Antibodies targeting oxford and methods of making and using the same

Abstract

An antibody or antigen-binding fragment thereof targeting OX40, comprising a VH, the VH comprising CDRs of: a VH CDR1 as set forth in the amino acid sequence of SEQ ID NO: 10; a VH CDR2 as set forth in the amino acid sequence of SEQ ID NO: 44; and a VH CDR3 as set forth in the amino acid sequence of SEQ ID NO: 86, SEQ ID NO: 84, or SEQ ID NO: 89, or mutations thereof. Also disclosed are methods of making, uses, and bispecific antibodies comprising the same. The antibody or antigen-binding fragment thereof is capable of specifically binding to OX40, promoting greater activation of NF-Kb, and activating the OX40 pathway in vitro and inducing activated T cell function. The bispecific antibody can recognize a tumor target TAA and can bind to OX40 on T cells, which can recruit and activate T cells near the tumor cells to kill the tumor cells.

Description

[0001] This application claims priority to Chinese patent application 202010618134.5, filed on June 30, 2020. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to the field of biological medicine, in particular to an antibody or antigen-binding fragment thereof targeting OX40, a preparation method and application thereof, and a bispecific antibody comprising the antibody or antigen-binding fragment thereof targeting OX40. BACKGROUND

[0003] OX40, also known as CD134, tumor necrosis factor receptor superfamily member 4 (TNFRSF4), is one of the tumor necrosis factor receptor superfamily members (TNFRSF), which is a 50kDa-55kDa type I transmembrane glycoprotein with intracellular part, transmembrane domain and extracellular region. It is involved in enhancing T cell response triggered by T cell receptor (TCR) and is a costimulatory receptor molecule. OX40 is mainly expressed on the surface of activated CD4+ and CD8+ T cells after TCR stimulation, and the expression of CD4+ T is higher than that of CD8+ T in vitro and at tumor sites (Fujita T et al., (2006) Immunol Lett. 106(1): 27-33; Montler R et al., (2016) Clin Transl Immunology. 5(4): e70). In addition, studies have shown that in a variety of human tumors, regulatory T cells (Tregs) express more OX40 than conventional CD4+ T cells (Timperi E et al., (2016) OncoImmunology.; 5(7): e1175800; Piconese S et al., (2014) Hepatology. 60(5): 1494-1507.), so there is also the possibility of preferentially using depleting mAb to target OX40hi communities. OX40 is also reported to be expressed on human neutrophils (this signaling pathway supports survival) and murine natural killer (NK) and NK T cells (Baumann R et al., (2004) Eur J Immunol. 34(8): 2268-2275; Croft et al., (2009) Nat Rev Immunol. 9(4): 271-285.).

[0004] The only known ligand for OX40 is OX40L (TNFSF4), which is a type II transmembrane protein containing a conserved tumor necrosis factor (TNF) homology domain that enables trimerization (Bodmer JL et al., (2002) Trends Biochem Sci. 27(1): 19-26). Upon activation, three OX40 molecules can bind to an OX40L trimer, which is a typical feature of ligand-receptor pairing in the TNFRSF (Banner DW et al., (1993) Cell. 73(3): 431-445.). OX40L is induced on human dendritic cells (DCs) upon exposure to thymic stromal lymphopoietin (Krause P et al., (2009) Blood. 113(11): 2451-2460). In addition, human monocytes, neutrophils, mast cells, lymphoid tissue inducer cells, smooth muscle cells, endothelial cells, and in vitro activated B cells all express OX40L under the right conditions (Byun M et al., (2013) J Exp Med. 210(9): 1743-1759; Karulf M et al., (2010) J Immunol. 185(8): 4856-4862).

[0005] For OX40, as with other members of the TNFRSF, transmembrane signaling is primarily mediated by members of the TNF receptor-associated factor (TRAF) family. TRAFs are trimeric proteins that interact with short motifs in the cytoplasmic tails of ligand-bound TNFRSF receptor trimers (McWhirter SM et al., (1999) Proc Natl Acad Sci USA. 96(15): 8408-8413.; Park YC et al., (1999) Nature. 398(6727): 533-538). For OX40, receptor-ligand interaction stimulates OX40 and TRAF2 into the cytoplasm, activating downstream PI3K / PKB, NF-κΒ and NFAT-mediated signaling pathways, leading to T cell division and survival and cytokine production (Croft et al., (2009) Nat Rev Immunol. 9(4): 271-285.; Watts, (2005) Annu. Rev. Immunol. 23, 23-68). Thus, both CD4+ and CD8+ T cells are potential targets for OX40-directed immunotherapy of cancer.

[0006] There are several different molecules targeting OX40 in clinical trials for metastatic cancer, one of which is OX40L-Fc fusion protein MEDI6383 (OX40L fusion Protein) currently in clinical phase I. Another is agonistic antibodies such as OX40 antibody MEDI6469 (9B12, mouse anti-human OX40 mAb, replaced by MEDI0562 humanized mAb), MEDI0562 (AstraZeneca, Tavolixizumab), Ivuxolimab (Pfizer, PF-04518600), GSK3174998 (GSK), BMS-986178 (BMS), Pogalizumab (MOXRO0916 / RG7888), etc. Among them, Pogalizumab (Pogalizumab), also known as Vonlerolizumab, is a humanized OX40 antibody developed by Roche, which is currently in clinical phase II for the treatment of solid tumors. Some preclinical studies have shown that anti-OX40 mAb produces harmful immunosuppressive side effects by promoting the accumulation of MDSC and the production of Th2 cytokines (Gough MJ et al., (2012) Immunology 136: 437e47.). In addition, although agonist mAbs targeting OX40 can confer tumor protection in mice, their effect is limited in less immunogenic environments (Kjaergaard J et al., (2000) Cancer Res. 60(19): 5514-5521).

[0007] Heavy chain antibodies were first reported by Belgian scientists in Nature in 1993, and heavy chain antibodies and nanobodies (VHH) are superior to traditional antibodies in many ways, with small molecular weight, the ability to penetrate the blood-brain barrier, and weak immunogenicity to humans. Heavy chain antibodies or nanobodies are particularly suitable for the development of bispecific antibodies, while solving the problems of light chain mispairing and heterodimerization. However, there is almost no related report on OX40 heavy chain antibodies in the prior art.

[0008] Therefore, there is an urgent need to develop safer and more effective combination therapy strategies targeting OX40, such as enhancing antigen utilization, enhancing inflammation or inhibiting immunosuppressive signals, for the treatment of various cancers. SUMMARY

[0009] The present application aims to provide an antibody targeting OX40, a preparation method and application thereof, and a bispecific antibody developed based on the antibody and application thereof, to overcome the deficiencies of the current antibodies targeting OX40. The antibody or antigen-binding fragment thereof of the present application has the activity of specifically binding to human OX40 and cyno OX40. In addition, the antibody or antigen-binding fragment thereof of the present application can promote the activation of NF-Kb, thereby stimulating the OX40 signaling pathway, and can activate the OX40 pathway in vitro and induce the function of activated T cells, and the activation is comparable to or stronger than that of the existing antibodies (e.g., Pogalizumab), while the antibody or antigen-binding fragment thereof of the present application has Fcγ receptor member FcγRIIB (CD32B) cross-linking dependence. When the antibody or antigen-binding fragment thereof of the present application is prepared into a bispecific antibody, the obtained bispecific antibody can bind to human OX40 and the corresponding tumor-associated antigen, one end of which can recognize the tumor target TAA (e.g., PSMA, EPCAM, CLDN18.2, B7H4, PD-L1) specifically expressed on the surface of tumor cells, and the other end can bind to the OX40 molecule on the T cell, thereby recruiting and activating the T cells near the tumor cells, so as to kill the tumor cells.

[0010] To solve the above technical problems, the present application provides an antibody targeting OX40 or an antigen-binding fragment thereof in the first aspect, which comprises a heavy chain variable region (VH),

[0011] wherein the VH comprises the following complementarity determining regions (CDRs) or mutations thereof: VH CDR1 as shown in the amino acid sequence of SEQ ID NO: 10; VH CDR2 as shown in the amino acid sequence of SEQ ID NO: 44; and / or VH CDR3 as shown in the amino acid sequence of SEQ ID NO: 86, SEQ ID NO: 84 or SEQ ID NO: 89;

[0012] wherein the mutation is an insertion, deletion or substitution of 3, 2 or 1 amino acids based on the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 of the VH.

[0013] In the present application, "amino acid mutation" in the similar "insertion, deletion or substitution of 3, 2 or 1 amino acid" refers to the mutation of amino acid in the sequence of the variant compared to the original amino acid sequence, including the insertion, deletion or substitution of amino acid based on the original amino acid sequence. An exemplary explanation is that the mutation of CDR can contain 3, 2 or 1 amino acid mutations, and the same or different number of amino acid residues between these CDRs can be optionally selected for mutation, for example, 1 amino acid mutation to CDR1, and no amino acid mutation to CDR2 and CDR3.

[0014] In the present application, the mutation can include mutations currently known to those skilled in the art, for example, some mutations that can be made to the antibody during the production or application of the antibody, for example, mutations to the sites of potential post-translational modifications (PTMs) that can exist, especially in the CDR region, including mutations related to aggregation, asparagine deamidation (sites (NG, NS, NH, etc.), aspartate isomerization (DG, DP) sensitive sites, N-glycosylation (N-{P}S / T) sensitive sites, and oxidation sensitive sites, etc.

[0015] Preferably, the mutation of VH CDR1 is mutation of F2, T3, S5, and / or S6 to L, S, P, I, D and / or C on the amino acid sequence as shown in SEQ ID NO: 10, preferably having F2L, T3S / P / I, S5D, and / or S6D / C amino acid substitution on the amino acid sequence as shown in SEQ ID NO: 10; the amino acid sequence thereof is, for example, as shown in any one of SEQ ID NO: 13-16, SEQ ID NO: 20-24.

[0016] Preferably, the mutation of VH CDR2 is mutation of S1, R3, G4, G5 and / or S6 to T, H, L, G, S, N, D, I and / or Q on the amino acid sequence as shown in SEQ ID NO: 44, preferably having S1T, R3H / L / G / S, G4S, G5N / D, S6N / I / Q / T 3, 2 or 1 amino acid substitution on the amino acid sequence as shown in SEQ ID NO: 44; the amino acid sequence thereof is, for example, as shown in any one of SEQ ID NO: 42-43, SEQ ID NO: 45-50, SEQ ID NO: 54-60.

[0017] Preferably, the mutation of VH CDR3 is T2, T5, T6, D9 and / or Y10 in the amino acid sequence of SEQ ID NO: 86 is mutated to M, I, V, S, W, Y, C, F and / or W, preferably having 2 or 1 amino acid substitution of T2M / I / V, T5S, T6W / Y, D9C and Y10F / W in the amino acid sequence of SEQ ID NO: 86; the amino acid sequence thereof is represented by, for example, any one of SEQ ID NO: 82-83, SEQ ID NO: 85, SEQ ID NO: 87-88, SEQ ID NO: 90, SEQ ID NO: 94-99.

[0018] The above-mentioned F2L generally refers to the mutation of the second amino acid F to L in the amino acid sequence of SEQ ID NO: 10, and other amino acid substitutions such as T3S / P / I, S5D, and / or S6D / C, and the like, and the like, the meaning of which should be understood by those skilled in the art.

[0019] Preferably, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH), wherein the VH comprises the following complementarity determining region (CDR) or mutation thereof: a VH CDR1 as set forth in any one of the amino acid sequences of SEQ ID NO: 10, SEQ ID NO: 13-16, SEQ ID NO: 20-24; a VH CDR2 as set forth in any one of the amino acid sequences of SEQ ID NO: 42-50, SEQ ID NO: 54-60; and / or a VH CDR3 as set forth in any one of the amino acid sequences of SEQ ID NO: 82-90, SEQ ID NO: 94-99.

[0020] In a certain preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH), wherein the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NO: 13, 42, and 82, respectively.

[0021] In a certain preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH), wherein the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NO: 10, 42, and 83, respectively.

[0022] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 44, and 83, respectively.

[0023] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 43, and 84, respectively.

[0024] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 13, 44, and 82, respectively.

[0025] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 15, 44, and 83, respectively.

[0026] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 44, and 83, respectively.

[0027] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 45, and 83, respectively.

[0028] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 46, and 85, respectively.

[0029] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 44, and 86, respectively.

[0030] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 16, 42, and 82, respectively.

[0031] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 47, and 87, respectively.

[0032] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 16, 44, and 83, respectively.

[0033] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 45, and 88, respectively.

[0034] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 48, and 89, respectively.

[0035] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 49, and 90, respectively.

[0036] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 49, and 83.

[0037] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 50, and 90.

[0038] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 20, 44, and 86.

[0039] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 21, 44, and 86.

[0040] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 54, and 86.

[0041] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 55, and 86.

[0042] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 56, and 86.

[0043] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 42, and 86.

[0044] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 57, and 86.

[0045] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 58, and 86.

[0046] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 59, and 86.

[0047] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 60, and 86.

[0048] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 44, and 94.

[0049] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 44, and 95.

[0050] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 44, and 96.

[0051] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 44, and 97.

[0052] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 44, and 98.

[0053] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 44, and 99.

[0054] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 54, and 95.

[0055] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 54, and 97.

[0056] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 55, and 95.

[0057] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 55, and 97.

[0058] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 56, and 95.

[0059] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 10, 56, and 97.

[0060] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 22, 54, and 86.

[0061] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 23, 54, and 86.

[0062] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 24, 54, and 86.

[0063] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth, respectively, in SEQ ID NOs: 21, 54, and 86.

[0064] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 54, and 99, respectively.

[0065] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 22, 54, and 99, respectively.

[0066] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 23, 54, and 99, respectively.

[0067] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 24, 54, and 99, respectively.

[0068] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 21, 54, and 99, respectively.

[0069] Preferably, the above-mentioned VH further comprises a heavy chain variable region framework region (VH FWR); which can be selected from, for example, germline IGHV3-23 or a back-mutation thereof. More preferably, the VH FWR is a heavy chain variable region framework region of a human antibody.

[0070] Preferably, the VH comprises any of the amino acid sequences set forth in SEQ ID NOs: 142-164 or SEQ ID NOs: 168-198 or a mutation thereof; the mutation is a deletion, substitution, or addition of one or more amino acid residues in the amino acid sequence of the VH, and the amino acid sequence of the mutation has at least 85% sequence identity to the amino acid sequence of the VH and maintains or improves the binding of the antibody to OX40; the at least 85% sequence identity is preferably at least 90% sequence identity, more preferably at least 95% sequence identity, most preferably at least 99% sequence identity.

[0071] In the present application, the amino acid sequences of the CDRs listed above are shown according to the Chothia definition (the sequences shown in the claims of the present application are also according to the Chothia definition). However, it is well known in the art that the CDRs of an antibody can be defined in various ways, for example, the Kabat definition based on sequence variability (see, Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, Bethesda, MD (1991)) and the Chothia definition based on the location of structural loop regions (see, J Mol Biol 273:927-48, 1997). In the present application, the amino acid residues in the variable domain sequences can also be determined using the Combined definition which combines the Kabat definition and the Chothia definition, i.e., a larger range is taken based on the combination of the ranges of the Kabat definition and the Chothia definition, as shown in Table a. It will be understood by those skilled in the art that, unless otherwise specified, the terms "CDR" and "complementarity determining region" of a given antibody or region thereof (e.g., a variable region) are to be taken as encompassing complementarity determining regions defined by any of the above-described known schemes as described herein. Although the scope of the present application is based on the sequences shown according to the Chothia definition, the amino acid sequences according to other CDR definitions should also fall within the scope of the present application.

[0072] Table a CDR definition methods for antibodies of the present application (see http: / / bioinf.org.uk / abs / )

[0073] Kabat Chothia Combined VH CDR1 H31-H35 H26-H32 H26-H35 VH CDR2 H50-H65 H52-H56 H50-H65 VH CDR3 H95-H102 H95-H102 H95-H102

[0074] wherein Haa-Hbb can refer to the amino acid sequence from position aa to position bb of the N-terminus of the heavy chain of the antibody. For example, H26-H32 can refer to the amino acid sequence from position 26 to position 32 according to the Chothia numbering of the N-terminus of the heavy chain of the antibody. It will be understood by those skilled in the art that when CDRs are numbered according to Chothia, there are some positions with insertion sites.

[0075] For example, the VH comprises the CDRs described in Table b according to the Chothia numbering.

[0076] Table b

[0077] Antibody Number HCDR1 HCDR2 HCDR3 PR002055 13 42 82 PR002056 10 42 83 PR002057 14 42 83 PR002058 10 43 84 PR002059 13 44 82 PR002060 15 44 83 PR002061 10 44 83 PR002062 10 45 83 PR002063 10 42 83 PR002064 10 45 83 PR002065 10 46 85 PR002066 10 44 83 PR002067 10 44 86 PR002068 16 42 82 PR002069 10 47 87 PR002070 16 44 83 PR002071 10 42 83 PR002072 10 45 88 PR002073 10 43 84 PR002074 10 48 89 PR002075 10 49 90 PR002076 10 49 83 PR002077 10 50 90 PR005362 20 44 86 PR005363 21 44 86 PR005364 10 54 86 PR005365 10 55 86 PR005366 10 56 86 PR005367 10 42 86 PR005368 10 57 86 PR005369 10 58 86 PR005370 10 59 86 PR005371 10 60 86 PR005372 10 44 94 PR005373 10 44 95

[0078] PR005374 10 44 96 PR005375 10 44 97 PR005376 10 44 98 PR005377 10 44 99 PR005378 10 54 95 PR005379 10 54 97 PR005380 10 55 95 PR005381 10 55 97 PR005382 10 56 95 PR005383 10 56 97 PR005384 22 54 86 PR005385 23 54 86 PR005386 24 54 86 PR005387 21 54 86 PR005388 10 54 99 PR005389 22 54 99 PR005390 23 54 99 PR005391 24 54 99 PR005392 21 54 99

[0079] Preferably, the OX40-targeting antibody or antigen-binding fragment thereof further comprises a heavy chain constant region Fc domain of a human antibody. The heavy chain constant region Fc domain of the human antibody, for example, includes a heavy chain constant region Fc domain of human IgG1, IgG2, IgG3, or IgG4.

[0080] Preferably, the OX40-targeting antibody or antigen-binding fragment thereof comprises a polypeptide chain comprising any one of the amino acid sequences as shown in SEQ ID NOs: 208-230 or SEQ ID NOs: 234-264 or a mutation thereof. The mutation is a deletion, substitution or addition of one or more amino acid residues in the amino acid sequence, and the mutated amino acid sequence has at least 85% sequence identity to the amino acid sequence and retains or improves the binding of the antibody to OX40; the at least 85% sequence identity is preferably at least 90% sequence identity; more preferably at least 95% sequence identity; most preferably at least 99% sequence identity.

[0081] Preferably, the OX40-targeting antibody or antigen-binding fragment thereof includes IgG, Fab, Fab', F(ab')2, Fv, scFv, HCAb, VH, bispecific antibody, multispecific antibody, single-domain antibody, or any other antibody that retains the ability to specifically bind to an antigen (may be partially retain the ability to specifically bind to an antigen) or a monoclonal antibody or polyclonal antibody prepared from the above-mentioned antibody.

[0082] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof is a blocking antibody.

[0083] In a preferred embodiment, the OX40-targeting antibody or antigen-binding fragment thereof is a weakly blocking or non-blocking antibody.

[0084] In the present application, the "Fab fragment" consists of one light chain and the CH1 and variable region of one heavy chain. The heavy chain of the Fab molecule cannot form a disulfide bond with another heavy chain molecule. The "Fc" region contains the two heavy chain fragments of the CH2 and CH3 domains of the antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains. The "Fab fragment" contains one light chain and a portion of one heavy chain that includes the VH domain and the CH1 domain and the region between the CH1 and CH2 domains, whereby an interchain disulfide bond can form between the two heavy chains of two Fab' fragments to form a F(ab')2 molecule. The "F(ab')2 fragment" contains two light chains and two heavy chains that include the constant region between the CH1 and CH2 domains, whereby an interchain disulfide bond forms between the two heavy chains. Thus the F(ab')2 fragment consists of two Fab' fragments held together by a disulfide bond between the two heavy chains. The term "Fv" is intended to mean the antibody fragment consisting of the VL and VH domains of a single arm of an antibody, but lacking the constant regions.

[0085] In the present application, the scFv (single chain antibody fragment) can be a single chain antibody of the art, which includes a heavy chain variable region, a light chain variable region, and a short peptide of 15 to 20 amino acids. Among them, the VL and VH domains form a monovalent molecule by pairing through a linker that enables them to be produced as a single polypeptide chain [see, for example, Bird et al., Science 242:423-426 (1988) and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988)]. Such scFv molecules can have a general structure of NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH. A suitable prior art linker consists of a repeating G4S amino acid sequence or a variant thereof. For example, a linker having the amino acid sequence (G4S)4 or (G4S)3 can be used, but a variant thereof can also be used.

[0086] In the present application, the term "multispecific antibody" is used in its broadest sense to encompass antibodies having polyepitopic specificity. These multispecific antibodies include, but are not limited to: antibodies comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH-VL unit has polyepitopic specificity; antibodies having two or more VL and VH regions, each VH-VL unit binding to a different target or a different epitope of the same target; antibodies having two or more single variable regions, each single variable region binding to a different target or a different epitope of the same target; full-length antibodies, antibody fragments, diabodies, and triabodies, antibody fragments covalently or non-covalently linked together, and the like.

