Anti-lilrb1 antibodies and uses thereof

Abstract

The present invention relates to an anti-LILRB1 antibody having improved specificity for LILRB1 and uses thereof. In particular, an anti-LILRB1 antibody or antigen binding fragment thereof and uses thereof in the treatment of cancer are provided.

Description

Technical Field

[0001] Cross-reference with related applications

[0002] This application claims the benefit of KR10-2020-0094053, filed with the Korean Intellectual Property Office on July 28, 2020, the entire disclosure of which is incorporated herein by reference.

[0003] This disclosure relates to an anti-LILRB1 antibody and its use. More specifically, it provides an anti-LILRB1 antibody or an antigen-binding fragment thereof and its use in cancer therapy. Background Technology

[0004] Leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1; also known as ILT2, CD85j, or LIR-1) is an inhibitory receptor expressed in cells such as B cells, T cells, NK cells, dendritic cells, macrophages, and other immune cells. LILRB1 participates in signal transduction mechanisms that inhibit immune cell activity by binding to both classical and non-classical class I MHC receptors.

[0005] Therefore, there is a need to develop substances that target LILRB1. Summary of the Invention

[0006] Technical issues

[0007] One embodiment provides an anti-LILRB1 antibody or an antigen-binding fragment thereof that binds to LILRB1. The anti-LILRB1 antibody or its antigen-binding fragment may have activity that inhibits immune escape from cancer cells. Furthermore, the anti-LILRB1 antibody or its antigen-binding fragment may have anti-cancer activity. This anti-cancer activity may target cancer cells that express or overexpress class I MHC on their surface.

[0008] Another embodiment provides a pharmaceutical composition for treating and / or preventing cancer, the composition comprising the anti-LILRB1 antibody or its antigen-binding fragment as an active ingredient. Another embodiment provides a method for treating and / or preventing cancer, the method comprising administering a pharmaceutically effective amount of the anti-LILRB1 antibody or its antigen-binding fragment to a subject in need. Another embodiment provides the use of the anti-LILRB1 antibody or its antigen-binding fragment for treating and / or preventing cancer or for preparing pharmaceutical compositions for treating and / or preventing cancer.

[0009] Another embodiment provides a pharmaceutical composition for inhibiting immune escape from cancer cells, the pharmaceutical composition comprising the anti-LILRB1 antibody or an antigen-binding fragment thereof. Another embodiment provides a method for inhibiting immune escape from cancer cells, the method comprising administering an effective amount of the anti-LILRB1 antibody or an antigen-binding fragment thereof to a subject who requires inhibition of immune escape from cancer cells. Another example provides the use of the anti-LILRB1 antibody or an antigen-binding fragment thereof for inhibiting immune escape from cancer cells or for preparing a pharmaceutical composition for inhibiting immune escape from cancer cells.

[0010] Technical solution

[0011] One embodiment provides an anti-LILRB1 antibody or an antigen-binding fragment thereof that binds to LILRB1. The anti-LILRB1 antibody or its antigen-binding fragment may have activity that inhibits immune escape from cancer cells. Furthermore, the anti-LILRB1 antibody or its antigen-binding fragment may have anti-cancer activity.

[0012] The anti-LILRB1 antibody or its antigen-binding fragment may include the following complementarity-determining region (CDR):

[0013] Based on the CDR definition according to Kabat numbering (Kabat, EA, Wu, TT, Perry, H., Gottesman, K. and Foeller, C. (1991), Sequences of Proteins of Immunological Interest, 5th edition, NIH Publication No. 91-3242; http: / / www.abysis.org / ),

[0014] CDR-L1 containing the amino acid sequence of SEQ ID NO: 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, or 217.

[0015] CDR-L2 containing the amino acid sequence of SEQ ID NO: 2, 14, 26, 38, 50, 62, 74, 86, 98, 110, 122, 134, 146, 158, 170, 182, 194, 206, or 218.

[0016] CDR-L3 containing the amino acid sequence of SEQ ID NO: 3, 15, 27, 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171, 183, 195, 207, or 219.

[0017] CDR-H1 containing the amino acid sequence of SEQ ID NO: 4, 16, 28, 40, 52, 64, 76, 88, 100, 112, 124, 136, 148, 160, 172, 184, 196, 208, or 220.

[0018] CDR-H2 containing the amino acid sequence of SEQ ID NO: 5, 17, 29, 41, 53, 65, 77, 89, 101, 113, 125, 137, 149, 161, 173, 185, 197, 209, or 221, and

[0019] CDR-H3 containing the amino acid sequence of SEQ ID NO: 6, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210 or 222.

[0020] In a particular embodiment, combinations of the six CDRs (CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3) that may be included in the anti-LILRB1 antibody or its antigen-binding fragment provided in this disclosure are shown in Table 1:

[0021] Table 1

[0022]

[0023]

[0024]

[0025]

[0026]

[0027] In one embodiment, the anti-LILRB1 antibody or its antigen-binding fragment may comprise:

[0028] Includes light chain variable regions of CDR-L1, CDR-L2, and CDR-L3, and

[0029] A heavy chain variable region comprising CDR-H1, CDR-H2 and CDR-H3, wherein the CDR is as described above.

[0030] In one embodiment, the anti-LILRB1 antibody or its antigen-binding fragment may comprise:

[0031] The light chain variable region containing the amino acid sequence of SEQ ID NO: 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 163, 175, 187, 199, 211, or 223, and

[0032] Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 9, 21, 33, 45, 57, 69, 81, 93, 105, 117, 129, 141, 153, 165, 177, 189, 201, 213 or 225.

[0033] In certain embodiments, combinations of light chain variable regions and heavy chain variable regions that may be included in the anti-LILRB1 antibody or its antigen-binding fragment provided in this disclosure are shown in Table 2:

[0034] Table 2

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041] In this disclosure, an antibody “containing or composed of a specific amino acid sequence” (e.g., CDR, variable region, or heavy / light chain) means all cases that substantially include the amino acid sequence and / or introduce non-significant mutations (e.g., substitution, deletion, and / or addition of amino acid residues) into the amino acid sequence that do not affect antibody activity.

[0042] When measured by surface plasmon resonance (SPR), the anti-LILRB1 antibody or its antigen-binding fragment provided in this disclosure can exhibit a resistance to LILRB1 (e.g., human LILRB1) of 10 mM or lower, 5 mM or lower, 1 mM or lower, 0.5 mM or lower, 0.2 mM or lower, 0.15 mM or lower, for example, 0.001 nM to 10 mM, 0.005 nM to 10 mM, 0.01 nM to 10 mM, ... 0.05 nM to 10 mM, 0.1 nM to 10 mM, 0.5 nM to 10 mM, 1 nM to 10 mM, 0.001 nM to 5 mM, 0.005 nM to 5 mM, 0.01 nM to 5 mM, 0.05 nM to 5 mM, 0.1 nM to 5 mM, 0.5 nM to 5 mM, 1 nM to 5 mM, 0.001 nM to 1 mM, 0.005 nM to 1 mM, 0.01 nM to 1 mM, 0.05 nM to 1mM, 0.1nM to 1mM, 0.5nM to 1mM, 1nM to 1mM, 0.001nM to 0.5mM, 0.005nM to 0.5mM, 0.01nM to 0.5mM, 0.05nM to 0.5mM, 0.1nM to 0.5mM, 0.5nM to 0.5mM, 1nM to 0.5mM, 0.001nM to 0.2mM, 0.005nM to 0.2mM, 0.01nM Binding affinity (K) of M to 0.2 mM, 0.05 nM to 0.2 mM, 0.1 nM to 0.2 mM, 0.5 nM to 0.2 mM, 1 nM to 0.2 mM, 0.001 nM to 0.15 mM, 0.005 nM to 0.15 mM, 0.01 nM to 0.15 mM, 0.05 nM to 0.15 mM, 0.1 nM to 0.15 mM, 0.5 nM to 0.15 mM, or 1 nM to 0.15 mM. D ).

[0043] Another embodiment provides a pharmaceutical composition comprising the anti-LILRB1 antibody or its antigen-binding fragment as an active ingredient. For example, the pharmaceutical composition may be a pharmaceutical composition for treating and / or preventing cancer. In one embodiment, the pharmaceutical composition may have activity that inhibits immune escape from cancer cells. The cancer cells may be cells that express or overexpress class I MHC on their cell surface.

[0044] Another embodiment provides a method for treating and / or preventing cancer, the method comprising administering (orally or parenterally) a pharmaceutically effective amount of the anti-LILRB1 antibody or its antigen-binding fragment to a subject (e.g., a mammal, including a human) who requires treatment and / or prevention of said cancer.

[0045] The methods provided in this disclosure may also include steps prior to the administration step of identifying subjects who require treatment and / or prevention of cancer and / or suppression of immune escape from cancer cells.

[0046] Another embodiment provides the use of the anti-LILRB1 antibody or its antigen-binding fragment for treating and / or preventing cancer or for preparing pharmaceutical compositions for treating and / or preventing cancer. Another example provides the use of the anti-LILRB1 antibody or its antigen-binding fragment for inhibiting immune escape from cancer cells or for preparing pharmaceutical compositions for inhibiting immune escape from cancer cells.

[0047] Another embodiment provides a nucleic acid molecule encoding at least one polypeptide selected from the following: the CDR of the above-mentioned anti-LILRB1 antibody (CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, CDR-H3, a combination of CDR-L1, CDR-L2 and CDR-L3 or a combination of CDR-H1, CDR-H2 and CDR-H3), comprising a light chain variable region of CDR-L1, CDR-L2 and CDR-L3, comprising a heavy chain variable region of CDR-H1, CDR-H2 and CDR-H3, a light chain comprising the light chain variable region, and a heavy chain comprising the heavy chain variable region.

[0048] Another embodiment provides a recombinant vector comprising the nucleic acid molecule. In one embodiment, the recombinant vector may comprise the light chain variable region or light chain and the heavy chain variable region or heavy chain separately (e.g., in two separate vectors) or together (e.g., in one vector). The recombinant vector may be an expression vector for expressing the light chain variable region or light chain and the heavy chain variable region or heavy chain in suitable cells.

[0049] Another embodiment provides a recombinant cell containing the nucleic acid molecule or recombinant vector.

[0050] Another embodiment provides a method for producing an anti-LILRB1 antibody or an antigen-binding fragment thereof, the method comprising expressing the antibody in the recombinant cells.

[0051] As described herein, the antigen-binding fragment of an anti-LILRB1 antibody can refer to a fragment derived from the anti-LILRB1 antibody and retaining the antigen (LILRB1) binding affinity of said antibody. In one embodiment, the antigen-binding fragment can be a polypeptide comprising the six CDRs of the anti-LILRB1 antibody as described above, and can be, for example, scFv, scFv-Fc, scFv-Cκ (κ constant region), scFv-Cλ (λ constant region), (scFv)2, Fab, Fab', or F(ab')2, but is not limited thereto.

[0052] The anti-LILRB1 antibody or its antigen-binding fragment may have regulatory activity on the LILRB1 protein, such as antagonistic or agonistic activity. Furthermore, the anti-LILRB1 antibody or its antigen-binding fragment may have activity that inhibits immune escape from cancer cells. Additionally, the anti-LILRB1 antibody or its antigen-binding fragment may have anti-cancer activity.

