Anti-C10ORF54 antibodies and uses thereof

Abstract

This disclosure relates to anti-C10ORF54 antibodies and their uses. Specifically, this disclosure generally relates to anti-C10orf54 antibodies, including antibody-drug conjugates containing said antibodies, and methods of using them.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 201580075579.0, application date December 11, 2015, and invention name “Anti-C10ORF54 Antibodies and Uses Thereof”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 090,880, filed December 11, 2014, the entire contents of which are incorporated herein by reference. Technical Field

[0004] The present disclosure generally relates to anti-C10orf54 antibodies, including antibody drug conjugates comprising the same, and methods of using the same. Background Art

[0005] C10orf54 is a single-pass type I transmembrane protein of 311 amino acids in length and contains a signal sequence and an IgV-like domain in its intracellular region. It is likely a member of the B7 protein family and has approximately 24% sequence identity with B7-H1 / PD-L1 (Flajnik et al., Immunogenetic 64:571-590 (2012)). The mouse ortholog of C10orf54 is called V-region immunoglobulin containing inhibitory factor of T cell activation (VISTA; also known as PD-L3). From CD4-positive regulatory T cells (T reg ) library (Wang et al., JEM 208(3):577-592(2011)). VISTA is mainly expressed on hematopoietic cells, and the expression of VISTA is highly regulated on bone marrow antigen presenting cells (APCs) and T cells (Wang et al., supra).

[0006] VISTA appears to have non-redundant functional activities with other Ig superfamily members, and may play a role in the development of autoimmunity and immune surveillance in cancer. For example, the expression of VISTA-Ig fusion protein has been shown to inhibit the proliferation of T cells and the production of cytokines in vitro, and the overexpression of VISTA on MCA105 tumor cells interferes with the host's protective anti-tumor immunity (Wang et al., supra). In addition, the administration of VISTA-specific monoclonal antibodies enhances the development of CD4-positive T cell responses and autoimmunity in vivo (Wang et al., supra). It has also been demonstrated that monoclonal antibodies against C10orf54 can prevent acute graft-versus-host disease in mice (Flies et al., J. Immunology 187 (4): 1537-1541 (2011)).

[0007] Citation or discussion of a reference herein shall not be construed as an admission that such is prior art to the present disclosure. Summary of the invention

[0008] The present disclosure provides antibodies that bind to C10orf54, including humanized antibodies and antibody drug conjugates comprising humanized antibodies, and methods of using antibodies and antibody drug conjugates, including for diagnosis and treatment of cancer. The present disclosure further provides proteins that bind to C10orf54, including binding proteins, such as antibodies that bind to one or more C10orf54 proteins or chimeric proteins. Such binding proteins, including antibodies, may be antagonists (e.g., inhibit one or more biological activities of C10orf54).

[0009] In a first aspect, antibodies that bind to C10orf54 are provided herein, including C10orf54 polypeptides, C10orf54 polypeptide fragments, or C10orf54 epitopes, collectively referred to herein as anti-C10orf54 antibodies. Also provided herein are anti-C10orf54 antibodies conjugated to drugs as antibody drug conjugates (ADCs), including ADCs of the formula AL-CTX, wherein A is an antibody, L is a linker, and CTX is a cytotoxin. In some embodiments, the anti-C10orf54 antibody is a humanized antibody that binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope. In certain embodiments, an anti-C10orf54 antibody comprises a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VL CDR3 of monoclonal antibody 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33) or a humanized variant thereof. In certain embodiments, an anti-C10orf54 antibody may further comprise VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0010] In certain embodiments, the antibody comprises less than 6 CDRs.In some embodiments, the antibody comprises or consists of one, two, three, four or five CDRs selected from VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and / or VL CDR3. In a specific embodiment, the antibody comprises or consists of one, two, three, four or five CDRs selected from the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and / or VL CDR3 of monoclonal antibody 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A or 305A described herein (e.g., Tables 12-33) or humanized variants thereof. In specific embodiments, the antibody further comprises VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3 and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0011] In specific embodiments, the antibody is a humanized antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding fragment, or any combination thereof. In specific embodiments, the antibody is a humanized monoclonal antibody described herein that binds a C10orf54 polypeptide (e.g., cell surface expressed or soluble C10orf54), a C10orf54 fragment, or a C10orf54 epitope (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VL CDR3), or an antigen-binding fragment thereof.

[0012] In a second aspect, provided herein are antibodies, including humanized antibodies, that (i) competitively block (e.g., in a dose-dependent manner) the binding of an anti-C10orf54 antibody provided herein to a C10orf54 polypeptide (e.g., cell surface expressed or soluble C10orf54), a C10orf54 fragment, or a C10orf54 epitope, and / or (ii) bind to an epitope of C10orf54 to which an anti-C10orf54 antibody (e.g., a humanized anti-C10orf54 antibody) provided herein binds. In other embodiments, the antibody competitively blocks (e.g., in a dose-dependent manner) binding of monoclonal antibodies 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A or 305A described herein (e.g., Tables 12-33) or humanized variants thereof to a C10orf54 polypeptide (e.g., cell surface expressed or soluble C10orf54), a C10orf54 fragment or a C10orf54 epitope. In other embodiments, the antibody binds to an epitope of C10orf54 bound by (e.g., recognized by) monoclonal antibody 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33) or a humanized variant thereof (e.g., a humanized anti-C10orf54 antibody).

[0013] In certain embodiments, an anti-C10orf54 antibody (e.g., a humanized anti-C10orf54 antibody) provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33, having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VL CDR3) is conjugated to or recombinantly fused to a diagnostic agent, a detectable agent, or a therapeutic agent. In some aspects, the therapeutic agent is a chemotherapeutic agent (e.g., a cystotoxic agent such as a cytotoxin). In some aspects, the detectable agent is a radioisotope, an enzyme, a fluorescent compound, a bioluminescent compound, or a chemiluminescent compound. In certain embodiments, an anti-C10orf54 antibody provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VL CDR3) is conjugated to a drug as an antibody drug conjugate (ADC). In some aspects, the antibody drug conjugate (ADC) is of the formula AL-CTX, wherein A is an antibody, L is a linker, and CTX is a cytotoxin.

[0014] In certain embodiments, compositions comprising an anti-C10orf54 antibody described herein (e.g., a humanized anti-C10orf54 antibody) are provided. In some embodiments, the composition comprises an antibody drug conjugate, wherein the antibody is an anti-C10orf54 antibody provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33, having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VLCDR3). Also provided herein are pharmaceutical compositions comprising an anti-C10orf54 antibody (including a humanized anti-C10orf54 antibody) provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2 and / or a VL CDR3).

[0015] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), CC8 (SEQ ID NO: 1249) and CC10 (SEQ ID NO: 1251), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248) and CC9 (SEQ ID NO: 1250).

[0016] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), and CC8 (SEQ ID NO: 1249), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), CC9 (SEQ ID NO: 1250), and CC10 (SEQ ID NO: 1251). In some aspects, such an antibody does not comprise one or more CDR sequences selected from the group consisting of: 30, 1099, 1104, 1105, 1110, 31, 1100, 1106, 1111, 1116, 32, 1101, 1107, 1112, 45, 1102, 1108, 1113, 40, 1103, 1114, 41, 1109, and 1115.

[0017] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245) and CC5 (SEQ ID NO: 1246), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), CC8 (SEQ ID NO: 1249), CC9 (SEQ ID NO: 1250) and CC10 (SEQ ID NO: 1251). In some aspects, such antibodies do not comprise one or more CDR sequences selected from the group consisting of: 36, 1081, 1086, 1087, 1092, 37, 1082, 1088, 1093, 1098, 38, 1083, 1089, 1094, 45, 1084, 1090, 1095, 46, 1085, 1096, 47, 1091, and 1097.

[0018] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), CC8 (SEQ ID NO: 1249), and CC9 (SEQ ID NO: 1250), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), CC9 (SEQ ID NO: 1250), and CC10 (SEQ ID NO: 1251). In some aspects, such antibodies do not comprise one or more CDR sequences selected from the group consisting of: 33, 1117, 1122, 1123, 1128, 34, 1118, 1124, 1129, 1134, 35, 1119, 1125, 1130, 42, 1120, 1126, 1131, 43, 1121, 1132, 44, 1127, and 1133.

[0019] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC3 (SEQ ID NO: 1244), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), CC8 (SEQ ID NO: 1249), and CC9 (SEQ ID NO: 1250), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), and CC10 (SEQ ID NO: 1251).

[0020] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), CC8 (SEQ ID NO: 1249), and CC10 (SEQ ID NO: 1251), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), CC9 (SEQ ID NO: 1250), and CC10 (SEQ ID NO: 1251).

[0021] In a third aspect, an isolated nucleic acid molecule is provided that encodes an anti-C10orf54 antibody described herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VHCDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VL CDR3) (including a VH chain, a VL chain, a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2 and / or a VL CDR3 of a humanized anti-C10orf54 antibody that binds a C10orf54 polypeptide, a C10orf54 polypeptide fragment or a C10orf54 epitope). In certain embodiments, the nucleic acid molecule encodes a VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of a monoclonal antibody 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33) or a humanized variant thereof. In certain embodiments, the nucleic acid molecule also encodes a VHFR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof. Also provided herein are vectors and host cells comprising nucleic acid molecules encoding anti-C10orf54 antibodies (eg, humanized anti-C10orf54 antibodies), and methods of producing anti-C10orf54 antibodies by culturing the host cells provided herein under conditions that promote the production of the anti-C10orf54 antibodies.

[0022] In a fourth aspect, provided herein are methods for treating, preventing or ameliorating a disease, disorder or condition, including one or more symptoms of a disease, disorder or condition, the method comprising administering to a subject a therapeutically effective amount of an anti-C10orf54 antibody described herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2 and / or a VL CDR3), including antibody drug conjugates (ADCs) containing an anti-C10orf54 antibody provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VLCDR3), thereby treating, preventing or ameliorating a disease, disorder or condition, including one or more symptoms of a disease, disorder or condition. In some embodiments, the anti-C10orf54 antibody is a humanized antibody that binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope. In one embodiment, the disease, disorder, or condition is caused by or associated with C10orf54, including being caused by or associated with cells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressor cells (MDSCs), suppressor dendritic cells (suppressor DCs), and / or regulatory T cells (Tregs)). In certain embodiments, the disease is cancer, such as leukemia, bladder cancer, skin cancer, colon cancer, breast cancer, liver cancer, kidney cancer, lung cancer, gastric cancer, pancreatic cancer, esophageal cancer, or fibrosarcoma. In one embodiment, the leukemia is acute myeloid leukemia (AML). In other embodiments, the disease is graft-versus-host disease (GVHD).Other methods provided include using an anti-C10orf54 antibody provided herein that has C10orf54 binding activity to a cell expressing C10orf54 (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VL CDR3), for example as an unconjugated antibody or a conjugated antibody (ADC), including for inhibiting and / or killing cells expressing C10orf54 (e.g., having anti-tumor activity to mediate an anti-tumor effect). In certain embodiments, the anti-C10orf54 antibodies provided herein, including ADCs containing an anti-C10orf54 antibody (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33) having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VLCDR3) are used to inhibit C10orf54-mediated inhibitory activity on T cells (e.g., to allow for an effective anti-tumor immune response). In certain embodiments, the anti-C10orf54 antibodies provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33)) have a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VLCDR1, a VL CDR2, and / or a VL CDR3) directly kills cells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressor cells (MDSCs), suppressor dendritic cells (suppressor DCs), and / or regulatory T cells (Tregs)) through, for example, antibody-dependent cellular cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC).In certain embodiments, the present invention comprises an anti-C10orf54 antibody provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33)), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VL CDR3), by, for example, allowing internalization of cytotoxic drugs, including direct killing of cells expressing C10orf54 by binding to cells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressor cells (MDSCs), suppressive dendritic cells (suppressor DCs), and / or regulatory T cells (Tregs)). In certain embodiments, an anti-C10orf54 antibody provided herein, or an antibody drug conjugate (ADC) comprising an anti-C10orf54 antibody provided herein, is used in a method of treating cancer (e.g., bladder cancer, breast cancer, colon cancer, connective tissue cancer, rectal cancer, gastric cancer, esophageal cancer, lung cancer, laryngeal cancer, kidney cancer, oral cancer, ovarian cancer, or prostate cancer, or sarcoma, melanoma, glioma, lymphoma, or leukemia) or treating a tumor associated with myeloid-derived suppressor cells (MDSCs) (e.g., colon cancer, mammary carcinoma, fibrosarcoma, thymoma, lung cancer, renal cell carcinoma, mesothelioma, glioma, lymphoma, sarcoma, prostate cancer, sarcoma, or head and neck cancer). In any of the above embodiments, the anti-C10orf54 antibody can be a humanized anti-C10orf54 antibody provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VL CDR3) that binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope.

[0023] In a fifth aspect, provided herein is a method of inhibiting cell growth and / or killing a cell having C10orf54 cell surface expression, comprising contacting the cell with an effective amount of an anti-C10orf54 antibody or an antibody drug conjugate comprising an anti-C10orf54 antibody provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VL CDR3). In one embodiment, the cell is a regulatory T cell (e.g., a CD4 + Foxp3 + Regulatory T cells). In certain embodiments, provided herein are methods of inhibiting tumor growth accompanied by inflammation in a subject, comprising administering an effective amount of an anti-C10orf54 antibody, including an ADC comprising an anti-C10orf54 antibody provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VLCDR3). In other embodiments, the cell is a myeloid-derived suppressor cell (e.g., CD11b + CD11b 高 myeloid-derived suppressor cells) or suppressor dendritic cells (e.g., CD11b + CD11b 高Dendritic cells). In other embodiments, the cell is a cancerous or precancerous cell. Other methods provided include using an anti-C10orf54 antibody provided herein that has C10orf54 binding activity to a cell expressing C10orf54 (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VLCDR2, and / or a VL CDR3) are included, for example, as an unconjugated antibody or a conjugated antibody (ADC) for inhibiting and / or killing cells expressing C10orf54 (e.g., having anti-tumor activity to mediate an anti-tumor effect). In certain embodiments, an anti-C10orf54 antibody, including an ADC containing an anti-C10orf54 antibody provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VLCDR1, a VL CDR2, and / or a VL CDR3) inhibits C10orf54-mediated inhibitory activity on T cells (e.g., to allow for an effective anti-tumor immune response). In certain embodiments, the anti-C10orf54 antibodies provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33)) have a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VL CDR3) directly kills cells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressor cells (MDSCs), suppressor dendritic cells (suppressor DCs), and / or regulatory T cells (Tregs) bearing C10orf54, for example, by antibody-dependent cellular cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC).In certain embodiments, the anti-C10orf54 antibodies provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33)) have a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VLCDR1, a VL CDR2, and / or a VL CDR3) directly kills cells expressing C10orf54 by, for example, allowing internalization of cytotoxic drugs, including by binding to cells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressor cells (MDSCs), suppressive dendritic cells (suppressor DCs), and / or regulatory T cells (Tregs)). In any of the above embodiments, the anti-C10orf54 antibody can be a humanized anti-C10orf54 antibody provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2 and / or a VL CDR3) that binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope.

[0024] In a sixth aspect, provided herein is a method of modulating an immune response in a subject, comprising administering to the subject an effective amount of an anti-C10orf54 antibody (e.g., a humanized anti-C10orf54 antibody) provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VL CDR3). In one embodiment, modulating comprises increasing T cell activation. In other embodiments, modulating comprises increasing T cell proliferation. In another embodiment, modulating comprises increasing cytokine production.

[0025] In a seventh aspect, provided herein is a method for detecting C10orf54 in a sample, comprising contacting the sample with an anti-C10orf54 antibody (e.g., a humanized anti-C10orf54 antibody) provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VLCDR1, a VL CDR2, and / or a VL CDR3), e.g., an antibody comprising a detectable agent. In certain embodiments, the sample comprises cells expressing C10orf54 on their surface.

[0026] In an eighth aspect, provided herein is a method for treating cancer, comprising administering to a subject an anti-C10orf54 antibody (e.g., a humanized anti-C10orf54 antibody) provided herein, or an antibody comprising an anti-C10orf54 antibody (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VL In some embodiments, the invention relates to an antibody drug conjugate (ADC) containing a C10orf54-expressing protein (CDR3) (e.g., an ADC of the formula AL-CTX, wherein A is an antibody, L is a linker, and CTX is a cytotoxic agent), comprising an amount effective to kill cells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressor cells (MDSCs), suppressor dendritic cells (suppressor DCs) and / or regulatory T cells (Tregs)). In some embodiments, the cancer is acute myeloid leukemia (AML). In any of the above embodiments, the anti-C10orf54 antibody can be a humanized anti-C10orf54 antibody provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2 and / or a VL CDR3) that binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope.

[0027] In a ninth aspect, provided herein is a method for killing a cell expressing C10orf54 (e.g., a tumor cell, a myeloid-derived suppressor cell (MDSC), a suppressor dendritic cell (suppressor DC), and / or a regulatory T cell (Treg)), comprising contacting a cell expressing C10orf54 (e.g., a tumor cell, a myeloid-derived suppressor cell (MDSC), a suppressor dendritic cell (suppressor DC), and / or a regulatory T cell (Treg)) with an amount of a cytokine provided herein. The anti-C10orf54 antibody provided herein or comprising an anti-C10orf54 antibody (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH In some embodiments, the invention relates to an antibody drug conjugate (ADC) comprising a plurality of antigen-binding proteins (e.g., an antibody-drug conjugate (ADC)) (e.g., an ADC of the formula AL-CTX, wherein A is an antibody, L is a linker, and CTX is a cytotoxic agent) and effectively kills cells (e.g., tumor cells, myeloid-derived suppressor cells (MDSCs), suppressor dendritic cells (suppressor DCs), and / or regulatory T cells (Tregs)). In some embodiments, the tumor cells are AML cells. In any of the above embodiments, the anti-C10orf54 antibody can be a humanized anti-C10orf54 antibody provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VLCDR1, a VL CDR2, and / or a VL CDR3) that binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope.

[0028] In a tenth aspect, provided herein are kits comprising an anti-C10orf54 antibody (e.g., a humanized anti-C10orf54 antibody) provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VL CDR3), wherein the antibody binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope. In some embodiments, the kit comprises an antibody drug conjugate (ADC), wherein the antibody is an anti-C10orf54 antibody (e.g., a humanized anti-C10orf54 antibody) provided herein (e.g., 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A described herein (e.g., Tables 12-33), having a VH domain, a VL domain, a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and / or a VL CDR3).

[0029] the term

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. The entire contents of all patents, applications, published applications and other publications are incorporated herein by reference. When a term has multiple definitions herein, the definitions in this section shall prevail unless otherwise stated.

[0031] The term "about" or "approximately" means within 20%, such as within 10% or within 5% (or 1% or less) of a given value or range.

[0032] As used herein, "administering" or "administering" refers to the act of injecting or otherwise physically delivering a substance (e.g., an anti-C10orf54 antibody provided herein) to a patient when the substance is present outside the body, such as by mucosal, intradermal, intravenous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art. When treating a disease or its symptoms, the administration of the substance is generally performed after the onset of the disease or its symptoms. When preventing a disease or its symptoms, the administration of the substance is generally performed before the onset of the disease or its symptoms.

[0033] As used herein, an "agonist" of C10orf54 refers to a molecule that is capable of activating or otherwise increasing one or more biological activities of C10orf54, e.g., a C10orf54 receptor, e.g., in a cell expressing C10orf54 or in a cell expressing a C10orf54 ligand. In some embodiments, an agonist of C10orf54 (e.g., an agonistic antibody provided herein) can act, e.g., by activating a cell expressing C10orf54 or a C10orf54 receptor or otherwise increasing activation and / or cell signaling pathways, thereby increasing a biological activity mediated by C10orf54 in a cell relative to the biological activity mediated by C10orf54 in the absence of the agonist. In certain embodiments, the antibodies provided herein are agonistic anti-C10orf54 antibodies.

[0034] The term "alkyl" as used herein refers to a straight chain, branched chain or cyclic (also referred to as "cycloalkyl" in this case) hydrocarbon containing 1-10 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. In certain embodiments, the alkyl group is optionally substituted.

[0035] The term "C 1-6 "Alkyl" refers to a straight chain, branched chain or cyclic (in this case also referred to as "cycloalkyl") hydrocarbon containing 1 to 6 carbon atoms.

[0036] The term "C 1-3 "Alkyl" refers to a straight or branched chain hydrocarbon containing 1 to 3 carbon atoms.