[0087] In the present application, the monoclonal antibody or mAb or Ab refers to an antibody obtained from a single clonal cell strain, which is not limited to a eukaryotic, prokaryotic or phage clonal cell strain.

[0088] In the present application, the single-domain antibody can be a conventional single-domain antibody in the art, which includes a heavy chain variable region and a heavy chain constant region.

[0089] To solve the above technical problems, the second aspect of the present application provides a bispecific binding protein containing at least two protein functional regions: protein functional region A and protein functional region B; the protein functional region A and the protein functional region B target different antigens, wherein the protein functional region B targets OX40, and the protein functional region A targets a non-OX40 antigen; the protein functional region B is selected from the antibodies or antigen-binding fragments thereof targeting OX40 according to the first aspect of the present application.

[0090] Preferably, the protein functional region A targets PD-L1, B7H4, PSMA, EPCAM or CLDN18.2.

[0091] Preferably, the protein functional region A is a PSMA antibody or antigen-binding fragment thereof, an EPCAM antibody or antigen-binding fragment thereof, a CLDN18.2 antibody or antigen-binding fragment thereof, a B7H4 antibody or antigen-binding fragment thereof, or a PD-L1 antibody or antigen-binding fragment thereof.

[0092] In a preferable embodiment, the PD-L1 antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprises VL CDR1, VL CDR2 and VL CDR3, and the amino acid sequences thereof are respectively shown as SEQ ID NO: 111, 119 and 129, and the VH comprises VH CDR1, VH CDR2 and VH CDR3, and the amino acid sequences thereof are respectively shown as SEQ ID NO: 10, 39 and 79.

[0093] In a preferable embodiment, the EPCAM antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprises VL CDR1, VL CDR2 and VL CDR3, and the amino acid sequences thereof are respectively shown as SEQ ID NO: 112, 120 and 130, and the VH comprises VH CDR1, VH CDR2 and VH CDR3, and the amino acid sequences thereof are respectively shown as SEQ ID NO: 11, 40 and 80.

[0094] In a preferred embodiment, the PSMA antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) and a heavy chain variable region (VH); the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are represented by SEQ ID NOs: 113, 121, and 131, respectively, and the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are represented by SEQ ID NOs: 12, 41, and 81, respectively.

[0095] In a preferred embodiment, the B7H4 antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) and a heavy chain variable region (VH); the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are represented by SEQ ID NOs: 114, 122, and 132, respectively, and the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are represented by SEQ ID NOs: 17, 51, and 91, respectively.

[0096] In a preferred embodiment, the CLDN18.2 antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) and a heavy chain variable region (VH); the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are represented by SEQ ID NOs: 112, 120, and 133, respectively, and the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are represented by SEQ ID NOs: 18, 52, and 92, respectively.

[0097] In a preferred embodiment, the bispecific binding protein contains at least two protein functional regions: protein functional region A and protein functional region B; the protein functional region A comprises a light chain variable region (VL) and a heavy chain variable region (VH); the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are represented by SEQ ID NOs: 111, 119, and 129, respectively, and the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are represented by SEQ ID NOs: 10, 39, and 79, respectively; the protein functional region B comprises a heavy chain variable region (VH), and the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are represented by SEQ ID NOs: 10, 44, and 86, respectively.

[0098] In a preferred embodiment, the bispecific binding protein contains at least two protein domains: protein domain A and protein domain B; the protein domain A comprises a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are shown in SEQ ID NO: 114, 122, and 132, respectively, and the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are shown in SEQ ID NO: 17, 51, and 91, respectively; the protein domain B comprises a heavy chain variable region (VH), the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are shown in SEQ ID NO: 10, 44, and 86, respectively.

[0099] In a preferred embodiment, the bispecific binding protein contains at least two protein domains: protein domain A and protein domain B; the protein domain A comprises a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are shown in SEQ ID NO: 112, 120, and 130, respectively, and the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are shown in SEQ ID NO: 11, 40, and 80, respectively; the protein domain B comprises a heavy chain variable region (VH), the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are shown in SEQ ID NO: 10, 44, and 86, respectively.

[0100] In a preferred embodiment, the bispecific binding protein contains at least two protein domains: protein domain A and protein domain B; the protein domain A comprises a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are shown in SEQ ID NO: 113, 121, and 131, respectively, and the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are shown in SEQ ID NO: 12, 41, and 81, respectively; the protein domain B comprises a heavy chain variable region (VH), the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are shown in SEQ ID NO: 10, 44, and 86, respectively.

[0101] In a preferred embodiment, the bispecific binding protein contains at least two protein domains: protein domain A and protein domain B; the protein domain A comprises a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are shown in SEQ ID NO: 112, 120, and 133, respectively, and the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are shown in SEQ ID NO: 18, 52, and 92, respectively; the protein domain B comprises a heavy chain variable region (VH), which comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are shown in SEQ ID NO: 10, 44, and 86, respectively.

[0102] In a preferred embodiment, the bispecific binding protein contains at least two protein domains: protein domain A and protein domain B; the protein domain A comprises a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprises an amino acid sequence shown in SEQ ID NO: 199, and the VH comprises an amino acid sequence shown in SEQ ID NO: 139; the protein domain B comprises a heavy chain variable region, which comprises an amino acid sequence shown in SEQ ID NO: 154.

[0103] In a preferred embodiment, the bispecific binding protein contains at least two protein domains: protein domain A and protein domain B; the protein domain A comprises a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprises an amino acid sequence shown in SEQ ID NO: 202, and the VH comprises an amino acid sequence shown in SEQ ID NO: 165; the protein domain B comprises a heavy chain variable region (VH), which comprises an amino acid sequence shown in SEQ ID NO: 154.

[0104] In a preferred embodiment, the bispecific binding protein contains at least two protein domains: protein domain A and protein domain B; the protein domain A comprises a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprises an amino acid sequence shown in SEQ ID NO: 200, and the VH comprises an amino acid sequence shown in SEQ ID NO: 140; the protein domain B comprises a heavy chain variable region (VH), which comprises an amino acid sequence shown in SEQ ID NO: 154.

[0105] In a preferred embodiment, the bispecific binding protein comprises at least two protein domains: protein domain A and protein domain B; the protein domain A comprises a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprises an amino acid sequence as set forth in SEQ ID NO: 201, and the VH comprises an amino acid sequence as set forth in SEQ ID NO: 141; the protein domain B comprises a heavy chain variable region (VH), the VH comprises an amino acid sequence as set forth in SEQ ID NO: 154.

[0106] In a preferred embodiment, the bispecific binding protein comprises at least two protein domains: protein domain A and protein domain B; the protein domain A comprises a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprises an amino acid sequence as set forth in SEQ ID NO: 203, and the VH comprises an amino acid sequence as set forth in SEQ ID NO: 166; the protein domain B comprises a heavy chain variable region (VH), the VH comprises an amino acid sequence as set forth in SEQ ID NO: 154.

[0107] Preferably, the protein domain A and / or the protein domain B is in the form of IgG, Fab, Fab’, F(ab’)2, Fv, scFv, VH, or HCAb; wherein the protein domain A and the protein domain B are not both IgG.

[0108] More preferably, the heavy chain constant region of the IgG is a human heavy chain constant region, more preferably a human IgG1, human IgG2, human IgG3 or human IgG4 heavy chain constant region; wherein the human IgG preferably comprises one, two or three mutations of L234A, L235A and P329G, more preferably comprises the mutations of L234A and L235A or comprises the mutations of L234A, L235A and P329G.

[0109] More preferably, the number of Fab, Fab’, F(ab’)2, Fv, scFv, VH is preferably one or more.

[0110] Preferably, the protein domain B is in the structure of a single VH, and the protein domain A is in the structure of IgG; the protein domain B is preferably connected to the C-terminus of the protein domain A.

[0111] In a preferred embodiment, the bispecific antibody comprises a first polypeptide chain and a second polypeptide chain, the first polypeptide chain is as shown in the formula: N’-VL _ A-CL-C’ and the second polypeptide chain is as shown in the formula: N’-VH _A -CH1-h-CH2-CH3-L-VH _B -C’;

[0112] wherein the VH _B is the VH of the protein functional region B, the VL _A and VH _A are the VL and VH of the protein functional region A, respectively, h is a hinge region, and L is a linker peptide. The hinge region can be any conventional hinge region known in the art, and typically contains a large number of prolines, and is flexible.

[0113] Preferably, the linker peptide L has a length of 0 or an amino acid sequence as set forth in any one of SEQ ID NOs. 278-295. In one embodiment, the CH3 of the second polypeptide chain described above is directly fused to VH_B, i.e., the length of L is 0. In another embodiment, the CH3 of the second polypeptide chain is linked to VH_B via a linker peptide L; L can be any of the sequences listed in Table 11 in the Examples.

[0114] Preferably, the protein functional region B is the structure of HCAb, and the protein functional region A is the structure of Fab; the protein functional region B is preferably linked to the C-terminus of the protein functional region A.

[0115] In a preferred embodiment, the bispecific antibody comprises a first polypeptide chain and a second polypeptide chain, the first polypeptide chain being as set forth in the formula: N’-VH _A -CH1-C’ and the second polypeptide chain being as set forth in the formula: N’-VL _A -CL-L1-VH _B -L2-CH2-CH3-C’.

[0116] In a preferred embodiment, the bispecific antibody comprises a first polypeptide chain and a second polypeptide chain, the first polypeptide chain being as set forth in the formula: N’-VL _A -CL-C’ and the second polypeptide chain being as set forth in the formula: N’-VH _A -CH1-L1-VH _B -L2-CH2-CH3-C’.

[0117] wherein the VH _B is the VH of the protein functional region B, the VL _A and VH _A are the VL and VH of the protein functional region A, respectively, and L1 and L2 are linker peptides.

[0118] In some embodiments, the VH_B of the second polypeptide chain is linked to the CH2 via a linker L2; L2 can be an IgG hinge region or a hinge region derived linker peptide sequence; L2 can be a sequence listed in Table 11, preferably a sequence of human IgGl hinge or human IgGl hinge (C220S) or G5-LH. In one embodiment, the CL of the second polypeptide chain is directly fused to the VH_B, i.e., the length of L1 is 0. In another embodiment, the CL of the second polypeptide chain is linked to the VH_B via a linker L1; L1 can be a sequence listed in Table 11 in the Examples.

[0119] In some embodiments, the bispecific binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises an amino acid sequence of SEQ ID NO: 265, and the second polypeptide chain comprises an amino acid sequence of SEQ ID NO: 271.

[0120] In some embodiments, the bispecific binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises an amino acid sequence of SEQ ID NO: 268, and the second polypeptide chain comprises an amino acid sequence of SEQ ID NO: 272.

[0121] In some embodiments, the bispecific binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises an amino acid sequence of SEQ ID NO: 273, and the second polypeptide chain comprises an amino acid sequence of SEQ ID NO: 274.

[0122] In some embodiments, the bispecific binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises an amino acid sequence of SEQ ID NO: 266, and the second polypeptide chain comprises an amino acid sequence of SEQ ID NO: 275.

[0123] In some embodiments, the bispecific binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises an amino acid sequence of SEQ ID NO: 267, and the second polypeptide chain comprises an amino acid sequence of SEQ ID NO: 276.

[0124] In a preferred embodiment, the bispecific binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises an amino acid sequence as set forth in SEQ ID NO: 269, and the second polypeptide chain comprises an amino acid sequence as set forth in SEQ ID NO: 277.

[0125] To solve the above technical problem, the third aspect of the present application provides a chimeric antigen receptor comprising the OX40-targeting antibody or antigen-binding fragment thereof according to the first aspect of the present application or the bispecific antibody according to the second aspect of the present application.

[0126] To solve the above technical problem, the fourth aspect of the present application provides an immune cell comprising the chimeric antigen receptor according to the third aspect of the present application. Preferably, the immune cell is a T cell or an NK cell.

[0127] To solve the above technical problem, the fifth aspect of the present application provides an isolated nucleic acid encoding the OX40-targeting antibody or antigen-binding fragment thereof according to the first aspect of the present application, or the bispecific antibody according to the second aspect of the present application, or the chimeric antigen receptor according to the third aspect of the present application.

[0128] The method for preparing the nucleic acid is a conventional method in the art, and preferably comprises the following steps: obtaining a nucleic acid molecule encoding the above antibody by gene cloning technology, or obtaining a nucleic acid molecule encoding the above antibody by artificial full-sequence synthesis.

[0129] As known by those skilled in the art, the base sequence encoding the amino acid sequence of the above antibody can be appropriately introduced with substitutions, deletions, modifications, insertions or additions to provide a homolog of a polynucleotide. The homolog of the polynucleotide in the present application can be prepared by substituting, deleting or adding one or more bases of the gene encoding the sequence of the antibody within the range of maintaining the activity of the antibody.

[0130] To solve the above technical problem, the sixth aspect of the present application provides a recombinant expression vector comprising the isolated nucleic acid according to the fifth aspect of the present application.

[0131] The recombinant expression vector can be obtained by a conventional method in the art, i.e., by linking the nucleic acid molecule described in the present application to various expression vectors to construct. The expression vector is a conventional vector in the art, as long as it can accommodate the aforementioned nucleic acid molecule.

[0132] Preferably, the expression vector comprises a eukaryotic cell expression vector and / or a prokaryotic cell expression vector.

[0133] To solve the above technical problems, the seventh aspect of the present application provides a transformant comprising the isolated nucleic acid according to the fifth aspect of the present application or the recombinant expression vector according to the sixth aspect of the present application.

[0134] The preparation method of the transformant can be a conventional preparation method in the art, for example, the recombinant expression vector is transformed into a host cell to obtain the transformant. The host cell of the transformant can be various host cells in the art, as long as the recombinant expression vector can be stably replicated by itself and the nucleic acid carried by the recombinant expression vector can be effectively expressed. Preferably, the host cell is a prokaryotic cell, preferably an E. coli cell such as TG1, BL21 (expressing single-chain antibody or Fab antibody), or a eukaryotic cell, preferably a HEK293 cell or a CHO cell (expressing full-length IgG antibody). The recombinant expression plasmid is transformed into the host cell to obtain the preferred recombinant expression transformant of the present application. The transformation method is a conventional transformation method in the art, preferably chemical transformation, heat shock or electroporation.

[0135] To solve the above technical problems, the eighth aspect of the present application provides a preparation method of an antibody or antigen-binding fragment thereof targeting OX40 or a bispecific antibody, which comprises culturing the transformant according to the seventh aspect of the present application, and obtaining the antibody or antigen-binding fragment thereof targeting OX40 or the bispecific antibody from the culture.

[0136] To solve the above technical problems, the ninth aspect of the present application provides an antibody drug conjugate, which comprises an antibody moiety and a conjugated moiety, the antibody moiety comprising the antibody or antigen-binding fragment thereof targeting OX40 according to the first aspect of the present application and / or the bispecific antibody according to the second aspect of the present application, and the conjugated moiety comprising but not limited to a detectable label, a drug, a toxin, a cytokine, a radionuclide, an enzyme, or a combination thereof, and the antibody moiety and the conjugated moiety are conjugated by a chemical bond or a linker.

[0137] To solve the above technical problems, the tenth aspect of the present application provides a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof targeting OX40 according to the first aspect of the present application, the bispecific antibody according to the second aspect of the present application, and a pharmaceutically acceptable carrier.

[0138] Preferably, the pharmaceutical composition further comprises other anti-tumor antibodies as active ingredients.

[0139] The pharmaceutically acceptable carrier can be a conventional carrier in the art, and can be any suitable physiologically or pharmaceutically acceptable pharmaceutical adjuvant. The pharmaceutical adjuvant is a conventional pharmaceutical adjuvant in the art, and preferably includes pharmaceutically acceptable excipients, fillers or diluents, etc. More preferably, the pharmaceutical composition includes 0.01-99.99% of the above-mentioned protein and / or the above-mentioned antibody drug conjugate, and 0.01-99.99% of the pharmaceutical carrier, the percentage being the mass percentage of the pharmaceutical composition.

[0140] The administration route of the pharmaceutical composition of the present application is preferably parenteral administration, injection administration or oral administration. The injection administration preferably includes intravenous injection, intramuscular injection, intraperitoneal injection, intradermal injection or subcutaneous injection, etc. The pharmaceutical composition is various dosage forms in the art, preferably in the form of solid, semi-solid or liquid, i.e. aqueous solution, non-aqueous solution or suspension, more preferably tablet, capsule, granule, injection or infusion, etc. More preferably, it is administered intravascularly, subcutaneously, intraperitoneally or intramuscularly. Preferably, the pharmaceutical composition can also be administered as an aerosol or coarse spray, i.e. nasally; or intrathecally, intramedullary or intraventricularly. More preferably, the pharmaceutical composition can also be transdermally, transcutaneously, topically, enterally, intravaginally, sublingually or rectally. The pharmaceutical composition of the present application can be prepared into various dosage forms as needed, and the beneficial dose for patients can be determined by a physician according to the patient's species, age, weight and general disease condition, administration mode, etc. The administration mode can be injection or other treatment, for example.

[0141] The administration dose level of the pharmaceutical composition of the present application can be adjusted according to the amount of composition required to achieve the desired diagnostic or therapeutic result. The administration regimen can also be a single injection or multiple injections, or adjusted. The selected dose level and regimen are reasonably adjusted depending on various factors including the activity and stability (i.e. half-life) of the pharmaceutical composition, the preparation, the administration route, the combination with other drugs or treatments, the disease or disorder to be detected and / or treated, and the health condition and previous medical history of the subject to be treated, etc.

[0142] The therapeutically effective dose of the pharmaceutical composition of the present application can be initially estimated in cell culture experiments or animal models, such as rodents, rabbits, dogs, pigs and / or primates. Animal models can also be used to determine the appropriate administration concentration range and route. Subsequently, it can be used to determine the useful dose and route of administration in humans. Generally, the determination and adjustment of effective amount or dose, and the evaluation of when and how to make such adjustments are known to those skilled in the art.

[0143] For combination therapy, the above-mentioned antibody targeting OX40, the above-mentioned antibody drug conjugate and / or the additional therapeutic or diagnostic agent can each be used as a single agent, over any time frame appropriate to perform the intended treatment or diagnosis. Thus, these single agents can be administered substantially simultaneously (i.e. as a single preparation or within a few minutes or hours of each other) or in sequential continuous administration.

[0144] For further guidance on formulations, dosages, administration, and measurable outcomes of treatment, see Berkow et al. (2000) The Merck Manual of Medical Information and Merck & Co. Inc., Whitehouse Station, New Jersey; Ebadi (1998) CRC Desk Reference of Clinical Pharmacology, among other works.

[0145] To solve the above technical problems, the eleventh aspect of the present application provides use of the antibody or antigen binding fragment thereof targeting OX40 according to the first aspect of the present application, the bispecific antibody according to the second aspect of the present application, the chimeric antigen receptor according to the third aspect of the present application, the immune cell according to the fourth aspect of the present application, the antibody drug conjugate according to the ninth aspect of the present application and / or the pharmaceutical composition according to the tenth aspect of the present application in the manufacture of a medicament, a kit and / or a device for administration for diagnosing, preventing and / or treating a tumor; or provides the antibody or antigen binding fragment thereof targeting OX40 according to the first aspect of the present application, the bispecific antibody according to the second aspect of the present application, the chimeric antigen receptor according to the third aspect of the present application, the immune cell according to the fourth aspect of the present application, the antibody drug conjugate according to the ninth aspect of the present application and / or the pharmaceutical composition according to the tenth aspect of the present application for use in diagnosing, preventing and / or treating a tumor.

[0146] Preferably, when the bispecific antibody is used for preparing a medicament for diagnosing, preventing and / or treating a tumor, the tumor is a PSMA, EPCAM, CLDN18.2, B7H4 and / or PD-L1 related positive tumor, such as breast cancer, pancreatic cancer, gastric cancer and / or prostate cancer, etc., or metastatic lesions thereof.

[0147] To solve the above technical problems, the twelfth aspect of the present application provides a method for detecting OX40 in a sample, which comprises using the antibody or antigen binding fragment thereof targeting OX40 according to the first aspect of the present application and / or the bispecific antibody according to the second aspect of the present application for detection.

[0148] Preferably, the detection method is for non-diagnostic purposes.

[0149] To solve the above technical problems, the present application provides a kit comprising the OX40-targeting antibody or antigen-binding fragment thereof according to the first aspect of the present application, the bispecific antibody according to the second aspect of the present application, the chimeric antigen receptor according to the third aspect of the present application, the immune cell according to the fourth aspect of the present application, the antibody-drug conjugate according to the ninth aspect of the present application, and / or the pharmaceutical composition according to the tenth aspect of the present application, and optionally, an instruction.

[0150] To solve the above technical problems, the present application provides a drug delivery device comprising: (1) an infusion module for administering the pharmaceutical composition according to the tenth aspect of the present application to a subject in need thereof, and (2) optionally, a pharmacodynamic monitoring module.

[0151] To solve the above technical problems, the present application also provides the use of the OX40-targeting antibody or antigen-binding fragment thereof according to the first aspect of the present application, the bispecific antibody according to the second aspect of the present application, the chimeric antigen receptor according to the third aspect of the present application, the immune cell according to the fourth aspect of the present application, the antibody-drug conjugate according to the ninth aspect of the present application, and / or the pharmaceutical composition according to the tenth aspect of the present application in the diagnosis, prevention and / or treatment of a tumor. Preferably, the tumor is as described in the eleventh aspect of the present application.

