Anti-CLEC2D antibody and method of use thereof

Abstract

To provide anti-CLEC2D antibodies and methods of use thereof.SOLUTION: The present application disclosure relates to anti-CLEC2D (CLEC2D encodes the gene for the Lectin Like Transcript-1-LLT1- protein, which is a functional ligand for the human NKR-P1A receptor) antibodies and related compositions and methods of use thereof. These antibodies are used as therapeutics, and in prognostic and diagnostic applications in various cancers and other diseases. The present disclosure relates to immunology, particularly to immuno-oncology.SELECTED DRAWING: None

Description

【Technical Field】 【0001】 Related Applications This application claims priority and benefit to Indian Provisional Patent Application No. 201941005395, filed on February 11, 2019, the entire content of which is incorporated herein by reference. 【0002】 The present disclosure relates to immunology, particularly immuno - oncology. Specifically, the present disclosure relates to novel antibody molecules against the CLEC2D antigen. The present disclosure also relates to multiple formats and amino acid compositions of the disclosed antibody molecules, the variable regions of the heavy and light chains of the antibody molecules, and the composition and length distribution of the CDRs against the CLEC2D antigen. The compositions of the present disclosure can be used either as a monotherapy or in combination with any other antibody molecule or any other therapeutic agent suitable for the treatment or prevention of diseases such as cancer. 【Background Art】 【0003】 The modulation of immune cell checkpoint receptors by antibody - based / directed therapeutic approaches has gathered some interest over the past decade. Many of these receptors are involved in the regulation of T - cell checkpoints. However, the regulation of checkpoints in B cells, natural killer (NK) cells, and myeloid cells has drawn attention. 【0004】 NK cells are part of the innate immune system that recognize a wide range of target cells, such as tumor cells or virus - infected cells, and induce cytotoxicity against them. In addition, NK cells are involved in the induction and progression of adaptive immune responses through the production of various cytokines. Generally, these responses are regulated by the interaction of a wide variety of activating and inhibitory receptors with ligands on the surface of target cells and immune cells. 【0005】 NK cell receptors are classified into two main structural classes: the immunoglobulin superfamily and the C-type lectin-like (CTL) superfamily. The NKR-P1 receptor (e.g., CD161) is a family of C-type lectin-like transmembrane molecules, which are important immunomodulatory genes, and are expressed on various cell types, including splenic dendritic cells, T cells, and granulocyte subtypes. Lectin-like transcript 1 (LLT1) molecules, or C-type lectin domain family 2 member D (CLEC2D) molecules, or osteoclast inhibitory lectin (OCIL) molecules are ligands for the CD161 receptor, and this interaction selectively modulates the functions of NK cells and T cells. There are six splice variants of CLEC2D, but isoform 1 is the standard sequence expressed on NK cells, T cells, monocytes / macrophages, activated B cells, and activated dendritic cells, and functions as the human NK cell activation receptor. The polypeptide chain of CLEC2D can be classified into an N-terminal cytoplasmic portion, a transmembrane region, a stalk region, and a C-terminal CTL external domain having two predicted N-glycosylation sites. 【0006】 The interaction between CLEC2D and CD161 leads to evasion of host defenses in several disease scenarios, including various cancers. Such immune evasion has been reported in human glioblastoma and other diseases. Furthermore, CLEC2D expression on B cells is thought to regulate crosstalk between NK cells and antigen-presenting cells (APCs). Blocking the CLEC2D-CD161 interaction would provide novel therapeutic options for treating various cancers. 【0007】 The downstream signaling of the CLEC2D-CD161 interaction is poorly understood. The CLEC2D / CD161 interaction inhibits NK cell function and promotes T cell proliferation and cytokine secretion. Therefore, the effects of the CLEC2D / CD161 interaction can be reversed by using monoclonal antibodies that specifically bind to CLEC2D to inhibit the interaction between CLEC2D and its known receptor CD161 or other unknown cellular mechanisms. [Overview of the Initiative] 【0008】 This disclosure provides an isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain is (a) at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to a sequence selected from SEQ ID NO: 46, SEQ ID NO: 65, SEQ ID NO: 59, and SEQ ID NO: 99, and (b) at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, or less identical to a sequence selected from SEQ ID NO: 57, SEQ ID NO: 91, SEQ ID NO: 98, SEQ ID NO: 84, SEQ ID NO: 58, SEQ ID NO: 88, SEQ ID NO: 96, SEQ ID NO: 47, SEQ ID NO: 17, and SEQ ID NO: 8 (c) At least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical sequences, (c) at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, and at least 99.(d) Sequences that are 9% or 100% identical, (d) Sequences selected from sequence number: 45, sequence number: 15, sequence number: 51, sequence number: 44, sequence number: 73, sequence number: 36, sequence number: 77, sequence number: 50, and sequence number: 6, with 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical, (e) Sequence number: 97, sequence number: 16, sequence number: 76, sequence number: 9, sequence number: 89, sequence number: 107, sequence number: 68, For arrays selected from column number: 29, array number: 67, array number: 74, array number: 32, array number: 81, array number: 106, array number: 31, array number: 62, array number: 48, array number: 75, array number: 12, array number: 102, array number: 54, array number: 80, array number: 26, array number: 30, array number: 92, array number: 108, and array number: 79, 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% identical or 100% identical sequences, (f) Sequence ID: 105, Sequence ID: 101, Sequence ID: 4, Sequence ID: 72, Sequence ID: 28, Sequence ID: 64, Sequence ID: 25, Sequence ID: 60, Sequence ID: 55, Sequence ID: 52, Sequence ID: 27, Sequence ID: 43, Sequence ID: 70, Sequence ID: 71, Sequence ID: 14, Sequence ID: 85, Sequence ID: 13, Sequence ID: 61, Sequence ID: 42, Sequence ID: 39, Sequence ID: 10, Sequence ID: 49, Sequence ID: 24, Sequence ID: For sequences selected from 40, Array No.: 63, Array No.: 78, Array No.: 2, Array No.: 94, and Array No.: 5, 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, and at least (g) Sequences that are 98%, at least 99%, at least 99.5%, or at least 99.9% identical, or 100% identical, selected from sequence numbers: 11, 35, 86, 22, 69, 41, 3, 66, 37, 56, 21, 38, 90, 100, 18, 20, 83, 1, and 19 For the selected sequences, 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.The antibody or its antigen-binding fragment binds to C-type lectin domain family 2 member D (CLEC2D). 【0009】 This disclosure provides an isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the light chain is (a) at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, and at least (b) sequences that are 99.9% or 100% identical, (b) sequences selected from sequence numbers: 222, 258, 219, 313, 294, 303, 317, 273, 266, 315, 257, 288, 301, 221, 240, 299, 247, 263, and 274, with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, and at least 99.(c) Sequences that are 9% or 100% identical, for sequences selected from sequence numbers: 231, 250, 260, 226, 271, 256, 272, 278, 302, 320, 295, 292, 229, 264, 252, 267, 304, 300, 311, and 324, a small amount of data is used. (d) Sequences that are at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical, (d) Sequence ID: 259, Sequence ID: 239, Sequence ID: 281, Sequence ID: 228, Sequence ID: 217, Sequence ID: 227, and Sequence ID: Sequences that are at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from 251, (e) Sequence ID: 307, Sequence ID: 262, Sequence ID: 253, Sequence ID: 27 6. For sequences selected from Array No.: 323, Array No.: 234, Array No.: 261, Array No.: 312, and Array No.: 290, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, and at least 99.(f) sequences that are 9% or 100% identical, (f) sequences selected from sequence numbers: 254, 289, 238, 268, 248, 284, 244, 310, 243, 285, 220, 255, 293, 298, 235, 319, 245, 224, 291, 277, and 232, with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 1 The antibody or its antigen-binding fragment binds to CLEC2D, and includes sequences that are 00% identical, as well as sequences selected from the group consisting of sequences that are 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from (g) SEQ ID NO: 282, SEQ ID NO: 308, SEQ ID NO: 287, SEQ ID NO: 321, SEQ ID NO: 236, SEQ ID NO: 265, SEQ ID NO: 270, at least 275, SEQ ID NO: 306, SEQ ID NO: 296, SEQ ID NO: 241, SEQ ID NO: 314, and SEQ ID NO: 223. 【0010】 This disclosure relates to (a) (i) sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence number 46, sequence number 65, sequence number 59, and sequence number 99; and (ii) sequences that are at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence number 46, sequence number 65, sequence number 59, and sequence number 99; and sequence number 84, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence number 46, sequence number 65, sequence number 59, and sequence number 99. 8, sequences selected from sequence number:96, sequence number:47, sequence number:17, and sequence number:8 that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical; (iii) sequences:93, sequence number:53, sequence number:95, sequence number:23, sequence number: (iv) Sequences that are at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence number 103 and sequence number 7, (iv) sequence number 45, sequence number 15, sequence number 51, For sequences selected from Array No. 44, Array No. 73, Array No. 36, Array No. 77, Array No. 50, and Array No. 6, 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, and at least 99.9% or 100% identical sequences, (v) SEQ ID NO: 97, SEQ ID NO: 16, SEQ ID NO: 76, SEQ ID NO: 9, SEQ ID NO: 89, SEQ ID NO: 107, SEQ ID NO: 68, SEQ ID NO: 29, SEQ ID NO: 67, SEQ ID NO: 74, SEQ ID NO: 32, SEQ ID NO: 81, SEQ ID NO: 106, SEQ ID NO: 31, SEQ ID NO: 62, SEQ ID NO: 48, SEQ ID NO: 75, SEQ ID NO: 12, SEQ ID NO: 102, SEQ ID NO: 54, SEQ ID NO: 80, SEQ ID NO: 26, SEQ ID NO: 30, SEQ ID NO: 92, SEQ ID NO: 10 8, and sequences selected from array number: 79 that are 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to the sequence selected from array number: 79. (vi) Sequence ID: 105, Sequence ID: 101, Sequence ID: 4, Sequence ID: 72, Sequence ID: 28, Sequence ID: 64, Sequence ID: 25, Sequence ID: 60, Sequence ID: 55, Sequence ID: 52, Sequence ID: 27, Sequence ID: 43, Sequence ID: 70, Sequence ID: 71, Sequence ID: 14, Sequence ID: 85, Sequence ID: 13, Sequence ID: 61, Sequence ID: 42, Sequence ID: 39, Sequence ID: 10, Sequence ID: 49, Sequence ID: 24, Sequence ID: 40, Sequence ID: 63, Sequence ID: 78, Sequence ID: 2 For sequences selected from , , , and , 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, and at least 99.(vii) sequences that are 9% or 100% identical, (vii) sequences selected from sequence numbers: 11, 35, 86, 22, 69, 41, 3, 66, 37, 56, 21, 38, 90, 100, 18, 20, 83, 1, and 19, with at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, (viii) sequences that are at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical, and (viii) sequences selected from sequence number 33, sequence number 34, sequence number 87, sequence number 82, and sequence number 104, at least 35%, at least 40%, at least 45%, at least 5 A heavy chain containing sequences selected from sequences that are 0%, 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical, as well as (b)(i) Sequence ID: 218, Sequence ID: 249, Sequence ID: 230, Sequence ID: 2 For sequences selected from 79, Array: 316, Array: 237, Array: 322, Array: 225, Array: 318, Array: 233, Array: 305, Array: 280, Array: 283, Array: 242, Array: 286, Array: 297, Array: 309, and Array: 246, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and at least 99%.(ii) sequences that are 5%, at least 99.9%, or 100% identical, (ii) sequences selected from sequence numbers 222, 258, 219, 313, 294, 303, 317, 273, 266, 315, 257, 288, 301, 221, 240, 299, 247, 263, and 274, at least 80%, at least 85% (iii) Sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical, (iii) Sequence ID: 231, Sequence ID: 250, Sequence ID: 260, Sequence ID: 226, Sequence ID: 271, Sequence ID: 256, Sequence ID: 272, Sequence ID: 278, Sequence ID: 302, Sequence ID: 320, Sequence ID: 295, Sequence ID: For sequences selected from 292, Array No.: 229, Array No.: 264, Array No.: 252, Array No.: 267, Array No.: 304, Array No.: 300, Array No.: 311, and Array No.: 324, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 10 (iv) For sequences selected from (i) 259, (ii) 239, (iv) 281, (ii) 228, (ii) 217, (ii) 227, and (ii) 251, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, and at least 99.(v) Sequences that are 9% or 100% identical, (v) Sequences selected from Sequence ID: 307, Sequence ID: 262, Sequence ID: 253, Sequence ID: 276, Sequence ID: 323, Sequence ID: 234, Sequence ID: 261, Sequence ID: 312, and Sequence ID: 290, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% , sequences that are at least 99.5%, at least 99.9%, or 100% identical, (vi) sequences selected from sequence numbers: 254, 289, 238, 268, 248, 284, 244, 310, 243, 285, 220, 255, 293, 298, 235, 319, 245, 224, 291, 277, and 232, at least Sequences that are 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical, as well as (vii) Sequence IDs: 282, 308, 287, 321, 236, 265, 270, For sequences selected from column number: 275, sequence number: 306, sequence number: 296, sequence number: 241, sequence number: 314, and sequence number: 223, 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, and at least 99.We provide an isolated antibody or its antigen-binding fragment, comprising a light chain containing a sequence selected from 9% or 100% identical sequences, wherein the antibody or its antigen-binding fragment binds to CLEC2D. 【0011】 This disclosure provides an isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain comprises a sequence selected from any one of SEQ ID NOs: 1 to 108. 【0012】 This disclosure provides an isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the light chain comprises a sequence selected from any one of SEQ ID NOs: 217 to 324. 【0013】 This disclosure provides an isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain comprises a sequence selected from any one of SEQ ID NOs: 1 to 108, and the light chain comprises a sequence selected from any one of SEQ ID NOs: 217 to 324. 【0014】 This disclosure provides an isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain comprises (i) a heavy chain (HC)CDR1 comprising a sequence selected from SEQ ID NOs: 433 to 485, (ii) an HC CDR2 comprising a sequence selected from SEQ ID NOs: 486 to 546, and (iii) an HC CDR3 comprising a sequence selected from SEQ ID NOs: 547 to 653, and the antibody or its antigen-binding fragment binds to CLEC2D. 【0015】 This disclosure provides an isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the light chain comprises (i) light chain (LC)CDR1 comprising a sequence selected from SEQ ID NOs: 654 to 726, (ii) LC CDR2 comprising a sequence selected from SEQ ID NOs: 727 to 783, and (iii) LC CDR3 comprising a sequence selected from SEQ ID NOs: 784 to 885, and the antibody or its antigen-binding fragment binds to CLEC2D. 【0016】 This disclosure provides an isolated antibody or its antigen-binding fragment comprising a heavy chain containing an HC CDR1 sequence selected from SEQ ID NOs: 433 to 485, an HC CDR2 sequence selected from SEQ ID NOs: 486 to 546, and an HC CDR3 sequence selected from SEQ ID NOs: 547 to 653; a light chain containing an LC CDR1 sequence selected from SEQ ID NOs: 654 to 726, an LC CDR2 sequence selected from SEQ ID NOs: 727 to 783, and an LC CDR3 sequence selected from SEQ ID NOs: 784 to 885, or a combination thereof. 