[0053] The LILRB1 protein that serves as the antigen of the anti-LILRB1 antibody or its antigen-binding fragment provided in this disclosure can be derived from mammals. For example, the LILRB1 antigen can be human LILRB1 (e.g., GenBank accession numbers NP_001265328.2, NP_001265327.2, NP_001075108.2, NP_001075107.2, NP_001075106.2, NP_006660.4, NM_001081637.2, NM_001081638.3, NM_001081639.3, NM_001278398.2, NM_001278399.2, etc.), but is not limited thereto.

[0054] Class I MHCs can be one of the classes of major histocompatibility complex (MHC) molecules. In one embodiment, the Class I MHC can be a human Class I MHC and can be selected from at least one of HLA (human leukocyte antigen)-A, HLA-B, HLA-C, HLA-E, HLA-F, and HLA-G, but is not limited thereto.

[0055] As described herein, the term "antibody" can refer to a protein that specifically binds to a particular antigen, and can be a protein produced in the immune system by stimulation of an antigen, or a protein produced through chemical synthesis or recombinant production, without particular limitation. The antibody may not be naturally occurring, for example, produced through recombinant or synthetic production. The antibody may be an animal antibody (e.g., a mouse antibody), a chimeric antibody, a humanized antibody, or a human antibody. The antibody may be a monoclonal or polyclonal antibody.

[0056] The anti-LILRB1 antibody or its antigen-binding fragment provided herein, except for the heavy chain CDR and light chain CDR portions or heavy chain variable and light chain variable regions as defined above, may be derived from any immunoglobulin subtype (e.g., IgA, IgD, IgE, IgG (IgG1, IgG2, IgG3, IgG4), IgM, etc.), and for example from the structural portions and / or light chain constant regions and / or heavy chain constant regions. In one embodiment, the anti-LILRB1 antibody provided herein may be an antibody in the form of human IgG such as IgG1, IgG2, IgG3, or IgG4, but is not limited thereto.

[0057] A complete antibody (e.g., IgG type) has a structure containing two full-length light chains and two full-length heavy chains, wherein each light chain is linked to a corresponding heavy chain via disulfide bonds. The constant regions of an antibody are divided into heavy chain constant regions and light chain constant regions. The heavy chain constant regions are of the γ, μ, α, δ, or ε type, and have γ1, γ2, γ3, γ4, α1, or α2 as their subclasses. The light chain constant regions are of the κ or λ type.

[0058] When used herein, the term "heavy chain" may be intended to cover a full-length heavy chain and fragments thereof, wherein the full-length heavy chain may comprise a variable region VH including an amino acid sequence sufficient to provide specificity for an antigen, three constant regions CH1, CH2, and CH3, and a hinge. The term "light chain" may be intended to cover a full-length light chain and fragments thereof, wherein the full-length light chain may comprise a variable region VL including an amino acid sequence sufficient to provide specificity for an antigen, and a constant region CL.

[0059] The term "complementarity-determining region (CDR)" can refer to a portion of the variable region of an antibody that provides antigen-binding specificity, and can refer to an amino acid sequence present in the hypervariable region of the heavy or light chain of an immunoglobulin. The heavy and light chains may each comprise three CDRs (CDRH1, CDRH2, and CDRH3; and CDRL1, CDRL2, and CDRL3). The CDRs can provide contact residues that play an important role in the binding of the antibody to its antigen or the epitope of the antigen. When used herein, the terms "specific binding" and "specific recognition" may have the same general meaning as known to those skilled in the art, and refer to the specific interaction between an antibody and an antigen to result in an immune response.

[0060] In this disclosure, unless otherwise stated, the term "antibody" can be understood as an antigen-binding fragment that has antigen-binding activity, including antibodies.

[0061] As used herein, the term "antigen-binding fragment" can refer to any type of polypeptide containing a portion capable of binding to an antigen (e.g., the six CDRs described herein), such as, but not limited to, scFv, (scFv)2, scFv-Fc, Fab, Fab′, or F(ab′)2. Furthermore, as stated above, the antigen-binding fragment can be scFv, or a fusion polypeptide wherein scFv is fused to the Fc region or constant region (e.g., κ or λ) of an immunoglobulin (e.g., IgA, IgD, IgE, IgG (IgG1, IgG2, IgG3, IgG4), IgM, etc.).

[0062] In the antigen-binding fragment, Fab has a structure containing a variable region of light and heavy chains, a constant region of light chains and a first constant region (CH1) of heavy chains, and has an antigen-binding site.

[0063] The difference between Fab′ and Fab is that Fab′ contains a hinge region with at least one cysteine ​​residue at the C-terminus of CH1.

[0064] F(ab′)2 antibody is formed through a disulfide bridge of cysteine ​​residues in the hinge region of Fab′.

[0065] Fv is the smallest antibody fragment consisting only of the heavy chain variable region and the light chain variable region. Recombinant techniques for generating Fv fragments are well known in the art.

[0066] Double-chain Fvs contain heavy-chain and light-chain variable regions linked together by non-covalent bonds. Single-chain Fvs typically contain heavy-chain and light-chain variable regions linked together by covalent bonds via peptide linkers or directly at the C-terminus to form a dimer structure similar to that of double-chain Fvs.

[0067] The antigen-binding fragment can be obtained using a protease (e.g., Fab can be obtained by restrictive cleavage of the intact antibody with papain, and the F(ab′)2 fragment can be obtained by cleavage with pepsin), or it can be prepared using genetic recombination technology.

[0068] The term "hinge region" can refer to the region between the CH1 and CH2 domains within the antibody heavy chain, which functions to provide flexibility for the antigen-binding sites in the antibody.

[0069] The anti-LILRB1 antibody can be a monoclonal or polyclonal antibody, such as a monoclonal antibody. Monoclonal antibodies can be prepared using methods known in the art, such as phage display technology. Alternatively, the anti-LILRB1 antibody can be constructed into a mouse-derived monoclonal antibody using conventional methods.

[0070] Simultaneously, individual monoclonal antibodies can be screened based on their binding potential against LILRB1 using typical ELISA (enzyme-linked immunosorbent assay) formats. Inhibitory activity can be verified through functional analyses such as competitive ELISA to validate molecular interactions of binding assemblies or functional analyses such as cell-based assays. Then, for monoclonal antibody members selected based on their strong inhibitory activity, their affinity (Kd value) for LILRB1 can be verified individually.

[0071] The ultimately selected antibody can be prepared and used as a humanized antibody, as well as a human immunoglobulin antibody whose remainder, except for the antigen-binding portion, is humanized. Methods for producing humanized antibodies are well known in the art.

[0072] In addition to the active ingredient (anti-LILRB1 antibody or its antigen-binding fragment), the pharmaceutical composition may also contain a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be any of those commonly used in antibody formulations. For example, the pharmaceutically acceptable carrier may be one or more of the following: lactose, dextran, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylparaben, propylparaben, talc, magnesium stearate, mineral oil, etc., but is not limited thereto. The pharmaceutical composition may also contain one or more of the following: diluents, excipients, lubricants, wetting agents, sweeteners, flavor enhancers, emulsifiers, suspending agents, preservatives, etc., commonly used in the preparation of pharmaceutical compositions.

[0073] The pharmaceutical composition or antibody, or its antigen-binding fragment, can be administered orally or parenterally in an effective amount. Parenteral administration can be via intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, intranasal administration, intrapulmonary administration, rectal administration, or local administration to the lesion. Since proteins or peptides are digested upon oral administration, the active ingredient in the composition for oral administration can be coated or formulated to prevent digestion in the stomach. Furthermore, the antibody or composition can be administered using an optional device capable of delivering the active ingredient to target cells (e.g., cancer cells).

[0074] The content or dosage of the anti-LILRB1 antibody or its antigen-binding fragment in the pharmaceutical composition can be formulated in various ways based on various factors, such as preparation method, administration method, patient's age, weight, sex, disease condition, food, administration time, administration interval, route of administration, excretion rate, and sensitivity. For example, the anti-LILRB1 antibody or its antigen-binding fragment can be administered at doses of 0.005 ug / kg to 1000 mg / kg, 0.005 ug / kg to 500 mg / kg, 0.005 ug / kg to 250 mg / kg, 0.005 ug / kg to 100 mg / kg, 0.005 ug / kg to 75 mg / kg, 0.005 ug / kg to 50 mg / kg, 0.01 ug / kg to 1000 mg / kg, 0.01 ug / kg to 50 ... Dosage may be administered in doses ranging from 0.01 ug / kg to 250 mg / kg, 0.01 ug / kg to 100 mg / kg, 0.01 ug / kg to 75 mg / kg, 0.01 ug / kg to 50 mg / kg, 0.05 ug / kg to 1000 mg / kg, 0.05 ug / kg to 500 mg / kg, 0.05 ug / kg to 250 mg / kg, 0.05 ug / kg to 100 mg / kg, 0.05 ug / kg to 75 mg / kg, or 0.05 ug / kg to 50 mg / kg, but is not limited to these. The daily dose may be formulated as a single-unit preparation or as an appropriate aliquot, or it may be manufactured in a multi-dose container.

[0075] The pharmaceutical composition may be formulated as a solution, suspension, syrup, emulsion, extract, powder, granule, tablet or capsule in an oil or aqueous medium, and may also contain a dispersant or stabilizer for the formulation.

[0076] The antibodies, pharmaceutical compositions, or methods provided in this disclosure can be administered to subjects selected from mammals, including primates such as humans and monkeys, rodents such as rats and mice, etc.

[0077] The cancer may be a solid tumor or a hematologic malignancy. The cancer may be, but is not limited to, one or more of the following: lung cancer (e.g., squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma), peritoneal cancer, skin cancer, squamous cell carcinoma, melanoma of the skin or eye, rectal cancer, perianal cancer, esophageal cancer, small bowel tumors, endocrine gland cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, leukemia (e.g., chronic or acute leukemia), lymphocytic lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular adenoma, breast cancer, colon cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland tumors, renal cell carcinoma, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, brain cancer, biliary tract cancer, gallbladder cancer, osteosarcoma, etc. The cancer may be a primary cancer or a metastatic cancer. The cancer can be a cancer characterized by the expression or overexpression of class I MHC on the surface of cancer cells, and can be, for example, colon adenocarcinoma, small cell lung cancer, breast cancer, pancreatic cancer, malignant melanoma, osteosarcoma, renal cell carcinoma, or gastric cancer. Overexpression of class I MHC can refer to overexpression in cancer cells treated with the antibody compared to normal cells. In one embodiment, the cancer can be a cancer in which T-cell-mediated immunotherapy does not show anti-cancer effects (drug resistance).

[0078] When used in this article, the term “treatment of cancer” can refer to all anti-cancer actions that prevent, alleviate or improve cancer symptoms or partially or completely remove cancer, such as cancer cell death, inhibiting cancer cell proliferation, inhibiting cancer metastasis, etc.

[0079] The anti-LILRB1 antibody or its antigen-binding fragment provided in this disclosure can be co-administered with another drug, such as at least one selected from conventionally used immunotherapy agents, anticancer agents, cytotoxic agents, etc. Therefore, one embodiment provides a pharmaceutical composition for co-administration of drugs for the treatment and / or prevention of cancer, the pharmaceutical composition comprising (1) an anti-LILRB1 antibody or its antigen-binding fragment, and (2) at least one selected from immunotherapy agents, anticancer agents, cytotoxic agents, etc. Another embodiment provides a method for treating and / or preventing cancer, the method comprising administering (1) an anti-LILRB1 antibody or its antigen-binding fragment, and (2) at least one selected from immunotherapy agents, anticancer agents, cytotoxic agents, etc., to a subject requiring treatment and / or prevention of said cancer. The immunotherapy agents, anticancer agents, and cytotoxic agents may include any drugs conventionally used in cancer therapy and / or having cytotoxic activity, for example, they may be at least one selected from proteins such as cell therapy agents, antibodies, nucleic acid molecules such as siRNA, and / or small molecule chemicals such as paclitaxel, docetaxel, etc., but are not limited thereto.