[0152] To solve the above technical problems, the present application also provides a kit-of-parts comprising kit A and kit B, wherein kit A is the OX40-targeting antibody or antigen-binding fragment thereof according to the first aspect of the present application, the bispecific antibody according to the second aspect of the present application, the chimeric antigen receptor according to the third aspect of the present application, the immune cell according to the fourth aspect of the present application, the antibody-drug conjugate according to the ninth aspect of the present application, or the pharmaceutical composition according to the tenth aspect of the present application, and kit B is another anti-tumor antibody or a pharmaceutical composition comprising the other anti-tumor antibody. Kit A and kit B can be used simultaneously, kit A can be used first and then kit B, or kit B can be used first and then kit A, depending on the actual needs in specific applications.

[0153] To solve the above technical problems, the present application also provides a method for the diagnosis, prevention and / or treatment of a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of the OX40-targeting antibody or antigen-binding fragment thereof according to the first aspect of the present application, the bispecific antibody according to the second aspect of the present application, the chimeric antigen receptor according to the third aspect of the present application, the immune cell according to the fourth aspect of the present application, the antibody-drug conjugate according to the ninth aspect of the present application, and / or the pharmaceutical composition according to the tenth aspect of the present application.

[0154] In the present application, the scientific and technical terms used in the present application have the meanings commonly understood by a person skilled in the art, unless otherwise stated. Also, the cell culture, molecular genetics, nucleic acid chemistry, immunological laboratory procedures used in the present application are conventional procedures widely used in the respective fields. Also, in order to better understand the present application, the definitions and explanations of the relevant terms are provided below.

[0155] In the present application, the term "variable" generally refers to the fact that certain portions of the sequence of the variable domain of an antibody vary strongly, which forms the binding and specificity of various specific antibodies to their specific antigens. However, the variability is not uniformly distributed throughout the variable region of the antibody. It is concentrated in three segments of the light chain and the heavy chain variable region, which are called complementarity determining regions (CDRs) or hypervariable regions (HVRs). The more highly conserved portions of the variable domain are called framework (FWR). The variable domains of the natural heavy and light chains each comprise four FWR regions, mostly adopting a β-sheet conformation, connected by three CDRs, forming loops connecting, and in some cases forming part of the β-sheet structure. The CDRs in each chain are held together in close proximity by the FWR regions and together with the CDRs from the other chain form the antigen binding site of the antibody, the constant regions are not directly involved in the binding of the antibody to the antigen, but they exhibit different effector functions, for example, participating in antibody-dependent cellular cytotoxicity.

[0156] The three-letter code and one-letter code of amino acids used in the present application are known to those skilled in the art, or as described in J. Biol. Chem, 243, p3558 (1968).

[0157] As used herein, the term "comprising" or "including" is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements, but according to the understanding of the context, it also includes the case of "consisting of".

[0158] In the present application, the HCAb described can be produced by a transgenic mouse carrying a human immunoglobulin immune library, Harbour HCAb mouse (Harbour Antibodies BV, WO 2002 / 085945 A3), which contains only "heavy chain" of full human antibody (Heavy Chain Only Antibody), which is only half the size of the conventional IgG antibody, which usually only has human antibody "heavy chain" variable domain and mouse Fc constant domain.

[0159] The term "antibody" as used herein can include an immunoglobulin, which is a four polypeptide chain structure connected by interchain disulfide bonds, consisting of two identical heavy chains and two identical light chains. The antigenicity of immunoglobulin heavy chain constant region is different due to different amino acid composition and arrangement order. Accordingly, immunoglobulin can be divided into five types, or called isotypes of immunoglobulin, namely IgM, IgD, IgG, IgA and IgE, and the corresponding heavy chains are μ chain, δ chain, γ chain, α chain and ε chain, respectively. The same type of Ig can be divided into different subtypes according to the difference of amino acid composition of hinge region and the number and position of heavy chain disulfide bond, such as IgG can be divided into IgG1, IgG2, IgG3 and IgG4. The light chain is divided into κ chain or λ chain through the constant region. Each of the five types of Ig can have κ chain or λ chain.

[0160] In the present application, the antibody light chain variable region described in the present application can further comprise a light chain constant region comprising human κ, λ chain or a variant thereof. In the present application, the antibody heavy chain variable region described in the present application can further comprise a heavy chain constant region comprising human IgG1, 2, 3, 4 or a variant thereof.

[0161] Within the light chain and the heavy chain, the variable region and the constant region are connected by a "J" region of about 12 or more amino acids, and the heavy chain further comprises a "D" region of about 3 or more amino acids. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region is composed of three domains (CH1, CH2 and CH3). Each light chain is composed of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region is composed of one domain CL. The constant region of the antibody can mediate the binding of immunoglobulin to host tissues or factors, including various cells of the immune system (for example, effector cells) and the first component (C1q) of the classical complement system. The sequence of about 110 amino acids near the N-terminus of the heavy chain and the light chain varies greatly, which is the variable region (V region); the remaining amino acid sequence near the C-terminus is relatively stable, which is the constant region (C region). The variable region includes three hypervariable regions (HVR) and four relatively conserved framework regions (FWR). The three hypervariable regions determine the specificity of the antibody, also known as the complementarity determining region (CDR). Each light chain variable region (VL) and heavy chain variable region (VH) is composed of three CDR regions and four FWR regions, arranged in the order of FWR1, CDR1, FWR2, CDR2, FWR3, CDR3, FWR4 from the amino terminal to the carboxyl terminal. The three CDR regions of the light chain refer to VL CDR1, VL CDR2 and VL CDR3; the three CDR regions of the heavy chain refer to VH CDR1, VH CDR2 and VH CDR3.

[0162] The term "human antibody" includes antibodies having variable and constant regions of immunoglobulin sequences of a human germline. Human antibodies of the application can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., those introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody" does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse (i.e., "humanized antibodies").

[0163] The term "specificity" with respect to an antibody, as used herein, means an antibody that recognizes a specific antigen but does not substantially recognize or bind other molecules in a sample. For example, an antibody that specifically binds an antigen from one species can also bind that antigen from one or more species. However, such cross-reactivity between species does not alter the classification of the antibody as specific. In another example, an antibody that specifically binds an antigen can also bind different allelic forms of the antigen. However, such cross-reactivity does not alter the classification of the antibody as specific. In some instances, the term "specific" or "specifically binds" can be used to refer to the interaction of an antibody, protein, or peptide with a second chemical entity, meaning that the interaction is dependent on the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical entity; for example, an antibody generally recognizes and binds a specific protein structure rather than a protein if that protein is denatured. If an antibody has specificity for an epitope "A," the presence of a molecule containing epitope A (or free, unlabeled A) in a reaction containing labeled "A" and the antibody will reduce the amount of labeled A bound to the antibody.

[0164] In the present application, the term "antigen-binding fragment" refers to antigen-binding fragments of antibodies and antibody analogs that generally include at least a portion of an antigen- binding or variable region of a parent antibody (e.g., one or more CDRs). The antibody fragment retains at least certain binding specificities of the parent antibody. Generally, the antibody fragment retains at least 10% of the parent binding activity when expressed on a molar basis. Preferably, the antibody fragment retains at least 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% or more of the binding affinity of the parent antibody to the target. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments, linear antibodies, single-chain antibodies, nanobodies, domain antibodies, and multispecific antibodies. Engineered antibody variants are reviewed in Holliger and Hudson (2005) Nat. Biotechnol. 23:1126-1136.

[0165] The term "chimeric antigen receptor" or "CAR" as used herein refers to a polypeptide comprising an extracellular domain (extracellular binding domain) capable of binding an antigen, a hinge domain, a transmembrane domain (transmembrane region), and a cytoplasmic signaling domain (i.e., an intracellular signaling domain). The hinge domain can be considered as a part to provide flexibility to the extracellular antigen binding region. The intracellular signaling domain refers to a protein that transmits a signal into a cell to modulate a cellular activity by generating a second messenger via a defined signaling pathway, or a protein that functions as an effector by corresponding to such a messenger, generating a signal that can promote the immune effector function of the CAR's cell (e.g., a CAR T cell). The intracellular signaling domain comprises a signaling domain and can also include a costimulatory intracellular domain derived from a costimulatory molecule.

[0166] "Identity," "mutation" refers to sequence similarity between two polynucleotide sequences or between two polypeptides. When a position in both of the compared sequences is occupied by the same base or amino acid monomer subunit, e.g., if a position in each of two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percent of identity between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared x 100. For example, if 6 of 10 positions in two sequences are matched or homologous when the two sequences are optimally aligned, then the two sequences are 60% identical. In general, the comparison is made at the nucleotide or amino acid level, when two sequences are optimally aligned.

[0167] The terms "polypeptide," "peptide," and "protein" (if single chain) are used interchangeably herein. The terms "nucleic acid," "nucleic acid sequence," "nucleotide sequence," or "polynucleotide sequence," and "polynucleotide" are used interchangeably.

[0168] The term "vector" as used herein is a composition comprising an isolated nucleic acid and useful for delivering the isolated nucleic acid into the interior of a cell. Many vectors are known in the art, including but not limited to linear polynucleotides, polynucleotides associated with ions or amphiphilic compounds, plasmids, and viruses. Thus, the term "vector" includes autonomously replicating plasmids or viruses. The term should also be construed to include non-plasmid and non-viral compounds that facilitate the transfer of nucleic acids into cells, such as polylysine compounds, liposomes, and the like. Examples of viral vectors include, but are not limited to, adenoviral vectors, adeno-associated viral vectors, retroviral vectors, and the like.

[0169] The expressions "cell", "cell line" are used interchangeably in the present application and all such designations include progeny. The term "host cell" refers to a cell that can be used to introduce a vector, including but not limited to prokaryotic cells such as E. coli, fungal cells such as yeast cells, or animal cells such as fibroblast cells, CHO cells, COS cells, NSO cells, HeLa cells, BHK cells, HEK 293 cells, or human cells.

[0170] The term "transfection" refers to the introduction of foreign nucleic acid into a eukaryotic cell. Transfection can be achieved by various means known in the art, including calcium phosphate-DNA co-precipitation, DEAE-dextran-mediated transfection, polybrene-mediated transfection, electroporation, microinjection, liposome fusion, lipofection, protoplast fusion, retroviral infection, and biolistics.

[0171] The term "immune cell" refers to a cell that can elicit an immune response, "immune cell" and other grammatical forms thereof can refer to an immune cell of any origin. "Immune cell" includes, for example, white blood cells (leukocytes) derived from hematopoietic stem cells (HSCs) produced in the bone marrow, lymphocytes (T cells, B cells, natural killer (NK) cells, and myeloid-derived cells (neutrophils, eosinophils, basophils, monocytes, macrophages, dendritic cells). The term "immune cell" can also be human or non-human. For example, an immune cell can be from blood, such as autologous T cells, allogeneic T cells, autologous NK cells, allogeneic NK cells, or can be derived from a cell line, such as NK cell lines prepared using EBV viral infection, NK cells induced to differentiate from embryonic stem cells and iPSCs, and the NK92 cell line, etc.

[0172] As used herein, the term "T cell" refers to a type of lymphocyte that matures in the thymus. T cells play an important role in cell-mediated immunity, and differ from other lymphocytes (e.g., B cells) in that T cell receptors are present on the cell surface. "T cells" include all types of immune cells that express CD3, including T helper cells (CD4+ cells), cytotoxic T cells (CD8+ cells), natural killer T cells, T regulatory cells (Tregs), and gamma-delta T cells. "Cytotoxic cells" include CD8+ T cells, natural killer (NK) cells, and neutrophils, which are capable of mediating cytotoxic reactions. As used herein, the term "NK cell" refers to a type of lymphocyte that originates in the bone marrow and plays an important role in the innate immune system. NK cells provide a rapid immune response against virally infected cells, tumor cells, or other stressed cells, even in the absence of antibodies and major histocompatibility complexes on the cell surface.

[0173] "Optional", "any", "any of", or "any one of" means that the subsequently described event or circumstance can or can not occur, and thus the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally comprising an antibody heavy chain variable region" means that an antibody heavy chain variable region of a particular sequence can or can not be present. As used herein, "a" and "an" are used in the singular or plural sense depending on the context in which it is used. The term "or" is used in the disjunctive sense and in the alternative, unless the content clearly dictates otherwise. "About" and "approximately" shall generally mean an acceptable degree of error for the quantity measured considering the nature of the measurement or the precision of the measuring instrument. Exemplary degrees of error generally include within 10% of and more generally within 5% of the stated amount. The methods and compositions disclosed herein encompass polypeptides and nucleic acids having the specified sequences, variant sequences, or sequences substantially identical or similar thereto, e.g., sequences that are at least 85%, 90%, 95%, 99%, or more identical to the specified sequences. In the case of amino acid sequences, the term "substantially identical" is used herein to refer to a first amino acid sequence.

[0174] As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier that is compatible, in pharmacological and / or physiological terms, with the subject and active ingredient, is well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), and includes, but is not limited to, pH adjusting agents, surfactants, adjuvants, ionic strength enhancers, diluents, agents to maintain osmotic pressure, agents to retard absorption, preservatives. For example, pH adjusting agents include, but are not limited to, phosphate buffers. Surfactants include, but are not limited to, cationic, anionic or non-ionic surfactants, such as Tween-80. Ionic strength enhancers include, but are not limited to, sodium chloride. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Agents to maintain osmotic pressure include, but are not limited to, sugars, NaCl, and the like. Agents to retard absorption include, but are not limited to, monostearate and gelatin. Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols and polyols (such as glycerol), and the like. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thiomersal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, and the like. Stabilizers have the meaning commonly understood by those skilled in the art as capable of stabilizing the desired activity of the active ingredient in the pharmaceutical, including, but not limited to, sodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose, lactose, dextran, or glucose), amino acids (such as glutamic acid, glycine), proteins (such as dried lactose, albumin or casein) or degradation products thereof (such as lactalbumin hydrolysate), and the like.

[0175] As used herein, the term EC50 50 refers to the concentration for 50% of maximal effect, i.e. the concentration that elicits 50% of the maximal effect.

[0176] As used herein, the terms "cancer", "cancerous", "cancer patient" are meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, regardless of histopathological type or stage of invasiveness. Examples include, but are not limited to, solid tumors, hematological cancers, soft tissue tumors, and metastatic lesions.

[0177] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined in any way, i.e. to obtain the preferred embodiments of the application.

[0178] The reagents and starting materials used in the present application are commercially available.

[0179] The positive progress effect of the present application is that:

[0180] 1、The OX40 antibody of the present application can be a full human antibody containing only "heavy chain", the size of the antibody containing only heavy chain is only half of the traditional IgG antibody, and the antibody can be used for bispecific antibody due to the absence of light chain, and the problem of light chain mismatch and heterodimerization can be solved; the full human antibody can be safely administered to human subjects without causing immunogenicity reaction.

[0181] 2、The antibody or antigen binding fragment thereof of the present application has the activity of specifically binding to human OX40 and cyno OX40. In addition, the antibody or antigen binding fragment thereof of the present application can promote the activation of NF-Kb, thereby having the stimulation effect on OX40 signaling pathway, and can activate OX40 pathway in vitro and induce the function of activated T cells, and the activation effect is equivalent to or stronger than that of the existing antibody (such as Pogalizumab), and the antibody or antigen binding fragment thereof of the present application has CD32b cross-linking dependence. In a preferred embodiment of the present application, the antibody targeting OX40 can bind to human OX40 and cyno OX40 protein, and the binding ability of the antibody is positively correlated with the concentration of the antibody. In a preferred embodiment of the present application, the antibody or antigen binding fragment thereof of the present application can specifically bind to OX40 overexpressing cell lines, and does not bind to other members of TNF tumor necrosis factor receptor superfamily. In a preferred embodiment of the present application, the antibody or antigen binding fragment thereof of the present application can be a full human antibody containing only "heavy chain" targeting OX40, and the size of these antibodies containing only heavy chain is only half of the traditional IgG antibody, and due to the absence of light chain, the antibody can be used for bispecific antibody, and the problem of light chain mismatch and heterodimerization can be solved.

[0182] 3、When the antibody or antigen binding fragment thereof of the present application is prepared into bispecific antibody, the bispecific antibody can bind to human OX40 and corresponding tumor related antigen, and the bispecific antibody of the present application does not affect the binding to tumor cells. In a preferred embodiment of the present application, the bispecific antibody has one or two or three or more binding sites with OX40, so as to optimize the activity of OX40 end. In a preferred embodiment of the present application, one end of the bispecific antibody can recognize and specifically bind to tumor cells, such as EPCAM, PSMA, CLDN18.2, B7H4 or PD-L1, so as to specifically activate T cells in tumor microenvironment and reduce the toxicity caused by OX40 activation. BRIEF DESCRIPTION OF DRAWINGS

[0183] Figure 1 The results of HCAb antibody binding to human OX40 protein are shown.

[0184] Figure 2 The image shows the results of the anti-OX40 HCAb antibody binding to the OX40 protein in cynomolgus monkeys.

[0185] Figure 3 The image shows the results of in vitro binding of anti-OX40 HCAb antibody to CHO-K1 / human OX40 cells.

[0186] Figure 4 The diagram shows the results of the anti-OX40 HCAb antibody blocking the binding of human OX40 ligand to human OX40 on the cell surface.

[0187] Figure 5 The figure shows the results of detecting the stimulatory effect of OX40 antibody on the OX40 signaling pathway using reporter gene cell lines.

[0188] Figure 6A The results showed that most OX40 antigen-binding proteins have the function of activating the OX40 pathway and inducing T cell activation.

[0189] Figure 6B The results showed that the OX40 antigen-binding protein is CD32b crosslink-dependent.

[0190] Figure 7 This demonstrates that the antibody of this application specifically binds to CHO-K1 / OX40 cells without binding to other members of the TNF tumor necrosis factor receptor superfamily.

[0191] Figure 8A The structural diagram of the tetravalent symmetrical IgG-VH molecule is shown.

[0192] Figure 8B The structural diagram of the Fab-HCAb tetravalent symmetrical molecule is shown.

[0193] Figure 9 The results of the bispecific antibody OX40×TAA binding to human OX40 are shown in the figure.

[0194] Figure 10 The results of the bispecific antibody OX40×TAA binding to the corresponding human tumor-associated antigen are shown in the figure.

[0195] Figure 11 The results showed that the bispecific antibodies against OX40×TAA activated the OX40-mediated T cell pathway under tumor cell cross-linking.

[0196] Figure 12 The results of the allogeneic mixed lymphocyte reaction of the bispecific antibody OX40×TAA are shown in the figure. Detailed Implementation

[0197] The examples shown below are intended to illustrate specific embodiments of the application and are not intended to limit the scope of the specification or claims in any way. The examples do not include detailed descriptions for conventional procedures, such as those for constructing vectors and plasmids, inserting genes encoding proteins into such vectors and plasmids, or introducing plasmids into host cells. Such procedures are well known to those of ordinary skill in the art and are described in numerous publications, including Sambrook, J., Fritsch, E. F. and Maniais, T. (1989) Molecular Cloning: A Laboratory Manual, 2nd edition, Cold spring Harbor Laboratory Press.

[0198] Example 1. Obtaining anti-OX40 fully human HCAb antibodies

[0199] Harbour HCAb mice (Harbour Antibodies BV, WO 2002 / 085945 A3) are transgenic mice carrying human immunoglobulin immune repertoires, capable of producing fully new "heavy chain only" antibodies, which are half the size of traditional IgG antibodies. The antibodies they produce only have human antibody "heavy chain" variable domains and mouse Fc constant domains. Due to this feature of not containing light chains, the antibodies almost solve the problem of light chain mispairing and heterodimerization, making this technology platform capable of developing products that the traditional antibody platform cannot achieve.

[0200] Example 1.1 Immunization of HCAb mice

[0201] HarbourHCAb human antibody transgenic mice at 6-8 weeks of age were immunized with two immunization protocols. Specifically, immunization protocol 1, mice were immunized with recombinant human OX40-ECD-Fc (ChemPartner, #21127-022) antigen protein. Each mouse received a total injection dose of 100 microliter at each immunization by subcutaneous injection through the inguinal or by intraperitoneal injection. In the first round of immunization, each mouse was immunized with 50 microgram of antigen protein mixed with complete Freund's adjuvant (Sigma, #F5881) at a volume ratio of 1:1. In each subsequent boost, each mouse received 25 microgram of antigen protein mixed with Ribi adjuvant (Sigma Adjuvant System, Sigma, #S6322). Immunization protocol 2, mice were immunized with HEK293 / OX40 (ChemPartner, Shanghai) stable cell line overexpressing human OX40. Each mouse received 2x10 6 Cell suspension. Each round of boost was at least two weeks apart, and usually no more than five rounds of boost. Immunization was at day 0, 14, 28, 42, 56, 70; and at day 49, 77, the mice serum antibody titer was detected. Five days before the HCAb mouse splenic B cell isolation, the last boost was performed at a dose of 25 microgram OX40-ECD-Fc (ChemPartner, #21127-022) antigen protein per mouse.

[0202] The mouse blood was collected, and the blood was diluted 10 times. Five concentrations (1:100, 1:1000, 1:10000, 1:100000, 1:1000000) were taken, and ELISA was performed on the ELISA plate coated with human OX40-ECD-Fc (detection method same as Example 2) to determine the titer of anti-human OX40 in the mouse blood, and flow cytometry (detection method same as Example 3) was used to detect the specific reactivity of two concentrations of mouse blood (1:100, 1:1000) to CHO-K1 / hOX40 cells (Chempartner, Shanghai) and CHO-K1 parent cells overexpressing OX40. The blank control group (PB) was the serum of the mouse before immunization.

