeutically will depend, for example, on the therapeutic goals, route of administration and the condition of the patient. Accordingly, it is advantageous for the therapist to dose and change the route of administration according to the requirements for obtaining the optimal therapeutic effect. Typically, the doctor will administer the antibody until a dose is reached that achieves the desired effect. The progress of therapy can be easily monitored by conventional tests or tests described herein.

[0123] 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 lungs, preferably as a liquid or sprayed powder (lyophilized). The composition may also be administered parenterally or subcutaneously as desired. When administered systemically, the therapeutic composition should be sterile, free from factors causing fever and in an acceptable enteric solution with respect to pH, isotonicity and stability. These conditions are known to experts in the field. Briefly, the dosage formulations of the compounds described herein are prepared for storage and administration by compounding the compound having the desired degree of purity with physiologically acceptable carriers, excipients and stabilizers. Such materials are nontoxic to 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 peptides such as polyarginine, proteins such as plasma albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; 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 surface tension reducing agents, such as TWEEN, PLURONICS or polyethylene glycol. [0124] Sterile injectable compositions can be prepared according to customary pharmaceutical practice as described in Remington: The Science and Practice of Pharmacy (20th ed., Lippincott Williams &amp; Wilkens Publishers (2003)). For example, it may be desirable to dissolve and suspend the active ingredient in a carrier such as water or a naturally occurring vegetable oil such as sesame, peanut or cottonseed oil or in a synthetic fatty carrier such as ethyl oleate or the like. Buffers, preservatives and antioxidants can be included according to accepted pharmaceutical practice. it may be desirable to dissolve and suspend the active ingredient in a carrier such as water or a naturally occurring vegetable oil such as sesame, peanut or cottonseed oil or in a synthetic fatty carrier such as ethyl oleate or the like. Buffers, preservatives and antioxidants can be included according to accepted pharmaceutical practice. it may be desirable to dissolve and suspend the active ingredient in a carrier such as water or a naturally occurring vegetable oil such as sesame, peanut or cottonseed oil or in a synthetic fatty carrier such as ethyl oleate or the like. Buffers, preservatives and antioxidants can be included according to accepted pharmaceutical practice.

[0125] 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-hydroxymethyl 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)), polylactanes (U.S. Patent 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 copolymers of lactic acid-glycolic acid such as LUPRON Depot ™ (microspheres for injection consisting of

And a poly-D - (-) - 3-hydroxybutyric acid (EP 133.988).

[0126] While polymers such as ethylene-vinyl acetate and lactic acid glycolic acid enable the release of molecules over 100 days, some hydrogels release proteins in a shorter time. 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 ° C, resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies for stabilizing proteins can be developed depending on the mechanism used. For example, if the mechanism of aggregation is found to involve the intramolecular formation of SS bonds by disulfide exchange, stabilization can be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content,

[0277] [0046] Sustained release compositions also include antibody crystal preparations suspended in suitable formulations capable of retaining the crystals in suspension. For subcutaneous or enteral injection, these preparations may give a sustained release effect. Other compositions also include antibodies trapped in liposomes. Liposomes containing such antibodies are prepared by methods known per se: US 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 522,322; EP 36.676; EP 88.046; EP 143,949; 142,641; Japanese patent application 83-118008; U.S. Patents 4,485,045 and 4,544,545; and EP 1022,324.

[0128] The dosage of the antibody formulation for a given patient will be determined by the physician treating him, taking into account various factors known to affect the effects of the drugs, including severity and type of disease, weight, sex, diet, time and route of administration, other medicines and other relevant clinical factors. Therapeutically effective doses can be determined either by in vitro or in vivo methods.

[0129] The effective amount of the antibodies described herein to be used therapeutically will depend, for example, on the therapeutic objectives, route of administration and the condition of the patient. Accordingly, it is advantageous for the therapist to dose and change the route of administration according to the requirements for obtaining the optimal therapeutic effect. A typical daily dose may range from about 0.001 mg / kg up to 100 mg / kg or more, depending on the factors mentioned above. Typically, the physician will administer the therapeutic antibody until a dose is reached that achieves the desired effect. The progress of therapy can be easily monitored by conventional tests or as described herein.

[0130] It will be appreciated that administration of the therapeutic entities of the present compositions and methods will be administered with suitable carriers, excipients and other factors that are included in the formulation.

EP 1 838 733B1 for better transfer, delivery, tolerances and the like. These formulations include, for example, powders, pastes, ointments, gels, waxes, oils, fats, fat-containing vesicles (cationic and anionic) (such as Lipofectin), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions. , Carbowax type emulsions (polyethylene glycols of various molecular weights), semisolid gels and semi-solid mixtures containing Carbowax. Any of the above mixtures may be suitable for the treatment and therapy of the present invention, provided that the active ingredient in the formulation is not inactivated by the formulation and that the formulation is physiologically compatible and tolerable in a given route of administration. See. also Baldrick P. "Pharmaceutical excipient development: the need for preclinical guidance. 967-78 (2000), Powell et al. "Compendium of excipients for parenteral formulations" pDa J Pharm Sci Technol. 52: 238-311 (1998) and references therein for additional information relating to formulations, excipients and carriers well known to pharmaceutical chemists. 967-78 (2000), Powell et al. "Compendium of excipients for parenteral formulations" pDa J Pharm Sci Technol. 52: 238-311 (1998) and references therein for additional information relating to formulations, excipients and carriers well known to pharmaceutical chemists.

Combinations [0131] Anti-angiogenic therapy as defined herein can be used as the sole therapy or it may include, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more categories of antineoplastic agents:

(i) cytostatic agents such as antiestrogens (e.g. tamoxifen, toremifene, raloxifene, droloxifene and iodoxifene), estrogen receptor-lowering regulators (e.g. fulvestrant), antiandrogens (e.g. bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g. goserelin, leuprorelin and buserelin), progestogens (e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, vorazole and exemestane) and 5 * reductase inhibitors such as finasteride;

(ii) agents that inhibit invasion of tumor cells (e.g. metalloproteinase inhibitors such as marymastat and inhibitors of plasminogen urokinase receptor activator);

(iii) inhibitors of growth factor function, e.g. inhibitors including growth factor antibodies, growth factor receptor antibodies (e.g., anti-erbb2 antibody, trastuzumab [Herceptin ™] and cetuximab anti-erbb1 antibody [C225]), farnesyl transferase inhibitors, kinase inhibitors tyrosine and serine-threonine kinase inhibitors, e.g. inhibitors of the epidermal growth factor family (e.g., tyrosine kinase inhibitors of the family

EP 1 838 733B1

EGFRs such as N (3-chloro-4-fluorophenyl) -7-methoxy (3-morpholinopropoxy) -quinazoline-4-amine (gefitinib, AZD-1839), N (3-ethynyl-phenyl) -,6-bis (2-methoxy-ethoxy) -quinazoline-4-amine (erlotinib, OSI 774) and 6 acrylamide N (3-chloro-4-fluorophenyl) -7 (3-morpholinopropoxy) quinazoline-4-amine (CI 1033)), e.g. inhibitors of the platelet-derived growth factor family and, for example, hepatocyte growth factor family inhibitors;

(iv) anti-angiogenic agents such as those that inhibit vascular endothelial growth factor (e.g. anti-vascular endothelial cell factor bevacizumab [Avastin ™]), anti-receptor endothelial growth factor antibodies such as anti-KDR antibodies and anti-fltl 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 which act through other mechanisms (e.g. linomide, inhibitors) integrin function avb3 and angiostatin);

(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;

(vi) antisense therapies, for example those directed to the goals listed above, such as ISIS 2503, anti-ras anti-sense therapy;

(vii) gene therapy approaches, including, for example, approaches to replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2 (GDEPT approaches (gene-directed gene prodrug therapy) such as those using cytosine deaminase, thymidine kinase, or a bacterial nitroreductase enzyme and approaches to increase patient tolerability to chemotherapy or radiotherapy, such as gene therapy for multidrug resistance, and (viii) immunotherapeutic approaches, including, for example, ex vivo and in vivo approaches to increase the immunogenicity of tumor cells of a patient such as cytokine transfection such as interleukin 2, interleukin 4 or granulocyte and macrophage colony stimulating factor, approaches to reduce T cell energy,approaches using transfected immune cells, such as cytokine-transfected dendritic cells, approaches using cytokine-mediated tumor cell lines, and anti-idiotype antibody approaches.

[0132] Anti-angiogenic therapies can be combined with factors that inhibit the action of vascular endothelial growth factor (VEGF) (e.g. anti-vascular endothelial growth factor antibody

Bevacizumab (Avastin®), anti-receptor endothelial growth factor antibodies such as anti-KDR antibodies and anti-fltl 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) as well as compounds that act via other mechanisms (e.g. linomide, integrin integrin inhibitors and angiostatin); Anti-angiogenic therapies can be combined with factors that inhibit the tyrosine kinase activity of the vascular endothelial growth factor receptor KDR (e.g., AZD2171 or AZD6474). Additional details on AZD2171 can be found in Wedge et al (2005) Cancer Research. 65 (10): 4389-400. Additional details on AZD6474 can be found in Ryan &amp; Wedge (2005) British Journal of Cancer.

[0133] Such combined therapy can be achieved by way of simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products use the compounds of the invention or their pharmaceutically acceptable salts in the dosage range indicated above and another pharmaceutically active agent within its authorized dosage range.

EXAMPLES [0134] The following examples, including experiments carried out and results achieved, are provided for purposes of illustration only and are not to be construed as limiting to the teachings herein.

EXAMPLE 1

IMMUNIZATION AND TARIFFING

Immunization [0135] Recombinant human Ang-2 obtained from R &amp; D Systems, Inc. was used as antigen. (Minneapolis, MN Cat. No. 623-AM / CF). Ang-2 monoclonal antibodies were developed through sequential immunization of XenoMouse® mice (XenoMouse XMG2 and XMg4 strains (strain 3C-1), Abgenix, Inc. Fremont, CA). XenoMouse animals in all injections were immunized via the foot pad. The total volume of each injection was 50 μΙ per mouse, 25 μΙ per foot pad. The first injection was made using 2.35 μ0 of recombinant human Ang-2 (rhAng-2, Cat. 623AM / CF, lot # BN023202A) in Dulbecco's PBS-free DBS (DPBS) and mixed 1: 1 v / vz 10 Pg^CpG (¹⁵ 1 ^ ^ murfasy ^Mouse ^adjuvant ^Nr. Kat ³°³¹°^1; series #¹¹⁵⁵³°^42;Qiagen) per mouse. In the next 6 increasing doses, 2.35 μg of rhANG-2 was administered in the absence of DPBS-causing agents,

EP 1 838 733B1 mixed with 25 pg Adju-Phos (aluminum phosphate gel, Cat. No. 1452-250, series # 8937, HCI Biosector) and 10 pg CpG per mouse and then in the final dose increasing 2.35 pg rhAng-2 in free of DspBs-causing factors without adjuvant. 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 Titration [0136] Anti-Ang-2 antibody titers in plasma of immunized XenoMouse mice were determined by ELISA. In a nutshell, Costar Labcoat Universal Binding Polystyrene 96-well Costar Labcoat Universal Binding Polystyrene plates (Corning, Acton, MA) were coated overnight with Ang-2 (1 pg / ml) in four steps of Antigen Coating Buffer (0.1 M carbonate buffer, pH 9.6 NaHCO3 8.4 g / L). The next day, the plates were washed 3 times with washing buffer (0.05% Tween 20 in 1x PBS) using a Biotek plate washer. The plates were then blocked with blocking buffer 200 μl / well (0.5% BSA, 0.1% Tween 20, 0.01% Thimerosal in 1x PBS) and incubated at room temperature for 1 h. After blocking for 1 hour, the plates were washed 3 times washing buffer using a Biotek plate washer. Plasma XenoMouse immunized animals either from Ang-2 or from non-immunized XenoMouse animals were titrated in 0.5% BSA / PBS buffer at 1: 3 dilutions in duplicates from the original 1: 100 dilution. The last hole was left empty. These plates were incubated at room temperature for 2 h, and then washed plates 3 times with washing buffer using a Biotek plate washer. An goat anti-human Fc-specific IgG conjugated to horseradish peroxidase (HRP, Pierce, Rockford, IL) was added to a final concentration of 1 pg / ml and incubated for 1 hour at room temperature. The plates were then washed 3 times with washing buffer using a Biotek plate washer. 3 in duplicates from the original dilution 1: 100. The last hole was left empty. These plates were incubated at room temperature for 2 h, and then washed plates 3 times with washing buffer using a Biotek plate washer. An goat anti-human Fc-specific IgG conjugated to horseradish peroxidase (HRP, Pierce, Rockford, IL) was added to a final concentration of 1 pg / ml and incubated for 1 hour at room temperature. The plates were then washed 3 times with washing buffer using a Biotek plate washer. 3 in duplicates from the original dilution 1: 100. The last hole was left empty. These plates were incubated at room temperature for 2 h, and then washed plates 3 times with washing buffer using a Biotek plate washer. An goat anti-human Fc-specific IgG conjugated to horseradish peroxidase (HRP, Pierce, Rockford, IL) was added to a final concentration of 1 pg / ml and incubated for 1 hour at room temperature. The plates were then washed 3 times with washing buffer using a Biotek plate washer. Rockford, IL) was added to a final concentration of 1 pg / ml and incubated for 1 hour at room temperature. The plates were then washed 3 times with washing buffer using a Biotek plate washer. Rockford, IL) was added to a final concentration of 1 pg / ml and incubated for 1 hour at room temperature. The plates were then washed 3 times with washing buffer using a Biotek plate washer.

[0137] After washing, the plates were developed by adding chromogenic TmB medium (BioFx BStP-0100-01) for 10-20 min or until the negative control wells began to show color. The ELISA was then stopped by the addition of Stop Solution (650 nM Stop reagent for TmB (BioFx BSTP-0100-01), reconstituted with 100 ml H2O per bottle). The determined titre in each XenoMouse animal was determined based on the optical density at 650 nm and shown in Tables 2 and 3 below. The titer value is the inverse of the largest plasma dilution with an OD reading twice the background. Thus, the higher the number, the greater the humoral immune response to Ang-2.

EP 1 838 733B1

Table 2. Group 1: 10 mice (strain XMG2)

<td></td><td>After 4 injections</td><td>After 6 injections</td>

<td>Mouse ID</td><td colspan="2" rowspan="2">Reactivity at rhAng-2</td>

<td></td>

<td>0825-1</td><td>92,000</td><td>231,000</td>

<td>0825-2</td><td>56,000</td><td>212,000</td>

<td>0825-3</td><td>73,000</td><td>331,000</td>

<td>0825-4</td><td>16,000</td><td>175,000</td>

<td>0825-5</td><td>95,000</td><td>236,000</td>

<td>0825-6</td><td>27,000</td><td>119,000</td>

<td>0825-7</td><td>100,000</td><td>239.000</td>

<td>0825-8</td><td>25,000</td><td>165,000</td>

<td>0825-9</td><td>68,000</td><td>136,000</td>

<td>0825-10</td><td>120,000</td><td>264,000</td>

<td>NC</td><td>35</td><td>65</td>

<td>PC</td><td>Sensitivity: 10 ng / ml</td><td>Sensitivity: 9 ng / ml</td>

<td colspan="3">* NC = strain xmg2, ova gp2, fp * PC = goat AB, anti-huAng-2 (r &amp; D Systems, Catalog No. AF623) 1 mg / ml</td>

Table 3. Scrap 2: 10 mice (strain XMG4)

<td></td><td>After 4 injections</td><td>After 6 injections</td>

<td>Mouse ID</td><td colspan="2">Reactivity at rhAng-2</td>

<td></td><td colspan="2">Titres based on hIgG</td>

<td>0824-1</td><td>750</td><td>4,600</td>

<td>0824-2</td><td>200</td><td>5,800</td>

<td>0824-3</td><td>500</td><td>7,400</td>

<td>0824-4</td><td>225</td><td>4,700</td>

<td>0824-5</td><td>300</td><td>5,800</td>

<td>0824-6</td><td>550</td><td>7,400</td>

<td>0824-7</td><td>1,600</td><td>11,000</td>

<td>0824-8</td><td>45</td><td>2,400</td>

<td>0824-9</td><td>600</td><td>6,900</td>

<td>0824-10</td><td>225</td><td>2,300</td>

<td>NC</td><td>&lt;100</td><td>35</td>

<td>PC</td><td>Sensitivity: 12 ng / ml</td><td>Sensitivity: 8 ng / ml</td>

<td colspan="3">C = 3 O1 N128-3 C = goat AB, anti-huAng-2 (R &amp; D Systems, Catalog No. AF623) 1 mg / ml</td>

EP 1 838 733B1

EXAMPLE 2

LYMPHOCYTE RECOVERY, B-CELL ISOLATION, FUZJE AND PRODUCTION OF HYBRIDS [0138] Immunized mice were sacrificed by vertebral displacement, and lymph node harvesting was collected and pooled within each cohort. The lymphoid cells were separated by milling 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 cells was added to the cell pellet to gently but completely re-suspend the cells. Cells were labeled by incubating them with magnetic beads at 4 ° C for 15 minutes, using 100 μΙ of CD90 + magnetic beads per 100 million cells. Magnetically labeled cell suspension containing up to 10⁸ positive cells (or up to 2x10⁹ all cells) were loaded onto an LS + column and the column was washed with DMEM. The total leak was collected as the CD90 negative fraction (most of these cells were expected to be B cells).

[0139] The fusion was performed by mixing washed, enriched B cells from the above and non-secreting P3X63Ag8.653 myeloma cells ordered from ATCC, Cat. CRL 1580 (Kearney et al., J. Immunol. 123, 1979, 1548-1550) in a 1: 1 ratio. A cell mixture precipitated gently by centrifugation at 800 x g. After the supernatant was completely removed, the cells were treated with 2-4 mL of Pronase solution (CalBiochem, Cat No. 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 brought to 40 ml of the total volume using the electric cell fusion solution (ECFS, 0.3M sucrose, Sigma, Cat. No. S7903, 0.1 mM Magnesium Acetate). , Sigma, Cat. No. M2545, 0.1 mM Calcium Acidate, Sigma, Cat. No. C4705). The supernatant was removed after centrifugation and the cells resuspended in 40 ml of ECFS.⁶ cells / m ..

[0140] Electric fusion of cells was performed using a fusion generator (ECM2001 model, Genetronic, Inc., San Diego, CA). The size of the used fusion chamber was 2.0 ml using the following instrument settings:

[0141] Alignment condition: voltage: 50 V, time: 50 sec.

[0142] Film disruption at: voltage: 3000 V, time: 30 sec. [0143] After retention time: 3 sec [0144] After ECF, the cell suspensions were carefully removed from the fusion chamber under sterile conditions and transferred to a sterile tube containing the same volume of Hybridoma Culture Medium (DMEM, JRH Biosciences), 15% FBS (Hyclone), supplemented with L-glutamine, pen / strep, OPI (oxacetate, pyruvate, cow insulin) (all from Sigma) and IL-6 (Boehringer Mannheim) . The cells were incubated for 15-30 minutes at 37 ° C and then centrifuged at 400 xg (1000 rpm) for five minutes. Cells gently

The medium was resuspended in a small volume of Hybridoma Selection Medium (Hybridoma Selection Medium supplemented with 0.5 x HA (Sigma, Cat. No. A9666)) and the volume was adjusted with a larger amount of Hybridoma Selection Medium based on the final 5x10 seeding.⁶ B cells in total into a 96-well plate and 200 μΙ per well. The cells were mixed gently and pipetted into 96-well plates and allowed to grow. On day 7 or 10, half of the medium was removed and the cells were fed again with the Hybridoma Selection Medium.

EXAMPLE 3

CHOICE OF POSSIBLE ANTIBODY TEST ELISA [0145] After 14 days of culture, supernatants with hybridoma were screened for Ang-2 specific monoclonal antibodies. ELISA plates (Fisher, Cat. No. 12-565-136) were coated with human Ang-2 (2 μg / ml) at 50 μΙ / well in Coating Buffer (0.1 M Carbon Buffer, pH 9.6, NaHCO 3 8, 4 g / L), and then incubated at 4 ° C overnight. After incubation, the plates were washed 3 times with Wash Buffer (0.05% Tween 20 in PBS). 200 μL / well Blocking Buffer (0.5% bSa, 0.1% Tween 20, 0. 01% Thimerosal in 1x PBS) was added and plates were incubated at room temperature for 1 hour. After incubation, the plates were washed 3 times with Rinsing Buffer. Hybridoma supernatants of 50 μl / well were added as well as positive and negative controls and plates were incubated at room temperature for 2 hours.

[0146] After incubation, the plates were washed three times with Wash Buffer. 100 μΙ / well of goat anti-hulgGFc-HRP detection antibody (Caltag, Cat. No. H10507) was added and plates were incubated at room temperature for 1 hour. In the second screening, positive cells from the first screening were screened in two sets, one for hIgG detection and the other for human kappa Ig light chain detection (goat anti-hlg kappa-HRP (Southern Biotechnology, Cat. No. 2060-05) to demonstrate full human composition of both IgG and Ig Kappa. After incubation, the plates were washed three times^s buffer ^dfor tapping. doide^pabout ¹⁰⁰ | J^l/^dOlé^{k TM}B (^biabout^FX l_at&gt;. ^Nr Kat TMSK-0100-01) and the plates were allowed to develop for about 10 minutes (until the negative control barely started to show color). Then 50 μΙ / well of the inhibiting solution (TMB Inhibition Solution (BioFX Lab. Cat. # STPR-0100-01) was added and the plates were read on an ELlSA plate reader at 450 nm. There were 185 human fully anti-AngG2 IgG kappa antibodies.

[0147] All antibodies that bound in the ELlSA assay were screened the other way for binding to Ang-1 via EL1SA to exclude those that cross-reacted with Ang-1. ELlSA plates (Fisher Cat. No. 12-565-136) were coated with recombinant Ang-1 at 50 μΙ / well (2 μg / ml, obtained from R &amp; D

EP 1 838 733B1

Systems, Cat. 293-AN-025 / CF) in a Coating Buffer (0.1 M Carbonate Buffer, pH 9.6, NaHCO3 8.4 g / L), and then incubated at 4 ° C overnight. In the experimental conditions described here, when the recombinant Ang-1 molecule was immobilized on an ELISA plate, no antibodies binding to Ang-1 were found. However, screening in the other direction described herein has technical limitations. First, the antibodies are from line materials, but not from cloned hybridoma cells. The binding signals from a particular clone that only account for a small percentage of the line may be below the detection sensitivity threshold. Second, some epitopes in the antigen may be hidden from the antibodies in this experiment due to the small conformational changes induced by the immobilization of the antigen. Because of all these reasons, the cross-reactivity of each Ang-1 antibody was further investigated using cloned antibodies and the Biacore system (see Example 8). As described in Example 8, it was found that one clone (mAb 3.19.3) indeed has a strong cross-reactivity with human recombinant Ang-1 (Examples 8, 9 and 12).

EXAMPLE 4

ANG-2 BINDING INHIBITION WITH TIE2 [0148] As discussed above, Ang-2 exerts its biological activity through binding to the Tie2 receptor. Monoclonal antibodies that inhibited Ang-2 / Tie2 binding were identified in a competitive binding assay using a modified ELISA. The mAbs used were micro-purification products from 50 ml of extensive supernatants of hybridoma pools that were specific for Ang-2 (see Example 3). Nunc Imm 96 well plates were coated with 100 μΙ of recombinant Tie2 / Fc fusion protein (R &amp; D Systems, Inc., Cat. No. 313-TI-100) in 4 μg / ml by incubation at 4 ° C overnight. The plates were washed four times with Phosphate Salt Buffer (^PBS) on^tACJ^{and Sk}an ™^ORace^her ³⁰⁰ (SKATRON). DoM was docked^{100 μΙ}ABX blocking buffer (0.5% BSA, 0.1% Tween, 0.01% Thimerosal in PbS) for 1 hour.

[0149] Biotinylated recombinant human Ang-2 (R &amp; D Systems, Inc. Cat # BT623) at 100 ng / ml was added to each well with or without anti-Ang-2 mAbs at 100 μg / ml. The plates were incubated at room temperature for two hours before unbound molecules were washed away. Bound biotinylated Ang-2 was then detected using 100 μl / well of Streptavidin-HRP conjugate at 1: 200 by incubation at room temperature for half an hour. After washing twice, the bound Streptavidin was detected with HrP medium (R &amp; D Systems, Cat. No. DY998). The plates were incubated for 30 minutes before 450 inhibition solution (100 μΙ / well, BioFX, Cat. No. BSTP-0100-01) was added to complete the reaction. The absorbance of light at 450 nm was determined with a Spectramax Plus reader.

[0150] A soluble recombinant Tie2 / Fc protein was used as a positive control in a 10-fold molar excess over Ang-2. At this concentration, Tie2 / Fc inhibited the binding of Ang-2 to immobilized Tie2 at 80%. At this arbitrary criterion, 74 of the 175 mAbs binding to Ang-2 showed inhibitory activity. For the convenience of operation, the best 27 neutralizers were chosen for further hybridoma cloning.

[0151] Each hybridoma cell was cloned using a limiting dilution method according to standard procedures. Three sister clones were collected from each hybridoma line. From each clone, the supernatant was tested using ELISA binding to human Ang-2 and binding to the other side of Ang-1 as described above to ensure that each antibody was specific only to Ang-2. IgG concentrations were determined in the exhausting supernatants, and one clone with the highest yield from the three sister clones from each hybridoma line was selected for IgG purification. 0.5 to 1 mg of IgG was further purified from each supernatant for further characterizationeryzacji. [0152] To measure the mAbs inhibitor activities against Ang-2 binding to Tie2, the titer of purified mAbs was determined based on the best candidates using a competitive binding assay. Each mAb concentration was tested twice. The concentration-response relationship was examined by curve fitting using Graphpad PrismD graphics software (non-linear Sigmoid curve). Maximum inhibition (efficiency) and IC50 (force) were calculated using the software. Ten monoclonal antibodies that exhibited both relatively high yield and potency were selected for further investigation. The yield and potency of these 10 mAbs are listed in Table 4.

Table 4. Performance and strength of the best 10 mAbs

<td>Maple</td><td>Efficiency*</td><td>EC50 (pg / ml)</td>

<td>3.31.2</td><td>.3751</td><td>0.04169</td>

<td>5.16.3</td><td>.3279</td><td>0.08532</td>

<td>5.86.1</td><td>.3844</td><td>.1331</td>

<td>5.88.3</td><td>.4032</td><td>.1557</td>

<td>3.3.2</td><td>.3881</td><td>.1684</td>

<td>5.103.1</td><td>.2317</td><td>.3643</td>

<td>5.101.1</td><td>.3639</td><td>.3762</td>

<td>3.19.3</td><td>.3945</td><td>.7976</td>

<td>5.28.1</td><td>.3892</td><td>2698</td>

<td>5.78.3</td><td>.2621</td><td>5.969</td>

<td colspan="3">* Yield is expressed as the ratio of Ang-2 bound to mAbs (30 pg / ml) relative to no mAbs.</td>

EP 1 838 733B1

EXAMPLE 5

SORT OF ANTIBODIES [0153] Epitope sorting was performed to determine which of the anti-Ang-2 antibodies would cross-compete with the other, and thus be susceptible to binding to the same epitope on Ang-2. The sorting 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 hereby incorporated by reference in their entirety. Briefly, the Luminex beads were combined with the mouse anti-huIgG (Pharmingen # 555784) according to the protocol for linking proteins provided on the Luminex website. Previously combined beads were prepared for association with the originally unknown antibody using the following procedure and protecting the beads from light. Individual test tubes were used for each unknown supernatant. The volume of supernatant needed was calculated using the following formula: (nX2 + 10) x 50 μΙ (where n = total number of samples). The concentration of 0.1 μg / ml was used in this test. The ball stock was gently mixed and diluted in the supernatant to a concentration of 2500 each ball in 50 μΙ per well or 0.5X10.⁵ beads / ml.

[0455] Samples were incubated overnight on a shaker in the dark at room temperature.

[0155] The filter plate was pre-wet by adding 200 μl per well of washing buffer, which was then aspirated. 50 μl of each ball was added to each well of the filter plate. Samples were washed once by adding 100 μΙ / well of wash buffer and aspiration. Antigen and controls of 50 μl / well were applied to the filter plate. The plate was covered, incubated in the dark for 1 hour on a shaker, and then the samples were washed 3 times. Then 50 μΙ / well of a secondary unknown antibody was added. A concentration of 0.1 μg / ml was used for the primary antibody. The plate was then incubated in the dark for 2 hours on a shaker, and then the samples were washed 3 times. 50 μΙ / well of biotinylated mouse anti-human IgG (Pharmingen # 555785) diluted 1 were added:

[0156] Samples were washed 3 times. 50 μl / well of Streptavidin-PE at a dilution of 1: 1000 was added and the samples incubated in the dark for 15 minutes with shaking at room temperature. After passing two rinses on Luminex 100, the samples were washed 3 times. The contents in each well were resuspended in 80 μl blocking buffer. The samples were mixed carefully by repeated pipetting to resuspend the beads. The samples were then analyzed on Luminex100. The results are shown below in Table 5.

EP 1 838 733B1

Table 5. Assignments for the best 24 of Ang-2 positive antibodies in the functional test

<td>Bin 1</td><td>Bin 2</td><td>Bin 3</td><td>Bin 4</td><td>Bin 5</td><td>Bin 6</td><td>Bin 7</td><td>Bin 8</td>

<td>3.3</td><td>3.38</td><td>5.56 *</td><td>5.28</td><td>5.78</td><td>3.19</td><td>6.3</td><td>5.35</td>

<td>3.28</td><td>5.103</td><td></td><td></td><td></td><td></td><td></td><td>5.40</td>

<td>3.31</td><td colspan="7"></td>

<td>5.14</td><td>5.2</td><td colspan="6"></td>

<td>5.16</td><td></td><td colspan="6"></td>

<td>5.39</td><td colspan="7" rowspan="10"></td>

<td>5.41</td>

<td>5.49</td>

<td>5.54</td>

<td>5.62</td>

<td>5.83</td>

<td>5.86</td>

<td>5.88</td>

<td>5.101</td>

<td>5.108</td>

* Note: mAb 5.56 had a similar binding pattern as 3.38 and 5.103 with minor differences and a much weaker signal.

EXAMPLE 6

DESIGNATION CLAIMS ANTI-ANG-2 ANTIBODIES USING BIACORE ANALYSIS

Low Resolution Screening of 27 Purified Antibodies

Monoclonal [0157] To measure the affinity of the antibody for the antigen, plasmon resonance marker (SPR) or Biacore was used. For this purpose, a high density surface of a goat anti-human antibody on a CM5 Biacore chip was prepared using routine amine binding. All purified mAbs were diluted to about 8 pg / ml in HBSP running buffer containing 100 pg / ml BSA and 10 mg / mL carboxymethyl dextran. Each mAb was bound on a separate surface using a 42-second contact time and a 5-minute wash to stabilize the mAb background.

[0158] Ang-2 was injected on all surfaces at 90.9 nM for 1 minute followed by a 10-minute dissociation. prepared

Data on the binding of two references by subtracting the signal from the flow control cell and subtracting the background drift of the buffer injected just prior to Ang-2 injection. Ang-2 binding data for each mAb was normalized to the amount of mAbs bound on each surface and normalized, drift-corrected responses were determined for 27 mAbs. Data was globally fitted to the 1: 1 interaction model to determine binding kinetics. The results of kinetic analysis of Ang-2 binding at 25 ° C are listed in the table below. The mAbs were sorted from the highest to the lowest affinity.

Table 6. Screening of 27 purified monoclonal antibodies using Biacore low resolution for Ang-2

<td>A sample</td><td>Connected Quantity (RU)</td><td>k (M '¹· s¹)</td><td>kd (s-¹)</td><td>Kd (pM)</td>

<td>5.16</td><td>157</td><td>3.6 X 10⁵</td><td>1.0 X 10-5 *</td><td>27</td>

<td>5.41</td><td>152</td><td>3.6 X 105</td><td>1.0 X 10-5 *</td><td>28</td>

<td>5.35</td><td>138</td><td>3.4 X 105</td><td>1.0 X 10-5 *</td><td>29</td>

<td>3.38</td><td>143</td><td>3.4 X 105</td><td>1.0 X 10-5 *</td><td>thirty</td>

<td>5.108</td><td>66</td><td>3.2 X 105</td><td>1.0 X 10-5 *</td><td>31</td>

<td>3.3</td><td>125</td><td>3.0 X 105</td><td>1.0 X 10-5 *</td><td>33</td>

<td>5.49</td><td>260</td><td>3.0 X 105</td><td>1.0 X 10-5 *</td><td>33</td>

<td>3.28</td><td>280</td><td>2.7 X 105</td><td>1.0 X 10-5 *</td><td>37</td>

<td>5.88</td><td>65</td><td>2.7 X 105</td><td>1.0 X 10-5 *</td><td>37</td>

<td>5.28</td><td>136</td><td>2.5 X 105</td><td>1.0 X 10-5 *</td><td>40</td>

<td>5.78</td><td>222</td><td>2.4 X 105</td><td>1.0 X 10-5 *</td><td>42</td>

<td>5.39</td><td>166</td><td>2.3 X 105</td><td>1.0 X 10-5 *</td><td>43</td>

<td>5.103</td><td>127</td><td>2.2 X 105</td><td>1.0 X 10-5 *</td><td>45</td>

<td>5.13</td><td>78</td><td>2.1 X 105</td><td>1.0 X 10-5 *</td><td>47</td>

<td>5.14</td><td>471</td><td>2.0 X 105</td><td>1.0 X 10-5 *</td><td>49</td>

<td>3.31</td><td>196</td><td>1.9 X 105</td><td>1.0 X 10-5 *</td><td>51</td>

<td>5.56</td><td>144</td><td>1.9 X 105</td><td>1.0 X 10-5 *</td><td>52</td>

<td>5.2</td><td>111</td><td>1.6 X 105</td><td>1.0 X 10-5 *</td><td>62</td>

<td>5.62</td><td>126</td><td>1.5 X 105</td><td>1.0 X 10-5 *</td><td>65</td>

<td>5.54</td><td>131</td><td>1.5 X 105</td><td>1.0 X 10-5 *</td><td>66</td>

<td>6.3</td><td>221</td><td>1.4 X 105</td><td>1.0 X 10-5 *</td><td>73</td>

<td>3.19</td><td>252</td><td>9.0 X 10⁴</td><td>1.0 X 10-5 *</td><td>111</td>

<td>5.40</td><td>130</td><td>7.8 X 104</td><td>1.0 X 10-5 *</td><td>129</td>

<td>5.83</td><td>157</td><td>6.8 X 104</td><td>1.0 X 10-5 *</td><td>147</td>

EP 1 838 733B1

<td>A sample</td><td>Connected Quantity (RU)</td><td>ka (M-¹s-¹)</td><td>k_d (s-¹)</td><td>Kd (pM)</td>

<td>5.101</td><td>217</td><td>1.5 X 10⁵</td><td>8.7 X 10-5</td><td>581</td>

<td>5.86</td><td>126</td><td>1.5 X 105</td><td>1.1 X 10-⁴</td><td>744</td>

<td>5.52</td><td>114</td><td>1.3 X 105</td><td>1.0 x 10-5 *</td><td>750</td>

[0159] Asterisks next to the results of k_d for all mAbs except for mAbs 5.101 and 5.86 indicate that these kd's were kept at the same level as the best estimate of the order of magnitude of the magnitude of the slow "off-load" data. The fit model for these samples did not detect a measurable change in "off-rate" over a relatively short dissociation time, and thus required that kd be constant so that the "on-rate" data could be adjusted. This data indicated that kd's also fit well into simulations with a kd of 10 '⁶ s'¹therefore, the interactions can be 10 times or more times stronger than those given above.

[0160] Dissociation data are typically measured for 4-6 hours in high resolution kinase experiments with mAbs having affinities below 1O pM. The maximum dissociation time that can be measured without drift artifacts from the bound mAb is 20 minutes. In such a relatively short time, almost negligible signal fading at high affinity mAbs is measured, so that the estimate of kd can vary by up to two orders of magnitude.

EXAMPLE 7

DESIGNATION CLAIMS ANTI-ANG-2 ANTIBODIES USING BIACORE ANALYSIS

Sieving Ang-2 on Medium / High Resolution with the help of Three

Purified Monoclonal Antibodies [0161] Purified mAbs 5.16, 5.35 and 5.41 were diluted to about 8 pg / ml in 10 mM sodium acetate, pH 5.0. Each diluted mAb was then immobilized on another cell flow surface (CM5 Biacore chip) using routine amine binding.

[0162] To collect "on-rate" data, eight concentrations (2-fold dilutions) ranging from 90.9 - 0.71 nM Ang-2 for 90 seconds in triplicate were injected at random with several spread injections of the double reference, followed by a four-minute dissociation. The antibody surfaces were reconstituted with two 9-second pulses using 10 mM glycine-HCl, pH 1.5 after each injection cycle.

[0163] To collect off-rate data, three Ang-2 samples were injected after 90.9 nM in HBS-P current buffer containing 100 pg / ml of BSA as described above, and dissociation data were recorded for eight hours. Samples were alternately injected with three cycles of empty injections. Regeneration was carried out as described above.

[0164] Data were globally fitted to the 1: 1 interaction model with mass transport using CLAMP (David G. Myszka and Thomas Morton (1998) p "CLAMP ©: a biosensor kinetic data analysis program," TIBS 23, 149 -150). The calculated binding constants are shown in Table 7 below.

Table 7. Screening of 3 purified monoclonal antibodies using a Biacore medium resolution for Ang-2

<td>A sample</td><td>Rmax</td><td>k (M^-1s^-1)</td><td>kd (s-¹)</td><td>Kd (pM)</td>

<td>5.16</td><td>36</td><td>3.41 X 10⁵</td><td>2.77 X 10-6</td><td>8.13</td>

<td>5.35</td><td>54</td><td>5.64 X 105</td><td>1.87 X 10-6</td><td>3.31</td>

<td>5.41</td><td>44</td><td>4.69 X 105</td><td>8.31 X 10-6 *</td><td>17.7 *</td>

[0165] Significant signal fading was measured at the 8-hour dissociation time. Thanks to the dissociation data from eight hours CLAMP was able to better estimate the kd for each mAb. In this case, kd's for both 5.16 and 5.35 are of the order of 10 '⁶ s'¹.

[0166] The cross-reactivity of antibodies to Ang-1 was then tested by measuring the affinity of mAbs to Ang-1, as described in Example 8 below.

EXAMPLE 8

DETERMINATION OF ANTI-ANG-1 ANTIBODIES USING BIACORE ANALYSIS [0167] Cross-reactivity of antibodies to Ang-1 was then tested by measuring the affinity of mAbs to Ang-1. Instead of immobilizing Ang-1, as described in an ELISA-based reverse binding (Example 3), Ang-2 mAbs were immobilized on Biacore CM5 chips and the Ang-1 solution was injected to determine "on-rate" and "off-rate". ". Six mAbs were tested in this test, including 3.3.2, 3.31.2, 5.16.3, 5.86.1,

5.88.3 and 3.19.3, as described below, to determine how strongly they cross-react with Ang-1.

Screening of the Medium Resolution of the Six Purified Antibodies

Monoclonal To measure the affinity of the antibody for the antigen, surface labeled resonance plasmon resonance (SPR) or Biacore 2000 equipment was used. For this purpose, a high density goat α-human antibody surface was prepared on the cM5 Biacore chip using routine amino bonding. 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 pg / ml in the current

EP 1 838 733B1 HBS-P buffer containing 100 pg / ml BSA. The binding level of each mAb was about 150 RU. After each binding cycle, a 5-minute wash was performed to stabilize the mAb reference level.

[0169] A single Ang-1 sample diluted to 87.4 nm in the current buffer was injected per minute on all binding surfaces. No binding was detected for five mAbs, although Ang-1 was found to bind to mAb 3.19.3. The experiment was repeated by increasing the binding level of the mAb to well above 500-600 RU and by injecting 380 nM Ang-1 for one minute. Again, it was found that mAb 3.19.3 binds to Ang-1.

[0170] Since Ang-1 showed only binding activity to mAb 3.19.3, the affinity of this mAb was determined for both Ang-1 and Ang-2. Because Ang-1 showed a slow "off-rate" rate in the above developmental experiments, a mid-resolution binding experience would not record 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

IDENTIFICATION OF MAB 3.19.3 TO ANG-1 AND ANG-2 USING BIACORE HIGH RESOLUTION ANALYSIS [0171] Purified mAb 3.19.3 was diluted to 12.5 pg / ml in 10 mM sodium acetate, pH 4.0. The mAbs were then immobilized on flow cells 1-3 (CM5 Biacore chip) using routine amine linkage, leaving flow cell 4 as a reference flow cell. [0172] To collect "on rate" data, eight concentrations (2-fold dilutions) ranging from 39.8 - 0.31 nM of Ang-1 were randomly injected (in current buffer HBS-P containing 100 pg / ml BSA ) for 90 seconds (flow rate 100 pL / min) in triplicate with several injections of buffer between them to obtain a double reference, and then for 4 minutes to dissociate. The antibody surfaces were reconstituted with a 6-second pulse with 10 mM NaOH after each injection cycle. [0173] To collect off-rate data, three Ang-1 samples were injected after 19.9 nM as described above, and dissociation data were recorded for six hours. Samples were alternately injected with three cycles of empty injections. Regeneration was carried out as described above.