【0017】 In some embodiments of the antibodies or antigen-binding fragments of this disclosure, the antibody or antigen-binding fragment binds to a human CLEC2D polypeptide containing a sequence selected from SEQ ID NOs: 886-909, a human CLEC2D polypeptide containing a sequence selected from SEQ ID NOs: 930-1003, a cynomolgus monkey CLEC2D polypeptide containing a sequence selected from SEQ ID NOs: 918-920, a mouse CLEC2D polypeptide containing a sequence selected from SEQ ID NOs: 911-915, a rat CLEC2D polypeptide containing the sequence of SEQ ID NO: 910, and / or a canine CLEC2D polypeptide containing a sequence selected from SEQ ID NOs: 916-917. 【0018】 This disclosure provides an isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain comprises the heavy chain complementarity-determining regions (CDRH)1, CDRH2, and CDRH3 amino acid sequences of an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Table 9A, and the light chain comprises the light chain complementarity-determining regions (CDRL)1, CDRL2, and CDRL3 amino acid sequences of an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Table 9A. 【0019】 This disclosure provides an isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain comprises a variable heavy chain amino acid sequence of an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Table 9A, and the light chain comprises a variable light chain amino acid sequence of an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Table 9A. 【0020】 This disclosure provides an isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain framework region sequence of a germline family of anti-CLEC2D antibodies selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9B disclosed herein, and the light chain comprises a light chain germline family framework region sequence of an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9B disclosed herein. 【0021】 In some embodiments of the antibodies or antigen-binding fragments of this disclosure, the antibody or antigen-binding fragment is a monoclonal antibody. 【0022】 In some embodiments of the antibodies or antigen-binding fragments of this disclosure, the antibodies or antigen-binding fragments block the binding of CLEC2D to a receptor. In some embodiments, the receptor includes a CD161 receptor, which includes a sequence selected from SEQ ID NOs: 921-929. 【0023】 In some embodiments of the antibodies or antigen-binding fragments of this disclosure, the antibody or antigen-binding fragment is human, mouse, or chimeric. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fv, Fav, F(ab')2, Fab', dsFv, scFv, sc(Fv)2, scFv-CH3, scFv-Fc, and diabody fragments. In some embodiments, the antibody or antigen-binding fragment binds to human CLEC2D with an affinity (KD) of less than 100 nM. 【0024】 This disclosure provides pharmaceutical compositions comprising peptides (e.g., antibodies or antigen-binding fragments thereof) or nucleic acids as described herein. 【0025】 This disclosure provides a pharmaceutical composition comprising the antibody or its antigen-binding fragment. 【0026】 This disclosure provides a pharmaceutical composition comprising a nucleic acid encoding the antibody or its antigen-binding fragment. 【0027】 In some embodiments of the pharmaceutical compositions of this disclosure, the pharmaceutical composition further comprises at least one of a buffer, a pharmaceutically acceptable diluent, a carrier, a solubilizer, an emulsifier, and a preservative. 【0028】 This disclosure provides isolated nucleic acids comprising polynucleotide sequences encoding amino acid heavy chain sequences selected from SEQ ID NOs: 109 to 216. 【0029】 This disclosure provides isolated nucleic acids comprising polynucleotide sequences encoding amino acid light chain sequences selected from SEQ ID NOs: 325 to 432. 【0030】 This disclosure provides isolated nucleic acids comprising polynucleotide sequences encoding heavy chains containing the CDRH1, CDRH2, and CDRH3 amino acid sequences, respectively, of anti-CLEC2D antibodies selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9A disclosed herein. 【0031】 This disclosure provides isolated nucleic acids comprising polynucleotide sequences encoding a light chain containing the CDRL1, CDRL2, and CDRL3 amino acid sequences, respectively, of anti-CLEC2D antibodies selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9A disclosed herein. 【0032】 This disclosure provides isolated nucleic acids comprising polynucleotide sequences encoding heavy chain amino acid sequences described in the variable heavy chain amino acid sequences of anti-CLEC2D antibodies selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9A disclosed herein. 【0033】 This disclosure provides isolated nucleic acids comprising polynucleotide sequences encoding light chain amino acid sequences described in the variable light chain amino acid sequences of anti-CLEC2D antibodies selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9A disclosed herein. 【0034】 This disclosure provides isolated nucleic acids comprising a polynucleotide sequence encoding a heavy chain, which includes a framework region amino acid sequence described in the heavy chain framework region amino acid sequence of an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9B disclosed herein. 【0035】 This disclosure provides isolated nucleic acids comprising a polynucleotide sequence encoding a light chain containing the framework region amino acid sequence described in the light chain framework region amino acid sequence of an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9B disclosed herein. 【0036】 This disclosure provides isolated nucleic acids comprising a polynucleotide sequence encoding a heavy chain amino acid sequence of the antibody or its antigen-binding fragment. 【0037】 This disclosure provides isolated nucleic acids comprising a polynucleotide sequence encoding the light chain amino acid sequence of the antibody or its antigen-binding fragment. 【0038】 This disclosure provides a composition comprising a first nucleic acid encoding a polypeptide selected from SEQ ID NOs: 109 to 216, and a second nucleic acid encoding a polypeptide selected from SEQ ID NOs: 325 to 432. 【0039】 This disclosure provides vectors comprising the nucleic acids of this disclosure. 【0040】 This disclosure provides cells comprising nucleic acids, nucleic acid compositions, or vectors of the Disclosure. In some embodiments, the cells are eukaryotic cells. In some embodiments, the eukaryotic cells are mammalian cells. In some embodiments, the mammalian cells are selected from the group consisting of CHO cells, 293 cells, NSO cells, PER.C6 cells, and B cells. In some embodiments, the mammalian cells are 293-6E cells or DG44 cells. In some embodiments, the cells express antibodies or antigen-binding fragments of the Disclosure. In some embodiments, the cells are germline cells. 【0041】 This disclosure provides cells that produce the antibody or antigen-binding fragment thereof. 【0042】 This disclosure provides a method for carrying out treatment of a disease in a subject requiring treatment, which includes administering a therapeutically effective amount of the antibody or antigen-binding fragment of this disclosure to the subject. 【0043】 This disclosure provides compositions for use in subjects requiring treatment of a disease, comprising a therapeutically effective amount of the antibody or its antigen-binding fragment or a nucleic acid encoding the antibody or its antigen-binding fragment. 【0044】 This disclosure provides compositions for use in the manufacture of pharmaceuticals for subjects requiring the prevention or treatment of a disease, comprising a therapeutically effective amount of the antibody or antigen-binding fragment thereof of this disclosure, or a nucleic acid encoding the antibody or antigen-binding fragment thereof of this disclosure. 【0045】 In some embodiments of the methods or compositions for use in this disclosure, the disease is rheumatoid arthritis. In some embodiments, the subject exhibits osteopenia resulting from having rheumatoid arthritis. In some embodiments, administration of a therapeutically effective amount of an antibody or its antigen-binding fragment delays or reverses osteopenia in the subject. 【0046】 In some embodiments of the methods or compositions for use in this disclosure, the disease is cancer. In some embodiments, cancer is selected from the group consisting of breast cancer, prostate cancer, endometrial cancer, uterine cancer, bladder cancer, kidney cancer, esophageal cancer, squamous cell carcinoma, uveal melanoma, glioma, glioblastoma, myeloma, pheochromocytoma, paraganglioma, follicular lymphoma, renal cell carcinoma, cendcal cancer, ovarian cancer, cervical cancer, lung cancer, colorectal cancer, brain cancer, pancreatic cancer, gastric cancer, intestinal cancer, testicular cancer, skin cancer, thyroid cancer, thymoma, head and neck cancer, liver cancer, pharyngeal cancer, adrenocortical carcinoma, cholangiocarcinoma, mesothelioma, sarcoma, leukemia, lymphoma, Hodgkin's disease, multiple myeloma, melanoma, astrocytoma, stomach cancer, and lung adenocarcinoma. In some embodiments, cancer cells express CLEC2D on their cell surface. In some embodiments, administration of a therapeutically effective amount of an antibody or its antigen-binding fragment results in an antitumor effect in the subject. 【0047】 In some embodiments of the methods or compositions for use in this disclosure, an antibody or its antigen-binding fragment is administered as a monotherapy. In some embodiments, an antibody or its antigen-binding fragment is administered in combination with at least one of the following: a T-cell oriented immunomodulator, a second immunomodulator, a cancer vaccine, a adoptive cell therapy agent, a tumor lysis virus, a second antibody therapy agent, a radiotherapy agent, an antibody-drug conjugate, a small interfering RNA, a chemotherapeutic agent, an immunotherapy agent, an immune checkpoint inhibitor, a mitotic inhibitor, or a combination thereof. In some embodiments, the adoptive cell therapy agent includes a CAR-T therapy agent. In some embodiments, administration of a therapeutically effective amount of an antibody or its antigen-binding fragment alleviates the signs or symptoms of a disease. 【0048】 This disclosure provides an antibody library containing at least about 10⁸ unique monoclonal antibody clones, of which at least about 80% are detectable and specifically bind to the CLEC2D antigen. 【0049】 In some embodiments of the antibody library of this disclosure, the CLEC2D antigen comprises an amino acid sequence selected from SEQ ID NOs: 886-920 and SEQ ID NOs: 930-1003. In some embodiments of the antibody library of this disclosure, the CLEC2D antigen comprises an amino acid sequence selected from SEQ ID NOs: 886-909 and SEQ ID NOs: 930-1003. In some embodiments, the CLEC2D antigen comprises the CLEC2D antigen expressed on the surface of tumor cells, a variant of the CLEC2D antigen, or a homolog of the CLEC2D antigen. In some embodiments, the variant of the CLEC2D antigen comprises a fragment of the CLEC2D protein. In some embodiments, the homolog of the CLEC2D antigen comprises human, mouse, dog, rat, or cynomolgus monkey CLEC2D. 【0050】 This disclosure provides a method for carrying out immunomodulation in subjects requiring such modification, which includes administering a therapeutically effective amount of the antibody or antigen-binding fragment of this disclosure or a nucleic acid encoding the antibody or antigen-binding fragment of this disclosure to the subject. 【0051】 This disclosure provides a method for carrying out the modulation (e.g., enhancement) of innate immunity in subjects requiring such modulation, which includes administering a therapeutically effective amount of the antibody or antigen-binding fragment of this disclosure or a nucleic acid encoding the antibody or antigen-binding fragment of this disclosure to the subject. 【0052】 This disclosure provides a method for carrying out enhanced cytotoxicity of natural killer cells in subjects requiring such enhancement, and includes administering a therapeutically effective amount of the antibody or its antigen-binding fragment or a nucleic acid encoding the antibody or its antigen-binding fragment to the subject. 【0053】 This disclosure provides a method for carrying out adaptive immune modulation (e.g., enhancement) in subjects requiring such modulation, which includes administering a therapeutically effective amount of the antibody or antigen-binding fragment of this disclosure or a nucleic acid encoding the antibody or antigen-binding fragment of this disclosure to the subject. 【0054】 This disclosure provides a method for screening a highly diverse antibody gene library with antibodies against CLEC2D antibodies, comprising: (a) creating a phage library by transforming multiple phages by inserting a library of antibody genes into phage protein genes (the phages in the phage library present the library of antibody genes on the surface of the phages); (b) creating an enriched phage library enriched with antibody genes encoding antibodies that bind to the CLEC2D antigen by panning the phage library with the CLEC2D antigen against individual phages that bind to the CLEC2D antigen; (c) repeating step (b) at least once or at least twice; (d) introducing antibody genes derived from the enriched phage library into a yeast surface display library; (e) isolating individual yeast cells that bind to the CLEC2D antigen from the yeast surface display library; (f) culturing the isolated individual yeast cells that bind to the CLEC2D antigen to create yeast surface display library clones; and (g) sequencing the yeast surface display library clones to isolate antibody genes that bind to the CLEC2D antigen. 【0055】 In some embodiments of the screening method of this disclosure, the panning step (b) includes panning a phage library with magnetic beads coated with CLEC2D. In some embodiments, the introduction step (d) includes cloning an antibody gene into a yeast expression vector to transform yeast cells. In some embodiments, the method further includes analyzing the surface expression of the antibody gene using a FLAG tag, c-Myc tag, polyhistidine tag, or V5 tag. In some embodiments, the testing step (e) includes isolating yeast cells expressing an antibody gene that binds to the CLEC2D antigen using flow cytometry. In some embodiments, the method further includes repeating the flow cytometry isolation at least 1×, at least 2×, at least 3×, at least 4×, or at least 5×. In some embodiments, the method further includes cloning an antibody gene that binds to CLEC2D into a mammalian expression vector. 【0056】 This disclosure provides a method for preparing a composition containing an anti-CLEC2D antibody or its antigen-binding fragment, comprising: (a) transforming mammalian cells with a vector comprising a sequence encoding a promoter and a sequence encoding an anti-CLEC2D antibody or antibody fragment (the sequence encoding the promoter and the sequence encoding the anti-CLEC2D antibody or antibody fragment being functionally linked); (b) culturing the mammalian cells under conditions suitable for the expression of the anti-CLEC2D antibody or antibody fragment; (c) centrifuging the cultured mammalian cells to prepare a supernatant; (d) filtering the supernatant; and (e) purifying the filtered supernatant using liquid chromatography. 【0057】 In some embodiments of the methods of this disclosure, filtration step (d) includes a 3 μm to 30 μm filter. In some embodiments, filtration step (d) further includes a 0.22 μm filter. In some embodiments, purification step (e) includes a protein A column. In some embodiments, the protein A column is treated with a high-salt wash buffer to remove host cell proteins. In some embodiments, the anti-CLEC2D antibody or its antibody fragments are eluted using 30 mM phosphate buffer at pH 3.0 to 4.0. In some embodiments, purification step (e) further includes an anion exchange chromatography (AEX) step. In some embodiments, the AEX step includes a Q Sepharose column. In some embodiments, the Q Sepharose is pre-equilibriumized with a pre-equilibriumization buffer containing 10 to 100 mM histidine. In some embodiments, the pre-equilibriumization buffer further includes citrate, phosphate, 2-(N-morpholino)ethanesulfonic acid (MES), acetate, or a combination thereof. In some embodiments, the pre-equilibrium buffer has a pH of 4.5–6.5. In some embodiments, the anti-CLEC2D antibody is eluted in step (e) with an elution buffer containing 200–1000 mM NaCl, KCl, or a combination thereof. In some embodiments, the elution buffer has a pH of 4.5–6.5. 