[0203] Example 1.2 Obtain HCAb antibody sequence against OX40

[0204] When the serum of the above mice was detected to reach a certain level of OX40 specific antibody titer, the B cells were isolated from the spleen cells of the mice, and the CD138 positive plasma cells and the human OX40 antigen positive B cell population were sorted by BD flow sorter (BD Biosciences, FACS AriaII Cell Sorter). The RNA of the B cells was extracted, the cDNA was reverse transcribed (SuperScript IV First-Strand synthesis system, Invitrogen, #18091200), and then the human VH gene was PCR amplified with specific primers. PCR forward primer 5'-GGTGTCCAGTGTSAGGTGCAGCTG-3' (SEQ ID NO: 255), PCR reverse primer 5'-AATCCCTGGGCACTGAAGAGACGGTGACC-3' (SEQ ID NO: 256). The amplified VH gene fragment was constructed into a mammalian cell expression plasmid pCAG vector encoding the sequence of the heavy chain Fc domain of human IgG1 antibody.

[0205] The constructed plasmid was transfected into mammalian host cells (such as human embryonic kidney cells HEK293) for expression to obtain HCAb antibodies. The supernatant of the HCAb expression was detected for binding with the stable cell line CHO-K1 / OX40 (CHO-K1 / huOX40, (Genscript, #M00561) overexpressing human OX40, and a positive antibody (pembrolizumab) was used as a positive control. Fluorescent cell sorter (SPT Labtech Ltd.) screening. The specific steps are as follows: the CHO-K1 / OX40 cells were washed with serum-free F12K medium (Thermo, #21127022), and resuspended in serum-free medium to 1x10 6 / ml. Draq5 fluorescent probe (Cell Signaling Technology, #4048L) (1 μl Draq5 to 1 ml CHO-K1 / OX40 cells, 1:1000 dilution) was added, and incubated in the dark for 30 minutes. After centrifugation of the cells, the cells were washed with medium, and the cell density was adjusted to 1x10 5 / ml. Alexa 488, AffiniPure Goat Anti-Human IgG, Fc gamma Fragment Specific secondary antibody (Jackson ImmunoResearch Laboratories Inc., #109-545-098), 30 μΐ per well of this mixture was added to a 384 well plate (Greiner Bio One, #781091). 10 μΐ of positive control or supernatant expressing HCAb was added to the 384 well plate and incubated for 2 hours. The fluorescence value was read on a Mirrorball instrument. The positive clone antibodies were further tested by ELISA with human OX40 protein (Acrobiosystem, #OX0-H5224) and cynomolgus OX40 protein (Novoprotein, #CB17) to verify the cross-binding activity. Meanwhile, the binding activity with CHO-K1 / hu OX40# cells was further tested by FACS. The nucleotide sequences encoding the variable domains of the antibody molecules of the clone antibodies were obtained using routine sequencing means and the corresponding amino acid sequences were obtained. After removing the duplicate sequences, the remaining sequenced clone antibody plasmids were transfected into HEK293 cells for expression, and the obtained supernatant was subjected to NF-kb functional test again, thus obtaining 64 functional full human OX40 monoclonal antibodies with unique sequences which simultaneously bind to CHO-K1 / hu OX40 and cynomolgus OX40 proteins. According to the human monkey binding ability and the NF-Kb functional test results, the top 23 antibodies were selected for recombinant expression.

[0206] It is well known to those skilled in the art that the CDRs of an antibody can be defined in various ways in the art, such as the Kabat definition rules based on sequence variability (see, Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, Bethesda, MD (1991)) and the Chothia definition rules based on the location of structural loop regions (see, J Mol Biol 273:927-48, 1997). In the present application, the Combined definition rules comprising the Kabat definition and the Chothia definition can also be used to determine the amino acid residues in the variable domain sequences. The Combined definition rules combine the ranges of the Kabat definition and the Chothia definition to take a larger range, as shown in Table a in the summary. The antibody sequence information of the above 23 antibodies obtained after sequencing is shown in Table 1 (PR002055-PR002077) below.

[0207] Example 1.3 Optimization of HCAb antibody sequences to improve the affinity of binding to OX40

[0208] This example utilizes the antibody engineering yeast display antibody mutagenesis library approach to improve the affinity of HCAb antibody PR002067 binding to OX40. In this example the CDR sequences of the antibody variable domains are analyzed by Chothia rules. Random mutations are introduced into the three CDRs of PR002067 to create a 3CDRs (CDR1, CDR2, CDR3) yeast display mutagenesis library. This affinity maturation selection is divided into four rounds.

[0209] In the first round, the 3 mutagenesis libraries are enriched for binding yeast cells using MACS, then expanded and induced to serve as the first round of FACS selection. In the second round, the yeast cells with higher binding are selected using 0.2 nM Bio-huOX40-his (Acro biosystem, #TN4-H82E4), then collected and expanded, and induced to serve as the next round of selection. In the third round, the yeast cells with higher binding are selected using 0.02 nM Bio-huOX40-his by reducing the selection concentration, then collected and expanded, and induced to serve as the next round of selection. In the fourth round, the yeast cells with higher binding are selected using 0.006 nM Bio-huOX40-his by further reducing the selection concentration. Finally, the yeast cells selected in the fourth round are sequenced to find hotspots for random combination. Then the variant molecules are prepared using conventional recombinant protein expression and purification techniques, the corresponding sequence numbers of which are listed in Table 1 (PR005362-PR005392), and the corresponding CDR sequences of which are listed in Table 1-1 (PR005362-PR005392). Finally, the binding ability of the recombinant mutant molecules is determined using methods such as FACS and BLI.

[0210] Table 1 Sequence number table of anti-OX40 antibodies

[0211] Antibody Number Heavy Chain VH FWR1 HCDR1 FWR2 HCDR2 FWR3 HCDR3 FWR4 PR002055 208 142 4 13 28 42 64 82 102 PR002056 209 143 4 10 29 42 65 83 102 PR002057 210 144 4 14 29 42 66 83 102 PR002058 211 145 4 10 29 43 66 84 102 PR002059 212 146 5 13 30 44 67 82 102 PR002060 213 147 4 15 29 44 68 83 102 PR002061 214 148 4 10 29 44 64 83 102 PR002062 215 149 4 10 31 45 69 83 102 PR002063 216 150 4 10 32 42 69 83 103 PR002064 217 151 6 10 31 45 69 83 102 PR002065 218 152 1 10 29 46 70 85 102 PR002066 219 153 7 10 29 44 67 83 104 PR002067 220 154 4 10 29 44 71 86 102 PR002068 221 155 4 16 33 42 65 82 104 PR002069 222 156 4 10 30 47 67 87 102 PR002070 223 157 7 16 29 44 72 83 102 PR002071 224 158 1 10 29 42 65 83 102 PR002072 225 159 4 10 34 45 73 88 105 PR002073 226 160 1 10 29 43 66 84 102 PR002074 227 161 4 10 35 48 74 89 102 PR002075 228 162 8 10 29 49 64 90 103 PR002076 229 163 4 10 29 49 64 83 103 PR002077 230 164 4 10 29 50 67 90 102 PR005362 234 168 4 20 29 44 71 86 102 PR005363 235 169 4 21 29 44 71 86 102 PR005364 236 170 4 10 29 54 78 86 102 PR005365 237 171 4 10 29 55 78 86 102 PR005366 238 172 4 10 29 56 78 86 102 PR005367 239 173 4 10 29 42 78 86 102 PR005368 240 174 4 10 29 57 78 86 102 PR005369 241 175 4 10 29 58 78 86 102 PR005370 242 176 4 10 29 59 78 86 102 PR005371 243 177 4 10 29 60 78 86 102 PR005372 244 178 4 10 29 44 71 94 102 PR005373 245 179 4 10 29 44 71 95 102 PR005374 246 180 4 10 29 44 71 96 102 PR005375 247 181 4 10 29 44 71 97 102 PR005376 248 182 4 10 29 44 71 98 102 PR005377 249 183 4 10 29 44 71 99 102 PR005378 250 184 4 10 29 54 78 95 102 PR005379 251 185 4 10 29 54 78 97 102 PR005380 252 186 4 10 29 55 78 95 102

[0212] PR005381 253 187 4 10 29 55 78 97 102 PR005382 254 188 4 10 29 56 78 95 102 PR005383 255 189 4 10 29 56 78 97 102 PR005384 256 190 4 22 29 54 78 86 102 PR005385 257 191 4 23 29 54 78 86 102 PR005386 258 192 4 24 29 54 78 86 102 PR005387 259 193 4 21 29 54 78 86 102 PR005388 260 194 4 10 29 54 78 99 102 PR005389 261 195 4 22 29 54 78 99 102 PR005390 262 196 4 23 29 54 78 99 102 PR005391 263 197 4 24 29 54 78 99 102 PR005392 264 198 4 21 29 54 78 99 102

[0213] Table 1-1 CDR sequence table of anti-OX40 antibodies

[0214] Antibody number HCDR1 HCDR2 HCDR3 PR002055 GLTFSSY SGGGGS GMTGSTDVDY PR002056 GFTFSSY SGGGGS GMTGTTDVDY PR002057 GFIFSSY SGGGGS GMTGTTDVDY PR002058 GFTFSSY SGGSGS GVTGTDFDF PR002059 GLTFSSY SGRGGS GMTGSTDVDY PR002060 GFTFSDY SGRGGS GMTGTTDVDY PR002061 GFTFSSY SGRGGS GMTGTTDVDY PR002062 GFTFSSY SGSGGS GMTGTTDVDY PR002063 GFTFSSY SGGGGS GMTGTTDVDY PR002064 GFTFSSY SGSGGS GMTGTTDVDY PR002065 GFTFSSY SGRGDI GMTGSTDVDF PR002066 GFTFSSY SGRGGS GMTGTTDVDY PR002067 GFTFSSY SGRGGS GTTGTTDVDY PR002068 GFSFSSY SGGGGS GMTGSTDVDY PR002069 GFTFSSY SGGGGN GVTGTTDVDY PR002070 GFSFSSY SGRGGS GMTGTTDVDY PR002071 GFTFSSY SGGGGS GMTGTTDVDY PR002072 GFTFSSY SGSGGS GMTGTTDVDF PR002073 GFTFSSY SGGSGS GVTGTDFDF PR002074 GFTFSSY SGGGNN GWELPLLEN PR002075 GFTFSSY SGSGGN GITGTTDVDY PR002076 GFTFSSY SGSGGN GMTGTTDVDY PR002077 GFTFSSY SGRGNI GITGTTDVDY PR005362 GLPFDCY SGRGGS GTTGTTDVDY PR005363 GLPFDSY SGRGGS GTTGTTDVDY PR005364 GFTFSSY SGRGGQ GTTGTTDVDY PR005365 GFTFSSY SGLGGQ GTTGTTDVDY PR005366 GFTFSSY SGRSGQ GTTGTTDVDY PR005367 GFTFSSY SGGGGS GTTGTTDVDY PR005368 GFTFSSY SGLGGS GTTGTTDVDY PR005369 GFTFSSY TGRGGQ GTTGTTDVDY PR005370 GFTFSSY SGHGGT GTTGTTDVDY PR005371 GFTFSSY SGRGGT GTTGTTDVDY PR005372 GFTFSSY SGRGGS GTTGSWDVCY PR005373 GFTFSSY SGRGGS GTTGTWDVDW

[0215] PR005374 GFTFSSY SGRGGS GTTGSWDVDW PR005375 GFTFSSY SGRGGS GTTGSYDVDW PR005376 GFTFSSY SGRGGS GTTGSTDVDW PR005377 GFTFSSY SGRGGS GTTGTWDVDY PR005378 GFTFSSY SGRGGQ GTTGTWDVDW PR005379 GFTFSSY SGRGGQ GTTGSYDVDW PR005380 GFTFSSY SGLGGQ GTTGTWDVDW PR005381 GFTFSSY SGLGGQ GTTGSYDVDW PR005382 GFTFSSY SGRSGQ GTTGTWDVDW PR005383 GFTFSSY SGRSGQ GTTGSYDVDW PR005384 GLPFSSY SGRGGQ GTTGTTDVDY PR005385 GLTFDSY SGRGGQ GTTGTTDVDY PR005386 GFPFDSY SGRGGQ GTTGTTDVDY PR005387 GLPFDSY SGRGGQ GTTGTTDVDY PR005388 GFTFSSY SGRGGQ GTTGTWDVDY PR005389 GLPFSSY SGRGGQ GTTGTWDVDY PR005390 GLTFDSY SGRGGQ GTTGTWDVDY PR005391 GFPFDSY SGRGGQ GTTGTWDVDY PR005392 GLPFDSY SGRGGQ GTTGTWDVDY

[0216] Example 1.4 Preparation of anti-OX40 fully human recombinant antibodies

[0217] The plasmid encoding the HCAb antibody obtained above was transfected into mammalian host cells (such as human embryonic kidney cells HEK293). Using conventional recombinant protein expression and purification techniques, purified anti-OX40 recombinant heavy chain antibody could be obtained. Specifically, HEK293 cells were subjected to FreeStyle... TM Expand the culture using F17 Expression Medium (Thermo, #A1383504). Adjust the cell concentration to 6 × 10⁶ cells / year before transient transfection. 5 Cells / ml were cultured at 37°C in an 8% CO2 shaker for 24 hours, with a cell concentration of 1.2 × 10⁻⁶ cells / ml. 6 Cells / ml. Prepare 30ml of cultured cells. Dissolve 30μg of the plasmid encoding the HCAb heavy chain in 1.5ml of serum-free Opti-MEM medium (Thermo, #31985088). Add 120μl of 1mg / ml PEI (Polysciences, Inc., #23966-2) to 1.5ml of Opti-MEM and let stand for 5 minutes. Slowly add the PEI to the plasmid and incubate at room temperature for 10 minutes. While shaking the culture flask, slowly add the plasmid-PEI mixture. Incubate at 37℃ in an 8% CO2 shaker for 5 days. Observe cell viability after 5 days. Collect the culture, centrifuge at 3300G for 10 minutes, and collect the supernatant. Then, centrifuge the supernatant at high speed to remove impurities. Equilibrate with PBS (pH 7.4) containing MabSelect. TM The sample was washed with 2-5 column volumes of PBS using a gravity column (Bio-Rad, #7311550) from GE Healthcare Life Science (#71-5020-91 AE). The supernatant was then passed through the column. The column was washed with 5-10 column volumes of PBS. The target protein was then eluted with 0.1M glycine at pH 3.5, followed by adjustment to neutral with Tris-HCl at pH 8.0. Finally, the solution was concentrated using an ultrafiltration tube (Millipore, #UFC901024) and replaced with PBS buffer to obtain a purified anti-human OX40 HCAb monoclonal antibody solution. The antibody concentration was determined by NanoDrop at 280 nm absorbance, and the antibody purity was determined by SEC-HPLC and SDS-PAGE.

[0218] Simultaneously, this application produced a positive control antibody, Pogalizumab analogue, against OX40, with the corresponding antibody number PR003475. Its corresponding amino acid sequence is derived from the IMGT database: heavy chain SEQ ID NO: 233, light chain SEQ ID NO: 270.

[0219] Example 1.5 Analysis of protein purity and polymers using HPLC-SEC

[0220] Analytical size exclusion chromatography (SEC) was used to analyze the purity and the aggregate form of the above obtained antibody protein samples. An analytical column TSKgel G3000SWxl (Tosoh Bioscience, 08541, 5 pm, 7.8 mm x 30 cm) was connected to a high pressure liquid chromatograph (HPLC) (Model: Agilent Technologies, Agilent 1260 Infinity II) and equilibrated with PBS buffer at room temperature for at least 1 hour. An appropriate amount of protein sample (at least 10 pg, sample concentration adjusted to 1 mg / ml) was injected into the system after filtration with a 0.22 pm filter, and the HPLC program was set as follows: the sample was flowed through the column with a flow rate of 1.0 ml / min using PBS buffer at pH 7.4 for a maximum time of 20 minutes; detection wavelength 280 nm. After collection, the chromatogram was integrated and the relevant data were calculated using ChemStation software, and an analysis report was generated, reporting the retention time of different molecular size components in the sample.

[0221] Example 1.6 Analysis of protein purity and hydrophobicity using HPLC-HIC

[0222] Analytical hydrophobic interaction chromatography (HIC) was used to analyze the purity and hydrophobicity of the above obtained antibody protein samples. An analytical column TSKgel Butyl-NPR (Tosoh Bioscience, 14947, 4.6 mm x 3.5 cm) was connected to a high pressure liquid chromatograph (HPLC) (Model: Agilent Technologies, Agilent 1260 Infinity II) and equilibrated with PBS buffer at room temperature for at least 1 hour. The method was set as a linear gradient from 100% mobile phase A (20 mM histidine, 1.8 M ammonium sulfate, pH 6.0) to 100% mobile phase B (20 mM histidine, pH 6.0) in 16 minutes, with a flow rate of 0.7 ml / min, a protein sample concentration of 1 mg / ml, an injection volume of 20 mΐ, and a detection wavelength of 280 nm. After collection, the chromatogram was integrated and the relevant data were calculated using ChemStation software, and an analysis report was generated, reporting the retention time of different molecular size components in the sample.

[0223] Example 1.7 Determination of thermal stability of protein molecules using DSF

[0224] Differential Scanning Fluorimetry (DSF) is a commonly used high-throughput method to determine the thermal stability of proteins. It uses a real-time quantitative PCR instrument to monitor the change in fluorescence intensity of a dye that binds to unfolded protein molecules, reflecting the process of protein denaturation, and thus the thermal stability of protein molecules. This example utilizes the DSF method to determine the thermal denaturation temperature (Tm) of protein molecules. 10 μg of protein is added to a 96-well PCR plate (Thermo, #AB-0700 / W), followed by 2 μl of 100x diluted SYPRO™ dye (Invitrogen, #2008138), and then buffer is added to a final volume of 40 μl per well. The PCR plate is sealed and placed in a real-time quantitative PCR instrument (Bio-Rad, Model CFX96 PCR System), incubated at 25°C for 5 minutes, and then gradually increased from 25°C to 95°C at a gradient of 0.2°C / 0.2 minutes, and at the end of the test, the temperature is reduced to 25°C. The FRET scan mode is used and the Bio-Rad CFX Maestro software is used for data analysis and calculation of the Tm of the sample. The results of the test are shown in Table 2 below.

[0225] Table 2. Physicochemical properties of OX40 antibodies

[0226]

[0227] Example 2. ELISA to detect the binding ability of HCAb mAb proteins to OX40

[0228] This example was to investigate the activity of the anti-OX40 HCAb monoclonal antibody prepared in Example 1 to bind to human and cynomolgus monkey OX40 proteins in vitro. Human OX40 protein (Acro biosystem, #OX0-H5224) and cynomolgus monkey OX40 protein (Novoprotein, #CB17) were used for antibody binding experiments at the protein level. Briefly, 20 μl of 1 ug / ml human OX40 protein and cynomolgus monkey OX40 protein dissolved in PBS were coated in each well of a 384-well plate (PerkinElmer, #6007509) at 4°C overnight. The next day, the 384-well plate was washed three times with PBS containing 0.05% Tween (MEDICAGO, #09-9410-100), and blocked with PBS containing 2% milk (Bio-Rad, #170-6404) at 37°C for 1 hour. The OX40 antibody to be tested and the positive antibody (Pogalizumab) were diluted at a starting concentration of 10 nM with 4-fold gradient dilution. After blocking, the 384-well plate was washed three times with PBST, and 10 μl of PBS or 10 μl of the 4-fold gradient-diluted antibody and positive control (Pogalizumab) was added to the plate, and incubated at room temperature for 1 hour. After washing three times, 20 μl of goat anti-human Fc horseradish peroxidase (Jackson ImmunoResearch Laboratories Inc., #109-035-098) was added to each well, and incubated at 37°C for 40 minutes. After washing three times, 20 μl of TMB (SeraCare, #5120-0077) was added to each well, and incubated at room temperature for 5-15 minutes. 20 μl of stop solution (BBI life sciences, #E661006-0200) was added to each well, and the OD values were read using a plate reader (Molecular Devices, model SpectraMax Plus). 450-650 The values were analyzed and plotted using Graphad 8.0.

[0229] As Figure 1 and Figure 2As shown in Table 3 and Table 4, the OX40 antibodies of the present embodiment can all bind to human OX40 and cyno OX40 proteins, and the detected antibody binding ability is positively correlated with the concentration of the antibody. Compared with the reference antibody Tab (Pogalizumab), the EC50 of PR002055, PR002056, PR002058, PR002059, PR002065, PR002069, PR002070, PR002074 and PR002076 in binding to human OX40 protein and cyno protein is equivalent or lower than that of Tab (Pogalizumab (Pogalizumab), a conventional IgG type antibody, the heavy and light chain sequences of which are shown in SEQ ID NO: 233 and SEQ ID NO: 270, respectively), indicating that these antibodies can more sensitively bind to human OX40 at a lower concentration, among which PR002055 is the best, and the EC50 thereof is less than 50 pM.