[0037] The term "alkenyl" as used herein refers to a hydrocarbon compound of a straight chain, branched chain or ring (in this case, also referred to as a "cycloalkenyl") containing 2-10 carbons and containing at least one carbon-carbon double bond formed by removing two hydrogens. In some embodiments, depending on the structure, the alkenyl is a monoradical or diradical (e.g., alkenylene). In some embodiments, the alkenyl is optionally substituted. The example of the alkenyl includes but is not limited to vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl and 2-methyl-1-heptenyl. In certain embodiments, the alkenyl is optionally substituted.

[0038] The term "C 2-6"Alkenyl" refers to a straight chain, branched or cyclic (in this case, also referred to as a "cycloalkyl") hydrocarbon containing 2 to 6 carbon atoms and at least one carbon-carbon double bond formed by the removal of two hydrogens.

[0039] The term "alkoxy" as used herein refers to an alkyl group as defined herein, appended to the parent molecular moiety through an oxygen atom. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexoxy.

[0040] "Amino acid" (or AA) or amino acid residue includes, but is not limited to, the 20 naturally occurring amino acids generally designated by three letter symbols, and also includes 4-hydroxyproline, hydroxylysine, demosine, isodesine, 3-methylhistidine, norvalin, β-alanine, γ-aminobutyric acid, homocysteine, homoserine, ornithine, and methionine sulfone. The amino acid residues of the present application also include the corresponding N-methyl amino acids, such as -N(CH 3 )CH 2 C(O)O-、-NHC(O)CH 2 CH 2 CH(NHCH 3 )C(O)O-, etc. In this application, amino acids, dipeptides, tripeptides, oligomers and amino acids referred to as -(AA) r -polypeptides may include corresponding non-N-alkylated amino acids and peptides (eg, non-N-methylated amino acids in the peptides), as well as mixtures of non-N-alkylated amino acids and N-alkylated amino acids in the peptides.

[0041] An "antibody drug conjugate" or "ADC" is an antibody conjugated to one or more cytotoxins via one or more linkers. An antibody drug conjugate (ADC) may have the formula AL-CTX, where A is an antibody, L is a linker, and CTX is a cytotoxin.

[0042] In the context of polypeptides, the term "analog" as used herein refers to a polypeptide having similar or identical functions to a C10orf54 polypeptide, a fragment of a C10orf54 polypeptide, or an anti-C10orf54 antibody, but does not necessarily comprise an amino acid sequence similar or identical to a C10orf54 polypeptide, a fragment of a C10orf54 polypeptide, or an anti-C10orf54 antibody, or has a structure similar or identical to a C10orf54 polypeptide, a fragment of a C10orf54 polypeptide, or an anti-C10orf54 antibody. A polypeptide having a similar amino acid sequence refers to a polypeptide that satisfies at least one of the following: (a) having a similar amino acid sequence to a C10orf54 polypeptide described herein (e.g., SEQ ID NO: 1079), a C10orf54 polypeptide fragment or an anti-C10orf54 antibody; (b) a polypeptide encoded by a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence encoding a C10orf54 polypeptide, a C10orf54 polypeptide fragment or an anti-C10orf54 antibody as described herein; A nucleotide sequence of a 10orf54 antibody (or a VH or VL region thereof) having at least 5 amino acid residues, at least 10 amino acid residues, at least 15 amino acid residues, at least 20 amino acid residues, at least 25 amino acid residues, at least 40 amino acid residues, at least 50 amino acid residues, at least 60 amino acid residues, at least 70 amino acid residues, at least 80 amino acid residues, at least 90 amino acid residues, at least 100 amino acid residues, at least 125 amino acid residues, or at least 150 amino acid residues (see, e.g., Sambrook et al. (2001)). Molecular Cloning:A Laboratory Manual , Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Maniatis et al. (1982) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, NY); and (c) a polypeptide encoded by a nucleotide sequence that is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to a nucleotide sequence encoding a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or an anti-C10orf54 antibody (or its VH or VL region) described herein. A polypeptide having a similar structure to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or an anti-C10orf54 antibody described herein refers to a polypeptide having a similar secondary, tertiary, or quaternary structure to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 antibody described herein. The structure of a polypeptide can be determined by methods known to those skilled in the art, including but not limited to X-ray crystallography, nuclear magnetic resonance, and crystallographic electron microscopy.

[0043] As used herein, an "antagonist" or "inhibitor" of C10orf54 refers to a molecule that is capable of inhibiting or otherwise reducing one or more biological activities of C10orf54, for example, in a cell expressing C10orf54 or in a cell expressing a C10orf54 ligand (such as a C10orf54 receptor). In some embodiments, an antagonist of C10orf54 (e.g., an antagonist antibody provided herein) can act by, for example, inhibiting or otherwise reducing activation and / or cell signaling pathways of a cell expressing C10orf54 or a C10orf54 receptor, thereby inhibiting a biological activity mediated by C10orf54 in a cell relative to the biological activity mediated by C10orf54 in the absence of the antagonist. In certain embodiments, the antibodies provided herein are antagonist anti-C10orf54 antibodies.

[0044] The terms "antibody" and "immunoglobulin" or "Ig" are used interchangeably herein and are intended to include polypeptide products of B cells within the immunoglobulin class of polypeptides, which are capable of binding to a specific molecular antigen and are composed of two identical pairs of polypeptide chains, wherein each pair has one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), each amino-terminal portion of each chain comprising a variable region of about 100 to about 130 or more amino acids, and each carboxyl-terminal portion of each chain comprising a constant region (see Borrebaeck (ed.) (1995) Antibody Engineering , 2nd edition, Oxford University Press; Kuby (1997) Immunology, 3rd ed., WH Freeman and Company, New York). In particular embodiments, specific molecular antigens that can be bound by the antibodies provided herein include target C10orf54 polypeptides, fragments or epitopes.

[0045] Antibodies also include, but are not limited to, synthetic antibodies, monoclonal antibodies, recombinantly produced antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, intracellular antibodies, anti-idiotypic (anti-Id) antibodies, and functional fragments of any of the above, wherein the functional fragment refers to a portion of an antibody heavy chain or light chain polypeptide that retains part or all of the antibody binding activity in the antibody from which the fragment is derived. Non-limiting examples of functional fragments include single-chain Fv (scFv) (e.g., including monospecific, bispecific, etc.), Fab fragments, F(ab') fragments, F(ab) 2 Fragment, F(ab') 2 Fragments, disulfide-linked Fv (sdFv), Fd fragments, Fv fragments, diabodies, triabodies, tetrabodies and minibodies. In particular, the antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, such as antigen binding domains or molecules, which contain an antigen binding site that binds to the C10orf54 antigen (e.g., one or more complementarity determining regions (CDRs) of an anti-C10orf54 antibody). Such antibody fragments can be found, for example, in Harlow and Lane, Antibodies: A Laboratory Manual , Cold Spring Harbor Laboratory, New York (1989); Myers (ed.), Molec.Biology and Biotechnology: Acomprehensive Desk Reference , New York: VCH Publisher, Inc.; Huston et al., Cell Biophysics, 22: 189-224 (1993); Plückthun and Skerra, Meth. Enzymol, 178: 497-515 (1989) and in Day, ED, Advanced Immunochemistry , 2nd edition, Wiley-Liss, Inc., New York, NY (1990). The antibodies provided herein can be any type of immunoglobulin molecule (e.g., IgG, IgE, IgM, IgD, IgA and IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), or any subclass (e.g., IgG2a and IgG2b). The anti-C10orf54 antibodies provided herein can be agonistic antibodies or antagonistic antibodies.

[0046] The terms "antibody that specifically binds to C10orf54", "antibody that specifically binds to a C10orf54 epitope", "anti-C10orf54 antibody" and similar terms are also used interchangeably herein to refer to an antibody that specifically binds to a C10orf54 polypeptide (e.g., a C10orf54 antigen or epitope). Such antibodies include humanized antibodies. An antibody that specifically binds to a C10orf54 antigen may cross-react with related antigens. In certain embodiments, an antibody that specifically binds to a C10orf54 antigen does not cross-react with other antigens. An antibody that specifically binds to a C10orf54 antigen can be identified, for example, by immunoassays, BIAcore or other techniques known to those of skill in the art. An antibody specifically binds to a C10orf54 antigen when the antibody binds to the C10orf54 antigen with a higher affinity than any cross-reactive antigen, as determined using experimental techniques such as radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA). Typically, a specific or selective reaction will be at least two times the background signal or noise, more typically more than 10 times the background. See, e.g. Paul, ed., 1989, Fundamental Immunology 2nd Edition , Raven Press, New York, pp. 332-336, for a discussion of antibody specificity. In certain embodiments, an antibody that "binds" an antigen of interest is an antibody that binds to the antigen with sufficient affinity so that the antibody can be used as a diagnostic and / or therapeutic agent in cells or tissues that target the expression of the antigen, and does not significantly cross-react with other proteins. In such embodiments, as determined by fluorescence activated cell sorting (FACS) analysis or radioimmunoprecipitation (RIA), the degree of binding of the antibody to a "non-target" protein will be less than about 10% of the binding of the antibody to its specific target protein. With regard to the binding of an antibody to a target molecule, the term "specific binding" or "specifically binding" or "specific to" an epitope on a specific polypeptide or specific polypeptide target refers to a binding that is measurably different from nonspecific interactions. Specific binding can be measured, for example, by comparing the binding of a molecule to a control molecule, which is typically a molecule with a similar structure that does not have binding activity. For example, specific binding can be determined by competing with a control molecule similar to the target, for example, an excess of unlabeled targets. In this case, if the binding of the labeled target to the probe is competitively inhibited by excess unlabeled target, specific binding is indicated. As used herein, the term "specific binding" or "specifically binds to" or "specific for" a particular polypeptide or epitope on a particular polypeptide target can be defined by, for example, having at least about 10 -4 M, or at least about 10 -5 M, or at least about 10 -6 M, or at least about 10 -7 M, or at least about 10 -8M, or at least about 10 -9 M, or at least about 10 -10 M, or at least about 10 -11 M, or at least about 10 -12 In some embodiments, the antibody that binds to C10orf54 has a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, or ≤0.1 nM. In some embodiments, the anti-C10orf54 antibody binds to a C10orf54 epitope that is conserved in C10orf54 from different species.

[0047] An "anti-C10orf54 antibody" or "antibody that binds to C10orf54" refers to an antibody that is capable of binding to C10orf54, including, for example, an antibody with sufficient affinity so that the antibody is useful as a diagnostic and / or therapeutic agent targeting C10orf54. Such antibodies include humanized antibodies. Preferably, the extent of binding of the anti-C10orf54 antibody to unrelated, non-C10orf54 proteins is less than about 10% of the binding of the antibody to C10orf54, as measured, for example, by fluorescence activated cell sorting (FACS) analysis or radioimmunoassay (RIA). An antibody that "specifically binds to" or is "specific for" C10orf54 is as defined above. In certain embodiments, the antibody that binds to C10orf54 has a dissociation constant (Kd) of <1 μM, <100 nM, <10 nM, <1 nM, or <0.1 nM. In certain embodiments, an anti-C10orf54 antibody binds to an epitope of C10orf54 that is conserved among C10orf54 from different species.

[0048] An "antigen" is a predetermined antigen to which an antibody can selectively bind. The target antigen can be a polypeptide, carbohydrate, nucleic acid, lipid, hapten or other naturally occurring or synthetic compound. In a specific embodiment, the target antigen is a polypeptide.

[0049] The terms "antigen binding fragment," "antigen binding domain," "antigen binding region," and similar terms refer to the portion of an antibody comprising the amino acid residues that interact with the antigen and confer specificity and affinity to the binding agent for the antigen (e.g., the complementarity determining region (CDR)).

[0050] As used herein, the term "binding" refers to the interaction between molecules to form a complex. The interaction can be a non-covalent interaction including, for example, hydrogen bonds, ionic bonds, hydrophobic interactions, and / or van der Waals interactions. A complex can also include the binding of two or more molecules bound together by covalent or non-covalent bonds, interactions, or forces. The strength of the total non-covalent interaction between a single antigen binding site on an antibody and a single epitope of a target molecule (such as C10orf54) is the affinity of the antibody or functional fragment for that epitope. The binding of an antibody to a monovalent antigen (k 1 ) and dissociation (k -1 ) ratio (k 1 / k -1 ) is the binding constant K, which is a measure of affinity. The value of K varies for different complexes of antibody and antigen and depends on k 1 and k -1 . The binding constant K of the antibodies provided herein can be determined using any of the methods provided herein or any other methods known to those skilled in the art. The affinity at one binding site does not always reflect the true strength of the interaction between the antibody and the antigen. When a complex antigen containing multiple repeated antigenic determinants (such as multivalent C10orf54) is contacted with an antibody containing multiple binding sites, the interaction between the antibody and the antigen at one site will increase the probability of a reaction at a second site. The strength of this multiple interaction between a multivalent antibody and an antigen is called avidity. The avidity of an antibody can be a better measure of its binding ability than the affinity of a single binding site of an antibody. For example, high avidity can compensate for low affinity, as can sometimes be found in pentameric IgM antibodies, which have lower affinity than IgG, but due to their multivalency, the affinity of IgM is high, which enables it to effectively bind to the antigen.

[0051] The term "C10orf54" or "C10orf54 polypeptide" and similar terms refer to a polypeptide encoded by the open reading frame 54 (C10orf54) gene of human chromosome 10 ("polypeptide", "peptide" and "protein" are used interchangeably herein), and its related polypeptides including SNP variants, C10orf54 is also known in the art as B7-H5, platelet receptor Gi24, GI24, stress-induced secretory protein 1, SISP1 and PP2135, which comprises the following amino acid sequence:

[0052]

[0053] C10orf54 polypeptides have been shown or predicted to contain several distinct regions in the amino acid sequence, including: a signal sequence (residues 1-32; see Zhang et al., Protein Sci. 13:2819-2824 (2004)); an immunoglobulin domain - IgV-like (residues 33-162); and a transmembrane region (residues 195-215). The mature C10orf54 protein includes amino acid residues 33-311 of SEQ ID NO: 1079. The extracellular domain of the C10orf54 protein includes amino acid residues 33-194 of SEQ ID NO: 1079. Related polypeptides include allelic variants (e.g., SNP variants); splice variants; fragments; derivatives; substitution, deletion and insertion variants; fusion polypeptides (e.g., chimeric proteins); and interspecies homologs, preferably retaining the activity of C10orf54 and / or sufficient to generate an anti-C10orf54 immune response. As will be appreciated by those skilled in the art, the anti-C10orf54 antibodies provided herein can bind to C10orf54 polypeptides, polypeptide fragments, antigens and / or epitopes, because an epitope is part of a larger antigen, which is part of a larger polypeptide fragment, which in turn is part of a larger polypeptide. C10orf54 can exist in native or denatured form. The C10orf54 polypeptides described herein can be isolated from a variety of sources, such as from human tissue types or other sources, or prepared by recombinant or synthetic methods. A "native sequence C10orf54 polypeptide" comprises a polypeptide having the same amino acid sequence as a corresponding C10orf54 polypeptide derived from nature. Such a native sequence C10orf54 polypeptide can be isolated from nature, or can be produced by recombinant or synthetic means. The term "native sequence C10orf54 polypeptide" specifically includes naturally occurring truncated or secreted forms of a specific C10orf54 polypeptide (e.g., an extracellular domain sequence), naturally occurring variant forms (e.g., alternatively spliced ​​forms), and allelic variants of naturally occurring polypeptides.

[0054] The cDNA nucleic acid sequence encoding the C10orf54 polypeptide includes:

[0055]

[0056] Orthologs of the C10orf54 polypeptide are also well known in the art. For example, the mouse ortholog of the C10irf54 polypeptide is the v-region immunoglobulin containing inhibitory factor of T cell activation (VISTA) (also known as PD-L3, PD-1H, PD-XL, Pro1412 and UNQ730), which shares about 70% sequence identity with the human polypeptide. Orthologs of C10orf54 can also be found in other organisms, including chimpanzees, cattle, rats and zebrafish.

[0057] "Cells expressing C10orf54", "cells expressing C10orf54" or their grammatical equivalents refer to cells expressing endogenous or transfected C10orf54 on the cell surface. Cells expressing C10orf54 include tumor cells with C10orf54, regulatory tumor cells (e.g., CD4 + Foxp3 + regulatory T cells), myeloid-derived suppressor cells (e.g., CD11b + CD11b 高 myeloid-derived suppressor cells) and / or suppressor dendritic cells (e.g., CD11b + CD11b 高 Dendritic cells). Cells expressing C10orf54 produce sufficient levels of C10orf54 on their surface so that anti-C10orf54 antibodies can bind to them. In some aspects, such binding can have a therapeutic effect on cancer. Cells that "overexpress" C10orf54 are cells that have significantly higher levels of C10orf54 on the cell surface compared to cells of the same tissue type known to express C10orf54. Such overexpression may be caused by gene amplification or increased transcription or translation. C10orf54 overexpression is determined in diagnostic or prognostic assays by assessing increased levels of C10orf54 protein present on the cell surface (e.g., by immunohistochemical analysis; FACS analysis). Alternatively, or additionally, the level of nucleic acid or mRNA encoding C10orf54 in cells can be measured, for example, by fluorescence in situ hybridization; (FISH; see WO98 / 45479 published in October 1998), Southern blotting, Northern blotting, or polymerase chain reaction (PCR) techniques, such as real-time quantitative PCR (RT-PCR). In addition to the above assays, various in vivo assays are available to those skilled in the art. For example, cells in a patient can be exposed to an antibody optionally labeled with a detectable agent, and binding of the antibody to the patient's cells can be evaluated, for example, by external scanning for radioactivity or by analyzing a biopsy taken from a patient previously exposed to the antibody. Tumor cells expressing C10orf54 include, but are not limited to, acute myeloid leukemia (AML) tumor cells.

[0058] "C10orf54-mediated disease," "C10orf54-mediated disorder," and "C10orf54-mediated condition" are used interchangeably and refer to any disease, disorder, or condition that is caused or contributed to, in whole or in part, by C10orf54. These diseases, disorders, or conditions include those caused by or associated with C10orf54, including those caused by or associated with cells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressor cells (MDSCs), suppressor dendritic cells (suppressor DCs), and / or regulatory T cells (Tregs)). In certain embodiments, C10orf54 is abnormally (e.g., highly) expressed on the surface of a cell. In some embodiments, C10orf54 may be abnormally upregulated on a particular cell type. In other embodiments, normal, abnormal or excess cell signaling results from the binding of C10orf54 to a C10orf54 ligand, which can bind to or interact with C10orf54.

[0059] The terms "cell proliferative disease" and "proliferative disease" refer to diseases associated with some degree of abnormal cell proliferation. In one embodiment, the cell proliferative disease is a tumor or cancer. As used herein, "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disease," "proliferative disease," and "tumor" are not mutually exclusive herein. The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), peritoneal cancer, hepatocellular carcinoma, stomach or gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, oral cancer, liver cancer, bladder cancer, urinary tract cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, melanoma, multiple myeloma and B-cell lymphoma, brain cancer, skin cancer, esophageal cancer, and head and neck cancer and related metastases.

[0060] The term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient or carrier with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Saline solutions and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dry skim milk, glycerol, propylene glycol, water, ethanol, etc. If desired, the composition can also contain a small amount of wetting agent or emulsifier or pH buffer. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, etc. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, PA. Such compositions will contain a prophylactically or therapeutically effective amount of the antibody, e.g., in isolated or purified form, together with a suitable amount of carrier to provide the form for administration to the patient. The formulation should suit the mode of administration.

[0061] As used herein, the term "chemical group" refers to two or more atoms bonded together as a single unit and forming part of a molecule.