【0058】 In one embodiment, the disclosure relates to the isolation of a novel monoclonal antibody that specifically binds to the CLEC2D antigen. The novel antibody modulates (e.g., inhibits) the interaction between CD161 and CLEC2D to alter NK cell / immune cell-mediated cytotoxicity and / or cytokine production. 【0059】 In another aspect, the disclosure relates to cancer cells expressing CLEC2D, which are specifically recognized by these novel antibodies capable of killing tumor cells by ADCC (antibody-dependent cell-mediated cytotoxicity) and / or CDC (complement-dependent cell-mediated cytotoxicity) and / or ADCP (antibody-dependent cell-mediated phagocytosis). 【0060】 In relevant embodiments, this disclosure relates to a method for producing an anti-CLEC2D antibody, comprising selecting an anti-CLEC2D antibody from a highly diverse antibody gene library. In one embodiment, the highly diverse antibody gene library is presented by a phage surface display and / or a yeast surface display. In one embodiment, the highly diverse antibody gene library presented by the phage and / or yeast is selected using a purified CLEC2D antigen as a target. In one embodiment, the selected anti-CLEC2D antibody gene is expressed in mammalian cells (e.g., Chinese hamster ovary (CHO) cells). In one embodiment, a single-cell clone expressing the anti-CLEC2D antibody is developed into a cell line to confirm anti-CLEC2D antibody expression. In one embodiment, overexpression of the selected antibody clone is achieved by a specific bioreactor process described cumulatively herein as the development of an upstream process, using a predetermined culture medium, supplements, and other appropriate components. In one embodiment, the anti-CLEC2D antibody expressed from the cell line is purified to homogeneity, for example, through various filtration and chromatography processes, which are referred to herein as downstream purification processes. 【0061】 This disclosure provides a method for carrying out treatment in subjects requiring treatment for a disease, which includes measuring the level of CLEC2D protein in the subject and administering a therapeutically effective dose of anti-CLEC2D antibody to the subject. 【0062】 In some embodiments of the methods of this disclosure, the disease is cancer. In some embodiments, cancer is breast cancer, prostate cancer, endometrial cancer, uterine cancer, bladder cancer, kidney cancer, esophageal cancer, squamous cell carcinoma. Carcinoma, uveal melanoma, glioma, glioblastoma, myeloma, pheochromocytoma, paraganglioma, follicular lymphoma, renal cell carcinoma, cervical cancer, ovarian cancer, lung cancer, colorectal cancer, brain cancer, pancreatic cancer, stomach cancer, intestinal cancer, testicular cancer, skin cancer, thyroid cancer, thymoma, head and neck cancer, liver cancer, pharyngeal cancer, adrenocortical carcinoma, cholangiocarcinoma, mesothelioma, sarcoma, leukemia, lymphoma, Hodgkin's disease, multiple myeloma, melanoma, astrocytoma, stomach cancer, lung adenocarcinoma, adenocarcinoma, acinar cell adenocarcinoma, adrenocortical carcinoma, alveolar cell carcinoma, undifferentiated carcinoma, basal cell carcinoma, basal cell carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, renal adenocarcinoma (renaladinol carcinoma), embryonal carcinoma, endometrioid carcinoma (anometroid carcinoma). Carcinoma, fibrous lamellar hepatocellular carcinoma, follicular carcinoma, giant cell carcinoma, hepatocellular carcinoma, intraepidermal carcinoma, carcinoma in situ, leptomanigio carcinoma, medullary carcinoma, black carcinoma, menigual carcinoma, mesometonephric carcinoma, oat cell carcinoma, squamous cell carcinoma, sweat gland carcinoma, transitional cell carcinoma, tubular cell carcinoma, ameloblastoma, sand sarcoma, staphyloid sarcoma, endometrial stromal sarcoma, Ewing's sarcoma, fasciculid sarcoma, giant cell sarcoma, granulocytic sarcoma, immunoblastic sarcoma, paraosteal ossogenic sarcoma, coppices sarcoma This includes sarcomas, leukocytic sarcomas (leukemia), lymphoid sarcomas (lymphosarcoma), medullary sarcomas, myeloid sarcomas (granulocytic sarcomas), austiogenci sarcomas, periosteosarcoma, reticulosarcomas (histiocytic lymphoma), round cell sarcomas, fusiform cell sarcomas, synovial sarcomas, telangiectatic otogenetic sarcomas, Burkitt lymphoma, NPDL, NML, NH, diffuse lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, B-cell lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, acute myeloid lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, mantle cell lymphoma, and follicular lymphoma. In some embodiments, the target cancer cells have high levels of CLEC2D protein compared to normal cells that do not have cancer.In some embodiments, high levels of CLEC2D are associated with poor prognostic effects. 【0063】 In some embodiments of the methods of this disclosure, the disease is an autoimmune disorder or an inflammatory disorder. In some embodiments, the autoimmune disorder or inflammatory disorder is type 1 diabetes, rheumatoid arthritis, lupus, inflammatory bowel disease, celiac disease, Crohn's disease, ulcerative colitis, psoriasis, or multiple sclerosis. 【0064】 In some embodiments of the methods of this disclosure, the disease is an autoimmune disorder or an inflammatory disorder. In some embodiments, the autoimmune disorder is type 1 diabetes, rheumatoid arthritis, lupus, inflammatory bowel disease, celiac disease, Crohn's disease, ulcerative colitis, psoriasis, or multiple sclerosis. 【0065】 In some embodiments of the methods of the present disclosure, the disease is an infectious disease. In some embodiments, the disease is HIV infection, human cytomegalovirus infection, hepatitis B infection, hepatitis C infection, Ebola virus infection, dengue fever, yellow fever, listeriosis, tuberculosis, cholera, malaria, leishmaniasis, or trypanosomiasis. 【0066】 In another embodiment, novel antibodies produced from CHO cell lines are characterized using multiple in vitro and in vivo assays, including various biophysical parameters, antigen recognition, tumor cell surface binding, tumor cell death, cytokine production, and downstream gene analysis to define the mechanism of action. These monoclonal antibodies are also tested for long-term stability and various formulations suitable for therapeutic, prognostic, and diagnostic applications for cancer, infectious diseases, autoimmune diseases, and chronic diseases. In another embodiment, in vivo tumor suppressor assays are performed to establish the antitumor activity of selected antibodies as monotherapies or in combination with other therapeutic products. 【0067】 In one embodiment, this disclosure further relates to the isolation of novel and unique monoclonal antibodies that specifically bind to the CLEC2D antigen. In some embodiments, the novel antibodies influence the interaction between CD161 and CLEC2D to alter immune cell (e.g., NK cells, B cells, or T cells)-mediated cytotoxicity and / or cytokine production. In some embodiments, various cancer cells expressing CLEC2D are recognized by these novel antibodies, and cytotoxic effects are revealed in various ways, including ADCC (antibody-dependent cell-mediated cytotoxicity) and / or CDC (complement-dependent cell-mediated cytotoxicity) and / or ADCP (antibody-dependent cell-mediated phagocytosis). In one embodiment, this disclosure provides focus points and hypotheses regarding the role of CLEC2D in lymphocyte crosstalk and immune tolerance. In another embodiment, the methods for identifying novel antibody molecules and related compositions provided herein in the field of approved therapeutics or therapeutics in preclinical or clinical trials include pharmaceutical features suitable for manufacturability / development. 【0068】 In one embodiment, the disclosure relates to a method for carrying out treatment of a disease or disorder in a subject requiring treatment, comprising administering a therapeutically effective amount of an antibody or an antigen-binding fragment thereof to the subject, wherein the antibody is an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Tables 9A and 9B disclosed herein. 【0069】 In one embodiment, the disclosure relates to a method for carrying out immunomodulation in subjects requiring such modification, comprising administering a therapeutically effective amount of antibody or antigen-binding fragment to the subject, wherein the antibody is an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Tables 9A and 9B disclosed herein. 【0070】 In one embodiment, the disclosure relates to a method for carrying out the modulation (e.g., enhancement) of innate immunity in subjects requiring such modulation, comprising administering a therapeutically effective amount of antibody or antigen-binding fragment to the subject, wherein the antibody is an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Tables 9A and 9B disclosed herein. 【0071】 In one embodiment, the disclosure relates to a method for carrying out adaptive immune modulation (e.g., enhancement) in subjects requiring such modulation, comprising administering a therapeutically effective amount of antibody or antigen-binding fragment to the subject, wherein the antibody is an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Tables 9A and 9B disclosed herein. 【0072】 In one embodiment, the disclosure relates to a method for carrying out an increase in natural killer cell cytotoxicity in a subject requiring such an increase, comprising administering a therapeutically effective amount of antibody or antigen-binding fragment to the subject, wherein the antibody is an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Tables 9A and 9B disclosed herein. In certain embodiments, for example, the following are provided: (Item 1) An isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain is a. Sequences selected from sequence number 46, sequence number 65, sequence number 59, and sequence number 99 that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical. b. Sequences selected from sequence number: 57, sequence number: 91, sequence number: 98, sequence number: 84, sequence number: 58, sequence number: 88, sequence number: 96, sequence number: 47, sequence number: 17, and sequence number: 8 that are at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical. c. Sequences selected from sequence number 93, sequence number 53, sequence number 95, sequence number 23, sequence number 103, and sequence number 7 that are at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical. d. Sequences selected from sequence number:45, sequence number:15, sequence number:51, sequence number:44, sequence number:73, sequence number:36, sequence number:77, sequence number:50, and sequence number:6 that are 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical. e. Sequence IDs: 97, 16, 76, 9, 89, 107, 68, 29, 67, 74, 32, 81, 106, 31, 62, 48, 75, 12, 102, 54, 80, 26, 30, 92, 108, and 79 For sequences selected from, sequences that are 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% identical, or 100% identical, f. Sequence IDs: 105, 101, 4, 72, 28, 64, 25, 60, 55, 52, 27, 43, 70, 71, 14, 85, 13, 61, 42, 39, 10, 49, 24, 40, 63, 78, 2, 94, and For the array selected from column number 5, arrays that are 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% identical, or 100% identical, g. Sequences that are 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% identical, or 100% identical, to sequences selected from sequence number: 11, 35, 86, 22, 69, 41, 3, 66, 37, 56, 21, 38, 90, 100, 18, 20, 83, 1, and 19, and 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% identical, and, h. Sequences selected from sequence number 33, sequence number 34, sequence number 87, sequence number 82, and sequence number 104 that are 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% identical, or 100% identical. Includes sequences selected from the group consisting of, The antibody or its antigen-binding fragment binds to member D (CLEC2D) of the C-type lectin domain family. The isolated antibody or its antigen-binding fragment. (Item 2) An isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the light chain is a. Sequences selected from sequence numbers 218, 249, 230, 279, 316, 237, 322, 225, 318, 233, 305, 280, 283, 242, 286, 297, 309, and 246 that are at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical. b. Sequences that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence numbers 222, 258, 219, 313, 294, 303, 277, 266, 315, 257, 288, 301, 221, 240, 299, 247, 263, and 274, c. Sequences that are at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence numbers 231, 250, 260, 226, 271, 256, 272, 278, 302, 320, 295, 292, 229, 264, 252, 267, 304, 300, 311, and 324. d. Sequences that are at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence number: 259, sequence number: 239, sequence number: 281, sequence number: 228, sequence number: 217, sequence number: 227, and sequence number: 251. e. Sequences selected from sequence number:307, sequence number:262, sequence number:253, sequence number:276, sequence number:323, sequence number:234, sequence number:261, sequence number:312, and sequence number:290 that are at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical. f. Sequences that are at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence numbers 254, 289, 238, 268, 248, 284, 244, 310, 243, 285, 220, 255, 293, 298, 235, 319, 245, 224, 291, 277, and 232, as well as sequences that are at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical, and g. Sequences that are 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence numbers 282, 308, 287, 321, 265, 270, 275, 306, 296, 241, 314, and 223. Includes sequences selected from the group consisting of, The antibody or its antigen-binding fragment binds to CLEC2D. The isolated antibody or its antigen-binding fragment. (Item 3) a. i. Sequences selected from sequence number 46, sequence number 65, sequence number 59, and sequence number 99 that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical, ii. Sequences that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence number 57, sequence number 91, sequence number 98, sequence number 84, sequence number 88, sequence number 96, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical. iii. Sequences that are at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence number 93, sequence number 53, sequence number 95, sequence number 23, sequence number 103, and sequence number 7. iv. Sequences selected from sequence number 45, sequence number 15, sequence number 51, sequence number 44, sequence number 73, sequence number 36, sequence number 77, sequence number 50, and sequence number 6 that are 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical. v. Sequence IDs: 97, 16, 76, 9, 89, 107, 68, 29, 67, 74, 32, 81, 106, 31, 62, 48, 75, 12, 102, 54, 80, 26, 30, 92, 108, and: For sequences selected from 79, sequences that are 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical. vi. SEQ ID NO: 105, SEQ ID NO: 101, SEQ ID NO: 4, SEQ ID NO: 72, SEQ ID NO: 28, SEQ ID NO: 64, SEQ ID NO: 25, SEQ ID NO: 60, SEQ ID NO: 55, SEQ ID NO: 52, SEQ ID NO: 27, SEQ ID NO: 43, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 14, SEQ ID NO: 85, SEQ ID NO: 13, SEQ ID NO: 61, SEQ ID NO: 42, SEQ ID NO: 39, SEQ ID NO: 10, SEQ ID NO: 49, SEQ ID NO: 24, SEQ ID NO: 40, SEQ ID NO: 63, SEQ ID NO: 78, SEQ ID NO: 2, SEQ ID NO: 94, And for sequences selected from the number of arrays: 5, sequences that are 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical. vii. Sequences