[0080] Another embodiment provides a polypeptide molecule comprising the heavy chain complementarity-determining region (CDR-H1, CDR-H2, CDR-H3 or a combination thereof), the light chain complementarity-determining region (CDR-L1, CDR-L2, CDR-L3 or a combination thereof), or a combination thereof, or a heavy chain variable region, a light chain variable region, or a combination thereof, of an anti-LILRB1 antibody as described above. The polypeptide molecule can be used as a precursor for antibody preparation or as a component of a protein scaffold (e.g., a peptibody), a bispecific antibody, or a multispecific antibody having an antibody-like structure. In another embodiment, a polypeptide molecule comprising the heavy chain complementarity-determining region (CDR-H1, CDR-H2, CDR-H3 or a combination thereof), the light chain complementarity-determining region (CDR-L1, CDR-L2, CDR-L3 or a combination thereof), or a combination thereof, or a heavy chain variable region, a light chain variable region, or a combination thereof, of an anti-LILRB1 antibody as described above, can be used as a target (antigen) recognition domain or a secreted antibody in cell therapeutic agents such as CAR-T for targeted therapy. In another embodiment, the polypeptide molecule can be used to construct cells that secrete anti-LILRB1 antibodies as cell therapeutic agents.

[0081] Another embodiment provides a nucleic acid molecule that encodes the heavy chain complementarity-determining region (CDR-H1, CDR-H2, CDR-H3 or a combination thereof), heavy chain variable region, or heavy chain of the anti-LILRB1 antibody.

[0082] Another embodiment provides a nucleic acid molecule that encodes the light chain complementarity-determining region (CDR-L1, CDR-L2, CDR-L3 or a combination thereof), light chain variable region, or light chain of the anti-LILRB1 antibody.

[0083] Another embodiment provides a recombinant vector comprising a nucleic acid molecule encoding a heavy chain variable region or heavy chain of the anti-LILRB1 antibody and a light chain variable region or light chain of the anti-LILRB1 antibody, wherein the nucleic acid molecules are in two separate vectors or all in one vector.

[0084] Another embodiment provides a recombinant cell containing the recombinant vector.

[0085] The term "vector" refers to a tool used to express a target gene in a host cell, examples of which are plasmid vectors, granular vectors, and viral vectors such as phage vectors, lentiviral vectors, adenoviral vectors, retroviral vectors, and adeno-associated virus vectors. The recombinant vector can be constructed from or by manipulating plasmids commonly used in the art (e.g., pSC101, pGV1106, pACYC177, ColE1, pKT230, pME290, pBR322, pUC8 / 9, pUC6, pBD9, pHC79, pIJ61, pLAFR1, pHV14, pGEX series, pET series, pUC19, etc.), phages (e.g., λgt4λB, λ-Charon, λΔz1, M13, etc.), or viral vectors (e.g., SV40, etc.).

[0086] In the recombinant vector, the nucleic acid molecule can be operatively linked to a promoter. The term "operative link" refers to a functional connection between the nucleotide sequence of interest and an expression regulatory sequence (e.g., a promoter sequence). When operatively linked, the regulatory element can control the transcription and / or translation of the polynucleotide of interest.

[0087] The recombinant vector can typically be constructed as a cloning vector or an expression vector. For recombinant expression vectors, vectors commonly used in the relevant art for expressing foreign proteins in plant, animal, or microbial cells can be used. Various different methods known in the art can be used for the construction of recombinant vectors.

[0088] For use in a host, such as a prokaryotic or eukaryotic cell, a recombinant vector can be constructed accordingly. For example, when a vector is constructed as an expression vector for use in a prokaryotic host, the vector typically includes a strong promoter for transcription (e.g., pL). λ Expression vectors include promoters (such as trp promoters, lac promoters, tac promoters, T7 promoters, etc.), ribosome-binding sites for initiating translation, and transcription / translation termination sequences. On the other hand, expression vectors used in eukaryotic hosts include, but are not limited to, operatively operable origins of replication in eukaryotic cells, such as the f1 origin, SV40 origin, pMB1 origin, adenovirus origin, AAV origin, and BBV origin. Furthermore, these expression vectors typically include promoters derived from mammalian cell genomes (e.g., metallothionein promoters) or mammalian viruses (e.g., adenovirus late promoter, vaccinia virus 7.5K promoter, SV40 promoter, cytomegalovirus promoter, HSV tk promoter, etc.), and polyadenylated sequences as transcription termination sequences.

[0089] Another embodiment provides a recombinant cell containing the recombinant vector.

[0090] The recombinant cells can be prepared by introducing the recombinant vector into a suitable host cell. Any host cell known in the art can be used in this disclosure, provided that the recombinant vector is allowed to be cloned and expressed sequentially in a stable manner. Examples of prokaryotic host cells that can be used in this disclosure include Escherichia coli species such as E. coli JM109, E. coli BL21, E. coli RR1, E. coli LE392, E. coli B, E. coli X 1776, E. coli W3110, Bacillus species such as Bacillus subtilis and Bacillus thuringiensis, Enterobacter strains such as Salmonella typhimurium, Serratia marcescens, and various different Pseudomonas species. Eukaryotic host cells that can be used for transformation can be selected from, but are not limited to, Saccharomyces cerevisiae, insect cells, and animal cells, such as Sp2 / 0, CHO (Chinese hamster ovary) K1, CHO DG44, CHO S, CHO DXB11, CHO GS-KO, PER.C6, W138, BHK, COS-7, 293, HepG2, Huh7, 3T3, RIN, MDCK, etc.

[0091] The nucleic acid molecules or recombinant vectors carrying them can be introduced (transfected) into host cells using methods known in the relevant art. For example, when the host cell is a prokaryotic cell, this transformation can be performed using CaCl2 or electroporation. For eukaryotic host cells, genetic introduction can be achieved using, but is not limited to, microinjection, calcium phosphate precipitation, electroporation, liposome-mediated transfection, or particle bombardment.

[0092] To select host cells for transformation, phenotypes associated with selection markers can be utilized according to methods known in the art. For example, when the selection marker is a gene conferring resistance to a certain antibiotic, the host cells can be grown in a culture medium in the presence of the antibiotic to select transformants of interest.

[0093] Another embodiment provides a method for preparing the anti-LILRB1 antibody or an antigen-binding fragment thereof, the method comprising expressing the nucleic acid molecule or a recombinant vector in host cells. The expression step can be performed by culturing recombinant cells containing the nucleic acid molecule (e.g., in a recombinant vector) under conditions allowing the expression of the nucleic acid molecule. The method may further include isolating and / or purifying the antibody or a fragment thereof from the cell culture after the expression or culture step.

[0094] Beneficial effects

[0095] By inhibiting the immune escape mechanisms of cancer cells and allowing immune cells to exhibit their anti-cancer effects, the anti-LILRB1 antibody or its antigen-binding fragment provided in this disclosure can have high anti-cancer activity. Attached Figure Description

[0096] Figure 1 The image shows the results of SDS-PAGE gel analysis of the purified anti-LILRB1 antibody in the examples.

[0097] Figure 2 This is a sensor map showing the results of SPR (surface plasmon resonance) measurements of anti-LILRB1 antibody 13 according to an example.

[0098] Figure 3 This is a graph showing the binding ability of anti-LILRB1 antibodies 8, 10, 11, 13 and 18 to CHO cells overexpressing LILRB1, according to one embodiment.

[0099] Figure 4 This is a graph showing the results of an IncuCyte S3 analysis of the cytotoxic activity of HLA-G-overexpressing HEK293 cells and natural killer cells KHYG-1, according to one embodiment, wherein those cells were treated with anti-LILRB1 antibodies (antibodies 10, 11, and 13) or human IgG4 isotype control antibodies (negative controls).

[0100] Figure 5 The figure shows the in vivo antitumor effects of anti-LILRB1 antibodies 10, 11 and 13 according to the embodiments. Detailed Implementation

[0101] The present invention will be described in detail below through examples.

[0102] The following examples are intended to illustrate the invention only and should not be construed as limiting the invention.

[0103] Example 1: Preparation of human antibodies against LILRB1

[0104] 1.1. Using phage display to select human antibodies against LILRB1

[0105] To select antibodies that specifically recognize human LILRB1, phage display screening was performed using a library of human Fab antibodies. Up to four rounds of phage panning were conducted using human LILRB1-Fc (catalog number 2017-T2) (RnD systems) as the antigen. Furthermore, since the antigen is in Fc fusion form, Fc control panning was also performed to remove Fc conjugates from the panning steps. The binding of the selected products to the antigen was confirmed by polyclonal phage ELISA.

[0106] 1.2. Monoclonal phage ELISA

[0107] Monoclonal phage ELISA was performed to select clones that specifically bound to the antigen from the phages obtained through panning in Example 1.1. For the antigen in Example 1.1, absorbance of 0.4 or higher was determined to be specific. 450nm The cutoff value is used to confirm positive clones and analyze the sequence of the corresponding gene. To confirm the specificity of the antigen, a unique Fab clone of the antigen is subjected to purified phage ELISA to obtain EC. 50 (pfu) value.

[0108] 1.3. Monoclonal Soluble Fab Analysis

[0109] Of the 47 unique clones that bound the antigen obtained through panning in Example 1.2, EC20 based on phage-specific ELISA will be used. 50 The coding genes of the top 19 clones of Fab were amplified by PCR to produce expression vectors. After expressing the antibody in TB medium, soluble proteins were obtained by periplasmic extraction. ELISA was performed after purification by affinity chromatography to confirm binding to the antigen.

[0110] Example 2: Converting the selected antibody into IgG

[0111] For genes selected from the Fab-type phage display library in Example 1.3, genes corresponding to each heavy chain variable region (VH) and light chain variable region (VL) were amplified by PCR. In the case of some clones with low expression levels, the light chain variable region (VL) gene was amplified by PCR in the same manner, and gene sequences corresponding to the heavy chain variable region (VH) were generated by grafting a CDR into the scaffold region (FR) sequence corresponding to the clone with high expression levels. The constructed heavy chain variable region (VH) and light chain variable region (VL) gene sequences were inserted into an expression vector (pCB-LIR-mAB, or alternatively, a vector containing a CMV promoter or a CMV / CHOβ-actin fusion promoter (KR10-1038126B1) and genes encoding the human IgG4 heavy chain constant region and κ light chain constant region) programmed to encode a human antibody in the form of IgG4 (IgG4 Fc: SEQ ID NO: 229, κ constant region: SEQ ID NO: 230). The DNA sequence of the prepared expression vector was confirmed by sequencing.

[0112] The CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, CDR-H3, light chain variable region, heavy chain variable region, amino acid sequences of the light chain and heavy chain, and nucleic acid sequences of the light chain variable region gene and heavy chain variable region gene for the 19 selected antibodies are shown in Tables 3 to 21 below. Each clone was assigned a clone number. Only the simple clone numbers are shown below.