[0174] Data were globally fitted to the 1: 1 interaction model with mass transport included, using CLAMP (David G. Myszka and Thomas Morton (1998) "CLAMP ©: a biosensor kinetic data analysis program," TIBS 23, 149-150) .

Biacore High Resolution Study with purified MAbs 3.19.3 [0175] Purified mAb 3.19.3 was diluted to 12.5 pg / ml in 10 mM sodium acetate, pH 4.0. The mAbs were then immobilized on the cells

Flow 1 through 3 (CM5 Biacore chip) using routine amine linkage, leaving flow cell 4 as a reference flow cell. [0176] To collect "on rate" data, eight concentrations (2-fold dilutions) ranging from 30.0-0.23 nM of Ang-2 were randomly injected (in current buffer HBS-P containing 100 pg / ml BSA ) for 90 seconds (flow rate 100 pL / min) in triplicate with several injections of buffer between them to obtain a double reference, and then for 4 minutes to dissociate. The antibody surfaces were reconstituted with a 6-second pulse with 15 mM NaOH after each injection cycle. [0177] To collect off-rate data, three Ang-2 samples were injected at 15.0 nM as described above, and dissociation data were recorded for six hours. Samples were alternately injected with three cycles of empty injections. Each surface was reconstituted with a 6-second pulse with 15 mM NaOH after each long off-rate injection cycle.

[0178] The data was globally fitted to the 1: 1 interaction model with the mass transport component included, using CLAMP (David G. Myszka and Thomas Morton (1998) "CLAMP ©: a biosensor kinetic data analysis program," TIBS 23, 149-150) .

Results and Discussion: Biacore High Resolution Study on ANG-1 and

ANG-2 using MAb 3.19.3 [0179] Two independent experiments were performed with each antigen. The results are shown in Table 8 below:

Table 8. Biacore high resolution results of Ang-1 and Ang-2 binding to purified mAb 3.19.3.

<td>Antygent</td><td>ka (M^-1s^-1)</td><td>k_d (s-¹)</td><td>Kd (pM)</td>

<td>Ang-1 (1^st)</td><td>1.33 X 10 ⁵</td><td>4.05 X 10-6</td><td>30.4</td>

<td>Ang-1 (2nd^nd)</td><td>1.82 X 105</td><td>5.51 X 10-6</td><td>30.2</td>

<td>Ang-2 (1^st)</td><td>1.89 X 105</td><td>1.00 X 10-6 *</td><td>5.3</td>

<td>Ang-2 (2nd^nd)</td><td>1.78 X 105</td><td>1.00 X 10-6 *</td><td>5.6</td>

[0180] In the above table, kd's for Ang-2 are marked with an asterisk, because these values ​​were kept constant while matching the 1: 1 interaction model in the CLAMP software. No significant signal of dissociation was recorded in Ang-2 experiments, so the best off-rate estimation was to keep kd at a constant level of 1 X 10 '⁶ sec '¹. Long-term "off-rate" data for Ang-2 has actually shown a trend growing for six hours of data collection. This trend has repeated on two different sensor chips in two different devices after both devices have been subjected to a "super clean" maintenance protocol. To more accurately measure the binding affinity of mAb 3.19.3 from Ang-1 and Ang-2

A further experiment (see Example 10) was performed to determine Kd mAb 3.19.3 against these antigens.

[0181] Interestingly, mAb 3.19.3 did not bind to Ang-1 in an ELISA-based binding assay (Example 3) when Ang-1 was immobilized on an ELISA plate. A probable explanation for this discrepancy is that when Ang-1 was immobilized on the surface of plastics, the subtle key epitope for binding mAb 3.19.3 was not adequately exposed. However, when Ang-1 was in the liquid phase, as in the experimental Biacore conditions, this epitope became available for mAb 3.19.3 and binding occurred. EXAMPLE 10

IDENTIFICATION OF MAB 3.19.3 TO HUMAN ANG-2 USING KINEX (KINETIC EXCLUSION ASSAY) HIGH RESOLUTION [0182] When the affinity of mAb 3.19.3 was measured for human Ang-2 using a high resolution Biacore (Example 9), it was found that no there was a significant signal of dissociation. Long-term "off-rate" data for Ang2 shows a growing trend for six hours of data collection. For this reason, the Kd binding of mAb 3.19.3 to human Ang-2 was determined using KinExA technology, with a view to obtaining a more reliable Kd value. The KinExA 3000 device was used for this purpose. First, 1 mL (~ 271 pg) from the Ang-2 inventory (R &amp; D Systems, Inc., Series # BNO32510A) was buffer-exchanged to 1xPBS, pH 7.0 using a 10 mL desalting column (column polyacrylamide Pierce D-Saltp molecular weight cutoff 6000, Series # GF97965). The concentration of the combined fractions was found to be 1.7 μΜ using the protein concentration assay method described by C. Nick Pace (Pace, et al., Protein Science, Vol. 4: 2411-2423, 1995). Then 200 mg polymethyl methacrylate beads (PMMA, Series # 206-01) were combined with 450 μL (~ 122 μg) of Ang-2 stock overnight at 24 ° C. The beads were then centrifuged and washed once with blocking buffer (1xPBS, 10 mg / ml BSA), centrifuged again and then incubated in blocking buffer for one hour at 24 ° C. After blocking, the beads were diluted in about 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 in the device. 2411-2423, 1995). Then 200 mg polymethyl methacrylate beads (PMMA, Series # 206-01) were combined with 450 μL (~ 122 μg) of Ang-2 stock overnight at 24 ° C. The beads were then centrifuged and washed once with blocking buffer (1xPBS, 10 mg / ml BSA), centrifuged again and then incubated in blocking buffer for one hour at 24 ° C. After blocking, the beads were diluted in about 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 in the device. 2411-2423, 1995). Then 200 mg polymethyl methacrylate beads (PMMA, Series # 206-01) were combined with 450 μL (~ 122 μg) of Ang-2 stock overnight at 24 ° C. The beads were then centrifuged and washed once with blocking buffer (1xPBS, 10 mg / ml BSA), centrifuged again and then incubated in blocking buffer for one hour at 24 ° C. After blocking, the beads were diluted in about 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 in the device.

K_d-controlled titration [0183] Twelve solutions containing the concentration of the mAb binding site

3.19.3 equal to 25.3 pM was titrated with increasing concentrations of Ang-2. The samples used with the Ang-2 buffer were used to prepare the samples. Each solution had a total volume of 25 mL and was allowed to reach equilibrium for 5 days at ~ 24 ° C. The titration solutions were prepared using measuring glass, and Ang-2 concentrations varied from 5.09 nM to 99.3 fM. The KinExA device used to analyze these solutions relied on

The bead packing stage in which the PMMA beads were packed into a glass capillary and the equilibrated solutions in duplicate were passed through a 0.25 mL / min bead column for 6 min (1.5 mL). The fluorescently labeled Cy-5 goat anti-human polyclonal antibody (Fc specific) was then passed through the bead package at 3.4 nM for 1 min at 0.5 mL / min to label the bound mAbs with free binding sites. Fluorescence emission from the bead package was measured at 670 nm with 620 nm excitation. The resulting fluorescence measurements were converted to "% free mAb binding sites" against the total antigen concentration using the accompanying KinExA software package (version 1.0.3, Sapidyne, Inc.). The resultant titration curve checked for Kd was adjusted using KinExA software to the 1: 1 equilibrium isotherm with the drift correction factor included. The value of Kd, which optimally matches the data, was 86.4 pM with the lower and upper limits of 95% confidence equal to 64.3 pM and 98.7 pM, respectively. The titration curve checked for mAb was not performed. EXAMPLE 11

BLOCKING INDUCED BY ANG-2 PHOSPHORATION OF TIE2 RELATING TO EKTOPIC EXPRESSION IN HEK293 CELLS [0184] As described above, Tie2 receptor-specific tyrosine kinase specific for cells. In vitro experiments on vascular endothelial cells show that Ang-1 induces Tie2 phosphorylation, while Ang-2 inhibits Ang1-induced receptor phosphorylation. However, when Tie2 is ectopically expressed, 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.

[0185] The Ang-2-induced phosphorylation of Tie2 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 the human Tie2 receptor. The plasmid vector pORK / pBS-SK having the Tie2 cDNA was obtained from ATCC (Cat. No. 69003, Genbank BC033514 sequence). The accuracy of the cDNA was confirmed by nucleotide sequencing. The 3.9 kb fragment containing 3375 bp cDNA which encodes human Tie2 was removed from the vector by EcoR1 digestion. The fragment was subcloned in the correct orientation into the EcoRI digested pCR3.1 vector according to standard procedures. The selected plasmid was expanded and purified according to standard protocols. [0186] The Tie2 containing construct prepared according to the above procedures was transfected into HEK293F cells by calcium phosphate transfection. 1x10⁶ HEK293F cells were grown in 100 mm cell culture dishes coated with 1% gelatin at 37 ° C with 5% CO 2. The cells were fed fresh medium for 2-3 hours prior to transfection. IN

A solution of 248 mM calcium phosphate was dissolved in 10 pg of plasmid DNA. Transfection was carried out 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 a mouse anti-Tie2 mAb (R &amp; D Cat # MAB313) and a goat anti-mouse IgG-PE conjugated antibody (Caltag, Cat. No. M300044) for detection [0187] To carry out the Tie2 phosphorylation assay. HEK 293F / Tie-2 transfectants were grown in 60 mm cell culture dishes at a density of 2 × 10⁶cells / plate on complete medium at 37 ° C with 5% CO 2 until they reached sub-confluency. The complete medium in each plate was replaced with 2 ml of medium without plasma. The cells were incubated for an additional 16 hours. The medium was then replaced with 2 ml of medium without plasma. After an additional 2 h 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 pg / ml) in the presence or absence of mAbs at 100 pg / ml. The actions were carried out in duplicate. Negative control was enabled without Ang-2 activity. Cells were washed with ice-cold TBS containing vanadate and lysed with 300 μl / plate of chilled NP-40 lysis buffer (50mM Hepes, pH 7.2, supplemented with 0.15M NaCl, 10% glycerol, 10mM pyrophosphate, 50mM NaF, 1% nP40, 100U / ml aprotinin, 1mM PMSF, 0.1mM orthovanadan, 10 μΜ of leupeptin and 10 μΜ of pepstatin A) by placing the plates on ice for 10 minutes. Cells subjected to these operations were scraped from microtube plates previously cooled on ice.

[0188] Cell lysates were subjected to short sonication and centrifuged at 12,000 xg for 10 minutes at 4 ° C in a table microfuge. The supernatants were collected in fresh microtubes and 1-5 μg of anti-Tie2 mAb (R &amp; D Systems, Inc.) was added to the supernatant, followed by gently rocking for 2 hours at 4 ° C. To the mixture was added 50 μl of immobilized Protein A ImmunoPure (PIERCE Cat. No. 20333) and incubated for at least 3 hours at 4 ° C on a rocking platform. The complexes were harvested by centrifugation at 12,000 xg for 10 minutes. After carefully removing the supernatant, the complexes were washed twice with the lysis buffer, centrifuged (12,000 xg, 4 ° C) for 4 minutes. The pellets were resuspended in 50 μl of 2X electrophoresis buffer (Invitrogen, Cat. No. LC-2676) with 1 mM β-mercaptoethanol or DTT and boiled for 5 minutes before centrifugation (12,000 xg, 4 ° C) for 5 minutes.

[0189] Samples were loaded into SDS-PAGE gel wells (e.g., 4-20% Tris-Glycine gel, Invitrogen, Cat. No. EC 6025). Electrophoresis was carried out in the Tris-Glycine buffer system. After electrophoresis, the gel was applied to a PVDF membrane (Invitrogen, Cat. No. LC 2005) according to a standard protocol. Phosphorylation of tyrosine was sampled with 4G10 anti-phosphotyrosine antibody at 1 μg / ml (Upstate, Cat. No. 05-321) by incubating for 1 hour at room temperature with shaking followed by washing three times with 1x TBST (TBS with 0.1% Tween- 20). Bound antibodies were detected by incubation with a goat anti-mouse IgG conjugated with

A horseradish peroxidase (Santa Cruz, Cat. No. sc-2302) at a dilution of 1: 10000 for 1 hour at room temperature followed by an extended chemiluminescence reaction using the SuperSignal West Dura Extended Duration Substrate system (PIERCE Cat. No. 34075) . The resulting gel was then removed using the Restore Western Blot Buffer Buffer (PIERCE, Cat. No. 21059) and re-assayed with specific RTK antibodies to verify the quality of the sample application.

[0190] It was found that when human Tie2 was ectopically expressed in HEK293F cells, autophosphorylation of Tie2 was not detectable. In response to the action of Ang-2 (2 pg / ml), a significant level of tyrosine phosphorylation was detected by mAbs against phosphorylated tyrosine (4G10) in Tie2 precipitated by immunoprecipitation by specific mAbs. At a concentration of 100 pg / ml, all of the anti-Ang-2 mAbs tested showed obvious inhibition of Tie2 phosphorylation, whereas the isotype mAb control had no inhibitory effect (Figure 1). The monoclonal antibody 5.103.1, which is not shown in Figure 1, had a similar inhibitory effect:

[0191] To rank the strength of Ang-2 mAbs to inhibit Ang-2 induced Tie2 phosphorylation in vitro, an ELISA based quantitative method for detecting Tie2 phosphorylation was established. Briefly, cell lysates were prepared from HEK293F / Tie2 transfectants that were exposed to Ang-2 with mAbs at various concentrations. Total Tie2 from the lysate was bound in a 96-well ELISA plate which was coated with the anti-hTie-2 mouse mAb. Phosporylated Tie2 was detected using the primary antibody 4G10-HRP (ordered from Upstate) and the HRP medium solution. The OD at 650 nm was determined using the SpectraMax reader. The concentration-response relationship was examined by curve fitting using Graphpad graphics software Prismian nonlinear sigmoid curve). Maximum inhibition (yield) and IC50 (force) were calculated as shown in Figure 2.

Table 9

<td>has b</td><td>EC50 (pg / ml)</td><td>95% CI</td>

<td>3.19.3</td><td>0.006</td><td>0.004 to 0.009</td>

<td>5.86.1</td><td>0.008</td><td>0.007 to 0.011</td>

<td>5.88.3</td><td>0.016</td><td>0.011 to 0.024</td>

<td>3.31.2</td><td>0.043</td><td>0.029 to 0.064</td>

<td>3.3.2</td><td>0.046</td><td>0.020 to 0.105</td>

<td>5.16.3</td><td>0089</td><td>0.046 to 0.174</td>

<td>5.103.3</td><td>0.095</td><td>0.046 to 0.199</td>

<td>5.101.1</td><td>0.733</td><td>0.487 to 1.105</td>

EP 1 838 733 B1 [0192] As reported above, it was found that mAb 3.19.3 cross-reacted with Ang-1. However, the results of the initial experiments did not confirm the inhibition of Angiopoietin-1 induced Tie-2 phosphorylation by mAb 3.19.3. It is noteworthy that the ectopic expression of Tie2 may affect its sensitivity to activation by various ligands, as evidenced by the fact that Ang-2 does not induce Tie2 phosphorylation in HUVECs, while inducing strong Tie2 phosphorylation when the receptor is ectopically expressed in HEK293 cells.

[0193] Given these results, further experiments were conducted to more fully investigate whether mAb 3.19.3 was able to inhibit the binding of both Ang-1 and Ang-2 to the Tie2 cell-bound. In addition, the inhibition of Angiopoietin-1 induced Tie-2 phosphorylation by mAb 3.19.3 was examined in more detail as described in Example 12 below.

EXAMPLE 12

MAB 3.19.3 INHIBITS ANGIOPOETININ-1 BINDING WITH TIE-2 AND ANG-1 EMULSIONED TIE2 PHOSPHORYLATION [0194] mAb 3.19.3 cross-reacts with human Ang-1 (Examples 8 and 9). However, initial experiments showed that mAb 3.19.3 did not inhibit Ang-1 induced Tie2 phosphorylation. This discrepancy can be explained as follows: (1) a high Ang-1 concentration, which is well above physiological concentration, may be required to generate a strong Tie2 phosphorylation signal; or (2) Ectopic expression of Tie2 in HEK293 can alter the conformation of Tie2 and thereby alter its susceptibility to various ligands. To test these hypotheses, mAb 3.19.3 was tested in a binding assay in which low concentrations of Ang-1 or Ang-2 (3 nM) bound to Tie2 cell surface. It was found that in this experiment mAb 3.19.3 inhibited the binding of both Ang-1 and Ang-2. Secondly, Angiomatic endothelial cells (EA.hy926 / B3) were used to study Ang-1-induced Tie2 phosphorylation. The results of this experiment, as described in more detail below, show that mAb 3.19.3 inhibits Ang-1-induced Tie2 phosphorylation in a dose-dependent manner.

[0195] Before harvesting, HEK293F / Tie2 transfectants were allowed to grow to 95% confluence in culture flasks. A cell suspension of 4 million cells / mL in a Buffer FACS was prepared and measured on a polypropylene 96-well plate at 50 μl per well. MAb was added to the cell suspension

3.19.3 in the concentrations indicated. Subsequently, recombinant human Ang-1 and Ang-2 solutions were added to the cell suspension, followed by incubation at room temperature for 2 hours. The cells were washed by centrifuging the plate at 1200 rpm for 5 minutes, removing the supernatant by aspiration and resuspending the cells with FACS Buffer at 200 ul per well. The washing procedures were repeated twice. The cells were then resuspended with 100ul mouse anti-6X-Histidine antibody diluted to 2 μg / ml in FACS Buffer and incubated at room temperature.

And room temperature for 30 minutes. After washing, the cells were suspended in 100 μl 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 was adjusted to 300 μl with the aid of FACS Buffer and measured using FACS Calibur.

[0196] The results are illustrated in Figure 3 and summarized in Table 10. As shown, soluble Tie2 / Fc inhibited in a dose-dependent manner the binding of both Ang-1 and Ang-2 by blocking ligands, while the isotype control of mAb, PK16. 3.1 had no effect on the binding of any of the ligands. MAb 3.19.3 showed concentration-dependent inhibition of both Ang-1 and Ang-2. Interestingly, with respect to Tie2 / Fc strength, the strength of mAb 3.19.3 binding to Ang-2 was greater than with Ang-1.

Table 10. Inhibition of Ang-1 and Ang-2 binding to Tie2.

<td></td><td colspan="2">EC50 (nM)</td>

<td></td><td>Ang-1</td><td>Ang-²</td>

<td>Tie2 / Fc</td><td>18.73</td><td>25.70</td>

<td>3.19.3</td><td>218.5</td><td>.7310</td>

[0197] These results indicated that mAb 3.19.3 not only bound to human Ang1, but also blocked its binding to the Tie2 receptor. This was further confirmed by the inhibition of Ang-1-induced Tie2 phosphorylation in immortalized endothelial cells as described below.

[0198] The inhibitory activity of mAb 3.19.3 on Ang-1 induced phosphorylation of Tie2 was measured as follows. As shown in Figures 4 and 5, the mAb clearly displayed an increasing inhibition of Tie-2 phosphorylation with increasing antibody concentration. The dose-response curve plot led to the calculation of an IC 50 of 99 nM.

Tie2 ligand-stimulated Angiopoietin-1 receptor phosphorylation assay [0199] EA.hy926 / B3 cells were seeded in 6-well plates using 2.5 x 105 EA.h and 926 cells / well in 2 ml of DMEM; HAT; 10% FCS and incubated for 3 days under standard growth conditions for mammalian cells.

[0200] The culture medium was replaced with 2 mL of DMEM (without FCS) and the cells were starved with no plasma for 2 hours in total. The test compounds were diluted in DMEM; 1% FCS up to twice the desired final concentration. After 1 hour 40 minutes of fasting with no plasma, the plasma was removed from the cells and replaced with 1 ml of dilutions of the test compounds. Controls not exposed to compounds were also similarly developed to provide samples that represent 100% of ligand stimulation standards. [0201] Incubation lasted for a further 10 minutes, and 100 μΙ of a 10 mM orthovanadan solution in DmEm was added to each well to obtain

The final concentration of 1 mM orthovanadan in each well is obtained. The cells were then incubated for the last 10 minutes of a 2-hour fasting period with no plasma.

[0202] After the end of the 2 hour fasting period with no plasma, 1 ml of Angiopoietin-1 (diluted to the appropriate concentration in DMEM and containing 1 mM orthovanadan) was added to each well and incubated at 37 ° C for a further 10 minutes.

[0203] The 6-well plate (s) were then cooled by placing on an ice-cold metal plate (kept on ice). The culture medium was removed and the cell layer was washed with 5 ml of cold PBS; 1 mM orthovanadan. 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 orthovanadane, 1mM EDTA, was added to each well. 1 mM PMSF, 30 μΙ / ml Aprotinin, 10 μρ / ΓηΙ Pepstatin, 10 μ ^ ΛηΙ Leupeptin) and left on ice for 10-20 minutes. The cells were scraped from the plate using a cell spatula and the entire cell lysate solution was transferred to a 1.5 ml Eppendorf tube and stored on ice. Samples were then centrifuged for 3 minutes at 13000 rpm at 4 ° C and all further steps were carried out at 4 ° C.

[0204] 50 μΙ of each lysate was retained for the BCA protein assay (Pierce, Cat. No. 23225) (in polypropylene microtiter plates with low protein binding from Greiner). Protein concentration was determined using the standard test conditions provided with the kit. Another 800 μΙ of each lysate sample was transferred to a 2 ml Eppendorf tube as preparation for immunoprecipitation (IP). 15 μl (3 mg) anti PY (Santa Cruz Cat. No. E2203) was added to the lysates and allowed to incubate for 2 hours at 4 ° C before addition of 600 μl of Magnabind beads (goat anti-mouse IgG, Pierce No. Kat.21354). Magnabind beads were prepared as follows: The required volume was transferred to 15 ml conical tubes. The tubes were then placed in the presence of a magnetic field and the liquid was removed. Fresh PBS was added using the initial volume and the beads were resuspended. This process was repeated twice. The lysate solution was then mixed with the beads, and the tubes were allowed to rotate overnight at 4 ° C on a rotary agitator.

[0205] The samples were exposed to the magnet for about 1 min and the liquid was carefully removed. 1 ml of lysis buffer was added and the tubes were rotated for 5 min for rinsing. The washing steps were repeated twice. The liquid was removed completely and the beads were resuspended in 12 μl of hot (94 ° C) 2x Laemmli + bME loading buffer and then allowed to stand for 15 min at room temperature. The tubes were exposed to magnet for 1 min and the liquid, which separated from the beads, was analyzed on a PAGE / SDS gel.

[0206] Samples were examined using PAGE / SDS gels using 4-12% BisTris NuPAGE / MOPS gels with 15 wells (Novex). A total of 12 μl of each immunoprecipitate was applied to the groove. The gels were run at 200 V / 120 mA / 25 Watts for 55 minutes, and then the samples were subjected to western blotting on a nitrocellulose membrane for 1 h 30 min at 50 V / 250 mA.

EP 1 838 733B1

All labeling was then treated with 5% Marvel in PBSTween for 1 hour at room temperature and then washed with PBS-Tween.

[0207] Rabbit anti-Tie-2 antibody (Santa Cruz Cat. No. C1303) was diluted 1: 500 in 0.5% Marvel / PBS-Tween and 12.5 mls was added to each labeling result and left overnight at 4 ° C. . The labeling results were then washed with PBS-Tween and goat anti-rabbit-POD antibody (Dako Cat. No. P 0448) (1: 5000 dil. 0.5% Marvel / PBS-Tween) was added to each labeling result and allowed to stand for 1 hour at room temperature. room temperature. The labeling results were washed with PBS-Tween and each labeling result was developed for 10 minutes using 12.5 mLs (equal to the volume of solution A and B) Supersignal (PIERCE Cat. No. 34080). Marking results were transferred to the X-Ray cassette and exposed to film (exposures 5 sec / 15 sec / 30 sec / 60 sec / 150 sec). Figure 4 is a Western blot showing the results of this test.

[0208] The images visible in the film for each sample were then evaluated using the FluorS BioRad image analysis system. The pixel density was measured as OD / mm 2 and expressed as a percentage volume. The percentage volume results were normalized to 1 mg protein / immunoprecipitation using the protein concentration determined by the BCA assay and the lysate volume of each sample used for immunoprecipitation. The percentage of phosphorylation in each sample was calculated relative to the 100% phosphorylation value of the control sample on each gel, with the percentage inhibition of each sample calculated on the basis of 100% phosphorylation, which alone represents 0% inhibition. Figure 5 is a graphical representation of these values ​​and shows that the IC50 for inhibition of Angiopoietin-1 stimulated phosphorylation of Tie-2 is 99 nM.

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

EXAMPLE 13

STRUCTURAL ANALYSIS ANG-2 ANTIBODIES [0209] Variable heavy chains and variable light chains of antibodies were sequenced to determine their DNA sequences. Complete sequential information for anti-Ang-2 antibodies is provided in the sequence listing with nucleotide and amino acid sequences for each combination of gamma and kappa chains. Variable heavy sequences were analyzed to determine the VH family, the D region sequence and the J region sequence. The sequences were translated to determine the primary amino acid sequence and compared to the germline germline VH, D and J germline sequences to assess somatic hypermutation. [0210] Table 11 is a table comparing the heavy chain antibody regions with their related heavy chain regions in-line

The germ line. Table 12 is a table comparing the antibody kappa light chain regions with their related light chain regions in the germline.

[0211] Variable (V) regions of immunoglobulin chains are encoded by multiple germline DNA segments that are joined into functional variable regions (VhDJh or VkJk) during B cell ontogenesis. The molecular and molecular diversity of antibody responses to Ang-2 has been studied in detail. The tests revealed several points specific for anti-Ang-2 antibodies.

[0212] Analysis of 152 individual Ang-2 specific antibodies determined that antibodies came from 21 different germline VH genes, 112 of them from the VH3 family, including 46 antibodies derived from the VH3-33 gene segment. Tables 11 and 12 show the results of this analysis.

[0213] It should be appreciated that the amino acid sequences within the sister clones collected from each hybridoma line are identical. For example, the heavy 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.

EP 1 838 733 B1

This bale 11. Analysis of w ^ r ^ (^ and ^ clh heavy

<td>Name chain</td><td>SEQ ID NO:</td><td>V</td><td>D</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td></td><td>558</td><td colspan="3">The germline</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKTEDTAVYYCTT</td><td>DYGDYGM DV</td><td>WGQGTT VTVSSA</td>

<td>4.2</td><td>141</td><td>VH3-15</td><td>D4-17</td><td>JH6B</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMT</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTVGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKTEDTAVYYCTT</td><td>DYGDYYN SGYGMDV</td><td>WGQGTT VTVSSA</td>

<td></td><td>559</td><td colspan="3">The germline</td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT GYYMH</td><td>WVRQAPG QGLEWMG</td><td>WINPNSGGTN YAQKFQG</td><td>RVTMTRDTSISTAYMEL SRLRSDDTAVYYCAR</td><td>IAVAGFD Y</td><td>WGQGTL VTVSSA</td>

<td>5.103.1</td><td>503</td><td>VH1-2</td><td>D6-19</td><td>JH4A</td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT GYYLY</td><td>WVpQAPG QGLEWMG</td><td>WIsPNSGGTN YAQKFQG</td><td>RVTMTRDTSISTAYMEL SRLRSDDTAVYYCAR</td><td>DQVIAVA GPFDY</td><td>WAQGTL VTVSSA</td>

<td></td><td>560</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>DYGGNFD Y</td><td>WGQGTL VTVSSA</td>

<td>3.42</td><td>137</td><td>VH3-33</td><td>D4-23</td><td>JH4B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGIH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSSKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>ANDYGGN GLFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>561</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>AFDI</td><td>WGQGTM VTVSSA</td>

<td>5.11</td><td>221</td><td>VH3-33</td><td>-ON-</td><td>JH3B</td><td>QVQLVESGGGVVQ PGRSLRLPCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>DKALAFD AND</td><td>WGQGTM VTVSSA</td>

<td></td><td>562</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>EL</td><td>WGQGTL VTVSSA</td>

<td>5.108</td><td>513</td><td>VH3-33</td><td>D1-7</td><td>JH5B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAMYYCAR</td><td>ELAL</td><td>WGQGTL VTVSSA</td>

<td>5.108.1</td><td>513</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAMYYCAR</td><td>ELAL</td><td>WGQGTL VTVSSA</td>

<td></td><td>563</td><td colspan="3">The germline</td><td>EVQLVESGGGVVR PGGSLRLSCAAS</td><td>GFTFD DYGMS</td><td>WVRQAPG KGLEWVS</td><td>GINWNGGSTG YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTALYHCAR</td><td>QWLWYFD L</td><td>WGRGTL VTVSSA</td>

<td>5.19</td><td>251</td><td>VH3-20</td><td>D6-19</td><td>JH2</td><td>EVQLVESGGGVVR PGGSLRLSCAAS</td><td>GFSFD DYGMS</td><td>WVRQAPG KGLEWVS</td><td>GINWNGGRTV YADSVKG</td><td>RFTISRDSAKNSLYLQM NSLRAEDTALYHCAR</td><td>NKQWLWY FDL</td><td>WGRGTL VTVSSA</td>

<td>5.6</td><td>205</td><td></td><td></td><td></td><td>EVQLVESGGGVVR PGGSLRLSCAAS</td><td>GFSFD DYGMS</td><td>WVRQAPG KGLEWVS</td><td>GINWNGGRTV YADSVKG</td><td>RFTISRDSAKNSLYLQM NSLRAEDTALYHCAR</td><td>NKQWLWY FDL</td><td>WGRGTL VTVSSA</td>

<td>5.8</td><td>211</td><td></td><td></td><td></td><td>EVQLVESGGGVVR PGGSLRLSCAAS</td><td>GFTFD DYGMS</td><td>WVRQAPG KGLEWVS</td><td>GINWNGGGTG YADSMKG</td><td>RFTISRDDAKNSLYLQM NSLRAEDTALYHCAR</td><td>NKQWLWY FDL</td><td>WGRGTL VTVSSA</td>

<td>5.35</td><td>297</td><td></td><td></td><td></td><td>EVQLVESGGGVVR PGGSLRLSCTTS</td><td>GFTFD DYGMS</td><td>WVRQAPG KGLEWVS</td><td>GINWNGGSTV YADSVKG</td><td>RFTISRDSAKNSLYLQM NSLRAEDTALYHCAR</td><td>NKQWLWY FDL</td><td>WGRGTL VTVSSA</td>

<td>5.38</td><td>309</td><td></td><td></td><td></td><td>EVKLVESGGGMVR PGGSLRLSCAAS</td><td>GFTFD DYGMS</td><td>WVRQAPG KGLEWVS</td><td>GINWNGGGTA YADSVKG</td><td>RFTISRDNAKNSLYLQL NSLRAEDTALYHCAR</td><td>NKQWLWY FDL</td><td>WGRGTL VTVSSA</td>

<td>5.44</td><td>329</td><td></td><td></td><td></td><td>EVQLVESGGGVVR TGGSLRLSCAAS</td><td>GFSFD DYGMS</td><td>WVRQAPG KGLEWVS</td><td>GINWNGGRTV YADSVKG</td><td>RFTISRDSAKNSLYLQM NSLRAEDTALYHCAR</td><td>NKQWLWY FDL</td><td>WGRGTL VTVSSA</td>

EP 1 838 733 B1

<td>Name chain</td><td>SEQ ID NO:</td><td>V</td><td>D</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td>5 35.1</td><td>297</td><td>"</td><td>"</td><td>"</td><td>EVQLVESGGGVVR PGGSLRLSCTTS</td><td>GFTFD DYGMS</td><td>WVRQAPG KGLEWVS</td><td>GINWNGGSTV YADSVKG</td><td>RFTISRDSAKNSLYLQM NSLRAEDTALYHCAR</td><td>NKQWLWY FDL</td><td>WGRGTL VTVSSA</td>

<td></td><td>564</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCA</td><td>YGGNSYY YYYGMDV</td><td>WGQGTT VTVSSA</td>

<td>3.1</td><td>7</td><td>VH3-33</td><td>D4-23</td><td>JH6B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAG</td><td>DYGEYFY YGMDV</td><td>WGQGTT VTVSSA</td>

<td>3.18</td><td>71</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SFGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWFDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAS</td><td>DYGDYFY YGMDV</td><td>WGQGTT VTVSSA</td>

<td>3.39</td><td>125</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCA</td><td>DRSYGGN SFYYYYY GMDV GMDV</td><td>WGQGTT VTVSSA</td>

<td>3.11</td><td>47</td><td>"</td><td>"</td><td>"</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAG</td><td>DYGDYFY YGMDV</td><td>WGQGTT VTVSSA</td>

<td>3.26</td><td>93</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAG</td><td>DYGEYFY YGMDV</td><td>WGQGTT VTVSSA</td>

<td></td><td>565</td><td colspan="3">The germline</td><td>EVQLVESGGVVVQ PGGSLRLSCAAS</td><td>GFTFD DYTMH</td><td>WVRQAPG KGLEWVS</td><td>LISWDGGSTY YADSVKG</td><td>RFTISRDNSKNSLYLQM NSLRTEDTALYYCAK</td><td>DIAVAGF DY</td><td>WGQGTL VTVSSA</td>

<td>5.28</td><td>277</td><td>VH3-43</td><td>D6-19</td><td>JH4B</td><td>EVQLVESGGIVVQ PGGSLRLSCAAS</td><td>GFTFD DYTMH</td><td>WVRQTPG KGLEWVS</td><td>LISWDGGSTY YADSVKG</td><td>RFTISRDNSKNSLYLQM NSLRTEDTALYYCAK</td><td>DIDIAVA GTGFDH</td><td>WGQGTL VTVSSA</td>

<td>5.28.1</td><td>277</td><td>"</td><td>"</td><td>"</td><td>EVQLVESGGIVVQ PGGSLRLSCAAS</td><td>GFTFD DYTMH</td><td>WVRQTPG KGLEWVS</td><td>LISWDGGSTY YADSVKG</td><td>RFTISRDNSKNSLYLQM NSLRTEDTALYYCAK</td><td>DIDIAVA GTGFDH</td><td>WGQGTL VTVSSA</td>

<td></td><td>566</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>NWNYFDY</td><td>WGQGTL VTVSSA</td>

<td>5.56.1</td><td>363</td><td>VH3-33</td><td>D1-7</td><td>JH4B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>EDNWNFY FDY</td><td>WGQGTL VTVSSA</td>

<td>5.56</td><td>363</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>EDNWNFY FDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>567</td><td colspan="3">The germline</td><td>QVQLQQWGAGLLK PSETLSLTCAVY</td><td>GGSFS GYYWS</td><td>WIRQPPG KGLEWIG</td><td>EINHSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>DYGDFDY</td><td>WGQGTL VTVSSA</td>

<td>3.37</td><td>121</td><td>VH4-34</td><td>D4-17</td><td>JH4B</td><td>QVQLQQWGAGLLK PSETLSLTCAVY</td><td>GGSFS GYYWS</td><td>WIRQPPG KGLEWIG</td><td>EIYHSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYSCAR</td><td>NDYGDHE GFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>568</td><td colspan="3">The germline</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSVS SGGYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>GYSYGYY FDY</td><td>WGQGTL VTVSSA</td>

<td>5.36</td><td>301</td><td>VH4-61</td><td>D5-5</td><td>JH4B</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSVS WSGYY WS</td><td>WIRQPPG KGLEWIG</td><td>YINYSRSTNH NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>EGRGDSY GYYFDY</td><td>WGQGTL VTVSSA</td>

<td>6.7</td><td>551</td><td>"</td><td>"</td><td>"</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSVS SGGYY WS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSRSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>EGRGYSY GYYFDY</td><td>WGQGTL VTVSSA</td>

<td>5.107</td><td>511</td><td></td><td></td><td></td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSVS SGGYY WS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSRSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>EGRGNSY GYYFDY</td><td>WGQGTL VTVSSA</td>

EP 1 838 733 B1

<td>Name chain</td><td>SEQ ID NO:</td><td>V</td><td>D</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td></td><td>569</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VISYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>WLRYYYY GMDV</td><td>WGQGTT VTVSSA</td>

<td>5.111</td><td>521</td><td>VH3-30</td><td>D5-12</td><td>JH6B</td><td>QVQLVESGGDVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VISYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM HLRAEDTAVYYCAR</td><td>DGGWLRL DGGWLRL DYYYYGM DV</td><td>WGQGTT VTVSSA</td>

<td></td><td>570</td><td colspan="3">The germline</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKTEDTAVYYCTT</td><td>YSSGWYW YFDL</td><td>WGRGTL VTVSSA</td>

<td>5.45</td><td>333</td><td>VH3-15</td><td>D6-19</td><td>JH2</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKTEDTAVYYCTT</td><td>SYSSGWF YWYFDI</td><td>WGRGTP VTVSSA</td>

<td></td><td>571</td><td colspan="3">The germline</td><td>EVQLVESGGGLVQ PGRSLRLSCAAS</td><td>GFTFS SYSMN</td><td>WVRQAPG KGLEWVS</td><td>YISSSSSTIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRDEDTAVYYCAR</td><td>AAAGFDY</td><td>WGQGTL VTVSSA</td>

<td>5.43</td><td>325</td><td>VH3-48</td><td>D6-13</td><td>JH4B</td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS TYSMN</td><td>WVRQAPG KGLEWIS</td><td>YISRSSRTIN HADSVKG</td><td>RFTVSRDNAKNSLYLQM ISLRDEDTAVYYCAR</td><td>KAAAGPF DY</td><td>WGQGTL VTVASA</td>

<td></td><td>572</td><td colspan="3">The germline</td><td>EVQLLESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYAMS</td><td>WVRQAPG KGLEWVS</td><td>AISGSGGSTY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAK</td><td>DYGGNFD Y</td><td>WGQGTL VTVSSA</td>

<td>5.97</td><td>491</td><td>VH3-23</td><td>D4-23</td><td>JH4B</td><td>EVQLLESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYAMS</td><td>WVRQAPG KGLEWVS</td><td>GISGSGGNTY HADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAK</td><td>DEDYGGN YSDFDY</td><td>WGQGTL VTVSSA</td>

<td>6.8</td><td>553</td><td></td><td></td><td></td><td>EVQLLESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYAMS</td><td>WVRQAPG KGLEWVS</td><td>AISGSGGSTY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAK</td><td>DEDYGGN SDFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>573</td><td colspan="3">The germline</td><td>QVQLQQSGPGLVK PSQTLSLTCAIS</td><td>GDSVS SNSAAWN</td><td>WIRQSPS RGLEWLG</td><td>RTYYRSKWYN DYAVSVKS</td><td>RITINPDTSKNQFSLQL NSVTPEDTAVYYCA</td><td>WFYWYFD L</td><td>WGRGTL VTVSSA</td>

<td>5.61</td><td>377</td><td>VH6-1</td><td>-D3-9</td><td>JH2</td><td>QVQLQQSGPGLVK PSQTLSLTCAIS</td><td>GDSVS SNSAA</td><td>WIRQSPS RGLEWLG WN</td><td>MTYYRSKWSN DYAVSLKS</td><td>RITINPDTSKNQFSLQL NSVTPEDTAVYYCAR</td><td>GNDFYWY FDL</td><td>WGRGTL VTVSSA</td>

<td></td><td>574</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>TGDY</td><td>WGQGTL VTVSSA</td>

<td>5.52</td><td>347</td><td>VH3-33</td><td>D1-1</td><td>JH4B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VRWYDESNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>DPFETGT TFDY</td><td>WGQGTL VTVSSA</td>

<td>5.52.1</td><td>351</td><td></td><td>"</td><td>"</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VRWYDESNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>DPFETGT TFDY</td><td>WGQGTL VTVSSA</td>

<td>5.53</td><td>355</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS DYGMH</td><td>WVRQAPG KGLEWMA</td><td>VLWYDESNKY YADSVKG</td><td>RFTISRDSSKNTLYLQM NSLRAEDTAVYYCAR</td><td>DPFETGT TFDY</td><td>WGQGTL VTVSSA</td>

<td>5.26</td><td>273</td><td>"</td><td>"</td><td>"</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDESNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>DPFETGT TFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>575</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VISYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>GYSSGWF DY</td><td>WGQGTL VTVSSA</td>

<td>5.20</td><td>253</td><td>VH3-30</td><td>D6-19</td><td>JH4B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS TYGMH</td><td>WVRQAPG KGLEWVA</td><td>VISYDGSKKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTALYYCAR</td><td>GGYSTGW GPDFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>576</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>CGGDCYY YYYYGMDV</td><td>WGQGTT VTVSSA</td>

EP 1 838 733 B1

<td>Name chain</td><td>SEQ ID NO:</td><td>V</td><td>D</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td>3.22</td><td>89</td><td>VH3-33</td><td>D2-21</td><td>JH6B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS NYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSRNTLYLQM NSLRAEDTAVYYCAR</td><td>EGGYCGG DCWVYGM DV</td><td>WGQGTL VTVSSA</td>

<td>5.51</td><td>345</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>ENCGGDC YQLNYYY YYGMDV</td><td>WGQGTT VTVSSA</td>

<td>5.47</td><td>330</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>ENCGGDC ENCGGDC YQLNYYY YYGMDV</td><td>WGQGTT VTVSSA</td>