[0062] A "chemotherapeutic agent" is a chemical agent (e.g., a compound or drug) used to treat cancer, regardless of its mechanism of action. Chemotherapeutic agents include compounds used in targeted therapy and conventional chemotherapy. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents, such as thiotepa and Cyclophosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzimidopamine, carbamazepine, meturedopa, and uredopa; ethyleneimines and methylamelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (particularly bullatacin and bullatacinone); delta-9-tetrahydrocannabinol (dronabinol, ); β-lapachone; lapachol; colchicine; betulinic acid; camptothecin (including the synthetic analogue topotecan CPT-11 (irinotecan, ), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; callystatin; CC-1065 (including its synthetic analogs adolesin, carzelesin, and biszelesin); podophyllotoxin; podophylloline; teniposide; cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycins (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistat in; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphthazine, clofosamide, estramustine, ifosfamide, mechlorethamine, oxazolidinone hydrochloride, melphalan, novitamin, phenylephrine, phenylephrine, trofosamide, uracil mustard; nitrosoureas such as carmustine, clozostatin, flutoxetine, lomustine, nimustine and ranimnustine; antibiotics such as enadiene antibiotics (e.g., calicheamicin, particularly calicheamicin gamma I and calicheamicin omega II (see, e.g., Agnew, Chem Intl. Ed. Engl. 33: 183-186 (1994); dynemicins, including dynemicin A; esperamicin; and neocarzinostatin chromophores and related chromophores (enediyne antibiotic chromophores), aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, actinomycin C, carabicin, caminomycin, carzinophilin, chromomycinis, actinomycin D, daunorubicin, detoxibacin, 6-diazo-5-oxo-L-norleucine, Doxorubicin (including morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolodoxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcomycin, mitomycins such as mitomycin C, mycophenolic acid, nocardiamycin, orixamycin, peplomycin, potfimromycin, puromycin, quelamycin, romazine, streptomycin, streptozotocin, tuberculin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5- Fluorouracil (5-FU); folic acid analogs such as folate (Denopterin), methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgen hormones such as dromostanolone propionate, propionate), testosterone, mesandrostane, testosterone lactone; antiadreners, such as aminoglutethimide, mitotane, triflurane; folic acid supplements, such as folinic acid; acetoglucuronide; aldehyde phosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecil; diazocine; elfornithine; elliptonium acetate; epothilones; epothilones; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansines, such as maytansine and ansamitocin; mitoguanidine; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triazinequinone; 2,2',2"-trichlorrotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, baculozolin A, and anguidine); urethane; vindesine Dacarbazine; mannitol mustard; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); thiotepa; taxanes, such as Paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE TM Cremophor-free, albumin-engineered paclitaxel nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, IL) and doxetaxel (Rhone-Poulenc Rorer, Antony, France); clofenac; gemcitabine ( 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine Oxaliplatin; leucovorin; vinorelbine Norvanone; edatrexate; daunorubicin; aminopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; capecitabine Any of the above pharmaceutically acceptable salts, acids or derivatives; and combinations of two or more of the above, such as CHOP, an abbreviation for cyclophosphamide, doxorubicin, vincristine and prednisolone combined therapy, and FOLFOX, oxaliplatin (ELOXATIN TM ) is an abbreviation for a treatment regimen combining 5-FU and leucovorin. Other chemotherapeutic agents include cytotoxic agents that can be used as antibody drug conjugates, such as maytansinoids (eg, DM1 and DM4) and auristatins (eg, MMAE and MMAF).

[0063] Also included in the definition of chemotherapeutic agents are: (i) anti-hormonal agents that modulate or inhibit the effects of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including Tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, troloxifene, keoxifene, LY 117018, onapristone, and (toremifene citrate); (ii) aromatase inhibitors, which inhibit the enzyme aromatase, which regulates the production of estrogen in the adrenal glands, such as, for example, 4(5)-imidazole, aminoundecyl imide, (Megestrol acetate), (exemestane, Pfizer), furamexine, fadomazole, RI (vorozole), (letrozole; Novartis) and (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; and tricitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors, such as ME inhibitors (WO 2007 / 044515); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, such as PKC-α, Raf and H-Ras, such as oblimersen ( Genta Inc.); (vii) ribozymes, such as VEGF expression inhibitors (e.g. ) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, e.g. and rIL-2; topoisomerase 1 inhibitors, such as rmRH; (ix) anti-angiogenic agents, such as bevacizumab ( Genentech); and any pharmaceutically acceptable salts, acids and derivatives of the foregoing.

[0064] The antibodies provided herein may include "chimeric" antibodies, as well as fragments of such antibodies, in which a portion of the heavy chain and / or light chain is identical or homologous to the corresponding sequence in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to the corresponding sequence in antibodies derived from other species or belonging to other antibody classes or subclasses (see U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)), as long as they exhibit the desired biological activity.

[0065] As used herein, the term "composition" is intended to encompass a product comprising specified ingredients (eg, antibodies provided herein), optionally in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients, optionally in the specified amounts.

[0066] "CDR" refers to one of the three hypervariable regions (H1, H2 or H3) within the non-framework region of the VH β-sheet framework of an immunoglobulin (Ig or antibody), or one of the three hypervariable regions (L1, L2 or L3) within the non-framework region of the VL β-sheet framework of an antibody. Thus, CDRs are variable region sequences interspersed within framework region sequences. CDR regions are well known to those skilled in the art and have been defined, for example, by Kabat as the most highly variable regions within an antibody variable (V) domain (Kabat et al., J. Biol. Chem. 252: 6609-6616 (1977); Kabat, Adv. Prot. Chem. 32: 1-75 (1978)). CDR region sequences are also structurally defined by Chothia as those residues that are not part of the conserved β-sheet framework and are therefore able to adapt to different conformations (Chothia and Lesk, J. Mol. Biol. 196: 901-917 (1987)). Both terms are well recognized in the art. CDR region sequences are also defined by AbM, Contact and IMGT. Fig.16A and 16B As shown. The positions of CDRs within canonical antibody variable domains have been determined by comparing many structures (Al-Lazikani et al., J. Mol. Biol. 273: 927-948 (1997); Morea et al., Methods 20: 267-279 (2000)). Because the number of residues in the hypervariable region varies among different antibodies, additional residues relative to the canonical positions are usually numbered next to the residue number in the canonical variable domain numbering scheme using a, b, c, etc. (Al-Lazikani et al., supra (1997)). Such nomenclature is also well known to those skilled in the art.

[0067] As used herein, the terms "hypervariable region", "HVR" or "HV" refer to regions in an antibody variable domain that are highly variable in sequence and / or form structurally defined loops. Typically, an antibody comprises six hypervariable regions; three in VH (H1, H2, H3), and three in VL (L1, L2, L3). Descriptions of many hypervariable regions are in use and are included herein. Kabat CDR is based on sequence variability and is the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition Public Health Service, National Institutes of Health, Bethesda, MD (1991)). Chothia refers to the position of the structural loop (Chothia and Lesk J Mol. Bioi. 196: 901-917 (1987)). When numbered using the Kabat numbering convention, the end of the Chothia CDR-HI loop differs between H32 and H34, depending on the length of the loop (this is because the Kabat numbering scheme places the insertion at H35A and H35B; if both 35A and 35B are absent, the loop ends at position 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34. The AbM hypervariable regions represent a compromise between the Kabat CDR and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. The "Contact" hypervariable regions are based on analysis of available complex crystal structures. Residues from each of these hypervariable regions are shown below.

[0068] Recently, a universal numbering system, ImMunoGeneTics (IMGT), has been developed and widely adopted. (Lafranc et al., Dev. Comp. Immunol. 27(1):55-77 (2003)). IMGT is a comprehensive information system specifically for immunoglobulins (IG), T cell receptors (TR) and major histocompatibility complex (MHC) of humans and other vertebrates. Therefore, CDRs are represented both according to amino acid sequence and position within the light chain or heavy chain. Since the "position" of CDRs within the structure of the immunoglobulin variable domain is conserved between species and exists in structures called loops, CDR and framework residues can be easily identified by using a numbering system that aligns variable domain sequences according to structural features. This information can be used to graft and replace CDR residues from an immunoglobulin from one species into a receptor framework, typically from a human antibody. The correspondence between Kabat numbering and the IMGT unique numbering system is also well known to those skilled in the art (e.g., Lefranc et al., supra) and is also described in detail in the literature. Fig.16A and 16B The exemplary system shown here combines Kabat and Chothia.

[0069] Table 1: CDR definitions

[0070]

[0071] The hypervariable region may include the following "extended hypervariable region": 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in VL, and 26-35 or 26-35A (H1), 50-65 or 49-65 (H2) and 93-102, 94-102 or 95-102 (H3) in VH. According to Kabat et al., supra, for each of these definitions, the variable domain residues are numbered 25. As used herein, the terms "HVR" and "CDR" are used interchangeably.

[0072] The term "constant region" or "constant domain" refers to the carboxyl terminal portion of the light chain and the heavy chain, which is not directly involved in the binding of the antibody to the antigen, but exhibits various effector functions, such as interaction with Fc receptors. The term refers to the portion of the immunoglobulin molecule that has a more conservative amino acid sequence relative to the other part of the immunoglobulin variable domain (containing the antigen binding site). The constant domain contains the CH1, CH2 and CH3 domains of the heavy chain and the CL domain of the light chain.

[0073] The term "cycloalkyl" as used herein refers to a monocyclic or polycyclic group containing only carbon and hydrogen, and includes saturated, partially unsaturated or fully unsaturated monocyclic or polycyclic groups. Cycloalkyl includes groups having 3 to 10 ring atoms.

[0074] In the context of polypeptides, the term "derivative" as used herein refers to a polypeptide comprising the amino acid sequence of a C10orf54 polypeptide, a fragment of a C10orf54 polypeptide, or an antibody that binds to a C10orf54 polypeptide, wherein the amino acid sequence is altered by the introduction of amino acid residue substitutions, deletions, or additions. The term "derivative" as used herein also refers to a C10orf54 polypeptide, a fragment of a C10orf54 polypeptide, or an antibody that binds to a C10orf54 polypeptide that has been chemically modified, such as by covalently attaching any type of molecule to the polypeptide. For example, but not limited to, a C10orf54 polypeptide, a fragment of a C10orf54 polypeptide, or an antibody that binds to a C10orf54 polypeptide may be chemically modified, such as by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, attachment to cellular ligands or other proteins, and the like. A derivative is modified in a manner that is different from the naturally occurring or starting peptide or polypeptide, regardless of the type or location of the attached molecule. Derivatives also include deletion of one or more chemical groups naturally present on a peptide or polypeptide. The derivatives of C10orf54 polypeptides, fragments of C10orf54 polypeptides, or C10orf54 antibodies may be chemically modified by chemical modification using techniques known to those skilled in the art, including but not limited to specific chemical cleavage, acetylation, formulation, metabolic synthesis of tunicamycin, etc. In addition, the derivatives of C10orf54 polypeptides, fragments of C10orf54 polypeptides, or C10orf54 antibodies may contain one or more non-classical amino acids. The polypeptide derivatives have similar or identical functions to the C10orf54 polypeptides, fragments of C10orf54 polypeptides, or C10orf54 antibodies described herein.

[0075] As used herein, the term "cytotoxic agent" or "cytotoxin" or "CTX" refers to a substance that inhibits or prevents cellular function and / or has a cytotoxic effect on cells (e.g., causes cell destruction). The term is intended to include alkylating agents, anthracyclines, cytoskeletal disruptors (taxanes), epothilones, histone deacetylase inhibitors (HDACs), inhibitors of topoisomerase I, inhibitors of topoisomerase II, kinase inhibitors, monoclonal antibodies, nucleotide analogs, peptide antibiotics, platinum-based agents, retinoids, vinca alkaloids or derivatives thereof, and radioactive isotopes. The term is also intended to include actinomycin, all-trans retinoic acid, azacytidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilones, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, tioguanine, topotecan, valrubicin, vinblastine, vincristine, vindesine, and vinorelbine. The term is also intended to include tubulin stabilizers, tubulin destabilizers, DNA alkylating agents, DNA minor groove binders, DNA intercalators, topoisomerase I inhibitors, topoisomerase II inhibitors, gyrase inhibitors, protein synthesis inhibitors, proteosome inhibitors, and antimetabolites. The term is also intended to include actinomycin D, Amonafide, Auristatin, Benzophenone, Benzothiazole, Calicheamicin, Camptothecin, CC-1065 (NSC 298223), Cemadotin, Colchicine, Combretastatin A4, Dolastatin, Doxorubicin, Elinefand, Emtansine (DM1), Etoposide, KF-12347 (Leinamycin), Maytansine, Methotrexate, Mitoxantrone, Nocodazole, Protease Inhibitor 1 (PSI 1), Bacitracin A, T-2 Toxin (Monocephalene Analog), Paclitaxel, Tubulysin, and vincristine. Preferred cytotoxins include auristatin, calicheamicin, maytansine and tubulysin. Other preferred cytotoxins include monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), calicheamicin gamma, mertansine, tubulysin T3 and tubulysin T4. Other preferred cytotoxins include calicheamicin, doxorubicin, camptothecin, duocarmycin, DM1, DM4, maytansine and tubulysin. Additional preferred cytotoxins include MMAE, MMAF and pyrrolobenzodiazepine (PBD).

[0076] The term "MMAF" generally refers to monomethyl auristatin F, whose chemical name is (S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamido)-3-methoxy-5-methylheptyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid. One of ordinary skill in the art will appreciate that MMAF is also described in the art as MeVal-Val-Dil-Dap-Phe, where "Dil" is dolaisoleuine and "Dap" is dolaproine.

[0077] The term "MMAE" generally refers to monomethyl auristatin E, whose chemical name is (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxohept-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide.

[0078] The term "pyrrolobenzoazepines" generally refers to the family of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimers, which are synthetic sequence-selective interstrand DNA minor groove cross-linkers developed from anthraquinones. Examples of pyrrolobenzoazepines include, but are not limited to, abbeymycin, chicamycin, DC-81, mazethramycin, neothramycin A and B, porothramycin, prothracarcin, sibanomicin (DC-102), sibiromycin, and tomamycin. Exemplary pyrrolidine benzoazepines include those disclosed in U.S. Pat. Nos. 7,049,311, 7,741,319, 8,697,688 (see, e.g., (26) in Example 5), and 8,765,740; International Publication Nos. WO2011 / 130598A1, WO2012 / 112708A1, WO2013 / 055987A1, WO2013 / 165940A1; and Jeffrey et al., Bioconjugate Chem. 2013, 24, 1256-1263 and Sutherland et al., Blood 2013, 122(8), 1455-1463; the entire contents of each of which are incorporated herein by reference.

[0079] The structures of T3 and T4 are provided below:

[0080]

[0081] The structure of MMAF is provided as follows:

[0082]

[0083] Its chemical name is "(S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid". Those of ordinary skill in the art will appreciate that MMAF is also described in the art as MeVal-Val-Dil-Dap-Phe, where "Dil" is dolaisoleuine and "Dap" is dolaproine.

[0084] The structure of MMAE is provided as follows:

[0085]

[0086] (MMAE), whose chemical name is "(S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxohept-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide". One of ordinary skill in the art will appreciate that MMAE is also described in the art as MeVal-Val-Dil-Dap-norephedrine, where "Dil" is dolaisoleuine and "Dap" is dolaproine.

[0087] The structures of three PBDs are provided as follows:

[0088]

[0089] Its chemical name is "(S)-11-hydroxy-7-methoxy-8-((5-(((S)-7-methoxy-2-methyl-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)pentyl)oxy)-2-methyl-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one"; and

[0090] The chemical name is "(S)-2-(4-aminophenyl)-8-(3-(((S)-2-cyclopropyl-7-methoxy-5-oxo-5,11a-dihydro-1H-phenylpropano[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)propoxy)-7-methoxy-1H-phenylpropano[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one" (see, for example, compound (26) in Example 5 of U.S. Patent No. 8,697,688); and

[0091]

[0092] Its chemical name is (S)-2-(4-aminophenyl)-7-methoxy-8-(3-(((S)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-5,11a-dihydro-1H-phenylpropano[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)propoxy)-1H-phenylpropano[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one.

[0093] Other cytotoxic agents include various anti-tumor or anti-cancer agents known in the art.

[0094] As used herein, the term "detectable probe" refers to a composition that provides a detectable signal. The term includes, but is not limited to, any fluorophore, chromophore, radiolabel, enzyme, antibody or antibody fragment, etc. that provides a detectable signal through its activity.

[0095] The term "diagnostic agent" refers to a substance administered to a subject that aids in the diagnosis of a disease. Such substances can be used to visualize, locate, and / or determine the location of a process that causes a disease. In certain embodiments, the diagnostic agent includes a substance conjugated to an antibody provided herein that, when administered to a subject or contacted with a subject sample, aids in the diagnosis of cancer, tumor formation, or any other C10orf54-mediated disease.

[0096] The term "detectable agent" refers to a substance that can be used to determine the presence or existence of a desired molecule in a sample or subject, such as an antibody provided herein. A detectable agent can be a substance that can be visualized or other substances that can be determined and / or measured (e.g., by quantification).

[0097] An "effective amount" is an amount sufficient to achieve a beneficial or desired result. An effective amount can be administered in one or more administrations, applications or doses. Such delivery depends on many variables, including the time period over which a single dosage unit is used, the bioavailability of the agent, the route of administration, and the like. In some embodiments, an effective amount also refers to the amount of an antibody provided herein that achieves a specified result (e.g., inhibiting the biological activity of C10orf54 in a cell, such as regulating T cell activation and / or proliferation). In some embodiments, the term refers to a therapeutic amount (e.g., an antibody or pharmaceutical composition provided herein) sufficient to reduce and / or improve the severity and / or duration of a given disease and / or its associated symptoms. The term also includes the amount required to reduce or improve the progression or course of a given disease, reduce or improve the recurrence, development or onset of a given disease, and / or improve or enhance the preventive or therapeutic effect of another treatment (e.g., a treatment other than the anti-C10orf54 antibody provided herein). In some embodiments, the effective amount of an antibody is from about 0.1 mg / kg (mg of antibody per kg of subject body weight) to about 100 mg / kg. In certain embodiments, the effective amount of an antibody provided herein is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, 3 mg / kg, 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, or about 100 mg / kg (or within a range thereof).

[0098] As used herein, the term "electrophilic leaving group" refers to a leaving group that accepts an electron pair to form a covalent bond. Typically, electrophiles are susceptible to attack by complementary nucleophiles, including reduced thiols from disulfide bonds of antibodies.

[0099] As used herein, the term "electrophilic leaving group that selectively reacts with thiols" refers to an electrophilic leaving group that selectively reacts with thiols relative to other nucleophiles. In certain embodiments, the electrophilic leaving group that selectively reacts with thiols selectively reacts with reduced thiols from disulfide bonds of antibodies.

[0100] When referring to a nucleic acid molecule, the term "encoding" or its grammatical equivalents refers to a nucleic acid molecule in its natural state, or when manipulated by methods well known to those skilled in the art, it can be transcribed to produce mRNA, which is then translated into a polypeptide and / or fragments thereof. The antisense strand is the complement of such a nucleic acid molecule, and the coding sequence can be deduced therefrom.

[0101] As used herein, the term "epitope" refers to a localized region on the surface of an antigen (e.g., a C10orf54 polypeptide or a C10orf54 polypeptide fragment) that is capable of binding to one or more antigen binding regions of an antibody and is antigenic or immunogenic in an animal, such as a mammal (e.g., a human), and is capable of eliciting an immune response. An epitope having immunogenic activity is a portion of a polypeptide that elicits an antibody response in an animal. An epitope having antigenic activity is a portion of a polypeptide to which an antibody binds, as determined by any method known in the art (e.g., by immunoassay). An antigenic epitope is not necessarily immunogenic. An epitope is generally composed of chemically active surface groups of a molecule, such as amino acids or sugar side chains, and has specific three-dimensional structural characteristics as well as specific charge characteristics. The region of a polypeptide that contributes to an epitope may be contiguous amino acids of a polypeptide, or an epitope may be a collection of two or more non-contiguous regions of a polypeptide. An epitope may or may not be a three-dimensional surface feature of an antigen. In certain embodiments, a C10orf54 epitope is a three-dimensional surface feature of a C10orf54 polypeptide. In other embodiments, the C10orf54 epitope is a linear feature of the C10orf54 polypeptide. Typically, an antigen has multiple or many different epitopes and reacts with many different antibodies.

[0102] The term "excipient" as used herein refers to an inert substance generally used as a diluent, carrier, preservative, binder or stabilizer, and includes, but is not limited to, proteins (e.g., serum albumin, etc.), amino acids (e.g., aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.), fatty acids and phospholipids (e.g., alkyl sulfonate, caprylate, etc.), surfactants (e.g., SDS, polysorbate, nonionic surfactants, etc.), sugars (e.g., sucrose, maltose, trehalose, etc.) and polyols (e.g., mannitol, sorbitol, etc.). See also Remington's Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, PA, the entire contents of which are incorporated herein by reference.