[0113] Table 3

[0114]

[0115]

[0116]

[0117] Table 4

[0118]

[0119]

[0120]

[0121] Table 5

[0122]

[0123]

[0124]

[0125] Table 6

[0126]

[0127]

[0128]

[0129] Table 7

[0130]

[0131]

[0132]

[0133] Table 8

[0134]

[0135]

[0136]

[0137] Table 9

[0138]

[0139]

[0140]

[0141] Table 10

[0142]

[0143]

[0144]

[0145] Table 11

[0146]

[0147]

[0148]

[0149] Table 12

[0150]

[0151]

[0152]

[0153] Table 13

[0154]

[0155]

[0156]

[0157] Table 14

[0158]

[0159]

[0160]

[0161] Table 15

[0162]

[0163]

[0164]

[0165] Table 16

[0166]

[0167]

[0168]

[0169] Table 17

[0170]

[0171]

[0172]

[0173] Table 18

[0174]

[0175]

[0176]

[0177] Table 19

[0178]

[0179]

[0180]

[0181] Table 20

[0182]

[0183]

[0184]

[0185] Table 21

[0186]

[0187]

[0188]

[0189] Example 3. Preparation of the selected antibody

[0190] The vectors constructed in Example 2 were prepared using the Plasmid Plus Maxi kit (Qiagen). These vectors were then used in ExpiCHO-S... TM Antibodies were expressed in the cells. This was achieved by adding 640 μL of ExpiFectamine. TM The CHO reagent (ThermoFisher) was used to transfect the vector into ExpiCHO-S TM In Gibco cells (1.2 x 10⁻⁶) 9 (1 cell / 200 mL culture volume). One day after transfection, the cells were cultured in ExpiCHO. TM In expression medium (Thermo Fisher), incubate at 32°C and 5% CO2 for a total of 7 to 11 days. On day 1, add 1200 μL of ExpiCHO to the culture. TM Enhancer (Thermo Fisher) and 48 mL ExpiCHO TM Thermo Fisher.

[0191] The cultured cells were centrifuged at 3500 rpm for 20 minutes at 4°C, and then filtered using a 0.22 μm cap filtration system (Corning). The culture supernatant was harvested and purified using AKTA Pure L (GE Healthcare). The culture supernatant was loaded into an AKTA Pure L column equipped with a Hitrap MabSelectSure 5 mL column (GE Healthcare) at a flow rate of 5 mL / min, and the column was washed with 10 column volumes (CV) of 1X PBS. The column was then loaded with elution buffer (0.1 M pH 3.4 sodium citrate buffer) to elute the proteins of interest. The eluent was concentrated using an Amicon Ultra filtration device (MWCO 10K, Merck), centrifuged, and buffer-exchanged with 1X PBS buffer.

[0192] Dilute the purified antibody sample with 1X PBS to a final concentration of approximately 1 mg / mL. Mix 10 μL of reducing sample loading buffer (3X) or non-reducing sample loading buffer (3X) with 20 μL of purified antibody sample and incubate at 95°C for 2 minutes, then remove and cool. Inject 10 μg of sample per well into an SDS-PAGE gradient gel (4–12%) mounted on the electrophoresis apparatus and develop on the gel. To analyze the molecular weight of the sample, use Precision Plus Protein... TM Two-color standards (BIO-RAD) were injected into a separate well. The gel was stained with Coomassie stain and then destained to obtain a gel image. Figure 1 ).

[0193] Example 4. Analysis of the binding affinity of the selected antibody

[0194] The binding affinity of 19 antibodies selected in Example 3 to the antigen LILRB1 was measured using a Biacore T200 (GE Healthcare). Anti-human IgG (Fc) antibody (GE Healthcare, catalog BR-1008-39, final concentration 25 μg / mL) was flow-flowed at 5 μL / min for 360 seconds and immobilized at 5000-7000 RU using an amine conjugation kit (GE Healthcare, catalog BR-1000-50) onto a Series S sensor chip CM5 (GE Healthcare, catalog BR-1005-30). Five different concentrations of the antigen human LILRB1 protein (LILRB1-His, RnD systems catalog 8989-T2) ranging from 25 nM to 400 nM were injected at a flow rate of 30 μL / min to determine the k-values ​​as shown in Table 22. aand k d Value, and calculate K from it. D Value. Antibody 10 showed a binding affinity of approximately 24.13 nM (K) to the LILRB1 antigen. D Furthermore, antibody 13 exhibits a binding affinity of approximately 30.27 nM for the LILRB1 antigen (K0). D (Table 22). The sensor map results for antibody 13 are shown in... Figure 2 middle.

[0195] Table 22

[0196] The antigen-binding affinity (K) of LILRB1 antibody D )

[0197] Clone ID <![CDATA[k a (x 10 5 )(1 / Ms)]]> <![CDATA[k d (x 10 -4 )(1 / s)]]> <![CDATA[K D (nM)]]> 8 0.6166 46.37 75.2 10 0.1233 2.977 24.13 11 0.08662 1.061 12.25 13 0.9729 2.945 30.27 14 1.621 663.1 409.1 16 1.157 96.35 83.3 18 1.439 6.221 4.32 22 0.6826 340.8 499.3

[0198] Example 5. Determination of the in vitro biological activity of the selected antibody

[0199] 5.1. Cell surface binding assay

[0200] To test whether the antibody selected in Example 4 bound to LILRB1 expressed on the cell surface, a cell surface binding assay was performed. CHO cells overexpressing LILRB1 were cultured in chemically defined medium and sputtered at 2 x 10⁻⁶ cells / year. 5 Cells were added to a density of 10 cells / well in a U-bottom 96-well tissue culture plate (BD Falcon). Each selected antibody was added to a final concentration of 10 μg / mL per well and incubated at 4°C for 30 min. To observe the LILRB1-specific binding levels of the selected antibodies, a human IgG4 isotype control antibody (Biolegend) was treated in the same manner. After washing with FACS buffer, cells were treated with anti-human Fc-biotin antibody (Life Technologies) and incubated at 4°C for 1 h. After washing with FACS buffer, streptavidin PE (BD Pharmigen) was added to each well and incubated at 4°C for 30 min. After washing with FACS buffer, the cells were resuspended and analyzed using an iQue screener (Sartorius). Figure 3 As shown, antibodies 8, 10, 11, 13, and 18 exhibited higher binding levels compared to human IgG4 isotype control antibodies.

[0201] 5.2. Analysis of the enhanced cancer cell killing ability of natural killer (NK) cells

[0202] To determine whether the antibody selected in Example 4 increased the degree of cancer cell lysis induced by NK cells, the cell death rate of HLA-G overexpressing HEK293 cells induced by NK cell KHYG-1 was analyzed. KHYG-1 cells (JCRB) were cultured at 4 x 10-1 5 Cells / well (2x10) 4 Add cells / mL to 96-well tissue culture plates (BD Falcon). Add the selected antibody to the wells to a final concentration of 10 μg / mL and incubate at 37°C for 1 hour. As a negative control, treat with human IgG4 isotype control antibody (Biolegend) in the same manner. HLA-G overexpressing HEK293 cells were stained in separate tubes with IncuCyte CytoLight (Sartorius) according to the manufacturer's instructions. After 1 hour, add HLA-G overexpressing HEK293 cells at 4 x 10⁻⁶ cells / mL. 5 Cells / well (2x10) 4 A volume of cells / mL was added to the plate. The plate was placed in an IncuCyte S3 (Sartorius) incubator equipped with 37°C and 5% CO2 and its images were acquired for 72 hours.

[0203] To compare the efficacy of each antibody, the normalized red region confluence value of the isotype control was converted to 1 as shown in Equation 1 below to obtain the relative cell viability (isotype = 1):

[0204] [Equation 1]

[0205] Relative cell viability = [Antibody normalized red region confluence value] / [Isotype normalized red region confluence value]

[0206] The results are shown in Figure 4 In. Figure 4 This can be explained as follows: the lower the relative cell viability, the higher the NK cell-mediated cytotoxicity induced by LILRB1mAb. For example... Figure 4 As shown, compared to the human IgG4 isotype control, all tested antibodies (antibodies 10, 11, and 13) increased cell death in HEK293 cells overexpressing HLA-G. These results demonstrate that the antibodies provided in this invention exhibit high cytotoxicity against cancer cells.

[0207] Example 6: Determination of in vivo biological activity of antibodies

[0208] The in vivo anticancer efficacy of three antibodies (antibodies 10, 11, and 13), whose binding ability to the antigen was confirmed in Example 3, was tested. For this purpose, it was tested whether administration of the three types of antibodies reduced tumor size when tumors were induced in mice by implanting human colorectal cancer cells (Bioware BriteCell Line HCT116 Red-Fluc colorectal cancer cells (PerkinElmer)) and THP-1-derived macrophages. As a negative control, human colorectal cancer xenograft mice prepared as described above were treated with a human IgG1 isotype control antibody (BioXcell, catalog number BP0297).

[0209] 6.1. Preparation of THP-1-derived macrophages

[0210] The THP-1-derived macrophages used above were prepared by differentiating THP-1 cells (ATCC) with 150 nM phorbol 12-myristate-13-acetate (PMA, Sigma), 20 ng / mL interferon-γ (Peprotech), and 10 pg / mL lipopolysaccharide (LPS, Sigma).

[0211] 6.2. Measuring anticancer efficacy in mouse models

[0212] Five-week-old female CIEA NOG mice (NOG immunodeficient mice, Central Institute of Experimental Animals, Japan) were fed with 3x10 6 3 x 10 HCT116 Red-Fluc colorectal cancer cells 6 A mixture of 1 THP-1-derived macrophage and each of the three antibodies (20 μg per mouse) was administered subcutaneously. From day 4 post-cell transplantation, each antibody was administered intraperitoneally twice weekly at a dose of 5 mg / kg.