[0230] Table 3. Binding activity of OX40 antibodies to human OX40 protein

[0231] Antibody EC50 (pM) ODmax PR002055 26.84 1.412 PR002056 56.97 1.713 PR002057 124.1 1.76 PR002058 62.92 1.935 PR002059 69.52 2.003 PR002060 82.81 2.094 PR002061 134.4 1.963 PR002062 103.1 1.939 PR002063 100.9 2.281 PR002064 81.43 2.28 PR002065 63.88 2.474 PR002066 118.1 2.47

[0232] PR002067 80.6 2.378 PR002068 91.97 2.418 PR002069 50.97 2.236 PR002070 72.89 2.405 PR002071 50.16 2.452 PR002072 57.72 2.471 PR002073 85.02 2.38 PR002074 51.15 2.349 PR002075 61.84 2.484 PR002076 64.97 2.8 PR002077 145.6 2.665 Pogalizumab 82.59 2.134

[0233] Table 4. Binding activity of OX40 antibodies to cyno OX40 protein

[0234] Antibody EC50 (pM) ODmax PR002055 45.22 1.743 PR002056 68.19 1.685 PR002057 132.8 1.764 PR002058 59.74 1.761 PR002059 77.35 1.904 PR002060 93.8 1.94 PR002061 151.8 1.872 PR002062 125.6 1.815 PR002063 275.8 2.318 PR002064 217.9 2.079 PR002065 103.5 1.918 PR002066 369.7 2.444 PR002067 232 2.163 PR002068 253.1 2.381 PR002069 129 2.238 PR002070 131.9 2.513 PR002071 201.5 2.927 PR002072 216.7 2.968 PR002073 145.7 2.552 PR002074 140.4 2.341 PR002075 414.9 3.072 PR002076 115.6 2.053 PR002077 440.9 2.729 Pogalizumab 194.3 2.226

[0235] Example 3 FACS detection of the binding ability of HCAb mAb to OX40 at the cellular level

[0236] This embodiment is to study the in vitro binding activity of anti-human OX40 HCAb mAb to human OX40. CHO-K1 stable cell strain overexpressing human OX40 (CHO-K1 / hu OX40) is used for antibody binding experiment at the cellular level. Briefly, the CHO-K1 / hu OX40 cells are digested and resuspended with F12K complete medium, and washed once with PBS. The cell density is adjusted to 1 x 105cells / ml, 1 x 104cells / ml and 1 x 103cells / ml with PBS, respectively, and 100 μl of each cell suspension is added to a 96-well plate, and incubated at 37°C for 24 hours. 6Cells were seeded at 100 μΐ cells / well in 96-well V-bottom plates (Corning, #3894) and centrifuged to remove supernatant. 100 μΐ of 2-fold final concentration of 3-fold dilution of test antibody was added to each well. Cells were incubated at 4°C for 1 hour in the dark. Then, cells were washed twice with 100 μΐ / well pre-cooled PBS, centrifuged at 500g, 4°C for 5 minutes, and the supernatant was discarded. 100 μΐ / well of 1:1000 dilution of secondary antibody (Alexa Fluor 488-conjugated AffiniPure Goat Anti-Human IgG, Fc Gamma Fragment Specific, Jackson, #109-545-06) was added, and the cells were incubated at 4°C for 30 minutes in the dark. Cells were washed twice with 100 μΐ / well pre-cooled PBS, centrifuged at 500g, 4°C for 5 minutes, and the supernatant was discarded. Finally, 200 μΐ / well pre-cooled PBS was used to resuspend the cells, and the fluorescence signal was read using a BD FACS CANTO II.

[0237] As shown in Table 5, all of the OX40 antibodies of the present application were able to bind to CHO-K1 / hu OX40 cells, and the detected antibody binding ability increased in positive correlation with the antibody concentration. Figure 3

[0238] Table 5. Binding activity of OX40 antibodies to CHO-K1 / hu OX40

[0239] Antibody EC50 (nM) MFI max PR002055 3.18 2244 PR002056 3.12 2928 PR002057 12.81 1668 PR002058 5.79 3559 PR002059 1.35 3628 PR002060 8.95 1857 PR002061 10.95 1738 PR002062 37.89 1902 PR002063 9 2244 PR002064 22.44 1573 PR002065 3.82 2865 PR002066 4.67 3012 PR002067 5.25 3012 PR002068 10.08 2129 PR002069 4.43 2992 PR002070 4.39 2532 PR002071 4 3059 PR002072 5.64 1405 PR002073 6.55 3258 PR002074 1.27 3541 PR002075 n.d. 501 PR002076 24.59 1380 PR002077 7.22 3982 Pogalizumab 0.34 4516

[0240] Example 4. Antigen binding proteins block OX40 binding to OX40 ligand

[0241] To investigate the ability of human OX40 binding proteins to block the binding of human OX40 to human OX40 ligand (OX40L) in vitro, a cell-based human OX40 / OX40L binding blocking assay was performed using a CHO-K1 cell line overexpressing human OX40 (CHO-K1 / hu OX40). Briefly, CHO-K1 / hu OX40 cells were digested and resuspended in F-12K complete medium, and the cell density was adjusted to 1 x 10 6 ​Cells were seeded at 100 μl cells / well in 96-well V-bottom plates (Corning, # 3894) and centrifuged to remove supernatant. 100 μl of 2-fold final concentration of 3-fold dilution of antigen binding protein to be tested was added to each well, mixed well, and incubated at 4°C for 1 hour in the dark. The highest final concentration of antigen binding protein was 100 nM, and there were 8 dilution concentrations. Pogalizumab was used as a positive control, and hlgG1 was used as a negative control. Two controls were also set up. One was a no-block control, which contained biotinylated human OX40L protein and secondary antibody but no antibody. The other was a 100% block control, which contained only secondary antibody. The cells were incubated at 4°C for 1 hour in the dark. Then, the cells were centrifuged at 4°C for 5 minutes, and the supernatant was discarded. Then, 50 μl of 0.1 μg / ml biotinylated human OX40L protein (Acro biosysytem, OXL-H82Q6) was added to each well except the 100% block control, and the cells were incubated at 4°C for 30 minutes in the dark. The cells were washed twice with 100 μl / well of pre-cooled PBS, centrifuged at 500g at 4°C for 5 minutes, and the supernatant was discarded. Then, 100 μl of 1:200 fluorescent secondary antibody PE Streptavidin (BD Biosicences, # 554061) was added to each well, and the cells were incubated at 4°C for 30 minutes in the dark. The cells were washed twice with 200 μl / well of pre-cooled PBS, centrifuged at 500g at 4°C for 5 minutes, and the supernatant was discarded. Finally, 200 μl of pre-cooled PBS was added to each well to resuspend the cells, and the fluorescence signal was read using a BD FACS CANTO II. The IC50 and the inhibition rate % were calculated as follows: inhibition rate % = {MFI average of no-block control - MFI of OX40 antibody - MFI of 100% block control} / {MFI average of no-block control - MFI of 100% block control} * 100.

[0242] The results are shown in Table 6. Figure 4 Figure 4 Table 6 shows that the OX40 antibodies (OX40 antigen binding proteins) described in the present application have weak blocking ability for the binding of human OX40 ligand to human OX40 on the cell surface. PR002059 showed a blocking effect comparable to that of the reference antibody Tab (Pogalizumab), and the remaining antibodies showed weak blocking effects. This indicates that most of the OX40 antigen binding proteins described in the present application are weakly blocking or non-blocking antibodies.

[0243] Table 6 shows that the OX40 antibodies (OX40 antigen binding proteins) described in the present application have weak blocking ability for the binding of human OX40 ligand to human OX40 on the cell surface. PR002059 showed a blocking effect comparable to that of the reference antibody Tab (Pogalizumab), and the remaining antibodies showed weak blocking effects. This indicates that most of the OX40 antigen binding proteins described in the present application are weakly blocking or non-blocking antibodies.

[0244] Antibody IC50 (nM) Max inhibition (%) PR002055 59.94 19 PR002056 43.71 34 PR002057 n.d. 12 PR002058 98.1 38 PR002059 15.94 79 PR002060 n.d. 12 PR002061 n.d. 16 PR002062 n.d. 13 PR002063 n.d. 17 PR002064 n.d. 20 PR002065 49.58 44 PR002066 67.61 58

[0245] PR002067 166.2 64 PR002068 23.06 25 PR002069 50.86 53 PR002070 67.57 46 PR002071 51.73 50 PR002072 n.d. 14 PR002073 75.21 24 PR002074 43.13 81 PR002075 n.d. 0 PR002076 n.d. 0 PR002077 41.1 34 Pogalizumab 5.575 99

[0246] ​Example 5. Detection of OX40 antibody (antigen binding protein) stimulation of OX40 signaling pathway using a reporter cell line

[0247] Each well was plated with 100 μl of 1.5 x 10 4 CHO-K1 cells expressing CD32b (CHO-K1 / CD32b) (Genscript, #M00587) or CHO-K1 (ATCC, #CCL-61) were plated into 96-well plates (Perkin Elmer, #6005225) and incubated at 37 °C in a 5% CO2 incubator overnight. The next day, 40 μl of 2-fold dilutions of the antigen binding proteins to be tested were added to each well after removing the supernatant from the 96-well plates, with a starting concentration of 200 nM, 5-fold dilutions, and hlgGl as a negative control. 40 μl of 4.5 x 10 4 HEK293 reporter cells that can sustain expression of OX40 and NF-kb response element luciferase reporter (HEK293 / OX40 / NF-kb reporter cells, BPS Biosciences, #60482) were added to each well. The plates were incubated at 37 °C in a 5% CO2 incubator for 6 hours. ONE-Glo TM Luciferase Reagent (Promega, #E6110) was then added and incubated at room temperature for 5 minutes. Luminescence was measured using a microplate reader.

[0248] The results are shown in Figure 5 and Table 7 below. Figure 5 The results of Table 7 and Table 7 show that all of the OX40 antigen binding proteins described herein are CD32b cross-linking dependent. In the presence of CHO-K1 / CD32b cross-linking, most of the OX40 antigen binding proteins described herein have a positive correlation between their concentration and the promotion of OX40-mediated NF-Kb signaling pathway. Compared with the reference antibody Tab (Pogalizumab), the maximum luminescence value of all OX40 antibodies is higher than that of the reference antibody, indicating that these antibodies can promote greater activation of NF-Kb. Among them, PR002059 is the best, with an EC50 comparable to that of the reference antibody, but a maximum luminescence value higher than that of the reference antibody.

[0249] Table 7. Stimulation of OX40 signaling pathway by antigen binding proteins

[0250] Antibody EC50 (nM) Max luminescence signal value PR002055 4.66 140624 PR002056 4.89 153884 PR002057 14.35 172165 PR002058 4.29 135546 PR002059 1.83 116834 PR002060 15.1 132365 PR002061 23.2 155668

[0251] PR002062 25.22 148937 PR002063 8.64 149686 PR002064 30.34 147258 PR002065 8.55 149211 PR002066 5.45 146566 PR002067 5.37 136921 PR002068 22.95 138931 PR002069 6.27 99697 PR002070 7.6 129161 PR002071 7.85 143752 PR002072 14.21 99625 PR002073 6.39 120867 PR002074 3.08 84796 PR002075 135.9 140219 PR002076 67.03 140541 PR002077 3.51 113373 Pogalizumab 0.91 18147 hlgGl iso / 2530

[0252] Example 6. Antigen binding proteins can activate OX40 pathway in vitro

[0253] CHO-K1 (ATCC, #CCL-61) or CHO-K1 / CD32b cells were treated with 10 μg / ml of mitomycin (Beijing Zhongsheng Ruite Technology, 10107409001) for 30 min at 37 °C. Then washed with F-12K medium with 10% FBS for 4 times. 1.5 x 10 4 cells of these two treated cells were plated in each well of a 96-well flat bottom plate (Corning, #3559) and incubated at 37 °C overnight. The next day, human CD3 positive T cells were isolated from human PBMCs using a MACS kit (Miltenyi Biotec, #130-096-535). The number of cells was first determined, and then the corresponding amount of MACS buffer and Pan-T cell biotin antibody was added according to the number of cells, mixed well, and incubated at 4 °C for 5 min. Then the corresponding amount of microbeads was added and incubated at 4 °C for 10 min. The CD3 positive T cells were collected by LS column. The culture medium of the 96-well plate of the previous day was removed, and the purified T cells were added at 1 x 10 5 cells per well. Then the corresponding concentration of OX40 antibody or control antibody was added, and OKT3 (eBiosciences, #16-0037-85) was added to a final concentration of 0.3 μg / ml. Incubate at 37 °C in a 5% CO2 incubator for 72 hours. After 72 hours, the supernatant was collected, and the content of IFN-γ was detected using an ELISA kit (Invitrogen, #88-7316-88). The ELISA detection method refers to the relevant kit operation instruction. The absorbance values at 450 nm and 570 nM were read by a microplate reader (Molecular Devices, model SpectraMax Plus), and the concentration of IFN-γ in the supernatant was calculated by the standard value reading (OD450-OD570). The data processing and graph analysis were performed using GraphPad Prism 8 software. The results are shown in Figure 6A Most of the OX40 antigen binding proteins described in the present application have the function of activating the OX40 pathway and inducing the activation of T cells. And their activation effect is stronger than that of the reference antibody Tab (Pogalizumab). As Figure 6B and Table 8, the OX40 antigen binding proteins in the present application have CD32b cross-linking dependence, and the activation effect on T cells is greater than that of the reference antibody.

[0254] Table 8 Activation effect of OX40 antibody on T cells

[0255] Antibody EC50 (nM) Max IFN-g release value PR002066 0.03102 1873 PR002067 0.08634 2003 Pogalizumab 0.003736 1142

[0256] Example 7 Detection of the binding affinity and dissociation constant of OX40 antibody to recombinant OX40 protein by BLI method

[0257] The binding kinetics between antigen and antibody were analyzed by Bio-Layer Interferometry (BLI) technology using Octet Red 96e (Fortebio) molecular interaction analyzer. The affinity was determined using Octet RED96 instrument (Pall Fortiebio) and ProA Affinity Sensor (Pall ForteBio, #18-5010) according to the detailed operation and method provided by the manufacturer.

[0258] First, the ProA Affinity Sensor placed in a row was equilibrated in the test buffer for 10 minutes, then 200 nM of OX40 antibody was captured by the ProA sensor with a capture height of 0.8 nm; the ProA sensor was equilibrated in the buffer for 120 s, then combined with 2-fold gradient dilution of human OX40 protein or cynomolgus OX40 protein (OX40HCAB used concentrations of 200-6.25 nM and 0 nM; Pogalizumab used 25-1.56 nM and 0 nM) for 180 s, dissociation for 800 s (the dissociation time of PR002063, PR002065, PR002066 and PR002077 with cynomolgus monkey was 400 s); finally, the ProA sensor was immersed in a 10 mM glycine-hydrochloric acid pH 1.5 solution for regeneration to elute the protein bound to the sensor. The Octet Red 96 recorded the binding and dissociation signals of OX40 antibody and OX40 protein in real time. When the data analysis was performed using Octet Data Analysis software (Fortebio, version 11.0), the reference signal was subtracted with 0 nM as the reference well, the data fitting was performed by selecting the “1:1 Global fitting” method, and the kinetic parameters of the binding of antigen and antigen binding protein were calculated to obtain the kon(1 / Ms) value, kdis(1 / s) value and KD(M) value. The results are shown in Table 9, and the KD(M) of most of the OX40 antigen binding proteins described in the application binding to human OX40 or cynomolgus OX40 are slightly higher than Pogalizumab, indicating that compared with the reference antibody, its binding affinity to OX40 is relatively weak, which may be related to the structural difference between the OX40HCAb of the application and Pogalizumab.

[0259] Table 9. Binding affinity of antibodies to human OX40 protein and cynomolgus OX40 protein

[0260]

[0261]

[0262] Example 8 Specific binding of antigen binding protein to OX40

[0263] OX40 belongs to the TNF tumor necrosis factor receptor superfamily, which is a large group of multifunctional receptors that mediate immune and non-immune cell functions. Six receptors have been identified as important immune costimulators, including CD40, OX40, 4-BB, CD27, GITR and CD30. Similarly, inducible T cell costimulator (ICOS) is another class of receptors that play an important role in the function and survival of activated T cells or memory T cells.

[0264] This example is to investigate the specificity of anti-human OX40 HCAb in vitro binding by flow cytometry detection of three receptors of the TNF tumor necrosis factor receptor superfamily and ICOS. Antibody binding experiments at the cellular level were performed using CHO-K1 cell lines overexpressing human OX40 (CHO-K1 / huOX40), CHO-K1 cell lines overexpressing human CD40 (CHO-K1 / hu CD40, Beijing Kangyuan Bochuang, #KC-1286), CHO-K1 cell lines overexpressing human 4-1BB (CHO-K1 / hu4-1BB, Genscript, #M00538) and HEK293 cell lines overexpressing human ICOS (HEK293T / ICOS, Genscript, #KC-0210). Briefly, these cells were digested and resuspended with F12K or DMEM complete medium, and the cell density was adjusted to 1 x 10 6 Cells / ml. 100 μl of cells / well were seeded in a 96-well V-bottom plate, centrifuged to remove the supernatant, and 100 μl / well of 3-fold concentration gradient diluted test antibody was added. The cells were incubated at 4°C in the dark for 1 hour. Then, 100 μl / well of pre-cooled PBS was added to rinse the cells twice, centrifuged at 500g, 4°C for 5 minutes, and the supernatant was discarded. Then, 100 μl / well of 1:1000 diluted fluorescent secondary antibody (Alexa Fluor 488-conjugated AffiniPure Goat Anti-Human IgG, Fcγ Fragment Specific, Jackson #109-545-06) was added, and the cells were incubated at 4°C in the dark for 30 minutes. The cells were washed twice with 100 μl / well of pre-cooled PBS, centrifuged at 500g, 4°C for 5 minutes, and the supernatant was discarded. Finally, 200 μl / well of pre-cooled PBS was used to resuspend the cells, and the NovoCyte flow cytometer (ACEA Biosciences) was used to read the fluorescence signal value.

[0265] The results, as shown in Figure 7 PR002067 described herein specifically binds to CHO-K1 / OX40 cells, but not to other members of the TNF tumor necrosis factor receptor superfamily.

[0266] Example 9 Structure and design of bispecific antibodies of OX40 and tumor targets

[0267] The anti-OX40 heavy chain antibodies selected from Example 1 to Example 8 and anti-PSMA (PR001331, H2L2 antibody, 202010096322.6), anti-OX40 heavy chain antibody and EPCAM (PR001081, H2L2 antibody, 202010114063.5), anti-OX40 heavy chain antibody and CLDN 18.2 (PR002726, H2L2 antibody, 201910941316.3), anti-OX40 heavy chain antibody and B7H4 (PR002408, H2L2 antibody, ), anti-OX40 heavy chain antibody and PD-L1 (PR000265, H2L2 antibody, 201910944996.4) antibodies for preparing bispecific antibodies can simultaneously bind to two targets, one end of which can recognize tumor target TAA (such as PSMA, EPCAM, CLDN18.2, B7H4, PD-L1) specifically expressed on the surface of tumor cells, and the other end can bind to OX40 molecules on T cells, which can recruit and activate T cells near tumor cells, thereby killing tumor cells.

[0268] The H2L2 antibody sequence information of the anti-tumor target (such as PSMA, EPCAM, CLDN18.2, B7H4, PD-L1) used in this example is shown in Table 10 below.

[0269] Table 10 H2L2 antibody sequence table of anti-tumor target

[0270]

[0271] The TAA x OX40 bispecific antibodies prepared in this example include various molecular structures:

[0272] 1) IgG-VH tetravalent symmetric structure molecule, the structure is as shown in Figure 8A , which comprises two polypeptide chains: polypeptide chain 1, also known as short chain, from the amino terminal end to the carboxyl terminal end, comprising VL_A-CL; polypeptide chain 2, also known as long chain, from the amino terminal end to the carboxyl terminal end, comprising VH_A-CH1-h-CH2-CH3-L-VH_B.

[0273] In one embodiment, the CH3 of polypeptide chain 2 is directly fused to VH_B, that is, the length of L is 0. In another embodiment, the CH3 of polypeptide chain 2 is connected to VH_B via a connecting peptide L; L can be the sequence listed in Table 11.

[0274] 2) Fab-HCAb tetravalent symmetric structure molecule, the structure is as shown in Figure 8BAs shown, it comprises two polypeptide chains: polypeptide chain 1, also called short chain, from amino terminus to carboxyl terminus, which comprises VH_A-CH1; polypeptide chain 2, also called long chain, from amino terminus to carboxyl terminus, which comprises VL_A-CL-L1-VH_B-L2-CH2-CH3. In this structure, VL_A of antibody A and VH_B of heavy chain antibody B are fused in the same polypeptide chain, which can avoid the mispairing byproduct produced by the association of VL_A and VH_B.

[0275] VH_B of polypeptide chain 2 is linked to CH2 via linker L2; L2 can be hinge region of IgG or hinge region derived linker peptide sequence; L2 can be the sequence listed in Table 11, preferably the sequence of human IgG1 hinge or human IgG1 hinge (C220S) or G5-LH.

[0276] In one embodiment, CL of polypeptide chain 2 is directly fused to VH_B, i.e. the length of L1 is 0. In another embodiment, CL of polypeptide chain 2 is linked to VH_B via linker L1; L1 can be the sequence listed in Table 11.

[0277] Table 11 Linker Peptide

[0278]

[0279] The bispecific antibody contains Fc domain of IgG1 with mutations L234A and L235A or L234A and L235A and P329G (numbered according to EU index).