[0103] In the context of a peptide or polypeptide, the term "fragment" as used herein refers to a peptide or polypeptide that comprises no more than the full-length amino acid sequence. Such fragments may, for example, result from amino-terminal truncation, carboxyl-terminal truncation and / or internal deletions of residues from the amino acid sequence. Fragments may, for example, result from alternative RNA splicing or from in vivo protease activity. In certain embodiments, a C10orf54 fragment includes a polypeptide comprising an amino acid sequence of at least 5 contiguous amino acid residues, at least 10 contiguous amino acid residues, at least 15 contiguous amino acid residues, at least 20 contiguous amino acid residues, at least 25 contiguous amino acid residues, at least 40 contiguous amino acid residues, at least 50 contiguous amino acid residues, at least 60 contiguous amino acid residues, at least 70 contiguous amino acid residues, at least 80 contiguous amino acid residues, at least 90 contiguous amino acid residues, at least 100 contiguous amino acid residues, at least 125 contiguous amino acid residues, at least 150 contiguous amino acid residues, at least 175 contiguous amino acid residues, at least 200 contiguous amino acid residues, or at least 250 contiguous amino acid residues of an amino acid sequence of a C10orf54 polypeptide or an antibody that binds to a C10orf54 polypeptide. In a specific embodiment, a fragment of a C10orf54 polypeptide or an antibody that binds to a C10orf54 antigen retains at least one, at least two, or at least three functions of the polypeptide or antibody.

[0104] The term "framework" or "FR" residues are those variable domain residues that flank the CDRs. FR residues are found, for example, in chimeric, humanized, human, domain antibodies, diabodies, linear antibodies, and bispecific antibodies. FR residues are those variable domain residues other than the hypervariable region residues as defined herein.

[0105] A "functional fragment" of an antibody will exhibit at least one function, if not some or all of the biological functions attributed to the intact antibody, which function includes at least specific binding to a target antigen.

[0106] As used herein, the term "fusion protein" refers to a polypeptide comprising the amino acid sequence of an antibody and the amino acid sequence of a heterologous polypeptide or protein (e.g., a polypeptide or protein that is not normally part of the antibody (e.g., a non-anti-C10orf54 antigen antibody)). When the term "fusion" is used in connection with C10orf54 or an anti-C10orf54 antibody, it refers to the connection of a peptide or polypeptide or a fragment, variant and / or derivative thereof to a heterologous peptide or polypeptide. In certain embodiments, the fusion protein retains the biological activity of C10orf54 or an anti-C10orf54 antibody. In certain embodiments, the fusion protein comprises a C10orf54 antibody VH domain, a VL domain, a VH CDR (one, two or three VH CDRs) and / or a VL CDR (one, two or three VL CDRs), wherein the fusion protein binds to a C10orf54 epitope.

[0107] When the term "heavy chain" is used in relation to an antibody, it refers to a polypeptide chain of about 50-70 kDa, wherein the amino terminal portion includes a variable region of about 120 to 130 or more amino acids, and the carboxyl terminal portion includes a constant region. Based on the amino acid sequence of the heavy chain constant region, the constant region can be one of five different types, called α, δ, ε, γ and μ. Different heavy chains are of different sizes: α, δ and γ contain about 450 amino acids, while μ and ε contain about 550 amino acids. When combined with a light chain, these different types of heavy chains produce the five well-known antibody types IgA, IgD, IgE, IgG and IgM, respectively, including the four subtypes of IgG, namely IgG1, IgG2, IgG3 and IgG4. The heavy chain can be a human heavy chain.

[0108] As used herein, the term "host" refers to an animal, such as a mammal (eg, a human).

[0109] The term "host cell" as used herein refers to a specific subject cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. The progeny of such a cell may differ from the parent cell transfected with the nucleic acid molecule due to mutations or environmental influences that may occur in the progeny, or the integration of the nucleic acid molecule into the host cell genome.

[0110] " Humanized " form of non-human (for example, murine) antibody refers to a chimeric antibody including human immunoglobulin (receptor antibody) with required specificity, affinity and ability, wherein the natural CDR residues are replaced by the residues of the corresponding CDR from non-human species (donor antibody), such as mouse, rat, rabbit or non-human primate. In some cases, one or more FR region residues of human immunoglobulin are replaced by corresponding non-human residues. In addition, humanized antibody can be included in the residues not found in receptor antibody or donor antibody. These modifications are carried out to further improve antibody performance. The heavy or light chain of humanized antibody can include substantially all at least one or more variable domains, wherein all or substantially all CDRs correspond to the CDRs of non-human immunoglobulins, and all or substantially all FRs are immunoglobulin sequences of people. In certain embodiments, humanized antibody will include at least a portion of immunoglobulin constant region (Fc), typically human immunoglobulin. For more details, see Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol, 2:593-596 (1992); Carter et al., Proc. Natl. Acd. Sci. USA 89:4285-4289 (1992); and U.S. Pat. Nos. 6,800,738 (issued October 5, 2004), 6,719,971 (issued September 27, 2005), 6,639,055 (issued October 28, 2003), 6,407,213 (issued June 18, 2002), and 6,054,297 (issued April 25, 2000).

[0111] An antibody that "inhibits the growth of cells expressing C10orf54 and / or kills cells expressing C10orf54" or a "growth inhibitory" or "cytotoxic" antibody is an antibody that causes measurable growth inhibition and / or killing of cells expressing or overexpressing the appropriate C10orf54 polypeptide. In some embodiments, such an antibody can inhibit the growth of cells expressing C10orf54 and / or kill cells expressing C10orf54. Such cells include regulatory T cells (e.g., CD4+Foxp3+ regulatory T cells), myeloid-derived suppressor cells (e.g., CD11b+ or CD11b high myeloid-derived suppressor cells), and / or suppressor dendritic cells (e.g., CD11b+ or CD11b high dendritic cells). In specific embodiments, the antibody inhibits the growth of and / or kills cancer cells, precancerous cells, or cells comprising a tumor. Certain growth inhibitory anti-C10orf54 antibodies inhibit the growth of and / or kill cells expressing C10orf54 by greater than 20%, e.g., from about 20% to about 50%, or greater than 50% (e.g., from about 50% to about 100%), compared to an appropriate control, which is typically cells that have not been treated with the antibody to be tested. In one embodiment, growth inhibition and / or killing can be measured in cell culture at an antibody concentration of about 0.1 to 30 g / ml, or about 0.5 nM to 200 nM, wherein growth inhibition is determined 1-10 days after exposure of the tumor cells to the antibody. In vivo growth inhibition and / or killing of cells can be determined in a variety of ways, as described below. In the case of inhibition of cancer cells or cells comprising a tumor, an antibody is growth inhibitory or the antibody kills in vivo if administration of an anti-C10orf54 antibody at about 1 g / kg to about 100 mg / kg body weight results in a decrease in tumor size or tumor cell proliferation within about 5 days to 3 months, e.g., about 5 to 30 days, of the first administration of the antibody.

[0112] As used herein, the term "in combination" in the context of administration involving other treatments refers to the use of more than one treatment. The use of the term "in combination" does not limit the order in which the treatments are administered to a subject having an infection. A first treatment is administered prior to (e.g., 1 minute, 45 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks), concurrently with, or after (e.g., 1 minute, 45 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks) administration of a second treatment to a subject, wherein the subject has, suffers from, or is susceptible to a C10orf54-mediated disease. Any additional treatments may be administered in any order with the other additional treatments. In certain embodiments, the antibody may be administered in combination with one or more therapies (e.g., a therapy that is not the antibody currently administered to prevent, treat, manage, and / or ameliorate a C10orf54-mediated disease). Non-limiting examples of therapies that may be administered in combination with the antibody include analgesics, anesthetics, antibiotics, or immunomodulators or United States Pharmacopeia and / or Physician's Desk Reference Any other reagents listed in .

[0113] An antibody that "induces cell death" is an antibody that causes live cells to become inactive. The cell is a cell type that specifically expresses or overexpresses the C10orf54 polypeptide. The cell may be cancerous, or a normal cell of a particular cell type, such as a regulatory T cell. Cell death can be determined in vitro in the absence of complement and immune effector cells to distinguish cell death caused by antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). Thus, an assay for cell death can be performed using heat-inactivated serum (e.g., in the absence of complement) and in the absence of immune effector cells. To determine whether an antibody is capable of inducing cell death, loss of membrane integrity is assessed by uptake of propidium iodide (PI), trypan blue (see Moore et al. Cytotechnology 17: 1-11 (1995)). In some embodiments, an antibody that induces cell death is an antibody that induces PI uptake in an assay for PI uptake in cells expressing C10orf54.

[0114] "Isolated" antibodies are substantially free of cellular material or other contaminating proteins from a cell or tissue source, and / or other contaminating components from which the antibody is derived, or when the antibody is chemically synthesized, substantially free of chemical precursors or other chemicals. The language "substantially free of cellular material" includes antibody preparations in which the antibody is separated from the cellular components of the cell, wherein the antibody is separated from or recombinantly produced from the cell. Therefore, antibodies substantially free of cellular material include antibody preparations with less than about 30%, 20%, 10% or 5% (by dry weight) of heterologous proteins (also referred to herein as "contaminating proteins"). In certain embodiments, when the antibody is recombinantly produced, it is substantially free of culture medium, such as culture medium representing less than about 20%, 10% or 5% of the volume of the protein preparation. In certain embodiments, when the antibody is produced by chemical synthesis, it is substantially free of chemical precursors or other chemicals, such as it is separated from chemical precursors or other chemicals involved in protein synthesis. Therefore, such antibody preparations have less than about 30%, 20%, 10%, 5% (by dry weight) of chemical precursors or compounds other than the antibody of interest. Contaminant components may also include, but are not limited to, substances that will interfere with the therapeutic use of the antibody, and may include enzymes, hormones, and other protein or non-protein solutes. In certain embodiments, the antibody is purified (1) to greater than 95% by weight, such as 99% by weight, as determined by the Lowry method (Lowry et al. J. Bio. Chem. 193: 265-275, 1951), (2) by using a spinning cup sequencer to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence, or (3) by SDS-PAGE to homogeneity under reducing or non-reducing conditions using Coomassie blue or preferably silver stain. Antibodies isolated within recombinant cells contain antibodies in situ because at least one component of the antibody's natural environment is absent. However, isolated antibodies are typically prepared by at least one purification step. In a specific embodiment, the antibodies provided herein are isolated or purified.

[0115] An "isolated" nucleic acid molecule is one that is separated from other nucleic acid molecules present in the natural source of the nucleic acid molecule. In addition, an "isolated" nucleic acid molecule, such as a cDNA molecule, may be substantially free of other cellular material, or substantially free of culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. In specific embodiments, the nucleic acid molecules encoding antibodies provided herein are isolated or purified.

[0116] The term "leaving group" as used herein refers to any group that leaves during a chemical reaction involving a group described herein, including, but not limited to, for example, halogens, sulfonates (propanesulfonate, methanesulfonate, toluenesulfonate, trifluoromethylsulfonate, etc.), p-nitrobenzoate, and phosphonate groups.

[0117] The term "light chain" as used in relation to antibodies refers to a polypeptide chain of about 25 kDa, wherein the amino terminal portion includes a variable region of about 100 to about 110 or more amino acids and the carboxyl terminal portion includes a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two different types, called λ and κ, based on the amino acid sequence of the constant domain. Light chain amino acid sequences are well known in the art. The light chain can be a human light chain.

[0118] "Linker" (called L or L 1 , L 2 and L 3 ) is a molecule with two reactive ends, one for conjugation with an antibody or with another linker, and the other for conjugation to a cytotoxin. The antibody conjugation reactive end of the linker is usually a site that can be conjugated to the antibody through a cysteine ​​thiol or lysine amine group on the antibody, and is therefore usually a thiol reactive group, such as a double bond (such as maleimide) or a leaving group such as chlorine, bromine or iodine or R-sulfanyl or sulfonyl, or an amine reactive group such as a carboxyl or as defined herein; however, the antibody conjugation reactive end of the linker is usually a site that can be conjugated to a cytotoxin by forming an amide bond with a basic amine or carboxyl group on a cytotoxin, and is therefore usually a carboxyl or basic amine group. In one embodiment, when the term "linker" is used to describe a linker in a conjugated form, one or both reactive ends will not be present (e.g., a leaving group of a thiol reactive group) or incomplete (e.g., just a carbonyl of a carboxylic acid) due to the formation of a bond between a linker and / or a cytotoxin. The linkers disclosed herein are cleavable under normal physiological and / or intracellular conditions, or remain stable (e.g., uncleaved or non-cleavable) under the same conditions. An example of a cleavable linker is a linker containing a dipeptide portion, wherein the peptide bond connecting the two peptides has the potential to be selectively cleaved by a lysosomal protease (e.g., cathepsin B). Valine-citrate (Val-Cit) is a dipeptide portion commonly used in cleavable linkers.

[0119] As used herein, the term "management" refers to the beneficial effects that a subject derives from a treatment (e.g., a prophylactic or therapeutic agent) that does not result in a cure of the disease. In certain embodiments, one or more treatments (e.g., a prophylactic or therapeutic agent, such as an antibody provided herein) are administered to a subject to "manage" a C10orf54-mediated disease, one or more symptoms thereof, to prevent disease progression or worsening.

[0120] The term "monoclonal antibody" refers to an antibody obtained from a homogeneous or substantially homogeneous population of antibodies, and each monoclonal antibody generally recognizes a single epitope on an antigen. In specific embodiments, a "monoclonal antibody" as used herein is an antibody produced by a single hybridoma or other cell, wherein the antibody binds only to the C10orf54 epitope, for example as determined by ELISA or other antigen binding or competitive binding assays known in the art. The term "monoclonal" is not limited to any specific method for making an antibody. For example, the monoclonal antibodies provided herein can be made by the hybridoma method as described by Kohler et al. Nature, 256:495 (1975), or can be isolated from a phage library using these techniques. Other methods for preparing clonal cell lines and monoclonal antibodies expressed thereby are well known in the art (see, e.g., Short Protocols in Molecular Biology Chapter 11 (2002) Fifth Edition, Ausubel et al., eds., John Wiley and Sons, New York). Additional exemplary methods for producing other monoclonal antibodies are provided in the Examples herein.

[0121] The term "naturally occurring" when used in connection with biological materials such as nucleic acid molecules, polypeptides, host cells, etc., refers to those found in nature and not subject to human manipulation.

[0122] As used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the US Pharmacopeia, the European Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0123] As used herein, "polyclonal antibody" refers to an antibody population produced in an immunogenic response to a protein having many epitopes, and thus includes a plurality of different antibodies directed against the same epitope and different epitopes within the protein. Methods for producing polyclonal antibodies are known in the art (see, e.g., see, e.g., Short Protocols in Molecular Biology Chapter 11 (2002) Fifth Edition, Ausubel et al., eds., John Wiley and Sons, New York).

[0124] As used herein, the terms "polynucleotide," "nucleotide," "nucleic acid," "nucleic acid molecule" and other similar terms are used interchangeably and include DNA, RNA, mRNA, and the like.

[0125] "Precancerous cells" refer to cells that have an abnormal appearance (e.g., a different size or shape) compared to cells of the surrounding tissue or normal cells of their cell type, but are not invasive. The presence of precancerous cells may indicate an increased risk of cancer. Precancerous cells expressing C10orf54 can be identified using the methods disclosed herein, which may include analyzing a cell sample from a patient.

[0126] As used herein, the terms "prevent," "preventing," and "suppressing" refer to the complete or partial inhibition of the development, recurrence, onset, and / or spread of a C10orf54-mediated disease and / or symptoms associated therewith as a result of administering a treatment or combination of treatments provided herein (e.g., a combination of prophylactic or therapeutic agents, such as antibodies provided herein).

[0127] As used herein, the term "prophylactic agent" refers to any agent that can completely or partially inhibit the development, recurrence, onset or spread of a C10orf54-mediated disease and / or symptoms associated therewith in a subject. In certain embodiments, the term "prophylactic agent" refers to an anti-C10orf54 antibody provided herein. In certain other embodiments, the term "prophylactic agent" refers to an agent other than an anti-C10orf54 antibody provided herein. In certain embodiments, the prophylactic agent is an agent that is known to be useful or has been used or is currently being used to prevent a C10orf54-mediated disease and / or symptoms associated therewith, or to hinder the onset, development, progression and / or severity of a C10orf54-mediated disease and / or symptoms associated therewith. In specific embodiments, the prophylactic agent is a humanized anti-C10orf54 antibody, such as a humanized anti-C10orf54 monoclonal antibody.

[0128] In certain embodiments, a "prophylactically effective serum titer" is a serum titer in a subject, preferably a human, that fully or partially inhibits the development, recurrence, onset or spread of a C10orf54-mediated disease and / or symptoms associated therewith in the subject.

[0129] The term "recombinant antibody" refers to an antibody prepared, expressed, generated or isolated by recombinant means. The recombinant antibody can be an antibody expressed using a recombinant expression vector transfected into a host cell, an antibody isolated from a recombinant combinatorial antibody library, an antibody isolated from a transgenic animal and / or a transchromosomal animal (e.g., mouse or cattle) of a human immunoglobulin gene (see, e.g., Taylor, LD et al. (1992) Nucl. Acids Res. 20: 6287-6295), or an antibody prepared, expressed, generated or isolated by any other means involving splicing of immunoglobulin gene sequences into other DNA sequences. Such recombinant antibodies may have variable and constant regions derived from human germline immunoglobulin sequences (see Kabat, EA et al. (1991) Sequence of Proteins of Immunological Interest , Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242). However, in certain embodiments, these recombinant antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis when transgenic animals for human Ig sequences are used), so that the amino acid sequences of the recombinant antibody VH and VL regions are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist in the human antibody germline repertoire in vivo.

[0130] As used herein, the term "serum titer" refers to the average serum titer in a population of at least 10, such as at least 20, or at least 40 subjects, up to about 100, 1000 or more.

[0131] As used herein, the term "side effect" includes the undesirable and adverse effects of a treatment (e.g., a prophylactic or therapeutic agent). Undesirable effects are not necessarily adverse. Adverse effects from a treatment (e.g., a prophylactic or therapeutic agent) may be harmful or uncomfortable or risky. Examples of side effects include diarrhea, cough, gastroenteritis, asthma, nausea, vomiting, anorexia, abdominal cramps, fever, pain, weight loss, dehydration, hair loss, dyspenea, insomnia, dizziness, mucositis, nerve and muscle effects, fatigue, dry mouth and loss of appetite, rash or swelling at the site of administration, flu-like symptoms such as fever, chills and fatigue, digestive problems and allergic reactions. Other undesirable effects experienced by patients are well known in the art. Many in Physician's Desk Reference (67th edition, 2013).

[0132] As used herein, the terms "subject" and "patient" are used interchangeably. As used herein, in certain embodiments, the subject is a mammal, such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats, etc.) or a primate (e.g., monkeys and humans). In specific embodiments, the subject is a human. In one embodiment, the subject is a mammal (e.g., a human) suffering from a C10orf54-mediated disease. In another embodiment, the subject is a mammal (e.g., a human) at risk of developing a C10orf54-mediated disease.

[0133] As used herein, "substantially all" means at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100%.

[0134] As used herein, the term "therapeutic agent" refers to any agent that can be used to treat, prevent, or alleviate a disease, disorder, or condition, including treating, preventing, or alleviating one or more C10orf54-mediated diseases, disorders, or conditions and / or symptoms associated therewith. In certain embodiments, the therapeutic agent refers to an antibody provided herein. In certain other embodiments, the therapeutic agent refers to an agent other than an antibody provided herein. In certain embodiments, the therapeutic agent is an agent that is known to be useful or has been or is being used to treat, prevent, or alleviate one or more symptoms of a C10orf54-mediated disease, disorder, condition, or symptoms associated therewith.

[0135] The combination of treatments (e.g., use of therapeutic agents) can be more effective than the additive effects of any two or more monotherapies. For example, a synergistic effect of a combination of therapeutic agents allows for the use of lower doses of one or more agents and / or less frequent administration to a subject suffering from a C10orf54-mediated disease. The ability to use lower doses of therapeutic treatments and / or less frequent administration of treatments reduces toxicity associated with administering the treatment to a subject without reducing the efficacy of the treatment in preventing, treating, or alleviating one or more symptoms of a C10orf54-mediated disease. In addition, a synergistic effect can improve the effectiveness of the treatment in preventing, treating, or alleviating one or more symptoms of a C10orf54-mediated disease. Finally, a synergistic effect of a combination of treatments (e.g., therapeutic agents) can avoid or reduce adverse or undesirable side effects associated with the use of any monotherapy.

[0136] The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent (e.g., an antibody provided herein or any other therapeutic agent provided herein) sufficient to reduce and / or improve the severity and / or duration of a given disease and / or symptoms associated therewith. A therapeutically effective amount of a therapeutic agent can be an amount required to reduce or improve the progression or course of a given disease, reduce or improve the recurrence, development or onset of a given disease, and / or improve or enhance the preventive or therapeutic effect of another treatment (e.g., a treatment other than administering an antibody provided herein).

[0137] In certain embodiments, a "therapeutically effective serum titer" is a serum titer in a subject, preferably a human, that reduces the severity, duration, and / or symptoms associated with a C10orf54-mediated disease in the subject.