that are 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence numbers 11, 35, 86, 22, 69, 41, 3, 66, 37, 56, 21, 38, 90, 100, 18, 20, 83, 1, and 19, as well as, viii. Sequences selected from sequence number 33, sequence number 34, sequence number 87, sequence number 82, and sequence number 104 that are 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical. A heavy chain containing a sequence selected from, b. i. Sequences that are at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence number: 218, 249, 230, 279, 316, 237, 322, 225, 318, 233, 305, 280, 283, 242, 286, 297, 309, and 246, ii. Sequences that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence numbers 222, 258, 219, 313, 294, 303, 317, 273, 266, 315, 257, 288, 301, 221, 240, 299, 247, 263, and 274, iii. Sequences that are at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence numbers 231, 250, 260, 226, 271, 256, 272, 278, 302, 320, 295, 292, 229, 264, 252, 267, 304, 300, 311, and 324, iv. Sequences selected from sequence number:259, sequence number:239, sequence number:281, sequence number:228, sequence number:217, sequence number:227, and sequence number:251 that are at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical. v. Sequences selected from sequence number:307, sequence number:262, sequence number:253, sequence number:276, sequence number:323, sequence number:234, sequence number:261, sequence number:312, and sequence number:290 that are at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical. vi. Sequences that are at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence numbers 254, 289, 238, 268, 248, 284, 244, 310, 243, 285, 220, 255, 293, 298, 235, 319, 245, 224, 291, 277, and 232, as well as, vii. Sequences that are 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to sequences selected from sequence numbers: 282, 308, 287, 321, 265, 270, 275, 306, 296, 241, 314, and 223. A light chain containing a sequence selected from, An isolated antibody or its antigen-binding fragment, comprising The antibody or its antigen-binding fragment binds to CLEC2D. The isolated antibody or its antigen-binding fragment. (Item 4) An isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain comprises a sequence selected from any one of SEQ ID NOs: 1 to 108, and the antibody or its antigen-binding fragment binds to CLEC2D. (Item 5) An isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the light chain comprises a sequence selected from any one of SEQ ID NOs: 217 to 324, and the antibody or its antigen-binding fragment binds to CLEC2D. (Item 6) An isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain comprises a sequence selected from any one of SEQ ID NOs: 1 to 108, the light chain comprises a sequence selected from any one of SEQ ID NOs: 217 to 324, and the antibody or its antigen-binding fragment binds to CLEC2D. (Item 7) An isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain is (i) Sequence ID: Heavy chain (HC)CDR1 containing a sequence selected from 433 to 485, (ii) HC CDR2 containing a sequence selected from sequence numbers 486 to 546, (iii) Sequence ID: HC CDR3 containing a sequence selected from 547 to 653, Includes, The antibody or its antigen-binding fragment binds to CLEC2D. The isolated antibody or its antigen-binding fragment. (Item 8) An isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the light chain is (i) Sequence ID: Light chain (LC) CDR1 containing a sequence selected from 654 to 726, (ii) LC CDR2 containing a sequence selected from sequence numbers 727 to 783, (iii) Sequence number: LC CDR3 containing a sequence selected from 784 to 885, Includes, The antibody or its antigen-binding fragment binds to CLEC2D. The isolated antibody or its antigen-binding fragment. (Item 9) a. A heavy chain containing an HC CDR1 sequence selected from sequence numbers 433 to 485, an HC CDR2 sequence selected from sequence numbers 486 to 546, and an HC CDR3 sequence selected from sequence numbers 547 to 653. b. A light chain containing an LC CDR1 sequence selected from sequence numbers 654-726, an LC CDR2 sequence selected from sequence numbers 727-783, and an LC CDR3 sequence selected from sequence numbers 784-885, or c. These combinations, An isolated antibody or its antigen-binding fragment, comprising The antibody or its antigen-binding fragment binds to CLEC2D. The isolated antibody or its antigen-binding fragment. (Item 10) a. Human CLEC2D polypeptide containing sequences selected from sequence numbers 886-909 and 930-1003. b. Cynomolgus monkey CLEC2D polypeptide containing a sequence selected from sequence numbers 918-920, c. Mouse CLEC2D polypeptide containing sequences selected from sequence numbers 911-915, d. Rat CLEC2D polypeptide containing the sequence of Sequence ID:910, and / or e. Canine CLEC2D polypeptide containing a sequence selected from sequence numbers 916-917. An antibody or antigen-binding fragment described in any one of items 1 to 9, which binds to the antibody. (Item 11) An isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain comprises one of the heavy chain complementarity-determining regions (CDRH)1, CDRH2, and CDRH3 amino acid sequences of any one of the anti-CLEC2D antibody numbers: A1 to N2 in Table 9A, and the light chain comprises one of the light chain complementarity-determining regions (CDRL)1, CDRL2, and CDRL3 amino acid sequences of any one of the anti-CLEC2D antibody numbers: A1 to N2 in Table 9A. (Item 12) An isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain comprises one heavy chain amino acid sequence of any one of the anti-CLEC2D antibody numbers: A1 to N2 in Table 9A, and the light chain comprises one light chain amino acid sequence of any one of the anti-CLEC2D antibody numbers: A1 to N2 in Table 9A. (Item 13) An isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain comprises the heavy chain complementarity-determining regions (CDRH)1, CDRH2, and CDRH3 amino acid sequences of an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9A, and the light chain comprises the light chain complementarity-determining regions (CDRL)1, CDRL2, and CDRL3 amino acid sequences of an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9A. (Item 14) An isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain comprises a variable heavy chain amino acid sequence of an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9A, and the light chain comprises a variable light chain amino acid sequence of an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9A, the isolated antibody or its antigen-binding fragment. (Item 15) An isolated antibody or its antigen-binding fragment comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain framework region sequence of a germline family of anti-CLEC2D antibodies selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9B, and the light chain comprises a light chain germline family framework region sequence of an anti-CLEC2D antibody selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9B, wherein the isolated antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain framework region sequence of a germline family of anti-CLEC2D antibodies selected from the group consisting of A1, B1, E1, P1, U1, Y1, E2, I2, and L2 in Table 9B. (Item 16) The anti-CLEC2D antibody is the isolated antibody or its antigen-binding fragment described in any one of items 62 to 64, with anti-CLEC2D antibody number A1 in Tables 9A and 9B. (Item 17) The anti-CLEC2D antibody is the isolated antibody or its antigen-binding fragment described in any one of items 62 to 64, with anti-CLEC2D antibody number B1 in Tables 9A and 9B. (Item 18) The anti-CLEC2D antibody is the isolated antibody or its antigen-binding fragment described in any one of items 62 to 64, with anti-CLEC2D antibody number E1 in Tables 9A and 9B. (Item 19) The anti-CLEC2D antibody is the isolated antibody or its antigen-binding fragment described in any one of items 62 to 64, with anti-CLEC2D antibody number P1 in Tables 9A and 9B. (Item 20) The anti-CLEC2D antibody is the isolated antibody or its antigen-binding fragment described in any one of items 62 to 64, with anti-CLEC2D antibody number U1 in Tables 9A and 9B. (Item 21) The anti-CLEC2D antibody is the isolated antibody or its antigen-binding fragment described in any one of items 62 to 64, with anti-CLEC2D antibody number Y1 in Tables 9A and 9B. (Item 22) The anti-CLEC2D antibody is the isolated antibody or its antigen-binding fragment described in any one of items 62 to 64, with anti-CLEC2D antibody number E2 in Tables 9A and 9B. (Item 23) The anti-CLEC2D antibody is the isolated antibody or its antigen-binding fragment described in any one of items 62 to 64, with anti-CLEC2D antibody number I2 in Tables 9A and 9B. (Item 24) The anti-CLEC2D antibody is the isolated antibody or its antigen-binding fragment described in any one of items 62 to 64, with anti-CLEC2D antibody number L2 in Tables 9A and 9B. (Item 25) A monoclonal antibody, as described in any one of items 1 through 24, or an antigen-binding fragment thereof. (Item 26) An antibody or antigen-binding fragment described in any one of items 1 through 24 that modulates or blocks the binding of CLEC2D to the receptor. (Item 27) The receptor comprises a CD161 receptor, wherein the CD161 receptor comprises a sequence selected from SEQ ID NOs: 921 to 929, the antibody or antigen-binding fragment described in item 26. (Item 28) An antibody or antigen-binding fragment described in any one of items 1 through 27, which is human, mouse, or chimeric. (Item 29) The antigen-binding fragment is an antibody or antigen-binding fragment according to any one of items 1 to 28, selected from the group consisting of Fv, Fav, F(ab')2, Fab', dsFv, scFv, sc(Fv)2, scFv-CH3, scFv-Fc, and diabody fragments. (Item 30) The aforementioned antibody is afucosylated, isolated antibody or antigen-binding fragment according to any one of items 1 to 29. (Item 31) The isolated antibody or antigen-binding fragment described in any one of items 1 to 30, wherein the antibody or antigen-binding fragment is afucosylated. (Item 32) The isolated antibody or antigen-binding fragment according to any one of items 1 to 31, wherein the antibody or antigen-binding fragment is afucosylated in the antibody region. (Item 33) The aforementioned antibody or antigen-binding fragment comprises an IgG1 Fc region, and is an isolated antibody or antigen-binding fragment according to any one of items 1 to 32. (Item 34) The aforementioned antibody or antigen-binding fragment comprises an IgG4 Fc region, as described in any one of items 1 to 32, and is an isolated antibody or antigen-binding fragment thereof. (Item 35) The aforementioned antibody or antigen-binding fragment comprises an IgG1 N~A Fc region, and is an isolated antibody or antigen-binding fragment according to any one of items 1 to 32. (Item 36) The aforementioned antibody or antigen-binding fragment comprises an IgG2 Fc region, as described in any one of items 1 to 32, and is an isolated antibody or antigen-binding fragment thereof. (Item 37) An antibody or antigen-binding fragment described in any one of items 1 to 35, which binds to human CLEC2D with an affinity (KD) of less than 100 nM. (Item 38) An antibody or antigen-binding fragment described in any one of items 1 to 37, which recognizes and binds to a structural epitope of the CLEC2D antigen and consists of amino acid sites that overlap and / or do not overlap with CD161 receptor-interacting amino acid residues. (Item 39) An antibody or antigen-binding fragment according to any one of items 1 to 37, comprising a variable heavy chain sequence and a variable light chain sequence, comprising amino acid sites that either overlap with and / or do not overlap with CD161 receptor-interacting amino acid residues, thereby inhibiting, repressing, or competing with another antibody that recognizes and binds to a structural epitope of the CLEC2D antigen. (Item 40) An antibody or antigen-binding fragment according to any one of items 1 to 37, comprising a variable heavy chain sequence and a variable light chain sequence that bind to a structural epitope of the CLEC2D antigen, including any of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, ASN95, or any combination thereof. (Item 41) An antibody or antigen-binding fragment described in any one of items 1 to 37, comprising a variable heavy chain sequence and a variable light chain sequence that inhibit, repress, or compete with the binding of another antibody to a structural epitope of the CLEC2D antigen, including any of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, ASN95, or any combination thereof. (Item 42) An antibody or antigen-binding fragment according to any one of items 1 to 37, comprising a variable heavy chain sequence and a variable light chain sequence that bind to a structural epitope of the CLEC2D antigen, comprising at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, ASN95 in sequence numbers 886-920 and 930-1003, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming a nonlinear scaffold for CD161 receptor interacting amino acid residues. (Item 43) SEQ ID NOs: 886-920 and 930-1003 amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PH An antibody or antigen-binding fragment according to any one of items 1 to 37, comprising a variable heavy chain sequence and a variable light chain sequence that bind to a structural epitope of the CLEC2D antigen, comprising at least one of E116 and ASN95, and constitute an allosteric and nonlinear scaffold for CD161 receptor non-interacting amino acid residues, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor. (Item 44) An antibody or antigen-binding fragment according to any one of items 1 to 43, comprising a variable heavy chain sequence and a variable light chain sequence, which, when bound to CLEC2D selected from SEQ ID NOs: 886-920 and 930-1003, binds to at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, ASN95, and induces tumor killing or cytotoxicity, either alone or in combination. (Item 45) The antibody or antigen-binding fragment according to item 44, which induces cytotoxicity in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, 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%, or at least 95% of the total number of cells treated with the antibody or antigen-binding fragment. (Item 46) A pharmaceutical composition comprising an antibody or antigen-binding fragment described in any one of items 1 through 45. (Item 47) A pharmaceutical composition according to item 46, further comprising at least one of a buffer, a pharmaceutically acceptable diluent, a carrier, a solubilizer, an emulsifier, and a preservative. (Item 48) SEQ ID NO: An isolated nucleic acid containing a polynucleotide sequence encoding an amino acid heavy chain sequence selected from 109 to 216. (Item 49) An isolated nucleic acid containing a polynucleotide sequence encoding an amino acid light chain sequence selected from sequence numbers 325 to 432. (Item 50) An isolated nucleic acid comprising a polynucleotide sequence encoding a heavy chain amino acid sequence described in item 1, item 3, item 4, item 6, item 7, and any one of items 9 through 37. (Item 51) An isolated nucleic acid comprising a polynucleotide sequence encoding a light chain amino acid sequence described in item 2, item 3, item 5, item 6, item 8, and any one of items 9 through 37. (Item 52) A composition comprising a first nucleic acid encoding a polypeptide selected from SEQ ID NOs: 109 to 216, and a second nucleic acid encoding a polypeptide selected from SEQ ID NOs: 325 to 432. (Item 53) A vector containing nucleic acids as described in any one of items 48 through 51. (Item 54) A cell, which is a eukaryotic cell, comprising a nucleic acid as described in any one of items 48 to 51, a composition as described in item 52, or a vector as described in item 53. (Item 55) The aforementioned eukaryotic cells are mammalian cells, as described in item 54. (Item 56) The mammalian cells are selected from the group consisting of CHO cells, 293 cells, NSO cells, PER.C6 cells, and B cells, as described in item 55. (Item 57) The aforementioned mammalian cells are 