[0280] The information of bispecific antibodies of IgG-VH tetravalent symmetric structure constructed in this example is shown in Table 12 below, and the information of bispecific antibodies of Fab-HCAb tetravalent symmetric structure constructed in this example is shown in Table 13 below, and the physicochemical properties thereof are shown in Table 14.

[0281] Table 12 Bispecific antibodies of IgG-VH tetravalent symmetric structure

[0282]

[0283]

[0284] Table 13 Bispecific antibodies of Fab-HCAb tetravalent symmetric structure

[0285]

[0286] Table 14 Expression and physicochemical properties of bispecific antibodies

[0287]

[0288] The CDR number information of the heavy chain and light chain sequence of the TAA x OX40 bispecific antibody constructed in this example is shown in Table 15 below, and the polypeptide chain number information is shown in Table 16 below.

[0289] Table 15 Sequence CDR number table of TAA x OX40 bispecific antibody

[0290]

[0291] Table 16 Polypeptide chain number table of TAA x OX40 bispecific antibody

[0292]

[0293] Example 10 FACS detection of the binding ability of bispecific antibody to OX40 cells

[0294] This example is to study the in vitro binding activity of OX40 x TAA bispecific antibody obtained in Example 9 to human OX40. CHO-K1 cell line overexpressing human OX40 (CHO-K1 / hu OX40 #) was used for antibody binding experiment at cell level. Briefly, CHO-K1 / hu OX40 cells were digested and resuspended with F12K complete medium, washed with PBS, and then the cell density was adjusted to 1 x 10 6 cells / ml with PBS. 100 μl of cells per well were inoculated in a 96-well V-bottom plate (Corning, #3894), and then 100 μl / well of 3-fold concentration gradient diluted test antibody at a final concentration was added. The cells were incubated at 4°C in the dark for 1 hour. Then, 100 μl / well of pre-cooled PBS was added to rinse the cells twice, centrifuged at 500g, 4°C for 5 minutes, and the supernatant was discarded. 100 μl / well of 1:1000 diluted fluorescent secondary antibody (Alexa Fluor 488-conjugated AffiniPure Goat Anti-Human IgG, Fcγ Fragment Specific, Jackson, #109-545-06) was added, and incubated at 4°C in the dark for 30 minutes. The cells were washed twice with 100 μl / well of pre-cooled PBS, centrifuged at 500g, 4°C for 5 minutes, and the supernatant was discarded. Finally, 200 μl / well of pre-cooled PBS was used to resuspend the cells, and the NovoCyte flow cytometer (ACEA Biosciences) was used to read the fluorescence signal value.

[0295] As Figure 9 shown in Table 17, the OX40 x TAA bispecific antibodies of the application can all bind to human OX40, and the detected antibody binding ability is positively correlated with the increase of antibody concentration. The binding ability is comparable to the reference antibody Tab (Pogalizumab).

[0296] Table 17 Bispecific antibodies of OX40 x TAA bind to human OX40 cells

[0297] Antibody EC50 (nM) MFI max PR003789 3.977 287338 PR004276 2.799 281894 PR004277 3.458 274396 PR004283 1.809 204612 PR004284 4.955 287445 PR004285 3.548 252325 Pogalizumab 1.153 317098 hlgGl ～70.97 6902

[0298] Example 11 FACS assay to detect the binding ability of bispecific antibodies to corresponding tumor associated antigen cells

[0299] This example is to investigate the in vitro binding activity of OX40 x TAA bispecific antibodies obtained in Example 9 to human tumor associated antigens (TAAs). SK-BR-3 (Chinese Academy of Sciences Cell Bank, #TCHu225) which highly expresses human B7H4, MDA-MB-231 (ATCC, HTB-26) which highly expresses human PD-L1, LNCAP (Nanjing Kebai, #CBP60346) which highly expresses human PSMA, or NUGC-4 (ExPASy, #CVCL_3082) which highly expresses human CLDN18.2, Capan-2 (ATCC, #HTB-80) which highly expresses human EPCAM were used for antibody binding experiments at the cellular level. Briefly, these cells were digested and resuspended with complete medium, and after washing with PBS, the cell density was adjusted to 1 x 10 6 cells / ml. 100 μl of cells per well were inoculated in a 96-well V-bottom plate (Corning, #3894), and after centrifugation to remove the supernatant, 100 μl of 3-fold concentration gradient diluted test antibody was added per well. The cells were incubated at 4°C in the dark for 1 hour. Then, 100 μl of pre-cooled PBS was added to wash the cells twice, and centrifuged at 500g at 4°C for 5 minutes, and the supernatant was discarded. 100 μl of 1:1000 diluted fluorescent secondary antibody (Alexa Fluor 488-conjugated AffiniPure Goat Anti-Human IgG, Fcγ Fragment Specific, Jackson, #109-545-06) was added per well, and incubated at 4°C in the dark for 30 minutes. The cells were washed twice with 100 μl of pre-cooled PBS, centrifuged at 500g at 4°C for 5 minutes, and the supernatant was discarded. Finally, 200 μl of pre-cooled PBS was used to resuspend the cells, and the NovoCyte flow cytometer (ACEA Biosciences) was used to read the fluorescence signal value.

[0300] As Figure 10As shown in Tables 18-1, 18-2, 18-3, 18-4, 18-5, the OX40 x TAA bispecific antibodies of the application can all bind to the corresponding human tumor associated antigen, and the detected antibody binding ability increases in positive correlation with the antibody concentration. Compared with the corresponding TAA parent monoclonal antibody, the bispecific antibody shows comparable EC50 and maximum value.

[0301] Table 18-1 OX40 x PD-L1 bispecific antibody binding to corresponding MDA-MB-231 cells

[0302] Antibody EC50 (nM) Median value of fluorescence intensity Maximum value of fluorescence intensity PR003789 1.040 128390 PR000265 0.6050 141594

[0303] Table 18-2 OX40 x B7H4 bispecific antibody binding to corresponding SK-BR-3 cells

[0304] Antibody EC50 (nM) Median value of fluorescence intensity Maximum value of fluorescence intensity PR004276 1.139 354678 PR004277 1.506 362253 PR002408 1.813 373359

[0305] Table 18-3 OX40 x EpCAM bispecific antibody binding to corresponding Capan-2 cells

[0306] Antibody EC50 (nM) Median value of fluorescence intensity Maximum value of fluorescence intensity PR004283 3.518 1544198 PR001081 2.584 1642796

[0307] Table 18-4 OX40 x Claudin18.2 bispecific antibody binding to corresponding NUGC-4 cells

[0308] Antibody EC50 (nM) Median value of fluorescence intensity Maximum value of fluorescence intensity PR004285 7.205 740185 PR002726 4.982 745505

[0309] Table 18-5 OX40 x PSMA bispecific antibody binding to corresponding LNCAP cells

[0310] Antibody EC50 (nM) Median value of fluorescence intensity Maximum value of fluorescence intensity PR004284 6.701 160857 PR001331 2.578 142270 PR000327 3.025 126604

[0311] Example 12 In vitro activation of OX40 pathway by bispecific antibodies

[0312] This example is to study the activity of OX40 x TAA bispecific antibodies in activating T cells by binding to the costimulatory molecule OX40 in target cells.

[0313] In this embodiment, target cells are cells expressing specific antigens (e.g., tumor-specific antigens), such as MDA-MB-231 (ATCC, HTB-26) highly expressing human PD-L1, or CHO-K1-huB7H4 (internal construct) highly expressing human B7H4, or HEK293-huPSMA (Beijing Kangyuan, #KC-1005) highly expressing human PSMA, or Capan-2 (ATCC, HTB-80) highly expressing human EPCAM, or NUGC4 (JCRB, JCRB0834) highly expressing human CLDN18.2. Effector cells are isolated human T cells.

[0314] Specifically, firstly, 0.3 μg / ml anti-CD3 antibody OKT3 (Thermo, #16-0037-81) was coated onto 96-well plates (Corning, #3599) at 100 μl / well. Next, the density of human T cells (isolated from human PBMCs using a T cell sorting kit (Miltenyi, #130-096-535)) was adjusted to 2 × 10⁻⁶ cells / well. 6 cells / ml, adjust the target cell density to 3×10 5 Cells / ml, then seeded 50 μl / well of each of the two cell suspensions into 96-well plates. Next, different concentrations of antibody molecules were added to 100 μl / well, with two replicates; hIgG1 iso (CrownBio, #C0001) and hIgG4 iso (CrownBio, #C0045) served as controls. The 96-well plates were incubated at 37°C in a 5% CO2 incubator for 2 days. After 48 hours of culture, the supernatant was collected, and the IL-2 concentration in the supernatant was detected using an IL-2 ELISA kit (Thermo, #88-7025-88). The ELISA assay method followed the relevant kit instructions. Absorbance values ​​at 450 nm and 570 nM were read using a Molecular Devices (SpectraMax Plus) reader, and the results were compared with standard readings (OD). 450 -OD 570 The IL-2 concentration was calculated by reverse calculation. The data was processed and graphically analyzed using the software GraphPad Prism 8.

[0315] The results are as follows Figure 11 As shown (due to individual differences, a single PBMC donor may not yield effective results, so at least two donors are generally selected for parallel experiments, which are labeled as donor 1 and donor 2 in the examples), it can be seen that the OX40 / TAA bispecific antibody described in this application can activate the XO40-mediated T cell pathway under tumor cell cross-linking, indicating that the OX40 bispecific antibody can specifically activate T cells in the presence of tumor target cells.

[0316] Example 13 Heterologous Mixed Lymphocyte Reaction (MLR)

[0317] This example is to investigate the activation of T cells by PD-L1 x OX40 bispecific antibody molecules using Mixed Lymphocyte Reaction (MLR).

[0318] First step, monocytes were isolated from PBMC cells (Mytogen) of the first donor using CD14 magnetic beads (Meltenyi, #130-050-201) according to the instruction of the kit. Then 50 ng / ml recombinant human IL-4 (PeproTech, #200-02-A) and 100 ng / ml recombinant human GM-CSF (PeproTech, #300-03-A) were added to induce the immature dendritic cells (iDC cells) for 6 days at 37°C. Then 1 μg / ml of Lipopolysaccharide (LPS, Sigma, #L6529) was added to induce the mature dendritic cells (mDC cells) for 24 hours. Second step, T lymphocytes were isolated from PBMC cells (Mytogen) of the second donor using T cell isolation kit (Meltenyi, #130-096-535). Third step, the obtained T cells and mDC cells were seeded into 96-well plates at a ratio of 5:1 (1 x 10 5 / well of T cells and 2 x 10 4 / well of mDC cells). Then 50 μl / well of different concentrations of antibody molecules were added, the final concentration of the antibody could be (10 nM, 1 nM), or 8 concentrations diluted from the highest concentration of 50 nM with a 3-fold concentration gradient, two replicates were added. hlgGl iso (CrownBio, #C0001) or blank wells were used as controls. Incubate at 37°C, 5% CO2 incubator for 5 days. Fourth step, the supernatants of day 3 and day 5 were collected respectively, and the IL-2 concentration in the supernatant of day 3 was detected by IL-2 ELISA kit (Thermo, #88-7025-88), and the IFN-γ concentration in the supernatant of day 5 was detected by IFN-γ ELISA kit (Thermo, #88-7316-77). The ELISA detection method refers to the operation instruction of the related kit. The absorbance values at 450 nm and 570 nM were read by a microplate reader (Molecular Devices, model SpectraMax Plus), and the OD450-OD570values were calculated. The standard curve was drawn by the OD450-OD570values of the standard samples, and the IL-2 concentration or IFN-γ concentration of the sample was calculated according to the standard curve. 450 -OD 570) Back-calculate IL-2 or IFN-γ concentration. Data processing and graph analysis were performed using GraphPad Prism 8 software.

[0319] Results are shown in Figure 12 As shown in Tables 19-1 and 19-2, anti-PD-L1 mAb PR000265 had more obvious activation effect in two independent MLR experiments (different donor pairs), but the bispecific antibody molecule PR003789 of PD-L1 x OX40 could further improve the function of T cells.

[0320] Table 19-1 PD-L1 x OX40 bispecific antibody MLR-induced cytokine release (donor 1)

[0321]

[0322] Table 19-2 PD-L1 x OX40 bispecific antibody MLR-induced cytokine release (donor 2)

[0323]

[0324] Summary

[0325] In order to overcome the shortcomings of the current antibodies targeting OX40, a class of fully human heavy chain antibodies is obtained by immunizing Harbour HCAb mice. The antibodies of the present application have the activity of specifically binding to human OX40 and cynomolgus OX40, can promote the activation of NF-Kb, thereby stimulating the OX40 signaling pathway, and can activate the OX40 pathway in vitro and induce the function of activated T cells. The activation effect is comparable to or stronger than the existing antibodies (such as Pogalizumab), and the antibodies or antigen binding fragments thereof of the present application have Fcγ receptor member FcγRIIB (CD32B) cross-linking dependence.

[0326] The antibody of the present application only contains "heavy chain" full human antibody, the size of these heavy chain only antibody is only half of the traditional IgG antibody, due to the characteristic of not containing light chain, so that the antibody can be used for bispecific antibody, while solving the problem of light chain mismatch and heterodimerization. The antibody of the present application is prepared into IgG-VH tetravalent symmetric structure of double antibody molecule and Fab-HCAb structure of double antibody molecule with H2L2 antibody of anti-tumor target, the obtained bispecific antibody can bind human OX40 and corresponding tumor related antigen, one end of which can recognize tumor target TAA (such as PSMA, EPCAM, CLDN18.2, B7H4, PD-L1) specifically expressed on the surface of tumor cells, and the other end can bind OX40 molecule on T cell, thereby specifically activating T cell in tumor microenvironment, reducing the toxicity caused by OX40 activation, and killing tumor cells.