[0138] As used herein, the term "treatment" refers to any procedure, method and / or agent that can be used to prevent, manage, treat and / or ameliorate a C10orf54-mediated disease. In certain embodiments, the terms "treatment" and "therapy" refer to biological treatments, supportive treatments and / or other treatments known to those skilled in the art, such as medical personnel, that can be used to prevent, manage, treat and / or ameliorate a C10orf54-mediated disease.

[0139] As used herein, the term "thiol" refers to a -SH group.

[0140] As used herein, the term "treat" refers to a reduction or improvement in the course, severity, and / or duration of a C10orf54-mediated disease resulting from the administration of one or more treatments (including, but not limited to, the administration of one or more therapeutic agents, such as antibodies provided herein). In specific embodiments, such terms refer to a reduction or inhibition of cancer or tumor formation. In other specific embodiments, such terms refer to a reduction or improvement in the progression, severity, and / or duration of graft-versus-host disease. In other specific embodiments, such terms refer to a reduction or improvement in the course, severity, and / or duration of a disease that responds to immune modulation, such modulation being due to increased T cell activation, increased T cell proliferation, or increased cytokine production.

[0141] "Tubulysin" includes natural products described as tubulysin, such as by Sasse et al. and other authors mentioned in the description of the related art, and tubulysin analogs described in U.S. Patent Application Publication No. US 2011 / 0021568A1. Tubulysin disclosed in the present application is described herein, and includes tubulysin of formula T3 and T4, and other tubulysins in which the terminal N-methylpiperidine is replaced with an unsubstituted piperidine, thereby allowing amide bonds to be formed with a linker.

[0142] The term "variable domain" or "variable region" refers to a portion of an antibody light or heavy chain that is usually located at the amino terminus of the light or heavy chain and is about 120 to 130 amino acids in length in the heavy chain and about 100 to 110 amino acids in the light chain and is used for the binding and specificity of each particular antibody to its particular antigen. The variable domains differ widely in sequence between different antibodies. The variation in sequence is concentrated in the CDRs, while the less variable portions of the variable domains are called framework regions (FRs). The CDRs of the light and heavy chains are primarily responsible for the interaction of the antibody with the antigen. In a specific embodiment, the variable region is a human variable region.

[0143] The term "variable domain residue numbering in Kabat" or "amino acid position numbering in Kabat" and variations thereof refer to the numbering system used to edit the heavy chain variable domain or light chain variable domain of an antibody in Kabat et al. Sequences of Proteins of Immunological Interest, Fifth Edition Public Health Service, National Institutes of Health, Bethesda, MD (1991). Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to the shortening, or insertion, FR or CDR of the variable domain. For example, the heavy chain variable domain may include a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and a residue inserted after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c, etc. according to Kabat). The residue Kabat numbering of a given antibody may be determined by comparing the homologous region of the antibody sequence and the "standard" Kabat numbering sequence. When referring to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain), the Kabat numbering system is generally used (e.g., Kabat et al. Sequences of Immunological Interest Fifth Edition Public Health Service, National Institutes of Health, Bethesda, Md (1991)). When referring to residues in the constant region of the immunoglobulin heavy chain, the "EU numbering system" or "EU index" is generally used (e.g., the EU index reported in Kabat et al. supra). The "EU index in Kabat" refers to the residue numbering of the human IgG 1EU antibody. Unless otherwise indicated herein, reference to residue numbering in the variable domain of an antibody means residue numbering by the Kabat numbering system. Other numbering systems have been described, including, for example, AbM, Chothia, Contact, and IMGT. Fig.16A and 16B Various numbering systems are shown in .

[0144] When the term "variant" is used in connection with C10orf54 or an anti-C10orf54 antibody, it refers to a peptide or polypeptide comprising one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid sequence substitutions, deletions, and / or additions compared to a native or unmodified sequence. For example, a C10orf54 variant may result from one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) changes made to a native C10orf54 amino acid sequence. As another example, a variant of an anti-C10orf54 antibody may result from one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) changes made to a native or previously unmodified anti-C10orf54 antibody amino acid sequence. Variants may be naturally occurring, such as alleles or splice variants, or may be artificially constructed. Polypeptide variants may be prepared from corresponding nucleic acid molecules encoding variants. In specific embodiments, C10orf54 variants or anti-C10orf54 antibody variants retain at least the functional activity of C10orf54 or anti-C10orf54 antibody, respectively. In specific embodiments, anti-C10orf54 antibody variants bind to C10orf54 and / or have an antagonistic effect on C10orf54 activity. In specific embodiments, anti-C10orf54 antibody variants bind to C10orf54 and / or have an agonistic effect on C10orf54 activity. In certain embodiments, the variants are encoded by single nucleotide polymorphism (SNP) variants of nucleic acid molecules, wherein the nucleic acid molecules encode C10orf54 or anti-C10orf54 antibody VH or VL regions or subregions.

[0145] The term "vector" refers to a material for introducing a nucleic acid molecule into a host cell. Suitable vectors include, for example, expression vectors, plasmids, phage vectors, viral vectors, episomes, and artificial chromosomes, which may include a selection sequence or a marker operable for stable integration into a host cell chromosome. In addition, the vector may include one or more selectable marker genes and appropriate expression control sequences. Selectable marker genes may be included, for example, to provide resistance to antibiotics or toxins, to supplement the defects of nutrient deficiency types, or to provide key nutrients not present in the culture medium. Expression control sequences may include constitutive and inducible promoters, transcription enhancers, transcription terminators, etc., known in the art. When two or more nucleic acid molecules (for example, the heavy chain and light chain of an antibody) are co-expressed, the two nucleic acid molecules may be inserted, for example, in a single expression vector or in a separate expression vector. For single vector expression, the encoding nucleic acid may be operably linked to a common expression control sequence or to different expression control sequences, for example, an inducible promoter and a constitutive promoter. The introduction of nucleic acid molecules into a host cell may be confirmed using methods well known in the art. These methods include, for example, nucleic acid analysis, such as Northern blot or polymerase chain reaction (PCR) to amplify mRNA, or immunoblotting for gene product expression, or other suitable analytical methods to test the expression of the introduced nucleic acid sequence or its corresponding gene product. It will be understood by those skilled in the art that the nucleic acid molecule is expressed in an amount sufficient to produce the desired product (e.g., an anti-C10orf54 antibody provided herein), and it will also be understood that the expression level can be optimized using methods well known in the art to obtain sufficient expression. BRIEF DESCRIPTION OF THE DRAWINGS

[0146] Figure 1A and 1B Shown are protein expression levels of C10orf54 identified and quantified by sTAg analysis in AML and BMMC samples and relevant controls.

[0147] Figure 2 Shown are FACS analyses of 23 primary AML-BM-MNC and 3 normal BM-MNC samples using the anti-C10orf54 antibody 76E1.

[0148] Figure 3A and 3B The humanized sequences of the murine monoclonal antibody 76E1 VH region are shown. SEQ ID NOs: 1, 7, 8, 12-15 and 82 are depicted.

[0149] Figure 4A and 4B The humanized sequences of the VH region of murine monoclonal antibody 141A are shown. SEQ ID NOs: 2, 7, 8, 16-19 and 82 are depicted.

[0150] Figure 5A and 5B The humanized sequence of the VH region of murine monoclonal antibody 175A is shown. SEQ ID NOs: 3, 7, 8, 20-23 and 82 are depicted.

[0151] Fig. 6A and 6B The humanized sequences of the VL region of the murine monoclonal antibody 76E1 are shown. SEQ ID NOs: 4, 9, 10, 24, 25 and 94 are depicted.

[0152] Fig. 7A and 7B The humanized sequences of the VL region of murine monoclonal antibody 141A are shown. SEQ ID NOs: 5, 10, 11, 26, 27 and 94 are depicted.

[0153] Fig. 8A and 8B The humanized sequences of the VL region of murine monoclonal antibody 175A are shown. SEQ ID NOs: 6, 9, 10, 28, 29 and 94 are depicted.

[0154] Fig. 9 Pseudo sequences of the VH and VL domains of murine monoclonal antibodies 76E1, 141A and 175A are shown (SEQ ID NOs: 1143-1148). The CDRs are in bold.

[0155] Fig.10 showed that anti-C10orf54 antibody treatment induced strong tumor growth inhibition in established Kasumi-3 tumors.

[0156] Fig.11 We showed that treatment with the murine 175A anti-C10orf54 antibody induced strong tumor growth inhibition in established Kasumi-3 tumors.

[0157] Fig.12 Shown are the results of a secondary ADC assay using an anti-C10orf54 antibody in a cell viability assay with a sarcoma cell line expressing C10orf54.

[0158] Fig.13 and 14 Shown are the activities of unconjugated and MMAF-conjugated anti-C10orf54 antibodies in a cell viability assay using a C10orf54-expressing sarcoma cell line and a parental sarcoma cell line.

[0159] Fig.15 Shown are the results of treatment with unconjugated and MMAF-conjugated anti-C10orf54 antibodies in a tumor model using a C10orf54-expressing sarcoma cell line and a parental sarcoma cell line.

[0160] Fig.16A and 16B Shown is a sequence alignment of the variable heavy and light chains of anti-C10orf54 murine antibodies designated 76E1, 141A and 175A (SEQ ID NOs: 1-6). The boundaries of the CDRs are indicated by Kabat, AbM, Chothia, Contact and IMGT numbering.

[0161] Fig.17A and 17B Shown is a sequence alignment of the variable heavy and variable light chains of exemplary humanized anti-C10orf54 antibodies designated hu76E1, hu141A, and hu175A (heavy chain SEQ ID NOs: 1135-1137, light chain SEQ ID NOs: 1139-1141), and the corresponding consensus sequence between hu76E1 and hu175A (heavy chain SEQ ID NO: 1138, light chain SEQ ID NO: 1142). The residues indicated immediately below the alignment represent specific residues that can be varied in the consensus sequence at the "X" position described above.

[0162] Figures 18A to 18D An alignment of the antibody VH and VL sequences disclosed herein by paratope grouping is shown. SEQ ID NOs: 1271-1280 for VH and VL are depicted. SEQ ID NOs: 1291, 1306, 1441, 1918, 1440, 1368, 1442, 1919, 1385, 1405, 1446, 1920, 1443, 1458, 1446, 1921, 1473, 1445, 1447, 1922, 1444, 1508, 1448, and 1923 for consensus CDR sequences within paratope groupings are also depicted.

[0163] Fig.19 Exemplary human germline sequences used for humanization of the anti-C10orf54 antibodies described herein are shown.

[0164] Fig. 20A and 20B Selected human VH and human VL sequences used for humanization of the anti-C10orf54 antibodies described herein are shown. SEQ ID NOs: 7, 1902-1904, 1907, 1905, 1906, 1912, 1910, 11, 1909, 1913 (in order from top to bottom) depict VH and VL sequences.

[0165] Fig.21AGraphical depictions of C10orf54 protein and chimeric protein constructs are shown. The designation "human" refers to construct CC1; "murine" refers to construct CC2; "hsIGVmmSTALK" refers to construct CC5; "mmIGVhsSTALK" refers to construct CC6; "hsABCmmC10" refers to construct CC7; "mmabChsC10" refers to construct CC8; "hsC10mmLOOP" refers to construct CC9; and "mmC10hsLOOP" refers to construct CC10, as described in Example 3. Also depicted is a sequence alignment of the amino acid sequences from human C10orf54 (residues 1 to 193 of SEQ ID NO: 1079) and mouse C10orf54 (residues 1 to 190 of SEQ ID NO: 1243), including a consensus sequence of these residues (SEQ ID NO: 1914).

[0166] Fig. 21B Phylogenetic trees of the C10orf54 antibody VH and VL genes are shown, including classification of paratope bins and flow cluster analysis as described in Example 3. The designation "full length human" refers to po CC1; "rat" refers to construct CC3; "full length cyno" refers to construct CC4; "hsIGVmmSTALK" refers to construct CC5; "hsABCmmC10" refers to construct CC7; "mmABChsC10" refers to construct CC8; "hsC10mmLOOP" refers to construct CC9; and "mmC10hsLOOP" refers to construct CC10, as described in Example 3.

[0167] Fig.22A and 22B The humanized sequences of the VH and VL regions of the murine monoclonal antibody 26A are shown, respectively. Fig.22A SEQ ID NOs: 1902, 82, 1266 and 1529-1531 are described in Fig. 22B 1532-1534 are described in. The humanized VH designated h26AH1 and the humanized VL designated h26AL1 are each "CDR swap" constructs with no changes in the human framework. The subsequent sequences have altered amino acid residues. # indicates deamidation substitution: Q / S / A / D.

[0168] Fig.23A and 23B The humanized sequences of the VH and VL regions of the murine monoclonal antibody 128A are shown, respectively. Fig.23A SEQ ID NOs: 1902, 82, 1258 and 1535-1537 are described in, and Fig. 23BSEQ ID NOs: 1907, 94, 1259 and 1538-1540 are described in. The humanized VH designated h128AH1 and the humanized VL designated h128AL1 are each "CDR swap" constructs with no changes in the human framework. The subsequent sequences have altered amino acid residues. # indicates deamidation substitution: Q / S / A / D.

[0169] Fig.24A and 24B The humanized sequences of the VH and VL regions of the murine monoclonal antibody 124A are shown, respectively. Fig.24A SEQ ID NOs: 1902, 82, 1281, 1541 and 1542 are described in Fig. 24B SEQ ID NOs: 1911, 94, 1282, 1546 and 1547 are described in. The humanized VH designated h124AH1 and the humanized VL designated h124AL1 are each "CDR swap" constructs with no changes in the human framework. The subsequent sequences have altered amino acid residues. # indicates deamidation substitutions: Q / S / A / D. @ indicates isoaspartic acid substitutions: Q / S / A.

[0170] Fig.25A and 25B The humanized sequences of the murine monoclonal antibody 259A VH and VL regions are shown, respectively. Fig.25A SEQ ID NOs: 1902, 82, 1275 and 1543-1545 are described in Fig.25B SEQ ID NOs: 1905, 94, 1276, 1548 and 1549 are described in. The humanized VH designated h124AH1 and the humanized VL designated h124AL1 are each "CDR swap" constructs with no changes in the human framework. The subsequent sequences have altered amino acid residues. # indicates deamidation substitutions: Q / S / A / D. @ indicates isoaspartic acid substitutions: E / S / A.

[0171] Fig.26A and 26B C10orf54 expression in MDSC subsets is shown. Fig.26A Shows Lin - / CD11b + Percentage of C10orf54 in MDSC subsets. Fig.26B Show Lin - / CD11b + The number of copies of C10orf54 in MDSC subsets. The MDSC populations are referred to as: monocytes (CD14 + / HLA - DR- ), granulocytes (CD15 + / HLA - DR - ) and immature myeloid cells (CD15 - / HLA - DR - ).

[0172] Fig. 27 Scatter plot showing the expression of C10orf54 in PBMC subsets of NSCLC patients.

[0173] Fig.28 Bar graph showing inhibition of T cell proliferation by exposure to C10orf54-Fc construct. 3 Incorporation of H-thymidine.

[0174] Fig.29 Bar graph showing the ability of anti-C10orf54 antibodies to attenuate C10orf54-mediated inhibition of naive T cell proliferation and cytokine secretion.

[0175] Figures 30A to 30C Comparison of naive and pan T cell populations is shown. 50,000 T cells per well were grown in plates pre-coated with 5 μg / ml anti-CD3 antibody and various concentrations of C10orf54-Fc. Cells were further co-stimulated with different concentrations of anti-CD28 antibody (control wells (0 μg / ml αCD28) had no anti-CD3 antibody added). Values ​​are the average of RLU / well (n=4). Fig. 30A Pan-specific T cells 2 days after stimulation are shown. Fig. 30B Naive T cells 2 days after stimulation are shown. Fig. 30C Naive T cells 3 days after stimulation are shown. DETAILED DESCRIPTION

[0176] Antibodies that bind to C10orf54 are provided herein, including C10orf54 polypeptides, C10orf54 polypeptide fragments, or C10orf54 epitopes. Such antibodies include humanized anti-C10orf54 antibodies. Also provided are antibodies that competitively block the binding of the anti-C10orf54 antibodies provided herein to the C10orf54 polypeptide (e.g., humanized anti-C10orf54 antibodies). The anti-C10orf54 antibodies provided herein (e.g., humanized anti-C10orf54 antibodies) can also be conjugated or recombinantly fused to a diagnostic agent, a detectable agent, or a therapeutic agent (e.g., an antibody drug conjugate). Compositions comprising anti-C10orf54 antibodies (e.g., humanized anti-C10orf54 antibodies) are also provided. For example, the detectable agent can be a detectable probe.

[0177] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), CC8 (SEQ ID NO: 1249) and CC10 (SEQ ID NO: 1251), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248) and CC9 (SEQ ID NO: 1250).

[0178] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), and CC8 (SEQ ID NO: 1249), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), CC9 (SEQ ID NO: 1250), and CC10 (SEQ ID NO: 1251). In some aspects, such antibodies do not comprise one or more CDR sequences selected from 30, 1099, 1104, 1105, 1110, 31, 1100, 1106, 1111, 1116, 32, 1101, 1107, 1112, 45, 1102, 1108, 1113, 40, 1103, 1114, 41, 1109, and 1115.

[0179] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245) and CC5 (SEQ ID NO: 1246), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), CC8 (SEQ ID NO: 1249), CC9 (SEQ ID NO: 1250) and CC10 (SEQ ID NO: 1251). In some aspects, such antibodies do not comprise one or more CDR sequences selected from 36, 1081, 1086, 1087, 1092, 37, 1082, 1088, 1093, 1098, 38, 1083, 1089, 1094, 45, 1084, 1090, 1095, 46, 1085, 1096, 47, 1091, and 1097.

[0180] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), CC8 (SEQ ID NO: 1249), and CC9 (SEQ ID NO: 1250), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), CC9 (SEQ ID NO: 1250), and CC10 (SEQ ID NO: 1251). In some aspects, such antibodies do not comprise one or more CDR sequences selected from 33, 1117, 1122, 1123, 1128, 34, 1118, 1124, 1129, 1134, 35, 1119, 1125, 1130, 42, 1120, 1126, 1131, 43, 1121, 1132, 44, 1127, and 1133.

[0181] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC3 (SEQ ID NO: 1244), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), CC8 (SEQ ID NO: 1249), and CC9 (SEQ ID NO: 1250), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), and CC10 (SEQ ID NO: 1251).

[0182] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), CC8 (SEQ ID NO: 1249), and CC10 (SEQ ID NO: 1251), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), CC9 (SEQ ID NO: 1250), and CC10 (SEQ ID NO: 1251).

[0183] Also provided herein are isolated nucleic acid molecules encoding the VH chain, VL chain, VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and / or VL CDR3 of an anti-C10orf54 antibody, wherein the anti-C10orf54 antibody binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope. Also provided are vectors and host cells comprising nucleic acid molecules encoding the anti-C10orf54 antibody, wherein the anti-C10orf54 antibody binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope. Also provided are methods for preparing antibodies, wherein the antibodies bind to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope.

[0184] Methods of using anti-C10orf54 antibodies (e.g., humanized anti-C10orf54 antibodies) are provided. The methods include treating, preventing, or ameliorating a disease, disorder, or condition, including one or more symptoms of a disease, disorder, or condition, comprising administering to a subject a therapeutically effective amount of an anti-C10orf54 antibody, including an antibody drug conjugate (ADC) containing an anti-C10orf54 antibody provided herein, thereby treating, preventing, or ameliorating a disease, disorder, or condition, including one or more symptoms of a disease, disorder, or condition. In some embodiments, the anti-C10orf54 antibody is a humanized antibody that binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope. In one embodiment, the disease, disorder or condition is caused by or associated with C10orf54, including being caused by or associated with cells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressor cells (MDSCs), suppressor dendritic cells (suppressor DCs), and / or regulatory T cells (Tregs). In certain embodiments, the disease is cancer, such as leukemia, bladder cancer, skin cancer, colon cancer, breast cancer, liver cancer, kidney cancer, lung cancer, stomach cancer, pancreatic cancer, esophageal cancer, or fibrosarcoma. In one embodiment, the leukemia is acute myeloid leukemia (AML). In other embodiments, the disease is graft-versus-host disease (GVHD). Other methods provided include using the anti-C10orf54 antibodies provided herein that have C10orf54 binding activity to cells expressing C10orf54, for example, as unconjugated antibodies or conjugated antibodies (ADCs), including for inhibiting and / or killing cells expressing C10orf54 (e.g., having anti-tumor activity to mediate anti-tumor effects). In certain embodiments, the anti-C10orf54 antibodies provided herein, including ADCs containing anti-C10orf54 antibodies, inhibit C10orf54-mediated inhibitory activity on T cells (e.g., to allow for effective anti-tumor immune responses). In certain embodiments, the anti-C10orf54 antibodies provided herein directly kill cells expressing C10orf54 (e.g., tumor cells bearing C10orf54, myeloid-derived suppressor cells (MDSCs), suppressor dendritic cells (suppressor DCs), and / or regulatory T cells (Tregs)) by, for example, antibody-dependent cellular cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC).In certain embodiments, an antibody drug conjugate (ADC) comprising an anti-C10orf54 antibody provided herein directly kills cells expressing C10orf54 by, for example, allowing internalization of a cytotoxic drug, including by binding to cells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressor cells (MDSCs), suppressor dendritic cells (suppressor DCs), and / or regulatory T cells (Tregs). In any of the above embodiments, the anti-C10orf54 antibody may be a humanized anti-C10orf54 antibody provided herein that binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope. In any of the above embodiments, the anti-C10orf54 antibody may be a humanized anti-C10orf54 antibody provided herein that binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope.