293-6E cells or DG44 cells, as described in item 56. (Item 58) Cells that produce an antibody or antigen-binding fragment described in any one of items 1 through 45. (Item 59) A method for providing treatment for a disease to a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment described in any one of items 1 to 45. (Item 60) The method according to item 59, wherein the disease or disorder is associated with specific or abnormal expression of CLEC2D on various cell surfaces of subjects requiring treatment for the disease or disorder. (Item 61) The method according to item 59, wherein the disease or disorder is associated with high expression of CLEC2D on the surface of various cells of subjects requiring treatment for the disease or disorder. (Item 62) The method according to any one of items 60 to 61, wherein the cells are immune cells. (Item 63) The immune cells are NK cells, as described in item 62. (Item 64) The cell is a cancer cell, as described in any one of items 60 to 61. (Item 65) The method according to any one of items 60 to 61, wherein the cells are cells infected with a microorganism. (Item 66) The method according to item 65, wherein the microorganism is a bacterium, virus, fungus, parasitic microorganism, or protozoan. (Item 67) The microorganism is an intracellular bacterium, as described in item 66. (Item 68) The disease is rheumatoid arthritis, as described in any one of items 59 to 67. (Item 69) The subject is the method described in item 68, which shows bone loss resulting from having rheumatoid arthritis. (Item 70) The method according to item 69, wherein administration of a therapeutically effective amount of the antibody or its antigen-binding fragment delays or reverses the bone loss in the subject. (Item 71) The disease is cancer, as described in any one of items 59 to 67. (Item 72) The cancer described above is selected from the group consisting of breast cancer, prostate cancer, endometrial cancer, bladder cancer, kidney cancer, esophageal cancer, squamous cell carcinoma, uveal melanoma, follicular lymphoma, renal cell carcinoma, cervical cancer, ovarian cancer, lung cancer, colorectal cancer, brain cancer, pancreatic cancer, head and neck cancer, liver cancer, leukemia, lymphoma, Hodgkin's disease, multiple myeloma, melanoma, astrocytoma, gastric cancer, and lung adenocarcinoma, according to item 71. (Item 73) The cancer is selected from the group consisting of adrenocortical carcinoma, urothelial carcinoma of the bladder, invasive breast cancer, squamous cell carcinoma and cervical adenocarcinoma, cholangiocarcinoma, colon adenocarcinoma, lymphoid tumor diffuse large B-cell lymphoma, esophageal cancer, glioblastoma multiforme, squamous cell carcinoma of the head and neck, pigmentaphobic renal carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, acute myeloid leukemia, brain low-grade glioma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma and paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, cutaneous melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid cancer, thymoma, endometrial carcinoma of the uterine body, carcinosarcoma of the uterus, and uveal melanoma, according to item 71. (Item 74) The method according to any one of items 71 to 73, wherein administration of a therapeutically effective amount of the antibody or its antigen-binding fragment produces an antitumor effect in the subject. (Item 75) The method according to any one of items 59 to 74, wherein administration of a therapeutically effective amount of the antibody or its antigen-binding fragment alleviates the signs or symptoms of the disease. (Item 76) The method according to any one of items 59 to 75, wherein the antibody or antigen-binding fragment described in any one of items 1 to 45 in a therapeutically effective amount modulates or inhibits the interaction of CLEC2D with its associated receptor CD161. (Item 77) A method for carrying out the modulation of the activation of an immune response to a disease, disorder, or infection caused by a microorganism in a subject requiring such modulation, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment described in any one of items 1 to 45, wherein the immune response is an innate immune response, an adaptive immune response, or a combination thereof. (Item 78) A method for performing an increased cytotoxicity of natural killer cells in a subject requiring such an increase, comprising administering a therapeutically effective amount of an antibody or antigen-binding fragment described in any one of items 1 to 45 to the subject. (Item 79) An antibody library comprising at least about 10⁸ unique monoclonal antibody clones, wherein at least about 80% of the antibody clones are detectable and specifically bind to the CLEC2D antigen. (Item 80) The CLEC2D antigen is an antibody library as described in item 79, comprising an amino acid sequence selected from sequence numbers 886-920 and 930-1003. (Item 81) The CLEC2D antigen is an antibody library as described in item 79 or item 80, comprising the CLEC2D antigen expressed on the surface of tumor cells, a variant of the CLEC2D antigen, or a homolog of the CLEC2D antigen. (Item 82) The antibody library described in item 81, wherein the variant of the CLEC2D antigen comprises a fragment of the CLEC2D protein. (Item 83) The homolog of the CLEC2D antigen is an antibody library as described in item 82, comprising human, mouse, dog, rat, or cynomolgus monkey CLEC2D. (Item 84) A method for screening a highly diverse antibody gene library with an antibody that binds to the CLEC2D antigen, a) Creating a phage library by inserting an antibody gene library into a phage protein gene and transforming multiple phages, wherein the phages in the phage library present the antibody gene library on their surface, b) To produce an enriched phage library in which antibody genes encoding antibodies that bind to the CLEC2D antigen are enriched by panning the phage library with the CLEC2D antigen against individual phages that bind to the CLEC2D antigen, c) Repeat step (b) at least once or at least twice. d) Introducing the antibody gene derived from the enriched phage library into a yeast surface display library. e) Isolating individual yeast cells that bind to the CLEC2D antigen from the yeast surface display library, f) Culturing the isolated yeast cells that bind to the CLEC2D antigen to produce a yeast surface display library clone, and g) Sequencing the yeast surface display library clones, This allows for the isolation of the antibody gene that binds to the CLEC2D antigen. The method, including the method described above. (Item 85) The method according to item 84, wherein the panning step (b) includes panning the phage library with magnetic beads coated with CLEC2D. (Item 86) The method according to item 84, wherein the introduction step (d) includes cloning the antibody gene into a yeast expression vector. (Item 87) The method according to item 86, further comprising analyzing the surface expression of the antibody gene using a FLAG tag, a c-Myc tag, a polyhistidine tag, or a V5 tag. (Item 88) The method according to item 84, wherein test step (e) comprises isolating yeast cells expressing an antibody gene that binds to the CLEC2D antigen using flow cytometry. (Item 89) The method according to item 88, further comprising repeating the flow cytometry isolation at least 1×, at least 2×, at least 3×, at least 4×, or at least 5× times. (Item 90) The method according to any one of items 84 to 89, further comprising cloning the antibody gene that binds to the CLEC2D antigen into a mammalian expression vector. (Item 91) A method for preparing a composition comprising an anti-CLEC2D antibody or its antigen-binding fragment, a) Transforming mammalian cells with a vector comprising a sequence encoding a promoter and a sequence encoding the anti-CLEC2D antibody or its antigen-binding fragment, wherein the sequence encoding the promoter and the sequence encoding the anti-CLEC2D antibody or its antigen-binding fragment are functionally linked, b) Culturing the mammalian cells under conditions suitable for the expression of the anti-CLEC2D antibody or its antigen-binding fragment, and c) Obtain the anti-CLEC2D antibody or its antigen-binding fragment from the cultured mammalian cells and prepare the supernatant. The method, including the method described above. (Item 92) The method according to item 91, wherein step (c) comprises collecting the supernatant of the cultured mammalian cells. (Item 93) The method according to item 91 or item 92, further comprising step (d) filtering the supernatant after step (c). (Item 94) The method according to any one of items 91 to 93, further comprising step (e) purifying the filtered supernatant. (Item 95) A method for carrying out treatment for a disease in a person who requires treatment, a. To measure the level of CLEC2D protein in the subject, and, b. Administer a therapeutically effective dose of CLEC2D antibody to the subject. The method, including the method described above. (Item 96) The disease is cancer, as described in item 95. (Item 97) The method according to item 96, wherein the target cancer cells have high levels of CLEC2D protein compared to normal cells that do not have cancer. (Item 98) High levels of CLEC2D are associated with inadequate prognosis, as described in item 95. (Item 99) The method described in item 95, wherein the disease is an autoimmune disorder or an inflammatory disorder. 【0073】 The features of this disclosure will be fully apparent from the following description in combination with the accompanying drawings. The patent file or application file contains at least one drawing drawn in color. Copies of the publication of this patent or patent application with the color drawing will be provided by the Patent Office upon request and payment of the necessary fees. The accompanying drawings will be used to further illustrate this disclosure, assuming that the drawings represent only some embodiments of this disclosure and are not intended to limit the scope of this disclosure. [Brief explanation of the drawing] 【0074】 [Figure 1] A-C illustrate the present disclosure in a schematic format. A illustrates a scenario in which CLEC2D and CD161 interact to result in immune cell evasion by tumor cells. B illustrates a scenario in which the interaction between CLEC2D and CD161 is blocked using an anti-CLEC2D antibody, resulting in tumor cell killing following a lysis signal. C illustrates a scenario in which the binding of the CLEC2D antigen to an anti-CLEC2D antibody results in NK cell activation and increased cytokine expression, followed by high target cell elimination by either direct killing or other immune cell involvement. [Figure 2A] This paper describes the expression and purification of the CLEC2D antigen in mammalian cells. It also describes the construction of a mammalian expression plasmid for expressing the CLEC2D external domain as a soluble antigen. The construct was prepared by gene synthesis and then confirmed by restriction digestion and Sanger sequencing. [Figure 2B] This shows the expression and purification of the CLEC2D antigen in mammalian cells. The IMAC chromatography profile showing the purification of soluble CLEC2D (Q72-V191) is also shown (the inset shows the elution characteristics of the CLEC2D antigen). [Figure 2C] This shows the expression and purification of the CLEC2D antigen in mammalian cells. The SDS-PAGE profiles of the packed, washed, and finally eluted CLEC2D protein are shown (indicating that the purified CLEC2D protein is homogeneous and pure, making it suitable for further downstream experiments). [Figure 2D] This shows the expression and purification of the CLEC2D antigen in mammalian cells. A Western blot of purified CLEC2D protein probed with a commercially available antibody against the CLEC2D antigen is also shown. [Figure 2E] This document shows the expression and purification of the CLEC2D antigen in mammalian cells. It also presents an ELISA assay demonstrating the binding specificity of commercially available antibodies to purified CLEC2D antigen at different concentrations. [Figure 2F] This document describes the expression and purification of the CLEC2D antigen in mammalian cells. It also shows SDS-PAGE analysis of purified CLEC2D antigen cultured under reducing conditions with PNGase enzyme for 3 or 6 hours, revealing the deglycosylation of the CLEC2D antigen. [Figure 3] A schematic diagram of an antibody library screening strategy is shown, which uses phage surface display systems and yeast surface display systems to screen naive antibody libraries against the target CLEC2D antigen. [Figure 4A] This shows phage panning of an antibody library using CLEC2D antigen coated on magnetic beads. It also shows the estimation of magnetic bead conjugate efficiency by flow cytometry. [Figure 4B] This shows phage panning of an antibody library using CLEC2D antigen coated on magnetic beads. It also shows restriction enzyme digestion of separate heavy chain clones after panning of the Fab library. [Figure 4C] This shows phage panning of an antibody library using CLEC2D antigen coated on magnetic beads. It also shows restriction enzyme digestion of separate kappa light chain clones after panning of the Fab library. [Figure 4D] This shows phage panning of an antibody library using CLEC2D antigen coated on magnetic beads. It also shows restriction enzyme digestion of separate heavy chain clones after panning of an ScFv library. [Figure 4E]Shows phage panning of an antibody library using CLEC2D antigen coated on magnetic beads. Shows restriction enzyme digestion of separate kappa light chain clones after panning of the ScFv library. [Figure 5A] Shows screening of antibodies against CLEC2D using yeast surface display. Shows a plate image representing yeast colonies for the preparation of a ScFv antibody library by electroporation. [Figure 5B] Shows screening of antibodies against CLEC2D using yeast surface display. Shows a plate image representing the preparation of a half heavy chain and light chain antibody library. [Figure 5C] Shows screening of antibodies against CLEC2D using yeast surface display. Shows a plate image showing the mating efficiency of haploid yeast strains containing a heavy chain antibody library or a light chain antibody library (the mating efficiency was estimated to be about 29%). [Figure 5D] Shows screening of antibodies against CLEC2D using yeast surface display. Shows representative flow cytometry analysis of the binding of antibody molecules expressed on the surface of yeast cells to the CLEC2D antigen (the ScFv library was sorted multiple times to enrich for high-affinity yeast clones). [Figure 5E] Shows screening of antibodies against CLEC2D using yeast surface display. Shows representative flow cytometry analysis of the binding of antibody molecules expressed on the surface of yeast cells to the CLEC2D antigen (the Fab library was sorted multiple times to enrich for high-affinity yeast clones). [Figure 5F] Shows screening of antibodies against CLEC2D using yeast surface display. Shows representative data on the enrichment of yeast clones after multiple rounds of sorting, from both the perspective of expression and antigen recognition. [Figure 5G] Shows screening of antibodies against CLEC2D using yeast surface display. Shows that individual yeast clones were isolated and tested with the CLEC2D antigen to identify yeast cell lines expressing high-affinity antibody clones. [Figure 5H] This report describes the screening of antibodies against CLEC2D using a yeast surface display. Representative flow cytometry data are shown to indicate the binding percentage of soluble CLEC2D antigen to monoclonal antibody clones. At least approximately 80% of the clones were detectable and specifically bound to the CLEC2D antigen. [Figure 6A] This shows peer group sequence analysis of clones screened using a yeast display platform. A bar graph shows the CDRH3 length distribution of the selected molecules. [Figure 6B] This shows peer group sequence analysis of clones screened using a yeast display platform. A bar graph showing the relative amino acid frequency