[0327] Although the specific embodiments of the present application are described above, those skilled in the art should understand that these are only illustrative, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present application. Therefore, the protection scope of the present application is defined by the appended claims. SEQUENCE LISTING <110> and platinum medicine (shanghai) limited liability company <120> antibody targeting OX40 and preparation method and application thereof <130> P22116537CP <140> CN202180030974.2 <141> 2021‑06‑29 <150> CN202010618134.5 <151> 2020‑06‑30 <160> 295 <170> PatentIn version 3.5 <210> 1 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> PR000265 HFWR1 Chothia, PR002065 HFWR1 Chothia, PR002071 HFWR1 Chothia <400> 1 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser 20 25 <210> 2 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> PR001081 HFWR1 Chothia, PR002408 HFWR1 Chothia <400> 2 Gln Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala Ser 20 25 <210> 3 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> PR001331 HFWR1 Chothia <400> 3 Gln Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala Ser 20 25 <210> 4 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> PR002055 HFWR1 Chothia, PR002056 HFWR1 Chothia, PR002057 HFWR1 Chothia <400> 4 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser 20 25 <210> 5 <211> 25 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002059 HFWR1 Chothia <400> 5 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Val Ser 20 25 <210> 6 <211> 25 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002064 HFWR1 Chothia <400> 6 Glu Val Gin Leu Val Glu Thr Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser 20 25 <210> 7 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> PR002066 HFWR1 Chothia, PR002070 HFWR1 Chothia <400> 7 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys lie Ala Ser 20 25 <210> 8 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> PR002075 HFWR1 Chothia <400> 8 Glu Val Gin Leu Val Glu Thr Gly Gly Gly Leu lie Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser 20 25 <210> 9 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> PR003475 HFWR1 Chothia <400> 9 Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser 20 25 <210> 10 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR000265 HCDR1 Chothia, PR002056 HCDR1 Chothia, PR002058 HCDR1 Chothia <400> 10 Gly Phe Thr Phe Ser Ser Tyr 1 5 <210> 11 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR001081 HCDR1 Chothia <400> 11 Gly Phe Thr Phe Ile Asn Tyr 1 5 <210> 12 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR001331 HCDR1 Chothia <400> 12 Gly Phe Thr Phe Ser Arg Tyr 1 5 <210> 13 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR002055 HCDR1 Chothia, PR002059 HCDR1 Chothia <400> 13 Gly Leu Thr Phe Ser Ser Tyr 1 5 <210> 14 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR002057 HCDR1 Chothia <400> 14 Gly Phe Ile Phe Ser Ser Tyr 1 5 <210> 15 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR002060 HCDR1 Chothia <400> 15 Gly Phe Thr Phe Ser Asp Tyr 1 5 <210> 16 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR002068 HCDR1 Chothia, PR002070 HCDR1 Chothia <400> 16 Gly Phe Ser Phe Ser Ser Tyr 1 5 <210> 17 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR002408 HCDR1 Chothia <400> 17 Gly Phe Thr Phe Arg Ser Phe 1 5 <210> 18 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR002726 HCDR1 Chothia <400> 18 Gly Phe Thr Phe Ser Ser Phe 1 5 <210> 19 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR003475 HCDR1 Chothia <400> 19 Gly Tyr Thr Phe Thr Asp Ser 1 5 <210> 20 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR005362 HCDR1 Chothia <400> 20 Gly Leu Pro Phe Asp Cys Tyr 1 5 <210> 21 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR005363 HCDR1 Chothia, PR005387 HCDR1 Chothia, PR005392 HCDR1 Chothia <400> 21 Gly Leu Pro Phe Asp Ser Tyr 1 5 <210> 22 <211> 7 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005384 HCDR1 Chothia, PR005389 HCDR1 Chothia <400> 22 Gly Leu Pro Phe Ser Ser Tyr 1 5 <210> 23 <211> 7 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005385 HCDR1 Chothia, PR005390 HCDR1 Chothia <400> 23 Gly Leu Thr Phe Asp Ser Tyr 1 5 <210> 24 <211> 7 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005386 HCDR1 Chothia, PR005391 HCDR1 Chothia <400> 24 Gly Phe Pro Phe Asp Ser Tyr 1 5 <210> 25 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> PR000265 HFWR2 Chothia <400> 25 Trp Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 1 5 10 15 Ala Asn lie <210> 26 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> PR001081 HFWR2 Chothia <400> 26 Asp Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 1 5 10 15 Ala Val lie <210> 27 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> PR001331 HFWR2 Chothia <400> 27 Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 1 5 10 15 Ala Val lie <210> 28 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> PR002055 HFWR2 Chothia <400> 28 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp lie 1 5 10 15 Ser Ala lie <210> 29 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> PR002056 HFWR2 Chothia, PR002057 HFWR2 Chothia, PR002058 HFWR2 Chothia <400> 29 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 1 5 10 15 Ser Ala lie <210> 30 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> PR002059 HFWR2 Chothia, PR002069 HFWR2 Chothia <400> 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Arg Glu Trp Val 1 5 10 15 Ser Ala lie <210> 31 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> PR002062 HFWR2 Chothia, PR002064 HFWR2 Chothia <400> 31 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Gin Glu Trp Val 1 5 10 15 Ser Ala He <210> 32 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> PR002063 HFWR2 Chothia <400> 32 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Arg Gly Leu Glu Trp Val 1 5 10 15 Ser Ala He <210> 33 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> PR002068 HFWR2 Chothia <400> 33 Ala Met Thr Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 1 5 10 15 Ser Ala He <210> 34 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> PR002072 HFWR2 Chothia <400> 34 Ala Met Ser Trp Val Arg Gin Ala Ser Gly Lys Gly Leu Glu Trp lie 1 5 10 15 Ser Ala lie <210> 35 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> PR002074 HFWR2 Chothia <400> 35 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 1 5 10 15 Ser Gly lie <210> 36 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> PR002408 HFWR2 Chothia <400> 36 Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 1 5 10 15 Ala Val lie <210> 37 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> PR002726 HFWR2 Chothia <400> 37 Val Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 1 5 10 15 Ser Thr He <210> 38 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> PR003475 HFWR2 Chothia <400> 38 Tyr Met Ser Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp He 1 5 10 15 Gly Asp Met <210> 39 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR000265 HCDR2 Chothia <400> 39 Lys Gin Glu Gly Ser Glu 1 5 <210> 40 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR001081 HCDR2 Chothia <400> 40 Trp Phe Asp Gly Ser Asn 1 5 <210> 41 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR001331 HCDR2 Chothia <400> 41 Trp Tyr Asp Gly Ser Asn 1 5 <210> 42 <211 > 6 <212> PRT <213> Artificial Sequence <220> <223> PR002055 HCDR2 Chothia, PR002056 HCDR2 Chothia, PR002057 HCDR2 Chothia <400> 42 Ser Gly Gly Gly Gly Ser 1 5 <210> 43 <211 > 6 <212> PRT <213> Artificial Sequence <220> <223> PR002058 HCDR2 Chothia, PR002073 HCDR2 Chothia <400> 43 Ser Gly Gly Ser Gly Ser 1 5 <210> 44 <211 > 6 <212> PRT <213> Artificial Sequence <220> <223> PR002059 HCDR2 Chothia, PR002060 HCDR2 Chothia, PR002061 HCDR2 Chothia <400> 44 Ser Gly Arg Gly Gly Ser 1 5 <210> 45 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR002062 HCDR2 Chothia, PR002064 HCDR2 Chothia, PR002072 HCDR2 Chothia <400> 45 Ser Gly Ser Gly Gly Ser 1 5 <210> 46 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR002065 HCDR2 Chothia <400> 46 Ser Gly Arg Gly Asp Ile 1 5 <210> 47 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR002069 HCDR2 Chothia <400> 47 Ser Gly Gly Gly Gly Asn 1 5 <210> 48 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR002074 HCDR2 Chothia <400> 48 Ser Gly Gly Gly Asn Asn 1 5 <210> 49 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR002075 HCDR2 Chothia, PR002076 HCDR2 Chothia <400> 49 Ser Gly Ser Gly Gly Asn 1 5 <210> 50 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR002077 HCDR2 Chothia <400> 50 Ser Gly Arg Gly Asn Ile 1 5 <210> 51 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR002408 HCDR2 Chothia <400> 51 Ser Tyr Asp Ala Ser Asn 1 5 <210> 52 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR002726 HCDR2 Chothia <400> 52 Ser Gly Ser Gly Arg Ser 1 5 <210> 53 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR003475 HCDR2 Chothia <400> 53 Tyr Pro Asp Asn Gly Asp 1 5 <210> 54 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR005364 HCDR2 Chothia, PR005378 HCDR2 Chothia, PR005379 HCDR2 Chothia <400> 54 Ser Gly Arg Gly Gly Gln 1 5 <210> 55 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR005365 HCDR2 Chothia, PR005380 HCDR2 Chothia, PR005381 HCDR2 Chothia <400> 55 Ser Gly Leu Gly Gly Gln 1 5 <210> 56 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> PR005366 HCDR2 Chothia, PR005382 HCDR2 Chothia, PR005383 HCDR2 Chothia <400> 56 Ser Gly Arg Ser Gly Gln 1 5 <210> 57 <211> 6 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005368 HCDR2 Chothia <400> 57 Ser Gly Leu Gly Gly Ser 1 5 <210> 58 <211> 6 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005369 HCDR2 Chothia <400> 58 Thr Gly Arg Gly Gly Gln 1 5 <210> 59 <211> 6 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005370 HCDR2 Chothia <400> 59 Ser Gly His Gly Gly Thr 1 5 <210> 60 <211> 6 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005371 HCDR2 Chothia <400> 60 Ser Gly Arg Gly Gly Thr 1 5 <210> 61 <211> 41 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR000265 HFWR3 Chothia <400> 61 Lys Tyr Tyr Val Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp 1 5 10 15 Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Ala Arg 35 40 <210> 62 <211> 41 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR001081 HFWR3 Chothia <400> 62 Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ala Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Ala Arg 35 40 <210> 63 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR001331 HFWR3 Chothia <400> 63 Lys Tyr Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Ala Arg 35 40 <210> 64 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR002055 HFWR3 Chothia, PR002061 HFWR3 Chothia, PR002075 HFWR3 Chothia <400> 64 Thr Tyr Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Ala Asn 35 40 <210> 65 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR002056 HFWR3 Chothia, PR002068 HFWR3 Chothia, PR002071 HFWR3 Chothia <400> 65 Ile Phe Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Ala Asn 35 40 <210> 66 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR002057 HFWR3 Chothia, PR002058 HFWR3 Chothia, PR002073 HFWR3 Chothia <400> 66 Thr Phe Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Ala Asp 35 40 <210> 67 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR002059 HFWR3 Chothia, PR002066 HFWR3 Chothia, PR002069 HFWR3 Chothia <400> 67 Thr Phe Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Ala Asn 35 40 <210> 68 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR002060 HFWR3 Chothia <400> 68 Thr Tyr Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Thr Ser Leu Arg Ala Glu 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Ala Asn 35 40 <210> 69 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR002062 HFWR3 Chothia, PR002063 HFWR3 Chothia, PR002064 HFWR3 Chothia <400> 69 Thr Phe Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Ala Asn 35 40 <210> 70 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR002065 HFWR3 Chothia <400> 70 Thr Phe Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 20 25 30 Asp Thr Ala Leu Tyr Tyr Cys Ala Asn 35 40 <210> 71 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR002067 HFWR3 Chothia, PR005362 HFWR3 Chothia, PR005363 HFWR3 Chothia <400> 71 Thr Phe Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 20 25 30 Asp Thr Ala Met Tyr Tyr Cys Val Asp 35 40 <210> 72 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR002070 HFWR3 Chothia <400> 72 Thr Phe Tyr Ala Asp Ser Val Arg Gly Arg Phe Asn Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Val Glu 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Ala Asn 35 40 <210> 73 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR002072 HFWR3 Chothia <400> 73 Thr Tyr Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Asp 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Ala Asn 35 40 <210> 74 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR002074 HFWR3 Chothia <400> 74 Thr Phe Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Met Arg 35 40 <210> 75 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR002408 HFWR3 Chothia <400> 75 Glu Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asp Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Gly 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Ala Lys 35 40 <210> 76 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR002726 HFWR3 Chothia <400> 76 Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu His Leu Gln Met Asn Ser Leu Arg Ala Glu 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Ala Lys 35 40 <210> 77 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR003475 HFWR3 Chothia <400> 77 Ser Ser Tyr Asn Gln Lys Phe Arg Glu Arg Val Thr Ile Thr Arg Asp 1 5 10 15 Thr Ser Thr Ser Thr Ala Tyr Leu Glu Leu Ser Ser Leu Arg Ser Glu 20 25 30 Asp Thr Ala Val Tyr Tyr Cys Val Leu 35 40 <210> 78 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> PR005364 HFWR3 Chothia, PR005365 HFWR3 Chothia, PR005366 HFWR3 Chothia <400> 78 Ile Phe Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Arg Asp 1 5 10 15 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 20 25 30 Asp Thr Ala Met Tyr Tyr Cys Val Asp 35 40 <210> 79 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR000265 HCDR3 Chothia <400> 79 Asp Arg Ala Val Ala Gly Ala Phe Asp Ile 1 5 10 <210> 80 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> PR001081 HCDR3 Chothia <400> 80 Glu Met Ala Ala Ala Gly Phe Tyr Leu 1 5 <210> 81 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> PR001331 HCDR3 Chothia <400> 81 Gly Pro Gly Tyr Gly Gly His Ser Asp Ala Phe Asp Ile 1 5 10 <210> 82 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR002055 HCDR3 Chothia, PR002059 HCDR3 Chothia, PR002068 HCDR3 Chothia <400> 82 Gly Met Thr Gly Ser Thr Asp Val Asp Tyr 1 5 10 <210> 83 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR002056 HCDR3 Chothia, PR002057 HCDR3 Chothia, PR002060 HCDR3 Chothia <400> 83 Gly Met Thr Gly Thr Thr Asp Val Asp Tyr 1 5 10 <210> 84 <211> 9 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002058 HCDR3 Chothia, PR002073 HCDR3 Chothia <400> 84 Gly Val Thr Gly Thr Asp Phe Asp Phe 1 5 <210> 85 <211> 10 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002065 HCDR3 Chothia <400> 85 Gly Met Thr Gly Ser Thr Asp Val Asp Phe 1 5 10 <210> 86 <211> 10 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002067 HCDR3 Chothia, PR005362 HCDR3 Chothia, PR005363 HCDR3 Chothia <400> 86 Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr 1 5 10 <210> 87 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR002069 HCDR3 Chothia <400> 87 Gly Val Thr Gly Thr Thr Asp Val Asp Tyr 1 5 10 <210> 88 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR002072 HCDR3 Chothia <400> 88 Gly Met Thr Gly Thr Thr Asp Val Asp Phe 1 5 10 <210> 89 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> PR002074 HCDR3 Chothia <400> 89 Gly Trp Glu Leu Pro Leu Leu Glu Asn 1 5 <210> 90 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR002075 HCDR3 Chothia, PR002077 HCDR3 Chothia <400> 90 Gly lie Thr Gly Thr Thr Asp Val Asp Tyr 1 5 10 <210> 91 <211 > 10 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002408 HCDR3 Chothia <400> 91 Gly Gly Gly Leu Arg Trp Tyr Phe Ala Tyr 1 5 10 <210> 92 <211 > 11 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002726 HCDR3 Chothia <400> 92 Asp Ala Ala Ala Ala Gly Thr Lys Phe Asp Tyr 1 5 10 <210> 93 <211 > 8 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR003475 HCDR3 Chothia <400> 93 Ala Pro Arg Trp Tyr Phe Ser Val 1 5 <210> 94 <211 > 10 <212> PRT <213> Artificial Sequence <220> <223> PR005372 HCDR3 Chothia <400> 94 Gly Thr Thr Gly Ser Trp Asp Val Cys Tyr 1 5 10 <210> 95 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR005373 HCDR3 Chothia, PR005378 HCDR3 Chothia, PR005380 HCDR3 Chothia <400> 95 Gly Thr Thr Gly Thr Trp Asp Val Asp Trp 1 5 10 <210> 96 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR005374 HCDR3 Chothia <400> 96 Gly Thr Thr Gly Ser Trp Asp Val Asp Trp 1 5 10 <210> 97 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR005375 HCDR3 Chothia, PR005379 HCDR3 Chothia, PR005381 HCDR3 Chothia <400> 97 Gly Thr Thr Gly Ser Tyr Asp Val Asp Trp 1 5 10 <210> 98 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR005376 HCDR3 Chothia <400> 98 Gly Thr Thr Gly Ser Thr Asp Val Asp Trp 1 5 10 <210> 99 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR005377 HCDR3 Chothia, PR005388 HCDR3 Chothia, PR005389 HCDR3 Chothia <400> 99 Gly Thr Thr Gly Thr Trp Asp Val Asp Tyr 1 5 10 <210> 100 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> PR000265 HFWR4 Chothia, PR001331 HFWR4 Chothia <400> 100 Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 1 5 10 <210> 101 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> PR001081 HFWR4 Chothia <400> 101 Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 102 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> PR002055 HFWR4 Chothia, PR002056 HFWR4 Chothia, PR002057 HFWR4 Chothia <400> 102 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 103 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> PR002063 HFWR4 Chothia, PR002075 HFWR4 Chothia, PR002076 HFWR4 Chothia <400> 103 Trp Gly Gln Gly Thr Arg Val Thr Val Ser Ser 1 5 10 <210> 104 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> PR002066 HFWR4 Chothia, PR002068 HFWR4 Chothia <400> 104 Trp Gly Gin Gly Thr Gin Val Thr Val Ser Ser 1 5 10 <210> 105 <211 > 11 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002072 HFWR4 Chothia <400> 105 Trp Gly Gin Gly Thr Pro Val Thr Val Ser Ser 1 5 10 <210> 106 <211 > 23 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR000265 LFWR1 Chothia <400> 106 Asp He Gin Met Thr Gin Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Val Thr Cys 20 <210> 107 <211 > 23 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR001081 LFWR1 Chothia, PR002726 LFWR1 Chothia <400> 107 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys 20 <210> 108 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> PR001331 LFWR1 Chothia <400> 108 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ile Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> 109 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> PR002408 LFWR1 Chothia <400> 109 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys 20 <210> 110 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> PR003475 LFWR1 Chothia <400> 110 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> 111 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> PR000265 LCDR1 Chothia <400> 111 Arg Ala Ser Gln Ser Ile Tyr Ile Trp Leu Ala 1 5 10 <210> 112 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> PR001081 LCDR1 Chothia, PR002726 LCDR1 Chothia <400> 112 Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala 1 5 10 <210> 113 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> PR001331 LCDR1 Chothia <400> 113 Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asn 1 5 10 <210> 114 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> PR002408 LCDR1 Chothia <400> 114 Arg Ala Ser Gin Ser lie Ser Ser Asn Leu Gly 1 5 10 <210> 115 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> PR003475 LCDR1 Chothia <400> 115 Arg Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn 1 5 10 <210> 116 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> PR000265 LFWR2 Chothia <400> 116 Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie Tyr 1 5 10 15 <210> 117 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> PR001081 LFWR2 Chothia, PR002408 LFWR2 Chothia, PR002726 LFWR2 Chothia <400> 117 Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie Tyr 1 5 10 15 <210> 118 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> PR001331 LFWR2 Chothia, PR003475 LFWR2 Chothia <400> 118 Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr 1 5 10 15 <210> 119 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR000265 LCDR2 Chothia <400> 119 Lys Ala Ser Ser Leu Glu Thr 1 5 <210> 120 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR001081 LCDR2 Chothia, PR002726 LCDR2 Chothia <400> 120 Asp Ala Ser Asn Arg Ala Thr 1 5 <210> 121 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR001331 LCDR2 Chothia <400> 121 Thr Ala Ser Ser Leu Leu Ser 1 5 <210> 122 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR002408 LCDR2 Chothia <400> 122 Gly Ala Ser Thr Arg Ala Thr 1 5 <210> 123 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> PR003475 LCDR2 Chothia <400> 123 Tyr Thr Ser Arg Leu Arg Ser 1 5 <210> 124 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> PR000265 LFWR3 Chothia <400> 124 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 <210> 125 <211> 32 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR001081 LFWR3 Chothia, PR002726 LFWR3 Chothia <400> 125 Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys 20 25 30 <210> 126 <211> 32 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR001331 LFWR3 Chothia <400> 126 Gly Val Pro Ser Arg Phe Ser Ala Ser Gly Ser Trp Thr Asp Phe Ser 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 <210> 127 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> PR002408 LFWR3 Chothia <400> 127 Gly lie Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr 1 5 10 15 Leu Thr lie Ser Ser Leu Gin Ser Glu Asp Phe Ala Val Tyr Tyr Cys 20 25 30 <210> 128 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> PR003475 LFWR3 Chothia <400> 128 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 <210> 129 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> PR000265 LCDR3 Chothia <400> 129 Gln Gin Tyr Tyr Gly Ser Ser Arg Thr 1 5 <210> 130 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR001081 LCDR3 Chothia <400> 130 Gln Gln Arg Ser Asn Trp Pro Pro Ile Thr 1 5 10 <210> 131 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> PR001331 LCDR3 Chothia <400> 131 Gln Gln Ser Phe Ser Thr Pro Tyr Thr 1 5 <210> 132 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR002408 LCDR3 Chothia <400> 132 Gln Gln Tyr Gln Ser Trp Pro Pro Leu Thr 1 5 10 <210> 133 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> PR002726 LCDR3 Chothia <400> 133 Gln Gln Arg Ser Asn Trp Pro Leu Thr 1 5 <210> 134 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> PR003475 LCDR3 Chothia <400> 134 Gln Gln Gly His Thr Leu Pro Pro Thr 1 5 <210> 135 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR000265 LFWR4 Chothia, PR003475 LFWR4 Chothia <400> 135 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 1 5 10 <210> 136 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR001081 LFWR4 Chothia <400> 136 Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 1 5 10 <210> 137 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> PR001331 LFWR4 Chothia <400> 137 Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys 1 5 10 <210> 138 <211> 10 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002408 LFWR4 Chothia, PR002726 LFWR4 Chothia <400> 138 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 1 5 10 <210> 139 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR000265 VH <400> 139 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Gln Glu Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Ala Val Ala Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 <210> 140 <211> 118 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR001081 VH <400> 140 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Asp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Met Ala Ala Ala Gly Phe Tyr Leu Trp Gly Arg Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 141 <211> 122 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR001331 VH <400> 141 Gln Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ile Asn Tyr 20 25 30 Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Gly Gly His Ser Asp Ala Phe Asp Ile Trp 100 105 110 Gly Gin Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 142 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002055 VH <400> 142 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Ala Ile Ser Gly Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Ser Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 143 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002056 VH <400> 143 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Gly Gly Gly Ser Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 144 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002057 VH <400> 144 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Gly Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asp Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 145 <211> 118 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002058 VH <400> 145 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Gly Ser Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asp Gly Val Thr Gly Thr Asp Phe Asp Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 146 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR002059 VH <400> 146 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Val Ser Gly Leu Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Arg Glu Trp Val 35 40 45 Ser Ala lie Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Ser Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 147 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR002060 VH <400> 147 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Thr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 148 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR002061 VH <400> 148 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 149 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR002062 VH <400> 149 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Gln Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 150 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR002063 VH <400> 150 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Gly Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Arg Val Thr Val Ser Ser 115 <210> 151 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR002064 VH <400> 151 Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Gin Glu Trp Val 35 40 45 Ser Ala He Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 152 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002065 VH <400> 152 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Asp Ile Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Ser Thr Asp Val Asp Phe Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 153 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR002066 VH <400> 153 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ile Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Gin Val Thr Val Ser Ser 115 <210> 154 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002067 VH <400> 154 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 155 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002068 VH <400> 155 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala lie Ser Gly Gly Gly Gly Ser lie Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Ser Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Gin Val Thr Val Ser Ser 115 <210> 156 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002069 VH <400> 156 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Arg Glu Trp Val 35 40 45 Ser Ala lie Ser Gly Gly Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Val Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 157 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002070 VH <400> 157 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ile Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Asn Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 158 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002071 VH <400> 158 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Gly Gly Gly Ser Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 159 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002072 VH <400> 159 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Ser Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Phe Trp Gly Gln Gly 100 105 110 Thr Pro Val Thr Val Ser Ser 115 <210> 160 <211> 118 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002073 VH <400> 160 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Gly Ser Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asp Gly Val Thr Gly Thr Asp Phe Asp Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 161 <211> 118 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002074 VH <400> 161 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Gly Gly Gly Asn Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Met Arg Gly Trp Glu Leu Pro Leu Leu Glu Asn Trp Gly Gin Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 162 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR002075 VH <400> 162 Glu Val Gin Leu Val Glu Thr Gly Gly Gly Leu He Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly He Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly Gly Gin Gly 95 100 105100 105 110 Thr Arg Val Thr Val Ser Ser 115 <210> 163 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR002076 VH <400> 163 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Arg Val Thr Val Ser Ser 115 <210> 164 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR002077 VH <400> 164 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Asn He Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly He Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 165 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR002408 VH <400> 165 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Ala Ser Asn Glu Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ile Ile Ser Arg Asp Asn Ser Lys Asp Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Gly Gly Leu Arg Trp Tyr Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 166 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> PR002726 VH <400> 166 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30 Val Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr He Ser Gly Ser Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu His 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ala Ala Ala Ala Gly Thr Lys Phe Asp Tyr Trp Gly Gin 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 167 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> PR003475 VH <400> 167 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Ser 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Asp Met Tyr Pro Asp Asn Gly Asp Ser Ser Tyr Asn Gln Lys Phe 50 55 60 Arg Glu Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Leu Ala Pro Arg Trp Tyr Phe Ser Val Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 168 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR005362 VH <400> 168 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Pro Phe Asp Cys Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 169 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005363 VH <400> 169 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Pro Phe Asp Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 170 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR005364 VH <400> 170 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Gly Gin He Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 171 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005365 VH <400> 171 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Leu Gly Gly Gin He Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 172 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005366 VH <400> 172 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala lie Ser Gly Arg Ser Gly Gin lie Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 173 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005367 VH <400> 173 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala lie Ser Gly Gly Gly Gly Ser lie Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 174 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005368 VH <400> 174 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Leu Gly Gly Ser Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 175 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR005369 VH <400> 175 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Gly Arg Gly Gly Gln Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr ​​​​​​​​​​​​​​​​​​​​​​​65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 176 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005370 VH <400> 176 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly His Gly Gly Thr He Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 177 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005371 VH <400> 177 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Thr Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 178 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005372 VH <400> 178 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Ser Trp Asp Val Cys Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 179 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005373 VH <400> 179 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Trp Asp Val Asp Trp Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 180 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR005374 VH <400> 180 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Ser Trp Asp Val Asp Trp Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 181 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR005375 VH <400> 181 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Ser Tyr Asp Val Asp Trp Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 182 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR005376 VH <400> 182 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Ser Thr Asp Val Asp Trp Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 183 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR005377 VH <400> 183 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Trp Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 184 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR005378 VH <400> 184 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Gln Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Trp Asp Val Asp Trp Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 185 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR005379 VH <400> 185 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Gln Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Ser Tyr Asp Val Asp Trp Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 186 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR005380 VH <400> 186 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Leu Gly Gly Gln Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Trp Asp Val Asp Trp Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 187 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR005381 VH <400> 187 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Leu Gly Gly Gln Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Ser Tyr Asp Val Asp Trp Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 188 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR005382 VH <400> 188 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Ser Gly Gin He Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Trp Asp Val Asp Trp Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 189 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005383 VH <400> 189 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Ser Gly Gln Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Ser Tyr Asp Val Asp Trp Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 190 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> PR005384 VH <400> 190 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Pro Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala lie Ser Gly Arg Gly Gly Gin lie Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 191 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005385 VH <400> 191 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Asp Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala lie Ser Gly Arg Gly Gly Gin lie Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 192 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005386 VH <400> 192 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Asp Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Gln Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 193 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005387 VH <400> 193 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Pro Phe Asp Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Gln Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 194 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005388 VH <400> 194 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Gly Gin He Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Trp Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 195 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005389 VH <400> 195 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Pro Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Gin Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Trp Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 196 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005390 VH <400> 196 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Asp Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Gln Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 197 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005391 VH <400> 197 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Asp Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Gly Gin He Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Trp Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 198 <211> 119 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005392 VH <400> 198 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Pro Phe Asp Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Gln Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Trp Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 199 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> PR000265 VL <400> 199 Asp Ile Gin Met Thr Gin Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Val Thr Cys Arg Ala Ser Gin Ser Ile Tyr Ile Trp 20 25 30 Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Ser Leu Gin Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gin Phe Thr Leu Thr Ile Ser Ser Leu Gin Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Tyr Gly Ser Ser Arg 85 90 95 Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys 100 105 <210> 200 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> PR001081 VL <400> 200 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 201 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> PR001331 VL <400> 201 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ile Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Ser Leu Leu Ser Gly Val Pro Ser Arg Phe Ser Ala 50 55 60 Ser Gly Ser Trp Thr Asp Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Phe Ser Thr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys 100 105 <210> 202 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> PR002408 VL <400> 202 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Asn 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 203 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> PR002726 VL <400> 203 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 204 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> PR003475 VL <400> 204 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu Arg Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly His Thr Leu Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 205 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> PR000265 HC <400> 205 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Gln Glu Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Ala Val Ala Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 206 <211> 448 <212> PRT <213> Artificial Sequence <220> <223> PR001081 HC <400> 206 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Asp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Met Ala Ala Ala Gly Phe Tyr Leu Trp Gly Arg Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gin Thr Tyr He Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 207 <211> 452 <212> PRT <213> Artificial Sequence <220> <223> PR001331 HC <400> 207 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ile Asn Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Gly Gly His Ser Asp Ala Phe Asp Ile Trp 100 105 110 Gly Gin Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Pro Gly Lys 450 <210> 208 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002055 HC <400> 208 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Ala Ile Ser Gly Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Ser Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 209 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002056 HC <400> 209 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Gly Gly Gly Ser He Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 210 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002057 HC <400> 210 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Gly Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asp Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 211 <211> 350 <212> PRT <213> Artificial Sequence <220> <223> PR002058 HC <400> 211 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Gly Ser Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asp Gly Val Thr Gly Thr Asp Phe Asp Phe Trp Gly Gin Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr 115 120 125 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 130 135 140 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr Pro 145 150 155 160 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 165 170 175 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 180 185 190 Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 195 200 205 Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 210 215 220 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 225 230 235 240 Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro 245 250 255 Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val 260 265 270 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 275 280 285 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 290 295 300 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 305 310 315 320 Gln Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 325 330 335 Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 212 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002059 HC <400> 212 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Val Ser Gly Leu Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Arg Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Ser Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 213 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002060 HC <400> 213 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Thr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 214 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002061 HC <400> 214 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 215 <211> 351 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002062 HC <400> 215 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Gln Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 216 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002063 HC <400> 216 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Gly Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Arg Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 217 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002064 HC <400> 217 Glu Val Gin Leu Val Glu Thr Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Gin Glu Trp Val 35 40 45 Ser Ala He Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 218 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002065 HC <400> 218 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Asp Ile Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Ser Thr Asp Val Asp Phe Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 219 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002066 HC <400> 219 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys lie Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala lie Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Gin Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 220 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002067 HC <400> 220 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 221 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002068 HC <400> 221 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Gly Gly Gly Ser He Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Ser Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Gin Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 222 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002069 HC <400> 222 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Arg Glu Trp Val 35 40 45 Ser Ala He Ser Gly Gly Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Val Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 223 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002070 HC <400> 223 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ile Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Asn lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Gin Val Thr Cys Val Val Val Asp Val Ser His Gin Asp Pro Gin 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 224 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002071 HC <400> 224 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Gly Gly Gly Ser He Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 225 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002072 HC <400> 225 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Ser Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Phe Trp Gly Gin Gly 100 105 110 Thr Pro Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 226 <211> 350 <212> PRT <213> Artificial Sequence <220> <223> PR002073 HC <400> 226 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Gly Ser Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asp Gly Val Thr Gly Thr Asp Phe Asp Phe Trp Gly Gin Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr 115 120 125 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 130 135 140 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr Pro 145 150 155 160 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 165 170 175 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 180 185 190 Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 195 200 205 Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 210 215 220 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 225 230 235 240 Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro 245 250 255 Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val 260 265 270 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 275 280 285 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 290 295 300 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 305 310 315 320 Gln Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 325 330 335 Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 227 <211> 350 <212> PRT <213> Artificial Sequence <220> <223> PR002074 HC <400> 227 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly He Ser Gly Gly Gly Asn Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Met Arg Gly Trp Glu Leu Pro Leu Leu Glu Asn Trp Gly Gin Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr 115 120 125 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 130 135 140 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 145 150 155 160 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 165 170 175 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 180 185 190 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 195 200 205 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 210 215 220 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 225 230 235 240 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 245 250 255 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 260 265 270 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 275 280 285 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 290 295 300 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 305 310 315 320 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 325 330 335 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 228 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002075 HC <400> 228 Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Ile Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Ile Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Arg Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 229 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR002076 HC <400> 229 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Met Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Arg Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 230 <211> 351 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR002077 HC <400> 230 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Asn Ile Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly lie Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 231 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> PR002408 HC <400> 231 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe 20 25 30 Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val He Ser Tyr Asp Ala Ser Asn Glu Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe He He Ser Arg Asp Asn Ser Lys Asp Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Gly Gly Leu Arg Trp Tyr Phe Ala Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gin Thr Tyr He Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro He Glu Lys 325 330 335 Thr He Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 232 <211> 450 <212> PRT <213> Artificial Sequence <220> <223> PR002726 HC <400> 232 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30 Val Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr lie Ser Gly Ser Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu His 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ala Ala Ala Ala Gly Thr Lys Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro He Glu 325 330 335 Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 233 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> PR003475 HC <400> 233 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Ser 20 25 30 Tyr Met Ser Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp He 35 40 45 Gly Asp Met Tyr Pro Asp Asn Gly Asp Ser Ser Tyr Asn Gin Lys Phe 50 55 60 Arg Glu Arg Val Thr He Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Leu Ala Pro Arg Trp Tyr Phe Ser Val Trp Gly Gin Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 234 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR005362 HC <400> 234 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Pro Phe Asp Cys Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 235 <211> 351 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005363 HC <400> 235 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Pro Phe Asp Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 236 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR005364 HC <400> 236 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala lie Ser Gly Arg Gly Gly Gin lie Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 237 <211> 351 <212> PRT <213> Artificial Sequence​​​​​​​​​ <220> <223> PR005365 HC <400> 237 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Leu Gly Gly Gin He Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 238 <211> 351 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <223> PR005366 HC <400> 238 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Ser Gly Gln Ile Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp He Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 239 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR005367 HC <400> 239 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Gly Gly Gly Ser He Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 240 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR005368 HC <400> 240 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala He Ser Gly Leu Gly Gly Ser He Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 165 170 175 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 180 185 190 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 195 200 205 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 210 215 220 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 225 230 235 240 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 245 250 255 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 260 265 270 Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 275 280 285 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 290 295 300 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 305 310 315 320 Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 325 330 335 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 350 <210> 241 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> PR005369 HC <400> 241 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala lie Thr Gly Arg Gly Gly Gin lie Phe Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Asp Gly Thr Thr Gly Thr Thr Asp Val Asp Tyr Trp Gly Gin Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys Asp Lys Thr His 115 120 125 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 130 135 140 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr 145 150 155 160 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Gin Asp Pro Glu 165 170 175 Val...