[0185] Other methods of using anti-C10orf54 antibodies are provided.

[0186] The method includes a method of inhibiting the growth of a cell having C10orf54 cell surface expression and / or killing a cell having C10orf54 cell surface expression, the method comprising contacting the cell with an effective amount of an anti-C10orf54 antibody or antibody drug conjugate provided herein. In one embodiment, the cell is a regulatory T cell (e.g., CD4 + Foxp3 + In other embodiments, the cells are myeloid-derived suppressor cells (e.g., CD11b + CD11b 高 myeloid-derived suppressor cells) or suppressor dendritic cells (e.g., CD11b + CD11b 高Dendritic cells). In other embodiments, the cell is a cancerous cell or a precancerous cell. Other methods provided include using a C10orf54 antibody provided herein that has C10orf54 binding activity to a cell expressing C10orf54, e.g., as an unconjugated antibody or a conjugated antibody (ADC), including for inhibiting and / or killing a cell expressing C10orf54 (e.g., having anti-tumor activity so as to mediate an anti-tumor effect). In certain embodiments, the anti-C10orf54 antibodies provided herein, including ADCs comprising anti-C10orf54 antibodies, inhibit C10orf54-mediated inhibitory activity on T cells (e.g., to allow for an effective anti-tumor immune response). In certain embodiments, the anti-C10orf54 antibodies provided herein directly kill cells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressor cells (MDSCs), suppressor dendritic cells (suppressor DCs), and / or regulatory T cells (Tregs)) by, for example, antibody-dependent cellular cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC). In certain embodiments, an antibody drug conjugate (ADC) comprising an anti-C10orf54 antibody provided herein directly kills cells expressing C10orf54 by, for example, allowing internalization of a cytotoxic drug, including by binding to cells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressor cells (MDSCs), suppressor dendritic cells (suppressor DCs), and / or regulatory T cells (Tregs)). In any of the above embodiments, the anti-C10orf54 antibody can be a humanized anti-C10orf54 antibody provided herein that binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope.

[0187] Methods include methods of modulating an immune response in a subject, comprising administering to the subject an effective amount of an anti-C10orf54 antibody (e.g., a humanized anti-C10orf54 antibody) provided herein. In one embodiment, the modulation comprises increasing T cell activation. In another embodiment, the modulation comprises increasing T cell proliferation. In another embodiment, the modulation comprises increasing the production of cytokines.

[0188] The methods include methods of detecting C10orf54 in a sample, comprising contacting the sample with an anti-C10orf54 antibody provided herein (eg, a humanized anti-C10orf54 antibody), such as an antibody comprising a detectable agent. In certain embodiments, the sample comprises cells expressing C10orf54 on their surface.

[0189] The method includes a method of treating cancer, comprising administering to a subject an anti-C10orf54 antibody or an antibody drug conjugate (ADC) comprising anti-C10orf54 (e.g., an ADC of the formula AL-CTX, wherein A is an antibody, L is a linker, and CTX is a cytotoxic agent) in a therapeutically effective amount, including an amount effective to kill cells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressor cells (MDSCs), suppressor dendritic cells (suppressor DCs)), and / or regulatory T cells (Tregs)). In some embodiments, the cancer is acute myeloid leukemia (AML). In any of the above embodiments, the anti-C10orf54 antibody can be a humanized anti-C10orf54 antibody provided herein that binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope.

[0190] The method includes a method of killing a cell expressing C10orf54 (e.g., a tumor cell, a myeloid-derived suppressor cell (MDSC), a suppressor dendritic cell (suppressor DC)) and / or a regulatory T cell (Treg)), the method comprising contacting the cell expressing C10orf54 (e.g., a tumor cell, a myeloid-derived suppressor cell (MDSC), a suppressor dendritic cell (suppressor DC)) and / or a regulatory T cell (Treg)) with an amount of an anti-C10orf54 antibody or an antibody drug conjugate (ADC) comprising an anti-C10orf54 antibody (e.g., an ADC of the formula AL-CTX, wherein A is an antibody, L is a linker, and CTX is a cytotoxic agent) effective to kill the cell (e.g., a tumor cell, a myeloid-derived suppressor cell (MDSC), a suppressor dendritic cell (suppressor DC) and / or a regulatory T cell (Treg)). In some embodiments, the tumor cell is an AML cell. In any of the above embodiments, the anti-C10orf54 antibody can be a humanized anti-C10orf54 antibody provided herein that binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope.

[0191] In one embodiment, provided herein is a kit comprising an anti-C10orf54 antibody (e.g., a humanized anti-C10orf54 antibody) provided herein, wherein the antibody binds to a C10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope. In some embodiments, the kit comprises an antibody drug conjugate (ADC), wherein the antibody is an anti-C10orf54 antibody (e.g., a humanized anti-C10orf54 antibody).

[0192] Antibody

[0193] In some embodiments, provided herein are antibodies that bind to C10orf54 (including C10orf54 polypeptides, C10orf54 polypeptide fragments, or C10orf54 epitopes). In some embodiments, the anti-C10orf54 antibody is a humanized antibody that binds to C10orf54 (including C10orf54 polypeptides, C10orf54 polypeptide fragments, or C10orf54 epitopes).

[0194] In certain embodiments, as shown in Table 2 and Figures 3-8, 22A, 22B, 23A, 23B, 24A, 24B, 25A and 25B, the anti-C10orf54 antibody comprises the VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and / or VL CDR3 of murine monoclonal antibody 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A or 305A. Thus, in some aspects, the VH domain comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 3. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1252. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1254. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1256. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1258. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1260. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1262. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1266. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1268. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1271. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1273. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1375. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1277. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1279. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1281. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1283. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1285. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1287.In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 1289. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 4. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 5. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 6. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1253. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1255. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1257. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1259. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1261. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1263. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1265. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1267. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1269. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1270. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1272. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1274. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1276. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1278. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1280. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1282. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1284. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1286. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 1288. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO:1290.

[0195] Table 2. Murine antibody sequences

[0196]

[0197]

[0198]

[0199]

[0200] *Bold amino acid residues represent CDR sequences (CDR1 - first bold sequence; CDR2 - second bold sequence; CDR3 - third bold sequence).

[0201] In certain embodiments, an anti-C10orf54 antibody comprises a VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof. For example, in some embodiments, an anti-C10orf54 antibody comprises a VH FR1, VH FR2, VH FR3, and / or VH FR4 described in the human germline sequences identified in Table 3. Thus, in some embodiments, an anti-C10orf54 antibody comprises a VH FR1, VH FR2, VH FR3, and / or VH FR4 of human germline IGHV1-18 (SEQ ID NO: 7) and IGHJ4-01 (SEQ ID NO: 82). In some embodiments, the anti-C10orf54 antibody comprises VHFR1, VH FR2, VH FR3, and / or VH FR4 of human germline IGHV3-48 (SEQ ID NO: 8) and IGHJ4-01 (SEQ ID NO: 82). In some embodiments, the anti-C10orf54 antibody comprises VH FR1, VH FR2, VH FR3, and / or VH FR4 of human germline IGHV1-46*01 (SEQ ID NO: 1902) and IGHJ4-01 (SEQ ID NO: 82). In some embodiments, the anti-C10orf54 antibody comprises VH FR1, VH FR2, VH FR3, and / or VH FR4 of human germline IGHV3-74*01 (SEQ ID NO: 1903) and IGHJ4-01 (SEQ ID NO: 82). In some embodiments, the anti-C10orf54 antibody comprises VHFR1, VH FR2, VH FR3, and / or VH FR4 of human germline IGHV4-61*01 (SEQ ID NO: 1904) and IGHJ4-01 (SEQ ID NO: 82). In some embodiments, the anti-C10orf54 antibody comprises VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGKV2-28 (SEQ ID NO: 9) and IGKJ2-1 (SEQ ID NO: 94). In some embodiments, the anti-C10orf54 antibody comprises VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGKV1-39 (SEQ ID NO: 10) and IGKJ2-1 (SEQ ID NO: 94). In some embodiments, an anti-C10orf54 antibody comprises VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGKV3-20 (SEQ ID NO: 10) and IGKJ2-1 (SEQ ID NO: 94).In some embodiments, the anti-C10orf54 antibody comprises the VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGHV1-46*01 (SEQ ID NO: 1920) and IGKJ2-1 (SEQ ID NO: 94). In some embodiments, the anti-C10orf54 antibody comprises the VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGHV3-74*01 (SEQ ID NO: 1903) and IGKJ2-1 (SEQ ID NO: 94). In some embodiments, the anti-C10orf54 antibody comprises the VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGHV4-61*01 (SEQ ID NO: 1904) and IGKJ2-1 (SEQ ID NO: 94). In some embodiments, the anti-C10orf54 antibody comprises the VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGKV2-28*01 (SEQ ID NO: 1905) and IGKJ2-1 (SEQ ID NO: 94). In some embodiments, the anti-C10orf54 antibody comprises the VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGKV2-29*02 (SEQ ID NO: 1906) and IGKJ2-1 (SEQ ID NO: 94). In some embodiments, the anti-C10orf54 antibody comprises the VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGKV1-39*01 (SEQ ID NO: 1907) and IGKJ2-1 (SEQ ID NO: 94). In some embodiments, the anti-C10orf54 antibody comprises the VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGKV3-20*01 (SEQ ID NO: 1908) and IGKJ2-1 (SEQ ID NO: 94). In some embodiments, the anti-C10orf54 antibody comprises the VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGKV3D-20*01 (SEQ ID NO: 1909) and IGKJ2-1 (SEQ ID NO: 94). In some embodiments, the anti-C10orf54 antibody comprises the VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGKV3-11*01 (SEQ ID NO: 1910) and IGKJ2-1 (SEQ ID NO: 94).In some embodiments, the anti-C10orf54 antibody comprises VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGKV2-30*01 (SEQ ID NO: 1911) and IGKJ2-1 (SEQ ID NO: 94). In some embodiments, the anti-C10orf54 antibody comprises VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGKV2-30*02 (SEQ ID NO: 1912) and IGKJ2-1 (SEQ ID NO: 94). In some embodiments, the anti-C10orf54 antibody comprises VL FR1, VL FR2, VL FR3, and / or VL FR4 of human germline IGKV4-1*01 (SEQ ID NO: 1913) and IGKJ2-1 (SEQ ID NO: 94).

[0202] Table 3. Human germline immunoglobulin amino acid sequences

[0203]

[0204]

[0205]

[0206] *Bold amino acid residues represent CDR sequences (CDR1 - first bold sequence; CDR2 - second bold sequence; CDR3 - third bold sequence).

[0207] In certain embodiments, an antibody that binds C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain and / or a VL domain, wherein the VH domain has an amino acid sequence identified in Table 4 or Figures 3-8, 22A, 22B, 23A, 23B, 24A, 24B, 25A, or 25B, and the VL domain has an amino acid sequence identified in Table 4 or Figures 3-8, 22A, 22B, 23A, 23B, 24A, 24B, 25A, or 25B.

[0208] Table 4. Amino acid sequences of humanized antibody VH and VL domains

[0209]

[0210]

[0211]

[0212]

[0213]

[0214] Thus, in some embodiments, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having an amino acid sequence of SEQ ID NO: 20, 21, 22, 23, 1529-1531, 1535-1537, or 1541-1545, and / or a VL domain having an amino acid sequence of SEQ ID NO: 28, 29, 1532-1534, 1538-1540, or 1546-1549. In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having an amino acid sequence of SEQ ID NO: 20 and / or a VL domain having an amino acid sequence of SEQ ID NO: 28. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 21 and / or a VL domain having the amino acid sequence of SEQ ID NO: 28. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 22 and / or a VL domain having the amino acid sequence of SEQ ID NO: 28. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 23 and / or a VL domain having the amino acid sequence of SEQ ID NO: 28. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 20 and / or a VL domain having the amino acid sequence of SEQ ID NO: 29. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 21 and / or a VL domain having the amino acid sequence of SEQ ID NO: 29. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 22 and / or a VL domain having the amino acid sequence of SEQ ID NO: 29.In one aspect, an antibody that binds C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO:23 and / or a VL domain having the amino acid sequence of SEQ ID NO:29.

[0215] In some embodiments, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having an amino acid sequence of SEQ ID NO: 12, 13, 14, or 15 and / or a VL domain having an amino acid sequence of SEQ ID NO: 24 or 25. Thus, in one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having an amino acid sequence of SEQ ID NO: 12 and / or a VL domain having an amino acid sequence of SEQ ID NO: 24. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 13 and / or a VL domain having the amino acid sequence of SEQ ID NO: 24. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 14 and / or a VL domain having the amino acid sequence of SEQ ID NO: 24. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 15 and / or a VL domain having the amino acid sequence of SEQ ID NO: 24. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 12 and / or a VL domain having the amino acid sequence of SEQ ID NO: 25. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 13 and / or a VL domain having the amino acid sequence of SEQ ID NO: 25. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 14 and / or a VL domain having the amino acid sequence of SEQ ID NO: 25.In one aspect, an antibody that binds C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO:15 and / or a VL domain having the amino acid sequence of SEQ ID NO:25.

[0216] In some embodiments, an antibody that binds C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having an amino acid sequence of SEQ ID NO: 16, 17, 18, or 19 and / or a VL domain having an amino acid sequence of SEQ ID NO: 26 or 27. Thus, in one aspect, an antibody that binds C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having an amino acid sequence of SEQ ID NO: 16 and / or a VL domain having an amino acid sequence of SEQ ID NO: 26. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 17 and / or a VL domain having the amino acid sequence of SEQ ID NO: 26. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 18 and / or a VL domain having the amino acid sequence of SEQ ID NO: 26. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 19 and / or a VL domain having the amino acid sequence of SEQ ID NO: 26. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 16 and / or a VL domain having the amino acid sequence of SEQ ID NO: 27. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 17 and / or a VL domain having the amino acid sequence of SEQ ID NO: 27. In one aspect, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO: 18 and / or a VL domain having the amino acid sequence of SEQ ID NO: 27.In one aspect, an antibody that binds C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH domain having the amino acid sequence of SEQ ID NO:19 and / or a VL domain having the amino acid sequence of SEQ ID NO:27.

[0217] In certain embodiments, an antibody provided herein that binds to a C10orf54 epitope comprises a VH region having a VH CDR1, a VH CDR2, and / or a VH CDR3 having an amino acid sequence identified in Tables 5-11 or 12-33 below; and / or a VL region having a VLCDR1, a VL CDR2, and / or a VL CDR3 having an amino acid sequence identified in Tables 5-11 or 12-33 below.

[0218] Table 5: Amino acid sequence derived from murine 175A antibody

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230] *Kabat amino acid position numbering

[0231] Table 6: Amino acid sequences derived from murine 76E1 antibody

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261] *Amino acid position numbering according to Kabat.

[0262] Table 7: Amino acid sequences derived from murine 141A antibody

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282] *Amino acid position numbering according to Kabat.

[0283] Table 8: Amino acid sequence derived from murine 26A antibody

[0284]

[0285]

[0286]

[0287]

[0288] Table 9: Amino acid sequences derived from murine 128A antibody

[0289]

[0290]

[0291]

[0292]

[0293] Table 10: Amino acid sequences derived from murine 124A antibody

[0294]

[0295]

[0296]

[0297]

[0298]

[0299] Table 11: Amino acid sequences derived from murine 259A antibody

[0300]

[0301]

[0302]

[0303]

[0304] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 36; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 37; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 38. In certain embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 46; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47. In other embodiments, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 6. In another embodiment, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 28. In other embodiments, the antibody further comprises a VL region having the amino acid sequence of SEQ ID NO: 29. In some embodiments, the antibody comprises (a) a VH region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 36; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 37; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 38; and (b) a VL region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 46; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 47. To the extent that the antibodies provided herein "bind to a C10orf54 epitope," it is contemplated that those antibodies also bind to a C10orf54 polypeptide, polypeptide fragment, or antigen thereof.

[0305] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 36; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 50; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 38. In certain embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 46; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47. In other embodiments, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 6. In another embodiment, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 28. In other embodiments, the antibody further comprises a VL region having the amino acid sequence of SEQ ID NO: 29. In some embodiments, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 36; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 50; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 38; and (b) a VL region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 46; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 47.

[0306] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 36; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 99; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 38. In certain embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 46; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47. In other embodiments, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 6. In another embodiment, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 28. In other embodiments, the antibody further comprises a VL region having the amino acid sequence of SEQ ID NO: 29. In some embodiments, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 36; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 99; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 38; and (b) a VL region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 46; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 47.

[0307] In another embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises: a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 46; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47. In some embodiments, the antibody further comprises a VH region having an amino acid sequence of SEQ ID NO: 20. In another embodiment, the antibody further comprises a VH region having an amino acid sequence of SEQ ID NO: 21. In other embodiments, the antibody further comprises a VH region having an amino acid sequence of SEQ ID NO: 22. In other embodiments, the antibody further comprises a VH region having an amino acid sequence of SEQ ID NO: 23.

[0308] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 30; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 31; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 32. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41. In other embodiments, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 24. In another embodiment, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 25. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 30; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 31; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 32; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41.

[0309] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 30; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 321; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 32. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41. In other embodiments, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 24. In another embodiment, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 25. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 30; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 321; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 32; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40; and (3) a VLCDR3 having an amino acid sequence of SEQ ID NO: 41.

[0310] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 30; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 835; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 32. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41. In other embodiments, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 24. In another embodiment, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 25. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 30; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 835; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 32; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40; and (3) a VLCDR3 having an amino acid sequence of SEQ ID NO: 41.

[0311] In some embodiments, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises: a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41. In some embodiments, the antibody further comprises a VH region having an amino acid sequence of SEQ ID NO: 12. In another embodiment, the antibody further comprises a VH region having an amino acid sequence of SEQ ID NO: 13. In other embodiments, the antibody further comprises a VH region having an amino acid sequence of SEQ ID NO: 14. In other embodiments, the antibody further comprises a VH region having an amino acid sequence of SEQ ID NO: 15.

[0312] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 33; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 34; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 35. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 43; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44. In other embodiments, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 26. In another embodiment, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 27. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 33; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 34; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 35; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 43; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44.

[0313] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 33; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 49; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 35. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 43; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44. In other embodiments, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 26. In another embodiment, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 27. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 33; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 49; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 35; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 43; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44.

[0314] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises: (a) a VH region comprising (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 33; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1070; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 35. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 43; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44. In other embodiments, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 26. In another embodiment, the antibody further comprises a VL region having an amino acid sequence of SEQ ID NO: 27. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 33; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1070; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 35; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 43; and (3) a VLCDR3 having an amino acid sequence of SEQ ID NO: 44.

[0315] As will be appreciated by those skilled in the art, for any of the VH and VL regions described herein, the boundaries between CDRs and framework sequences can be determined using any method well known in the art, including IMGT, Kabat, Chothia, Contact, AbM, or Kabat plus Chothia (e.g., "exemplary" described herein). Thus, any anti-C10orf54 antibody having one or more CDR or framework sequences described herein includes CDR or framework amino acid sequences determined using IMGT, Kabat, Chothia, Contact, AbM, or Kabat plus Chothis. For example, exemplary CDR sequences for the VH and VL regions that may be included in the anti-C10orf54 antibodies of the present disclosure are shown in Tables 12-33 (see also Tables 5-11).

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339] In certain embodiments, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises: a VH region comprising: (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 30, 33, 36, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, and 1717-1720; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: NO: 31, 34, 37, 849, 1082, 1088, 1092, 1093, 1098, 1100, 1106, 1111, 1118, 1124, 1129, 1134, 1161, 1336-1344, 1348-1384, 1556-1559, 1829-1847 and 1917; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 32, 35, 38, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 and 1385-1424.