distribution of heavy chain CDRH3 is also shown (Kabat nomenclature). [Figure 6C] This shows peer group sequence analysis of clones screened using a yeast display platform. A pie chart showing the heavy chain consensus family distribution is also presented. [Figure 6D] This shows peer group sequence analysis of clones screened using a yeast display platform. A pie chart showing the light chain consensus family distribution is also presented. [Figure 7A] A shows the mammalian expression construct used to produce full-length monoclonal antibodies. It shows a vector designed to clone the selective antibody variable heavy chain gene after screening using a phage display platform and a yeast display platform. The construct was prepared by gene synthesis and then confirmed by restriction digestion and Sanger sequencing. B shows the mammalian expression construct used to produce full-length monoclonal antibodies. It shows a vector designed to clone the selective antibody variable light chain (kappa) gene after screening using a phage display platform and a yeast display platform. The construct was prepared by gene synthesis and then confirmed by restriction digestion and Sanger sequencing. [Figure 7B]A shows the mammalian expression construct used to produce full-length monoclonal antibodies. It shows a vector designed to clone the selective antibody variable heavy chain gene after screening using a phage display platform and a yeast display platform. The construct was prepared by gene synthesis and then confirmed by restriction digestion and Sanger sequencing. B shows the mammalian expression construct used to produce full-length monoclonal antibodies. It shows a vector designed to clone the selective antibody variable light chain (kappa) gene after screening using a phage display platform and a yeast display platform. The construct was prepared by gene synthesis and then confirmed by restriction digestion and Sanger sequencing. [Figure 8A] This document describes a mammalian expression system for expressing full-length CLEC2D on the cell surface. It shows that the CLEC2D gene expression construct was created through gene synthesis, and then confirmed by restriction digestion and Sanger sequencing. [Figure 8B] This shows a mammalian expression system for expressing full-length CLEC2D on the cell surface. Flow cytometry using a commercially available anti-CLEC2D antibody (4C7) is shown demonstrating CLEC2D expression on the surface of transfected CHO cells (C4548). [Figure 8C] This shows a mammalian expression system for expressing full-length CLEC2D on the cell surface. Surface expression of CLEC2D, monitored using anti-CLEC2D (4C7) antibody on fixed and impermeabilized cells, is shown using a confocal microscope (60×). Binding of the anti-CLEC2D antibody was observed on C4548 cells, while no binding was observed in untransfected CHO cells. The nuclei were counterstained with DAPI (blue). Scale bar is 10 μm. [Figure 9A]This shows anti-CLEC2D monoclonal antibody clones purified from transiently transfected CHO cells. Antibodies were purified using protein A column chromatography. Representative anti-CLEC2D antibody SDS-PAGE profiles are shown. Purified antibodies were subjected to SDS-PAGE analysis under both non-reducing and reducing conditions. Anti-CLEC2D antibody clones purified from C3566 are shown in lane 9, the upper panel of the reducing and non-reducing gels. All clones in the lower panel, except for the clone in lane 4, showed good profiles on both the reducing and non-reducing gels. Clones showing degradation products were not examined for further testing. Similar criteria were applied to other clones as described in the Examples section. [Figure 9B] This paper shows anti-CLEC2D monoclonal antibody clones purified from transiently transfected CHO cells. Antibodies were purified using protein A column chromatography. Flow cytometry shows the interaction of the purified anti-CLEC2D antibody with CLEC2D antigen expressed on the surface of CHO cells. Representative antibody clones, exemplified by C4577, C2907, C3566, C5582, and C5397, were evaluated for CLEC2D binding on CHO cell lines that were either transfected with or not transfected with full-length CLEC2D constructs. A rightward shift in MFI indicates binding to the surface-expressed CLEC2D antigen of the corresponding clone. [Figure 9C-1]This image shows anti-CLEC2D monoclonal antibody clones purified from transiently transfected CHO cells. The antibodies were purified using protein A column chromatography. Representative images of the interaction between anti-CLEC2D antibodies and CLEC2D antigen expressed on PC3 tumor cells are shown. As shown in Table 22, qualitative evaluation of binding was performed (from "+" indicating low binding to "+++" indicating very high binding). For example, no surface binding was detected for antibody C4252, while low binding was observed for antibody C0610, resulting in a (+) evaluation. On the other hand, the other clones showed specific and even more significant surface binding. The nuclei were counterstained with DAPI (purple). The scale bar is 10 μm. [Figure 9C-2] This image shows anti-CLEC2D monoclonal antibody clones purified from transiently transfected CHO cells. The antibodies were purified using protein A column chromatography. Representative images of the interaction between anti-CLEC2D antibodies and CLEC2D antigen expressed on PC3 tumor cells are shown. As shown in Table 22, qualitative evaluation of binding was performed (from "+" indicating low binding to "+++" indicating very high binding). For example, no surface binding was detected for antibody C4252, while low binding was observed for antibody C0610, resulting in a (+) evaluation. On the other hand, the other clones showed specific and even more significant surface binding. The nuclei were counterstained with DAPI (purple). The scale bar is 10 μm. [Figure 10A] This paper demonstrates the development of a stable CHO cell line expressing anti-CLEC2D antibody. Binding tests are shown, performed using surface-expressed CLEC2D cells and monitored using flow cytometry with supernatants obtained from CHO minipool samples transfected with the anti-CLEC2D antibody expression plasmid. The histograms represent the degree of binding to the surface CLEC2D antigen expressed on C4548 cells across various clones. The multiplier change in MFI is plotted against the binding of individual minipools. Higher multiplier changes indicate stronger binding of the anti-CLEC2D antibody to the CLEC2D antigen. [Figure 10B]This study demonstrates the development of a stable CHO cell line expressing anti-CLEC2D antibody. It also shows single-cell clone screening (the anti-CLEC2D antibody expressed from the single-cell clone was purified and used for flow cytometry experiments). Higher magnification changes in the fluorescence signal indicate stronger binding of the anti-CLEC2D antibody to the CLEC2D antigen. [Figure 10C] This paper describes the development of a stable CHO cell line expressing anti-CLEC2D antibodies. Flow cytometry analysis of monoclonal antibodies produced from the stable CHO cell line is shown (anti-CLEC2D antibodies expressed from single-cell clone lines were purified before use for flow cytometry experiments). Flow cytometry was used to test the binding of anti-CLEC2D antibodies expressed by multiple monoclonal cell lines (e.g., C4608, C5093, C5511, C6481, C6726, C7720, C9103, C5848, and C3452) to the CLEC2D antigen expressed on the surface of CHO cells. The estimated increase in average fluorescence intensity across multiple stable clones was found to be in the range of 3 to 10 times. [Figure 10D] This document describes the development of a stable CHO cell line expressing anti-CLEC2D antibodies. Representative images of the interaction between CLEC2D antigen expressed on PC3 tumor cell lines and anti-CLEC2D monoclonal antibodies produced from clonal CHO cell lines are shown. As described herein, various anti-CLEC2D antibodies showed specific and significant surface binding to the CLEC2D antigen on the surface of PC3 cells. The nuclei were counterstained with DAPI (purple). The scale bar is 10 μm. [Figure 10E] This paper describes the development of a stable CHO cell line expressing anti-CLEC2D antibody. Quantitative RT-PCR results are shown for anti-CLEC2D antibody-stable cell clones C4608 and C5511 to confirm the stable introduction of antibody heavy and light chain genes. The GAPDH housekeeping gene was used as an internal standard. The study was conducted on 60-generation CHO monoclonal cell lines expressing anti-CLEC2D antibody. [Figure 11A]This report presents the functional characterization analysis of monoclonal anti-CLEC2D antibodies. It shows the binding of anti-CLEC2D antibodies C4608, C5511, C6481, C2438, C3452, and C0949 to surface-expressed CLEC2D on the prostate cancer cell line PC3. A rightward shift in MFI indicates antibody binding to the surface-expressed CLEC2D antigen on the PC3 cell line. [Figure 11B] This report presents a functional characterization analysis of a monoclonal anti-CLEC2D antibody. Representative flow cytometry analyses of cytotoxicity assays performed on PC3 target cells using PBMCs as effector cells in a 1:5 ratio and a fixed concentration of 100 ug / mL anti-CLEC2D antibody are shown. The clones evaluated for functionality in this specification were C5511, C4608, and C6481, along with PBMCs derived from donor 1, while antibodies purified from clones C5392 and C3452 were tested with PBMCs derived from donor 2. Percentage of live PC3 cells are indicated by APC (eFluor 670)-positive cells, and dead cells are indicated by Sytox green-positive cells. Corresponding single-cell clones were labeled for each plot. [Figure 11C] This paper presents a functional characterization analysis of a monoclonal anti-CLEC2D antibody. Representative flow cytometry analysis of a cytotoxicity assay performed on PC3 target cells using PBMCs as effector cells (1:5) along with an anti-CLEC2D antibody (C5511) at concentrations increasing from 10 μg / mL to 200 ug / mL reveals high-dose-dependent cytotoxicity of tumor cells. [Figure 11D] This report presents a functional characterization analysis of a monoclonal anti-CLEC2D antibody. Representative flow cytometry analyses of cytotoxicity assays performed on PC3 target cells using PBMCs as effector cells and fixed-concentration anti-CLEC2D antibody C5511 are shown. The tumor:effector cell ratio (T:E) was increased from 1:5 to 1:10. The data revealed that a higher level of tumor cell cytotoxicity was associated with an increased effector cell ratio. [Figure 11E-1]This report presents a functional characterization analysis of a monoclonal anti-CLEC2D antibody. An endpoint cytotoxicity assay revealed significant cytotoxicity of tumor cells at a concentration of 10 μg / mL. The assay also used confocal microscopy to identify the optimal concentration of anti-CLEC2D antibody for target cell killing. The upper panel shows all control treatments where cytotoxicity was not observed as predicted, while the lower panel shows high PC3 tumor cell death when treated with increasing concentrations of anti-CLEC2D antibody (C6726) in the presence of PBMCs (T:E=1:5). Maximum cell death was observed at a concentration of 50 ug / ml of anti-CLEC2D antibody. PC3 tumor cells - green, PBMCs - red, dead cells - blue. [Figure 11E-2] This report presents a functional characterization analysis of a monoclonal anti-CLEC2D antibody. An endpoint cytotoxicity assay revealed significant cytotoxicity of tumor cells at a concentration of 10 μg / mL. The assay also used confocal microscopy to identify the optimal concentration of anti-CLEC2D antibody for target cell killing. The upper panel shows all control treatments where cytotoxicity was not observed as predicted, while the lower panel shows high PC3 tumor cell death when treated with increasing concentrations of anti-CLEC2D antibody (C6726) in the presence of PBMCs (T:E=1:5). Maximum cell death was observed at a concentration of 50 ug / ml of anti-CLEC2D antibody. PC3 tumor cells - green, PBMCs - red, dead cells - blue. [Figure 11F-1] This paper presents a functional characterization analysis of monoclonal anti-CLEC2D antibodies. It also shows an endpoint cytotoxicity assay using selective anti-CLEC2D antibodies to kill target cells, performed using confocal microscopy. Cytotoxicity was not observed in PC3 tumor cells only, PBMCs only, or in control treatments such as PBMCs with isotype human IgG1 antibodies. Cytotoxicity of PC3 tumor cells was observed when using anti-CLEC2D antibody (C6726, C5848, C4608, C5511, and C6481) clones. Magnified images clearly show that PC3 tumor cells were surrounded by effector cells, inducing tumor cell death. PC3 tumor cells - green, PBMCs - red, dead cells - blue. [Figure 11F-2] Functional characterization of monoclonal anti-CLEC2D antibodies is shown. An endpoint cell cytotoxicity assay using a selected anti-CLEC2D antibody to kill target cells using a confocal microscope is shown. Cytotoxicity was not observed in control treatments such as only PC3 tumor cells, only PBMCs, and PBMCs with an isotype human IgG1 antibody. Cytotoxicity of PC3 tumor cells was observed when using anti-CLEC2D antibody (C6726, C5848, C4608, C5511, and C6481) clones. Enlarged images showed that PC3 tumor cells were surrounded by effector cells and tumor cell death was induced. PC3 tumor cells - green, PBMCs - red, dead cells - blue. [Figure 12A] NK cell-mediated cytotoxicity of tumor cells using anti-CLEC2D antibodies is shown. Cytotoxicity of PC3 tumor cells when treated with purified NK cells and 100 ug / ml of anti-CLEC2D antibodies (C6481 and C5511) is shown. The data revealed 86% NK cell-mediated cytotoxicity of PC3 tumor cells at a T:E of 1:1. The percentage of PC3 dead cells indicates Sytox green-positive cells. [Figure 12B] NK cell-mediated cytotoxicity of tumor cells using anti-CLEC2D antibodies is shown. It shows that no target cell death was observed when cultured with either an isotype control (human IgG1 antibody) or only NK cells with a T:E ratio increased from 1:0.5 to 1:10. The scale bar is 10 μm. [Figure 12C] NK cell-mediated cytotoxicity of tumor cells using anti-CLEC2D antibodies is shown. It shows that only anti-CLEC2D antibodies cannot induce cytotoxicity of PC3 tumor cells. The scale bar is 10 μm. [Figure 12D] NK cell-mediated cytotoxicity of tumor cells using anti-CLEC2D antibodies is shown. It shows that with anti-CLEC2D antibody C5511 (50 ug / mL), PC3 tumor cell death increased increasingly as the T:E ratio increased from 1:0.5 to 1:5 and 1:10. The scale bar is 10 μm. [Figure 13] This image shows cytotoxicity of isolated T cells and PC3 tumor cells treated with 100 ug / ml anti-CLEC2D antibodies (C5511 and C6481). The percentage of dead PC3 tumor cells is indicated by Sytox green-positive cells. [Figure 14A] This image shows live-cell imaging of PC3 tumor cells with anti-CLEC2D antibody-dependent cytotoxicity. Live-cell imaging reveals cytotoxicity of PC3 tumor cells over the culture period with human PBMC cells and 200 μg / ml anti-CLEC2D antibody. The assay was performed for 20 hours in a humidifier maintained at 37°C and 5% CO2 during image acquisition. In contrast, no cytotoxicity was observed in tumor cells cultured with control human IgG1 antibody (200 μg / ml). Live PC3 tumor cells are green, PBMC cells are red, and dead cells are blue. The scale bar is 20 μm. [Figure 14B] This image shows live-cell imaging of PC3 tumor cells with anti-CLEC2D antibody-dependent cytotoxicity. Live-cell imaging reveals cytotoxicity of PC3 tumor cells over the culture period with human NK cells and 200 μg / ml anti-CLEC2D antibody. The assay was performed for 20 hours in a humidifier maintained at 37°C and 5% CO2 during image acquisition. In contrast, no cytotoxicity was observed in tumor cells cultured with control human IgG1 antibody (200 μg / ml). Live PC3 tumor cells are green, NK cells are red, and dead cells are blue. The scale bar is 20 μm. [Figure 15A] This shows a predictive model for the anti-CLEC2D antibody. A cartoon representation of the epitope recognition (molecular chain A - dark