<td></td><td>577</td><td colspan="3">The germline</td><td>QVQLQESGPGLVK PSQTLSLTCTVS</td><td>GGSIS SGGYY WS</td><td>WIRQHPG KGLEWIG</td><td>YIYYSGSTYY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>WDFDY</td><td>WGQGTL VTVSSA</td>

<td>3.21</td><td>85</td><td>VH4-31</td><td>D7-27</td><td>JH4B</td><td>QVQLQESGPGLVK PSQTLSLTCTVS</td><td>GGSIS SGGYF</td><td>WIRQHPG KGLEWIG</td><td>YIYYSIGRY NPSLKS WS</td><td>RVTISVDASKNQFSLKL SSVTAADTAVYHCAR</td><td>EGSYWDF DY</td><td>WGQGTL VTVSSA</td>

<td></td><td>578</td><td colspan="3">The germline</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS SYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>P</td><td>WGQGTL VTVSSA</td>

<td>5.66</td><td>389</td><td>VH4-59</td><td>-ON-</td><td>JH5B</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS SYYWS</td><td>WIRQPPG KGLEWIG</td><td>FIYYSGTTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>AYDP</td><td>WGQGTL VTVSSA</td>

<td></td><td>579</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>NWNYYYY GMDV</td><td>WGQGTT VTVSSA</td>

<td>5.73</td><td>409</td><td>VH3-33</td><td>D1-20</td><td>JH6B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>GDNWNYE GDGMDV</td><td>WGQGTT VTVSSA</td>

<td>5.29</td><td>281</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>APYDWNS YYGLDV</td><td>WGQGTT VTVSSA</td>

<td>5.104</td><td>507</td><td></td><td>"</td><td>"</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKD</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>APYDWNS YYGLDV</td><td>WGQGTT VTVSSA</td>

<td></td><td>580</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VISYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>YYGSGSY GMDV</td><td>WGQGTT VTVSSA</td>

<td>5.21</td><td>255</td><td>VH3-30</td><td>D3-10</td><td>JH6B</td><td>QVQLVESAGGVVQ PGRSLRLSCAAS</td><td>GFTFS IYGMH</td><td>WVRQAPG KGLEWVA</td><td>VISYDGSNKY YADSVKG</td><td>RFTISRDDSKNTLYLQM NSLRAEDTAVYYCAR</td><td>NYYGSGS PYGMDV</td><td>WGQGTT VTVSSA</td>

<td></td><td>581</td><td colspan="3">The germline</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSVS SGGYY WS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>YYGSGYY YYGMDV</td><td>WGQGTT VTVSSA</td>

<td>3.2</td><td>11</td><td>VH4-61</td><td>D3-10</td><td>JH6B</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSVS S SGGYY WN</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>DQDYYGS GRGYYYY GMDV</td><td>WGQGTT VTVSS</td>

<td></td><td>582</td><td colspan="3">The germline</td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT GYYMH</td><td>WVRQAPG QGLEWMG</td><td>WINPNSGGTN YAQKFQG</td><td>RVTMTRDTSISTAYMEL SRLRSDDTAVYYCAR</td><td>NWNYFDY</td><td>WGQGTL VTVSSA</td>

<td>6.3.1</td><td>539</td><td>VH1-2</td><td>D1-7</td><td>JH4B</td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT GYFMH</td><td>WVPQAPG QGLEWMG</td><td>WINPNSGGTN YAQNFQG</td><td>RVTMTRDTSISTAYMEL SRLRSDDTPVYYCAR</td><td>DPWQNWN SYFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>583</td><td colspan="3">The germline</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKTEDTAVYYCT</td><td>YGWYFDL</td><td>WGRGTL</td>

EP 1 838 733 B1

<td>Name chain</td><td>SEQ ID NO:</td><td>V</td><td>D</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td>5.46</td><td>337</td><td>VH3-15</td><td>D4-17</td><td>JH2</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTMSRDDSKNTLYLQM NSLKTEDTAVYYCTI</td><td>LYGDFWY FDL</td><td>VTVSSA WGRGTL VTVSSA</td>

<td>3.9</td><td>39</td><td></td><td>"</td><td>"</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKTEDTAVYYCTT</td><td>EYGDFWY FDF</td><td>WGRGTL VTVSSA</td>

<td></td><td>584</td><td colspan="3">The germline</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS SYYWS</td><td>WIRQPAG KGLEWIG</td><td>RIYTSGSTNY NPSLKS</td><td>RVTMSVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>WWYFDL</td><td>WGRGTL VTVSSA</td>

<td>5.68</td><td>397</td><td>VH4-4</td><td>D2-21</td><td>JH2</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS SHYWI</td><td>WIRQPAG KGLEWIG</td><td>RIYSSGSTNY NPSLKS</td><td>RVTMSGDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>GWGSWY FDL</td><td>WGRGTL VTVSSA</td>

<td></td><td>585</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>Y</td><td>WGQGTL VTVSSA</td>

<td>5.67</td><td>393</td><td>VH3-33</td><td>-ON-</td><td>JH4B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>ELAY</td><td>WGQGTL VTVSSA</td>

<td></td><td>586</td><td colspan="3">The germline</td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT GYYMH</td><td>WVRQAPG QGLEWMG</td><td>WINPNSGGTN YAQKFQG</td><td>RVTMTRDTSISTAYMEL SRLRSDDTAVYYCAR</td><td>We have sent GMDV</td><td>WGQGTT VTVSSA</td>

<td>5.78.1</td><td>429</td><td>VH1-2</td><td>D2-2</td><td>JH6B</td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT GYYMH</td><td>WVRQAPG QGLEWMG</td><td>WINPNSGGTN YAQKFQG</td><td>RVTMTRDTSISTAYMEL SRLRSDDTAVYYCAR</td><td>DRGWNYA DYYYYGM DV</td><td>WGQGTT VTVSSA</td>

<td></td><td>587</td><td colspan="3">The germline</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS SYSMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSSSYIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>VGAFDY</td><td>WGQGTL</td>

<td>4.18</td><td>187</td><td>VH3-21</td><td>D1-26</td><td>JH4B</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS SYRMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSSSHIY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DRGVGAP FDY</td><td>VTVSSA WGQGTL VTVSSA</td>

<td>3.40</td><td>129</td><td></td><td></td><td></td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS SYRMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSSSHIY HVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DRGVGAP FDY</td><td>WGQGTL</td>

<td>5.80</td><td>435</td><td></td><td></td><td></td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS SYRMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSGSYIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYFAR</td><td>DRGVGAA FDY</td><td>VTVSSA WGQGTL VTVSSA</td>

<td>3.41</td><td>133</td><td></td><td></td><td></td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS SYRMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSSSHIY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DRGVGAP FDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>588</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>YSYFDY</td><td>WGQGTL VTVSSA</td>

<td>5.22</td><td>259</td><td>VH3-33</td><td>D6-6</td><td>JH4B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>GGPLYSN SFYYFDY</td><td>WGQGTL VTVSSA</td>

<td>5.31</td><td>289</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>IIWFDGSNEY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYFCAR</td><td>GGPLYSN SFYYFDY</td><td>WGQGTL VTVSSA</td>

<td>5.37</td><td>305</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS NYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSHKY YADSVKG</td><td>RFTISRDNSKNSLYLQM NSLRAEDTAVYYCAR</td><td>GGPLYSN SFYYFDY</td><td>WGQGTL VTVSSA</td>

<td>5.112</td><td>525</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>ILWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>GGPLYTN SFYYFDY</td><td>WGQGTL VTVSSA</td>

EP 1 838 733 B1

<td>Name chain</td><td>SEQ ID NO:</td><td>V</td><td>D</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td>5.10</td><td>217</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPD KGLEWVA</td><td>VIWYDGSYKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>GGPLYSN SFYYFDY</td><td>WGQGTL VTVSSA</td>

<td>5.76</td><td>419</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCVAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>GGPLYSN SFYYFDY</td><td>WGQGTL VTVSSA</td>

<td>5.17</td><td>243</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVT</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDSSKNTLYLQM NSLRAEDTAVYYCAR</td><td>GGPLYSN SFYYFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>589</td><td colspan="3">The germline</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS SYYWS</td><td>WIRQPAG KGLEWIG</td><td>RIYTSGSTNY NPSLKS</td><td>RVTMSVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>DDYSYYY YYGMDV</td><td>WGQGTT VTVSSA</td>

<td>5.81</td><td>439</td><td>VH4-4</td><td>D4-11</td><td>JH6B</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS SYYWS</td><td>WIRQPAG KGLEWIG</td><td>RIYTSGSTNY NPSLKS</td><td>RVTMSVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>DDYSHSY YYYYGMD V</td><td>WGQGTT VTVSSA</td>

<td></td><td>590</td><td colspan="3">The germline</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKTEDTAVYYCTT</td><td>YGGNSYG MDV</td><td>WGQGTT VTVSSA</td>

<td>4.5</td><td>151</td><td>VH3-15</td><td>D4-23</td><td>JH6B</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMN</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKTEDTAVYYCTT</td><td>AYGGNSD QEDYGMD V</td><td>WGQGTT VTVSSA</td>

<td></td><td>591</td><td colspan="3">The germline</td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSEKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>GIAVAFD Y</td><td>WGQGTL VTVSSA</td>

<td>3.31.1</td><td>99</td><td>VH3-7</td><td>D6-19</td><td>JH4B</td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSDKY YVDSVKG</td><td>RFTISRDNAKNSLYLRM NSLRAEDTAVFYCAR</td><td>DMGSGWF DYFDY</td><td>WGQGTL VTVSSA</td>

<td>5.13.1</td><td>229</td><td></td><td></td><td></td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSEKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DPGIAVA GPFDY</td><td>WGQGTL VTVSSA</td>

<td>5.13</td><td>229</td><td></td><td></td><td></td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSEKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DPGIAVA GPFDY</td><td>WGQGTL VTVSSA</td>

<td>5.62</td><td>381</td><td></td><td></td><td></td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSEKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DPGIAVA GPFDY</td><td>WGQGTL VTVSSA</td>

<td>3.28.1</td><td>97</td><td></td><td></td><td></td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SSWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSDKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCVR</td><td>DKGSGWF DY</td><td>WGQGTL VTVSSA</td>

<td>5.41</td><td>321</td><td></td><td></td><td></td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKEDGSEKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVFYCAR</td><td>DRSSGFF DY</td><td>WGQGTL VTVSSA</td>

<td>5.109</td><td>517</td><td></td><td></td><td></td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSEQY SVDSVKG</td><td>RFTISRDNAKNSLYLQM NTLRAEDTAVYYCVR</td><td>DPGIEVA GPFDY</td><td>WGQGTL VTVSSA</td>

<td>3.3</td><td>15</td><td></td><td></td><td></td><td>EVQLVESGGGLVQ PGGSLRLSCAVS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSEKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DQGIAVA GPFDY</td><td>WGQGTL VTVSSA</td>

<td>3.3.1</td><td>19</td><td></td><td></td><td></td><td>EVQLVESGGGLVQ PGGSLRLSCAVS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSEKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DQGIAVA GPFDY</td><td>WGQGTL VTVSSA</td>

<td>5.41.1</td><td>321</td><td></td><td></td><td></td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKEDGSEKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVFYCAR</td><td>DRSSGFF DY</td><td>WGQGTL VTVSSA</td>

<td>5.62.1</td><td>381</td><td></td><td></td><td></td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSEKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DPGIAVA GPFDY</td><td>WGQGTL VTVSSA</td>

EP 1 838 733 B1

<td>Name chain</td><td>SEQ ID NO:</td><td>V</td><td>D</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td>5.83</td><td>447</td><td></td><td></td><td></td><td>EVQLVESGGGLVQ PGGSLRLSCEAS</td><td>GFTFS TYWMT</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSEKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DAGMEVA GPFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>592</td><td colspan="3">The germline</td><td>EVQLLESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYAMS</td><td>WVRQAPG KGLEWVS</td><td>AISGSGGSTY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAK</td><td>QWLVFDY</td><td>WGQGTL VTVSSA</td>

<td>5.40.2</td><td>317</td><td>VH3-23</td><td>D6-19</td><td>JH4B</td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYAMS</td><td>WVRQAPG KGLEWVS</td><td>AISGSGYSTY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAK</td><td>DLQQWLV PTVFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>593</td><td colspan="3">The germline</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS SYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>QWLDY</td><td>WGQGTL VTVSSA</td>

<td>5.15</td><td>235</td><td>V4-59</td><td>D6-19</td><td>JH4B</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS GYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>DRQWLDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>594</td><td colspan="3">The germline</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS SYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>AFDI</td><td>WGQGTM VTVSSA</td>

<td>3.13</td><td>55</td><td>VH4-59</td><td>-ON-</td><td>JH3B</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS NYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>DRADAFDI</td><td>WGQGTM VTVSSA</td>

<td>3.7</td><td>31</td><td></td><td></td><td></td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS NYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>DRADAFDI</td><td>WGQGTM VTVSSA</td>

<td>3.12</td><td>51</td><td></td><td></td><td></td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS NYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>DRADAFDI</td><td>WGQGTM VTVSSA</td>

<td>3.33</td><td>111</td><td></td><td></td><td></td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GDSIS NYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>ERGDAFDI</td><td>WGQGRV VTVSSA</td>

<td>4.16</td><td>183</td><td></td><td></td><td></td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS NYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>DRADAFDI</td><td>WGQGTM VTVSSA</td>

<td>3.35</td><td>119</td><td></td><td></td><td></td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GDSIS NYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQLSLKL SSVTAADTAVYYCAR</td><td>ERGDAFDI</td><td>WGQGRV VTVSSA</td>

<td>3.32</td><td>107</td><td></td><td>"</td><td>"</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS NYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>DRADAFDI</td><td>WGQGTM VTVSSA</td>

<td></td><td></td><td colspan="3">595 The germline</td><td>QVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS DYYMS</td><td>WIRQAPG KGLEWVS</td><td>YISSSGSTIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>GAFDI</td><td>WGQGTM VTVSSA</td>

<td>5.90</td><td>475</td><td>VH3-11</td><td>D3-16</td><td>JH3B</td><td>QVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS DYYMS</td><td>WIRQAPG KGLEWVS</td><td>YISSSGSSKN YADSVKG</td><td>RITISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>ERGDAFDI</td><td>WGQGTM VTVSSA</td>

<td></td><td>596</td><td colspan="3">The germline</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS SYYWS</td><td>WIRQPAG KGLEWIG</td><td>RIYTSGSTNY NPSLKS</td><td>RVTMSVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>YNWNYWY FDL</td><td>WGRGTL VTVSSA</td>

<td>5.18</td><td>247</td><td>VH4-4</td><td>D1-20</td><td>JH2</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS SYYWS</td><td>WIRQPAG KGLEWIG</td><td>RIYTSGFTNY NPSLKS</td><td>RVTMSVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>YNWNYWY FDL</td><td>WGRGIL VTVSSA</td>

<td></td><td>597</td><td colspan="3">The germline</td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT GYYMH</td><td>WVRQAPG QGLEWMG</td><td>WINPNSGGTN YAQKFQG</td><td>RVTMTRDTSISTAYMEL SRLRSDDTAVYYCAR</td><td>IAVAGFD Y</td><td>WGQGTL VTVSSA</td>

<td>5.54.1</td><td>357</td><td>VH1-2</td><td>D6-19</td><td>JH4B</td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT GYYMH</td><td>WVRQAPG QGLEWMG</td><td>WINPNSGGTN YAQKFQG</td><td>RVTMTRDTSISTAYMEL SRLRSDDTAVYYCAR</td><td>DGGSIAV AGHFEY</td><td>WGQGTL VTVSSA</td>

EP 1 838 733 B1

<td>Name chain</td><td>SEQ ID NO:</td><td>V</td><td>D</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td>5.14.1</td><td>233</td><td></td><td>"</td><td>"</td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT GYYMY</td><td>WVRQAPG QGLEWMG</td><td>WINPNSGGTN YAQKFQG</td><td>RVTMTRDTSISTAYMEL SRLRSDDTAVYYCAR</td><td>DQGITVA GPFDY</td><td>WGQGSL VTVSSA</td>

<td>5.101.1</td><td>497</td><td></td><td></td><td></td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT GYYMH</td><td>WVPQAPG QGLEWMG</td><td>WINPNSGGTN YAQKFQG</td><td>RVTMTRDTSISTAYMEL RLRSDDTAVYYCAR</td><td>DGGSIPV SGHFDY</td><td>WGQGTL VTVSSA</td>

<td>5.83.1</td><td>449</td><td>"</td><td>"</td><td>"</td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT GYYMH</td><td>WVRQAPG QGLEWMG</td><td>WINPNSGGTN YAQKFQG</td><td>RVTMTRDTSISTAYMEL SRLRSDDTAVYYCAR</td><td>DGGSIAV AGHFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>598</td><td colspan="3">The germline</td><td>EVQLVESGGGLIQ PGGSLRLSCAAS</td><td>GFTVS SNYMS</td><td>WVRQAPG KGLEWVS</td><td>VIYSGGSTYY ADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCA</td><td>YSSGWYY GMDV</td><td>WGQGTT VTVSSA</td>

<td>6.9</td><td>555</td><td>VH3-53</td><td>D6-19</td><td>JH6B</td><td>EVQLVESGGGLIQ SGGSLRLSCAAS</td><td>GFTVS SKYMS</td><td>WVRQAPG KGLEWVS</td><td>VIYSGGFTYY ADSVKG</td><td>RFTVSRDNSKNTLYLQM NSLGAEDTAVYYCAT</td><td>YSSGWHY YGMDV</td><td>WGQGTT VTVSSA</td>

<td></td><td>599</td><td colspan="3">germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>GDLLLRY GRL</td><td>GPRDHG HRLLS</td>

<td>3.10</td><td>43</td><td>VH3-33</td><td>D4-17</td><td>JH6B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIRYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLNLQM NSLRAEDTAVYYCAR</td><td>DRDGDYP LLLLGMD</td><td>WGQGTT VTVSSA</td>

<td>4.13</td><td>171</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAA</td><td>DYGDSDY YYYYGMD V</td><td>WGQGTT VTVSSA</td>

<td></td><td>600</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>DIVATIN YYYGMDV</td><td>WGQGTT VTVSSA</td>

<td>5.2</td><td>195</td><td>VH3-33</td><td>D5-12</td><td>JH6B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWFDGFNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYHCAR-</td><td>DRGYSGY DHYYGMD DRGYSGY V</td><td>WGQGTL VTVSSA</td>

<td>5.12</td><td>225</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGGNKY YTDSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>DEDIVAT INYYYGMDV</td><td>WGQGTT VTVSSA</td>

<td></td><td>601</td><td colspan="3">The germline</td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSEKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DIWYFDL</td><td>WGRGTL VTVSSA</td>

<td>5.4</td><td>201</td><td>VH3-7</td><td>D3-22</td><td>JH2</td><td>EVQLVESGGDLVQ PGGSLRLSCAAS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSEKY FDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DIRWYED L</td><td>WGRGTL VTVSSA</td>

<td></td><td>602</td><td colspan="3">The germline</td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSEKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>WYFDL</td><td>WGRGTL VTVSSA</td>

<td>5.91</td><td>479</td><td>VH3-7</td><td>-ON-</td><td>JH2</td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSEKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DSWWYFD L</td><td>WGRGTL VTVSSA</td>

<td></td><td>603</td><td colspan="3">The germline</td><td>EVQLVESGGGLVQ PGGSLRLSCAAS</td><td>GFTFS SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKQDGSEKY YVDSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>AAAFDY</td><td>WGQGTL VTVSSA</td>

<td>5.88</td><td>461</td><td>VH3-7</td><td>D6-13</td><td>JH4B</td><td>EVQMVESGGGLVQ PGGSLRLSCAAS</td><td>GFTLR SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKEDGSEKY HVDSVKG</td><td>RFTISRDNAENSLFLQM SSLRAEDTAVYYCAR</td><td>DMEASAG LFDY</td><td>WGQGTL VTVSSA</td>

<td>5.88.1</td><td>465</td><td></td><td></td><td></td><td>EVQMVESGGGLVQ PGGSLRLSCAAS</td><td>GFTLR SYWMS</td><td>WVRQAPG KGLEWVA</td><td>NIKEDGSEKY HVDSVKG</td><td>RFTISRDNAENSLFLQM SSLRAEDTAVYYCAR</td><td>DMEASAG LFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>604</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCA</td><td>YSNYYFD Y</td><td>WGQGTL VTVSSA</td>

EP 1 838 733 B1

<td>Name chain</td><td>SEQ ID NO:</td><td>V</td><td>D</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td>5.89</td><td>473</td><td>VH3-33</td><td>D4-11</td><td>JH4B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFR SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSYKN YGDSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>DYSNYEE YFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>605</td><td colspan="3">The germline</td><td>QITLKESGPTLVK PTQTLTLTCTFS</td><td>GFSLS VGGVG</td><td>WIRQPPG KALEWLA</td><td>LIYWNDDKRY SPSLKS</td><td>RLTITKDTSKNQVVLTM TNMDPVDTATYYCAH</td><td>RSSSWFD Y</td><td>WGQGTL VTVSSA</td>

<td>5.115</td><td>529</td><td>VH2-5</td><td>D6-13</td><td>JH4B</td><td>QITLKESGPTLVK PTQTLTLTCTLS</td><td>GFSLS ISGVG VG</td><td>WIRQPPG KALEWLA</td><td>FIYWNDDKRY SPSLKS</td><td>RLTITKDTSKNQVVLTM TNMDPVDTATYYCAH</td><td>RPDSSSW DFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>606</td><td colspan="3">The germline</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS SYSMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSSSYIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>GIAFDY</td><td>WGQGTL VTVSSA</td>

<td>5.64</td><td>385</td><td>VH3-21</td><td>D2-2</td><td>JH4B</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFN SYRMN</td><td>WVRQAPG KGLEWVS</td><td>SITSSSHYIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DRGIAAP FDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>607</td><td colspan="3">The germline</td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT GYYMH</td><td>WVRQAPG QGLEWMG</td><td>WINPNSGGTN YAQKFQG</td><td>RVTMTRDTSISTAYMEL SRLRSDDTAVYYCAR</td><td>GIAAAGF DY</td><td>WGQGTL VTVSSA</td>

<td>5.39.1</td><td>313</td><td>VH1-2</td><td>D6-13</td><td>JH4B</td><td>QVQLVQSGAEVTK PGASVKVSCKAS</td><td>GYTFT AYHMY</td><td>WVRQAPG QGLEWMG</td><td>WINPNSGGTN YAQKFQG</td><td>RVTMTRDTSISTAYMEL SRLRSDDSPVYYCAR</td><td>DQGIAAA GPFDY</td><td>WGQGTL VTVSSA</td>

<td>5.16.1</td><td>239</td><td></td><td></td><td></td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT GFYMY</td><td>WVRQAPG QGLEWMG</td><td>WINPNSSGTN HAQKFQG</td><td>RVTMTRDTSISTAYMEL SRLRSDDTAVYYCAR</td><td>DQDIATA GPFDY</td><td>WGQGTL VTVSSA</td>

<td>5.86.1</td><td>453</td><td></td><td></td><td></td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT GYHMY</td><td>WVRQAPG QGLEWLG</td><td>WINPNSGGTN YAQKFQG</td><td>RVTMTRDTSISTAYMEL SRLRSDDTAVYYCVR</td><td>DQGIAAA GPFDY</td><td>WCQGTL VTVSSA</td>

<td></td><td>608</td><td colspan="3">The germline</td><td>QVQLQESGPGLVK</td><td>GGSIS</td><td>WIRQPAG</td><td>RIYTSGSTNY</td><td>RVTMSVDTSKNQFSLKL</td><td>GITFDP</td><td>WGQGTL</td>

<td></td><td></td><td></td><td></td><td></td><td>PSETLSLTCTVS</td><td>SYYWS</td><td>KGLEWIG</td><td>NPSLKS</td><td>SSVTAADTAVYYCAR</td><td></td><td>VTVSSA</td>

<td>5.79</td><td>433</td><td>VH4-4</td><td>D1-20</td><td>JH5B</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS SYYWS</td><td>WIRQPAG KGLEWIG</td><td>RIYTSGSTNY NPSLKS</td><td>RVTMSVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>GITGYGG FDP</td><td>WGQGTL VTVSSA</td>

<td>5.23</td><td>263</td><td></td><td></td><td></td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GDSIN SYYWS</td><td>WIRQPAG KGLEWIG</td><td>RIYTSGSTNY NPSLKS</td><td>RVTMSVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>GITGYGG FDP</td><td>WGQGTL VTVSSA</td>

<td></td><td>609</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCG</td><td>GMDV</td><td>WGQGTT VTVSSA</td>

<td>5.87</td><td>457</td><td>VH3-33</td><td>ID3-16</td><td>JH6B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAG</td><td>GATAMDV</td><td>CGQGST GTVSSA</td>

<td></td><td>610</td><td colspan="3">The germline</td><td>EVQLVQSGAEVKK PGESLKISCKGS</td><td>GYSFT SYWIG</td><td>WVRQMPG KGLEWMG</td><td>IIYPGDSDTR YSPSFQG</td><td>QVTISADKSISTAYLQW SSLKASDTAMYYCAR</td><td>NWNFDI MMNFDI</td><td>WGQGTM VTVSSA</td>

<td>3.6</td><td>27</td><td>VH5-51</td><td>D1-7</td><td>JH3B</td><td>EVQLVQSGAEVKK PGESLKISCKGS</td><td>GYSFS NYWIA</td><td>WVRQMPG KGLEWMG</td><td>IIYPGDSDTR YSPSFQG</td><td>QVTISADKSISTAYLQW SSLKASDTAMYYCAR</td><td>HENWN FFDTFDI</td><td>WGQGTM VTVSSA</td>

<td></td><td>611</td><td colspan="3">The germline</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS SYSMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSSSYIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>IFGVVNW YFDL</td><td>WGRGTL VTVSSA</td>

<td>4.6</td><td>155</td><td>VH3-21</td><td>D3-3</td><td>JH2</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS SYSMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSSSYIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DGAIFGV VNWYFDL</td><td>WGRGTL VTVSSA</td>

<td>5.94</td><td>487</td><td></td><td></td><td></td><td>EVQLVESGGGLFK PGGSLRLSCAAS</td><td>GFTFS SYSMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSSSYIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DGAIFGV VNWYFDL</td><td>WGRGTL VTVSSA</td>

EP 1 838 733 B1

<td>Name chain</td><td>SEQ ID NO:</td><td>V</td><td>D</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td>5.58</td><td>367</td><td></td><td></td><td></td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS SYSMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSSSYIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DGAIFGV VNWYFDL</td><td>WGRGTL VTVSSA</td>

<td>4.9</td><td>163</td><td></td><td></td><td></td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS SYSMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSSSYIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DGAIFGV VNWYFDL</td><td>WGRGTL VTVSSA</td>

<td>5.70</td><td>399</td><td></td><td></td><td></td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS SYSMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSSSYIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DGAIFGV VNWYFDL</td><td>WGRGTL VTVSSA</td>

<td>4.15</td><td>179</td><td></td><td></td><td></td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS SYSMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSSSYIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DGAIFGV VNWYFDL</td><td>WGRGTL VTVSSA</td>

<td>4.8</td><td>159</td><td></td><td></td><td></td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS SYSMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSSSYIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DGAIFGV VNWYFDL</td><td>WGRGTL VTVSSA</td>

<td>4.7</td><td>157</td><td></td><td></td><td></td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS SYSMN</td><td>WVRQAPG KGLEWVS</td><td>SISSSSSYIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>DGAIFGV VNWYFDL</td><td>WGRGTL VTVSSA</td>

<td></td><td>612</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>QNYDFWS GYGMDV</td><td>WGQGTT VTVSSA</td>

<td>4.11</td><td>167</td><td>VH3-33</td><td>D3-3</td><td>JH6B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMY</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>DFFQNYD FWSGSPV GYGMDV</td><td>WGQGTT VTVSSA</td>

<td></td><td>613</td><td colspan="3">The germline</td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT SYGIS</td><td>WVRQAPG QGLEWMG</td><td>WISAYNGNTN YAQKLQG</td><td>RVTMTTDTSTSTAYMEL RSLRSDDTAVYYCAR</td><td>VGADY</td><td>WGQGTL VTVSSA</td>

<td>6.6</td><td>547</td><td>VH1-18</td><td>D1-26</td><td>JH4B</td><td>LVQSGAEVKKPGA SVKVSCKAS</td><td>GYTFT SYGIS</td><td>WVRQAPG QGLEWMG</td><td>WISAYNGNTN YAQKLQD</td><td>RVTMTTDTSTSTAYMEL RSLRSDDTAVYYCAR</td><td>GVGAKDY</td><td>WGQGTL VTVSSA</td>

<td>3.34</td><td>115</td><td></td><td></td><td></td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT SYGIS</td><td>WVRQAPG QGLEWMG</td><td>WISTYNDNTN YAQKLQG</td><td>RVTMTTDTSTSTAYMEL RSLRSDDTAVYYCAR</td><td>GVGATDY</td><td>WGQGTL VTVSSA</td>

<td>5.30</td><td>285</td><td></td><td></td><td></td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT SYGIS</td><td>WVRQAPG QGLEWMG</td><td>WISAHNGNTN YAQKLQG</td><td>RVTMTTDTSTSTAYMEL RSLRSDDTAVYYCAR</td><td>GVGSKDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>614</td><td colspan="3">The germline</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKTEDTAVYYCT</td><td>SSGWYYY YYGMDV</td><td>WGQGTT VTVSSA</td>

<td>5.55</td><td>361</td><td>VH3-15</td><td>D6-19</td><td>JH6B</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKTEDTAVYYCTI</td><td>GSSGWYE AYYYYGM</td><td>WGQGTT VTVSSA</td>

<td>5.7</td><td>209</td><td></td><td></td><td></td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKYTLYLQM NSLKTEDTAVYYCTI</td><td>GSSGWYE AYYYYGM</td><td>WGQGTT VTVSSA</td>

<td>5.5</td><td>203</td><td></td><td></td><td></td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKYTLYLQM NSLKTEDTAVYYCTI</td><td>GSSGWYE AYYYYGM DV</td><td>WGQGTT VTVSSA</td>

<td></td><td>615</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VISYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>DFWSNWF DP</td><td>WGQGTL VTVSSA</td>

<td>3.19</td><td>75</td><td>VH3-30</td><td>D3-3</td><td>JH5B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFT NYGMH</td><td>WGRQAPG KGLEWVA</td><td>VISHDGNNKY YVDSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>EGIDFWS GLNWFDP</td><td>WGQGTL VTVSSA</td>

<td>3.19.1</td><td>75</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFT NYGMH</td><td>WGRQAPG KGLEWVA</td><td>VISHDGNNKY YVDSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>EGIDFWS GLNWFDP</td><td>WGQGTL VTVSSA</td>

EP 1 838 733 B1

<td>Name chain</td><td>SEQ ID NO:</td><td>V</td><td>D</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td></td><td>616</td><td colspan="3">The germline</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKTEDTAVYYCT</td><td>YGDAFDI</td><td>WGQGTM VTVSSA</td>

<td>5.72</td><td>405</td><td>VH3-15</td><td>D4-17</td><td>JH3B</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKTEDTAVYYCTN</td><td>YYGDFYA FDI</td><td>WGQGTM VTVSSA</td>

<td>3.14</td><td>59</td><td></td><td></td><td></td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKTEDTAVYYCII</td><td>FYGDFDA FDI-</td><td>WGQGTM VTVSSA</td>

<td>3.17</td><td>67</td><td></td><td></td><td></td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMH</td><td>WVRQAPG KGLDWVG</td><td>RIKSKTDGGT ADYAAPVKG</td><td>RFTISRDDSENTLYLQM NSLKTEDTAVYYCTN</td><td>DYGDFYA FDI</td><td>WGQGTM VTVSSA</td>

<td></td><td>617</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>GYCSGGY GMDV</td><td>WGQGTT VTVSSA</td>

<td>5.82</td><td>443</td><td>VH3-33</td><td>D2-15</td><td>JH6B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>IIWFDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM VSLRAEDTAVYYCAR</td><td>KGYCSGG V</td><td>WGQGTT VTVSSA</td>

<td>5.59</td><td>371</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>IIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLHLQM NSLRAEDTAVYYCAR</td><td>KGYCSGG V</td><td>WGQGTT VTVSSA</td>

<td>5.92</td><td>481</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>KGYCSGG V</td><td>WGQGTT VTVSSA</td>

<td></td><td>618</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>RYFDWDY</td><td>WGQGTL VTVSSA</td>

<td>6.5</td><td>545</td><td>VH3-33</td><td>D3-9</td><td>JH4B</td><td>QVQLVESGGGWQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>GPLRYFD WPSDY</td><td>WGQGTL VTVSSA</td>

<td>6.2</td><td>535</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVS</td><td>LIWYAGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>GPLRYFD WPSDY</td><td>WGQGTL VTVSSA</td>

<td>3.8</td><td>35</td><td></td><td></td><td></td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>GPLRYFD WPPDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>619</td><td colspan="3">The germline</td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT SYGIS</td><td>WVRQAPG QGLEWMG</td><td>WISAYNGNTN YAQKLQG</td><td>RVTMTTDTSTSTAYMEL RSLRSDDTAVYYCAR</td><td>YSSFDY</td><td>WGQGTL VTVSSA</td>

<td>5.74</td><td>413</td><td>VH1-18</td><td>D6-19</td><td>JH4B</td><td>QVQLVQSGAEVKK PGASVKVSCKAS</td><td>GYTFT SYCIS</td><td>WVRQAPG RGLEWMG</td><td>WICSYNGNTN CAQKLQG</td><td>RVTMTTDTSTTTAYMEL RGLRSDDTAVYYCAR</td><td>ESLYSSG WFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>620</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>DFWSNWF DP</td><td>WGQGTL VTVSSA</td>

<td>5.71</td><td>401</td><td>VH3-33</td><td>D3-3</td><td>JH5B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>EGLDFWS PFYNWFD</td><td>WGQGTL VTVSSA</td>

<td></td><td>621</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td></td><td>WGQGTL VTVSSA</td>

<td>4.14</td><td>175</td><td>VH3-33</td><td>-ON-</td><td>JH5B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>ELAS</td><td>WGQGTL VTVSSA</td>

<td>6.1</td><td>533</td><td></td><td></td><td></td><td>QVLLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VIWFDGSKKY YADSVKG</td><td>RFTISRDNSKNSLYLQM NSLRAEDTAVYYCAR</td><td>ELEL</td><td>WGLGTL VTVSSA</td>

EP 1 838 733 B1

<td>Name chain</td><td>SEQ ID NO:</td><td>V</td><td>D</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td></td><td>622</td><td colspan="3">The germline</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS SYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCA</td><td>TGDY</td><td>WGQGTL VTVSSA</td>

<td>5.106</td><td>509</td><td>VH4-59</td><td>D7-27</td><td>JH4B</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS SYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNF NPSLKS</td><td>RVTTSVDTSKNQFSLNL RSVTAADTAVYYCAR</td><td>GTGASDY</td><td>WGQGTL VTVSSA</td>

<td>5.48</td><td>341</td><td></td><td></td><td></td><td>QVQLQESAPGLVK PSETLSLTCTVS</td><td>GGSIS SYYWS</td><td>WIRQPPG KGLEWIG</td><td>YISYSGSTNY NPSLKS</td><td>RVTTSVDTSKNQFSLKL GTGASDY SSVTAADTAVYYCTR</td><td>GTGASDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>623</td><td colspan="3">The germline</td><td>QVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS DYYMS</td><td>WIRQAPG KGLEWVS</td><td>YISSSGSTIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>AFDI</td><td>WGQGTM VTVSSA</td>

<td>5.102</td><td>501</td><td>VH3-11</td><td>-ON-</td><td>JH3B</td><td>QVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS DYYMS</td><td>WIRQAPG KGLEWVS</td><td>YISSSGSTIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>ERGDAFDI</td><td>WGQGTM VTVSSA</td>

<td>5.24</td><td>267</td><td></td><td></td><td></td><td>QVRLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS DYYMS</td><td>WIRQAPG KGLEWAS</td><td>YISSSGYSIY YADSVKG</td><td>RFTISRDNAKNSLYLQM NSLRAEDTAVYYCAR</td><td>ERGDAFDI</td><td>WGQGTM VTVSSA</td>

<td></td><td>624</td><td colspan="3">The germline</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKTEDTAVYYCT</td><td>YGDYYFD Y</td><td>WGQGTL VTVSSA</td>

<td>5.1</td><td>191</td><td>VH3-15</td><td>D4-17</td><td>JH4B</td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NAWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLYLQM NSLKIEDTAVYYCTI</td><td>FROM TGDYPES</td><td>WGQGTL VTVSSA</td>

<td>5.33</td><td>293</td><td></td><td></td><td></td><td>EVQLVESGGGLVK PGGSLRLSCAAS</td><td>GFTFS NTWMS</td><td>WVRQAPG KGLEWVG</td><td>RIKSKTDGGT TDYAAPVKG</td><td>RFTISRDDSKNTLCLQL NSLKTEDTAVYYCSA</td><td>GYGDYPY FDF</td><td>WGQGTL VTVSSA</td>

<td></td><td>625</td><td colspan="3">The germline</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIS SYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>FDY</td><td>WGQGTL VTVSSA</td>

<td>4.3</td><td>145</td><td>VH4-59</td><td>-ON-</td><td>JH4B</td><td>QVQLQESGPGLVK PSETLSLTCTVS</td><td>GGSIN NYYWS</td><td>WIRQPPG KGLEWIG</td><td>YIYYSGSTNY NPSLKS</td><td>RVTISVDTSKNQFSLKL SSVTAADTAVYYCAR</td><td>ERGDSFDY</td><td>WGQGTL VTVSSA</td>

<td></td><td>626</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VISYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>QLWDY</td><td>WGQGTL VTVSSA</td>

<td>5.60</td><td>373</td><td>VH3-30</td><td>D5-5</td><td>JH4B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS GYDIH</td><td>WVRQAPG KGLEWVA</td><td>VISYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>ERQLWLI DY</td><td>WGQGTL VTVSSA</td>

<td></td><td>627</td><td colspan="3">The germline</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS SYGMH</td><td>WVRQAPG KGLEWVA</td><td>VISYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>GIAVAYG MDV</td><td>WGQGTT VTVSSA</td>

<td>5.75</td><td>417</td><td>VH3-30</td><td>D6-19</td><td>JH6B</td><td>QVQLVESGGGVVQ PGRSLRLSCAAS</td><td>GFTFS GYGMH</td><td>WVRQAPG KGLEWVA</td><td>VISYDGSNKY YADSVKG</td><td>RFTISRDNSKNTLYLQM NSLRAEDTAVYYCAR</td><td>DRGIAVA GYYGMDV</td><td>WGQGNT VTVSSA</td>

EP 1 838 733 B1

Table 12. Light chain analysis

<td>Name chain</td><td>KNOT ID No.:</td><td>V</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td></td><td>628</td><td colspan="2">The germline</td><td>EIVLTQSPGTLS LSPGERATLSC</td><td>RASQSVSSSY LA</td><td>WYQQKPGQ APRLLIY</td><td>GASSRAT</td><td>GIPDRFSGSGSGTDFT LTISRLEPEDFAVYYC</td><td>QQYGSSPWT</td><td>FGQGTKVEIKR</td>

<td>5.77</td><td>423</td><td>A27</td><td>JK1</td><td>EVVLTQSPGTLS LSPGDRATLSC</td><td>RASQSVSSSY LA</td><td>WYNQKPGQ APRLLIF</td><td>GASSRAT</td><td>GIPDRFSGSGSGTDFT LTISRLEPEDFAVYYC</td><td>LQYGSSPWT</td><td>FGQGTKVEIKR</td>

<td></td><td>629</td><td colspan="2">The germline</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>QASQDISNYL N</td><td>WYQQKPGK APKLLIY</td><td>DASNLET</td><td>GVPSRFSGSGSGTDFT FTISSLQPEDIATYYC</td><td>QQYDN</td><td>FGQGTKLEIKR</td>

<td>5.61</td><td>379</td><td>018</td><td>JK2</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>QASQDISNYL N</td><td>WYQQKPGK APKLLIY</td><td>DASNLET</td><td>GVPSRFSGSGSGTDFT FTISRLQPEDIATYYC</td><td>QQYDNLCS</td><td>FGQGTKLEIKR</td>

<td></td><td>630</td><td colspan="2">The germline</td><td>DIQMTQSPSSVS ASVGDRVTITC</td><td>RASQGISSWL AND</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQANSFPWT</td><td>FGQGTKVEIKR</td>

<td>5.3</td><td>199</td><td>L5</td><td>JK1</td><td>DIQMTQSPSSVS ASVGDRVTITC</td><td>RASQGIRSWL AND</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQANSFPWT</td><td>FGQGTKVEIKR</td>

<td>3.2</td><td>13</td><td>L5</td><td>JK1</td><td>DIQMTQSPSSVS ASVGDRVTITC</td><td>RASQGISSWL AND</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDEATYYC</td><td>QQAYSFRT</td><td>FGQGTKVEIKR</td>

<td>5.34</td><td>295</td><td>L5</td><td>JK1</td><td>DIQMTQSPSSVS ASYGDRVTITC</td><td>RASQGISSWL AND</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQANSFPWT</td><td>FGQGTKVEIKR</td>