[0213] The changes in tumor volume induced by antibody administration were measured and shown. Figure 5 In the middle. For example Figure 5 As shown, in mouse models transplanted with HCT116 colorectal cancer cells and THP-1-derived macrophages, all tested antibodies (antibodies 10, 11, and 13) demonstrated statistically significant effects in inhibiting tumor growth. <110> LG CHEM, LTD. <120> Anti-LILRB1 antibodies and their uses <130> OPP20212368KR <150> KR 10-2020-0094053 <151> 2020-07-28 <160> 230 <170> koPatentIn 3.0 <210> 1 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (5_CDR-L1) <400> 1 Arg Ala Ser Gln Ser Ile Ala Asn Tyr Leu Asn 1 5 10 <210> 2 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (5-CDR-L2) <400> 2 Ala Thr Ser Thr Leu Gln Ser 1 5 <210> 3 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (5_CDR-L3) <400> 3 Gln Gln Ser Tyr Ser Phe Pro Trp Thr 1 5 <210> 4 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthesized (5-CDR-H1) <400> 4 Ala Tyr Gly Ile His 1 5 <210> 5 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (5-CDR-H2) <400> 5 Trp Ile Ile Pro Leu Ser Gly Gly Ala His Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 6 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthesized (5-CDR-H3) <400> 6 Leu Tyr Gly Trp Ala Glu Tyr Phe Asp Val 1 5 10 <210> 7 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (5-light chain variable region) <400> 7 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 Ser Ile Ala 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 Ala Thr Ser Thr Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 8 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthetic (5_light chain_variable region_gene) <400> 8 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatcgca aattacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgca acttccactc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtggac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 9 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Synthetic (5-heavy chain variable region) <400> 9 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ala Tyr 20 25 30 Gly Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ile Pro Leu Ser Gly Gly Ala His Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Tyr Gly Trp Ala Glu Tyr Phe Asp Val Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 10 <211> 357 <212> DNA <213> Artificial sequence <220> <223> Synthetic (5-heavy chain variable region gene) <400> 10 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt gcatacggta tccattgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggtgg attatcccac tgtctggtgg tgcacattat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagactgtac 300 ggttgggcag aatacttcga tgtttggggt cagggtactc tggttaccgt ctcatcg 357 <210> 11 <211> 214 <212> PRT <213> Artificial sequence <220> <223> Synthetic (5-light chain κ) <400> 11 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 Ser Ile Ala 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 Ala Thr Ser Thr Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 12 <211> 445 <212> PRT <213> Artificial sequence <220> <223> Synthetic (5_heavy chain) <400> 12 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ala Tyr 20 25 30 Gly Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ile Pro Leu Ser Gly Gly Ala His Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Tyr Gly Trp Ala Glu Tyr Phe Asp Val Trp Gly Gln 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 Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 13 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (6_CDR-L1) <400> 13 Arg Ala Ser Gln Ser Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 14 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (6_CDR-L2) <400> 14 Ala Ala Ser Thr Leu Gln Ser 1 5 <210> 15 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (6_CDR-L3) <400> 15 Gln Gln Ser Tyr Ser Phe Pro Trp Thr 1 5 <210> 16 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic (6-CDR-H1) <400> 16 Ser Tyr Thr Ile Ser 1 5 <210> 17 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (6-CDR-H2) <400> 17 Trp Ile Ser Pro Glu Leu Gly Thr Ser Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 18 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthesized (6-CDR-H3) <400> 18 Leu Arg Tyr Gly Gln Thr Leu Tyr Gly Phe Asp Ile 1 5 10 <210> 19 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (6-light chain variable region) <400> 19 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 Ser 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 Ala Ala Ser Thr Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 20 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (6-light chain variable region gene) <400> 20 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatctct aattacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgca gcatccactc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtggac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> twenty one <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic (6-heavy chain variable region) <400> twenty one Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Thr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Pro Glu Leu Gly Thr Ser Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Arg Tyr Gly Gln Thr Leu Tyr Gly Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> twenty two <211> 363 <212> DNA <213> Artificial sequence <220> <223> Synthetic (6-heavy chain variable region gene) <400> twenty two caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt tcttacacca tttcttgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggtgg atttctccag aactgggtac ctctaactat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagactgcgt 300 tacggtcaga ctctgtacgg tttcgatatc tggggtcagg gtactctggt taccgtctca 360 tcg 363 <210> 23 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic (6_light chain_κ) <400> 23 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 Ser 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 Ala Ala Ser Thr Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 24 <211> 447 <212> PRT <213> Artificial sequence <220> <223> Synthetic (6_heavy chain) <400> 24 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Thr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Pro Glu Leu Gly Thr Ser Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Arg Tyr Gly Gln Thr Leu Tyr Gly Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu 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 Leu Gly 435 440 445 <210> 25 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (7_CDR-L1) <400> 25 Arg Ala Ser Gln Ser Ile Ser Asn Trp Leu Asn 1 5 10 <210> 26 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (7_CDR-L2) <400> 26 Gly Thr Ser Ser Leu Gln Ser 1 5 <210> 27 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (7_CDR-L3) <400> 27 Gln Gln Ser Tyr Ser Phe Pro Phe Thr 1 5 <210> 28 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthesized (7_CDR-H1) <400> 28 Ser Tyr Gly Met His 1 5 <210> 29 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (7-CDR-H2) <400> 29 Trp Ile Ile Pro Val Ser Gly Gly Ala Thr Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 30 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthesized (7-CDR-H3) <400> 30 Gly Ser Trp Ala Tyr Tyr Ala Glu Phe Asp Tyr 1 5 10 <210> 31 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (7-light chain variable region) <400> 31 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 Ser Ile Ser Asn Trp 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Thr Ser Ser Leu Gln 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 Ser Tyr Ser Phe Pro Phe 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 32 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (7-light chain variable region gene) <400> 32 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatctct aattggctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacggt acttcctctc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtttac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 33 <211> 120 <212> PRT <213> Artificial sequence <220> <223> Synthetic (7-heavy chain variable region) <400> 33 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ile Pro Val Ser Gly Gly Ala Thr Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Trp Ala Tyr Tyr Ala Glu Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 34 <211> 360 <212> DNA <213> Artificial sequence <220> <223> Synthetic (7-heavy chain variable region gene) <400> 34 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt tcttacggta tgcattgggt gcggcaggcg 120 tcctgcaaag cctcaggcgg gacttttagt tcttacggta tgcattgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggtgg attatcccag tttctggtgg tgcaacctat 180 cccggccagg gtctcgaatg gatggggtgg attatcccag tttctggtgg tgcaacctat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagaggttct 300 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagaggttct 300 tgggcatact acgctgaatt cgattactgg ggtcagggca ctttagtgac cgtctcatcg 360 tgggcatact acgctgaatt cgattactgg ggtcagggca ctttagtgac cgtctcatcg 360 360 360 <210> 35<210> 35 <211> 214<211> 214 <212> PRT<212> PRT <213> 人工序列<213> Artificial sequence <220><220> <223> 合成的 (7_轻链_κ) <223> Synthetic (7_light chain_κ) <400> 35 <400> 35 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Trp Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Trp 20 25 30 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 35 40 45 Tyr Gly Thr Ser Ser Leu Gln 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 Ser Tyr Ser Phe Pro Phe 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 36 <211> 446 <212> PRT <213> Artificial sequence <220> <223> Synthetic (7_heavy chain) <400> 36 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ile Pro Val Ser Gly Gly Ala Thr Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Trp Ala Tyr Tyr Ala Glu 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 Cys Ser Arg Ser Thr Ser Glu Ser 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 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu 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 Leu Gly 435 440 445 <210> 37 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (8_CDR-L1) <400> 37 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 1 5 10 <210> 38 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (8_CDR-L2) <400> 38 Ala Ala Ser Thr Leu Gln Ser 1 5 <210> 39 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (8_CDR-L3) <400> 39 Gln Gln Ser Tyr Ser Phe Pro Tyr Thr 1 5 <210> 40 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthesized (8-CDR-H1) <400> 40 Ser Tyr Gly Ile His 1 5 <210> 41 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (8-CDR-H2) <400> 41 Trp Ile Ile Pro Ile Ser Gly Thr Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 42 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (8-CDR-H3) <400> 42 Val Gly Gly Val Gly Leu Tyr Val Phe Asp Val 1 5 10 <210> 43 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (8-light chain variable region) <400> 43 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 Ser Ile Ser 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 Ala Ala Ser Thr Leu Gln 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 Ser Tyr Ser Phe Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 44 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (8-light chain variable region gene) <400> 44 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatctct tcttacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgca gcatccactc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtacac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 45 <211> 120 <212> PRT <213> Artificial sequence <220> <223> Synthetic (8-heavy chain variable region) <400> 45 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Gly Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ile Pro Ile Ser Gly Thr Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gly Gly Val Gly Leu Tyr Val Phe Asp Val Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 46 <211> 360 <212> DNA <213> Artificial sequence <220> <223> Synthetic (8-heavy chain variable region gene) <400> 46 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt tcttacggta tccattgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggtgg attatcccaa tctctggtac caccaactat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagagttggt 300 ggtgttggtc tgtacgtttt cgatgtttgg ggtcagggta ctctggttac cgtctcatcg 360 360 <210> 47 <211> 214 <212> PRT <213> Artificial sequence <220> <223> Synthetic (8_light chain_κ) <400> 47 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 Ser Ile Ser 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 Ala Ala Ser Thr Leu Gln 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 Ser Tyr Ser Phe Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 48 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic (8_Heavy Chain) <400> 48 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Gly Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ile Pro Ile Ser Gly Thr Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gly Gly Val Gly Leu Tyr Val Phe Asp Val 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 Cys Ser Arg Ser Thr Ser Glu Ser 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 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu 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 Leu Gly 435 440 445 <210> 49 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (9_CDR-L1) <400> 49 Arg Ala Ser Gln Ser Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 50 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (9_CDR-L2) <400> 50 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> 51 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (9_CDR-L3) <400> 51 Gln Gln Ser Tyr Ser Phe Pro Trp Thr 1 5 <210> 52 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic (9_CDR-H1) <400> 52 Ser Tyr Ala Ile His 1 5 <210> 53 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (9-CDR-H2) <400> 53 Trp Ile Val Pro Gly Leu Gly Val Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 54 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthesized (9-CDR-H3) <400> 54 Gln Ala Thr Leu Tyr Gln Thr Glu Tyr Met Asp Val 1 5 10 <210> 55 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (9-light chain variable region) <400> 55 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 Ser 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 Ala Ala Ser Ser Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 56 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (9-light chain variable region gene) <400> 56 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatctct aattacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgca gcatcctctc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtggac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 57 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic (9-heavy chain variable region) <400> 57 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Val Pro Gly Leu Gly Val Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Ala Thr Leu Tyr Gln Thr Glu Tyr Met Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 58 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Synthetic (9-heavy chain variable region gene) <400> 58 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt tcttacgcaa tccattgggt gcggcaggcg 120 tcctgcaaag cctcaggcgg gacttttagt tcttacgcaa tccattgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggtgg attgttccag gtctgggtgt taccaactat 180 cccggccagg gtctcgaatg gatggggtgg attgttccag gtctgggtgt taccaactat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagacaggca 300 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagacaggca 300 actctgtacc agactgaata catggatgtt tggggtcagg gtactctggt taccgtctca 360 actctgtacc agactgaata catggatgtt tggggtcagg gtactctggt taccgtctca 360 tcg 363 tcg 363 <210> 59<210> 59 <211> 214<211> 214 <212> PRT<212> PRT <213> 人工序列<213> Artificial sequence <220><220> <223> 合成的 (9_轻链_κ) <223> Synthetic (9_light chain_κ) <400> 59 <400> 59 [[ID=!28]]Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile [[ID=!37]] 35 40 45 35 40 45 It should be noted that there seems to be an error in the original text where "[[ID=!2!!8]]" and "[[ID=!3!!7]]" are likely incorrect tags. I've translated them as they are but they might need to be corrected in the source for a more accurate representation.Tyr Ala Ala Ser Ser Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 60 <211> 447 <212> PRT <213> Artificial sequence <220> <223> Synthetic (9_heavy chain) <400> 60 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Val Pro Gly Leu Gly Val Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Ala Thr Leu Tyr Gln Thr Glu Tyr Met Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu 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 Leu Gly 435 440 445 <210> 61 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (10_CDR-L1) <400> 61 Arg Ala Ser Gln Ser Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 62 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (10_CDR-L2) <400> 62 Ala Ala Ser Asn Leu Gln Ser 1 5 <210> 63 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (10_CDR-L3) <400> 63 Gln Gln Ser Tyr Ser Phe Pro Phe Thr 1 5 <210> 64 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic (10_CDR-H1) <400> 64 Ser His Tyr Met His 1 5 <210> 65 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (10-CDR-H2) <400> 65 Trp Ile Ser Pro Tyr Leu Gly Ser Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 66 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthesized (10-CDR-H3) <400> 66 Asp Glu Thr Gly Ser Thr Tyr Gly Ala Phe Asp Tyr 1 5 10 <210> 67 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (10-light chain-variable region) <400> 67 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 Ser 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 Ala Ala Ser Asn Leu Gln 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 Ser Tyr Ser Phe Pro Phe 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 68 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (10-light chain variable region gene) <400> 68 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatctct aattacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgca gcatccaatc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtttac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 69 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic (10-heavy-chain variable region) <400> 69 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser His 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Pro Tyr Leu Gly Ser Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Glu Thr Gly Ser Thr Tyr Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 70 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Synthetic (10-heavy chain variable region gene) <400> 70 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt tctcattaca tgcattgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggtgg atttctccat acctgggttc taccaactat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagagatgaa 300 actggttcta cttacggtgc attcgattac tggggtcagg gtactctggt taccgtctca 360 tcg 363 <210> 71 <211> 214 <212> PRT <213> Synthetic sequence <220> <223> Synthetic (10_light chain_κ) <400> 71 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 Ser 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 Ala Ala Ser Asn Leu Gln 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 Ser Tyr Ser Phe Pro Phe 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 72 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Synthetic (10_heavy chain) <400> 72 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser His 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Pro Tyr Leu Gly Ser Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Glu Thr Gly Ser Thr Tyr Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu 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 Leu Gly 435 440 445 <210> 73 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (11_CDR-L1) <400> 73 Arg Ala Ser Gln Ser Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 74 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (11_CDR-L2) <400> 74 Asp Ala Ser Thr Leu Gln Ser 1 5 <210> 75 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (11_CDR-L3) <400> 75 Gln Gln Ser Tyr Ser Phe Pro Trp Thr 1 5 <210> 76 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic (11_CDR-H1) <400> 76 Ser Tyr Tyr Val His 1 5 <210> 77 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (11_CDR-H2) <400> 77 Trp Ile Ser Pro Tyr Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 78 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthesized (11_CDR-H3) <400> 78 Asp Tyr Tyr Val Ser Ala Tyr Gly Ala Phe Asp Tyr 1 