blue, molecular chain B - blue-green) & CD161 (molecular chain C - orange-red, molecular chain D - purple) complex (PDB ID 5MGT) is shown. [Figure 15B] This shows a predictive model for the anti-CLEC2D antibody. The red selection indicates that the residues within 6 Å of the NKR-P1 molecular chain are represented. [Figure 15C]This shows a predictive model for anti-CLEC2D antibodies. A ribbon representation of the purified anti-CLEC2D antibody structure is shown. Corresponding clones for specific anti-CLEC2D monoclonal antibodies are appropriately labeled. The variable light chain is shown in a darker shade, while the heavy chain variable region is shown in white. [Figure 15D] This shows a predictive model for anti-CLEC2D antibodies. It shows structures selected after PIZSA scoring and structure clustering that belong to C4608 and contribute to one of the clusters that interact with CLEC2D (darker shade). [Figure 15E] This shows a predictive model for anti-CLEC2D antibodies. It visualizes residues selected for mutation to confirm whether the G00001-G00004-G00007-G00010-G00015 cluster combination derived from C4608 contains a binding site for the CLEC2D antigen. [Figure 15F] This shows a predictive model for anti-CLEC2D antibodies. It shows structures selected after PIZSA scoring and structure clustering that belong to C5511 and contribute to one of the clusters that interact with CLEC2D (darker shade). [Figure 15G] This shows a predictive model for anti-CLEC2D antibodies. It visualizes residues selected for mutation to confirm whether the G00001-G00005-G00011-G00019-G00020 cluster combination derived from C5511 contains a binding site for the CLEC2D antigen. [Figure 16A] This shows the identified epitope compartments on the CLEC2D antigen for anti-CLEC2D antibody clones C4608 and C5511. It also shows the surface representation of the contact points between anti-CLEC2D antibody C4608 and the CLEC2D antigen. In the depiction, darker shades indicate the location of residues interacting with the CLEC2D antigen. [Figure 16B]This diagram shows the identification epitope compartments on the CLEC2D antigen for anti-CLEC2D antibody clones C4608 and C5511. It also shows the contact points of anti-CLEC2D antibody C4608 with the CLEC2D antigen, overlapping with the CD161 binding region on CLEC2D. In the depiction, darker shades indicate the locations of residues that interact with the CLEC2D antigen. [Figure 16C] This shows the identified epitope compartments on the CLEC2D antigen for anti-CLEC2D antibody clones C4608 and C5511. It also shows the surface representation of the contact points between anti-CLEC2D antibody C5511 and the CLEC2D antigen. In the depiction, darker shades indicate the location of residues interacting with the CLEC2D antigen. [Figure 16D] This diagram shows the identification epitope compartments on the CLEC2D antigen for anti-CLEC2D antibody clones C4608 and C5511. It also shows the contact points between anti-CLEC2D antibody C5511 and the CLEC2D antigen, overlapping with the CD161 binding region on CLEC2D. In the depiction, darker shades indicate the locations of residues that interact with the CLEC2D antigen. [Figure 16E] This shows the identification epitope compartments on the CLEC2D antigen for anti-CLEC2D antibody clones C4608 and C5511. It also shows anti-CLEC2D antibody-mediated inhibition of the interaction between CLEC2D and CD161 (monitoring to confirm the efficiency of CLEC2D antigen bead conjugate). [Figure 16F] This shows the identification epitope compartments on the CLEC2D antigen for anti-CLEC2D antibody clones C4608 and C5511. It also shows that the binding of CD161-FC to the CLEC2D antigen on magnetic beads was observed in a concentration-dependent manner. [Figure 16G] The image shows the identification epitope compartments on the CLEC2D antigen for anti-CLEC2D antibody clones C4608 and C5511. The solid black arrows indicate flow cytometry monitoring of CD161 binding in the presence or absence of anti-CLEC2D antibody compared to control, as an indicator of inhibition of CD161 and CLEC2D binding. [Figure 17A]This shows NK cell activation induced by an anti-CLEC2D antibody. It demonstrates that the anti-CLEC2D antibody C5511 induces CD69 expression, leading to NK cell activation and subsequent cytotoxicity. Corresponding experimental conditions are described for each plot. IL2 treatment was performed as a positive control for CD69 overexpression. [Figure 17B] This shows NK cell activation induced by anti-CLEC2D antibody. Anti-CLEC2D antibody-mediated CD69 expression is higher on NK cells compared to the initial CD69 expression level on PC3 cells. [Figure 18A] This study demonstrates the effect of the anti-CLEC2D antibody C5511 on cytokine expression by effector cells. It shows that the increase in IFNγ expression levels was monitored using anti-CLEC2D antibody C5511 at concentrations of 10 μg / mL and 100 μg / mL. [Figure 18B] This study demonstrates the effect of the anti-CLEC2D antibody C5511 on cytokine expression by effector cells. It shows that anti-CLEC2D antibody C5511 was used at a concentration of 100 ug / mL, both in the presence and absence of PC3 cells (E:T=10:1). IFNγ expression in the CD3+ gated population was monitored. [Figure 18C] This study demonstrates the effect of the anti-CLEC2D antibody C5511 on cytokine expression by effector cells. It shows that anti-CLEC2D antibody C5511 was used at a concentration of 100 ug / mL, both in the presence and absence of PC3 cells (E:T=10:1). IFNγ expression in the CD3-gated population was monitored. [Figure 18D] This study demonstrates the effect of anti-CLEC2D antibody C5511 on cytokine expression by effector cells. It shows that anti-CLEC2D antibody C5511 was used at a concentration of 100 μg / mL, both with and without isolated NK cells. Overexpression of IFNγ was observed with anti-CLEC2D antibody C5511. [Figure 19A] This shows the mammalian expression constructs used to produce full-length monoclonal antibodies. The constructs were prepared by gene synthesis and then confirmed by restriction digestion and Sanger sequencing. A vector designed to clone the selective antibody variable heavy chain gene into the IgG4 backbone is also shown. [Figure 19B] This shows the mammalian expression constructs used to produce full-length monoclonal antibodies. The constructs were prepared by gene synthesis and then confirmed by restriction digestion and Sanger sequencing. A vector designed to clone the selective antibody variable heavy chain gene into the IgG1 N-A main chain is also shown. [Figure 19C] This shows the mammalian expression constructs used to produce full-length monoclonal antibodies. The constructs were prepared by gene synthesis and then confirmed by restriction digestion and Sanger sequencing. Flow cytometry analysis of the binding of anti-CLEC2D antibodies (C3256 and C3276) with IgG4 isotype backbone to CLEC2D antigen expressed on the surface of CHO cells is shown. Binding, estimated from the rightward peak shift, was compared with that of untransfected CHO cells. [Figure 19D] The mammalian expression constructs used to produce full-length monoclonal antibodies are shown. The constructs were prepared by gene synthesis and then confirmed by restriction digestion and Sanger sequencing. Cytotoxicity of anti-CLEC2D antibodies using various antibody isotypes is shown. IgG1 isotype (C3452 and C4608) anti-CLEC2D antibodies and IgG4 isotype (C3256 and C3276) anti-CLEC2D antibodies showed significant cytotoxicity when cultured with newly isolated PBMCs and PC3 tumor cells. [Figure 19E] The mammalian expression constructs used to produce full-length monoclonal antibodies are shown. The constructs were prepared by gene synthesis and then confirmed by restriction digestion and Sanger sequencing. Flow cytometry demonstrated that the anti-CLEC2D antibodies produced as afucosylated monoclonal antibodies C0613, C1301, C6268, C1699, C2437, C9832, C8900, and C7749 bound to the CLEC2D antigen expressed on the surface of CHO cells. [Figure 19F]The mammalian expression constructs used to produce full-length monoclonal antibodies are shown. The constructs were prepared by gene synthesis and then confirmed by restriction digestion and Sanger sequencing. The images show NK cell-mediated cytotoxicity of PC3 tumor cells using afcosylated anti-CLEC2D antibodies (C7749, C8800, C9832) at concentrations lower than 5× compared to C5511. The data clearly demonstrate that afcosylated anti-CLEC2D antibodies achieved nearly equivalent cell death at concentrations lower than 5×, indicating that afcosylated anti-CLEC2D antibodies are more cytotoxic. [Figure 19G] This shows the mammalian expression constructs used to produce full-length monoclonal antibodies. The constructs were prepared by gene synthesis and then confirmed by restriction digestion and Sanger sequencing. This shows the measurement of CDC-mediated cytotoxicity by the anti-CLEC2D antibody C5511 using Ramos tumor cell lines and PC3 tumor cell lines. Rituximab was used as a positive control. [Figure 20A] This study demonstrates the antitumor effects in a mouse model of cancer xenografting. HuNOG-EXL mice were used for PC3 xenografting, and animals with tumors were randomly selected for injection of an anti-CLEC2D antibody product. The plots show tumor volume against time to demonstrate the significant antitumor effects observed with anti-CLEC2D antibody alone or in combination with anti-PDL1 antibody. [Figure 20B] This study demonstrates the antitumor effect in a mouse model of cancer xenografting. HuNOG-EXL mice were used for PC3 xenografting, and animals with tumors were randomly selected for injection of an anti-CLEC2D antibody product. Images showing immune cell infiltration in the tumor microenvironment, as stained by CD3+ T cells, are shown. [Figure 20C] This study demonstrates the antitumor effect in a mouse model of cancer xenografting. HuNOG-EXL mice were used for PC3 xenografting, and animals with tumors were randomly selected for injection of an anti-CLEC2D antibody product. Images of mice with xenografts showing Alexa 647-labeled anti-CLEC2D antibody injected into the tumor over a 96-hour period are shown. [Figure 20D]This study demonstrates the antitumor effect in a mouse model of cancer xenograft. HuNOG-EXL mice were used for PC3 xenografting, and animals with tumors were randomized for injection of the anti-CLEC2D antibody product. The effect of the test compound on tumor volume in humanized (huNOG-EXL) mice with subcutaneous PC-3 tumor xenografts is shown (up to day 36). Each treatment group consisted of 5 animals and was named the C5511 mAb group, the solvent-control IgG1 group, and the C6481 mAb group. Values ​​are expressed as the mean of 2-5 animals in each group. Statistical analysis was performed by two-way ANOVA using GraphPad Prism (version 8.3.0) followed by the Bonferroni post-hoc test. **p<0.01, statistically significant when comparing the C5511 mAb group to the solvent-control IgG1 group (day 36).** [Figure 20E] This study demonstrates the antitumor effect in a mouse model of cancer xenograft. HuNOG-EXL mice were used for PC3 xenografting, and animals with tumors were randomized for injection of the anti-CLEC2D antibody product. The effect of the test compound on tumor volume in humanized (huNOG-EXL) mice with subcutaneous PC-3 tumor xenografts is shown (up to day 24). Each treatment group consisted of 5 animals and was named the C5511 mAb group, the solvent-control IgG1 group, and the C6481 mAb group. Values ​​are expressed as the mean of 2-5 animals in each group. Statistical analysis was performed by two-way ANOVA using Graph Pad Prism (version 8.3.0) followed by the Bonferroni post-hoc test. ***p<0.001 and *p<0.05, the C5511 mAb group and the C6481 mAb group were statistically significant when compared to the solvent-control IgG1 group, respectively (day 24). [Figure 20F]This study demonstrates the antitumor effect in a mouse model of cancer xenograft. HuNOG-EXL mice were used for PC3 xenografting, and animals with tumors were randomized for injection of an anti-CLEC2D antibody product. The effect of the test compound on delta tumor volume in humanized (huNOG-EXL) mice with subcutaneous PC-3 tumor xenografts is shown (up to day 36). Each treatment group consisted of 5 animals and was named the C5511 mAb group, the solvent-control IgG1 group, and the C6481 mAb group. Values ​​are expressed as the mean of 2-5 animals in each group. Statistical analysis was performed by a two-way ANOVA using GraphPad Prism (version 8.3.0) followed by a Bonferroni post-hoc test. **p<0.01, statistically significant (day 36) comparison of the C5511 mAb group with the solvent-control IgG1 group.** [Figure 20G] This study demonstrates the antitumor effect in a mouse model of cancer xenograft. HuNOG-EXL mice were used for PC3 xenografting, and animals with tumors were randomized for injection of the anti-CLEC2D antibody product. The effect of the test compound on delta tumor volume in humanized (huNOG-EXL) mice with subcutaneous PC-3 tumor xenografts is shown (up to day 24). Each treatment group consisted of 5 animals and was named the C5511 mAb group, the solvent-control IgG1 group, and the C6481 mAb group. Values ​​are expressed as the mean of 2-5 animals in each group. Statistical analysis was performed by two-way ANOVA using Graph Pad Prism (version 8.3.0) followed by the Bonferroni post-hoc test. ***p<0.001 and *p<0.05, the C5511 mAb group and the C6481 mAb group were statistically significant when compared to the solvent-control IgG1 group, respectively (day 24). [Figure 20H]This study demonstrates the antitumor effect in a mouse model of cancer xenograft. HuNOG-EXL mice were used for PC3 xenografting, and animals with tumors were randomized for injection of an anti-CLEC2D antibody product. The effect of the test compound on relative tumor volume in humanized (huNOG-EXL) mice with subcutaneous PC-3 tumor xenografts is shown (up to day 36). Each treatment group consisted of 5 animals and was named the C5511 mAb group, the solvent-control IgG1 group, and the C6481 mAb group. Values ​​are expressed as the mean of 2-5 animals in each group. Statistical analysis was performed by a two-way ANOVA using GraphPad Prism (version 8.3.0) followed by a Bonferroni post-hoc test. *p<0.05, statistically significant when comparing the C5511 mAb group to the solvent-control IgG1 group (day 36). [Figure 20I] This study demonstrates the antitumor effect in a mouse model of cancer xenograft. HuNOG-EXL mice were used for PC3 xenografting, and animals with tumors were randomized for injection of the anti-CLEC2D antibody product. The effect of the test compound on relative tumor volume in humanized (huNOG-EXL) mice with subcutaneous PC-3 tumor xenografts is shown (up to day 24). Each treatment group consisted of 5 animals and was named the C5511 mAb group, the solvent-control IgG1 group, and the C6481 mAb group. Values ​​are expressed as the mean of 2-5 animals in each group. Statistical analysis was performed by two-way ANOVA using Graph Pad Prism (version 8.3.0) followed by the Bonferroni post-hoc test. ***p<0.001 and *p<0.05, the C5511 mAb group and the C6481 mAb group were statistically significant when compared to the solvent-control IgG1 group, respectively (day 24). [Figure 20J]This study demonstrates the antitumor effect in a mouse model of cancer xenograft. HuNOG-EXL mice were used for PC3 xenografting, and animals with tumors were randomized for injection of an anti-CLEC2D antibody product. The effect of the test compound on delta-relative tumor volume in humanized (huNOG-EXL) mice with subcutaneous PC-3 tumor xenografts is shown (up to day 36). Each treatment group consisted of 5 animals and was named the C5511 mAb group, the solvent-control IgG1 group, and the C6481 mAb group. Values ​​are expressed as the mean of 2-5 animals in each group. Statistical analysis was performed by a two-way ANOVA using GraphPad Prism (version 8.3.0) followed by a Bonferroni post-hoc test. *p<0.05, statistically significant when comparing the C5511 mAb group to the solvent-control IgG1 group (day 36). [Figure 20K] This study demonstrates the antitumor effect in