<td>3.22</td><td>91</td><td>L5</td><td>JK1</td><td>DIQMTQSPFSVS ASVGDRVTITC</td><td>RASQGISNWL AND</td><td>WYQQKPGK APKLLIY</td><td>TASSLQN</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQINSFPWT</td><td>FGQGTKVEIKR</td>

<td>5.73</td><td>411</td><td>L5</td><td>JK1</td><td>DIQMTQSPSSVS ASVGDRVTITC</td><td>RASQGISRWL AND</td><td>WYQQKPGK APKLLIY</td><td>VASSLQS</td><td>GVPSRFSGSGSGTDFT</td><td>QQANSFPRT</td><td>FGQGTKVEIKR</td>

<td>5.1</td><td>193</td><td>L5</td><td>JK1</td><td>DIQMTQSPSSVS ASVGDRVTITC</td><td>RASQGIRSWL AND</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>LTISSLQPEDFATYYC GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQANSFPWT</td><td>FGQGTKVEIKR</td>

<td>3.9</td><td>41</td><td>L5</td><td>JK1</td><td>DIQMTQSPSSVS ASVGDRVTITC</td><td>RASQGISSWL AND</td><td>WYQQKPGK APNLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFI LTISSLQPEDFATYYC</td><td>QQSNSFPRT</td><td>FGQGTKVEIKR</td>

<td>5.81</td><td>441</td><td>L5</td><td>JK1</td><td>DIQMTQSPSSVS ASVGDRVTITC</td><td>RASQGISSWL AND</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQANSFPRT</td><td>FGQGTKVEIKR</td>

<td></td><td>631</td><td colspan="2">The germline</td><td>ETTLTQSPAFMS ATPGDKVNISC</td><td>KASQDIDDDM N</td><td>WYQQKPGE AAIFIIQ</td><td>EATTLVP</td><td>GIPPRFSGSGYGTDFT LTINNIESEDAAYYFC</td><td>LQHDNFPLT</td><td>FGGGTKVEIKR</td>

<td>5.24</td><td>269</td><td>B2</td><td>JK4</td><td>ETTLTQSPAFMS ATPGDKVNISC</td><td>KASQDIDDDM N</td><td>WYQQKPGE VAIFIIQ</td><td>EATTLVP</td><td>GIPPRFSGSGYGTDFT LTINNIESEDAAYYFC</td><td>LQHDNFPLT</td><td>FGGGTKVEIKR</td>

<td></td><td>632</td><td colspan="2">The germline</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGISNYL AND</td><td>WYQQKPGK VPKLLIY</td><td>AASTLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDVATYYC</td><td>QKYNSAPFT</td><td>FGPGTKVDIKR</td>

<td>5.56.1</td><td>365</td><td>A20</td><td>JK3</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGISYYL AND</td><td>WYQQKPGK VPKLLIY</td><td>AASTLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDVATYYC</td><td>QKYNSAPFT</td><td>FGPGTKVDIKR</td>

<td></td><td>633</td><td colspan="2">The germline</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC LTISSLQSEDFAVYYC</td><td>QQYNNWPLT</td><td>FGGGTKVEIKR</td>

EP 1 838 733 B1

<td>Name chain</td><td>KNOT ID No.:</td><td>V</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td>5.6</td><td>207</td><td>L2</td><td>JK4</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTELT LTISSLQSEDFAVYYC</td><td>QQYNNWPLT</td><td>FGGGTKVEIKR</td>

<td>5.44</td><td>331</td><td>L2</td><td>JK4</td><td>EIVMTQSPATLS VSPGERATLSC VSPGERATLSC</td><td>RASQSISSNL AND</td><td>WYQQKPGQ APRLLIY APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQPEDFAVYYC</td><td>QQYNNWPLT</td><td>FGRGTKVEIKR</td>

<td>5.38</td><td>311</td><td>L2</td><td>JK4</td><td>EIVMTQSPATLS VSPGERVTLSC</td><td>RASQSVSGNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QHYNNWPLT</td><td>FGGGTKVEIKR</td>

<td>5.35</td><td>299</td><td>L2</td><td>JK4</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>EQYNNWPLT</td><td>FGGGTKVEIKR</td>

<td>5.8</td><td>213</td><td>L2</td><td>JK4</td><td>EIVMTQSPATLS VSLGERATLSC</td><td>RASQSVRSNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTELT LTISSLQSEDFAVYYC</td><td>HQYNNWPLT</td><td>FGGGTKVEIKR</td>

<td>5.35.1</td><td>299</td><td>L2</td><td>JK4</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>EQYNNWPLT</td><td>FGGGTKVEIKR</td>

<td></td><td>634</td><td colspan="2">The germline</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGIRNDL G</td><td>WYQQKPGKAPKRLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTEFT LTISSLQPEDFATYYC</td><td>LQHNSYPFT</td><td>FGPGTKVDIKR</td>

<td>4.13</td><td>173</td><td>A30</td><td>JK3</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGIRDDL G</td><td>WFQQKPGKAPKRLTY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTEFT LTISSLQPEDFATYYC</td><td>LQYNSYPFT</td><td>FGPGTKVDIKR</td>

<td></td><td>635</td><td colspan="2">The germline</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNNWPFT</td><td>FGPGTKVDIKR</td>

<td>5.28.1</td><td>279</td><td>L2</td><td>JK3</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVTSNL AND</td><td>WYQQKPGQAPRLLIY</td><td>WYQQKPGQ GALIRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNNWPFT</td><td>FGPGTKVDIKR</td>

<td>5.28</td><td>279</td><td>L2</td><td>JK3 3</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVTSNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GALIRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNNWPFT</td><td>FGPGTKVDIKR</td>

<td></td><td>636</td><td colspan="2">The germline</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGIRNDL G</td><td>WYQQKPGK APKRLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTEFT LTISSLQPEDFATYYC</td><td>LQHNSYB</td><td>FGQGTKLEIKR</td>

<td>4.4</td><td>149</td><td>A30</td><td>JK2</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGIRNDL G</td><td>WYQQKPGK APKRLIY</td><td>AASSLQS</td><td>GVPSRFSGSRSGTEFT LTISSLQPEDFATYYC</td><td>LQHNSYPPS</td><td>FGQGTKLEIKR</td>

<td>3.33</td><td>113</td><td>A30</td><td>JK2</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGIRNDL G</td><td>WYQQKPGK APKRLIY</td><td>AASSLQS</td><td>GVPSRFSGSRSGTEFT LTISSLQPEDFATYYC</td><td>LQHNSYPPS</td><td>FGQGTKLEIKR</td>

<td>3.39</td><td>127</td><td>A30</td><td>JK2</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGIRNDL G</td><td>WYQQKPGK APKRLIY</td><td>AASSLQS</td><td>GVPSRFSGSRSGTEFT LTISSLQPEDFATYYC</td><td>LQHNSYPPS</td><td>FGQGTKLEIK^R</td>

<td></td><td>637</td><td colspan="2">The germline</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGIRNDL G</td><td>WYQQKPGK APKRLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTEFT LTISSLQPEDFATYYC</td><td>LQHNSYPRT</td><td>FGQGTKVEIKR</td>

<td>3.26</td><td>95</td><td>A30</td><td>JK1</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGIRNDL G</td><td>WYQQKPGK APKRLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>LQHNNYPRT</td><td>FGQGTKVEIKR</td>

<td>3.11</td><td>49</td><td>A30</td><td>JK1</td><td>DIQMTQSPSSLS TSVGDRVTITC</td><td>RASQGIRNDL G</td><td>WYQQKPGK APKRLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTEFT LTISSLRPEDFATYYC</td><td>LQLNSYPRT</td><td>FGQGTKVEIKR</td>

<td>3.1</td><td>9</td><td>A30</td><td>JK1</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGIRNDL G</td><td>WYQQKPGK APKRLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTEFT LTISSLQPEDFATYYC</td><td>LQHNSYPRT</td><td>FGQGTKVEIKR</td>

<td>4.15</td><td>181</td><td>A30</td><td>JK1</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGIRNDL G</td><td>WYQQKPGK APKRLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTEFT LTISSLQPEDFATYYC</td><td>LQHNSYPPT</td><td>FGQGTKVEIKR</td>

EP 1 838 733 B1

<td>Name chain</td><td>KNOT ID No.:</td><td>V</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td>3.18</td><td>73</td><td>A30</td><td>JK1</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGIRNDL G</td><td>WYQQKPGK APKRLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTEFT LTISSLQPEDFATYYC</td><td>LQYNSYPRT</td><td>FGQGTKVEIKR</td>

<td></td><td>638</td><td colspan="2">The germline</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNNWPRT</td><td>FGQGTKVEIKR</td>

<td>5.16.1</td><td>241</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRLLIF</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNNWWT</td><td>FGRGTKVEIKR</td>

<td>5.40.2</td><td>319</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL V</td><td>WYQQKPGQ APRLLIY</td><td>DSSTRAT</td><td>GIPVRFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNHWWT</td><td>FGQGTKVEIKR</td>

<td>5.41.1</td><td>323</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRFLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNHWWT</td><td>FGQGTKVEIKR</td>

<td>6.4</td><td>543</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSLISNLA</td><td>WYQQKPGQ APRQLLF</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>HQYNNWWT</td><td>FGQGTKVEIKR</td>

<td>5.103.1</td><td>505</td><td>L2</td><td>JK1</td><td>ETVMTQSPATLS VSPGERVTLSC</td><td>RASQSVISSL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNNWWT</td><td>FGQGTKVEIKR</td>

<td>5.54.1</td><td>359</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSLISNLA</td><td>WYQQKPGQ APRLLIF</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAIYYC</td><td>HQYNNWWT</td><td>FGQGTKVEIKR</td>

<td>5.13</td><td>231</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNHWWT</td><td>FGQGTKVEIKR</td>

<td>3.31.1</td><td>101</td><td>L2</td><td>JK1</td><td>EVVMTQSPATLS VSPGERATLSC</td><td>RASQSVGSNL AND RASQVGSNLA</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYCC</td><td>QQYNHWWT</td><td>FGQGTKVEIKR</td>

<td>5.88.1</td><td>467</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERAILSC</td><td>RASQSISSNL A RAS</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNYWWT</td><td>FGQGTKVEIKR</td>

<td>3.3</td><td>17</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQTVSSDL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASIRAT</td><td>GIPARFSGSGSGTEFT QQYYNWWT LTISSLQSEDFAVYSC</td><td>QQYYNWWT</td><td>FGQGTKVEIKR</td>

<td>5.62</td><td>383</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GAFTRAT</td><td>GIPARFSGSGSGTEFT</td><td>QQYNHWWT</td><td>FGQGTKVGIKR</td>

<td>5.101</td><td>499</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSLISNLA</td><td>WYQQKPGQ APRLLIF</td><td>GASTRAT</td><td>LTISSLQSEDFAVYYC GIPARFSGSGSGTEFT</td><td>HQYNNWWT</td><td>FGQGTKVEIKR</td>

<td>5.52</td><td>349</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLA VSPGERATLSC</td><td>RARQSVSSNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTMAT</td><td>LTISSLQSEDFAVYYC GFPARFSGRGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNNWWT</td><td>FGQGTKVEIKR</td>

<td>5.1 6</td><td>241</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRLLIF</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNNWWT</td><td>FGRGTKVEIKR</td>

<td>5.39</td><td>315</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGDRATLSC</td><td>RASQSVSSNF AND</td><td>WYQQKPGQ APRLLIY</td><td>GSSTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYHYWWT</td><td>FGQGTKVEFKR</td>

<td>3.6</td><td>29</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSISSNL AND</td><td>WFQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNNWPRT</td><td>FGQGTTVEIKR</td>

<td>5.39.1</td><td>315</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGDRATLSC</td><td>RASQSVSSNF AND</td><td>WYQQKPGQ APRLLIY</td><td>GSSTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYHYWWT</td><td>GQGTKVEFKR</td>

EP 1 838 733 B1

<td>Name chain</td><td>KNOT ID No.:</td><td>V</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td>5.15</td><td>237</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQTVISNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFALYYC</td><td>QQYNNWWT</td><td>FGQGTKVEIKR</td>

<td>5.83.1</td><td>451</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSLISNLA</td><td>WYQQKPGQ APRLLIF</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>HQYNNWWT</td><td>FGQGTKVEIKR</td>

<td>5.41</td><td>323</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRFLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNHWWT</td><td>FGQGTKVEIKR</td>

<td>5.62.1</td><td>383</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GAFTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNHWWT</td><td>FGQGTKVGIKR</td>

<td>5.64</td><td>387</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GFPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNNWWT QQYNNWWT</td><td>FGQGTKVEIKR</td>

<td>5.101.1</td><td>499</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS</td><td>RASQSLISNLA</td><td>WYQQKPGQ VSPGERATLSC APRLLIF LTISSLQSEDFAVYYC</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT</td><td>HQYNNWWT</td><td>FGQGTKVEIKR</td>

<td>5.103</td><td>505</td><td>L2</td><td>JK1</td><td>ETVMTQSPATLS VSPGERVTLSC</td><td>RASQSVISSL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYNNWWT</td><td>FGGGTKVEIKR FGQGTKVEIKR</td>

<td>5.54</td><td>359</td><td>L2</td><td>JK1 1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSLISNLA</td><td>WYQQKPGQ APRLLIF</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAIYYC</td><td>HQYNNWWT HQYNNWWT</td><td>FGQGTKVEIKR</td>

<td>5.13.1</td><td>231</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSNL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASTRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYYC</td><td>QQYN HWWT QQYNHWWT</td><td>FGGGTKVEIKR FGQGTKVEIKR</td>

<td>5.109</td><td>519</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSYL AND</td><td>WYQQKPGQ APRLLIY</td><td>GAFTRAT</td><td>GIPARFRGSGSGPEFT LTISSLQSEDFAVYYC ISSLQSEDFAVYYC</td><td>QQYSHWWT</td><td>FGQGTKVEIKR</td>

<td>5.108.1</td><td>515</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQSVSSYL AND</td><td>WYQQKPGQ APRLLIY</td><td>GAFTRAT</td><td>GIPARFRGSGSGPEFT LTISSLQSEAFAVYYC</td><td>QQYSHWWT</td><td>FGQGTKVEIKR</td>

<td>3.3.1</td><td>21</td><td>L2</td><td>JK1</td><td>EIVMTQSPATLS VSPGERATLSC</td><td>RASQTVSSDL AND</td><td>WYQQKPGQ APRLLIY</td><td>GASIRAT</td><td>GIPARFSGSGSGTEFT LTISSLQSEDFAVYSC</td><td>QQYYNWWT</td><td>FGQGTKVEIKR</td>

<td></td><td>639</td><td colspan="2">The germline</td><td>DIVMTQSPLSLP VTPGEPASISC</td><td>RSSQSLLHSN GYNYLD</td><td>WYLQKPGQ LGSNRAS SPQLLIY</td><td>LGSNRAS</td><td>GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQALQTPIT QALQTPIT</td><td>FGQGTRLEIKR</td>

<td>5.92</td><td>483</td><td>A3</td><td>JK5</td><td>DIVMTQSPLSLP VTPGEPASISC</td><td>RSSQSLLYSN GYNYLD</td><td>WYLQKPGQ SPQVLIY</td><td>LGSNRAS</td><td>GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQALQTPIT</td><td>FGQGTRLEIKR</td>

<td>5.82</td><td>445</td><td>A3</td><td>JK5</td><td>DIVMTQSPLSLP VTPGEPASISC</td><td>RSSQSLLHSN GYNYLD</td><td>WYLQKPGQ SPQLLIY VTPGEPASISC YNYLD SPQLLIY LKISRVEAEDVGVYYC</td><td>LGSNRAS</td><td>GVPDRFGGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQALQTPIT</td><td>FGQGTRLEIKR</td>

<td></td><td>640</td><td colspan="2">The germline</td><td>DVVMTQSPLSLP VTLGQPASISC</td><td>RSSQSLVYSD G NTYLN</td><td>WFQQRPGQ SPRRLIY</td><td>KVSNWDS</td><td>GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQGTHWPPL T</td><td>FGGGTKVEIKR</td>

<td>3.41</td><td>135</td><td>A1</td><td>JK4</td><td>DVVMTQSPLSLP VTLGQPASISC</td><td>RSSQSLVYSD G NTYLN</td><td>WFQQRPGQ SPRRLIY</td><td>KVSNWDS</td><td>GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQGTHWPLT</td><td>FGGGTNVEIKR</td>

<td>3.40</td><td>131</td><td>A1</td><td>JK4</td><td>DWMTQSPLSLP VTLGQPASISC</td><td>RSSQSLVYSD G NTYLN</td><td>WFQQRPGQ SPRRLIY</td><td>KDSNWDS</td><td>GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQGTHWPLT</td><td>FGGGTNVEIKR</td>

<td>3.13</td><td>57</td><td>A1</td><td>JK4</td><td>DVVMTQSPLSLP</td><td>RSSQSLVYSD</td><td>WFQQRPGQ SPRRLIY</td><td>KVSNWDS</td><td>GVPDRFSGSGSGTDFT</td><td>MQGTHWPPL T</td><td>FGGGTKVEIKR.</td>

EP 1 838 733 B1

<td>Name chain</td><td>KNOT ID No.:</td><td>V</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td></td><td></td><td></td><td></td><td>VTLGQPASISC</td><td>G NTYLN</td><td></td><td></td><td>LKISRVEAEDVGVYYC</td><td></td><td></td>

<td>3.12</td><td>53</td><td>A1</td><td>JK4</td><td>DVVMTQSPLSLP VTLGQPASISC</td><td>RSSQSLVYSD G NTYLN</td><td>WFQQRPGQ SPRRLIY</td><td>KVSNWDS</td><td>GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQGTHWPPL T</td><td>FGGGTKVEIKR</td>

<td>3.32</td><td>109</td><td>A1</td><td>JK4</td><td>DVVMTQSPLSLP VTLGQPASISC</td><td>RSSQSLVYSD G NTYLN</td><td>WFQQRPGQ SPRRLIY</td><td>KVSNWDS</td><td>GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQGTHWPPL T</td><td>FGGGTKVEIKR</td>

<td>4.18</td><td>189</td><td>A1</td><td>JK4</td><td>DVVMTQSPLSLP VTLGQPASISC</td><td>RSSQSLVYSD G NTYLN</td><td>WFQQRPGQ SPRRLIY</td><td>KVSNWDS</td><td>GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQGTHWPLT</td><td>FGGGTNVEIKR</td>

<td>4.16</td><td>185</td><td>A1</td><td>JK4</td><td>DVVMTQSPLSLP VTLGQPASISC</td><td>RSSQSLVYSD G NTYLN</td><td>WFQQRPGQ SPRRLIY</td><td>KVSNWDS</td><td>GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQGTHWPPL T</td><td>FGGGTKVEIKR</td>

<td>3.7</td><td>33</td><td>A1</td><td>JK4</td><td>DVVMTQSPLSLP VTLGQPASISC</td><td>RSSQSLVYSD G NTYLN</td><td>WFQQRPGQ SPRRLIY</td><td>KSNWDS</td><td>GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQGTHWPPL T</td><td>FGGGTKVEIKR</td>

<td>4.14</td><td>177</td><td>A1</td><td>JK4</td><td>DVVMTQSPLSLP VTLGQPASISC</td><td>RSSQSLVYSD G NTYLN</td><td>WFQQRPGQ SPRRLIY</td><td>KVSNWDS VSNWDS</td><td>GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQGTHWPPL T</td><td>FGGGTKVEIKR</td>

<td>3.15</td><td>63</td><td>A1</td><td>JK4</td><td>DVVMTQSPLSLP VTLGQPASISC</td><td>RSSQSLVYSD G NTYLN</td><td>WFQ1QRPGQ SPRRLIY</td><td>KVSNWDS</td><td>GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQGTHWPPL T</td><td>FGGGTKVEIKR</td>

<td></td><td>641</td><td colspan="2">The germline</td><td>DIVMTQSPLSLP VTPGEPASISC</td><td>RSSQSLLHSN GYNYLD</td><td>WYLQKPGQ SPQLLIY</td><td>LGSNRAS</td><td>GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQALQTPLT</td><td>FGGGTRVEIKR</td>

<td>3.10</td><td>45</td><td>A3</td><td>JK4</td><td>DIVMTQSPLSLP VTPGEPASISC</td><td>RSSQSLLHSN GYNYLD</td><td>WYLQKPGQ SPQLLIY</td><td>LGSNRAS</td><td>GVPDRFSGSGSGTDST LKISRVEAEDVGVYYC</td><td>MQALQTPLT</td><td>FGGGTKVEIKR</td>

<td>3.37</td><td>123</td><td>A3</td><td>JK4</td><td>DIVMTQSPLSLP VTPGEPASISC</td><td>RSSQSLLHSD GYNYLD</td><td>WYLQKPGQ SPQLLIY</td><td>LGSNRAS</td><td>GVPDRFSGSGSCTDFT LKISRVEAEDVGIYYC</td><td>MQALQTPHF</td><td>FGGGTKVEIKR</td>

<td></td><td>642</td><td colspan="2">The germline</td><td>DIVMTQSPDSLA VSLGERATINC</td><td>KSSQSVLYSS N NKNYLA</td><td>WYQQKPGQ PPKLLIY</td><td>WASTRES</td><td>GVPDRFSGSGSGTDFT LTISSLQAEDVAVYYC</td><td>QQYYSTPIT</td><td>FGQGTRLEIKR</td>

<td>5.78</td><td>427</td><td>B3</td><td>JK5</td><td>DIVMTQSPDSLA VSLGERATINC</td><td>KSSQSVLYSS N NQNFLA</td><td>WYQQKPGQ PPKLLIY</td><td>WASTRES</td><td>GVPDRFSGSGSGTDFT LTISSLQAEDVAVYYC</td><td>HQYYSTPIT</td><td>FGQGTRLEIKR</td>

<td>5.90</td><td>477</td><td>B3</td><td>JK5</td><td>DIVMTQSPDSLA VSLGEKATINC</td><td>KSSQSVIYSS N NQNFLA</td><td>WYQHKPGQ PPKLLIY</td><td>WASTRES</td><td>GVPDRFSDSGSGTDFT LTISSLQAEDVAVYYC</td><td>HQYYSTPIT</td><td>FGQGTRLEIKR</td>

<td>5.78.1</td><td>431</td><td>B3</td><td>JK5</td><td>DIVMTQSPDSLA VSLGERATINC</td><td>KSSQSVLYSS N NQNFLA</td><td>WYQQKPGQ PPKLLIY</td><td>WASTRES</td><td>GVPDRFSGSGSGTDFT LTISSLQAEDVAVYYC</td><td>HQYYSTPIT</td><td>FGQGTRLEIKR</td>

<td></td><td>643</td><td colspan="2">The germline</td><td>DWMTQSPLSLP VTLGQPASISC</td><td>RSSQSLVYSD G NTYLN</td><td>WFQQRPGQ SPRRLIY</td><td>KVSNWDS</td><td>GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQGTHW</td><td>FGQGTKLEIKR</td>

<td>4.3</td><td>147</td><td>A1</td><td>JK2</td><td>DVVMTQSPLSLP VTLGQPASISC</td><td>RSSRSLVYSD G NTYLN</td><td>WFQQRPGQ SPRRLIY</td><td>KVSNWDS</td><td>GVPDRFSGSGSGTDFT GVPDRFSGSGSGTDF-T LKISRVEAADVGVYYC</td><td>MQGTHWPCS</td><td>FGQGTKLEIKR</td>

<td></td><td>644</td><td colspan="2">The germline</td><td>DIVMTQSPDSLA VSLGERATINC</td><td>KSSQSVLYSS N NKNYLA</td><td>WYQQKPGQ PPKLLIY</td><td>WASTRES</td><td>GVPDRFSGSGSGTDFT LTISSLQAEDVAVYYC</td><td>QQYYSTT</td><td>FGGGTKVEIKR</td>

<td>5.43</td><td>327</td><td>B3</td><td>K4</td><td>DIVMTQSPDSLA VSLGERATINC</td><td>KSSQSVLYSS N NKNYLA</td><td>WYQQKPGQ PPKLLIY</td><td>WSSTRES</td><td>GVPDRFSGSGSGTDFT</td><td>QQYYSTPLT</td><td>FGGGTKVEIKR</td>

<td></td><td>645</td><td colspan="2">The germline</td><td>DWMTQSPLSLP VTLGQPASISC</td><td>RSSQSLVYSD G NTYLN</td><td>WFQQRPGQ SPRRLIY</td><td>KVSNWDS</td><td>LTISSLQAEDVAVYYC KVSNWDS GVPDRFSGSGSGTDFT.</td><td>MQGTHWPPT</td><td>FGQGTKVEIKR</td>

100

EP 1 838 733 B1

<td>Name chain</td><td>KNOT ID No.:</td><td>V</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td></td><td></td><td colspan="2"></td><td></td><td></td><td></td><td></td><td>LKISRVEAEDVGVYYC</td><td></td><td></td>

<td>3.20</td><td>83</td><td>A1</td><td>JK1</td><td>DVVMTQSPLSLP VTLGQPASISC</td><td>RSSQSLVYSD G NTYLN</td><td>WFQQRPGQ SPRRLIY</td><td>KVSKWDS</td><td>GVPDRFSGSGSGTDFT</td><td>MQGTHWPPT</td><td>FGQGTKVEIKR</td>

<td></td><td>646</td><td colspan="2">The germline</td><td>DIVMTQSPLSLP VTPGEPASISC</td><td>RSSQSLLHSN GYNYLD</td><td>WYLQKPGQ</td><td>LGSNRAS</td><td>LKISRVEAEDVGVYYC GVPDRFSGSGSGTDFT</td><td>MQALQWT</td><td>FGQGTKVEIKR</td>

<td>5.9</td><td>647</td><td>A3</td><td>JK1</td><td>DIVMTQSPLSLP VTPGEPASISC</td><td>RSSQSLLHSN GYNYLD</td><td>SPQLLIY WYLQKPGQ SPQLLIY</td><td>LGSNRAS</td><td>LKISRVEAEDVGVYYC GVPDRFSGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQALQTPWT</td><td>FGQGTKVEIKR</td>

<td>4.11</td><td>169</td><td>A3</td><td>JK1</td><td>DIVMTQSPLSLP VTPGEPASISC</td><td>RSSQSLLYSN GYNYLD</td><td>WYLQKPGQ SPQLLIY</td><td>LGSNRAS</td><td>GVPDRFGGSGSGTDFT LKISRVEAEDVGVYYC</td><td>MQALQTPWT</td><td>FGQGTKVEIKR</td>

<td></td><td>648</td><td colspan="2">The germline</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISSYL N</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSTT</td><td>FGGGTKVEIKR</td>

<td>5.115</td><td>531</td><td>012</td><td>JK4</td><td>DIEMTQSPSSLS ASVGDRVTITC</td><td>RASQNISSYL N</td><td>WYQQKPGK</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT</td><td>QQSYSSPLT</td><td>FGGGTKVEIKR</td>

<td>5.66</td><td>391</td><td>012</td><td>JK4</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISSYE N</td><td>APKLLIY WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>LTISSLQPEDFATYYC GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYTPLT</td><td>FGGGTKVEIKR</td>

<td>5.72</td><td>407</td><td>012</td><td>JK4</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQTISSYL N</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQTYSKSLT</td><td>FGGGTKVEIKR</td>

<td>5.114</td><td>527</td><td>012</td><td>JK4</td><td>DIEMTQSPSSLS ASVGDRVTITC</td><td>RASQNISSYL N</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSSPLT</td><td>FGGGTKVEIKR</td>

<td>4.5</td><td>153</td><td>012</td><td>JK4</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISIYLN</td><td>WYQQRPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSTPLT</td><td>FGGGTKVEIKR</td>

<td></td><td>649</td><td colspan="2">The germline</td><td>DIVMTQSPDSLA VSLGERATINC</td><td>KSSQSVLYSS N NKNYLA</td><td>WYQQKPGQ PPKLLIY</td><td>WASTRES</td><td>GVPDRFSGSGSGTDFT LTISSLQAEDVAVYYC</td><td>QQYYST</td><td>FGQGTKLEIKR</td>

<td>3.42</td><td>139</td><td>B3</td><td>JK2</td><td>DIVMTQSPDSLA VSLGERATINC</td><td>RSSQSILFSS N NKNYLA</td><td>WYQQKPGQ PPKLLLY</td><td>WASTRES</td><td>GVPARFSGSGSGTDFT LTISSLQAEDVAVYYC</td><td>QQYYSTPCS QYYSTPCS</td><td>FGQGTRLEIKR</td>

<td>5.60</td><td>375</td><td>B3</td><td>JK2</td><td>DIVMTQSPDSLA VSLGERATINC</td><td>KSSQSVLYSS N NKNYLV</td><td>WYQQKPGQ PPKLLIY</td><td>WASTRES</td><td>GVPDRFSGSGSGTDFT LTISSLQAEDVAVYYC</td><td>QQYYNTPCS</td><td>FGQGTKLEIKR</td>

<td></td><td>650</td><td colspan="2">The germline</td><td>EIVLTQSPGTLS LSPGERATLSC</td><td>RASQSVSSSY LA</td><td>WYQQKPGQ APRLLIY</td><td>GASSRAT</td><td>GIPDRFSGSGSGTDFT LTISRLEPEDFAVYYC</td><td>QQYGIT</td><td>FGQGTRLEIKR</td>

<td>5.58</td><td>369</td><td>A27</td><td>JK5</td><td>EIVLTQSPGTLS</td><td>RASQSVSSSY L</td><td>WYQQKAGQ</td><td>GASSRAT</td><td>GIPDRFSGSGSGTDFT</td><td>QQYGWSSIT</td><td>FGQGTRLEIKR</td>

<td>3.19.1</td><td>77</td><td>A27</td><td>JK5</td><td>EIVLTQSPGTLS. LSPGERATLSC</td><td>RASQSITGSY LA</td><td>WYQQKPGQ APRLLIC</td><td>GASSWAT</td><td>GIPDRFSGSGSGTDFT</td><td>QQYSSSPIT</td><td>FGQGTRLEIKR</td>

<td></td><td>651</td><td colspan="2">The germline</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGISNYL AND</td><td>WFQQKPGK APKSLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQYNSYPLT</td><td>FGGGTKVEIKR</td>

<td>3.16</td><td>65</td><td>L1</td><td>JK4</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGISSYL AND</td><td>WFQQKPGK APKSLIY</td><td>AASSLQS</td><td>GVPSKFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQYNSYPLT</td><td>FGGGTKVEIKR</td>

<td>5.67</td><td>395</td><td>L1</td><td>JK4</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGISNYIL AND</td><td>WFQQKPGK APESLIY</td><td>AASSLQT</td><td>GVPSKFSGNGSGTDFT LTISSLQPEDFATYYC</td><td>QQYNSYPLT</td><td>FGGGTKVEIKR</td>

101

EP 1 838 733 B1

<td>Name chain</td><td>KNOT ID No.:</td><td>V</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td></td><td>652</td><td colspan="2">The germline</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISSYL N</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSTPFT</td><td>FGPGTKVDIKR</td>

<td>5.86</td><td>455</td><td>AT 12</td><td>JK3</td><td>DIRMTQSPSSLS ASVGDRVTITC</td><td>RASQRISTYL N</td><td>WYQQKPGK APKFLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYTTPFT</td><td>FGPGTKVDIKR</td>

<td>5.71</td><td>403</td><td>AT 12</td><td>JK3</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISNYL N</td><td>WYQQKPGK APKLLIF</td><td>TASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYFC</td><td>QQSYSTPFT</td><td>FGPGTKVGIKR</td>

<td>5.25</td><td>271</td><td>AT 12</td><td>JK3</td><td>DIRMTQSPSSLS ASVGDRVTITC</td><td>RASQRISSYL N</td><td>WFQQKPGK APKFLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSTPFT</td><td>FGPGTKVDIKR</td>

<td>5.74</td><td>415</td><td>AT 12</td><td>JK3</td><td>DIRMTQSPSSLS ASVGDRVTITC</td><td>RASQRISTYL N</td><td>WYQQKPGK APKFLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYTTPFT</td><td>FGPGTKVDIKR</td>

<td>3.14</td><td>61</td><td>AT 12</td><td>JK3</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISSYL N</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQAEDFATYYC</td><td>QQSLT</td><td>FGPGTKVDIKR</td>

<td>5.111</td><td>523</td><td>AT 12</td><td>JK3</td><td>DIQMTQSPSSLS ASVGDRVTFTC</td><td>RASQSIITFLN</td><td>WFQHKPGK APKLLFY</td><td>GASSLES</td><td>GVPSRFSGSGSGTNFT LTISSLQPEDFATYYC</td><td>QQSYSDPFT</td><td>FGPGTKVDIKR</td>

<td>5.87</td><td>459</td><td>AT 12</td><td>JK3</td><td>DIRMTQSPSSLS ASVGDRVTITC</td><td>RASQGIRTYL N</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQNYTTPFT</td><td>FGPGTKVDIKR</td>

<td>4.2</td><td>143</td><td>AT 12</td><td>JK3</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISFYL N</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSSPFT</td><td>FGPGTKVDIKR</td>

<td>5.86.1</td><td>455</td><td>AT 12</td><td>JK3</td><td>DIRMTQSPSSLS ASVGDRVTITC</td><td>RASQRISTYL N</td><td>WYQQKPGK APKFLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYTTPFT</td><td>FGPGTKVDIKR</td>

<td>3.17</td><td>69</td><td>AT 12</td><td>JK3</td><td>DIQMTQSPSSLS ASVGDRITITC</td><td>RARQSISSYL N</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYFC</td><td>QQSYSTPFT</td><td>FGPGAKVDIKR</td>

<td>5.11</td><td>223</td><td>AT 12</td><td>JK3</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISNYL N</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSIPFT</td><td>FGPGTKVDIKR</td>

<td>5.45</td><td>335</td><td>AT 12</td><td>JK3</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISSYL N</td><td>WYQQKPGK APELLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYINPFT</td><td>FGPGTKVDIKR</td>

<td>5.12</td><td>227</td><td>AT 12</td><td>JK3</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISNYL N</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSIPFT</td><td>FGPGTKVDIKR</td>

<td></td><td>653</td><td colspan="2">The germline</td><td>EIVLTQSPGTLS LSPGERATLSC</td><td>RASQSVSSSY LA</td><td>WYQQKPGQ APRLLIY</td><td>GASSRAT</td><td>GIPDRFSGSGSGTDFT LTISRLEPEDFAVYYC</td><td>QQYGSST</td><td>FGGGTKVEIKR</td>

<td>6.2</td><td>537</td><td>A27</td><td>JK4</td><td>EIVLTQSPGTLS LSPGERATLSC</td><td>RASQSFSSSY LA</td><td>WFQQKPGQ APRLLIY</td><td>GASNRAT</td><td>GIPDRFSGSGSGTDFT LTISRLEPEDFAVYYC</td><td>HHFGTSPLT</td><td>FGGGTKVEIKR</td>

<td></td><td>654</td><td colspan="2">The germline</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>QASQDISNYL N</td><td>WYQQKPGK APKLLIY</td><td>DASNLET</td><td>GVPSRFSGSGSGTDFT FTISSLQPEDIATYYC</td><td>QQYDNLPIT</td><td>FGQGTRLEIKR</td>

<td>5.23</td><td>265</td><td>AT 18</td><td>JK5</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>QASQDISNYL N</td><td>WYQQKPGK APNLLIY</td><td>DASNLET</td><td>GVPSRFSGSGSGTDFT FTISSLQPEDIATYYC</td><td>QQYYNLPIT</td><td>FGQGTRLEIKR</td>

<td>5.17</td><td>245</td><td>AT 18</td><td>JK5</td><td>DIQMTQSPSSLS TSVGDRVTITC</td><td>QASQDIRNYL N</td><td>APKLLIH</td><td>DASNLET</td><td>FTITSLQPEDIATYYC</td><td>QQYANLPIT</td><td>FGQGTRLEIKR</td>

<td>5.29</td><td>283</td><td>AT 18</td><td>JK5</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>QASQDIRNYL N</td><td>WYQQKPGK APKLLIY</td><td>DASNLET</td><td>GVPSRFSGSGSGTDFT FTISSLQPEDIATYYC</td><td>QQYDNLPIT</td><td>FGQGTRLEIKR</td>

102

EP 1 838 733 B1

<td>Name chain</td><td>KNOT ID No.:</td><td>V</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td>5.76</td><td>421</td><td>AT 18</td><td>JK5</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>QASQDIRNYL N</td><td>WYQQKPGT APKLLIY</td><td>DASNLET</td><td>GVPSRFSGSGSGTDFT FTISSLQPEDIATYYC</td><td>QQYDNLPIT</td><td>FGQGTRLEIKR</td>

<td>5.10</td><td>219</td><td>AT 18</td><td>JK5</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>QASQDIRNYL N</td><td>WYQQKPGK APKLLIY</td><td>DASNLET</td><td>GVPSRFSGSGSGTDFT FTISSLQPEDIATYYC</td><td>QQYDNLPIT</td><td>FGQGARLEIKR</td>

<td>5.22</td><td>261</td><td>AT 18</td><td>JK5</td><td>DIRMTQSPSSLS ASVGDSVTITC</td><td>QASQDIRNYL N</td><td>WYQQKPGK APKLLIY</td><td>DASNLET</td><td>GVPSRFSGSGSGTDFT FTISSLQPEDIATYYC</td><td>QQYDNLPIT</td><td>FGQGTRLEIKR</td>

<td>5.37</td><td>307</td><td>AT 18</td><td>JK5</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>QASQDIRNYL N</td><td>WYQQKPGK APKLLIY</td><td>DASNLET</td><td>GVPSRFSGSGSGTDFT FTISSLQPEDIATYYC</td><td>QQYDNLPIT</td><td>FGQGTRLEIKR</td>

<td>5.31</td><td>291</td><td>AT 18</td><td>JK5</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>QASQDIRNYL N</td><td>WYQQKPGK APKLLIY</td><td>DASNLET</td><td>GVPSRFSGSGSGTDFT FTISSLQPEDIATYYC</td><td>QQYDNLPIT</td><td>FGQGTRLEIKR</td>

<td></td><td>655</td><td colspan="2">The germline</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGISNYL AND</td><td>WFQQKPGK APKSLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQYNSYT</td><td>FGPGTKVDIKR</td>

<td>3.34</td><td>117</td><td>L1</td><td>JK3</td><td>DIQMTQSPSSLS ASVGDRVSIIC</td><td>RASQGISNYL AND</td><td>WFQQKPGK APKSLIY</td><td>AASSLQS</td><td>GVPSKFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQYNSYPST</td><td>FGPGTKVDIKR</td>

<td>5.99</td><td>495</td><td>L1</td><td>JK3</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQDISNYL AND</td><td>WFQQKPGK APKSLIY</td><td>AASSLQS</td><td>GVPSQFSGSGSGTDFT</td><td>QQYNNYPFT</td><td>FGPGTKVDVKR</td>

<td></td><td>656</td><td colspan="2">The germline</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISSYL N</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>LTISSLQPEDFATYYC GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSTP</td><td>FGQGTKLEIKR</td>

<td>6.3.1</td><td>541</td><td>AT 12</td><td>JK2</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSIRSYL N</td><td>WYQQKPGK APKVLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSTLCS</td><td>FGQGTKLEIKR</td>

<td>5.97</td><td>493</td><td>AT 12</td><td>JK2</td><td>ASVGTRVTITC DIQMTQSPSSLS</td><td>RASQSIRSYL N</td><td>WYQQKPGK APKLLIY</td><td>AASSLQR</td><td>GVPSRFSGSGSGTDFT LTISSLQAEDFATYYC</td><td>QQSYTTPLCS</td><td>FGQGTRLEIKR</td>

<td>5.27</td><td>275</td><td>AT 12</td><td>JK2</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISSYL N</td><td>WYQQKPGK APKILIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSCSTPPE CS</td><td>FGQGTKLEIKR</td>

<td>5.21</td><td>257</td><td>AT 12</td><td>JK2</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISSYL N</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSRSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSVPCS</td><td>FGQGTKLEIKR</td>

<td>6.3</td><td>657</td><td>AT 12</td><td>JK2</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSIRSYL N</td><td>WYQQKPGK APKVLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSTLCS</td><td>FGQGTKLEIKR</td>

<td>5.93</td><td>485</td><td>AT 12</td><td>JK2</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISSYL N</td><td>WYQQKPGK APKVLIY</td><td>GASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSTLCS</td><td>FGQGTKLEIKR</td>

<td></td><td>658</td><td colspan="2">The germline</td><td>DIQMTQSPSSVS ASVGDRVTITC</td><td>RASQGISSWL AND</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQANSFPLT</td><td>FGGGTKVEIKR</td>

<td>5.95</td><td>489</td><td>L5</td><td>JK4</td><td>DIQMTQSPSSVS ASVGDRVTITC</td><td>RASQGISSWL AND</td><td>WYQQKPGK APKLLIF</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQANSFPLT</td><td>FGGGTKVEIKR</td>

<td>5.52.1</td><td>353</td><td>L5</td><td>JK4</td><td>DIQMTQSPSSVS ASVGDRVTITC</td><td>RASQGISSWL AND</td><td>WYQQKPGK APKLLIY</td><td>AVSSLES</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQALT</td><td>FGGGTKVEIKR</td>

<td></td><td>659</td><td colspan="2">The germline</td><td>EIVLTQSPGTLS LSPGERATLSC</td><td>RASQSVSSSY LA</td><td>WYQQKPGQ APRLLIY</td><td>GASSRAT</td><td>GIPDRFSGSGSGTDFT LTISRLEPEDFAVYYC</td><td>QQYGSSPFT</td><td>FGPGTKVDIKR</td>

<td>3.8</td><td>37</td><td>A27</td><td>JK3</td><td>EIVLTQSPGTLS LSPGERATLSC</td><td>RASQSVSSSY LA</td><td>WYQQKPGQ APRLLIY</td><td>GASNRAT</td><td>GIPDRFSASGSGTDFT LTISRLEPEDFAVYYC</td><td>QQFGTSPFT</td><td>FGPGTKVDIKR</td>

103

EP 1 838 733 B1

<td>Name chain</td><td>KNOT ID No.:</td><td>V</td><td>J</td><td>FR1</td><td>CDR1</td><td>FR2</td><td>CDR2</td><td>FR3</td><td>CDR3</td><td>J</td>

<td>3.21</td><td>87</td><td>A27</td><td>JK3</td><td>EIVLTQSPGTLS LSPGERATLSC</td><td>RASQSVSSSY LA</td><td>WYQQKPGQ APRLLIY</td><td>GTSSRAT</td><td>GIPDRFSGSGSGTDFT LTISRLEPEDFAVYYC</td><td>QQYGSSLFT</td><td>FGPGTKVDIKR</td>

<td></td><td>660</td><td colspan="2">The germline</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>QSQDISNYLN</td><td>WYQQKPGK APKLLIY</td><td>DASNLET</td><td>GVPSRFSGSGSGTDFT FTISSLQPEDIATYYC</td><td>QQYDNLT</td><td>FGGGTKVEIKR</td>

<td>5.18</td><td>249</td><td>AT 18</td><td>JK4</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>QASQDITNYL N</td><td>WYQKKPGK APKVLIY</td><td>DASNLET</td><td>GVPSRFSGSGSGTGFT FTISSLQPEDIATYYC</td><td>QQYDHIPLT</td><td>FGGGTKVEIKR</td>

<td>5.48</td><td>343</td><td>AT 18</td><td>JK4</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>QASQDITNYL N</td><td>WYQQKPGK APKLLIY</td><td>DASNLET</td><td>GVPSRFSGSGSGTDFT FTISSLQPEDIATYFC</td><td>QQYDNLPLT</td><td>FGGGTKVEIKR</td>

<td></td><td>661</td><td colspan="2">The germline</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISSYL N</td><td>WYQQKPGK APKLLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSTPT</td><td>FGQGTKVEIKR</td>

<td>5.36</td><td>303</td><td>AT 12</td><td>JK1</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQSISSYL N</td><td>WYQQKPGK APKLLIY</td><td>GASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQSYSIPRT</td><td>FGQGTKVEIKR</td>

<td></td><td>662</td><td colspan="2">The germline</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGISNYL AND</td><td>WFQQKPGK APKSLIY</td><td>AASSLQS</td><td>GVPSRFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQYNSYPRT</td><td>FGQGTKVEIKR</td>

<td>5.80</td><td>437</td><td>L1</td><td>JK1</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQDISNYL AND</td><td>WFQQKPGKAPKSLIY</td><td>AASSLQS</td><td>GVPSKFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQYNSYPRT</td><td>FGQGTKVEIKR</td>

<td>6.10</td><td>557</td><td>L1</td><td>JK1</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQDISNYL AND</td><td>WFQQKPGKAPKSLIY</td><td>AVSSLQS</td><td>GVPSKFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQYNSYPRT</td><td>FGQGTKVEIKR</td>

<td>9.9</td><td>165</td><td>L1</td><td>JK1</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGISNYL AND</td><td>WFQQKPGK APKSLIY</td><td>AASSLQS</td><td>GVPSKFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQYNSYPST</td><td>FGQGTKVEIKR</td>

<td>4.8</td><td>161</td><td>L1</td><td>JK1</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGISNYL AND</td><td>WFQQKPGK APKSLIY</td><td>AASSLQS</td><td>GVPSKFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQYNSYPST</td><td>FGQGTKVEIKR</td>

<td>5.30</td><td>287</td><td>L1</td><td>JK1</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQDISNYL AND</td><td>WFQQKPGK APKSLIY</td><td>AASSLQS</td><td>GVPSKFSGSGSGTDFT LTISSLQPEDFATYYC</td><td>QQYNSYPRT</td><td>FGQGTKVEIKR</td>

<td>6.6</td><td>549</td><td>L1</td><td>JK1</td><td>DIQMTQSPSSLS ASVGDRVTITC</td><td>RASQGISNYL AND</td><td>WFQQKPGK APKSLIY</td><td>AASSLES</td><td>LTISSLQPEDFATYYC</td><td>QQYNSYPRT</td><td>FGQGTKVESKR</td>

104

EP 1 838 733B1

EXAMPLE 14

DETERMINATION OF CANCELLANEOUS CLASSES OF ANTIBODY [0214] Chothia, et al. described the structure of the antibody as the "canonical class" of the hypervariable regions in each immunoglobulin chain (J Mol Biol. 1987 Aug 20; 196 (4): 901-17). The atomic structures of the Fab and VL fragments of a series of immunoglobulins were examined to determine the relationship between their amino acid sequences and the three-dimensional structures of their antigen binding sites. Chothia, et al. they found that the conformation of the main chain of hypervariable regions was originally due to the relatively small number of residues, by their packing, hydrogen bonds or the ability to adopt atypical conformations fi, psi or omega. It was found that these residues occur in places within the hypervariable regions and in the preserved beta-sheet backbone. By studying sequences of immunoglobulins having an unknown structure, Chothia et al. showed that many immunoglobulins have hypervariable regions that are similar in size to known structures and moreover contain identical residues at the sites responsible for the observed conformation.