[0340] In certain embodiments, an antibody that binds C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises: a VL region comprising: (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 42, 45, 253-271, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896, and 1915; (2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: NO:40, 43, 46, 157, 843-846, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 and 1898-1900; and (3) a VL CDR3 having an amino acid sequence selected from SEQ ID NO:41, 44, 47, 1091, 1097, 1109, 1115, 1127, 1133 and 1493-1525.

[0341] In certain embodiments, the antibody comprises (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 30, 33, 36, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, and 1717-1720; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: NO: 31, 34, 37, 849, 1082, 1088, 1092, 1093, 1098, 1100, 1106, 1111, 1118, 1124, 1129, 1134, 1161, 1336-1344, 1348-1384, 1556-1559, 1829-1847 and 1917; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 32, 35, 38, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 and 1385-1424; and (b) a VL region comprising: (1) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: NO: 42, 45, 253-271, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896, 1915; (2) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 40, 43, 46, 157, 843-846, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, and 1898-1900; and (3) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: VL CDR3 of the amino acid sequence of NO: 41, 44, 47, 1091, 1097, 1109, 1115, 1127, 1133 and 1493-1525.

[0342] To the extent that the antibodies provided herein "bind to an epitope of C10orf54," it is contemplated that those antibodies also bind to a C10orf54 polypeptide, polypeptide fragment, or antigen thereof.

[0343] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), CC8 (SEQ ID NO: 1249) and CC10 (SEQ ID NO: 1251), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248) and CC9 (SEQ ID NO: 1250). In some aspects, the antibody comprises: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 30, 1099, 1104, 1105, 1110, 1291-1305, 1311-1315, and 1321-1325; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 849, 1082, 1088, 1093, 1098, 1336-1344, 1348-1367, 1373, 1374, and 1556-1559; and (3) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 38, 1083, 1089, 1094, 1385-1404, and 1409-1412. CDR3; and / or (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 1102, 1108, 1113, 1425-1430, 1432-1457, 1681-1684, and 1915; (2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 40, 157, 1103, 1114, 1473-1481, 1526-1528, 1630-1633, and 1685-1688; and (3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1493-1507, 1511-1516, and 1523-1525.In certain aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1291, 1292, 1293, 1294, or 1295; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1336, 1337, 1338, 1339, or 1340; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1385, 1386, 1387, or 1388; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1425, 1426, 1427, or 1428; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1473, 1474, or 1475; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1385, 1386, 1387, or 1388. VL CDR3 of the amino acid sequence of NO:1493, 1494 or 1495. In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1291, 1292, 1293, 1294, or 1295; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1341, 1342, 1338, 1343, or 1344; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1389, 1390, 1391, or 1392; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1425, 1426, 1427, or 1428; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1473, 1474, or 1475; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1389, 1390, 1391, or 1392. VL CDR3 of the amino acid sequence of NO:1496, 1497 or 1498.In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1291, 1292, 1293, 1294, or 1295; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1348, 1337, 1338, 1349, or 1350; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1385, 1386, 1387, or 1388; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1429, 1426, 1427, 1430, 1681, 1682, 1683, or 1684; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1348, 1337, 1338, 1349, or 1350; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1385, 1386, 1387, or 1388. NO:1473, 1474, 1475, 1685, 1686, 1687 or 1688; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:1493, 1494 or 1495. In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1291, 1292, 1293, 1294, or 1295; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1348, 1337, 1338, 1349, or 1350; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1385, 1386, 1387, or 1388; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1429, 1426, 1427, or 1430; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1473, 1474, or 1475; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1385, 1386, 1387, or 1388. VL CDR3 of the amino acid sequence of NO:1493, 1494 or 1495.In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1291, 1292, 1293, 1294, or 1295; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1351, 1337, 1338, 1352, or 1353; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1385, 1386, 1387, or 1388; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1425, 1426, 1427, or 1428; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1473, 1474, or 1475; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1385, 1386, 1387, or 1388. NO: 1493, 1494 or 1495. In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 30, 1099, 1104, 1105 or 1110; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1359, 1360, 1361, 1362 or 1363; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1397, 1398, 1399 or 1400; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1437, 1451, 1438, 1452, 1451, 1439, 1453, 1450 or 1915; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1359, 1360, 1361, 1362 or 1363; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1397, 1398, 1399 or 1400. NO:1526, 1479, 1527, 1480, 157, 1528 or 1481; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:1523, 1502, 1524, 1503, 1525 or 1504.In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1301, 1302, 1303, 1304, or 1305; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1364, 1365, 1361, 1366, or 1367; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1401, 1402, 1403, or 1404; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1454, 1455, 1456, or 1457; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40, 1103, or 1114; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1505, 1506, or 1507. CDR3. In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1311, 1312, 1313, 1314 or 1315; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 37, 1082, 1088, 1093 or 1098; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1409, 1410, 1411 or 1412; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45, 1102, 1108 or 1113; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40, 1103 or 1114; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1511, 1512 or 1513. In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1321, 1322, 1323, 1324 or 1325; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 849, 1082, 1088, 1373 or 1374; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 38, 1083, 1089 or 1094; and (b) a VL region comprising: (1) a VLCDR1 having an amino acid sequence of SEQ ID NO: 45, 1102, 1108 or 1113; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40, 1103 or 1114; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1514, 1515 or 1516.

[0344] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), and CC8 (SEQ ID NO: 1249), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), CC9 (SEQ ID NO: 1250), and CC10 (SEQ ID NO: 1251). In some aspects, such an antibody does not comprise one or more CDR sequences selected from the group consisting of: 30, 1099, 1104, 1105, 1110, 31, 1100, 1106, 1111, 1116, 32, 1101, 1107, 1112, 45, 1102, 1108, 1113, 40, 1103, 1114, 41, 1109, and 1115.In some aspects, the antibody comprises: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 30, 1099, 1110, 1104, 1105, 1296-1300, 1306-1310, 1316-1320, and 1717-1720; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 31, 37, 1082, 1088, 1092, 1098, 1100, 1106, 1111, 1116, 1354-1358, 1368-1372, 1829-1847, and 1917; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: NO: 32, 38, 1083, 1089, 1094, 1101, 1107, 1112, 1393-1396, 1405-1408, 1413, 1414; and / or (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 45, 253-271, 1102, 1108, 1113, 1431-1434, 1458-1465, 1744-1822, 1878-1896; (2) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 40, 843-846, 1103, 1114, 1476-1478, 1482-1487, 1898-1900 CDR2; and (3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 41, 1109, 1115, 1499-1501, 1508-1513. In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1296, 1297, 1298, 1299 or 1300; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1354, 1355, 1356, 1357 or 1358; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1393, 1394, 1395 or 1396; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1431, 1432, 1433 or 1434; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1476, 1477 or 1478; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1393, 1394, 1395 or 1396. VL CDR3 of the amino acid sequence of NO:1499, 1500 or 1501.In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1306, 1307, 1308, 1309 or 1310; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1368, 1369, 1370, 1371 or 1372; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1405, 1406, 1407 or 1408; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1458, 1459, 1460 or 1461; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1482, 1483 or 1484; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1484 VL CDR3 of the amino acid sequence of NO:1508, 1509 or 1510. In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1306, 1307, 1308, 1309, or 1310; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1368, 1369, 1370, 1371, 1372, 1829, 1830, 1831, 1832, 1833, 1834, 1835, 1836, 1837, 1838, 1839, 1840, 1841, 1842, 1843, 1844, 1845, 1846, 1847; and (3) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1405, 1406, 1407, or 1408. CDR3; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1458, 1459, 1460, 1461, 1878, 1879, 1880, 1881, 1882, 1883, 1884, 1885, 1886, 1887, 1888, 1889, 1890, 1891, 1892, 1893, 1894, 1895 or 1896; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1485, 1486, 1487, 1897, 1898, 1899 or 1900; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1508, 1509 or 1510.In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1316, 1317, 1318, 1319 or 1320; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 37, 1082, 1088, 1092 or 1098; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 38, 1083, 1089 or 1094; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1462, 1463, 1464 or 1465; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40, 1103 or 1114; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1511, 1512 or 1513.In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1316, 1317, 1318, 1319, 1320, 1717, 1718, 1719 or 1720; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 37, 1082, 1088, 1917 or 1098; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1413, 1414, 1089 or 1094; and (b) a VL region comprising: (1) a VH CDR2 having an amino acid sequence of SEQ ID NO: 37, 1082, 1088, 1917 or 1098; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1413, 1414, 1089 or 1094. NO: 1462, 1463, 1464, 1465, 1744, 45, 1745, 1746, 1747, 1748, 1749, 1750, 17 51, 1752, 1753, 1754, 1755, 1756, 1757, 1758, 1759, 1760, 253, 254, 255, 256 , 257, 258, 259, 1761, 1762, 1763, 1764, 1765, 1766, 1767, 1768, 1769, 1770, 1771, 1772, 1773, 1774, 1775, 1776, 1777, 1778, 1779, 1780, 1781, 1782, 1783 3. 1784, 1785, 1786, 1787, 260, 1788, 1789, 1790, 1791, 264, 268, 1792, 1793, 1794, 1795, 1796, 261, 1797, 1798, 1799, 1800, 265, 269, 1801, 1802, 1803, or 1822; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO:40, 1103, 1114, 843, 844, 846 or 845; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO:1511, 1512 or 1513.

[0345] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245) and CC5 (SEQ ID NO: 1246), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), CC8 (SEQ ID NO: 1249), CC9 (SEQ ID NO: 1250) and CC10 (SEQ ID NO: 1251). In some aspects, such antibodies do not comprise one or more CDR sequences selected from the group consisting of: 36, 1081, 1086, 1087, 1092, 37, 1082, 1088, 1093, 1098, 38, 1083, 1089, 1094, 45, 1084, 1090, 1095, 46, 1085, 1096, 47, 1091, and 1097.

[0346] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), CC8 (SEQ ID NO: 1249), and CC9 (SEQ ID NO: 1250), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), CC9 (SEQ ID NO: 1250), and CC10 (SEQ ID NO: 1251). In some aspects, such antibodies do not comprise one or more CDR sequences selected from the group consisting of: 33, 1117, 1122, 1123, 1128, 34, 1118, 1124, 1129, 1134, 35, 1119, 1125, 1130, 42, 1120, 1126, 1131, 43, 1121, 1132, 44, 1127, and 1133. In some aspects, the antibody comprises: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 33, 1117, 1122, 1123, and 1128; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 34, 1082, 1088, 1118, 1124, 1129, and 1134; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 1119, 1125, 1130, 1415, and 1416; and / or (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 42, 1120, 1126, and 1131; (2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 43, 1121, and 1132. CDR2; (3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 44, 1127 and 1133.In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 33, 1117, 1122, 1123 or 1128; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 34, 1082, 1088, 1129 or 1134; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 35, 1415, 1125 or 1416; and / or (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 42, 1120, 1126 or 1131; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 43, 1121 or 1132; and (3) a VLCDR3 having an amino acid sequence of SEQ ID NO: 44, 1127 or 1133.

[0347] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC3 (SEQ ID NO: 1244), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), CC8 (SEQ ID NO: 1249), and CC9 (SEQ ID NO: 1250), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), and CC10 (SEQ ID NO: 1251). In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1326, 1327, 1328, 1329 or 1330; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1375, 1376, 1377, 1378 or 1379; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1417, 1418, 1419 or 1420; and / or (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1466, 1467 or 1468; (2) a VLCDR2 having an amino acid sequence of SEQ ID NO: 1488, 1489 or 1490; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1517, 1518 or 1519. CDR3.

[0348] In certain embodiments, the antibodies provided herein bind to a first group of C10orf54 proteins or chimeric proteins designated as CC1 (SEQ ID NO: 1079), CC4 (SEQ ID NO: 1245), CC5 (SEQ ID NO: 1246), CC8 (SEQ ID NO: 1249), and CC10 (SEQ ID NO: 1251), and do not bind to a second group of C10orf54 proteins or chimeric proteins designated as CC2 (SEQ ID NO: 1243), CC3 (SEQ ID NO: 1244), CC6 (SEQ ID NO: 1247), CC7 (SEQ ID NO: 1248), CC9 (SEQ ID NO: 1250), and CC10 (SEQ ID NO: 1251). In some aspects, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1331, 1332, 1333, 1334, or 1335; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1380, 1381, 1382, 1383, or 1384; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1421, 1422, 1423, or 1424; and / or (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1469, 1470, 1471, or 1472; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1491, 1488, or 1492; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1491, 1488, or 1492. VLCDR3 of the amino acid sequence of NO:1520, 1521 or 1522.

[0349] According to the amino acid sequences disclosed in Tables 12-33, in some embodiments, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 36, 1081, 1086, 1087, 1092, 30, 1099, 1104, 1105, 1110, 33, 1117, 1122, 1123, 1128, or 1291-1335; (2) a VH CDR1 having an amino acid sequence of SEQ ID NO: 36, 1081, 1086, 1087, 1092, 30, 1099, 1104, 1105, 1110, 33, 1117, 1122, 1123, 1128, or 1291-1335; NO: 37, 1082, 1088, 1093, 1098, 31, 1100, 1106, 1111, 1116, 34, 1118, 1124, 1129, 1134, or 1336-1384; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 38, 1083, 1089, 1094, 32, 1101, 1107, 1112, 35, 1119, 1125, 1130, or 1385-1424. In certain embodiments, an antibody that binds C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VL region comprising: (1) a VLCDR1 having an amino acid sequence of SEQ ID NO: 45, 1084, 1090, 1095, 1102, 1108, 1113, 42, 1120, 1126, 1131, or 1425-1472; (2) a VLCDR2 having an amino acid sequence of SEQ ID NO: 46, 1085, 1096, 40, 1103, 1114, 43, 1121, and 1132; and / or (3) a VL region having an amino acid sequence of SEQ ID NO: VL CDR3 of the amino acid sequence of NO: 47, 1091, 1097, 41, 1109, 1115, 44, 1127, 1133 or 1493-1525.In some embodiments, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 36, 1081, 1086, 1087, 1092, 30, 1099, 1104, 1105, 1110, 33, 1117, 1122, 1123, 1128, or 1291-1335; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 37, 1082, 1088, 1093, 1098, 31, 1100, 1106, 1111, 1116, 34, 1118, 1124, 1129, 1134, or 1336-1384; and / or (3) a VH CDR2 having an amino acid sequence of SEQ ID NO: NO: 38, 1083, 1089, 1094, 32, 1101, 1107, 1112, 35, 1119, 1125, 1130 or 1385-1424; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45, 1084, 1090, 1095, 1102, 1108, 1113, 42, 1120, 1126, 1131 or 1425-1472; (2) a VL CDR1 having an amino acid sequence of SEQ ID NO: 46, 1085, 1096, 40, 1103, 1114, 43, 1121, 1132, 1473-1492 or 1526-1528 CDR2; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 47, 1091, 1097, 41, 1109, 1115, 44, 1127, 1133 or 1493-1525.

[0350] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1081; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1082; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1083. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1084; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1085; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1081; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1082; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1083; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1084; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1085; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47.

[0351] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1086; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 37; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 38. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 46; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1086; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 37; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 38; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 46; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47.

[0352] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1087; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1088; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1089. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1090; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1085; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1091. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1087; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1088; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1089; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1090; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1085; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1091.

[0353] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1092; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1093; (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1094. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1095; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1096; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1097. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1092; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1093; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1094; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1095; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1096; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1097.

[0354] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 36; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1098; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 38. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 46; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 36; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1098; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 38; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 46; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47.

[0355] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1099; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1100; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1101. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1102; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1103; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1099; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1100; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1101; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1102; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1103; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41.

[0356] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1104; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 31; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 32. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1104; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 31; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 32; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41.

[0357] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) contains a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1105; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1106; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1107. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1108; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1103; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1109. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1105; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1106; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1107; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1108; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1103; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1109.

[0358] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1110; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1111; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1112. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1113; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1114; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1115. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1110; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1111; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1112; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1113; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1114; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1115.

[0359] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 30; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1116; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 32. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 30; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1116; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 32; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41.

[0360] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) contains a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1117; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1118; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1119. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1120; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1121; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1117; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1118; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1119; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1120; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1121; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44.

[0361] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1122; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 34; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 35. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 43; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1122; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 34; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 35; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 43; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44.

[0362] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1123; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1124; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1125. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1126; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1121; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1127. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1123; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1124; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1125; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1126; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1121; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1127.

[0363] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1128; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1129; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1130. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1131; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1132; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1133. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1128; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1129; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 1130; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 1131; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1132; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1133.

[0364] In one embodiment, an antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 33; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1134; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 35. In some embodiments, the antibody further comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 43; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44. In one embodiment, the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 33; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 1134; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 35; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 43; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44.

[0365] In certain embodiments, a humanized anti-C10orf54 antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises one or more Fig.17A and 17B As used herein, a "consensus sequence" refers to an amino acid sequence having conserved amino acids that are common among certain sequences, as well as variable amino acids that vary within a given amino acid sequence. The provided CDR consensus sequences include CDRs corresponding to CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3. The consensus sequences of the CDRs of the anti-C10orf54 antibodies are shown in Fig.17A and 17B Therefore, in some embodiments, the humanized anti-C10orf54 antibody comprises a VH region comprising: (1) having GYTFSX 1 X 2 The VH CDR1 of the amino acid sequence of WIE (SEQ ID NO: 1149), wherein X 1 R or T, X 2is Y or H; (2) has EILPGSGSTX 1 YNEKFKG (SEQ ID NO: 1150), wherein X 1 is N or S; and / or (3) has xxxxxxxxxx 1 X 2 Y (SEQ ID NO: 1151), wherein x is any amino acid residue, X 1 M or F, X 2 is G or D. In certain embodiments, the humanized anti-C10orf54 antibody comprises a VL region comprising: (1) a VL CDR1 having an amino acid sequence of RSSQSIVHSNGNTYLE (SEQ ID NO: 45); (2) a VL CDR2 having an amino acid sequence of KX 1 VL CDR2 of the amino acid sequence of SNRFS (SEQ ID NO: 1152), wherein X 1 is V or L; and / or (3) has FQGSHX 1 PX 2 T (SEQ ID NO: 1153), wherein X 1 V or F, X 2 is W or Y. In certain embodiments, the humanized anti-C10orf54 antibody comprises: (a) a VH region comprising: (1) a GYTFSX 1 X 2 The VH CDR1 of the amino acid sequence of WIE (SEQ ID NO: 1149), wherein X 1 is R or T, and X 2 is Y or H; (2) has EILPGSGSTX 1 YNEKFKG (SEQ ID NO: 1150), wherein X 1 is N or S; and / or (3) has xxxxxxxxxx 1 X 2 Y (SEQ ID NO: 1151), wherein x is any amino acid residue, X 1 M or F, X 2 is G or D; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence of RSSQSIVHSNGNTYLE (SEQ ID NO: 45); (2) a VL CDR2 having a KX 1 VL CDR2 of the amino acid sequence of SNRFS (SEQ ID NO: 1152), wherein X 1is V or L; and / or (3) has FQGSHX 1 PX 2 T (SEQ ID NO: 1153), wherein X 1 V or F, X 2 W or Y.

[0366] In some embodiments, the antibodies provided herein include a VH region, which includes or consists of a VH domain. In other embodiments, the antibodies provided herein include a VH region, which includes or consists of a VH chain. In some embodiments, the antibodies provided herein include a VL region, which includes or consists of a VL domain. In other embodiments, the antibodies provided herein include a VL region, which includes or consists of a VL chain. In some embodiments, the antibodies provided herein have (i) a VH domain or a VH chain; and / or (ii) a combination of a VL domain or a VL chain.

[0367] In some embodiments, the antibodies provided herein comprise or consist of six CDRs, e.g., VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and / or VL CDR3 identified in Tables 5-33. In certain embodiments, the antibodies provided herein may comprise less than six CDRs. In some embodiments, the antibodies comprise or consist of one, two, three, four or five CDRs selected from VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and / or VL CDR3. In a specific embodiment, the antibody comprises or consists of one, two, three, four or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and / or VL CDR3 of murine monoclonal antibody 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A or 305A, or a humanized variant thereof identified in Tables 5-33 described herein. Thus, in some embodiments, the antibody comprises or consists of one, two, three, four, or five CDRs of any of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 identified in Tables 5-33.