Claims

1. An antibody or antigen-binding fragment thereof targeting OX40, characterized in that, which comprises a heavy chain variable region (VH), wherein the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 10, 44, and 86, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 13, 42, and 82, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 10, 42, and 83, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 14, 42, and 83, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 10, 43, and 84, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 13, 44, and 82, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 15, 44, and 83, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 10, 44, and 83, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 10, 45, and 83, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 10, 46, and 85, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 16, 42, and 82, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 10, 47, and 87, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 16, 44, and 83, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 10, 45, and 88, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 10, 48, and 89, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 49, and 90, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 49, and 83, respectively; or, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 50, and 90, respectively.

2. The antibody or antigen-binding fragment thereof targeting OX40 of claim 1, wherein, the VH comprises any one of the amino acid sequences set forth in SEQ ID NOs: 142-164.

3. The antibody or antigen-binding fragment thereof targeting OX40 of claim 2, wherein, the antibody or antigen-binding fragment thereof targeting OX40 further comprises a heavy chain constant region Fc domain of a human antibody; the heavy chain constant region Fc domain of the human antibody comprises a heavy chain constant region Fc domain of human IgG1, IgG2, IgG3, or IgG4.

4. The antibody or antigen-binding fragment thereof targeting OX40 of claim 3, wherein, the antibody or antigen-binding fragment thereof targeting OX40 comprises a polypeptide chain comprising any one of the amino acid sequences set forth in SEQ ID NOs: 208-230.

5. The antibody or antigen-binding fragment thereof targeting OX40 of claim 1 or 2, wherein the antibody or antigen-binding fragment thereof targeting OX40 comprises a HCAb, a VH, a bispecific antibody, a multispecific antibody, a single domain antibody, or any other antibody that retains partial ability of the antibody to specifically bind to an antigen, or a monoclonal antibody or polyclonal antibody prepared from the aforementioned antibody.

6. A bispecific binding protein, characterized in that, which comprises at least two protein functional regions: a protein functional region A and a protein functional region B; the protein functional region A and the protein functional region B target different antigens, wherein the protein functional region B targets OX40, and the protein functional region A targets a non-OX40 antigen; the protein functional region B is selected from the antibody or antigen-binding fragment thereof targeting OX40 of any one of claims 1-5.

7. The bispecific binding protein of claim 6, wherein, the protein functional region A targets PD-L1, B7H4, PSMA, EPCAM, or CLDN18.

2.

8. The bispecific binding protein of claim 7, wherein, the protein functional region A is a PD-L1 antibody or antigen-binding fragment thereof, a B7H4 antibody or antigen-binding fragment thereof, a PSMA antibody or antigen-binding fragment thereof, an EPCAM antibody or antigen-binding fragment thereof, or a CLDN18.2 antibody or antigen-binding fragment thereof.

9. The bispecific binding protein of claim 8, wherein: the PD-L1 antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprising a VL CDR1, a VL CDR2, and a VL CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 111, 119, and 129, respectively, and the VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, the amino acid sequences of which are set forth in SEQ ID NOs: 10, 39, and 79, respectively; or, the EPCAM antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 112, 120, and 130, respectively, and a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 11, 40, and 80, respectively; or, the PSMA antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 113, 121, and 131, respectively, and a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 12, 41, and 81, respectively; or, the B7H4 antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 114, 122, and 132, respectively, and a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 17, 51, and 91, respectively; or, the CLDN18.2 antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 112, 120, and 133, respectively, and a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 18, 52, and 92, respectively.

10. The bispecific binding protein of claim 6, wherein, the protein functional region A is a PD-L1 antibody or antigen-binding fragment thereof comprising a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 111, 119, and 129, respectively, and a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 10, 39, and 79, respectively, and the protein functional region B comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are set forth in SEQ ID NOs: 10, 44, and 86, respectively; or, the protein functional region A is a B7H4 antibody or antigen-binding fragment thereof, comprising a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprising a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are shown in SEQ ID NOs: 114, 122, and 132, respectively, and the VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are shown in SEQ ID NOs: 17, 51, and 91, respectively; and the protein functional region B comprises a heavy chain variable region (VH), the VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are shown in SEQ ID NOs: 10, 44, and 86, respectively; or, the protein functional region A is a EPCAM antibody or antigen-binding fragment thereof, comprising a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprising a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are shown in SEQ ID NOs: 112, 120, and 130, respectively, and the VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are shown in SEQ ID NOs: 11, 40, and 80, respectively; and the protein functional region B comprises a heavy chain variable region (VH), the VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are shown in SEQ ID NOs: 10, 44, and 86, respectively; or, the protein functional region A is a PSMA antibody or antigen-binding fragment thereof, comprising a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprising a VL CDR1, a VL CDR2, and a VL CDR3, whose amino acid sequences are shown in SEQ ID NOs: 113, 121, and 131, respectively, and the VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are shown in SEQ ID NOs: 12, 41, and 81, respectively; and the protein functional region B comprises a heavy chain variable region (VH), the VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, whose amino acid sequences are shown in SEQ ID NOs: 10, 44, and 86, respectively; or, The protein functional region A is a CLDN18.2 antibody or antigen-binding fragment thereof, comprising a light chain variable region (VL) and a heavy chain variable region (VH), the VL comprising a VL CDR1, a VL CDR2 and a VL CDR3, the amino acid sequences of which are shown in SEQ ID NO: 112, 120 and 133 respectively, and the VH comprising a VH CDR1, a VH CDR2 and a VH CDR3, the amino acid sequences of which are shown in SEQ ID NO: 18, 52 and 92 respectively; the protein functional region B comprises a heavy chain variable region (VH), the VH comprising a VH CDR1, a VH CDR2 and a VH CDR3, the amino acid sequences of which are shown in SEQ ID NO: 10, 44 and 86 respectively.

11. The bispecific binding protein of claim 10, wherein, the protein functional region A comprises a light chain variable region (VL) comprising an amino acid sequence shown in SEQ ID NO: 199 and a heavy chain variable region (VH) comprising an amino acid sequence shown in SEQ ID NO: 139; and the protein functional region B comprises a heavy chain variable region (VH) comprising an amino acid sequence shown in SEQ ID NO: 154; or, the protein functional region A comprises a light chain variable region (VL) comprising an amino acid sequence shown in SEQ ID NO: 202 and a heavy chain variable region (VH) comprising an amino acid sequence shown in SEQ ID NO: 165; and the protein functional region B comprises a heavy chain variable region (VH) comprising an amino acid sequence shown in SEQ ID NO: 154; or, the protein functional region A comprises a light chain variable region (VL) comprising an amino acid sequence shown in SEQ ID NO: 200 and a heavy chain variable region (VH) comprising an amino acid sequence shown in SEQ ID NO: 140; and the protein functional region B comprises a heavy chain variable region (VH) comprising an amino acid sequence shown in SEQ ID NO: 154; or, the protein functional region A comprises a light chain variable region (VL) comprising an amino acid sequence shown in SEQ ID NO: 201 and a heavy chain variable region (VH) comprising an amino acid sequence shown in SEQ ID NO: 141; and the protein functional region B comprises a heavy chain variable region (VH) comprising an amino acid sequence shown in SEQ ID NO: 154; or, the protein functional region A comprises a light chain variable region (VL) comprising an amino acid sequence shown in SEQ ID NO: 203 and a heavy chain variable region (VH) comprising an amino acid sequence shown in SEQ ID NO: 166; and the protein functional region B comprises a heavy chain variable region (VH) comprising an amino acid sequence shown in SEQ ID NO:

154. the protein functional region A comprises a light chain variable region (VL) comprising an amino acid sequence shown in SEQ ID NO: 203 and a heavy chain variable region (VH) comprising an amino acid sequence shown in SEQ ID NO: 166; and the protein functional region B comprises a heavy chain variable region (VH) comprising an amino acid sequence shown in SEQ ID NO:

154.

12. The bispecific binding protein of claim 6, wherein, The protein functional region A is in the form of IgG, Fab, Fab', F(ab')2, Fv, scFv, VH, or HCAb.

13. The bispecific binding protein of claim 12, wherein, The number of the Fab, Fab', F(ab')2, Fv, scFv, VH is one or more.

14. The bispecific binding protein of claim 6 wherein, The protein functional region B is in the structure of a single VH, and the protein functional region A is in the structure of IgG.

15. The bispecific binding protein of claim 14, wherein, The protein functional region B is connected to the C-terminal end of the protein functional region A.

16. The bispecific binding protein of claim 14, wherein, The bispecific binding protein comprises a first polypeptide chain and a second polypeptide chain, the first polypeptide chain is as shown in the formula: N'-VL_A-CL-C', and the second polypeptide chain is as shown in the formula: N'-VH_A-CH1-h-CH2-CH3-L-VH_B-C'; The VH_B is the VH of the protein functional region B, the VL_A and the VH_A are respectively the VL and the VH of the protein functional region A, and the h is a hinge region.

17. The bispecific binding protein of claim 16, wherein, The amino acid sequence of the L is as shown in any one of SEQ ID NO. 278-295, or the amino acid sequence thereof is GS.

18. The bispecific binding protein of claim 16, wherein, The length of the L is 0.

19. The bispecific binding protein of claim 6 wherein, The protein functional region B is in the structure of HCAb, and the protein functional region A is in the structure of Fab.

20. The bispecific binding protein of claim 19, wherein, The protein functional region B is connected to the C-terminal end of the protein functional region A.

21. The bispecific binding protein of claim 19, wherein: The bispecific binding protein comprises a first polypeptide chain and a second polypeptide chain, the first polypeptide chain is as shown in the formula: N'-VH_A-CH1-C', and the second polypeptide chain is as shown in the formula: N'-VL_A-CL-L1-VH_B-L2-CH2-CH3-C'; Or, the bispecific binding protein comprises a first polypeptide chain and a second polypeptide chain, the first polypeptide chain is as shown in the formula: N'-VL_A-CL-C', and the second polypeptide chain is as shown in the formula: N'-VH_A-CH1-L1-VH_B-L2-CH2-CH3-C'; The VH_B is the VH of the protein functional region B, the VL_A and the VH_A are respectively the VL and the VH of the protein functional region A, and the L1 and the L2 are connecting peptides.

22. The bispecific binding protein of claim 21, wherein, The amino acid sequence of the L1 or the L2 is as shown in any one of SEQ ID NO. 278-295, or the amino acid sequence thereof is GS.

23. The bispecific binding protein of claim 22, wherein, The amino acid sequence of the L1 is as shown in SEQ ID NO. 286, and the amino acid sequence of the L2 is as shown in SEQ ID NO.

285.

24. The bispecific binding protein of claim 21, wherein, The length of the L1 or the L2 is 0.

25. The bispecific binding protein of any one of claims 6-24, wherein, The bispecific binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein, the first polypeptide chain comprises an amino acid sequence as shown in SEQ ID NO: 265, and the second polypeptide chain comprises an amino acid sequence as shown in SEQ ID NO: 271; or, the first polypeptide chain comprises an amino acid sequence as shown in SEQ ID NO: 268, and the second polypeptide chain comprises an amino acid sequence as shown in SEQ ID NO: 272; or, the first polypeptide chain comprises an amino acid sequence as set forth in SEQ ID NO: 273, and the second polypeptide chain comprises an amino acid sequence as set forth in SEQ ID NO: 274; or, the first polypeptide chain comprises an amino acid sequence as set forth in SEQ ID NO: 266, and the second polypeptide chain comprises an amino acid sequence as set forth in SEQ ID NO: 275; or, the first polypeptide chain comprises an amino acid sequence as set forth in SEQ ID NO: 267, and the second polypeptide chain comprises an amino acid sequence as set forth in SEQ ID NO: 276; or, the first polypeptide chain comprises an amino acid sequence as set forth in SEQ ID NO: 269, and the second polypeptide chain comprises an amino acid sequence as set forth in SEQ ID NO:

277.

26. A chimeric antigen receptor, characterized in that, the antibody or antigen-binding fragment thereof targeting OX40 or the bispecific binding protein according to any one of claims 1-25.

27. An immune cell, wherein, the chimeric antigen receptor according to claim 26.

28. An isolated nucleic acid encoding the antibody or antigen-binding fragment thereof targeting OX40 or the bispecific binding protein according to any one of claims 1-25 or the chimeric antigen receptor according to claim 26.

29. A recombinant expression vector comprising the isolated nucleic acid according to claim 28.

30. The recombinant expression vector of claim 29, wherein the expression vector comprises a eukaryotic cell expression vector and / or a prokaryotic cell expression vector.

31. A transformant comprising the isolated nucleic acid according to claim 28 or the recombinant expression vector according to claim 29 or 30.

32. The transformant of claim 31, wherein, the host cell of the transformant is a prokaryotic cell and / or a eukaryotic cell.

33. The transformant of claim 32, wherein, the prokaryotic cell is an E. coli cell, and the eukaryotic cell is a HEK293 cell or a CHO cell.

34. The transformant of claim 33, wherein the E. coli cell is a TG1 cell or a BL21 cell.

35. A method for preparing an antibody or antigen-binding fragment thereof targeting OX40 or a bispecific binding protein, comprising culturing the transformant according to any one of claims 31-34, and obtaining the antibody or antigen-binding fragment thereof targeting OX40 or the bispecific binding protein from the culture.

36. An antibody drug conjugate, characterized in that, the antibody drug conjugate comprises an antibody moiety and a conjugated moiety, the antibody moiety comprising the antibody or antigen-binding fragment thereof targeting OX40 according to any one of claims 1-5 and / or the bispecific binding protein according to any one of claims 6-25, and the conjugated moiety comprising, but not limited to, a detectable label, a drug, a toxin, a cytokine, a radionuclide, an enzyme, or a combination thereof, the antibody moiety and the conjugated moiety being conjugated via a chemical bond or a linker.

37. A pharmaceutical composition comprising, the pharmaceutical composition comprises the antibody or antigen-binding fragment thereof targeting OX40 according to any one of claims 1-5, the bispecific binding protein according to any one of claims 6-25, and a pharmaceutically acceptable carrier.

38. The pharmaceutical composition of claim 37, wherein, the pharmaceutical composition further comprises another anti-tumor antibody as an active ingredient.

39. Use of the antibody or antigen-binding fragment thereof targeting OX40 of any one of claims 1-5, the bispecific binding protein of any one of claims 6-25, the chimeric antigen receptor of claim 26, the immune cell of claim 27, the antibody drug conjugate of claim 36, and / or the pharmaceutical composition of claim 37 or 38 in the manufacture of a medicament, a kit, and / or a drug delivery device for the diagnosis, prevention, and / or treatment of a tumor.

40. A method of detecting OX40 in a sample comprising using the antibody or antigen binding fragment thereof targeting OX40 of any one of claims 1-5 and / or the bispecific binding protein of any one of claims 6-25 for the detection; wherein, The method of detecting OX40 in the sample is for non-diagnostic purposes.

41. A kit characterized in that, The kit comprises the antibody or antigen-binding fragment thereof targeting OX40 of any one of claims 1-5, the bispecific binding protein of any one of claims 6-25, the chimeric antigen receptor of claim 26, the immune cell of claim 27, the antibody drug conjugate of claim 36, and / or the pharmaceutical composition of claim 37 or 38.

42. The kit of claim 41, wherein The kit further comprises an instruction.

43. A drug delivery device characterized in that, The drug delivery device comprises: (1) an infusion module comprising the pharmaceutical composition of claim 37 or 38, and (2) optionally, a pharmacodynamic monitoring module.

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