[0215] Their discovery suggested that these hypervariable regions have conformations close to the conformations in known structures. In the case of five of the hypervariable regions, the conformation repertoire seems to be limited to a relatively small number of discrete structural classes. These occurring surface conformations of the main chain of hypervariable regions are called "canonical structures". Further work of 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 conformations a chain for at least five of the six hypervariable antibody regions.

[0216] The CDRs of each antibody described above were tested to determine their canonical class. As is known, the canonical classes were assigned only CDR1 and CDR2 of the antibody heavy chain as well as 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 * HCDR1-HCDR2-LCDR1-LCDR2-LCDR3, where "HCDR" refers to the heavy chain CDR, and "LCDR" refers to the light chain CDR. Thus, for example, canonical class 1-3-2-1-5 refers to an antibody that possesses HCDR1, which belongs to canonical class 1, HCDR2, which belongs to canonical class 3, LCDR1, which belongs to the canonical class 2, LCDR2, which belongs to the canonical class 1 and LCDR3, which belongs to the canonical class 5.

[0217] Assignment to a given canonical class was done when there was 70% or more of the amino acid identity in the antibody with the amino acids defined for each canonical class. If

105

The identity to the canonical class was marked with an asterisk ("*") to indicate that the best canonical class was estimated based on the length of each CDR and all of the data. If there was no canonical class match with the same length of CDR, the canonical class assignment is marked "Y". The amino acids defined for each antibody can be found, for example, in the Chothia et al. Articles referred to above. Table 13 provides data on the canonical classes for each of the Ang-2 antibodies.

Table 13. The canonical classes of antibodies against Ang-2

<td>Antibody</td><td>The canonical class</td>

<td>5.18</td><td>1-1-2-1-1</td>

<td>5.81</td><td>1-1-2-1-1</td>

<td>5.66</td><td>1-1-2-1-1</td>

<td>5.48</td><td>1-1-2-1-1</td>

<td>5.23</td><td>1-1-2-1-1</td>

<td>3.33</td><td>1-1-2-1-1</td>

<td>5.15</td><td>1-1-2-1-3 *</td>

<td>4.3</td><td>1-1-4-1-1</td>

<td>3.12</td><td>1-1-4-1-5 *</td>

<td>4.16</td><td>1-1-4-1-5 *</td>

<td>3.13</td><td>1-1-4-1-5 *</td>

<td>3.7</td><td>1-1-4-1-5 *</td>

<td>3.32</td><td>1-1-4-1-5 *</td>

<td>3.37</td><td>1-1-4-1-Y</td>

<td>5.30</td><td>1-2-2-1-1</td>

<td>3.6</td><td>1-2-2-1-1</td>

<td>6.6</td><td>1-2-2-1-1</td>

<td>3.34</td><td>1-2 * -2-1-1</td>

<td>5.74</td><td>1-2 * -2-1-1</td>

<td>5.38</td><td>1-3-2-1-1</td>

<td>5.28.1</td><td>1-3-2-1-1</td>

<td>5.6</td><td>1-3-2-1-1</td>

<td>5.44</td><td>1-3-2-1-1</td>

<td>5.28</td><td>1-3-2-1-1</td>

<td>5.86.1</td><td>1-3-2-1-1</td>

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<td>Antibody</td><td>The canonical class</td>

<td>5.3 5.1</td><td>1-3-2-1-1</td>

<td>5.35</td><td>1-3-2-1-1</td>

<td>5.8</td><td>1-3-2-1-1</td>

<td>5.22</td><td>1-3-2-1-1</td>

<td>4.15</td><td>1-3-2-1-1</td>

<td>5.67</td><td>1-3-2-1-1</td>

<td>5.87</td><td>1-3-2-1-1</td>

<td>5.10</td><td>1-3-2-1-1</td>

<td>5.71</td><td>1-3-2-1-1</td>

<td>5.21</td><td>1-3-2-1-1</td>

<td>5.80</td><td>1-3-2-1-1</td>

<td>3.18</td><td>1-3-2-1-1</td>

<td>3.11</td><td>1-3-2-1-1</td>

<td>3.26</td><td>1-3-2-1-1</td>

<td>5.31</td><td>1-3-2-1-1</td>

<td>5.76</td><td>1-3-2-1-1</td>

<td>4.9</td><td>1-3-2-1-1</td>

<td>5.17</td><td>1-3-2-1-1</td>

<td>3.39</td><td>1-3-2-1-1</td>

<td>5.37</td><td>1-3-2-1-1</td>

<td>3.22</td><td>1-3-2-1-1</td>

<td>5.29</td><td>1-3-2-1-1</td>

<td>5.73</td><td>1-3-2-1-1</td>

<td>5.12</td><td>1-3-2-1-1</td>

<td>3.1</td><td>1-3-2-1-1</td>

<td>5.11</td><td>1-3-2-1-1</td>

<td>4.8</td><td>1-3-2-1-1</td>

<td>5.24</td><td>1-3-2-1-1</td>

<td>6.3.1</td><td>1-3-2-1-1 *</td>

<td>5.56.1</td><td>1-3-2-1-1 *</td>

<td>5.111</td><td>1-3-2-1 * -1</td>

<td>4.13</td><td>1-3-2-1 * -1</td>

<td>5.52</td><td>1-3 -2-1-3 * *</td>

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<td>Antibody</td><td>The canonical class</td>

<td>5.16.1</td><td>1-3-2-1-3 *</td>

<td>5.39.1</td><td>1-3-2-1-3 *</td>

<td>5.103.1</td><td>1-3-2-1-3 *</td>

<td>5.101.1</td><td>1-3-2-1-3 *</td>

<td>5.54.1</td><td>1-3-2-1-3 *</td>

<td>5.83.1</td><td>1-3-2-1-3 *</td>

<td>5.62</td><td>1-3-2-1-3 *</td>

<td>5.88.1</td><td>1-3-2-1-3 *</td>

<td>5.40.2</td><td>1-3-2-1-3 *</td>

<td>5.109</td><td>1-3-2-1-3 *</td>

<td>5.64</td><td>1-3-2-1-3 *</td>

<td>5.13</td><td>1-3-2-1-3 *</td>

<td>3.3</td><td>1-3-2-1-3 *</td>

<td>5.41</td><td>1-3-2-1-3 *</td>

<td>3.3.1</td><td>1-3-2-1-3 *</td>

<td>3.31.1</td><td>1-3-2-1-3 *</td>

<td>5.41.1</td><td>1-3-2-1-3 *</td>

<td>5.62.1</td><td>1-3-2-1-3 *</td>

<td>5.108.1</td><td>1-3-2-1-3 *</td>

<td>5.13.1</td><td>1-3-2-1-3 *</td>

<td>5.97</td><td>1-3-2-1-5 *</td>

<td>5.52.1</td><td>1-3-2-1-Y</td>

<td>5.78.1</td><td>1-3-3-1-1</td>

<td>5.60</td><td>1-3-3-1-1</td>

<td>5.43</td><td>1-3-3-1-1</td>

<td>5.90</td><td>1-3-3-1 * -1</td>

<td>3.42</td><td>1-3-3-1 * -1</td>

<td>4.11</td><td>1-3-4-1-1</td>

<td>3.40</td><td>1-3-4-1-1</td>

<td>5.82</td><td>1-3-4-1-1</td>

<td>4.18</td><td>1-3-4-1-1</td>

<td>3.41</td><td>1-3-4-1-1</td>

<td>5.92</td><td>1-3-4-1-1</td>

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<td>Antibody</td><td>The canonical class</td>

<td>3.10</td><td>1-3-4 -1-1 *</td>

<td>4.14</td><td>1-3-4-1-5 *</td>

<td>3.19.1</td><td>1-3-8 -1-1 *</td>

<td>6.2</td><td>1-3-8 -1-1 *</td>

<td>3.8</td><td>1-3-8 -1-1 *</td>

<td>5.58</td><td>1-3-8-1-1 *</td>

<td>4.5</td><td>1-4 * -2-1-1</td>

<td>5.1</td><td>1-4 * -2-1-1</td>

<td>4.2</td><td>1-4 * -2-1-1</td>

<td>3.9</td><td>1-4 * -2-1-1</td>

<td>5.45</td><td>1-4 * -2-1-1</td>

<td>3.17</td><td>1-4 * -2-1-1</td>

<td>5.72</td><td>1-4 * -2-1-1 *</td>

<td>3.14</td><td>1-4 * -2-1-Y</td>

<td>5.115</td><td>3-1-2-1-1</td>

<td>5.36</td><td>3-1 * -2-1-1</td>

<td>3.2</td><td>3-1-2-1-3 *</td>

<td>3.21</td><td>3-1-8-1-1 *</td>

<td>5.61</td><td>3-Y-2-1-3 *</td>

[0218] Table 14 is the analysis of the number of antibodies per class. The right column shows the number of antibodies possessing the given canonical class indicated in the left column

Table 14. Number of anti-Ang-2 antibodies in each canonical class

<td>H1-H2-L1-L2-L3</td><td>The number of mAbs</td>

<td>1-1-2-1-1</td><td>6</td>

<td>1-1-2-1-3 *</td><td>1</td>

<td>1-1-4-1-1</td><td>1</td>

<td>1-1-4-1-5 *</td><td>5</td>

<td>1-1-4-1-Y</td><td>1</td>

<td>1-2-2-1-1</td><td>5</td>

<td>1-3-2-1-1</td><td>38</td>

<td>1-3-2-1-3 *</td><td>21</td>

<td>1-3-2-1-5 *</td><td>1</td>

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<td>H1-H2-L1-L2-L3</td><td>The number of mAbs</td>

<td>1-3-2-1-Y</td><td>1</td>

<td>1-3-3-1-1</td><td>5</td>

<td>1-3-4-1-1</td><td>7</td>

<td>1-3-4-1-5 *</td><td>1</td>

<td>1-3-8 -1-1 *</td><td>4</td>

<td>1-4 * -2-1-1</td><td>7</td>

<td>1-4 * -2-1-Y</td><td>1</td>

<td>3-1-2-1-1</td><td>2</td>

<td>3-1-2-1-3 *</td><td>1</td>

<td>3-1-8-1-1 *</td><td>1</td>

<td>3-Y-2-1-3 *</td><td>1</td>

<td colspan="2">Comments: 1. Those with * mean that the assignment was made to the best matching class, although there were some exceptions in the defining entries 2. Y means that there is no matching canonical class with the same length of CDR</td>

EXAMPLE 15

MAPPING OF EPITOPES ANG-2 ANTIBODIES [0219] The binding domain of 27 antibodies neutralizing Ang-2 activity was analyzed.

[0220] The humanized Ang-2 was ordered from R &amp; D systems (623-AN). Goat anti-human-Ang-2 polyclonal antibodies (R &amp; D systems AF623) were chosen because of their ability to recognize rhAng-2 in direct ELISA and Western blotting. Polyclonal antibodies were biotinylated for HRP conjugated streptavidin detection.

[0221] All restriction enzymes were provided by New England Biolabs and used according to the manufacturer's instructions. All DNA plasmids were purified using centrifuge spin columns (Invitrogen, Carlsbad, CA). The oligonucleotide primers used for cloning and site-directed mutagenesis were synthesized by Qiagen Operon. [0222] Antibodies: 27 human anti-Ang-2 antibodies derived from the hybridoma line were selected based on their ability to inhibit the binding of rhAng-2 to its receptor. Antibodies are listed below in Table 15.

Table 15.

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<td></td><td>Hybridoma code</td><td>OD650 in the inhibition test</td>

<td>1</td><td>x5.56</td><td>.0863</td>

<td>2</td><td>x3.38</td><td>.0792</td>

<td>3</td><td>x3.19</td><td>.0633</td>

<td>4</td><td>x3.28 *</td><td>.0588</td>

<td>5</td><td>X3.3</td><td>.0558</td>

<td>6</td><td>x3.31 *</td><td>.0516</td>

<td>7</td><td>x5.88 *</td><td>.0874</td>

<td>8</td><td>x5.49 *</td><td>.0856</td>

<td>9</td><td>x5.101</td><td>.0824</td>

<td>10</td><td>x5.41 *</td><td>.0776</td>

<td>11</td><td>x5.108 *</td><td>.0688</td>

<td>12</td><td>x5.62</td><td>.0650</td>

<td>13</td><td>x5.39</td><td>.0519</td>

<td>14</td><td>x5.16 *</td><td>0.0500</td>

<td>15</td><td>x5.83</td><td>.0484</td>

<td>16</td><td>x5.54</td><td>.0440</td>

<td>17</td><td>x5.14</td><td>.0430</td>

<td>18</td><td>x5.86</td><td>0.0419</td>

<td>19</td><td>x5.78</td><td>.0984</td>

<td>20</td><td>x5.103 *</td><td>.1013</td>

<td>21</td><td>x5.28</td><td>.0821</td>

<td>22</td><td>x5.40</td><td>.0691</td>

<td>23</td><td>x5.35 *</td><td>.0663</td>

<td>24</td><td>x6.3</td><td>.0617</td>

<td>25</td><td>x5.13</td><td>.0744</td>

<td>26</td><td>x5.2</td><td>.0690</td>

<td>27</td><td>x5.52</td><td>.0627</td>

Characterization of Epitopes 27 neutralizing anti-Ang-2 antibodies

Dot Blots [0223] RhAng-2 (R &amp; D systems) was dropped in its native or reduced form on a nitrocellulose membrane using a Bio-Dot Microfiltration unit. All human monoclonal antibodies (MAbs) derived

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Human anti-Ang-2 binds to unreduced Ang-2 but not to the reduced form, indicating that all mAbs recognize conformational epitopes that are apparently destroyed along with protein reduction. Cloning and Expression of Ang1 and Ang-2 Proteins [0224] To better understand the structural basis of the interaction of mAbs and Ang-2, a number 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 exhibit only 60% homology in their protein sequence, they both share the same modular structure composed of a coiled-coil domain at the amino terminus and a fibrinogen-like domain at the carboxyl terminus.

Cloning of human Ang-1 and Ang-2 [0225] Two alternative splicing forms of human Ang-2 human cDNA were amplified from human umbilical vein endothelial cell line (HUVEC, human umbilical vein endothelial cell). PCR amplification of the HUVEC cDNA using Ang-2 specific primers showed both full-length Ang-2 (1491 bp) and the Ang-2443 variant with 1330 base pairs (Injune et al., (2000) JBC 275: 18550). Ang-2 443^{is a variant} g^enerowans^{m on the road}alternative splicing of exon B and missing part of the coiled-coil domain (amino acids 96-148). Both Ang-2 cDNA was cloned into the pCD3.1 expression vector and expressed in 293F cells as shown in Figure 6. Human Ang-1 cDNA was obtained by RT-pCr using total RNA extracted from the human breast cell line MDA-MB231. CDNA 1.5 Kb was cloned into the expression vector pCR3.1 and expression was detected in the supernatant of transiently transfected 293F cells. ELISA [0226] Binding of 27 mAbs to supernatants prepared from transient transfection of Ang-2 and Ang1 cDNA was examined using an antibody ELISA binding assay. Ang-2, Ang-2 443^{and Ang-1 bound to an EL | SA plate coated with goats}polyclonal antibodies against (respectively) human Ang-2 or Ang-1. Binding of the best 27 human monoclonal antibodies was detected with HRP conjugated goat anti-human antibody followed by a colorimetric substrate for horseradish peroxidase (Enhanced K-Blue TMB substrate Neogen Corporation). The absorbance of each well on the ELISA plate was measured at 450 nm on an automatic microplate reader. Transfection of 293F Cells [0277] Human embryonic 293F kidney cells were maintained in 10% of the cow's plasma in Dulbecco's modified Eagle's medium

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EP 1 838 733 B1 supplemented with penicillin and streptomycin. 293F cells were transiently transfected with calcium phosphate. After 72 hours, the medium was harvested and filtered for ELISA and Western Blot analysis.

[0228] All 27 antibodies have been shown to bind specifically to Ang-2 / Ang-2443 antigens. Cross-reactivity with human Ang-1 was not detected. Amino acids 96-148 in the Ang-2 coiled-coil domain, which are missing in the Ang-2443 protein sequence, were excluded as the binding domain for each of the 27 antibodies.

Construction of Ang-1 / Ang-2 Chimeric Molecules [0229] The restriction cleavage sites common in the human genes Ang-1 and Ang-2 were used to construct the chimeric chimeric Angiopoietin-like proteins of the frame.

[0230] Four constructs were made: Human Ang-1/2 BsmI, Ang-2/1 BsmI, Ang-1 / 2SspI and Ang-2/1 SspI. All proteins were expressed and secreted in detectable amounts measured by ELISA using polyclonal antibodies against human Ang-1 and Ang-2.

[0231] Amino acid junction points are in the following positions:

BsmI- 117 (Ang-2) / 119 ((Ag-l)

Sspl-353 (Ang-2) / 354 (Ang-1) [0232] The difference of one amino acid is due to the presence of 497 residues in human Ang-1 compared to the 496 residues in human Ang-2. All constructs were expressed in 293F cells and detected with goat anti-human antibodies against Ang-1 and Ang-2. The best 27 antibodies were tested for their ability to bind chimeric Ang-1/2 molecules. All 27 antibodies showed a similar binding pattern only with the Ang-1 / 2BsmI construct. The results of these experiments indicate that the binding domain for all antibodies is found between residues 117-496, most likely in the fibrinogen binding domain, where the epitope is broken down in the Ang proteins of the SspI fusion around amino acid 535.

Construction of Ang-2 Chimeric Mouse / Human Molecules [0233] Because Ang-2 shares ~ 55% amino acid identity with Ang-1, it was difficult to find a common restriction site for use in cloning chimeric molecules. Human and mouse Ang-2 are more similar, having about 85% sequence homology. Mouse cDNA Ang-2

113

Cloned in the pCMCsport expression vector was ordered from Invitrogen. Selected 27 antibodies were tested for their immunoreactivity with recombinant mouse Ang-2. Six of 27 cross-reacted with mouse Ang-2 with 100% of their human-Ang-2 immunoreactivity, indicating that the mouse antigen retains most of the immunoreactivity of human Ang-2 (Data is summarized in Table 16).

[0234] The human-mouse chimeric system was chosen to map epitopes based on the finding that most of the antibodies bind specifically to the human Ang-2 antigen and do not cross-react with mouse Ang-2. Various Ang-2 cDNA constructs were generated and cloned into a mammalian expression vector.

[0235] The mouse / human Ang-2 constructs were prepared using a common StuI restriction site located in the fibrinogen binding domain with the amino acid site at residue 311. All human Ang-2 mAbs were able to bind Stu mouse / human Ang. 2, indicating that the binding domain is located 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 Stul-Tfil fragment replaced the mouse sequence in the Ang-2 mouse cDNA. (Figure 9).

[0236] All antibodies specific for human Ang-2 showed a positive ELISA signal with 15-100% of their immunoreactivity against human Ang-2. In the region between amino acids 310-400, the binding domain of two antibodies with the unique use of the VH 5.35.1 (VH3-20) and 5.28.1 (VH3-43) gene is mapped as shown in Table 17.

[0237] Antibodies that cross-react with mouse Ang-2 were expected to have 100% reactivity and could not be mapped using chimeric mouse / human constructs.

Targeted Mutagenesis [0238] To define important residues involved in the binding site of various antibodies, several human Ang-2 residues were mutated and screened for binding in an ELISA test against the entire antibody panel.

[0239] Since the direct binding detected by the ELISA is insensitive to small and medium differences in affinity, the large changes in binding observed after the substitution of a single amino acid are likely to identify key sites that interact with the antibody. In addition, anti-human Ang-2 polyclonal antibodies retain 100% reactivity with each construct, indicating that the mutagenesis procedure did not introduce any broad structural changes in the Ang-2 molecule. Two independent substitutions of Val to Met at position 345 (V345M) and His at Gln at position 375 (H375Q) were ignored by all 27 antibodies, indicating that these residues are not reactive, or that alterations of conformational epitopes require more than one amino acid substitution. The substitution of two residues at positions 365 and 367 dramatically changed the binding of one antibody, Mab 5.35.1. Analysis

114

The sequence 5.35.1 showed the unique use of VH3-20 and the unique CDR3 on both heavy and light chains. All the fusion points of the Ang-2 chimeric molecules and the point mutations are marked in Figure 8. Figure 9 is a comparison of the murine Ang-1 amino acid sequence (SEQ ID NO: 5), human Ang-1 (SEQ ID NO: 2) of mouse Ang-2 ( SEQ ID NO: 4) and human Ang-2 (SEQ ID NO: 3). The arrowhead indicates the cutting point for the hydrophobic lead sequences. The arrows define the boundaries of the coiled-coil and fibrinogen domains. The filled circles show conserved cysteine ​​residues (image taken from Maisonpierre et al., 1997, Science 277: 55). [0240] Data on binding to Ang-2 molecules are summarized below in Table 16:

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Table 16.

<td>Maple</td><td>bin</td><td>Binding domain</td><td>Human Ang-2-443</td><td>Mouse CX</td><td>M / H BsmI</td><td>M / H Stul 310-496</td><td>Stu-Tfil 310-400</td><td>V345M</td><td>N365Q367</td><td>H375Q</td>

<td>5.39.1</td><td>1</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>25%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.16.1 *</td><td>1</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>thirty%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.86.1</td><td>1</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>23%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.54.1</td><td>1</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>77%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.14.1</td><td>1</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>31%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.83.1</td><td>1</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>86%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.101.1</td><td>1</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>28%</td><td>100%</td><td>100%</td><td>100%</td>

<td>6.3.1</td><td>7</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>27%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.103.1 *</td><td>2</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>40%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.78.1</td><td>5</td><td>Domain Fib.-Similar</td><td>100%</td><td>Yes</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.35.1 *</td><td>8</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td><td>15%</td><td>100%</td>

<td>5.40.2 *</td><td>8</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>65%</td><td>100%</td><td>100%</td><td>100%</td>

<td>3.19.1</td><td>6</td><td>Domain Fib.-Similar</td><td>100%</td><td>Yes</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.108.1 *</td><td>1</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>36%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.52.1</td><td></td><td>Domain Fib.-Similar</td><td>100%</td><td>Yes</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.56.1</td><td>3</td><td>Domain Fib.-Similar</td><td>100%</td><td>Yes</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.2</td><td></td><td>Domain Fib.-Similar</td><td>100%</td><td>Yes</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.28.1</td><td>4</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.41.1 *</td><td>1</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>thirty%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.13.1</td><td></td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>27%</td><td>100%</td><td>100%</td><td>100%</td>

<td>3.3.1</td><td>1</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>15%</td><td>100%</td><td>100%</td><td>100%</td>

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EP 1 838 733 B1

<td>Maple</td><td>bin</td><td>Binding domain</td><td>Human Ang-2-443</td><td>Mouse CX</td><td>M / H BsmI</td><td>M / H Stul 310-496</td><td>Stu-Tfil 310-400</td><td>V345M</td><td>N365Q367</td><td>H375Q</td>

<td>3.31.1 *</td><td>1</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>15%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.62.1</td><td>1</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>thirty%</td><td>100%</td><td>100%</td><td>100%</td>

<td>3.28.1 *</td><td>1</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>31%</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.88.1 *</td><td>1</td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>20%</td><td>100%</td><td>100%</td><td>100%</td>

<td>3.38</td><td></td><td>Domain Fib.-Similar</td><td>100%</td><td>Yes</td><td>100%</td><td>100%</td><td>ND</td><td>100%</td><td>100%</td><td>100%</td>

<td>5.49 *</td><td></td><td>Domain Fib.-Similar</td><td>100%</td><td>No</td><td>100%</td><td>100%</td><td>35%</td><td>100%</td><td>100%</td><td>100%</td>

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EP 1 838 733B1

Data are presented as percent binding compared to human Ang-2.

Table 17: Sequence analysis and cross reactivity with murine Ang-2.

<td>Code hybridoma</td><td>OD650 in the inhibition test</td><td>Mice Ang2 XR</td><td>bin</td><td>VH</td><td>DH</td><td>jh</td><td>VK</td><td>jk</td>

<td>x5.56</td><td>.0863</td><td>Yes</td><td>3</td><td>VH3-33</td><td>D1-7</td><td>JH4b</td><td>A20</td><td>JK3</td>

<td>x3.38</td><td>.0792</td><td>Yes</td><td>2</td><td></td><td></td><td></td><td></td><td></td>

<td>x3.19</td><td>.0633</td><td>Yes</td><td>6</td><td>VH3-30</td><td>D3-3</td><td>JH5b</td><td>A27</td><td>JK5</td>

<td>x3.28 *</td><td>.0588</td><td>No</td><td>1</td><td>VH3-7</td><td>D6-19</td><td>JH4b</td><td>L2</td><td>JK1</td>

<td>X3.3</td><td>.0558</td><td>No</td><td>1</td><td>VH3-7</td><td>D6-19</td><td>JH4b</td><td>L2</td><td>JK1</td>

<td>x3.31 *</td><td>.0516</td><td>No</td><td>1</td><td>VH3-7</td><td>D6-19</td><td>JH4b</td><td>L2</td><td>JK1</td>

<td>x5.88 *</td><td>.0874</td><td>No</td><td>1</td><td>VH3-7</td><td>D6-19</td><td>JH4b</td><td>L2</td><td>JK1</td>

<td>x5.49 *</td><td>.0856</td><td>No</td><td>1</td><td></td><td></td><td></td><td></td><td></td>

<td>x5.101</td><td>.0824</td><td>No</td><td>1</td><td>VH1-2</td><td>D6-19</td><td>JH4b</td><td>L2</td><td>JK1</td>

<td>x5.41 *</td><td>.0776</td><td>No</td><td>1</td><td>VH3-7</td><td>D6-19</td><td>JH4b</td><td>L2</td><td>JK1</td>

<td>x5.108 *</td><td>.0688</td><td>No</td><td>1</td><td>VH3-33</td><td>D1-7</td><td>JH5b</td><td>L2</td><td>JK1</td>

<td>x5.62</td><td>.0650</td><td>No</td><td>1</td><td>VH3-7</td><td>D6-19</td><td>JH4b</td><td>L2</td><td>JK1</td>

<td>x5.39</td><td>.0519</td><td>No</td><td>1</td><td>VH1-2</td><td>D6-13</td><td>JH4b</td><td>L2</td><td>JK1</td>

<td>x5.16 *</td><td>0.0500</td><td>No</td><td>1</td><td>VH1-2</td><td>D6-13</td><td>JH4b</td><td>L2</td><td>JK1</td>

<td>x5.83</td><td>.0484</td><td>No</td><td>1</td><td>VH1-2</td><td>D6-19</td><td>JH4b</td><td>L2</td><td>JK1</td>

<td>x5.54</td><td>.0440</td><td>No</td><td>1</td><td>VH1-2</td><td>D6-19</td><td>JH4b</td><td>L2</td><td>JK1</td>

<td>x5.14</td><td>.0430</td><td>No</td><td>1</td><td>VH1-2</td><td>D6-19</td><td>JH4b</td><td></td><td></td>

<td>x5.86</td><td>0.0419</td><td>No</td><td>1</td><td>VH1-2</td><td>D6-13</td><td>JH4b</td><td>AT 12</td><td>JK3</td>

<td>10/05/1978</td><td>.0984</td><td>Yes</td><td>5</td><td>VH1-2</td><td>D2-2</td><td>JH6b</td><td>B3</td><td>JK5</td>

<td>x5.103 *</td><td>.1013</td><td>No</td><td>2</td><td>VH1-2</td><td>D6-19</td><td>JH4a</td><td>L2</td><td>JK1</td>

<td>x5.28</td><td>.0821</td><td>No</td><td>4</td><td>VH3-43</td><td>D6-19</td><td>JH4b</td><td>L2</td><td>JK3</td>

<td>x5.40</td><td>.0691</td><td>No</td><td>8</td><td>VH3-23</td><td>D6-19</td><td>JH4B</td><td>L2</td><td>JK1</td>

<td>x5.35 *</td><td>.0663</td><td>No</td><td>8</td><td>VH3-20</td><td>D6-19</td><td>JH2</td><td>L2</td><td>JK4</td>

<td>x6.3</td><td>.0617</td><td>No</td><td>7</td><td>VH1-2</td><td>D1-7</td><td>JH4b</td><td>AT 12</td><td>JK2</td>

<td>x5.13</td><td>.0744</td><td>No</td><td></td><td>VH3-7</td><td>D6-19</td><td>JH4b</td><td>L2</td><td>JK1</td>

<td>x5.2</td><td>.0690</td><td>Yes</td><td></td><td>VH3-33</td><td>D5-12</td><td>JH6b</td><td></td><td></td>

<td>x5.52</td><td>.0627</td><td>Yes</td><td></td><td>VH3-33</td><td>D1-1</td><td>JH4b</td><td>L5</td><td>JK4</td>

[0241] Analysis of the IgH and IgL sequences was performed using sequence analysis software tools and by aligning VH genes with the germline database. The software also evaluates D elements, the reading frame, N region insertion, P nucleotide addition, nucleotide loss, and CDR3 length. Analysis of 27 individual antibodies specific for CR64 gave only 7 germline VH genes, of which 10 from the same VH1 family. The choice of neutralizing antibodies showed antibodies expressing the same Ig Vh and in some cases the same VhDJh rearrangements and that the H and L chain pairs were conserved. This finding suggests that for any given epitope, only a few members of the germline range are used to form a corresponding epitope

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For each antigenic epitope, only a limited number of L- and H- chain genes can be paired to create a specific paratope.

[0242] The repeated use of similar structures of Vh, Vk and variable regions (CDRs) by different monoclonal antibodies is related to the fact that all Ang-2 neutralizing activity is restricted to a fibrinogen-type domain and is in accordance with the work published by Procopio et al. (1999, JBC 274: 30196), showing that the action of Ang-2 on Tie2 binds to a fibrinogen domain. Epitope mapping data indicate that monoclonal antibodies bind Ang-2 through a broad interaction surface that covers most of the fibrinogen domain.

EXAMPLE 16

DETERMINATION OF CROSS-REACTIVITY OF ANG-2 MOUNTAINS [0243] Cross-reactivity of anti-human Ang-2 mAbs with murine Ang-2 was examined by ELISA. For this purpose, the mouse Ang-2 expression vector was constructed and the eukaryotic cells were transiently transfected to generate murine Ang-2.

[0244] The expression construct of mouse Angiopoietin-2 (mAng-2) was obtained from Research Genetics, a distributor of the IMAGE consortium (see www at image.11nl.gov). The mouse Ang-2 cDNA (GenBank Accession No. BC027216, IMAGE: 3494566) was derived from the NCI_CGAP_Lu29 library, which is a library of lung cancer. The CDNA was cloned into the pCMV-SPORT6 expression vector (Invitrogen Carlsbad, CA) at SalI (5 ') and NotI (3') sites and contained an open reading frame of 496 amino acids of full-length Ang-2 (mAng-2) as well as no translational regions surrounding 5 'and 3', resulting in a total of 2471 base pairs.

[0245] Ten pg of the above mAng-2 plasmid was transfected into HEK293F cells using the calcium phosphate method. On the previous day, approximately 1X10 was sown on a 10 cm cultivation plate⁶ HEK293F cells. The medium was changed 5 hours after transfection overnight and the cells were cultured for another 2-3 days before the supernatants containing the secreted mAng-2 protein were harvested. Expression of mAng-2 was confirmed by ELISA using a polyclonal antibody obtained from Systems (catalog number AF623). [0246] Nunc Imm 96-well plates were coated with conditioned media harvested from HEK293F / murine Ang-2 transfectants of 100 μΙ in each well. The plates were incubated at 4 ° C overnight and then washed four times with Phosphate Salt Buffer at the Skan Washer 300 station (SkAtRON). Down^{łki bl}about^kowano ^{100 μΙ b}at^foru ^blabout^kshots^andce^gAB^X (°⁵% ^BSAND ^0.1% ^Tween, 0.01% Thimerosal in PBS) for 1 hour. Diluted in blocking buffer anti-Ang-2 mAbs at appropriate concentrations in a volume of 100 μl / well were added to the wells and incubated at room temperature for at least 1 hour. MAbs and each of their dilutions were tested in duplicate. After washing twice, bound mAbs were detected with goat

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The compound was purified by the anti-human antibody conjugated to Fc-HPPO (Caltag, Code H10507) at a dilution of 1 / 1,000 at room temperature for one hour. To set the detection of the chromogenic reaction, 100 μΙ of the TMB substrate (TMB-microwell, BioFX, Cat. No. TMSK-1000-01) was added after three washes of each well of PBS. The plates were incubated for 30 minutes before the inhibition solution 650 (100 μΙ / well, BioFX, Cat. No. BSTP-010001) was added to complete the reaction. The absorbance of light at 650 nm was determined by a Spectramax Plus reader.

[0247] The best 27 neutralizing antibodies were tested in this test. The absorbance of light showed that under the experimental conditions monoclonal antibodies 3.19.3, 3.38, 5.2.1, 5.52.1, 5.56.1 and 5.78.1 were able to bind to murine Ang-2. For confirmation each binding antibody was titrated with ELISA. Mean OD values ​​of 650 nm (± SD) are plotted versus the log-log concentration of mAbs [mu] g / ml) and are shown in Figure 10. Clones 5.2.1, 5.28.1, 3.19.3 and 3.31.2 are shown in the figure. The monoclonal antibodies 5.2.1 and 3.19.3 bound mouse Ang-2 in a dose-dependent manner, reaching a saturation at about 10 μg / ml (FIG.

10). The binding curves of these two mAbs were typical sigmoidal dose-response curves. No dose-dependence or saturation relationships were observed in the range of antibody concentrations 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 reactivity to murine Ang-2.

EXAMPLE 17

ANG-2 MOON BONDGE INHIBITION WITH HUMAN TIE2 [0248] Monoclonal antibody 3.19.3 was selected for further testing its ability to inhibit the binding of murine Ang-2 to human Tie2. For this purpose, the ELISA plate was coated with 4 μg / ml of hTie2 / Fc (R &amp; D Systems, Inc.) of 100 μΙ / well and the wells were routinely blocked at 4 ° C overnight. Recombinant mouse Ang-2 (mAng-2) was used from the supernatant of the 293T / mAng-2 transfectant cultures described above. 100 μl of the mAng-2 supernatant from mAb 3.19.3 at various concentrations was added to pre-coated wells and incubated at room temperature for 1 h.

[0249] As a control, recombinant human Ang-2 (R &amp; D Systems, Inc.) mixed with the antibody was also included. Each mAb concentration was tested three times. Bound murine and human Ang-2 were detected using a goat polyclonal anti-human-Ang-2 antibody (Santa Cruz Biotechnology, Santa Cruz, CA) that cross-reacts with mouse Ang-2, combined with secondary rabbit anti-goat IgG-HRP. The OD650 was determined 30 min after addition of the HRP substrate. It was discovered that mAb 3.19.3 inhibited the binding of both human and mouse Ang-2 to human Tie2 in a dose-dependent manner (FIG.

11).

EXAMPLE 18

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DETERMINATION OF CROSS REACTIVITY WITH SMALL METHODATION [0250] Because Ang-2 is specifically expressed in angiogenic endothelial cells, simian cells were histochemically stained with anti-Ang2 antibodies as a way to indirectly determine if each antibody cross-reacts with the monkey Ang-2.

[0251] Ten of the best neutralizing mAbs selected as described in Example 4 (Table 4) were tested in this experiment using a monocyte-rich ovarian tissue. The fully dried 6 pm fragment of the frozen monkey ovary tissue (cynomolgus monkey) was fixed with acetone at 4 ° C for 5 minutes. After three washes with PBS slides, endogenous tissue peroxidase was blocked with 0.3% H2O2 for 10 minutes. The tissues were then 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 normal 10% goat serum for 10 minutes. After draining the plasma, 10 mAbs of anti-Ang-2 (10 pg / ml) were applied to the sections and incubated for 2 hours. Bound Ang-2 mAbs were detected with 10 pg / ml of mouse anti-human IgG for 15 minutes, and then incubated with goat anti-mouse IgG peroxidase-conjugated for 30 minutes. The staining was performed using the AEC substrate system (DAKO, Cat. No. 3464) under microscopic observation for an optimal result.