5 10 <210> 79 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (11-light chain variable region) <400> 79 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 Ser 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 Asp Ala Ser Thr Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 80 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (11-light chain variable region gene) <400> 80 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatctct aattacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgat gcatccactc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtggac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 81 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic (11-heavy-chain-variable region) <400> 81 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Tyr Val His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Pro Tyr Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Tyr Tyr Val Ser Ala Tyr Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 82 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Synthetic (11-heavy chain variable region gene) <400> 82 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt tcttactacg ttcattgggt gcggcaggcg 120 tcctgcaaag cctcaggcgg gacttttagt tcttactacg ttcattgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggtgg atttctccat actctggtgg taccaactat 180 cccggccagg gtctcgaatg gatggggtgg atttctccat actctggtgg taccaactat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagagattac 300 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagagattac 300 tacgtttctg catacggtgc attcgattac tggggtcagg gtactctggt taccgtctca 360 tacgtttctg catacggtgc attcgattac tggggtcagg gtactctggt taccgtctca 360 tcg 363 tcg 363 <210> 83<210> 83 <211> 214<211> 214 <212> PRT<212> PRT <213> 人工序列<213> Synthetic sequence <220><220> <223> 合成的 (11_轻链_κ) <223> Synthetic (11_light chain_κ) <400> 83 <400> 83 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 35 40 45 Tyr Asp Ala Ser Thr Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 84 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Synthetic (11_Heavy Chain) <400> 84 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Tyr Val His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Pro Tyr Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Tyr Tyr Val Ser Ala Tyr Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu 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 Leu Gly 435 440 445 <210> 85 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (12_CDR-L1) <400> 85 Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 86 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (12_CDR-L2) <400> 86 Ala Thr Ser Ser Leu Gln Ser 1 5 <210> 87 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (12_CDR-L3) <400> 87 Gln Gln Ser Tyr Ser Phe Pro Trp Thr 1 5 <210> 88 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthesized (12_CDR-H1) <400> 88 Ser Tyr Asp Ile His 1 5 <210> 89 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (12-CDR-H2) <400> 89 Arg Ile Val Pro Tyr Leu Gly Val Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 90 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthesized (12-CDR-H3) <400> 90 Arg Gln Ser Gln Ser Ser Val Tyr Ala Phe Asp Ile 1 5 10 <210> 91 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (12-light chain variable region) <400> 91 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 Ala Thr Ser Ser Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 92 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (12-light chain variable region gene) <400> 92 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca ggatatctct aattacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgca acttcctctc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtggac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 93 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic (12-heavy-chain variable region) <400> 93 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Val Pro Tyr Leu Gly Val Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Gln Ser Gln Ser Ser Val Tyr Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 94 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Synthetic (12-heavy chain variable region gene) <400> 94 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt tcttacgata tccattgggt gcggcaggcg 120 tcctgcaaag cctcaggcgg gacttttagt tcttacgata tccattgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggcgt attgttccat acctgggtgt taccaactat 180 cccggccagg gtctcgaatg gatggggcgt attgttccat acctgggtgt taccaactat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagacgtcag 300 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagacgtcag 300 tctcagtctt ctgtttacgc attcgatatc tggggtcagg gcactttagt gaccgtctca 360 tctcagtctt ctgtttacgc attcgatatc tggggtcagg gcactttagt gaccgtctca 360 tcg 363 tcg 363 <210> 95<210> 95 <211> 214<211> 214 <212> PRT<212> PRT <213> 人工序列<213> Synthetic sequence <220><220> <223> 合成的 (12_轻链_κ) <223> Synthetic (12_light chain_κ) <400> 95 <400> 95 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 35 40 45 Tyr Ala Thr Ser Ser Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 96 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Synthetic (12_Heavy Chain) <400> 96 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Val Pro Tyr Leu Gly Val Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Gln Ser Gln Ser Ser Val Tyr Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu 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 Leu Gly 435 440 445 <210> 97 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (13_CDR-L1) <400> 97 Arg Ala Ser Gln Ser Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 98 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (13_CDR-L2) <400> 98 Ala Ala Ser Arg Leu Gln Ser 1 5 <210> 99 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (13_CDR-L3) <400> 99 Gln Gln Ser Tyr Ser Phe Pro Phe Thr 1 5 <210> 100 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic (13_CDR-H1) <400> 100 Gly Tyr Tyr Ile His 1 5 <210> 101 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (13_CDR-H2) <400> 101 Trp Ile Ser Pro Ser Ser Gly Gly Thr Ile Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 102 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic (13_CDR-H3) <400> 102 Asp Ile Ser Val Arg Val Val Gln Ala Phe Asp Tyr 1 5 10 <210> 103 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (13-light chain-variable region) <400> 103 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 Ser 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 Ala Ala Ser Arg Leu Gln 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 Ser Tyr Ser Phe Pro Phe 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 104 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (13-light chain variable region gene) <400> 104 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatctct aattacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgca gcatcccgtc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtttac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 105 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic (13-heavy chain variable region) <400> 105 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Gly Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Pro Ser Ser Gly Gly Thr Ile Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ile Ser Val Arg Val Val Gln Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 106 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Synthetic (13-heavy chain variable region gene) <400> 106 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt ggttactaca tccattgggt gcggcaggcg 120 tcctgcaaag cctcaggcgg gacttttagt ggttactaca tccattgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggtgg atttctccat cttctggtgg taccatctat 180 cccggccagg gtctcgaatg gatggggtgg atttctccat cttctggtgg taccatctat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagagatatc 300 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagagatatc 300 tctgttcgtg ttgttcaggc attcgattac tggggtcagg gtactctggt taccgtctca 360 tctgttcgtg ttgttcaggc attcgattac tggggtcagg gtactctggt taccgtctca 360 tcg 363 tcg 363 <210> 107<210> 107 <211> 214<211> 214 <212> PRT<212> PRT <213> 人工序列<213> Artificial sequence <220><220> <223> 合成的 (13_轻链_κ) <223> Synthetic (13_light chain_κ) [[ID=Tyr Ala Ala Ser Arg Leu Gln 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 Ser Tyr Ser Phe Pro Phe 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 108 <211> 447 <212> PRT <213> Artificial sequence <220> <223> Synthetic (13_heavy chain) <400> 108 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Gly Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Pro Ser Ser Gly Gly Thr Ile Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ile Ser Val Arg Val Val Gln Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu 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 Leu Gly 435 440 445 <210> 109 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (14_CDR-L1) <400> 109 Arg Ala Ser Gln Ser Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 110 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (14_CDR-L2) <400> 110 Ala Thr Ser Asn Leu Gln Ser 1 5 <210> 111 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (14_CDR-L3) <400> 111 Gln Gln Ser Tyr Ser Phe Pro Trp Thr 1 5 <210> 112 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic (14_CDR-H1) <400> 112 Ser Tyr Tyr Met His 1 5 <210> 113 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (14-CDR-H2) <400> 113 Trp Ile Ser Pro Tyr Leu Gly Ile Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 114 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic (14-CDR-H3) <400> 114 Ala Gly Tyr Gln Gln Ala Gln Tyr Trp Phe Asp Tyr 1 5 10 <210> 115 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (14-light chain variable region) <400> 115 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 Ser 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 Ala Thr Ser Asn Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 116 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (14-light chain variable region gene) <400> 116 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatctct aattacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgca acttccaatc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtggac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 117 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic (14-heavy chain variable region) <400> 117 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Pro Tyr Leu Gly Ile Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Tyr Gln Gln Ala Gln Tyr Trp Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 118 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Synthetic (14-heavy chain variable region gene) <400> 118 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt tcttactaca tgcattgggt gcggcaggcg 120 tcctgcaaag cctcaggcgg gacttttagt tcttactaca tgcattgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggtgg atttctccat acctgggtat caccaactat 180 cccggccagg gtctcgaatg gatggggtgg atttctccat acctgggtat caccaactat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagagcaggt 300 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagagcaggt 300 taccagcagg cacagtactg gttcgattac tggggtcagg gcactttagt gaccgtctca 360 taccagcagg cacagtactg gttcgattac tggggtcagg gcactttagt gaccgtctca 360 tcg 363 tcg 363 <210> 119<210> 119 <211> 214<211> 214 <212> PRT<212> PRT <213> 人工序列<213> Artificial sequence <220><220> <223> 合成的 (14_轻链_κ) <223> Synthetic (14_light chain_κ) <400> 119 <400> 119 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30 20 25 30 <0002�39> Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 35 40 45 Tyr Ala Thr Ser Asn Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 120 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Synthetic (14_Heavy Chain) <400> 120 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Pro Tyr Leu Gly Ile Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Tyr Gln Gln Ala Gln Tyr Trp Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu 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 Leu Gly 435 440 445 <210> 121 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (15_CDR-L1) <400> 121 Arg Ala Ser Gln Ser Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 122 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (15_CDR-L2) <400> 122 Ala Thr Ser Ser Leu Gln Ser 1 5 <210> 123 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (15_CDR-L3) <400> 123 Gln Gln Ser Tyr Ser Phe Pro Tyr Thr 1 5 <210> 124 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic (15_CDR-H1) <400> 124 Ser Tyr Ala Met Ser 1 5 <210> 125 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (15-CDR-H2) <400> 125 Trp Ile Ile Pro Ile Ser Gly Thr Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 126 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic (15-CDR-H3) <400> 126 Gln His Ser Val Gly Ser Val Phe Asp Tyr 1 5 10 <210> 127 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (15-light chain-variable region) <400> 127 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 Ser 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 Ala Thr Ser Ser Leu Gln 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 Ser Tyr Ser Phe Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 128 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (15-light chain variable region gene) <400> 128 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatctct aattacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgca acttcctctc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtacac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 129 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Synthetic (15-heavy-chain-variable region) <400> 129 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ile Pro Ile Ser Gly Thr Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln His Ser Val Gly Ser Val Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 130 <211> 357 <212> DNA <213> Artificial sequence <220> <223> Synthetic (15-heavy chain variable region gene) <400> 130 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt tcttacgcaa tgtcttgggt gcggcaggcg 120 tcctgcaaag cctcaggcgg gacttttagt tcttacgcaa tgtcttgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggtgg attatcccaa tctctggtac caccaactat 180 cccggccagg gtctcgaatm gatggggtgg attatcccaa tctctggtac caccaactat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagacagcat 300 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagacagcat 300 tctgttggtt ctgttttcga ttactggggt cagggtactc tggttaccgt ctcatcg 357 tctgttggtt ctgttttcga ttactggggt cagggtactc tggttaccgt ctcatcg 357 <210> 131<210> 131 <211> 214<211> 214 <212> PRT<212> PRT <213> 人工序列<213> Artificial sequence <220><220> <223> 合成的 (15_轻链_κ) <223> Synthetic (15_light chain_κ) <400> 131 <400> 131 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 35 40 45 Tyr Ala Thr Ser Ser Leu Gln 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 Ser Tyr Ser Phe Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 132 <211> 445 <212> PRT <213> Artificial sequence <220> <223> Synthetic (15_heavy chain) <400> 132 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ile Pro Ile Ser Gly Thr Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln His Ser Val Gly Ser Val Phe Asp Tyr Trp Gly Gln 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 Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 133 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (16_CDR-L1) <400> 133 Arg Ala Ser Gln Asp Ile Ser Ser Trp Leu Asn 1 5 10 <210> 134 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (16_CDR-L2) <400> 134 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> 135 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (16_CDR-L3) <400> 135 Gln Gln Ser Tyr Ser Phe Pro Trp Thr 1 5 <210> 136 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic (16_CDR-H1) <400> 136 Ser Tyr Tyr Met Thr 1 5 <210> 137 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (16-CDR-H2) <400> 137 Gly Ile Ser Pro Ile Leu Gly Val Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 138 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic (16-CDR-H3) <400> 138 Leu Leu Val Gly Val Ser Glu Thr Tyr Phe Asp Tyr 1 5 10 <210> 139 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (16-light chain variable region) <400> 139 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 Ser Trp 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 140 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (16-light chain variable region gene) <400> 140 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca ggatatctct tcttggctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgca gcatcctctc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtggac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 141 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic (16-heavy-chain variable region) <400> 141 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ser Pro Ile Leu Gly Val Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Leu Val Gly Val Ser Glu Thr Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 142 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Synthetic (16-heavy chain variable region gene) <400> 142 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt tcttactaca tgacctgggt gcggcaggcg 120 tcctgcaaag cctcaggcgg gacttttagt tcttactaca tgacctgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggggt atttctccaa tcctgggtgt taccaactat 180 cccggccagg gtctcgaatg gatggggggt atttctccaa tcctgggtgt taccaactat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagactgctg 300 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagactgctg 300 gttggtgttt ctgaaactta cttcgattac tggggtcagg gtactctggt taccgtctca 360 gttggtgttt ctgaaactta cttcgattac tggggtcagg gtactctggt taccgtctca 360 tcg 363 tcg 363 <210> 143<210> 143 <211> 214<211> 214 <212> PRT<212> PRT <213> 人工序列<213> Artificial sequence <220><220> <223> 合成的 (16_轻链_κ) <223> Synthetic (16_light chain_κ) <400> 143 <400> 143 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Trp Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Trp 20 25 30 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 35 40 45 Tyr Ala Ala Ser Ser Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 144 <211> 447 <212> PRT <213> Synthetic sequence <220> <223> Synthetic (16_heavy chain) <400> 144 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ser Pro Ile Leu Gly Val Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Leu Val Gly Val Ser Glu Thr Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu 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 Leu Gly 435 440 445 <210> 145 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (17_CDR-L1) <400> 145 Arg Ala Ser Gln Ser Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 146 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (17_CDR-L2) <400> 146 Ala Ala Ser Asn Met His Ser 1 5 <210> 147 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (17_CDR-L3) <400> 147 Gln Gln Ser His Ser Phe Pro Trp Thr 1 5 <210> 148 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic (17_CDR-H1) <400> 148 Thr Tyr Ala Met Ser 1 5 <210> 149 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (17-CDR-H2) <400> 149 Gly Ile Ser Pro Thr Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 150 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic (17_CDR-H3) <400> 150 Val Arg Tyr Ala Gly Trp Thr Gly Tyr Phe Asp Leu 1 5 10 <210> 151 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (17-light chain-variable region) <400> 151 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 Ser 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 Ala Ala Ser Asn Met His 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 Ser His Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 152 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (17-light chain variable region gene) <400> 152 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatctct aattacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgca gcatccaata tgcactctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tctcactctt ttccgtggac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 153 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic (17-heavy chain-variable region) <400> 153 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ser Pro Thr Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Arg Tyr Ala Gly Trp Thr Gly Tyr Phe Asp Leu Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 154 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Synthetic (17-heavy chain variable region gene) <400> 154 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt acctacgcaa tgtcttgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggggt atttctccaa ccctgggtat cgcaaactat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagagttcgt 300 tacgcaggtt ggactggtta cttcgatctg tggggtcagg gtactctggt taccgtctca 360 tcg 363 <210> 155 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic (17_light chain_κ) <400> 155 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 Ser 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 Ala Ala Ser Asn Met His 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 Ser His Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 156 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Synthetic (17_Heavy Chain) <400> 156 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ser Pro Thr Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Arg Tyr Ala Gly Trp Thr Gly Tyr Phe Asp Leu Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu 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 Leu Gly 435 440 445 <210> 157 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (18_CDR-L1) <400> 157 Arg Ala Ser Gln Ser Ile Ser Arg Trp Leu Asn 1 5 10 <210> 158 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (18_CDR-L2) <400> 158 Ala Ala Ser Arg Leu Gln Ser 1 5 <210> 159 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (18_CDR-L3) <400> 159 Gln Gln Ser Glu Ser Phe Pro Trp Thr 1 5 <210> 160 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic (18_CDR-H1) <400> 160 Ser Tyr Asp Ile Asn 1 5 <210> 161 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic (18-CDR-H2) <400> 161 Trp Ile Ile Pro Thr Ser Gly Ser Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 162 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic (18-CDR-H3) <400> 162 Asp Ser Gln Ser Ser Tyr Ile Gly Tyr Phe Asp Val 1 5 10 <210> 163 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (18-light chain variable region) <400> 163 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 Ser Ile Ser Arg Trp 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Arg Leu Gln 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 Ser Glu Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 164 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (18-light chain variable region gene) <400> 164 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatctct cgttggctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgca gcatcccgtc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tctgaatctt ttccgtggac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 165 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic (18-heavy-chain variable region) <400> 165 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ile Pro Thr Ser Gly Ser Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Gln Ser Ser Tyr Ile Gly Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 166 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Synthetic (18-heavy chain variable region gene) <400> 166 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt tcttacgata tcaactgggt gcggcaggcg 120 tcctgcaaag cctcaggcgg gacttttagt tcttacgata tcaactgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggtgg attatcccaa cctctggttc taccaactat 180 cccggccagg gtctcgaatg gatggggtgg attatcccaa cctctggttc taccaactat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagagattct 300 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagagattct 300 cagtcttctt acatcggtta cttcgatgtt tggggtcagg gtactctggt taccgtctca 360 cagtcttctt acatcggtta cttcgatgtt tggggtcagg gtactctggt taccgtctca 360 tcg 363 tcg 363 <210> 167<210> 167 <211> 214<211> 214 <000362<212> PRT<212> PRT <213> 人工序列<213> Artificial sequence <220><220> <223> 合成的 (18_轻链_κ) <223> Synthetic (18_light chain_κ) <400> 167 <400> 167 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly <00036 1 5 10 15 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Arg Trp Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Arg Trp <000363 20 25 30 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 35 40 45 Tyr Ala Ala Ser Arg Leu Gln 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 Ser Glu Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 168 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Synthetic (18_Heavy Chain) <400> 168 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ile Pro Thr Ser Gly Ser Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Gln Ser Ser Tyr Ile Gly Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu 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 Leu Gly 435 440 445 <210> 169 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (19_CDR-L1) <400> 169 Arg Ala Ser Gln Ser Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 170 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (19_CDR-L2) <400> 170 Asp Thr Ser Ser Leu Gln Ser 1 5 <210> 171 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (19_CDR-L3) <400> 171 Gln Gln Ser Tyr Ser Thr Pro Tyr Thr 1 5 <210> 172 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic (19_CDR-H1) <400> 172 Ala Tyr Gly Ile Ser 1 5 <210> 173 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic (19_CDR-H2) <400> 173 Arg Ile Ile Pro Tyr Leu Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 174 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic (19_CDR-H3) <400> 174 Leu Ser Tyr Gly Ile Gly Tyr Glu Ser Phe Asp Val 1 5 10 <210> 175 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (19-light chain-variable region) <400> 175 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 Ser 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 Asp Thr Ser Ser Leu Gln 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 Ser Tyr Ser Thr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 176 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (19-light chain variable region gene) <400> 176 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatctct aattacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgat acttcctctc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactcta ctccgtacac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 177 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic (19-heavy-chain-variable region) <400> 177 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ala Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Tyr Leu Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Ser Tyr Gly Ile Gly Tyr Glu Ser Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 178 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Synthetic (19-heavy chain variable region gene) <400> 178 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt gcatacggta tctcttgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggcgt attatcccat acctgggtac cgcaaactat 180 gcacaaaaat tccaaggccg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagactgtct 300 tacggtatcg gttacgaatc tttcgatgtt tggggtcagg gcactttagt gaccgtctca 360 tcg 363 <210> 179 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic (19_Light Chain_κ) <400> 179 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 Ser 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 Asp Thr Ser Ser Leu Gln 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 Ser Tyr Ser Thr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 180 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Synthetic (19_Heavy Chain) <400> 180 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ala Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Tyr Leu Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Ser Tyr Gly Ile Gly Tyr Glu Ser Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu 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 Leu Gly 435 440 445 <210> 181 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (20_CDR-L1) <400> 181 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 1 5 10 <210> 182 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (20_CDR-L2) <400> 182 Asp Thr Ser Thr Leu Gln Ser 1 5 <210> 183 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (20_CDR-L3) <400> 183 Gln Gln Ser Tyr Ser Phe Pro Trp Thr 1 5 <210> 184 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic (20_CDR-H1) <400> 184 Ser Tyr Ala Met Ser 1 5 <210> 185 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (20-CDR-H2) <400> 185 Ser Ile Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 186 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic (20_CDR-H3) <400> 186 Glu Leu Gly Gly Tyr Gly Phe Ser Tyr Phe Asp Tyr 1 5 10 <210> 187 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (20-light chain variable region) <400> 187 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 Ser Ile Ser 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 Asp Thr Ser Thr Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 188 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (20-light chain variable region gene) <400> 188 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatctct tcttacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgat acttccactc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtggac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 189 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic (20-heavy-chain-variable region) <400> 189 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ser Ile Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Leu Gly Gly Tyr Gly Phe Ser Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 190 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Synthetic (20-heavy chain variable region gene) <400> 190 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt tcttatgcaa tgtcttgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggtct atctcttctt ctggtggttc tacttactat 180 gccgattcag tgaagggtcg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagagaactg 300 ggtggttacg gtttctctta cttcgattac tggggtcagg gcactttagt gaccgtctca 360 tcg 363 <210> 191 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic (20_Light Chain_κ) <400> 191 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 Ser Ile Ser 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 Asp Thr Ser Thr Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 192 <211> 447 <212> PRT <213> Artificial sequence <220> <223> Synthetic (20_heavy chain) <400> 192 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45<l Gly Ser Ile Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Leu Gly Gly Tyr Gly Phe Ser Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu 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 Leu Gly 435 440 445 <210> 193 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (21_CDR-L1) <400> 193 Arg Ala Ser Gln Ser Ile Arg Asn Tyr Leu Asn 1 5 10 <210> 194 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (21_CDR-L2) <400> 194 Ala Thr Ser Ser Leu Gln Ser 1 5 <210> 195 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (21_CDR-L3) <400> 195 Gln Gln Ser Tyr Ser Phe Pro Trp Thr 1 5 <210> 196 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic (21_CDR-H1) <400> 196 Asp Tyr Ala Met Ser 1 5 <210> 197 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthesized (21_CDR-H2) <400> 197 Gly Ile Ser Gly Ser Asp Ile Tyr Tyr Ala Asp Ser Val Lys Gly 1 5 10 15 <210> 198 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (21_CDR-H3) <400> 198 Ala Val Ser Tyr Trp Ser Tyr Thr Phe Asp Tyr 1 5 10 <210> 199 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (21-light chain variable region) <400> 199 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 Ser Ile Arg 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 Ala Thr Ser Ser Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 200 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (21-light chain variable region gene) <400> 200 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatccgt aattacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgca acttcctctc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtggac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 201 <211> 118 <212> PRT <213> Artificial sequence <220> <223> Synthetic (21-heavy-chain-variable region) <400> 201 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ser Gly Ser Asp Ile Tyr Tyr Ala Asp Ser Val Lys Gly 50 55 60 Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met Glu 65 70 75 80 Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 85 90 95 Ala Val Ser Tyr Trp Ser Tyr Thr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 202 <211> 354 <212> DNA <213> Artificial sequence <220> <223> Synthetic (21-heavy chain variable region gene) <400> 202 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt gattatgcaa tgtcttgggt gcggcaggcg 120 tcctgcaaag cctcaggcgg gacttttagt gattatgcaa tgtcttgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggggt atctctggtt ctgatatcta ctatgccgat 180 cccggccagg gtctcgaatg gatggggggt atctctggtt ctgatatcta ctatgccgat 180 tcagtgaagg gtcgcgtaac tattaccgcc gacgaatcaa cctccaccgc ctacatggaa 240 tcagtgaagg gtcgcgtaac tattaccgcc gacgaatcaa cctccaccgc ctacatggaa 240 ctcagctctc tgaggtcaga agacacggcc gtctattatt gcgccagagc agtttcttac 300 ctcagctctc tgaggtcaga agacacggcc gtctattatt gcgccagagc agtttcttac 300 tggtcttaca cttttgatta ctggggtcag ggcactttag tgaccgtctc atcg 354 tggtcttaca cttttgatta ctggggtcag ggcactttag tgaccgtctc atcg 354 <210> 203<210> 203 <211> 214<211> 214 <212> PRT<212> PRT <213> Synthetic sequence<213> Synthetic sequence <220><220> <223> Synthetic (21_light chain_κ) <223> Synthetic (21_light chain_κ) <400> 203 <400> 203 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Arg Asn Tyr Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Arg Asn Tyr 20 25 30 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 35 40 45 Tyr Ala Thr Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Tyr Ala Thr Ser Ser Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 204 <211> 444 <212> PRT <213> Artificial sequence <220> <223> Synthetic (21_heavy chain) <400> 204 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ser Gly Ser Asp Ile Tyr Tyr Ala Asp Ser Val Lys Gly 50 55 60 Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met Glu 65 70 75 80 Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 85 90 95 Ala Val Ser Tyr Trp Ser Tyr Thr Phe Asp Tyr Trp Gly Gln 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 Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys 210 215 220 Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 <210> 205 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (22_CDR-L1) <400> 205 Arg Ala Ser Gln Ser Ile Gly Ser Tyr Leu Asn 1 5 10 <210> 206 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (22_CDR-L2) <400> 206 Asp Ala Ser Thr Leu Gln Ser 1 5 <210> 207 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (22_CDR-L3) <400> 207 Gln Gln Ser Tyr Ser Phe Pro Trp Thr 1 5 <210> 208 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthesized (22_CDR-H1) <400> 208 Ser Tyr Ala Met His 1 5 <210> 209 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (22_CDR-H2) <400> 209 Gly Ile Ser Ser Ser Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 210 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthesized (22_CDR-H3) <400> 210 Ala Leu Gly Val Val Gly Gly Thr Trp Phe Asp Tyr 1 5 10 <210> 211 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (22-light chain variable region) <400> 211 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 Ser Ile Gly 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 Asp Ala Ser Thr Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 212 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (22-light chain variable region gene) <400> 212 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatcggt tcttacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgat gcatccactc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtggac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 213 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic (22-heavy chain variable region) <400> 213 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ser Ser Ser Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Leu Gly Val Val Gly Gly Thr Trp Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 214 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Synthetic (22-heavy chain variable region gene) <400> 214 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt tcttatgcaa tgcactgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatggggggt atctcttctt ctggtggtac tacttactat 180 gccgattcag tgaagggtcg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagagcactg 300 ggtgttgttg gtggtacttg gttcgattac tggggtcagg gcactttagt gaccgtctca 360 tcg 363 <210> 215 <211> 214 <212> PRT <213> Artificial sequence <220> <223> Synthetic (22_light chain_κ) <400> 215 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 Ser Ile Gly 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 Asp Ala Ser Thr Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 216 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Synthetic (22_Heavy Chain) <400> 216 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ser Ser Ser Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Leu Gly Val Val Gly Gly Thr Trp Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu 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 Leu Gly 435 440 445 <210> 217 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic (23_CDR-L1) <400> 217 Arg Ala Ser Gln Ser Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 218 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic (23_CDR-L2) <400> 218 Asp Thr Ser Thr Leu Gln Ser 1 5 <210> 219 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic (23_CDR-L3) <400> 219 Gln Gln Ser Tyr Ser Phe Pro Trp Thr 1 5 <210> 220 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic (23_CDR-H1) <400> 220 Asp Tyr Ala Met His 1 5 <210> 221 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthesized (23_CDR-H2) <400> 221 Ala Ile Ser Gly Ser Gly Gly Tyr Thr His Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 222 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic (23_CDR-H3) <400> 222 Ser Ala Thr Phe Gly Val Trp Glu Thr Phe Asp Val 1 5 10 <210> 223 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic (23-light chain variable region) <400> 223 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 Ser 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 Asp Thr Ser Thr Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 224 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Synthetic (23-light chain variable region gene) <400> 224 gacattcaaa tgacgcagag tccctcctca ctgagtgcta gcgtgggcga tcgtgtgaca 60 attacttgtc gcgctagcca gtctatctct aattacctga actggtatca gcagaaaccg 120 ggcaaggcgc caaaattgct gatttacgat acttccactc tgcagtctgg tgtaccgtcc 180 cgtttctctg gcagcggttc tggtacggat tttaccctga ccatctcaag cctccagcct 240 gaagattttg ccacctatta ttgtcagcaa tcttactctt ttccgtggac gttcgggcag 300 ggaactaaag tggaaattaa a 321 <210> 225 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic (23-heavy chain variable region) <400> 225 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Ser Gly Ser Gly Gly Tyr Thr His Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Ala Thr Phe Gly Val Trp Glu Thr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 226 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Synthetic (23-heavy chain variable region gene) <400> 226 caagttcagc tggtccagag cggcgcagag gtgaagaagc ccggcagttc tgttaaggtt 60 tcctgcaaag cctcaggcgg gacttttagt gattatgcaa tgcactgggt gcggcaggcg 120 cccggccagg gtctcgaatg gatgggggca atctctggtt ctggtggtta cactcactat 180 gccgattcag tgaagggtcg cgtaactatt accgccgacg aatcaacctc caccgcctac 240 atggaactca gctctctgag gtcagaagac acggccgtct attattgcgc cagatctgca 300 actttcggtg tttgggaaac tttcgatgtt tggggtcagg gcactttagt gaccgtctca 360 tcg 363 <210> 227 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic (23_Light Chain_κ) <400> 227 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 Ser 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 Asp Thr Ser Thr Leu Gln 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 Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 228 <211> 447 <212> PRT <213> Artificial sequence <220> <223> Synthetic (23_heavy chain) <400> 228 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Ser Gly Ser Gly Gly Tyr Thr His Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Ala Thr Phe Gly Val Trp Glu Thr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu 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 Leu Gly 435 440 445 <210> 229 <211> 326 <212> PRT <213> artificial sequence <220> <223> synthetic (IgG4_Fc) <400> 229 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 305 310 315 320 Leu Ser Leu Ser Leu Gly 325 <210> 230 <211> 107 <212> PRT <213> Synthetic sequence <220> <223> Synthetic (κ constant region) <400> 230 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105