[0368] In some embodiments, the antibodies provided herein comprise one or more (e.g., one, two, or three) VH CDRs listed in Tables 5-33. In other embodiments, the antibodies provided herein comprise one or more (e.g., one, two, or three) VL CDRs listed in Tables 5-33. In other embodiments, the antibodies provided herein comprise one or more (e.g., one, two, or three) VH CDRs listed in Tables 5-33, and one or more VL CDRs listed in Tables 5-33. Thus, in certain embodiments, the antibodies comprise a VH CDR1 having an amino acid sequence of any one of SEQ ID NOs: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335, and 1717-1720. In another embodiment, the antibody comprises a VH CDR2 having the amino acid sequence of any one of SEQ ID NOs: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847, and 1917. In another embodiment, the antibody comprises a VH CDR3 having an amino acid sequence of any one of SEQ ID NOs: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130, and 1385-1424. In certain embodiments, the antibody comprises a VH CDR1 and / or a VH CDR2 and / or a VH CDR3 independently selected from the VH CDR1, VH CDR2, VH CDR3 shown in any one of the VH regions shown in Tables 5-33. In certain embodiments, the antibody comprises a VL CDR1 having the amino acid sequence of any one of SEQ ID NOs: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896, and 1915.In another embodiment, the antibody comprises a VL CDR2 having an amino acid sequence of any one of SEQ ID NOs: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, and 1898-1900. In another embodiment, the antibody comprises a VL CDR3 having an amino acid sequence of any one of SEQ ID NOs: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133, and 1493-1525. In certain embodiments, the antibody comprises a VL CDR1 and / or a VL CDR2 and / or a VL CDR3 independently selected from the VL CDR1, VL CDR2, VL CDR3 shown in any one of the VL regions shown in Tables 5-33.

[0369] Also provided herein are antibodies comprising one or more of the VH CDRs listed in Tables 5-33 and one or more (eg, one, two, or three) VL CDRs. In particular, provided herein is an antibody comprising a VH CDR1 (SEQ ID NOS: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335, or 1717-1720) and a VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896, or 1915); CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720) and VL CDR2 (SEQ ID NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 or 1898-1900); VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720) and VL CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR2 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917) and VL CDR1 (SEQ ID NO: NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915); VH CDR2 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915); V 14, 1534, 1556-1559, 1829-1847, or 1917) and a VL CDR2 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-138 ... NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 or 1898-1900); VH CDR2 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917) and VL CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR3 (SEQ ID NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130, or 1385-1424) and VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896, or 1915); VH CDR3 (SEQ ID NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130, or 1385-1424) and VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 85, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, or 1898-1900); VH CDR3 (SEQ ID NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, or 1898-1900); VH CDR4 (SEQ ID NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, or 1898-1900); NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424) and VL CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR2 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-133 NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917) and VLCDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915); VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR2 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915); VH CDR1 (SEQ ID NO: 36, NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917) and VL CDR2 (SEQ ID NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 or 1898-1900);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR2 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-133 NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917) and VL CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR2 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VH CDR3 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424 and VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915), VH CDR2 (SEQ ID NO: NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VH CDR3 (SEQ ID 85, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, or 1898-1900);VH CDR2 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VH CDR3 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424) and VL CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525); VH CDR1 (SEQ ID NO: NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915) and VL CDR2 (SEQ ID NO: NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 or 1898-1900);The VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915) and VL CDR3 (SEQ ID NO: NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525); VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VL CDR2 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525); VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528), 1630-1633, 1685-1688 or 1898-1900) and VL CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR2 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VL CDR1 (SEQ ID NO: 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915) and a VL CDR2 (SEQ ID NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 or 1898-1900); a VH CDR2 (SEQ ID NO: NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915) and VL CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR2 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VL CDR2 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 or 1898-1900) and VL CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525); VH CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525); NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424), VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915) and VL CDR2 (SEQ ID NO: NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 or 1898-1900);The VH CDR3 (SEQ ID NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130, or 1385-1424), VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896, or 1915) and VL CDR3 (SEQ ID NO: NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525); VH CDR3 (SEQ ID NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424), VL CDR2 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525); VH CDR3 (SEQ ID NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424), NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 or 1898-1900) and VL CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR2 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-133 NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VHCDR3 (SEQ ID 8, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896, or 1915);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR2 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-133 NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VH CDR3 (SEQ ID 85, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, or 1898-1900);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR2 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-133 NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VHCDR3 (SEQ ID NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424) and VL CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR2 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-133 NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VL CDR1 (SEQ ID 4, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, or 1898-1900);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR2 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-133 NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915) and VL CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR2 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-133 NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VL CDR2 (SEQ ID NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 or 1898-1900) and VL CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR3 (SEQ ID NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424), VL CDR2 (SEQ ID NO: 3 1903, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, or 1898-1900); VH CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896, or 1915) and VL CDR2 (SEQ ID NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, or 1898-1900); NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR3 (SEQ ID NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424), VL CDR1 (SEQ ID NO: 3 NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915) and VL CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR3 (SEQ ID NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424), VL CDR2 (SEQ ID NO: 3 1097, 1109, 1115, 1127, 1133, or 1493-1525); VH CDR2 (SEQ ID NO: SEQ ID NO: SEQ ID NO: 106, 112, 1134, 1143, 1152, 1163, 1176, 1182, 1192, 1204, 1210, 1224, 1230, 1245, 1250, 1264, 1276, 1280, 1291, 1306, 1311, 1321, 1332, 1473-1492, 1526-1528, 1630-1633, 1685-1688, or 1898-1900); VL CDR3 (SEQ ID NO: SEQ ID NO: SEQ ID NO: SEQ ID NO: NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VH CDR3 (SEQ ID NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424), VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915) and VL CDR2 (SEQ ID NO: NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 or 1898-1900);VH CDR2 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VH CDR3 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424), VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915) and VL CDR3 (SEQ ID NO: NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR2 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VH CDR3 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424), VL CDR2 (SEQ ID NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 or 1898-1900) and VL CDR3 (SEQ ID NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 or 1898-1900). NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR2 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-133 NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VH CDR3 (SEQ ID NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424), VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915) and VL CDR2 (SEQ ID NO: NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 or 1898-1900);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR2 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-133 NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VH CDR3 (SEQ ID NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424), VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915) and VL CDR3 (SEQ ID NO: NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR2 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-133 NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VH CDR3 (SEQ ID 8, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130, or 1385-1424), a VL CDR2 (SEQ ID NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, or 1898-1900), and a VL CDR3 (SEQ ID NO: 5 NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR2 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-133 NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VL CDR1 (SEQ ID 4, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, or 1898-1900), and a VL CDR2 (SEQ ID NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, or 1898-1900). NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR1 (SEQ ID NO: 36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1291-1335, 1291-1335 or 1717-1720), VH CDR3 (SEQ ID NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424), VL CDR2 (SEQ ID NO: 3 1903, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, or 1898-1900), and a VL CDR2 (SEQ ID NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688, or 1898-1900). NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);VH CDR2 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), VH CDR3 (SEQ ID NO: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1336-1384, 1556-1559, 1829-1847 or 1917), NO: 38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125, 1130 or 1385-1424), VL CDR1 (SEQ ID NO: 45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1425-1472, 1681-1684, 1744-1822, 1878-1896 or 1915), VL CDR2 (SEQ ID NO: 4 NO: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121, 1132, 1473-1492, 1526-1528, 1630-1633, 1685-1688 or 1898-1900) and VL CDR3 (SEQ ID NO: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127, 1133 or 1493-1525);or the VH CDRs listed in Tables 5-33 (SEQ ID NOs: 36, 30, 59-62, 33, 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 38, 32, 319, 35, 883-885, 1081, 1086, 1087, 1092 , 1099, 1104, 1105, 1110, 1117, 1122, 1123, 1128, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129, 1134, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125 and 1130) and VL any combination of CDRs (SEQ ID NOs: 45, 253-271, 42, 46, 272-275, 40, 843-846, 43, 1045-1048, 47, 41, 44, 1056-1058, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126, 1131, 1085, 1096, 1103, 1114, 1121, 1132, 1091, 1097, 1109, 1115, 1127, and 1133). ;

[0370] In certain embodiments, the humanized anti-C10orf54 antibody binds to a C10orf54 polypeptide, polypeptide fragment, or epitope with an affinity comparable to that of one or more of the murine monoclonal antibodies designated 5B, 46A, 97A, 128A, 146C, 208A, 215A, 26A, 164A, 230A, 76E1, 53A, 259A, 33A, 39A, 124A, 175A, 321D, 141A, 51A, 353A, or 305A. The humanized anti-C10orf54 antibody may also include one, two, three, or four human or humanized framework regions of an immunoglobulin heavy chain variable region, and / or one, two, three, or four human or humanized framework regions of an immunoglobulin light chain variable region. Also provided are heavy and / or light chain FR regions containing one or more reverse mutations in which a human FR residue is exchanged for a corresponding residue present in a parental murine heavy or light chain or another equivalent residue. In some aspects, the amino acid sequences of heavy and light chain CDR1, CDR2, and CDR3 of some humanized anti-C10orf54 antibodies may also include one or more mutations, wherein the CDR residues are as identified in Tables 5-33. The amino acid sequences of FR1, FR2, FR3, and FR4 of the heavy and light chains that can be used for humanizing anti-C10orf54 antibodies are as identified in Tables 5-11 and Figures 3-9, 17, and 22-25.

[0371] In certain embodiments, a humanized antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region comprising: (1) a VHFR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827, and 1828; (2) a VHFR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 52, 106, 56, 122-124, 63, 64, and 323-326; (3) a VHFR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 53, 54, 56, 122-124, 63, 64, and 323-326; NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 and 1848-1875; and / or (4) a VH FR4 having the amino acid sequence of SEQ ID NO: 54, 320, 168054, 320, 1680. Thus, in some embodiments, the humanized antibody comprises a VH region comprising VH FR1, wherein VH FR1 has an amino acid sequence selected from the group consisting of SEQ ID NOs: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827, and 1828. In some embodiments, the humanized antibody comprises a VH region comprising VH FR2, wherein VH FR2 has an amino acid sequence selected from the group consisting of SEQ ID NOs: 52, 106, 56, 122-124, 63, 64, and 323-326. In some embodiments, the humanized antibody comprises a VH region comprising a VH FR3, wherein VH FR3 has an amino acid sequence selected from the group consisting of SEQ ID NOs: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742, and 1848-1875. In some embodiments, the humanized antibody comprises a VH region comprising a VH FR4, wherein VH FR4 has an amino acid sequence of SEQ ID NOs: 54, 320, 1680, 54, 320, 1680.

[0372] In certain embodiments, a humanized antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VL region comprising: (1) an amino acid sequence selected from the group consisting of SEQ ID NOs: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877, and 1878; (2) a VL FR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 76, 80, 284, 92, 1038-1044, 1062-1067, and 1823-1826; (3) a VL FR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 and 1901; and / or (4) a VL FR4 having the amino acids of SEQ ID NO: 78. Thus, in some aspects, the humanized antibody comprises a VL region comprising a VL FR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 and 1878. In some aspects, the humanized antibody comprises a VL region comprising a VL FR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 76, 80, 284, 92, 1038-1044, 1062-1067, and 1823-1826. In some aspects, the humanized antibody comprises a VL region comprising a VL FR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714, and 1901. In some aspects, the humanized antibody comprises a VL region comprising a VL FR4 having amino acids of SEQ ID NO: 78.

[0373] In certain embodiments, a humanized antibody that binds to C10orf54 (e.g., a C10orf54 polypeptide, a C10orf54 polypeptide fragment, a C10orf54 epitope) comprises a VH region and a VL region, wherein the VH region further comprises: (1) a VH FR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827, and 1828; (2) a VH FR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 52, 106, 56, 122-124, 63, 64, and 323-326; (3) a VH FR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 and 1848-1875; and / or (4) a VHFR4 having an amino acid sequence of SEQ ID NO: 54, 320, 168054, 320, 1680; wherein the VL region further comprises: (1) a VL having an amino acid sequence selected from the group consisting of SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 and 1878 FR1; (2) a VL FR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 76, 80, 284, 92, 1038-1044, 1062-1067 and 1823-1826; (3) a VL FR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 and 1901; and / or (4) a VL FR4 having the amino acids of SEQ ID NO: 78.

[0374] Also provided herein are antibodies comprising one or more (eg, one, two, three, or four) VHFRs and one or more VL FRs listed in Tables 5-11. In particular, provided herein is an antibody comprising a VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828) and a VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 18781037, 1059-1061, 1615-1629, 1743, 1877 or 1878); a VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828) and a VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878 NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828) and VLFR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-18261044, 1062-1067 or 1823-1826); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828) and VL FR3 (SEQ ID NO: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828) and VL FR4 (SEQ ID NO: 78); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326) and VL FR1 (SEQ ID NO: NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878);VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-18261044, 1062-1067 or 1823-1826); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326) and VL FR3 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826); NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 19011068, 1069, 1689-1714 or 1901); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326) and VL FR4 (SEQ ID NO: 78); VH FR3 (SEQ ID NO: NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875) and VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828); VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875); NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875) and VL FR4 (SEQ ID NO: 78); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326) and VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878); VH FR1 (SEQ ID NO: NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); ... NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326) and VL FR4 (SEQ ID NO: 78); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875) and VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VH FR2 (SEQ ID NO: NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875); NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875) and VL FR4 (SEQ ID NO: 78); VH FR1 (SEQ ID NO: 54, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875) and VL FR4 (SEQ ID NO: 78); NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826); VH FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878); or 1828), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR4 (SEQ ID NO: 78); ... NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR1 (SEQ ID NO: NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR1 (SEQ ID NO: NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901). NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR4 (SEQ ID NO: 78); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78); VH FR3 (SEQ ID NO: 5 or 1878); VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878); VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR3 (SEQ ID NO: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR1 (SEQ ID NO: NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR4 (SEQ ID NO: 78); VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR2 (SEQ ID NO: NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR2 (SEQ ID NO: 5 ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78);VH FR4 (SEQ ID NO: 54, 320, 168054, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826); VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826). NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR4 (SEQ ID NO: NO:78); VH FR4 (SEQ ID NO:54, 320, 1680), VL FR2 (SEQ ID NO:76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO:77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR4 (SEQ ID NO:54, 320, 1680), VL FR2 (SEQ ID NO:76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO:78);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875) and VL FR1 (SEQ ID NO: ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 5 NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875) and VL FR3 (SEQ ID NO: ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 5 NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875) and VL FR4 (SEQ ID NO: 78); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR4 (SEQ ID NO: 54, 320, 1680) and VLFR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR4 (SEQ ID NO: 54, 320, 1680) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826); ... NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR4 (SEQ ID NO: 54, 320, 1680) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR1 (SEQ ID NO: NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VHFR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR4 (SEQ ID NO: 54, 320, 1680) and VL FR4 (SEQ ID NO: 78);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680) and VL FR1 (SEQ ID NO: NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR3 (SEQ ID NO: NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826); VH FR1 (SEQ ID NO: NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680) and VL FR3 (SEQ ID NO: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680) and VL FR4 (SEQ ID NO: 78); VH FR2 (SEQ ID NO: NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680) and VL FR1 (SEQ ID NO: NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: NO: 54, 320, 1680) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680) and VL FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875). NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680) and VL FR4 (SEQ ID NO: 54, 320, 1680). NO: 78); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR2 (SEQ ID NO: NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR3 (SEQ ID NO: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR1 (SEQ ID NO: NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR4 (SEQ ID NO: 78); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR3 (SEQ ID NO: or 1878); VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878); VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);VHFR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030 ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR3 (SEQ ID NO: NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR4 (SEQ ID NO: 78); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR3 (SEQ ID NO: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VHFR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR4 (SEQ ID NO: ID NO:78); VH FR2 (SEQ ID NO:52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR1 (SEQ ID NO:75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);

[0136] The present invention relates to a VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), a VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and a VL FR3 (SEQ ID NO: 5 NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR1 (SEQ ID NO: NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR4 (SEQ ID NO: 78); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR2 (SEQ ID NO: NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); ... NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR4 (SEQ ID NO: 78); VH FR3 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR4 (SEQ ID NO: 78); VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR2 (SEQ ID NO: NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR3 (SEQ ID NO: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR4 (SEQ ID NO: 78); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR2 (SEQ ID NO: 5 NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78); ... NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VLFR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 190 NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901);VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78); VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78); VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901);VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78); VH FR1 (SEQ ID NO: NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78); VH FR1 (SEQ ID NO: NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR3 (SEQ ID NO: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78);VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78); VH FR3 (SEQ ID NO: 54, 320, 1680), VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901). NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR2 (SEQ ID NO: NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR3 (SEQ ID NO: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826), VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78); VH FR2 (SEQ ID NO: ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78); VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78). NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78);VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826), VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78); VH FR3 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826), VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78); NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR1 (SEQ ID NO: NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78);VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR3 (SEQ ID NO: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78); VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826), VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78); VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: 78); VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), IDNO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901);VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78); VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78); NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78); VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826), VL FR3 (SEQ ID NO: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 5 NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680) and VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: NO: 54, 320, 1680) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: 54, 320, 1680) and VLFR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VH FR4 (SEQ ID NO: NO: 54, 320, 1680) and VLFR4 (SEQ ID NO: 78); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR1 (SEQ ID NO: NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR4 (SEQ ID NO: 78);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR2 (SEQ ID NO: NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR3 (SEQ ID NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826) and VL FR4 (SEQ ID NO: 78);VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR3 (SEQ ID NO: 53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882, 903-1030, 1560-1614, 1653-1679, 1721-1742 or 1848-1875), VL FR3 (SEQ ID NO: NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901) and VL FR4 (SEQ ID NO: 78); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR2 (SEQ ID NO: 76, 80, 284, 92, 1038-1044, 1062-1067 or 1823-1826);

[00136] The invention relates to a VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), a VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR4 (SEQ ID NO: 54, 320, 1680), a VL FR1 (SEQ ID NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878), and a VL FR3 (SEQ ID NO: 5 NO: 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, 1689-1714 or 1901); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326), VH FR4 (SEQ ID NO: 54, 320, 1680), VL FR1 (SEQ ID NO: NO: 75, 252, 79, 277-283, 91, 1031-1037, 1059-1061, 1615-1629, 1743, 1877 or 1878) and VL FR4 (SEQ ID NO: 78); VH FR1 (SEQ ID NO: 51, 105, 55, 115-121, 39, 58, 895-902, 1550-1555, 1649-1652, 1715, 1716, 1827 or 1828), VH FR2 (SEQ ID NO: 52, 106, 56, 122-124, 63, 64 or 323-326)...

Claims

1. An isolated antibody or antigen-binding fragment thereof that binds to C10orf54 protein, wherein the antibody is antibody 26A, comprising: - a heavy chain comprising the following three CDRs, namely, CDR-H1 consisting of the sequence of SEQ ID NO: 1296, CDR-H2 consisting of the sequence of SEQ ID NO: 1358, and CDR-H3 consisting of the sequence of SEQ ID NO: 1393; and - a light chain comprising the following three CDRs, namely CDR-L1 consisting of the sequence of SEQ ID NO: 1435, CDR-L2 consisting of the sequence of SEQ ID NO: 1476, and CDR-L3 consisting of the sequence of SEQ ID NO: 1499.

2. The isolated antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody is a monoclonal antibody.

3. The isolated antibody or antigen-binding fragment thereof according to any one of claims 1 or 2, wherein the antibody is humanized.

4. The isolated antibody or antigen-binding fragment thereof according to claim 3, wherein the antibody comprises a heavy chain variable domain having a sequence selected from the group consisting of the amino acid sequences of SEQ ID NO: 1529, SEQ ID NO: 1530 and SEQ ID NO: 1531, and a light chain variable domain having a sequence selected from the group consisting of the amino acid sequences of SEQ ID NO: 1532, SEQ ID NO: 1533 and SEQ ID NO: 1534.

5. The isolated antibody or antigen-binding fragment thereof according to claim 1 or 2, wherein the antibody is a Fab fragment, a F(ab')2 fragment, a single-chain Fv (sFv), a diabody, a triabody or a minibody.

6. An antibody drug conjugate comprising the isolated antibody of any one of claims 1 to 5 conjugated to a cytotoxic agent.

7. A polynucleotide comprising a nucleotide sequence encoding the isolated antibody of any one of claims 1 to 5. An expression vector comprising the polynucleotide according to claim 7 .

9. A host cell comprising the expression vector according to claim 8.

10. A method for producing the isolated antibody or antigen-binding fragment thereof of any one of claims 1 to 5, the method comprising the step of culturing the host cell of claim 9 under conditions that promote production of the antibody.

11. A pharmaceutical composition comprising: the isolated antibody according to any one of claims 1 to 5, or the antibody-drug conjugate according to claim 6; and a pharmaceutically acceptable diluent, carrier or excipient.

12. A kit comprising the isolated antibody of any one of claims 1 to 5.

13. The kit of claim 12, wherein the antibody is conjugated to a detectable substrate.

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