[0252] All 10 mAbs were found to stain angiogenic vascular endothelial cells in ovarian tissue; while isotype control does not stain. This showed that 10 mAbs from Table 4 would cross-react with mouse Ang-2.

EXAMPLE 19

MAB 3.19.3 IN VIVO ANGIOGENESIS IN A MATRIGEL INCREASE TREATMENT [0253] In order to evaluate the in vivo anti-angiogenic potential of anti-Ang-2 monoclonal antibodies, the angiogenesis test of Matrigel cartridges was performed. It was found that MCF-7 cells produce Ang-2 in vitro or after implantation as an interspecific transplant into immunodeficient mice. When MCF-7 was included in the Matrigel and implanted subcutaneously in nude mice, a strong vascular growth was found in the gel. To establish the Matrigel insert model, female BALB / c / nu / nu mice aged 6-8 weeks with body weights ranging from 18 to 20 g (Charles River Laboratories, Wilmington, MA) were used. In the right flank of nude mice, a total of 0.5 mL of Matrigel containing 2X10 was injected subcutaneously⁶ MCF-7 cells with or without Ang-2 antibodies or control agents (including Matrigel alone, Tie2 / Fc isotype controls, IgG2 and IgG4 and anti-VEGF mAb). Five mice were used in each test group. All mAbs tested were adjusted to a concentration of 100 pg / ml.

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[0254] After seven days, the Matrigel pads were collected and evaluated for the density of blood vessels. For this purpose, the vertebral displacement of the mice was performed under deep anesthetic conditions. The Matrigel insoles were exposed by removing the covering of the skin. The Matrigel inserts were then removed and digital images recorded. The Matrigel inserts were carefully cut and cut into two parts. One part was frozen instantly in TissueTek and the other part was fixed in buffered formalin. Both parts were embedded in paraffin to prepare sections. Three 5 to 7 μm thick sections were cut from each mouse and stained with hematoxylin and eosin. The sections were then examined under a phase contrast microscope.

[0255] Frozen Matrigel inserts were sectioned (10 pm sections) in a Cryocut microtome. Two independent mouse sections were made and used for staining. The sections were blocked with BSA (0.1%) and then subjected to a monoclonal antibody reacting with murine CD31, conjugated with phycoerythrin (dilutions according to the manufacturer's recommendations). After careful washing, the sections were covered with anti-fade reagent (Vecta Shield) and observed under a UV microscope using a red filter. Representative digital images were recorded (two images at 100 X and 200 X magnification). The testes were counterstained with DAPI. Immunofluorescent CD31 staining images were examined in the Skeletinization program. Data was processed to give the average density of vessels, nodes and lengths for each group. The results can be found in Figures 12A and 12B,

[0256] This experiment showed that compared to Matrigel alone, MCF-7 cells that were included in the Matrigel were able to induce a significant level of angiogenesis. Induced angiogenesis could be inhibited by the anti-VEGF antibody positive control. Angiogenesis was also significantly inhibited by the soluble recombinant Tie2 / Fc protein, suggesting that Ang-2 produced by MCF-7 cells plays a role in angiogenesis in this model. By binding to any of the Ang-2, Tie2 / Fc would effectively reduce the level of Ang-2 that is in contact with MCF-7 cells.

[0257] It is not clear how the IgG2 isotype negative control antibody, PK16.1.3, influenced angiogenesis, but it was found that the antibody occasionally interacts with tumor growth in certain interspecific models (data not shown). The IgG4 isotype control antibody had no effect on angiogenesis in this model. As seen in Figures 12A and 12B, clones 5.88.3, ​​3.3.2, 3.19.3 and 5.28.1 significantly inhibited angiogenesis (P &lt;0.05, t test carried out by VasculoGen), while others had weaker effects.

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[0258] It is well established that Ang-2 is expressed in endothelial cells in the tumor and is therefore considered an autocrine angiogenic agent. However, Ang-2 expression has also been found in many types of tumor cells in vitro and in vivo. In addition to the 3.19.3 mAbs tested here, they do not cross-react with mouse Ang-2. In this in vivo model, the mAbs only neutralized the human Ang-2 produced by the MCF-7 cell, but not the murine Ang-2. The inhibitory activity of these mAbs suggests that ang-2 expressed in the tumor may be a paracrine factor of angiogenesis. The total anti-angiogenic activity of mAbs could be partially attributed to tumor-2 neutralization in addition to Ang-2 neutralization expressed in the vascular endothelium.

EXAMPLE 20

DETERMINATION OF THERAPEUTIC EFFICIENCY OF MAB 3.19.3 IN A PREVENTIVE A421 INTERCHANGEAL TRACT MODEL [0259] Clone 3.19.3 anti-Ang-2 mAb not only bound to mouse Ang-2 but also inhibited the binding of mouse Ang-2 to human Tie2. The antitumor activity of the monoclonal antibody was examined in a murine model of interspecific epithelial carcinoma of human skin using the A431 cell line.

[0260] A431 cells were routinely grown in flasks until they reached sub-confluency. Female mice with immunodeficiency (Balb / c / nu / nu) at 6-8 weeks of age were used to develop the model. The a431 cells were harvested and resuspended in Matrigel. A cell suspension containing 5 x 10⁶cells were injected intradermally in the side of mice. Mice were randomly assigned to different groups, each containing 11 mice. On the same day, and then twice a week, mice were injected intraperitoneally with 0.5 mg mAb 3.19.3 or an isotype control antibody. The dimensions of each tumor were measured twice a week. Tumor volume was calculated as: Volume = Length x (Width)² x 0.5 (cm³).

[0261] As illustrated in Figure 13, mAb 3.19.3 significantly delayed the growth of A431 tumor in interspecific transplantation. Mean tumor volume in the isotype control group reached approximately 1.5 cm3 at the end of the experiment, while the growth rate in the treated group significantly decreased after Day 10 and amounted to approximately 0.5 cm3. On Day 23 the volume ratio L / K (Treatment / Control) was 1/3, indicating 66% inhibition of growth.

[0262] The results suggest that at the dose used in the mAb 3.16.3 experiment it was able to significantly delay the growth of A431 interspecific transplantation in nude mice by binding to mouse Ang-2 and blocking this ligand binding to its Tie2 receptor. Probably the anti-tumor effect of the monoclonal antibody results from the inhibition of angiogenesis in the host, as demonstrated by the Matrigel insert assays. Mechanism of action in relation to anti-angiogenesis

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EP 1 838 733 B1 was further demonstrated in Example 22 using Micron Dill (MVD), as a pharmacodynamic marker.

[0263] The mechanism of action of mAb 3.19.3 may not be limited to blocking Ang-2 / Tie2 binding and downstream signaling. As indicated in Example 7, it was found that this mAb binds to Ang-1 and blocks the binding of Ang-1 to Tie2. Interestingly, the mAb also blocks the Ang-1 induced Tie2 phosphorylation. Ang-1 is known to be involved in vascular maturation. When comparing the inhibition potency of mAb 3.19.3 in Ang-1 binding versus Ang-2 with Tie2 (Example 12), it is evident that mAb

3.19.3 is primarily an Ang-2 antagonist. Without being bound by any particular theory, it is possible that the double blocking of signaling from Ang-2 and Ang-1 impairs angiogenesis and, as a result, tumor growth.

EXAMPLE 21

MAB 3.19.3 INHIBIT THE INCREASE OF THE GUZA IN SPECIFIED INTERCHANGE INDICATED MODELS [0264] Ang-2 is stimulated by angiogenic endothelial cells and correlates with the progression of many types of tumor. It is wise to postulate that a monoclonal antibody that blocks the binding of the Ang-2 / Tie2 compound will be able to inhibit angiogenesis and thus inhibit tumor growth. In this experiment, the therapeutic efficacy of anti-Ang-2 mAbs has been demonstrated. Because mAb 3.19.3 cross-reacts and neutralizes mouse Ang-2 / Tie2 signaling, this mAb was selected to demonstrate the in vivo efficacy of tumor growth inhibition.

[0265] To test whether the anti-Ang-2 3.19.3 mAb also inhibits a fixed tumor and tumors other than A-431, an interspecific model of human colon adenocarcinoma LoVo was used. Doses of mAbs

3.19.3 at 0.5, 2 and 10 mg / kg were administered intraperitoneally twice a week. Treatment did not start until the tumors had stabilized at an average volume of 0.2 cm³. Also on these established tumors, mAb 3.19.3 showed an inhibitory effect compared to the isotype control. Figure 14A shows that 79% inhibition was achieved at 0.5 and 2 mg / kg (p values ​​are 0.022 and 0.027, respectively), and at 10 mg / kg, 75% inhibition of tumor growth was found (p = 0.006).

[0266] The inhibitory effect on tumor growth was reproduced in an additional interspecific model, human colon adenocarcinoma SW480, which was allowed to grow to an average volume of 0.2 cm3. Although at 0.5 mg / kg it was not found that mAb 3.19.3 had a significant effect, at both 2 and 10 mg / kg, the mAb inhibited tumor growth by 60% (p = 0.003 and 0.006 respectively) on Day 53. after tumor implantation (Figure 14B).

[0267] 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 do not have cross-reactivity with

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For example, the murine Ang-2 showed no significant inhibitory effect on tumor growth (data not shown) even though human Ang-2 was expressed in tumor cells. These results suggest that a host Ang-2 antagonist is required to block angiogenesis and tumor growth.

[0268] As discussed above, mAb 3.19.3 cross-reacts with Ang-1. However, the strength of mAb 3.19.3 for Ang-1 / Tie2 binding was much lower than for Ang-2 / Tie2 binding (Example 12). For this reason, it is reasonable to conclude that the therapeutic efficacy seen in these models is primarily due to the antagonism of Ang-2. However, blocking of Ang-1 in vivo in models could not be completely ruled out. No obvious toxicity effect such as weight loss or bleeding was observed throughout the duration of the experiments.

EXAMPLE 22

EFFECTIVENESS OF MAO 3.19.3 IN VIVO IN ADDITIONAL MODELS OF THE INTERCHANGEAL GUZA COMPOSITION [0269] Antitumor activity of the monoclonal antibody 3.19.3 was tested in mouse interspecific models of human cancer using 9 different tumor cell lines.

[0270] Colon adenocarcinoma cells (Lovo, SW480, Colo205, HT29, HCT116), epidermal carcinoma (A431), lung cancer (Calu-6) and breast adenocarcinoma (MCF7, MDA-MB-231) were routinely grown in flasks until cells they have achieved subconfluence. Female mice with immunodeficiency at the age of 7-10 weeks were used to develop the model. The cells were harvested, resuspended in Matrigel and then subcutaneously injected into each mouse. Mice were then randomly distributed into cohorts containing 10-12 mice. Mice were injected intraperitoneally with 0.5 mg of mAb 3.19.3 or isotype control antibody, and then twice a week. The isotype control antibody was included in all experiments. The dimensions of each tumor were measured twice a week. Tumor volume was calculated as: Volume = Length x (Width)² x 0.5 (cm³). Graphic comparisons of tumor growth inhibition are shown for T29 interspecific transplants (Figure 15A) and Calu6 (Figure 15B).

[0271] As seen in Table 16, mAb 3.19.3 showed significant activity in all 7 subcutaneous interspecific transplanted models tested and both orthotopic models with non-optimized dose and schedule.

Table 18. Summary of performance of mAb 3.19.3 in vivo

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<td>Tumor models</td><td>% Inhibition</td><td>% Inhibition</td>

<td>transplants interspecies SubQ</td><td>2 mg / kg twice a week</td><td>10mg / kg twice a week</td>

<td>Colo205</td><td>35</td><td>46</td>

<td>A431</td><td>43</td><td>66</td>

<td>HT29</td><td>ND</td><td>54</td>

<td>Calu-6</td><td>ND</td><td>38</td>

<td>HCT116</td><td>ND</td><td>33</td>

<td>Models orthotopic models</td><td></td><td></td>

<td>MCF7</td><td>* 35</td><td>74</td>

<td>MDA-MB-231</td><td>50</td><td>58</td>

<td colspan="3">P &lt;0.05 in all cases * Inhibition of growth was not statistically significant NO - not marked</td>

[0272] MDA-MB-231 tumor tissue was analyzed by CD31 + vessel staining density. The staining density CD31 was measured by the threshold and manual mesh counting method. 11 tumors per group and at least 20 tumor images were tested. As seen in Figure 15C, treatment of mice with antibody 3.19.3 reduced the CD31 staining density by 40% compared to the control IgG antibody. This was statistically significant for both counting methods, the threshold measurement method (p &lt;0.015) and manual mesh counting (p &lt;0.00004) in the unilateral T-test. Similar counts of CD31 + vessels were performed on ex vivo tissue in Colo205 and HCT116 interspecific transplants. . These samples also showed a similar significant reduction in CD31 + vessels.

EXAMPLE 23

USE OF ANTI-ANG-2 ANTIBODY IN TREATMENT OF DISEASES AFFILIATED WITH ANGIOGENES [0273] To determine the in vivo effects of anti-Ang-1 and anti-Ang-2 antibody treatment of human patients with various solid tumors, human patients are administered a periodically effective amount of anti-anti-angiogenic antibody. -Ang-1 and anti-Ang-2. During therapy, human patients are periodically monitored to determine whether tumor growth has been inhibited. After treatment, patients treated with anti-Ang-1 and anti-Ang-2 antibody, compared to untreated patients, show a relative correction in one or more

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EP 1 838 733B1 of the following: smaller tumors, prolonged progression or longer survival time.

EXAMPLE 24

APPLICATION OF ANTI-ANG-2 ANTIBODY AS A DIAGNOSTIC FACTOR

Detection of Ang-2 Antigen in a Sample [0274] An immunoenzyme assay (ELISA, Enzyme-Linked Immunosorbent Assay) can be used to detect an Ang-1 or Ang-2 antigen in a sample. The assay is incubated for several hours in microtiter plate wells, such as a 96-well microtiter plate or a 384-well microtiter plate, the first fully human monoclonal antibody directed against Ang-1 and Ang-2. The immobilized antibody serves as a binding antibody for any antigen that may be present in the test sample. The wells are washed and treated with a blocking agent such as milk protein or albumin to prevent non-specific adsorption of the analyte.

[0275] The wells are then subjected to a test sample suspected of containing an antigen or solution containing a standard amount of antigen. Such a sample may be, for example, a plasma sample from a subject suspected of having antigen levels in the circulation considered to be diagnostic for pathology.

[0276] After washing the test sample or standard, the well is treated with a second fully human anti-Ang-1 and anti-Ang-2 monoclonal antibody that is labeled by conjugation with biotin. You can also use monoclonal or mouse or derived from another species. The labeled anti-Ang-1 and anti-Ang-2 antibody serves as a detection antibody. After elution of the excess antibody, the wells are subjected to avidin-conjugated horseradish peroxidase (HRP) and the appropriate chromogenic substrate. The concentration of antigen in the test samples is determined by comparison with a standard curve developed on the basis of standard samples.

[0277] This ELISA assay provides a highly specific and highly sensitive assay for the detection of the Ang-1 and Ang-2 antigen in a test sample.

Antigen Ang-2 Concentration Assays in Patients [0278] The sandwich ELISA test is designed to measure levels of Ang-1 and Ang-2 in human plasma. Two fully human monoclonal anti-Ang-2 antibodies from the sandwich ELISA recognize different epitopes on the Ang-2 molecule. Alternatively, monoclonal antibodies derived from mouse or other species may also be used. The ELISA test may or may not be carried out as follows: ELISA plates (Fisher)

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EP 1 838 733 B1 is coated with 50pL anti-Ang-2 binding antibody in coating buffer (0.1 M NaHCO 3, pH 9.6) at a concentration of 2pg / mL. After incubation at 4 ° C overnight, the plates are treated with 200 μL blocking buffer (0.5% BSA, 0.1% Tween 20, 0.01% Thimerosal in PBS) for 1 hour at 25 ° C. The plates are washed (3x) with 0.05% Tween 20 in PBS (washing buffer, WB, washing buffer). Normal or patient plasma (Clinomics, Bioreclaimation) is diluted in blocking buffer containing 50% human plasma. The plates are incubated with plasma samples overnight at 4 ° C, washed with WB and then incubated with biotinylated anti-Ang-2 detection antibody at 100pL / well for 1 hour at 25 ° C. After washing, the plates are incubated with HRP-Streptavidin for 15 minutes, it is washed as before and then treated with 100pL / well of offenylenediamine in H2O2 (Sigma developer solution) to obtain a color. The reaction is stopped with H2SO4 (2M) after 50 [mu] L / well and analyzed using an ELISA plate reader at 492 nm. The concentration of Ang-2 antigen in plasma samples is calculated by comparison with dilutions of the purified Ang-2 antigen using a four-curve curve fitting program.

EQUIVALENTS [0279] This written specification is considered sufficient to allow an expert to practice the invention. The above description and Examples detail some preferred embodiments of the invention and describe the best method considered by the inventors. It should be appreciated, however, that irrespective of how detailed the above may appear in the text, the invention can be implemented in many ways and should be interpreted in accordance with the attached claims.

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EP 1 838 733 B1

SEQUENCE LIST [0280] &lt;110&gt; ABGENIX, INC.

ASTRAZENECA AB Green, Larry L.

Zhou, Qing Keyt, Bruce A.

Yang, Xiao-Dong Emery, Stephen Charles Blakey, David C.

&lt;120&gt; ANTIBODIES AGAINST ANGIOPOITININ-2 AND THEIR APPLICATIONS &lt;130&gt; ABXAZ.002VPC &lt;150&gt; US 60 / 638.354 &lt;151&gt; 2004-12-21 &lt;150&gt; US 60 / 711,289 &lt;151&gt; 2005-08-25 &lt;160 &gt; 662 &lt;170&gt; FastSEQ for Windows Version 4.0 &lt;210&gt; 1 &lt;211&gt; 496 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; An artificially created chimeric human / mouse polypeptide sequence &lt;400&gt; 1

<td>Underworld</td><td>Trp</td><td>Gin</td><td>How much</td><td>How much</td><td>phe</td><td>Leu</td><td>Thr</td><td>phe</td><td>Gly</td><td>Trp</td><td>Asp</td><td>Leu</td><td>val</td><td>Leu</td><td>ala</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Cheese</td><td>ala</td><td>Tyr</td><td>Cheese</td><td>own</td><td>phe</td><td>Arg</td><td>lys</td><td>Cheese</td><td>val</td><td>Asp</td><td>Cheese</td><td>Thr</td><td>Gly</td><td>Arg</td><td>Arg</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>GLn</td><td>Tyr</td><td>Gin</td><td>val</td><td>GLn</td><td>own</td><td>Gly</td><td>Pro</td><td>Cys</td><td>Cheese</td><td>Tyr</td><td>Thr</td><td>phe</td><td>Leu</td><td>Leu</td><td>Pro</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Glu</td><td>Thr</td><td>Asp</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>Cheese</td><td>Cheese</td><td>Cheese</td><td>Cheese</td><td>Pro</td><td>Tyr</td><td>Underworld</td><td>Cheese</td><td>own</td><td>ala</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>val</td><td>Gin</td><td>Arg</td><td>Asp</td><td>ala</td><td>Pro</td><td>Leu</td><td>Asp</td><td>Tyr</td><td>Asp</td><td>Asp</td><td>Cheese</td><td>val</td><td>GLn</td><td>Arg</td><td>Leu</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>GLn</td><td>val</td><td>Leu</td><td>Glu</td><td>own</td><td>How much</td><td>Leu</td><td>Glu</td><td>own</td><td>own</td><td>Thr</td><td>Gin</td><td>Trp</td><td>Leu</td><td>Underworld</td><td>lys</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Leu</td><td>Glu</td><td>own</td><td>Tyr</td><td>How much</td><td>Gin</td><td>Asp</td><td>own</td><td>Underworld</td><td>lys</td><td>lys</td><td>Glu</td><td>Underworld</td><td>val</td><td>Glu</td><td>How much</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Gin</td><td>Gin</td><td>own</td><td>val</td><td>val</td><td>Gin</td><td>own</td><td>GLn</td><td>Thr</td><td>ala</td><td>val</td><td>Underworld</td><td>How much</td><td>Glu</td><td>How much</td><td>Gly</td>

<td></td><td></td><td>115</td><td></td><td></td><td></td><td></td><td>120</td><td></td><td></td><td></td><td></td><td>125</td><td></td><td></td><td></td>

<td>Thr</td><td>Cheese</td><td>Leu</td><td>Leu</td><td>own</td><td>Gin</td><td>Thr</td><td>ala</td><td>ala</td><td>Gin</td><td>Thr</td><td>Arg</td><td>lys</td><td>Leu</td><td>Thr</td><td>Asp</td>

<td></td><td>130</td><td></td><td></td><td></td><td></td><td>135</td><td></td><td></td><td></td><td></td><td>140</td><td></td><td></td><td></td><td></td>

<td>val</td><td>Glu</td><td>ala</td><td>Gin</td><td>val</td><td>Leu</td><td>own</td><td>Gin</td><td>Thr</td><td>Thr</td><td>Arg</td><td>Leu</td><td>Glu</td><td>Leu</td><td>Gin</td><td>Leu</td>

<td>145</td><td></td><td></td><td></td><td></td><td>150</td><td></td><td></td><td></td><td></td><td>155</td><td></td><td></td><td></td><td></td><td>160</td>

<td>Leu</td><td>Gin</td><td>His</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>Thr</td><td>own</td><td>lys</td><td>Leu</td><td>Glu</td><td>lys</td><td>Gin</td><td>How much</td><td>Leu</td><td>Asp</td>

<td></td><td></td><td></td><td></td><td>165</td><td></td><td></td><td></td><td></td><td>170</td><td></td><td></td><td></td><td></td><td>175</td><td></td>

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EP 1 838 733 B1

<td colspan="5">Gln Thr Ser Glu Ile</td><td rowspan="2">own</td><td rowspan="2">lys</td><td rowspan="2">Leu</td><td colspan="5" rowspan="2">Gln Asn Lys Asn Ser 185</td><td rowspan="2">phe 190</td><td rowspan="2">Leu</td><td rowspan="2">Glu</td>

<td></td><td colspan="4">180</td>

<td>Gln</td><td>lys</td><td>val</td><td>Leu</td><td>Asp</td><td>Underworld</td><td>Glu</td><td>Gly</td><td>lys</td><td>His</td><td>Cheese</td><td>Glu</td><td>Gln</td><td>Leu</td><td>Gln</td><td>Cheese</td>

<td></td><td></td><td>195</td><td></td><td></td><td></td><td></td><td>200</td><td></td><td></td><td></td><td></td><td>205</td><td></td><td></td><td></td>

<td>Underworld</td><td>lys</td><td>Glu</td><td>Gln</td><td>lys</td><td>Asp</td><td>Glu</td><td>Leu</td><td>Gln</td><td>val ·</td><td>Leu</td><td>val</td><td>Cheese</td><td>lys</td><td>Gln</td><td>Cheese</td>

<td></td><td>210</td><td></td><td></td><td></td><td></td><td>215</td><td></td><td></td><td></td><td></td><td>220</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>val</td><td>How much</td><td>Asp</td><td>GLU</td><td>Leu</td><td>Glu</td><td>lys</td><td>lys</td><td>Leu</td><td>val</td><td>Thr</td><td>ala</td><td>Thr</td><td>val</td><td>• Asn</td>

<td>225</td><td></td><td></td><td></td><td></td><td>230</td><td></td><td></td><td></td><td></td><td>235</td><td></td><td></td><td></td><td></td><td>240</td>

<td>own</td><td>Cheese</td><td>Leu</td><td>Leu</td><td>Gln</td><td>lys</td><td>Gln</td><td>Gln</td><td>His</td><td>Asp</td><td>Leu</td><td>Underworld</td><td>Glu</td><td>Thr</td><td>val</td><td>own</td>

<td></td><td></td><td></td><td></td><td>245</td><td></td><td></td><td></td><td></td><td>250</td><td></td><td></td><td></td><td></td><td>255</td><td></td>

<td>Cheese</td><td>Leu</td><td>Leu</td><td>Thr</td><td>Underworld</td><td>Underworld</td><td>Cheese</td><td>Cheese</td><td>Pro</td><td>own</td><td>Cheese</td><td>lys</td><td>Cheese</td><td>Cheese</td><td>val</td><td>ALa</td>

<td></td><td></td><td></td><td>260</td><td></td><td></td><td></td><td></td><td>265</td><td></td><td></td><td></td><td></td><td>270</td><td></td><td></td>

<td>How much</td><td>Arg</td><td>lys</td><td>Glu</td><td>Glu</td><td>Gln</td><td>Thr</td><td>Thr</td><td>phe</td><td>Arg</td><td>Asp</td><td>Cys</td><td>ala</td><td>Glu</td><td>How much</td><td>phe</td>

<td></td><td></td><td>275</td><td></td><td></td><td></td><td></td><td>280</td><td></td><td></td><td></td><td></td><td>285</td><td></td><td></td><td></td>

<td>lys</td><td>Cheese</td><td>Gly</td><td>Leu</td><td>Thr</td><td>Thr</td><td>Cheese</td><td>Gly</td><td>How much</td><td>Tyr</td><td>Thr</td><td>Leu</td><td>Thr</td><td>phe</td><td>Pro</td><td>own</td>

<td></td><td>290</td><td></td><td></td><td></td><td></td><td>295</td><td></td><td></td><td></td><td></td><td>300</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Thr</td><td>Glu</td><td>Glu</td><td>How much</td><td>lys</td><td>ala</td><td>Tyr</td><td>Cys</td><td>Asp</td><td>Underworld</td><td>Glu</td><td>ala</td><td colspan="2">Gly Gly</td><td>Gly</td>

<td>305</td><td></td><td></td><td></td><td></td><td>310</td><td></td><td></td><td></td><td></td><td>315</td><td></td><td></td><td></td><td></td><td>320</td>

<td>Gly</td><td>Trp</td><td>Thr</td><td>How much</td><td>How much</td><td>Gln</td><td>Arg</td><td>Arg</td><td>Glu</td><td>Asp</td><td>Gly</td><td>Cheese</td><td>val</td><td>Asp</td><td>phe</td><td>Gln</td>

<td></td><td></td><td></td><td></td><td>325</td><td></td><td></td><td></td><td></td><td>330</td><td></td><td></td><td></td><td></td><td>335</td><td></td>

<td>Arg</td><td>Thr</td><td>Trp</td><td>lys</td><td>Glu</td><td>Tyr</td><td>lys</td><td>val</td><td>Gly</td><td>phe</td><td>Gly</td><td>own</td><td>Pro</td><td>Cheese</td><td>Gly</td><td>Glu</td>

<td></td><td></td><td></td><td>340</td><td></td><td></td><td></td><td></td><td>345</td><td></td><td></td><td></td><td></td><td>350</td><td></td><td></td>

<td>Tyr</td><td>Trp</td><td>Leu</td><td>Gly</td><td>own</td><td>Glu</td><td>phe</td><td>val</td><td>Cheese</td><td>Gln</td><td>Leu</td><td>Thr</td><td>own</td><td>GLn</td><td>Gln</td><td>Arg</td>

<td></td><td></td><td>355</td><td></td><td></td><td></td><td></td><td>360</td><td></td><td></td><td></td><td></td><td>365</td><td></td><td></td><td></td>

<td>Tyr</td><td>val</td><td>Leu</td><td>lys</td><td>How much</td><td>His</td><td>Leu</td><td>lys</td><td>Asp</td><td>Trp</td><td>Glu</td><td>Gly</td><td>own</td><td>Glu</td><td>ALa</td><td>Tyr</td>

<td></td><td>370</td><td></td><td></td><td></td><td></td><td>375</td><td></td><td></td><td></td><td></td><td>380</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Leu</td><td>Tyr</td><td>Glu</td><td>His</td><td>phe</td><td>Tyr</td><td>Leu</td><td>Cheese</td><td>Cheese</td><td>GLU</td><td>Glu</td><td>Leu</td><td>own</td><td>Tyr</td><td>Arg</td>

<td>385</td><td></td><td></td><td></td><td></td><td>390</td><td></td><td></td><td></td><td></td><td>395</td><td></td><td></td><td></td><td></td><td>400</td>

<td>How much</td><td>His</td><td>Leu</td><td>Thr</td><td>Gly</td><td>Leu</td><td>Thr</td><td>Gly</td><td>Thr</td><td>ala</td><td>ALa</td><td>lys</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>How much</td>

<td></td><td></td><td></td><td></td><td>405</td><td></td><td></td><td></td><td></td><td>410</td><td></td><td></td><td></td><td></td><td>415</td><td></td>

<td>Cheese</td><td>Gln</td><td>Pro</td><td>Gly</td><td>Cheese</td><td>Asp</td><td>phe</td><td>Cheese</td><td>Thr</td><td>lys</td><td>Asp</td><td>Cheese</td><td>Asp</td><td>own</td><td>Asp</td><td>lys</td>

<td></td><td></td><td></td><td>420</td><td></td><td></td><td></td><td></td><td>425</td><td></td><td></td><td></td><td></td><td>430</td><td></td><td></td>

<td>Cys</td><td>How much</td><td>Cys</td><td>lys</td><td>Cys</td><td>Cheese</td><td>Gln</td><td>Underworld</td><td>Leu</td><td>Cheese</td><td colspan="2">Gly GLy</td><td>Trp</td><td>Trp</td><td>phe</td><td>Asp</td>

<td></td><td></td><td>435</td><td></td><td></td><td></td><td></td><td>440</td><td></td><td></td><td></td><td></td><td>445</td><td></td><td></td><td></td>

<td>ala</td><td>Cys</td><td>Gly</td><td>Pro</td><td>Cheese</td><td>own</td><td>Leu</td><td>own</td><td>Gly</td><td>Gln</td><td>Tyr</td><td>Tyr</td><td>Pro</td><td>Gln</td><td>lys</td><td>GLn</td>

<td></td><td>450</td><td></td><td></td><td></td><td></td><td>455</td><td></td><td></td><td></td><td></td><td>460</td><td></td><td></td><td></td><td></td>

<td>own</td><td>Thr</td><td>own</td><td>lys</td><td>phe</td><td>own</td><td>Gly</td><td>How much</td><td>lys</td><td>Trp</td><td>Tyr</td><td>Tyr</td><td>Trp</td><td>lys</td><td>Gly</td><td>Cheese</td>

<td>465</td><td></td><td></td><td></td><td></td><td>470</td><td></td><td></td><td></td><td></td><td>475</td><td></td><td></td><td></td><td></td><td>480</td>

<td>Gly</td><td>Tyr</td><td>Cheese</td><td>Leu</td><td>lys</td><td>ala</td><td>Thr</td><td>Thr</td><td>Underworld</td><td>Underworld</td><td>How much</td><td>Arg</td><td>Pro</td><td>ala</td><td>Asp</td><td>phe</td>

<td></td><td></td><td></td><td></td><td>485</td><td></td><td></td><td></td><td></td><td>490</td><td></td><td></td><td></td><td></td><td>495</td><td></td>

&lt;210&gt; 2 &lt;211&gt; 497 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 2

<td>Underworld</td><td>Thr</td><td>val</td><td>phe</td><td>Leu</td><td>Cheese</td><td>phe</td><td>ala</td><td>phe</td><td>Leu</td><td>ala</td><td>ALa</td><td>How much</td><td>Leu</td><td>Thr</td><td>His</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>How much</td><td>Gly</td><td>Cys</td><td>Cheese</td><td>own</td><td>Gln</td><td>Arg</td><td>Arg</td><td>Cheese</td><td>Pro</td><td>Glu</td><td>own</td><td>Cheese</td><td>Gly</td><td>Arg</td><td>Arg</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Tyr</td><td>own</td><td>Arg</td><td>How much</td><td>GLn</td><td>His</td><td>Gly</td><td>Gln</td><td>Cys</td><td>ALa</td><td>Tyr</td><td>Thr</td><td>phe</td><td>How much</td><td>Leu</td><td>Pro</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Glu</td><td>His</td><td>Asp</td><td>Gly</td><td>own</td><td>Cys</td><td>Arg</td><td>Glu</td><td>Cheese</td><td>Thr</td><td>Thr</td><td>Asp</td><td>Gln</td><td>Tyr</td><td>own</td><td>Thr</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>own</td><td>ala</td><td>Leu</td><td>Gln</td><td>Arg</td><td>Asp</td><td>ala</td><td>Pro</td><td>His</td><td>val</td><td>Glu</td><td>Pro</td><td>Asp</td><td>phe</td><td>Cheese</td><td>Cheese</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Gln</td><td>lys</td><td>Leu</td><td>Gln</td><td>His</td><td>Leu</td><td>Glu</td><td>His</td><td>val</td><td>Underworld</td><td>Glu</td><td>own</td><td>Tyr</td><td>Thr</td><td>Gln</td><td>Trp</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Leu</td><td>Gln</td><td>lys</td><td>Leu</td><td>Glu</td><td>own</td><td>Tyr</td><td>How much</td><td>val</td><td>Glu</td><td>own</td><td>Underworld</td><td>lys</td><td>Cheese</td><td>GLU</td><td>Underworld</td>

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EP 1 838 733 B1 &lt;210&gt; 3 &lt;211&gt; 496 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 3

Met Trp Gln Ile Val Phe Phe Thr Leu Ser Cys Asp Leu Val Leu Ala 1 5 10 15 &lt;210&gt; 4 &lt;211&gt; 496 &lt;212&gt; PRT &lt;213&gt; Mus musculus &lt;400&gt; 4

<td>Cys</td><td>How much</td><td>Cys</td><td>lys</td><td>Cys</td><td>Cheese</td><td>Gln</td><td>Underworld</td><td>Leu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Trp</td><td>Trp</td><td>phe</td><td>Asp</td>

<td></td><td></td><td>435</td><td></td><td></td><td></td><td></td><td>440</td><td></td><td></td><td></td><td></td><td>445</td><td></td><td></td><td></td>

<td>ala</td><td>Cys</td><td>Gly</td><td>Pro</td><td>Cheese</td><td>own</td><td>Leu</td><td>• Asn</td><td>Gly</td><td>Gln</td><td>Tyr</td><td>Tyr</td><td>Pro</td><td>Gln</td><td>lys</td><td>Gln</td>

<td></td><td>450</td><td></td><td></td><td></td><td></td><td>455</td><td></td><td></td><td></td><td></td><td>460</td><td></td><td></td><td></td><td></td>

<td>own</td><td>Thr</td><td>own</td><td>lys</td><td>phe</td><td>own</td><td>Gly</td><td>How much</td><td>lys</td><td>Trp</td><td>Tyr</td><td>Tyr</td><td>Trp</td><td>lys</td><td>Gly</td><td>Cheese</td>

<td>465</td><td></td><td></td><td></td><td></td><td>470</td><td></td><td></td><td></td><td></td><td>475</td><td></td><td></td><td></td><td></td><td>480</td>

<td>Gly</td><td>Tyr</td><td>Cheese</td><td>Leu</td><td>lys</td><td>ala</td><td>Thr</td><td>Thr</td><td>Underworld</td><td>Underworld</td><td>How much</td><td>Arg</td><td>Pro</td><td>ala</td><td>Asp</td><td>'Phe</td>

<td></td><td></td><td></td><td></td><td>485</td><td></td><td></td><td></td><td></td><td>490</td><td></td><td></td><td></td><td></td><td>495</td><td></td>

&lt;210&gt; 5 &lt;211&gt; 498 &lt;212&gt; PRT &lt;213&gt; Mus musculus

131

EP 1 838 733 B1 &lt;400&gt; 5

<td colspan="3">Met Thr Val 1</td><td>phe</td><td>Leu 5</td><td>Cheese</td><td>phe</td><td>ala</td><td>phe</td><td>phe 10</td><td colspan="3">Ala Ala Ile</td><td colspan="3">Leu Thr His 15</td>

<td>How much</td><td>Gly</td><td>Cys</td><td>Cheese</td><td>own</td><td>GLn</td><td>Arg</td><td>Arg</td><td>own</td><td>Pro</td><td>Glu</td><td>own</td><td>Gly</td><td>Gly</td><td>Arg</td><td>Arg</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Tyr</td><td>own</td><td>Arg</td><td>How much</td><td>Gin</td><td>His</td><td>Gly</td><td>GLn</td><td>Cys</td><td>ala</td><td>Tyr</td><td>Thr</td><td>phe</td><td>How much</td><td>Leu</td><td>Pro</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Glu</td><td>His</td><td>Asp</td><td>Gly</td><td>own</td><td>Cys</td><td>Arg</td><td>GLU</td><td>Cheese</td><td>ala</td><td>Thr</td><td>Glu</td><td>GLn</td><td>Tyr</td><td>own</td><td>Thr</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>own</td><td>ala</td><td>Leu</td><td>Gin</td><td>Arg</td><td>Asp</td><td>ala</td><td>Pro</td><td>His</td><td>val</td><td>Glu</td><td>Pro</td><td>Asp</td><td>phe</td><td>Cheese</td><td>val</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Gin</td><td>lys</td><td>Leu</td><td>Gin</td><td>His</td><td>Leu</td><td>Glu</td><td>His</td><td>val</td><td>Underworld</td><td>Glu</td><td>own</td><td>Tyr</td><td>Thr</td><td>GLn</td><td>Trp</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Leu</td><td>Gin</td><td>lys</td><td>Leu</td><td>Glu</td><td>own</td><td>Tyr</td><td>How much</td><td>val</td><td>Glu</td><td>own</td><td>Underworld</td><td>lys</td><td>Cheese</td><td>Glu</td><td>Underworld</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>ala</td><td>Gin</td><td>How much</td><td>Gin</td><td>Gin</td><td>own</td><td>ala</td><td>val</td><td>GLn</td><td>own</td><td>His</td><td>Thr</td><td>ala</td><td>Thr</td><td>Underworld</td><td>Leu</td>

<td></td><td></td><td>115</td><td></td><td></td><td></td><td></td><td>120</td><td></td><td></td><td></td><td></td><td>125</td><td></td><td></td><td></td>

<td>Glu</td><td>How much</td><td>Gly</td><td>Thr</td><td>Cheese</td><td>Leu</td><td>Leu</td><td>Cheese</td><td>GLn</td><td>Thr</td><td>ala</td><td>Glu</td><td>GLn</td><td>Thr</td><td>Arg</td><td>lys</td>

<td></td><td>130</td><td></td><td></td><td></td><td></td><td>135</td><td></td><td></td><td></td><td></td><td>140</td><td></td><td></td><td></td><td></td>

<td>Leu</td><td>Thr</td><td>Asp</td><td>val</td><td>Glu</td><td>Thr</td><td>Gin</td><td>val</td><td>Leu</td><td>own</td><td>GLn</td><td>Thr</td><td>Cheese</td><td>Arg</td><td>Leu</td><td>Glu</td>

<td>145</td><td></td><td></td><td></td><td></td><td>150</td><td></td><td></td><td></td><td></td><td>155</td><td></td><td></td><td></td><td></td><td>16-0</td>

<td>How much</td><td>Gin</td><td>Leu</td><td>Leu</td><td>Glu</td><td>own</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>Thr</td><td>Tyr</td><td>lys</td><td>Leu</td><td>Glu</td><td>lys</td><td>GLn</td>

<td></td><td></td><td></td><td></td><td>165</td><td></td><td></td><td></td><td></td><td>170</td><td></td><td></td><td></td><td></td><td>175</td><td></td>

<td>Leu</td><td>Leu</td><td>Gin</td><td>Gin</td><td>Thr</td><td>own</td><td>Glu</td><td>How much</td><td>Leu</td><td>lys</td><td>How much</td><td>His</td><td>Glu</td><td>lys</td><td>own</td><td>Cheese</td>

<td></td><td></td><td></td><td>180</td><td></td><td></td><td></td><td></td><td>185</td><td></td><td></td><td></td><td></td><td>190</td><td></td><td></td>

<td>Leu</td><td>Leu</td><td>Glu</td><td>His</td><td>lys</td><td>How much</td><td>Leu</td><td>Glu</td><td>Underworld</td><td>Glu</td><td>Gly</td><td>lys</td><td>His</td><td>lys</td><td>Glu</td><td>Glu</td>

<td></td><td></td><td>195</td><td></td><td></td><td></td><td></td><td>200</td><td></td><td></td><td></td><td></td><td>205</td><td></td><td></td><td></td>

<td>Leu</td><td>Asp</td><td>Thr</td><td>Leu</td><td>lys</td><td>Glu</td><td>Glu</td><td>lys</td><td>Glu</td><td>own</td><td>Leu</td><td>GLn</td><td>Gly</td><td>Leu</td><td>val</td><td>Cheese</td>

<td></td><td>210</td><td></td><td></td><td></td><td></td><td>215</td><td></td><td></td><td></td><td></td><td>220</td><td></td><td></td><td></td><td></td>

<td>Arg</td><td>Gin</td><td>Thr</td><td>phe</td><td>How much</td><td>How much</td><td>Gin</td><td>Glu</td><td>Leu</td><td>Glu</td><td>lys</td><td>GLn</td><td>Leu</td><td>Cheese</td><td>Arg</td><td>ala</td>

<td>225</td><td></td><td></td><td></td><td></td><td>230</td><td></td><td></td><td></td><td></td><td>235</td><td></td><td></td><td></td><td></td><td>240</td>