Claims

1. An anti-LILRB1 antibody or an antigen-binding fragment thereof, said anti-LILRB1 antibody or antigen-binding fragment comprising a complementarity-determining region (CDR) as described below: CDR-L1, wherein the amino acid sequence of CDR-L1 is shown in SEQ ID NO: 97; CDR-L2, wherein the amino acid sequence of CDR-L2 is shown in SEQ ID NO: 98; CDR-L3, wherein the amino acid sequence of CDR-L3 is shown in SEQ ID NO: 99; CDR-H1, wherein the amino acid sequence of CDR-H1 is shown in SEQ ID NO: 100; CDR-H2, wherein the amino acid sequence of CDR-H2 is shown in SEQ ID NO: 101; and CDR-H3, wherein the amino acid sequence of CDR-H3 is shown in SEQ ID NO:

102. The CDR is defined based on the Kabat number.

2. The anti-LILRB1 antibody or its antigen-binding fragment according to claim 1, wherein the anti-LILRB1 antibody or its antigen-binding fragment comprises: The light chain variable region, wherein the amino acid sequence of the light chain variable region is shown in SEQ ID NO: 103, and the heavy chain variable region, wherein the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:

105.

3. The anti-LILRB1 antibody or its antigen-binding fragment according to claim 1, wherein the antibody is a human IgG1 or IgG4 antibody.

4. The anti-LILRB1 antibody or its antigen-binding fragment according to claim 1, wherein the antigen-binding fragment is scFv, (scFv)2, Fab, Fab', F(ab')2 of the anti-LILRB1 antibody, comprising a fusion polypeptide of scFv fused to immunoglobulin Fc or a fusion polypeptide of scFv fused to a light chain constant region.

5. A pharmaceutical composition comprising an anti-LILRB1 antibody or an antigen-binding fragment thereof according to any one of claims 1 to 4.

6. A nucleic acid molecule encoding an anti-LILRB1 antibody or an antigen-binding fragment thereof according to any one of claims 1 to 4.

7. A recombinant vector comprising the nucleic acid molecule according to claim 6.

8. A recombinant cell comprising the nucleic acid molecule according to claim 6 or the recombinant vector according to claim 7.

9. A method for preparing an anti-LILRB1 antibody or an antigen-binding fragment thereof, the method comprising culturing recombinant cells according to claim 8.

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