<td>Thr</td><td>own</td><td>own</td><td>own</td><td>Cheese</td><td>How much</td><td>Leu</td><td>GLn</td><td>lys</td><td>GLn</td><td>Gin</td><td>Leu</td><td>GLU</td><td>Leu</td><td>Underworld</td><td>Asp</td>

<td></td><td></td><td></td><td></td><td>245</td><td></td><td></td><td></td><td></td><td>250</td><td></td><td></td><td></td><td></td><td>255</td><td></td>

<td>Thr</td><td>val</td><td>His</td><td>own</td><td>Leu</td><td>val</td><td>Cheese</td><td>Leu</td><td>Cys</td><td>Thr</td><td>lys</td><td>GLU</td><td>Gly</td><td>val</td><td>Leu</td><td>Leu</td>

<td></td><td></td><td></td><td>260</td><td></td><td></td><td></td><td></td><td>265</td><td></td><td></td><td></td><td></td><td>270</td><td></td><td></td>

<td>lys</td><td>Gly</td><td>Gly</td><td>lys</td><td>Arg</td><td>Glu</td><td>Glu</td><td>Glu</td><td>lys</td><td>Pro</td><td>phe</td><td>Arg</td><td>Asp</td><td>Cys</td><td>ala</td><td>Asp</td>

<td></td><td></td><td>275</td><td></td><td></td><td></td><td></td><td>280</td><td></td><td></td><td></td><td></td><td>285</td><td></td><td></td><td></td>

<td>val</td><td>Tyr</td><td>Gin</td><td>ala</td><td>Gly</td><td>phe</td><td>own</td><td>lys</td><td>Cheese</td><td>Gly</td><td>How much</td><td>Tyr</td><td>Thr</td><td>How much</td><td>Tyr</td><td>phe</td>

<td></td><td>290</td><td></td><td></td><td></td><td></td><td>295</td><td></td><td></td><td></td><td></td><td>300</td><td></td><td></td><td></td><td></td>

<td>own</td><td>own</td><td>Underworld</td><td>Pro</td><td>Glu</td><td>Pro</td><td>lys</td><td>lys</td><td>val</td><td>phe</td><td>Cys</td><td>own</td><td>Underworld</td><td>Asp</td><td>val</td><td>own</td>

<td>305</td><td></td><td></td><td></td><td></td><td>310</td><td></td><td></td><td></td><td></td><td>315</td><td></td><td></td><td></td><td></td><td>320</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>Trp</td><td>Thr</td><td>val</td><td>How much</td><td>GLn</td><td>His</td><td>Arg</td><td>Glu</td><td>Asp</td><td>Gly</td><td>Cheese</td><td>Leu</td><td>Asp</td>

<td></td><td></td><td></td><td></td><td>325</td><td></td><td></td><td></td><td></td><td>330</td><td></td><td></td><td></td><td></td><td>335</td><td></td>

<td>phe</td><td>Gin</td><td>Arg</td><td>Gly</td><td>Trp</td><td>lys</td><td>GLU</td><td>Tyr</td><td>lys</td><td>Underworld</td><td>Gly</td><td>phe</td><td>Gly</td><td>own</td><td>Pro</td><td>Cheese</td>

<td></td><td></td><td></td><td>340</td><td></td><td></td><td></td><td></td><td>345</td><td></td><td></td><td></td><td></td><td>350</td><td></td><td></td>

<td>Gly</td><td>Glu</td><td>Tyr</td><td>Trp</td><td>Leu</td><td>Gly</td><td>own</td><td>Glu</td><td>phe</td><td>How much</td><td>phe</td><td>ala</td><td>How much</td><td>Thr</td><td>Cheese</td><td>GLn</td>

132

ΕΡ 1 838 733 Β1

<td colspan="2"></td><td colspan="2">355</td><td colspan="5">360</td><td colspan="7">365</td>

<td>Arg</td><td>Gin</td><td>Tyr</td><td>Underworld</td><td>Leu</td><td>Arg</td><td>How much</td><td>Glu</td><td>Leu</td><td>Underworld</td><td>Asp</td><td>Trp</td><td>Glu</td><td>Gly</td><td>own</td><td>Arg</td>

<td></td><td>370</td><td></td><td></td><td></td><td></td><td>375</td><td></td><td></td><td></td><td></td><td>380</td><td></td><td></td><td></td><td></td>

<td>ala</td><td>Tyr</td><td>Cheese</td><td>Gin</td><td>Tyr</td><td>Asp</td><td>Arg</td><td>phe</td><td>His</td><td>How much</td><td>Gly</td><td>own</td><td>Glu</td><td>lys</td><td>Gin</td><td>own</td>

<td>385</td><td></td><td></td><td></td><td></td><td>390</td><td></td><td></td><td></td><td></td><td>395</td><td></td><td></td><td></td><td></td><td>400</td>

<td>Tyr</td><td>Arg</td><td>Leu</td><td>Tyr</td><td>Leu</td><td>lys</td><td>Gly</td><td>His</td><td>Thr</td><td>Gly</td><td>Thr</td><td>ala</td><td>Gly</td><td>lys</td><td>Gin</td><td>Cheese</td>

<td></td><td></td><td></td><td></td><td>405</td><td></td><td></td><td></td><td></td><td>410</td><td></td><td></td><td></td><td></td><td>415</td><td></td>

<td>Cheese</td><td>Leu</td><td>How much</td><td>Leu</td><td>His</td><td>Gly</td><td>ala</td><td>Asp</td><td>phe</td><td>Cheese</td><td>Thr</td><td>lys</td><td>Asp</td><td>ala</td><td>Asp</td><td>own</td>

<td></td><td></td><td></td><td>420</td><td></td><td></td><td></td><td></td><td>425</td><td></td><td></td><td></td><td></td><td>430</td><td></td><td></td>

<td>Asp</td><td>own</td><td>Cys</td><td>Underworld</td><td>Cys</td><td>lys</td><td>Cys</td><td>ala</td><td>Leu</td><td>Underworld</td><td>Leu</td><td>Thr</td><td>Gly</td><td>Gly</td><td>Trp</td><td>Trp</td>

<td></td><td></td><td>435</td><td></td><td></td><td></td><td></td><td>440</td><td></td><td></td><td></td><td></td><td>445</td><td></td><td></td><td></td>

<td>phe</td><td>Asp</td><td>ala</td><td>Cys</td><td>Gly</td><td>Pro '</td><td>Cheese</td><td>own</td><td>Leu</td><td>own</td><td>Gly</td><td>Underworld</td><td>phe</td><td>Tyr</td><td>Thr</td><td>ala</td>

<td></td><td>450</td><td></td><td></td><td></td><td></td><td>455</td><td></td><td></td><td></td><td></td><td>460</td><td></td><td></td><td></td><td></td>

<td>Gly</td><td>Gin</td><td>own</td><td>His</td><td>Gly</td><td>lys</td><td>Leu</td><td>own</td><td>Gly</td><td>How much</td><td>lys</td><td>Trp</td><td>His</td><td>Tyr</td><td>phe</td><td>lys</td>

<td>465</td><td></td><td></td><td></td><td></td><td>470</td><td></td><td></td><td></td><td></td><td>475</td><td></td><td></td><td></td><td></td><td>480</td>

<td>Gly</td><td>Pro</td><td>Cheese</td><td>Tyr</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>Cheese</td><td>Thr</td><td>Thr</td><td>Underworld</td><td>Underworld</td><td>How much</td><td>Arg</td><td>Pro</td><td>Leu</td>

<td></td><td></td><td></td><td></td><td>485</td><td></td><td></td><td></td><td></td><td>490</td><td></td><td></td><td></td><td></td><td>495</td><td></td>

<td>Asp</td><td>phe</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 6 &lt;211&gt; 366 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 6 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gggggactac 300 ggtgagtact tctactacgg tatggacgtc tggggccaag ggaccacggt caccgtctcc 360 tcagcc 366 &lt;210&gt; 7 &lt;211&gt; 122 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 7

<td>Gin</td><td>val</td><td>Gin</td><td>Leu</td><td>val</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly</td><td>val</td><td>val</td><td>Gin</td><td>Pro</td><td>Gly</td><td>Arg</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>ala</td><td>ala</td><td>Cheese</td><td>Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Cheese</td><td>Cheese</td><td>Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Gly</td><td>Underworld</td><td>His</td><td>Trp</td><td>val</td><td>Arg</td><td>Gin</td><td>ala</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>val</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>ala</td><td>val</td><td>How much</td><td>Trp</td><td>Tyr</td><td>Asp</td><td>Gly</td><td>Cheese</td><td>own</td><td>lys</td><td>Tyr</td><td>Tyr</td><td>ala</td><td>Asp</td><td>Cheese</td><td>val</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>lys</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>own</td><td>Cheese</td><td>lys</td><td>own</td><td>Thr</td><td>Leu</td><td>Tyr</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Leu</td><td>Gin</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>ala</td><td>Gly</td><td>Asp</td><td>Tyr</td><td>Gly</td><td>Glu</td><td>Tyr</td><td>phe</td><td>Tyr</td><td>Tyr</td><td>Gly</td><td>Underworld</td><td>Asp</td><td>val</td><td>Trp</td><td>Gly</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Gin</td><td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>115</td><td></td><td></td><td></td><td></td><td>120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 8 &lt;211&gt; 324 &lt;212&gt; DNA &lt;213&gt; Homo sapiens

133

EP 1 838 733 B1 &lt;400&gt; 8 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca ggggcataga aatgaattag gacggtatca gacgagacca 120 ggaaaagccc ggactatgct g aa a ^ ^ ^ tgcaaaęrtgg gggcccaaca 180 gtgttcagct ag ^^ ^ GATC tgggacagaa ttcactctca caatcagcag cccgcaggcc 240 gaagaatttg caacttatta ctgtctacag caaaagagtc accctcggac ggtcggccaa 300 ttgaaaagtt tgtagaCcga acga '324 &lt;210&gt; 9 &lt;211&gt; 108 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 9

<td>Asp</td><td>How much</td><td>Gln</td><td>Underworld</td><td>Thr</td><td>Gln</td><td>Cheese</td><td>Pro</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>ala</td><td>Cheese</td><td>val</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Asp</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Thr</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gln</td><td>Gly</td><td>How much</td><td>Arg</td><td>own</td><td>Asp</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Leu</td><td>Gly</td><td>Trp</td><td>Tyr</td><td>Gln</td><td>Gln</td><td>lys</td><td>Pro</td><td>Gly</td><td>lys</td><td>ala</td><td>Pro</td><td>lys</td><td>Arg</td><td>Leu</td><td>How much</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Tyr</td><td>ala</td><td>ala</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gln</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td><td>Cheese</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Glu</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>He</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gln</td><td>Pro</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Leu</td><td>Gln</td><td>His</td><td>own</td><td>Cheese</td><td>Tyr</td><td>Pro</td><td>Arg</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Thr</td><td>phe</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 10 &lt;211&gt; 386 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 10 agttttagta tgaggtagtc gggcccagga ctggggaagc cCtctataac cctgtccctc 60 gaattagaCt tctctggtgg ctccgtaggc agtgttgtCt acgacttaga ctggaaatgg 120 agtaaaaagt gtggtggact ggtatgttgc ggataCatct acgagtgttg gagcaccaac 180 Cgaggaaaat caaCcaaggt tcgagtcacc ataccagtag acacgaagga gaaccagttc 240 Ccaatgaata tggtctattt gaccgctgcg gacacggccg tggacgactg gggagagat 300 agggattaat gCttCtcggt gagggttaac tactacaacg gtattgacgt cttgggccaa 360 tttaaagatg tcgcattcCa ctcagc 386 &lt;210&gt; 11 &lt;211&gt; 128 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 11

<td>Gln</td><td>val</td><td>Gln</td><td>Leu</td><td>Gln</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Pro</td><td>Gly</td><td>Leu</td><td>val</td><td>lys</td><td>Pro</td><td>Cheese</td><td>Glu</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Thr</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Thr</td><td>Cys</td><td>Thr</td><td>val</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Cheese</td><td>val</td><td>Cheese</td><td>Cheese</td><td>Gly</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Gly</td><td>Tyr</td><td>Tyr</td><td>Trp</td><td>own</td><td>Trp</td><td>How much</td><td>Arg</td><td>Gln</td><td>Pro</td><td>Pro.</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Trp</td><td>How much</td><td>Gly</td><td>Tyr</td><td>How much</td><td>Tyr</td><td>Tyr</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Thr</td><td>own</td><td>Tyr</td><td>own</td><td>Pro</td><td>Cheese</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

134

EP 1 838 733 B1

<td>Leu</td><td>lys</td><td>Cheese</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Cheese</td><td>val</td><td>Asp</td><td>Thr</td><td>Cheese</td><td>lys</td><td>own</td><td>Gln</td><td>phe</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Cheese</td><td>Leu</td><td>lys</td><td>Leu</td><td>Cheese</td><td>Cheese</td><td>val</td><td>Thr</td><td>ala</td><td>ala</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Cys</td><td>ala</td><td>Arg</td><td>Asp</td><td>Gln</td><td>Asp</td><td>Tyr</td><td>Tyr</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Arg</td><td>Gly</td><td>Tyr</td><td>Tyr</td><td>Tyr</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Tyr</td><td>Gly</td><td>Underworld</td><td>Asp</td><td>val</td><td>Trp</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td>

<td></td><td></td><td>115</td><td></td><td></td><td></td><td></td><td>120</td><td></td><td></td><td></td><td></td><td>125</td><td></td><td></td><td></td>

&lt;210&gt; 12 &lt;211&gt; 322 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 12 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggttatagc agctggttag cctggtacaa gcagaaacca. 120 ttgaaagccc ctaagctcct gaactatgct gcatccagtt tcaaatgtgg gggcccatca 180 aggttcagcg gcagtggatc tgggacagaa tccactctca ccatgtgatg cctgcagcct 240 gaagaatttg caacttacta ttgtcaacag gcttacagtt ccgggacgtt cggccaaggg 300 attaagtttg aaatcaaacg aa 322 &lt;210&gt; 13 &lt;211&gt; 107 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 13

<td>Asp 1</td><td>How much</td><td colspan="2">Gln Met</td><td>Thr 5</td><td>Gln</td><td colspan="2">Pro cheese</td><td>Cheese</td><td colspan="2">Ser Val 10</td><td>Cheese</td><td>ala</td><td>Cheese</td><td colspan="2">Val Gly 15</td>

<td>Asp</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Thr</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gln</td><td>Gly</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Trp</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Leu</td><td>ala</td><td>Trp</td><td>Tyr</td><td>Gln</td><td>Gin '</td><td>lys</td><td>Pro</td><td>Gly</td><td>lys</td><td>ala</td><td>Pro</td><td>lys</td><td>Leu</td><td>Leu</td><td>How much</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Tyr</td><td>ala</td><td>ala</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gln</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td><td>Cheese</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gln</td><td>Pro</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gln</td><td>Gln</td><td>ala</td><td>Tyr</td><td>Cheese</td><td>phe</td><td>Arg</td><td>Thr</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>phe</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 14 &lt;211&gt; 366 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 14 gagttgcatc tggtggagtc tgggggaggc ttggtccagc ctgggggggc cctgagaccc 60 tcctgtgcag tctctggatt cacctctagt aggctatgga tgagctgggg ccgccaggcc 120 ttatggaagg tgctggagtc ggtggccaac ataaagcaag atggaagtga gaaaatacat 180 tgaaggtctg attccacatc tccagagaca acgccaagaa ctcaccggat 240 ttgcaaatga atagcctgag agccgaggac aattgtgttt attactgtgc gagtgtacaa 300 ggtatagcag tggttggctt ctttgaataa tggggccagg gaagtttggt caccggctcc 360 tcagcc 366 &lt;210&gt; 15 &lt;211&gt; 122

135

EP 1 838 733 B1 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 15

<td>Glu.</td><td>val</td><td>Gin</td><td>Leu</td><td>val</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Leu</td><td>val</td><td>Gin</td><td>Pro</td><td>Gly</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>ala</td><td>val</td><td>Cheese</td><td>Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Cheese</td><td>Cheese</td><td>Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Trp</td><td>Underworld</td><td>Cheese</td><td>Trp</td><td>val</td><td>Arg</td><td>Gin</td><td>ala</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>val</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45 '</td><td></td><td></td><td></td>

<td>ala</td><td>own</td><td>How much</td><td>lys</td><td>Gin</td><td>Asp</td><td>Gly</td><td>Cheese</td><td>Glu</td><td>lys</td><td>Tyr</td><td>Tyr</td><td>val</td><td>Asp</td><td>Cheese</td><td>val</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>lys</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>own</td><td>ala</td><td>lys</td><td>own</td><td>Cheese</td><td>Leu</td><td>Tyr</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Leu</td><td>GLn</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>ala</td><td>Arg</td><td>Asp</td><td>Gin</td><td>Gly</td><td>How much</td><td>ala</td><td>val</td><td>ala</td><td>Gly</td><td>Pro</td><td>phe</td><td>Asp</td><td>Tyr</td><td>Trp</td><td>Gly</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Gin</td><td>Gly</td><td>Thr</td><td>Leu</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>115</td><td></td><td></td><td></td><td></td><td>120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 16 &lt;211&gt; 322 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 16 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggcccgtga ggaCggtagc agcggaCtag cctggtacca gcagaaacct 120 ggccaggctc ccaggcgcct ccactatgga gccacccata gggccactgg taccccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtgtattc ccgtcagcag tattataact ggtggacgtt cggccaaggg 300 accaaggtgg aaatccaacg aa 322 &lt;210&gt; 17 &lt;211&gt; 107 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 17

<td>Glu</td><td>How much</td><td>val</td><td>Underworld</td><td>Thr</td><td>Gin</td><td>Cheese</td><td>Pro</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>val</td><td>Cheese</td><td>Pro</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Glu</td><td>Arg</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>GLn</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>Asp</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Leu</td><td>ala</td><td>Trp</td><td>Tyr</td><td>Gin</td><td>Gin</td><td>lys</td><td>Pro</td><td>Gly</td><td>GLn</td><td>ala</td><td>Pro</td><td>Arg</td><td>Leu</td><td>Leu</td><td>How much</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Tyr</td><td>Gly</td><td>ala</td><td>Cheese</td><td>How much</td><td>Arg</td><td>ala</td><td>Thr</td><td>Gly</td><td>How much</td><td>Pro</td><td>ala</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Glu</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>GLn</td><td>Cheese</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>val</td><td>Tyr</td><td>Cheese</td><td>Cys</td><td>GLn</td><td>GLn</td><td>Tyr</td><td>Tyr</td><td>own</td><td>Trp</td><td>Trp</td><td>Thr</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>phe</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 18 &lt;211&gt; 366 &lt;212&gt; DNA &lt;213&gt; Homo sapiens

136

ΕΡ 1 838 733 Β1 &lt;400&gt; 18 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag tctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gaaatactat 180 gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240 ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcaa 300 ggtatagcag tggctgggcc ctttgactac tggggccagg gaaccctggt caccgtctcc 360 tcagcc 366 &lt;210&gt; 19 &lt;211&gt; 122 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 19

<td>Glu</td><td>val</td><td>Gln</td><td>Leu</td><td>val</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Leu</td><td>val</td><td>Gln</td><td>Pro</td><td>Gly</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>ala</td><td>val</td><td>Cheese</td><td>Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Cheese</td><td>Cheese</td><td>Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Trp</td><td>Underworld</td><td>Cheese</td><td>Trp</td><td>val</td><td>Arg</td><td>Gln</td><td>ala</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>val</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>ala</td><td>own</td><td>How much</td><td>lys</td><td>Gln</td><td>Asp</td><td>Gly</td><td>Cheese</td><td>Glu</td><td>lys</td><td>Tyr</td><td>Tyr</td><td>val</td><td>Asp</td><td>Cheese</td><td>val</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>lys</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>own</td><td>ala</td><td>lys</td><td>own</td><td>Cheese</td><td>Leu</td><td>Tyr</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Leu</td><td>Gln</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>ala</td><td>Arg</td><td>Asp</td><td>Gln</td><td>Gly</td><td>How much</td><td>ala</td><td>val</td><td>ala</td><td>Gly</td><td>Pro</td><td>phe</td><td>Asp</td><td>Tyr</td><td>Trp</td><td>Gly</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Gln</td><td>Gly</td><td>Thr</td><td>Leu</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td><td></td><td></td>

115 120 &lt;210&gt; 20 &lt;211&gt; 322 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 20 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gactgttagc agcgacttag cctggtacca gcagaaacct 120 ggccaggctc ccaggctcct catctatgga gcatccatta gggccactgg tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttattc ctgtcagcag tattataact ggtggacgtt cggccaaggg 300 accaaggtgg aaatcaaacg aa 322 &lt;210&gt; 21 &lt;211&gt; 107 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 21

<td>Glu</td><td>How much</td><td>val</td><td>Underworld</td><td>Thr</td><td>Gln</td><td>Cheese</td><td>Pro</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>val</td><td>Cheese</td><td>Pro</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Glu</td><td>Arg</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gln</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>Asp</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Leu</td><td>ala</td><td>Trp</td><td>Tyr</td><td>Gln</td><td>Gln</td><td>lys</td><td>Pro</td><td>Gly</td><td>Gln</td><td>ala</td><td>Pro</td><td>Arg</td><td>Leu</td><td>Leu</td><td>How much</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Tyr</td><td>Gly</td><td>ala</td><td>Cheese</td><td>How much</td><td>Arg</td><td>ala</td><td>Thr</td><td>Gly</td><td>How much</td><td>Pro</td><td>ala</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

137

ΕΡ 1 838 733 Β1

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Glu</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Leu cheese</td><td>Gin</td><td>Cheese</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td>80</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>val</td><td>Tyr</td><td>Cheese</td><td>.Cys</td><td>Gin</td><td>Gin</td><td>Tyr</td><td>Tyr</td><td>Asn Trp</td><td>Trp</td><td>Thr</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td>95</td><td></td>

<td>phe</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 22 &lt;211&gt; 366 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 22 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag tctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gaaatactat 180 gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240 ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcaa 300 ggtatagcag tggctgggcc ctttgactac tggggccagg gaaccctggt caccgtctcc 360 tcagcc 366 &lt;210&gt; 23 &lt;211&gt; 122 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 23

<td>Glu</td><td>val</td><td>Gin</td><td>Leu</td><td>val</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Leu</td><td>val</td><td>Gin</td><td>Pro</td><td>Gly</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>ala</td><td>val</td><td>Cheese</td><td>Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Cheese</td><td>Cheese</td><td>Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Trp</td><td>Underworld</td><td>Cheese</td><td>Trp</td><td>val</td><td>Arg</td><td>Gin</td><td>ala</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>val</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>ala</td><td>own</td><td>How much</td><td>lys</td><td>Gin</td><td>Asp</td><td>Gly</td><td>Cheese</td><td>Glu</td><td>lys</td><td>Tyr</td><td>Tyr</td><td>val</td><td>Asp</td><td>Cheese</td><td>val</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>lys</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>own</td><td>ala</td><td>lys</td><td>own</td><td>Cheese</td><td>Leu</td><td>Tyr</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Leu</td><td>Gin</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>ala</td><td>Arg</td><td>Asp</td><td>Gin</td><td>Gly</td><td>How much</td><td>ala</td><td>val</td><td>ala</td><td>Gly</td><td>Pro</td><td>phe</td><td>Asp</td><td>Tyr</td><td>Trp</td><td>Gly</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Gin</td><td>Gly</td><td>Thr</td><td>Leu</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td><td></td><td></td>

115 120 &lt;210&gt; 24 &lt;211&gt; 322 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 24 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gactgttagc agcgacttag cctggtacca gcagaaacct 120 ggccaggctc ccaggctcct catctatgga gcatccatta gggccactgg tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttattc ctgtcagcag tattataact ggtggacgtt cggccaaggg 300 accaaggtgg aaatcaaacg aa 322 &lt;210&gt; 25 &lt;211&gt; 107

138

EP 1 838 733 B1 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 25

<td colspan="10">Glu Ile Val Met Thr Gln Ser Pro Ala Thr</td><td rowspan="2">Leu</td><td rowspan="2">Cheese</td><td rowspan="2">val</td><td rowspan="2">Cheese</td><td rowspan="2">Pro 15</td><td rowspan="2">Gly</td>

<td colspan="3">1</td><td colspan="2">5</td><td colspan="5">. 10</td>

<td>Glu</td><td>Arg</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gln</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>Asp</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Leu</td><td>ala</td><td>Trp</td><td>Tyr</td><td>Gln</td><td>Gln</td><td>lys</td><td>Pro</td><td>Gly</td><td>Gln</td><td>ala</td><td>Pro</td><td>Arg</td><td>Leu</td><td>Leu</td><td>How much</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Tyr</td><td>Gly</td><td>ala</td><td>Cheese</td><td>How much</td><td>Arg,</td><td>ala</td><td>Thr</td><td>Gly</td><td>How much</td><td>Pro</td><td>ala</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Glu</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gln</td><td>Cheese</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>val</td><td>Tyr</td><td>Cheese</td><td>Cys</td><td>Gln</td><td>Gln</td><td>Tyr</td><td>Tyr</td><td>own</td><td>Trp</td><td>Trp</td><td>Thr</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>phe</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 26 &lt;211&gt; 366 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 26 gaggtgcagc tggtgcagtc tggagcagaggtraraaaaaęrc ccggggagtc tctgaagatc 60 tcctgtaagg. gttctggata cagcttttcc aaacaccęrga ttcgctgggt gcgccagatg · 120 cccgggaaag gcctggagtg gatggęjgatGaacttacctg · gagacacaga taccagatac 180 agcccgtcct taaaaggaaa ggacaccaac ttcggcgaca agtccatcag taccgcctac 240 ctgcagtgga gcagcctgaa ggccacggac aacccccagt aattacgtgc gagacatgag-300 aactggaact tttttgatac taaagaaaac ttgggccaag gggacaagga caecgacaca 360 tcagcc 366 &lt;210&gt; 27 &lt;211&gt; 122 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 27

<td>Glu</td><td>val</td><td>Gln</td><td>Leu</td><td>val</td><td>Gln</td><td>Cheese</td><td>Gly</td><td>ala</td><td>Glu</td><td>val</td><td>lys</td><td>lys</td><td>Pro</td><td>Gly</td><td>Glu</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Cheese</td><td>Leu</td><td>lys</td><td>How much</td><td>Cheese</td><td>Cys</td><td>lys</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Tyr</td><td>Cheese</td><td>phe</td><td>Cheese</td><td>own</td><td>Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Trp</td><td>How much</td><td>ala</td><td>Trp</td><td>val</td><td>Arg</td><td>Gln</td><td>Underworld</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>Underworld</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Gly</td><td>How much</td><td>How much</td><td>Tyr</td><td>Pro</td><td>Gly</td><td>Asp</td><td>Cheese</td><td>Asp</td><td>Thr</td><td>Arg</td><td>Tyr</td><td>Cheese</td><td>Pro</td><td>Cheese</td><td>phe</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Gln</td><td>Gly</td><td>Gln</td><td>val</td><td>Thr</td><td>How much</td><td>Cheese</td><td>ala</td><td>Asp</td><td>lys</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>Thr</td><td>ala</td><td>Tyr</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Leu</td><td>Gln</td><td>Trp</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>lys</td><td>ala</td><td>Cheese</td><td>Asp</td><td>Thr</td><td>ala</td><td>Underworld</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>ala</td><td>Arg</td><td>His</td><td>Glu</td><td>own</td><td>Trp</td><td>own</td><td>phe</td><td>phe</td><td>Asp</td><td>Thr</td><td>phe</td><td>Asp</td><td>How much</td><td>Trp</td><td>Gly</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Gln</td><td>Gly</td><td>Thr</td><td>Underworld</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td><td></td><td></td>

115 120 &lt;210&gt; 28 &lt;211&gt; 324 &lt;212&gt; DNA &lt;213&gt; Homo sapiens

139

EP 1 838 733 B1 &lt;400&gt; 28 gaaatcgtgc tgacgcagtc tccagccacc ctgtctg-tęft -ctccagggga aagagccacc 60 ctctcctgca gggccagtcc gagtattcgc agcaactCgg cctggttcca gcagccccct 120 ggccaggctc cccggctcct catctctggt gcatccacca gggcccctgg taccccagcc 180 cggttccgtg gcagtgggtc tgggacagag tccactccca ccatcagcag cctgccgtct 240 gaagactttg cagtttctta ctgtccaccg taccacaact ggcctcggac gtcgggccaa 300 ggaatcctga tggcgatccc acga 324 &lt;210&gt; 29 &lt;211&gt; 108 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 29

<td>Glu</td><td>How much</td><td>val</td><td>Underworld</td><td>Thr</td><td>Gln</td><td>Cheese</td><td>Pro</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>val</td><td>Cheese</td><td>Pro</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Glu</td><td>Arg</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>ALa</td><td>Cheese</td><td>Gln</td><td>Cheese</td><td>He</td><td>Cheese</td><td>Cheese</td><td>own</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Leu</td><td>Alc</td><td>Trp</td><td>phe</td><td>Gln</td><td>Gln</td><td>lys</td><td>Pro</td><td>Gly</td><td>Gln</td><td>ALC</td><td>Pro</td><td>AIRg</td><td>Leu</td><td>Leu</td><td>How much</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Tyr</td><td>Gly</td><td>Alc</td><td>Cheese</td><td>Thr</td><td>Arg</td><td>Alc</td><td>Thr</td><td>Gly</td><td>How much</td><td>Pro</td><td>ALC</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Glu</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>.Gln</td><td>Cheese</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>Alc</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gln</td><td>Gln</td><td>Tyr</td><td>own</td><td>own</td><td>Trp</td><td>Pro</td><td>Arg</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Thr</td><td>phe</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Glu</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 30 &lt;211&gt; 351 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;4oo&gt; 30 ccagtatcgc tggaggagtc gggcccagga ctggtgaagc cttcggagac cctatctttc 60 ccttgcctta tcttCggatg ctccatcagt aactactact ggacatgggC tcgatcgcct 120 cccagaccga gactggagtg gattggatat atctattcca gtgggagcac cccctacaBC 180 agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240 cccctacact ctgagaccta tgcggacacg gcctagaaCt actgtgcgag cgcccaggct 300 gatgcttttg atactcgggg ccaagggaca atggtccccg tctcttccgc c 351 &lt;210&gt; 31 &lt;211&gt; 117 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 31

<td>Gln</td><td>val</td><td>Gln</td><td>Leu</td><td>Gln</td><td>GLU</td><td>Cheese</td><td>Gly</td><td>Pro</td><td colspan="2">Gly Leu</td><td>val</td><td>lys</td><td>Pro</td><td>Cheese</td><td>Glu</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Thr</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Thr</td><td>Cys</td><td>Thr</td><td>val</td><td>Cheese</td><td colspan="2">Gly Gly</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>own</td><td>Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Tyr</td><td>Trp</td><td>Cheese</td><td>Trp</td><td>How much</td><td>Arg</td><td>Gln</td><td>Pro</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>How much</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Gly</td><td>Tyr</td><td>How much</td><td>Tyr</td><td>Tyr</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Thr</td><td>own</td><td>Tyr</td><td>own</td><td>Pro</td><td>Cheese</td><td>Leu</td><td>lys</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Cheese</td><td>val</td><td>Asp</td><td>Thr</td><td>Cheese</td><td>lys</td><td>own</td><td>Gln</td><td>phe</td><td>Cheese</td><td>Leu</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

140

EP 1 838 733 B1

<td>lys</td><td>Leu</td><td>Cheese</td><td>Cheese</td><td>Val Thr</td><td>ALa</td><td>ala</td><td>Asp</td><td>Thr ALa</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>ALa</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td>95</td><td></td>

<td>Arg</td><td>Asp</td><td>Arg</td><td>ala</td><td>Asp Ala</td><td>phe</td><td>Asp</td><td>How much</td><td>Trp Gly</td><td>Gin</td><td>Gly</td><td>Thr</td><td>Underworld</td><td>val</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>115</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 32 &lt;211&gt; 342 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 32 gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60 atctcctgca ggtctagtca aagcctcgtt tacagtgatg gaaacaccta cttgaattgg 120 ttcaagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180 tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240 agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300 ccgctcactt tcggcggagg gaccaaggtg gagatcaaac ga 342 &lt;210&gt; 33 &lt;211&gt; 114 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 33

<td colspan="7">Asp Val Val Met Thr Gin Cheese</td><td rowspan="2">Pro</td><td colspan="7">Leu Ser Leu Pro Val Thr Leu</td><td rowspan="2">Gly</td>

<td>1</td><td colspan="6">5</td><td colspan="6">10</td><td>15</td>

<td>Gin</td><td>Pro</td><td>ala</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>Cheese</td><td>Cheese</td><td>Gin</td><td>Cheese</td><td>Leu</td><td>val</td><td>Tyr</td><td>Cheese</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Asp</td><td>Gly</td><td>own</td><td>Thr</td><td>Tyr</td><td>Leu</td><td>own</td><td>Trp</td><td>phe</td><td>Gin</td><td>Gin</td><td>Arg</td><td>Pro</td><td>Gly</td><td>Gin</td><td>Cheese</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Pro</td><td>Arg</td><td>Arg</td><td>Leu</td><td>How much</td><td>Tyr</td><td>lys</td><td>val</td><td>Cheese</td><td>own</td><td>Trp</td><td>Asp</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Asp</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>lys</td><td>How much</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Cheese</td><td>Arg</td><td>val</td><td>Glu</td><td>ALa</td><td>Glu</td><td>Asp</td><td>val</td><td>Gly</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Underworld</td><td>Gin</td><td>Gly</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Thr</td><td>His</td><td>Trp</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Thr</td><td>phe</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>lys</td><td>Arg</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 34 &lt;211&gt; 366 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 34 caggtgcagc tggtggagtc tggggggggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctgcatt caccttccat agctatggca tgcactgggt ccgccaggcc 120 ccgcccaggg ccctggggtc ggtggcagtt atgtggtgtg atggaagtaa taaatactat 180 ^ agaetc ^ tgaagggccg attcaacctc tttacgcaca attccaagaa cacggtggat 240 ctgcggatga gtggcctagg agccgaggac acggccgtgt attactgtgc 300 ttacgatatt ttgactggcc ccctggctaa tgcggccgcg gaaccctggt caccggctcc 360 tcagcc 366 &lt;210&gt; 35 &lt;211&gt; 122

141

ΕΡ 1 838 733 Β1 &lt;212&gt; PRT &lt;213&gt; Homo sapiens

<td colspan="2">&lt;400&gt; 35</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Gin</td><td>val</td><td>Gin</td><td>Leu</td><td>val</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly</td><td>val</td><td>val</td><td>Gin</td><td>Pro</td><td>Gly</td><td>Arg</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>ala</td><td>ala</td><td>Cheese</td><td>Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Cheese</td><td>Cheese</td><td>• Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Gly</td><td>Underworld</td><td>His</td><td>Trp</td><td>val</td><td>Arg</td><td>Gin</td><td>ala</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>val</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45 </td><td></td><td></td><td></td>

<td>ala</td><td>val</td><td>How much</td><td>Trp</td><td>Tyr</td><td>Asp</td><td>Gly</td><td>Cheese</td><td>own</td><td>lys</td><td>Tyr</td><td>Tyr</td><td>ala</td><td>Asp</td><td>Cheese</td><td>val</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>lys</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>own</td><td>Cheese</td><td>lys</td><td>own</td><td>Thr</td><td>Leu</td><td>Tyr</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Leu</td><td>Gin</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>ala</td><td>Arg</td><td>Gly</td><td>Gly</td><td>Leu</td><td>Arg</td><td>Tyr</td><td>phe</td><td>Asp</td><td>Trp</td><td>Pro</td><td>Pro</td><td>Asp</td><td>Tyr</td><td>Trp</td><td>Gly</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Gin</td><td>Gly</td><td>Thr</td><td>Leu</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td><td></td><td></td>

115 120 &lt;210&gt; 36 &lt;211&gt; 327 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 36 gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120 cctggccagg ctcccaggct cctcatctat ggtgcatcca acagggccac tggcatccca 180 gacaggttca gtgccagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttgcagtgta ttactgtcag cagtttggta cctcaccatt cactttcggc 300 cctgggacca aagtggatat caaacga 327 &lt;210&gt; 37 &lt;211&gt; 109 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 37

<td colspan="5">Glu Ile Val Leu Thr</td><td rowspan="2">Gin</td><td rowspan="2">Cheese</td><td colspan="3" rowspan="2">Pro Gly Thr 10</td><td rowspan="2">Leu</td><td colspan="2" rowspan="2">Leu cheese</td><td rowspan="2">Cheese</td><td rowspan="2">Pro 15</td><td rowspan="2">Gly</td>

<td>1</td><td colspan="4">5</td>

<td>Glu</td><td>Arg</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gin</td><td>Cheese</td><td>val</td><td>Cheese</td><td>Cheese</td><td>Cheese</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Tyr</td><td>Leu</td><td>ala</td><td>Trp</td><td>Tyr</td><td>Gin</td><td>Gin</td><td>lys</td><td>Pro</td><td>Gly</td><td>Gin</td><td>ala</td><td>Pro</td><td>Arg</td><td>Leu</td><td>Leu</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>How much</td><td>Tyr</td><td>Gly</td><td>ala</td><td>Cheese</td><td>own</td><td>Arg</td><td>ala</td><td>Thr</td><td>Gly</td><td>How much</td><td>Pro</td><td>Asp</td><td>Arg</td><td>phe</td><td>Cheese</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>ala</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Leu</td><td>Glu</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Pro</td><td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gin</td><td>Gin</td><td>phe</td><td>Gly</td><td>Thr</td><td>Cheese</td><td>Pro</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>phe</td><td>Thr</td><td>phe</td><td>Gly</td><td>Pro</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Asp</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 38 &lt;211&gt; 366 &lt;212&gt; DNA &lt;213&gt; Homo sapiens

142

EP 1 838 733 B1 &lt;400&gt; 38 gaggtgcagc tcctgtgcag ccagggaagg gactacgctg ctgtatctgc gaatacggtg tcagcc tggtggagtc cctctggatt ggctggagtg cacccgtgaa aaatgaacag acttttggta tgggggaggc cacattcagt ggttggccgt aggcacattc cctgaaaacc cttcgatatc ttggtaaagc aacgcctgga attaaaagca accaactcaa gaggacacag tggggccgtg ctggggggtc tgagctgggt aaacttatgt gagaagaatc ccgtgtatta gcaccctggt ccttagactc ccgccaggcc tgggacaaca aaaaaacacg ctgtatcatg cactgtctcc

120

180

240

300

360

366 &lt;210&gt; 39 &lt;211&gt; 122 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 39

<td>Glu Val Gln</td><td>Leu</td><td>val</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Leu</td><td>val</td><td>lys</td><td>Pro</td><td>Gly</td><td>Gly</td>

<td>1</td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Leu Arg cheese</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>ala</td><td>ala</td><td>Cheese</td><td>Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Cheese</td><td>own</td><td>ala</td>

<td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Trp Met Ser</td><td>Trp</td><td>val</td><td>Arg</td><td>Gin</td><td>ala</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>val</td>

<td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Gly Arg Ile</td><td>lys</td><td>Cheese</td><td>lys</td><td>Thr</td><td>Asp</td><td>Gly</td><td>Gly</td><td>Thr</td><td>Thr</td><td>Asp</td><td>Tyr</td><td>ala</td><td>ala</td>

<td>50</td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Pro Val Lys</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>Asp</td><td>Cheese</td><td>lys</td><td>own</td><td>Thr</td>

<td>65</td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Leu Tyr Leu</td><td>Gin</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>lys</td><td>Thr</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td>

<td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Tyr Cys Thr</td><td>Thr</td><td>Glu</td><td>Tyr</td><td>Gly</td><td>Asp</td><td>phe</td><td>Trp</td><td>Tyr</td><td>phe</td><td>Asp</td><td>phe</td><td>Trp</td><td>Gly</td>

<td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Arg Gly Thr</td><td>Leu</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>115</td><td></td><td></td><td></td><td></td><td>120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>&lt;210&gt; 40</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>&lt;211&gt; 324</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>&lt;212&gt; DNA</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="4">&lt;213&gt; Homo sapiens</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>&lt;400&gt; 40</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

gacatccaga tgacccagtc tccatcttcc ttttctgcat ctgtaggaga cagagtcacc 60 atcacttgtc ggggttaCca gggtattagc atctgtttag tcttgtatca ęFcagaaacca 120 tggaaagttt ctadccccct gatctatgct tc^andtctagtt tgcaaagtgt ggtcccatca 180 agtttcagct gctgtggtac tgttacagat ttcattctca ccatcagcag cctgcagcct 240 gaagattttg caaactacta ttgtcaacag tctaacagtt tccctcggac gtcgggccaa 300 ggtactaagt tggaaatcaa acga · 324 &lt;210&gt; 41 &lt;211&gt; 108 &lt;212&gt; PRT &lt;213&gt; Homo sapiens

<td colspan="16">&lt;400&gt; 41</td>

<td>Asp</td><td>How much</td><td>Gln</td><td>Underworld</td><td>Thr</td><td>Gln</td><td>Cheese</td><td>Pro</td><td>Cheese</td><td>Cheese</td><td>val</td><td>Cheese</td><td>ala</td><td>Cheese</td><td>val</td><td>Gl'y</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Asp</td><td>Arg</td><td>val</td><td>thr '</td><td>How much</td><td>Thr</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gln</td><td>Gly</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Trp</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Leu</td><td>ala</td><td>Trp</td><td>Tyr</td><td>Gln</td><td>Gln</td><td>lys</td><td>Pro</td><td>Gly</td><td>lys</td><td>ala</td><td>Pro</td><td>own</td><td>Leu</td><td>Leu</td><td>How much</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Tyr</td><td>ala</td><td>ala</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gln</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td><td>Cheese</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

143

ΕΡ 1 838 733 Β1

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>How much</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gln</td><td>Pro</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gln</td><td>Gln</td><td>Cheese</td><td>own</td><td>Cheese</td><td>phe</td><td>Pro</td><td>Arg</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Thr</td><td>phe</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 42 &lt;211&gt; 374 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 42 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt ataaggtatg atggaagtaa taaatactat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgaat 240 ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcgg 300 gacggtgact atcctctgct actactgggt atggacgtct ggggccaagg gaccacggtc 360 accgtctcct cagc 374 &lt;210&gt; 43 &lt;211&gt; 125 &lt;212&gt; PRT &lt;213&gt; Homo sapiens

<td colspan="16">&lt;400&gt; 43</td>

<td>Gln</td><td>val</td><td>Gln</td><td>Leu</td><td>val</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly</td><td>val</td><td>val</td><td>Gln</td><td>Pro</td><td>Gly</td><td>Arg</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>ala</td><td>ala</td><td>Cheese</td><td>Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Cheese</td><td>Cheese</td><td>Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Gly</td><td>Underworld</td><td>His</td><td>Trp</td><td>val</td><td>Arg</td><td>Gln</td><td>ala</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>val</td>

<td></td><td></td><td>35 '</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>ala</td><td>val</td><td>How much</td><td>Arg</td><td>Tyr</td><td>Asp</td><td>Gly</td><td>Cheese</td><td>own</td><td>lys</td><td>Tyr</td><td>Tyr</td><td>ala</td><td>Asp</td><td>Cheese</td><td>val</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>lys</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>own</td><td>Cheese</td><td>lys</td><td>own</td><td>Thr</td><td>Leu</td><td>own</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Leu</td><td>Gln</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>ala</td><td>Arg</td><td>Asp</td><td>Arg</td><td>Asp</td><td>Gly</td><td>Asp</td><td>Tyr</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Leu</td><td>Leu</td><td>Gly</td><td>Underworld</td><td>Asp</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>val</td><td>Trp</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td>

<td></td><td></td><td>115</td><td></td><td></td><td></td><td></td><td>120</td><td></td><td></td><td></td><td></td><td>125</td><td></td><td></td><td></td>

&lt;210&gt; 44 &lt;211&gt; 339 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 44 gatattgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60 atctcctgca ggtctagtca gagcctcctg catagtaatg gatacaacta tttggattgg 120 tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc 180 tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattctac actgaaaatc 240 agcagagtgg aggctgagga tgttggggtt tattactgca tgcaagctct acaaactcct 300 ctcactttcg gcggagggac caaggtggag atcaaacga 339 &lt;210&gt; 45 &lt;211&gt; 113

144

ΕΡ 1 838 733 Β1 &lt;212&gt; PRT &lt;213&gt; Homo sapiens

<td colspan="16">&lt;400&gt; 45</td>

<td>Asp</td><td>How much</td><td>val</td><td>Underworld</td><td>Thr</td><td>Gin</td><td>Cheese</td><td>Pro</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Pro</td><td>val</td><td>Thr</td><td>Pro</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Glu</td><td>Pro</td><td>ala</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>Cheese</td><td>Cheese</td><td>Gin</td><td>Cheese</td><td>Leu</td><td>Leu</td><td>His</td><td>Cheese</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>own</td><td>Gly</td><td>Tyr</td><td>own</td><td>Tyr</td><td>Leu</td><td>Asp</td><td>Trp</td><td>Tyr</td><td>Leu</td><td>Gin</td><td>lys</td><td>Pro</td><td>Gly</td><td>Gin</td><td>Cheese</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Pro</td><td>Gin</td><td>Leu</td><td>Leu</td><td>How much</td><td>Tyr</td><td>Leu</td><td>Gly</td><td>Cheese</td><td>own</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>'55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Asp</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>Cheese</td><td>Thr</td><td>Leu</td><td>lys</td><td>How much</td>

<td>65-</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Cheese</td><td>Arg</td><td>val</td><td>Glu</td><td>ala</td><td>Glu</td><td>Asp</td><td>val</td><td>Gly</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Underworld</td><td>Gin</td><td>ala</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Leu</td><td>Gin</td><td>Thr</td><td>Pro</td><td>Leu</td><td>Thr</td><td>phe</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td><td>lys</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Arg</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 46 &lt;211&gt; 366 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 46 gtcaggtgca gctggtggag tctgggggag gcgtggtcca gcctgggagg tccctgagac 60 tctcctgtgc agcgtctgga ttcaccttca gtagctatgg catgcactgg gtccgccagg 120 ctccaggcaa ggggctggag tgggtggcag ttatatggta tgatggaagt aataaatact 180 atgcagactc cgtgaagggc cgattcacca tctccagaga caattccaag aacacgctgt 240 atctgcaaat gaacagcctg agagccgagg acacggctgt gtattactgt gcgggggact 300 acggtgacta cttctactac ggtatggacg tctggggcca agggaccacg gtcaccgtct 360 cctcag 366 &lt;210&gt; 47 &lt;211&gt; 122 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 47

<td>Gin</td><td>val</td><td>Gin</td><td>Leu</td><td>val</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly</td><td>val</td><td>val</td><td>Gin</td><td>Pro</td><td>Gly</td><td>Arg</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>ala</td><td>ala</td><td>Cheese</td><td>Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Cheese</td><td>Cheese</td><td>Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Gly</td><td>Underworld</td><td>His</td><td>Trp</td><td>val</td><td>Arg</td><td>Gin</td><td>ala</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>val</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>ala</td><td>val</td><td>How much</td><td>Trp</td><td>Tyr</td><td>Asp</td><td>Gly</td><td>Cheese</td><td>own</td><td>lys</td><td>Tyr</td><td>Tyr</td><td>ala</td><td>Asp</td><td>Cheese</td><td>val</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>lys</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>own</td><td>Cheese</td><td>lys</td><td>own</td><td>Thr</td><td>Leu</td><td>Tyr</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Leu</td><td>Gin</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>ala</td><td>Gly</td><td>Asp</td><td>Tyr</td><td>Gly</td><td>Asp</td><td>Tyr</td><td>phe</td><td>Tyr</td><td>Tyr</td><td>Gly</td><td>Underworld</td><td>Asp</td><td>val</td><td>Trp</td><td>Gly</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Gin</td><td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>115</td><td></td><td></td><td></td><td></td><td>120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 48 &lt;211&gt; 324 &lt;212&gt; DNA &lt;213&gt; Homo sapiens

145

ΕΡ 1 838 733 Β1 &lt;400&gt; 48 gacatccaga tgacccagtc tccatcctcc ctgtctacat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120 gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcggcct 240 gaagattttg caacttatta ctgtctacag cttaatagtt accctcggac gttcggccaa 300 gggaccaagg tggaaatcaa acga 324 ¹ &lt;210&gt; 49 &lt;211&gt; 108 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 49

<td colspan="16">Asp Ile Gin Met Thr Gin Cheese Pro Cheese Cheese Leu Cheese Thr Cheese Val Gly</td>

<td colspan="3">1</td><td colspan="2">5</td><td colspan="5">10</td><td colspan="6">15</td>

<td>Asp</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Thr</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gin</td><td>Gly</td><td>How much</td><td>Arg</td><td>own</td><td>Asp</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Leu</td><td>Gly</td><td>Trp</td><td>Tyr</td><td>Gin</td><td>Gin</td><td>lys</td><td>Pro</td><td>Gly</td><td>lys</td><td>ala</td><td>Pro</td><td>lys</td><td>Arg</td><td>Leu</td><td>How much</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Tyr</td><td>ala</td><td>ala</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gin</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td><td>Cheese</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Glu</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>Pro</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Leu</td><td>Gin</td><td>Leu</td><td>own</td><td>Cheese</td><td>Tyr</td><td>Pro</td><td>Arg</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Thr</td><td>phe</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 50 &lt;211&gt; 351 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 50 caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60 acctgcactg tctctggtgg ctccatcagt aattactact ggagctggat ccggcagccc 120 ccagggaagg gactggagtg gattggatat atctattaca gtgggagcac caactacaac 180 ccctccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240 aaactgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agaccgggct 300 gatgcttttg atatctgggg ccaagggaca atggtcaccg tctcttcagc c 351 &lt;210&gt; 51 &lt;211&gt; 117 &lt;212&gt; PRT &lt;213&gt; Homo sapiens

<td colspan="16">&lt;400&gt; 51</td>

<td>Gin</td><td>val</td><td>Gin</td><td>Leu</td><td>Gin</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Pro</td><td>Gly</td><td>Leu</td><td>val</td><td>lys</td><td>Pro</td><td>Cheese</td><td>Glu</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Thr</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Thr</td><td>Cys</td><td>Thr</td><td>val</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>own</td><td>Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Tyr</td><td>Trp</td><td>Cheese</td><td>Trp</td><td>How much</td><td>Arg</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>How much</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Gly</td><td>Tyr</td><td>How much</td><td>Tyr</td><td>Tyr</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Thr</td><td>own</td><td>Tyr</td><td>own</td><td>Pro</td><td>Cheese</td><td>Leu</td><td>lys</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

146

ΕΡ 1 838 733 Β1

<td>Cheese</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Cheese</td><td>val</td><td>Asp</td><td>Thr</td><td>Cheese</td><td>lys</td><td>own</td><td>Gin</td><td>phe</td><td>Cheese</td><td>Leu</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75.</td><td></td><td></td><td></td><td></td><td>80</td>

<td>lys</td><td>Leu</td><td>Cheese</td><td>Cheese</td><td>val</td><td>Thr</td><td>ala</td><td>ala</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>ala</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Arg</td><td>Asp</td><td>Arg</td><td>ala</td><td>Asp</td><td>ala</td><td>phe</td><td>Asp</td><td>How much</td><td>Trp</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Thr</td><td>Underworld</td><td>val</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

115 &lt;210&gt; 52 &lt;211&gt; 342 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 52 gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60 atctcctgca ggtctagtca aagcctcgtt tacagtgatg gaaacaccta cttgaattgg 120 tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180 tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240 agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300 ccgctcactt tcggcggagg gaccaaggtg gagatcaaac ga 342 &lt;210&gt; 53 &lt;211&gt; 114 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 53

<td>Asp</td><td>val</td><td>val</td><td>Underworld</td><td>Thr</td><td>Gin</td><td>Cheese</td><td>Pro</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Pro</td><td>val</td><td>Thr</td><td>Leu</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Gin</td><td>Pro</td><td>ala</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>Cheese</td><td>Cheese</td><td>Gin</td><td>Cheese</td><td>Leu</td><td>val</td><td>Tyr</td><td>Cheese</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Asp</td><td>Gly</td><td>own</td><td>Thr</td><td>Tyr</td><td>Leu</td><td>own</td><td>Trp</td><td>phe</td><td>Gin</td><td>Gin</td><td>Arg</td><td>Pro</td><td>Gly</td><td>Gin</td><td>Cheese</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Pro</td><td>Arg</td><td>Arg</td><td>Leu</td><td>How much</td><td>Tyr</td><td>lys</td><td>val</td><td>Cheese</td><td>own</td><td>Trp</td><td>Asp</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Asp</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>lys</td><td>How much</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Cheese</td><td>Arg</td><td>val</td><td>Glu</td><td>ala</td><td>Glu</td><td>Asp</td><td>val</td><td>Gly</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Underworld</td><td>Gin</td><td>Gly</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Thr</td><td>His</td><td>Trp</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Thr</td><td>phe</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>lys</td><td>Arg</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 54 &lt;211&gt; 351 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 54 caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60 acctgcactg tctctggtgg ctccatcagt aattactact ggagctggat ccggcagccc 120 ccagggaagg gactggagtg gattggatat atctattaca gtgggagcac caactacaac 180 ccctccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240 aaactgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agaccgggct 300 gatgcttttg atatctgggg ccaagggaca atggtcaccg tctcttcagc c 351

147

ΕΡ 1 838 733 Β1 &lt;210&gt; 55 &lt;211&gt; 117 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 55

<td>Gin</td><td>val</td><td>Gin</td><td>Leu</td><td>Gin</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Pro</td><td>Gly</td><td>Leu</td><td>val</td><td>lys</td><td>Pro</td><td>Cheese</td><td>Glu</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Thr</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Thr</td><td>Cys</td><td>Thr</td><td>val</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>own</td><td>Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Tyr</td><td>Trp</td><td>Cheese</td><td>Trp</td><td>How much</td><td>Arg</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>How much</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Gly</td><td>Tyr</td><td>How much</td><td>Tyr</td><td>Tyr</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Thr</td><td>own</td><td>Tyr</td><td>own</td><td>Pro</td><td>Cheese</td><td>Leu</td><td>lys</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Cheese</td><td>val</td><td>Asp</td><td>Thr</td><td>Cheese</td><td>lys</td><td>own</td><td>Gin</td><td>phe</td><td>Cheese</td><td>Leu</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>lys</td><td>Leu</td><td>Cheese</td><td>Cheese</td><td>val</td><td>Thr</td><td>ala</td><td>ala</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>ala</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Arg</td><td>Asp</td><td>Arg</td><td>ala</td><td>Asp</td><td>ala</td><td>phe</td><td>Asp</td><td>How much</td><td>Trp</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Thr</td><td>Underworld</td><td>val</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>115</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 56 &lt;211&gt; 342 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 56 gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60 atctcctgca ggtctagtca aagcctcgtt tacagtgatg gaaacaccta cttgaattgg 120 tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180 tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240 agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300 ccgctcactt tcggcggagg gaccaaggtg gagatcaaac ga 342 &lt;210&gt; 57 &lt;211&gt; 114 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 57

<td colspan="6">Asp Val Val Met Thr Gin</td><td rowspan="2">Cheese</td><td colspan="8">Pro Leu Leu Ser Pro Val Thr Leu</td><td rowspan="2">Gly</td>

<td colspan="4">1</td><td colspan="2">5</td><td colspan="4">10</td><td colspan="4">15</td>

<td>Gin</td><td>Pro</td><td>ala</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>Cheese</td><td>Cheese</td><td>Gin</td><td>Cheese</td><td>Leu</td><td>val</td><td>Tyr</td><td>Cheese</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Asp</td><td>Gly</td><td>own</td><td>Thr</td><td>Tyr</td><td>Leu</td><td>own</td><td>Trp</td><td>phe</td><td>Gin</td><td>Gin</td><td>Arg</td><td>Pro</td><td>Gly</td><td>Gin</td><td>Cheese</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Pro</td><td>Arg</td><td>Arg</td><td>Leu</td><td>How much</td><td>Tyr</td><td>lys</td><td>val</td><td>Cheese</td><td>own</td><td>Trp</td><td>Asp</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Asp</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>lys</td><td>How much</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Cheese</td><td>Arg</td><td>val</td><td>Glu</td><td>ala</td><td>Glu</td><td>Asp</td><td>val</td><td>Gly</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Underworld</td><td>Gin</td><td>Gly</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Thr</td><td>His</td><td>Trp</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Thr</td><td>phe</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

Lys Arg &lt;210&gt; 58 &lt;211&gt; 366

148

ΕΡ 1 838 733 Β1 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 58 gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60 tcctgtgcag cctctggatt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180 gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaaaacacg 240 ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ttgtatcatt 300 ttctacggtg actttgatgc tfttgatatc tggggccaag ggacaatggt caccgtctct 360 tcagcc 366 &lt;210&gt; 59 &lt;211&gt; 122 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 59

<td>Glu</td><td>val</td><td>Gln</td><td>Leu</td><td>val</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Leu</td><td>val</td><td>lys</td><td>Pro</td><td>Gly</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>ala</td><td>ala</td><td>Cheese</td><td>Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Cheese</td><td>own</td><td>ala</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Trp</td><td>Underworld</td><td>Cheese</td><td>Trp</td><td>val</td><td>Arg</td><td>Gln</td><td>ala</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>val</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Gly</td><td>Arg</td><td>How much</td><td>lys</td><td>Cheese</td><td>lys</td><td>Thr</td><td>Asp</td><td>Gly</td><td>Gly</td><td>Thr</td><td>Thr</td><td>Asp</td><td>Tyr</td><td>ala</td><td>ala</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Pro</td><td>val</td><td>lys</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>Asp</td><td>Cheese</td><td>lys</td><td>own</td><td>Thr</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Leu</td><td>Tyr</td><td>Leu</td><td>Gln</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>lys</td><td>Thr</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Tyr</td><td>Cys</td><td>How much</td><td>How much</td><td>phe</td><td>Tyr</td><td>Gly</td><td>Asp</td><td>phe</td><td>Asp</td><td>ala</td><td>phe</td><td>Asp</td><td>How much</td><td>Trp</td><td>Gly</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Gln</td><td>Gly</td><td>Thr</td><td>Underworld</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>115</td><td></td><td></td><td></td><td></td><td>120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 60 &lt;211&gt; 313 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 60 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaagct 240 gaagattttg caacttacta ctgtcaacag agtttaactt tcggccctgg gaccaaagtg 300 gatatcaaac gaa 313 &lt;210&gt; 61 &lt;211&gt; 104 &lt;212&gt; PRT &lt;213&gt; Homo sapiens

<td colspan="16">&lt;400&gt; 61</td>

<td>Asp</td><td>How much</td><td>Gln</td><td>Underworld</td><td>Thr</td><td>Gln</td><td>Cheese</td><td>Pro</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>ala</td><td>Cheese</td><td>val</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Asp</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Thr</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>£ ln</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Leu</td><td>own</td><td>Trp</td><td>Tyr</td><td>Gln</td><td>Gln</td><td>lys</td><td>Pro</td><td>Gly</td><td>lys</td><td>ala</td><td>Pro</td><td>lys</td><td>Leu</td><td>Leu</td><td>How much</td>

149

EP 1 838 733 B1

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Tyr</td><td>ala</td><td>ala</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gln</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td><td>Cheese</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gln</td><td>ala</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>GLn</td><td>Gln</td><td>Cheese</td><td>Leu</td><td>Thr</td><td>phe</td><td>Gly</td><td>Pro</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Asp</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

100 &lt;210&gt; 62 &lt;211&gt; 342 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 62 gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60 atctcctgca ggtctagacc aagccccgat tacagtgatg .gagacaccta ctggaatagg 120 ttceageaga ggccaggcca. atctccaagg cggctaattt ataaggtttc taacggggac 180 tctggggtcc cagacagaga cagcggcagg- ggggcaggca ctgatttcac actgaaaatc 240 agaagggtgg aggctggaga tgttgggggt tattactgca tgcaaggtac acactggcct 300 ccgctcactt tecggcggag gaccaaggtg gaggacaaac branch 342 &lt;210&gt; 63 &lt;211&gt; 114 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 63

<td>Asp</td><td>val</td><td>val</td><td>Underworld</td><td>Thr</td><td>Gln</td><td>Cheese</td><td>Pro</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Pro</td><td>val</td><td>Thr</td><td>Leu</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Gln</td><td>Pro</td><td>ala</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>Cheese</td><td>Cheese</td><td>Gln</td><td>Cheese</td><td>Leu</td><td>val</td><td>Tyr</td><td>Cheese</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Asp</td><td>Gly</td><td>own</td><td>Thr</td><td>Tyr</td><td>Leu</td><td>own</td><td>Trp</td><td>phe</td><td>Gln</td><td>Gln</td><td>Arg</td><td>Pro</td><td>Gly</td><td>Gln</td><td>Cheese</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Pro</td><td>Arg</td><td>Arg</td><td>Leu</td><td>How much</td><td>Tyr</td><td>lys</td><td>val</td><td>Cheese</td><td>own</td><td>Trp</td><td>Asp</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Asp</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>lys</td><td>How much</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Cheese</td><td>Arg</td><td>val</td><td>Glu</td><td>ala</td><td>Glu</td><td>Asp</td><td>val</td><td>Gly</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Underworld</td><td>Gln</td><td>Gly</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Thr</td><td>His</td><td>Trp</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Thr</td><td>phe</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td>

<td></td><td></td><td></td><td>100</td><td>•</td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

Lys Arg &lt;210&gt; 64 &lt;211&gt; 324 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 64 gacatccaaa tggaccagtc tccatcctca ctgtctgcat ctgtaggaga ^ c ^ a ^^ cc gagc 60 atcacttgtc gggcgagtca ggggcatagc aggtatttag cccgggttca ggcggaacca 120 gggaaagaac ctaagtccct ggatcatget gcaacccaat tgcaaagtgg gica ^^ aca 180 aagttcagcg gcagtggatc tgggacagga ttcactctca ccatcagcag cccgcagccc 240 gaagaatttg caactcatta ctgccaacag tataataggt accctctcac tttcggcgga 300 gggaccaagg tggggatcca acga 324 &lt;210&gt; 65 &lt;211&gt; 108

150

EP 1 838 733 B1 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 65

<td>Asp</td><td>How much</td><td>Gin</td><td>Underworld</td><td>Thr</td><td>Gin</td><td>Cheese</td><td>Pro</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>ala</td><td>Cheese</td><td>val</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Asp</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Thr</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>GLn</td><td>Gly</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Leu</td><td>ala</td><td>Trp</td><td>phe</td><td>GLn</td><td>GLn,</td><td>lys</td><td>Pro</td><td>Gly</td><td>lys</td><td>ala</td><td>Pro</td><td>lys</td><td>Cheese</td><td>Leu</td><td>How much</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Tyr</td><td>ala</td><td>ala</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>GLn</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td><td>Cheese</td><td>lys</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>GLn</td><td>Pro</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>GLn</td><td>GLn</td><td>Tyr</td><td>own</td><td>Cheese</td><td>Tyr</td><td>Pro</td><td>Leu</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Thr</td><td>phe</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 66 &lt;211&gt; 366 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 66 gaggtgcaac tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc tcctgtgcag tttttggatt cactttcagt aacgcctgga tgcactgggt ccgccagggt ttaggtaagg tgctttactg ggtgggccgt attaaaagca aaactgatgg tgggacagca gactatgttg eatttgtgaa eggcggagac acctactcaa gaggaggatc agaaaacacg ttgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtaata ctgtaccaat gactaeggtg atttctatgc ttttggtatc tggggccaag ggttattggt caacgtcttt tcagct

120 180 240 300 360 366 &lt;210&gt; 67 &lt;211&gt; 122 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 67

<td>GLU</td><td>val</td><td>GLn</td><td>Leu</td><td>val</td><td>GLU</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Leu</td><td>val</td><td>lys</td><td>Pro</td><td>Gly</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>ala</td><td>ala</td><td>Cheese</td><td>Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Cheese</td><td>own</td><td>ala</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Trp</td><td>Underworld</td><td>His</td><td>Trp</td><td>val</td><td>Arg</td><td>GLn</td><td>ala</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Asp</td><td>Trp</td><td>val</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Gly</td><td>Arg</td><td>How much</td><td>lys</td><td>Cheese</td><td>lys</td><td>Thr</td><td>Asp</td><td>Gly</td><td>Gly</td><td>Thr</td><td>ala</td><td>Asp</td><td>Tyr</td><td>ala</td><td>ala</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Pro</td><td>val</td><td>lys</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>Asp</td><td>Cheese</td><td>Glu</td><td>own</td><td>Thr</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Leu</td><td>Tyr</td><td>Leu</td><td>GLn</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>lys</td><td>Thr</td><td>GLU</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Tyr</td><td>Cys</td><td>Thr</td><td>own</td><td>Asp</td><td>Tyr</td><td>Gly</td><td>Asp</td><td>phe</td><td>Tyr</td><td>ala</td><td>phe</td><td>Asp</td><td>How much</td><td>Trp</td><td>Gly</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>GLn</td><td>Gly</td><td>Thr</td><td>Underworld</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>115</td><td></td><td></td><td></td><td></td><td>120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 68 &lt;211&gt; 324 &lt;212&gt; DNA &lt;213&gt; Homo sapiens

151

ΕΡ 1 838 733 Β1 &lt;400&gt; 68 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagaatcacc 60 atcacttgcc gggcaaggca gagcattagc agctatttaa attggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttactt ctgtcaacag agttacagta ccccattcac tttcggccct 300 ggggccaaag tggatatcaa acga 324 &lt; 210&gt; 69 &lt;211&gt; 108 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 69

<td>Asp</td><td>How much</td><td>Gln</td><td>Underworld</td><td>Thr</td><td>Gln</td><td>Cheese</td><td>Pro</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>ala</td><td>Cheese</td><td>val</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Asp</td><td>Arg</td><td>How much</td><td>Thr</td><td>How much</td><td>Thr</td><td>Cys</td><td>Arg</td><td>ala</td><td>Arg</td><td>Gln</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Leu</td><td>own</td><td>Trp</td><td>Tyr</td><td>Gln</td><td>Gln</td><td>lys</td><td>Pro</td><td>Gly</td><td>lys</td><td>ala</td><td>Pro</td><td>lys</td><td>Leu</td><td>Leu</td><td>How much</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Tyr</td><td>ala</td><td>ala</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gln</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td><td>Cheese</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gln</td><td>Pro</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>phe</td><td>Cys</td><td>Gln</td><td>Gln</td><td>Cheese</td><td>Tyr</td><td>Cheese</td><td>Thr</td><td>Pro</td><td>phe</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Thr</td><td>phe</td><td>Gly</td><td>Pro</td><td>Gly</td><td>ala</td><td>lys</td><td>val</td><td>Asp</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 70 &lt;211&gt; 366 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 70 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cgtctggatt caccttcagt agctttggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atatggtttg atggaagtaa taaatactat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagtgactac 300 ggtgactact tctactacgg tatggacgtc tggggccaag ggaccacggt caccgtctcc 360 tcagcc 366 &lt;210&gt; 71 &lt;211&gt; 122 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 71

<td>Gln</td><td>val</td><td>Gln</td><td>Leu</td><td>val</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly</td><td>val</td><td>val</td><td>Gln</td><td>Pro</td><td>Gly</td><td>Arg</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>ala</td><td>ala</td><td>Cheese</td><td>Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Cheese</td><td>Cheese</td><td>phe</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Gly</td><td>Underworld</td><td>His</td><td>Trp</td><td>val</td><td>Arg</td><td>Gln</td><td>ala</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>val</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>ala</td><td>val</td><td>How much</td><td>Trp</td><td>phe</td><td>Asp</td><td>Gly</td><td>Cheese</td><td>own</td><td>lys</td><td>Tyr</td><td>Tyr</td><td>ala</td><td>Asp</td><td>Cheese</td><td>val</td>

152

EP 1 838 733 B1

<td></td><td colspan="4">50</td><td colspan="3">55</td><td colspan="8">60</td>

<td>lys</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>own</td><td>Cheese</td><td>lys</td><td>own</td><td>Thr</td><td>Leu</td><td>Tyr</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Leu</td><td>Gin</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>ala</td><td>Cheese</td><td>Asp</td><td>Tyr</td><td>Gly</td><td>Asp</td><td>Tyr</td><td>phe</td><td>Tyr</td><td>Tyr</td><td>Gly</td><td>Underworld</td><td>Asp</td><td>val</td><td>Trp</td><td>Gly</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Gin</td><td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>115</td><td></td><td></td><td></td><td></td><td>120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 72 &lt;211&gt; 324 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 72 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gggaattaga aatgatttag gctggtatca gcagaaacca 120 aagaaaaccc ctaaaagcct ggaccatgcc gcatccaggt tgcaaagtgg ggtcccatca 180 agatteageg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240 gaagaatttg caactcatta ctgtctacag tataatagtt accctcggac gtcaggccaa 300 aggacccagg. tggaaatcca aega 324 &lt;210&gt; 73 &lt;211&gt; 108 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 73

<td>Asp</td><td>How much</td><td>Gin</td><td>Underworld</td><td>Thr</td><td>GLn</td><td>Cheese</td><td>Pro</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>ala</td><td>Cheese</td><td>val</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Asp</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Thr</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>GLn</td><td>Gly</td><td>How much</td><td>Arg</td><td>own</td><td>Asp</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Leu</td><td>Gly</td><td>Trp</td><td>Tyr</td><td>Gin</td><td>GLn</td><td>lys</td><td>Pro</td><td>Gly</td><td>lys</td><td>ala</td><td>Pro</td><td>lys</td><td>Arg</td><td>Leu</td><td>How much</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Tyr</td><td>ala</td><td>ala</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>GLn</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td><td>Cheese</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Glu</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>GLn</td><td>Pro</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Leu</td><td>Gin</td><td>Tyr</td><td>own</td><td>Cheese</td><td>Tyr</td><td>Pro</td><td>Arg</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Thr</td><td>phe</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 74 &lt;211&gt; 372 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 74 ccggtgcagc tggtggagac tgggggaggc gtggtccagc ctgggaggtc ccagagactc 60 tcctgtgcag cccctggaat caccttcact aactatggea tgcactgggg ccgccaggct 120 ccagacaagg ggacggaggg aatggcagtt atatcacatg ctggaaataa taagtattat 180 atagcctccg tgaagggcccf attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agctgaggac aeggacgtgt attactgtgc gagagaggga 300 atcgattttt ggaaaggatC caactggttc gacccctggg attagggacc cctggcaacc 360

<td>gtctcctcag cc</td><td>372</td>

<td>&lt;210&gt; 75 &lt;211&gt; 124</td><td></td>

153

EP 1 838 733 B1 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 75

<td>Gln</td><td>val</td><td>Gln</td><td>Leu</td><td>val</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly</td><td>val</td><td>val</td><td>Gln</td><td>Pro</td><td>Gly</td><td>Arg</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>ala</td><td>ala</td><td>Cheese</td><td>Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Thr</td><td>own</td><td>Tyr</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Gly</td><td>Underworld·</td><td>His</td><td>Trp</td><td>Gly</td><td>Arg</td><td>Gln</td><td>ala</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>val</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>ala</td><td>val</td><td>How much</td><td>Cheese</td><td>His</td><td>Asp</td><td>Gly</td><td>own</td><td>own</td><td>lys</td><td>Tyr</td><td>Tyr</td><td>val</td><td>Asp</td><td>Cheese</td><td>val</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>lys</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>own</td><td>Cheese</td><td>lys</td><td>own</td><td>Thr</td><td>Leu</td><td>Tyr</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Leu</td><td>Gln</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>ala</td><td>Arg</td><td>Glu</td><td>Gly</td><td>How much</td><td>Asp</td><td>phe</td><td>Trp</td><td>Cheese</td><td>Gly</td><td>Leu</td><td>own</td><td>Trp</td><td>phe</td><td>Asp</td><td>Pro</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Trp</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr</td><td>Leu</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>115</td><td></td><td></td><td></td><td></td><td>120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 76 &lt;211&gt; 327 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 76 gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccact 60 ctctcctgca gggccagtca gaggattacc ggcagctact tagcctggta ccagcagaaa 120 cctggccagg ctcccagact cctcatctgt ggtgcatcca gctgggccac tggcatccca 180 gacaggttca 'ataacaatga gtctgggaca gacttcactc tcaccatcag tagactggag 240 cctgaagatt ttgcagtgta ttactgtcag cagtatagta gttcaccgat caccttcggc 300 caaaaaacac gaggagagat taaacga 327 &lt;210&gt; 77 &lt;211&gt; 109 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 77

<td>Glu</td><td>How much</td><td>val</td><td>Leu</td><td>Thr</td><td>Gin</td><td>Cheese</td><td>Pro</td><td>Gly</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>Pro</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Glu</td><td>Arg</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gin</td><td>Cheese</td><td>How much</td><td>Thr</td><td>Gly</td><td>Cheese</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Tyr</td><td>Leu</td><td>ala</td><td>Trp</td><td>Tyr</td><td>Gin</td><td>Gin</td><td>lys</td><td>Pro</td><td>Gly</td><td>Gin</td><td>ala</td><td>Pro</td><td>Arg</td><td>Leu</td><td>Leu</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>How much</td><td>Cys</td><td>Gly</td><td>ala</td><td>Cheese</td><td>Cheese</td><td>Trp</td><td>ala</td><td>Thr</td><td>Gly</td><td>How much</td><td>Pro</td><td>Asp</td><td>Arg</td><td>phe</td><td>Cheese</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td rowspan="2">GLL</td>

<td>Gly</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Leu</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Pro</td><td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gin</td><td>Gin</td><td>Tyr</td><td>Cheese.</td><td>Cheese</td><td>Cheese</td><td>Pro</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>How much</td><td>Thr</td><td>phe</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr</td><td>Arg</td><td>Leu</td><td>Glu</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 78 &lt;211&gt; 372

154

ΕΡ 1 838 733 Β1 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 78 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcact aactatggca tgcactgggg ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atatcacatg atggaaataa taagtattat 180 gtagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagaggga 300 atcgattttt ggagtggcct caactggttc gacccctggg gccagggaac cctggtcacc 360 gtctcctcag cc 372 &lt;210 79 &lt;211&gt; 124 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 79

<td>Gin 1</td><td>val</td><td>Gin</td><td>Leu</td><td>val 5</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu 20</td><td>Cheese</td><td>Cys</td><td>ala</td><td>ala</td><td>Cheese 25</td>

<td>Gly</td><td>Underworld</td><td>His 35 ·</td><td>Trp</td><td>Gly</td><td>Arg</td><td>Gin</td><td>ala 40</td><td>Pro</td>

<td>ala</td><td>val 50</td><td>How much</td><td>Cheese</td><td>His</td><td>Asp</td><td>Gly 55</td><td>own</td><td>own</td>

<td>lys 65</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much 70</td><td>Cheese</td><td>Arg</td><td>Asp</td>

<td>Leu</td><td>Gin</td><td>Underworld</td><td>own</td><td>Cheese 85</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td>

<td>ala</td><td>Arg</td><td>Glu</td><td>Gly 100</td><td>How much</td><td>Asp</td><td>phe</td><td>Trp</td><td>Cheese 105</td>

<td>Trp</td><td>Gly</td><td>Gin 115</td><td>Gly</td><td>Thr</td><td>Leu</td><td>val</td><td>Thr 120</td><td>val</td>

<td>Gly</td><td>val</td><td colspan="2">Val Gin</td><td colspan="2">Pro Gly</td><td>Arg</td>

<td>10 Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Thr</td><td>15 own</td><td>Tyr</td>

<td>Gly</td><td>lys</td><td>Gly</td><td>Leu</td><td>thirty Glu</td><td>Trp</td><td>val</td>

<td>lys</td><td>Tyr</td><td>Tyr</td><td>45 val</td><td>Asp</td><td>Cheese</td><td>val</td>

<td>own</td><td>Cheese</td><td>60 lys</td><td>own</td><td>Thr</td><td>Leu</td><td>Tyr</td>

<td>Asp</td><td>75 Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>80 Cys</td>

<td>90 Gly</td><td>Leu</td><td>own</td><td>Trp</td><td>phe</td><td>95 Asp</td><td>Pro</td>

<td>Cheese</td><td>Cheese</td><td>ala</td><td></td><td>110</td><td></td><td></td>

&lt;210&gt; 80 &lt;211&gt; 327 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 80 gaaattgtgt tgacgcagtc tccaggcacc ctctcctgca gggccagtca gagtattacc cctggccagg ctcccagact cctcatctgt gacaggttca gtggcagtgg gtctgggaca cctgaagatt ttgcagtgta ttactgtcag caagggacac gactggagat taaacga &lt;210&gt; 81 &lt;211&gt; 109 &lt;212&gt; PRT &lt;213&gt; Homo sapiens ctgtctttgt ctccagggga aagagccact 60 ggcagctact tagcctggta ccagcagaaa 120 ggtgcatcca gctgggccac tggcatccca 180 gacttcactc tcaccatcag tagactggag 240 cagtatagta gttcaccgat caccttcggc 300

327

<td colspan="8">&lt;400&gt; 81</td>

<td>Glu 1</td><td>How much</td><td>val</td><td>Leu</td><td>Thr 5</td><td>Gin</td><td>Cheese</td><td>Pro</td>

<td>Glu</td><td>Arg</td><td>ala</td><td>Thr 20</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>Arg</td>

<td>Tyr</td><td>Leu</td><td>ala 35</td><td>Trp</td><td>Tyr</td><td>Gin</td><td>Gin</td><td>lys 40</td>

<td>How much</td><td>Cys</td><td>Gly</td><td>ala</td><td>Cheese</td><td>Cheese</td><td>Trp</td><td>ala</td>

<td>Gly</td><td>Thr 10</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>Pro 15</td><td>Gly</td>

<td>ala 25</td><td>Cheese</td><td>Gin</td><td>Cheese</td><td>How much</td><td>Thr thirty</td><td>Gly</td><td>Cheese</td>

<td>Pro</td><td>Gly</td><td>Gin</td><td>ala</td><td>Pro 45</td><td>Arg</td><td>Leu</td><td>Leu</td>

<td>Thr</td><td>Gly</td><td>How much</td><td>Pro</td><td>Asp</td><td>Arg</td><td>phe</td><td>Cheese</td>

155

ΕΡ 1 838 733 Β1

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Gly</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Leu</td><td>Glu</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Pro</td><td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gin</td><td>Gin</td><td>Tyr</td><td>Cheese</td><td>Cheese</td><td>Cheese</td><td>Pro</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>How much</td><td>Thr</td><td>phe</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Thr</td><td>Arg</td><td>Leu</td><td>Glu</td><td>How much</td><td>lys</td><td>Arg</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 82 &lt;211&gt; 339 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 82 gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60 atctcctgca ggtctagtca aagcctcgta tacagtgatg gaaacaccta cttgaattgg 120 tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taagtgggac 180 tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240 agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300 ccgacgttcg gccaagggac caaggtggaa atcaaacga 339 &lt;210&gt; 83 &lt;211&gt; 113 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 83

<td>Asp</td><td>val</td><td>val</td><td>Underworld</td><td>Thr</td><td>Gin</td><td>Cheese</td><td>Pro</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Pro</td><td>val</td><td>Thr</td><td>Leu</td><td>Gly</td>

<td>1</td><td></td><td></td><td></td><td>5</td><td></td><td></td><td></td><td></td><td>10</td><td></td><td></td><td></td><td></td><td>15</td><td></td>

<td>Gin</td><td>Pro</td><td>ala</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>Cheese</td><td>Cheese</td><td>Gin</td><td>Cheese</td><td>Leu</td><td>val</td><td>Tyr</td><td>Cheese</td>

<td></td><td></td><td></td><td>20</td><td></td><td></td><td></td><td></td><td>25</td><td></td><td></td><td></td><td></td><td>thirty</td><td></td><td></td>

<td>Asp</td><td>Gly</td><td>own</td><td>Thr</td><td>Tyr</td><td>Leu</td><td>own</td><td>Trp</td><td>phe</td><td>Gin</td><td>Gin</td><td>Arg</td><td>Pro</td><td>Gly</td><td>Gin</td><td>Cheese</td>

<td></td><td></td><td>35</td><td></td><td></td><td></td><td></td><td>40</td><td></td><td></td><td></td><td></td><td>45</td><td></td><td></td><td></td>

<td>Pro</td><td>Arg</td><td>Arg</td><td>Leu</td><td>How much</td><td>Tyr</td><td>lys</td><td>val</td><td>Cheese</td><td>lys</td><td>Trp</td><td>Asp</td><td>Cheese'</td><td>Gly</td><td>val</td><td>Pro</td>

<td></td><td>50</td><td></td><td></td><td></td><td></td><td>55</td><td></td><td></td><td></td><td></td><td>60</td><td></td><td></td><td></td><td></td>

<td>Asp</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>lys</td><td>How much</td>

<td>65</td><td></td><td></td><td></td><td></td><td>70</td><td></td><td></td><td></td><td></td><td>75</td><td></td><td></td><td></td><td></td><td>80</td>

<td>Cheese</td><td>Arg</td><td>val</td><td>Glu</td><td>ala</td><td>Glu</td><td>Asp</td><td>val</td><td>Gly</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Underworld</td><td>Gin</td><td>Gly</td>

<td></td><td></td><td></td><td></td><td>85</td><td></td><td></td><td></td><td></td><td>90</td><td></td><td></td><td></td><td></td><td>95</td><td></td>

<td>Thr</td><td>His</td><td>Trp</td><td>Pro</td><td>Pro</td><td>Thr</td><td>phe</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Thr</td><td>lys</td><td>val</td><td>Glu</td><td>How much</td><td>lys</td>

<td></td><td></td><td></td><td>100</td><td></td><td></td><td></td><td></td><td>105</td><td></td><td></td><td></td><td></td><td>110</td><td></td><td></td>

<td>Arg</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 84 &lt;211&gt; 360 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 84 caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60 acctgcactg tctctggtgg ctccatcagt agtggtggtt acttctggag ctggatccgc 120 cagcacccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagaacctac 180 tacaacccgt ccctcaagag tcgagttacc atatcagtag acgcgtctaa gaaccagttc 240 tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtatcactg tgcgagagag 300 gggtcgtact gggactttga ctactggggc cagggaaccc tggtcaccgt ctcctcagcc 360 &lt;210&gt; 85 &lt;211&gt; 120

156

ΕΡ 1 838 733 Β1 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 85