a mouse model of cancer xenograft. HuNOG-EXL mice were used for PC3 xenografting, and animals with tumors were randomized for injection of the anti-CLEC2D antibody product. The effect of the test compound on delta-relative tumor volume in humanized (huNOG-EXL) mice with subcutaneous PC-3 tumor xenografts is shown (up to day 24). Each treatment group consisted of 5 animals and was named the C5511 mAb group, the solvent-control IgG1 group, and the C6481 mAb group. Values ​​are expressed as the mean of 2-5 animals in each group. Statistical analysis was performed by two-way ANOVA using GraphPad Prism (version 8.3.0) followed by the Bonferroni post-hoc test. ***p<0.001 and *p<0.05, the C5511 mAb group and the C6481 mAb group were statistically significant when compared to the solvent-control IgG1 group, respectively (day 24). [Figure 21A] This document presents the characterization of the purified anti-CLEC2D antibody product. It also shows the SDS-PAGE analysis of the purified C5511 antibody under non-reducing and reducing conditions. [Figure 21B] This section describes the characterization of the purified anti-CLEC2D antibody product. It also shows the TIC chromatogram (three copies) of the intact mass spectrometry analysis of the anti-CLEC2D antibody. [Figure 21C] This document presents the characterization of the purified anti-CLEC2D antibody product. It also shows the WCX chromatogram analysis of the anti-CLEC2D antibody. [Figure 21D] This document describes the characterization of the purified anti-CLEC2D antibody product. It also shows the size exclusion chromatogram of the anti-CLEC2D antibody. [Figure 21E] This report presents the characterization of purified anti-CLEC2D antibody products. It shows the ELISA assay expression of anti-CLEC2D antibodies against purified biotinylated CLEC2D antigen. The data were fitted to a single-site binding model to calculate the Kd of the anti-CLEC2D antibodies. The report also shows CLEC2D antigen affinity-based binding studies for representative anti-CLEC2D antibodies. [Figure 21F] This section presents a characterization analysis of purified anti-CLEC2D antibody products. It also shows CLEC2D antigen affinity-based binding studies for representative anti-CLEC2D antibodies. [Figure 21G] This shows the characterization of the purified anti-CLEC2D antibody product. It demonstrates that the purified CLEC2D antigen external domain was used as the antigen source in the BIACORE study. The monitored response is plotted against time. [Figure 21H] This section presents the characterization of purified anti-CLEC2D antibody products. It also shows affinity-based binding studies of representative anti-CLEC2D antibody molecules using FcRn at pH 5.9. [Figure 21I] This section presents the characterization of purified anti-CLEC2D antibody products. It also shows affinity-based binding studies of representative anti-CLEC2D antibody molecules using FcRn at pH 7.4. [Figure 22A] This paper presents anti-CLEC2D antibodies suitable for appropriate diagnostic and prognostic applications. It also describes the selection of an anti-CLEC2D antibody (C0949) based on its binding characteristics. Four anti-CLEC2D antibodies (C2779, C2438, C0949, and C2543) were evaluated for binding to CLEC2D on PC3 target cells. C0949 showed good binding and a central shift of the peak. [Figure 22B] This document presents an anti-CLEC2D antibody suitable for diagnostic and prognostic applications. It demonstrates that the anti-CLEC2D antibody C0949 recognizes the CLEC2D antigen on multiple prostate cancer cell lines. [Figure 22C] This paper presents an anti-CLEC2D antibody suitable for diagnostic and prognostic applications. It demonstrates that the anti-CLEC2D antibody C0949 recognizes the CLEC2D antigen on multiple tumor cell lines. Specific binding and the multiplier change in average fluorescence were calculated using the ratio of mean FITC fluorescence between the test and the control. [Figure 23A] This shows that anti-CLEC2D antibodies recognize the CLEC2D antigen on prostate cancer tumor cells. The expression levels of the CLEC2D antigen in different prostate cancer stages after TCGA data analysis are also shown. [Figure 23B] This study demonstrates that anti-CLEC2D antibodies recognize the CLEC2D antigen on prostate cancer tumor cells. It also shows the expression levels of the CLEC2D antigen on prostate cancer cell lines PC3, DU145, 22RV1, and LnCap. [Figure 23C-1] This study demonstrates that anti-CLEC2D antibodies recognize the CLEC2D antigen on prostate cancer tumor cells. It shows the expression levels of the CLEC2D antigen on prostate cancer cell lines PC3, LnCap, 22RV1, and DU145, induced using LPS, poly(I:C), IFN-γ, PBMC supernatant, PBMC cells, NK cells, and T cells. The upper panel shows the anti-CLEC2D antibody, and the lower panel shows the merged image. [Figure 23C-2] This study demonstrates that anti-CLEC2D antibodies recognize the CLEC2D antigen on prostate cancer tumor cells. It shows the expression levels of the CLEC2D antigen on prostate cancer cell lines PC3, LnCap, 22RV1, and DU145, induced using LPS, poly(I:C), IFN-γ, PBMC supernatant, PBMC cells, NK cells, and T cells. The upper panel shows the anti-CLEC2D antibody, and the lower panel shows the merged image. [Figure 23C-3] This study demonstrates that anti-CLEC2D antibodies recognize the CLEC2D antigen on prostate cancer tumor cells. It shows the expression levels of the CLEC2D antigen on prostate cancer cell lines PC3, LnCap, 22RV1, and DU145, induced using LPS, poly(I:C), IFN-γ, PBMC supernatant, PBMC cells, NK cells, and T cells. The upper panel shows the anti-CLEC2D antibody, and the lower panel shows the merged image. [Figure 23C-4] This study demonstrates that anti-CLEC2D antibodies recognize the CLEC2D antigen on prostate cancer tumor cells. It shows the expression levels of the CLEC2D antigen on prostate cancer cell lines PC3, LnCap, 22RV1, and DU145, induced using LPS, poly(I:C), IFN-γ, PBMC supernatant, PBMC cells, NK cells, and T cells. The upper panel shows the anti-CLEC2D antibody, and the lower panel shows the merged image. [Figure 23D] This demonstrates that the anti-CLEC2D antibody recognizes the CLEC2D antigen on prostate cancer tumor cells. A human tissue microarray slide stained with the anti-CLEC2D antibody C2685 is shown, illustrating the staining of tumor cells within malignant prostate cancer tissue. [Figure 24A] This study demonstrates that anti-CLEC2D antibodies recognize the CLEC2D antigen on various other tumor cells. It also presents TCGA data analysis of CLEC2D antigen expression in various cancers. [Figure 24B] This study demonstrates that anti-CLEC2D antibodies recognize the CLEC2D antigen on various other tumor cells. It shows the expression levels of the CLEC2D antigen on various tumor cell lines: HepG2 (liver cancer), LN229 (glioblastoma), SKOV3 (ovarian cancer), BT474 (breast cancer), NCI-H929 (myeloma), and Ramos (lymphoma). [Figure 24C-1] This study demonstrates that anti-CLEC2D antibodies recognize the CLEC2D antigen on various other tumor cells. It shows the expression levels of the CLEC2D antigen on BT474 (breast cancer), SKOV3 (ovarian cancer), LN229 (glioblastoma), Ramos (lymphoma), NCI-H929 (myeloma), and HepG2 (liver cancer) cells induced with LPS, poly(I:C), and IFNγ. [Figure 24C-2] This study demonstrates that anti-CLEC2D antibodies recognize the CLEC2D antigen on various other tumor cells. It shows the expression levels of the CLEC2D antigen on BT474 (breast cancer), SKOV3 (ovarian cancer), LN229 (glioblastoma), Ramos (lymphoma), NCI-H929 (myeloma), and HepG2 (liver cancer) cells induced with LPS, poly(I:C), and IFNγ. [Figure 24C-3]This study demonstrates that anti-CLEC2D antibodies recognize the CLEC2D antigen on various other tumor cells. It shows the expression levels of the CLEC2D antigen on BT474 (breast cancer), SKOV3 (ovarian cancer), LN229 (glioblastoma), Ramos (lymphoma), NCI-H929 (myeloma), and HepG2 (liver cancer) cells induced with LPS, poly(I:C), and IFNγ. [Figure 24D] This study demonstrates that anti-CLEC2D antibodies recognize the CLEC2D antigen on various other tumor cells. It shows cytotoxicity mediated by the anti-CLEC2D antibody C5511 at 100 μg / ml on SKOV3 (ovarian cancer) cells, and cytotoxicity mediated by both anti-CLEC2D antibodies C5511 and C6481 at 100 μg / ml on HepG2 (liver cancer) cell lines. The percentage of dead cells was indicated by Sytox green-positive cells. [Figure 25A] This document describes a lymphocyte proliferation assay using an anti-CLEC2D antibody with flow cytometry analysis. The antibody wet-coating protocol is also presented. [Figure 25B] This document describes a lymphocyte proliferation assay using an anti-CLEC2D antibody with flow cytometry analysis. It also presents an air-drying antibody coating protocol. [Figure 25C] This document describes a lymphocyte proliferation assay using an anti-CLEC2D antibody with flow cytometry analysis. It also presents a high-density pre-culture protocol. [Figure 25D] This paper describes a lymphocyte proliferation assay using anti-CLEC2D antibodies with flow cytometry analysis. It shows the measurement of IFNγ cytokine secretion from effector cells when PBMCs were cultured for extended periods with anti-CLEC2D antibodies (C5511, C4608, C6481). Treatment with OKT3 antibody was used as a positive control. PBMCs were treated with anti-CD3 antibody OKT3 (1 μg / ml) and anti-CLEC2D antibodies C4608, C5511, and C6481 (1 μg / ml, 10 μg / ml, 50 μg / ml, and 100 μg / ml) and cultured for 4 days. The state of the fluorescent proliferation dye was monitored using a flow cytometer. Untreated PBMCs were used as a control. [Figure 25E]This paper describes a lymphocyte proliferation assay using anti-CLEC2D antibodies with flow cytometry analysis. It shows the measurement of IL2 cytokine secretion from effector cells when PBMCs were cultured for extended periods with anti-CLEC2D antibodies (C5511, C4608, C6481). Treatment with OKT3 antibody was used as a positive control. PBMCs were treated with anti-CD3 antibody OKT3 (1 μg / ml) and anti-CLEC2D antibodies C4608, C5511, and C6481 (1 μg / ml, 10 μg / ml, 50 μg / ml, and 100 μg / ml) and cultured for 4 days. The state of the fluorescent proliferation dye was monitored using a flow cytometer. Untreated PBMCs were used as a control. [Figure 26] The following histograms show, overlaid with flow cytometry analysis, the binding of anti-CLEC2D antibodies (C3566 and C5511) to rat, mouse, and cynomolgus monkey-derived CLEC2D antigen homologs expressed on the surface of CHO cells. [Modes for carrying out the invention] 【0075】 Modulation of immune cell checkpoint receptors by antibody-based / targeted therapeutic approaches has attracted considerable attention over the past few years. The greatest efforts have been focused on modulating T cell checkpoints. However, increasing attention is also being paid to modulating B cell, NK cell, and myeloid cell checkpoints. The innate immune system includes natural killer (NK) cells, which have the ability to recognize a wide range of target cells, such as tumor cells or virus-infected cells, and induce cytotoxicity. NK cells do not require any prior antigen sensitization. In addition to direct cytotoxicity, NK cells are also involved in inducing and driving adaptive immune responses through the production and secretion of cytokines. Generally, these responses are regulated by a proper balance of signals induced by the interaction of a wide range of surface-activated and surface-inhibiting receptors with ligands on the surface of target cells. Modulation of NK cell numbers and their associated functions via various substances, such as monoclonal antibodies and cytokines, can lead to improved antitumor activity. These substances can be offered as potential therapeutic agents, either alone or in combination. Therefore, by suppressing both the activating and / or inhibitory surface receptors, the anti-cancer activity of NK cells can be unleashed. 【0076】 Blocking these interactions could offer novel treatment options for some cancers. However, the discovery, understanding, and design of these methods need to be coordinated, and the therapeutic procedures need to be further adapted for individual receptors as targets for various cancers, which remain unaddressed. 【0077】 Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have meanings generally understood by those skilled in the art. Furthermore, unless otherwise specifically required by context, singular terms shall include plural forms and plural terms shall include singular forms where deemed appropriate for the context and / or use. Various singular / plural substitutions may be explicitly stated herein for clarity. Generally, technical terms used in connection with the biotechnology, immunology, molecular and cellular biology, and recombinant DNA technologies described herein are well known and commonly used in the art. Specific references and other documents cited herein are expressly incorporated herein by reference. In the event of any conflict, this specification (including definitions) shall prevail. Substances, methods, figures, and examples are illustrative and not intended to limit. 【0078】 Furthermore, unless otherwise specified, the methods, preparation, and use of the disclosed antibody-naive libraries employ prior art in molecular biology, biochemistry, computational chemistry, cell culture, recombinant DNA technology, polymerase chain reaction (PCR), and related fields. These techniques, their principles, and conditions are described in the literature and are well known to those skilled in the art. 【0079】 Before disclosing and describing antibody-naive libraries and methods for producing nucleic acids encoding antibody-naive libraries, and other embodiments of this disclosure, it should be understood that the terminology used herein is solely for the purpose of describing specific embodiments and is not intended to limit them. It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple subjects unless otherwise specifically indicated by the context. 【0080】 In one embodiment, the terms “library” and “libraries” are used interchangeably within this disclosure and relating to the products of this disclosure. In one embodiment, it means a collection or pool of nucleic acid sequences. In one embodiment, it means a collection or pool of amino acid sequences. In some embodiments, it means a collection or pool of organisms including a collection or pool of amino acid sequences or nucleic acid sequences. In some embodiments, the organisms are bacteriophages (phages) or yeast (e.g., Saccharomyces cerevisiae). 【0081】 In one embodiment, the terms “pooling,” “pooled,” “pool,” and “pools” in the context of this disclosure mean mixing samples / nucleic acid sequences / nucleic acid fragments / gene clones / amplification products / antibodies obtained from multiple donors, i.e., two or more donors, by employing the method of this disclosure. 【0082】 In one embodiment, the term "PBMC" refers to any peripheral blood cells having a round nucleus, consisting of lymphocytes (T cells, B cells, NK cells) and monocytes, erythrocytes, platelets, and granulocytes (neutrophils, basophils, and eosinophils). 【0083】 antigen As used herein, the terms “antigen” or “immunogen” mean any foreign substance that induces an immune response in the body. In one embodiment, the antigen is a cellular protein. In one embodiment, the antigen is a cell surface protein. 【0084】 Antigens may be isolated or induced from any species. Representative species include Homo sapiens, Mus musculus, Rattus norvegicus, Canis lupis familiaris, and Cynomolgus macaca. Examples include, but are not limited to, fascicularis. In some embodiments, the antigen is a fragment of a wild-type protein isolated or derived from Homo sapiens, Mus musculus, Rattus norvegicus, Canis lupis familiaris, or Cynomolgus macaca fascicularis. In some embodiments, the antigen is a mutant variant of a protein derived from Homo sapiens, Mus musculus, Rattus norvegicus, Canis lupis familiaris, or Cynomolgus macaca fascicularis. In some embodiments, the antigen can be mutated to improve its solubility and / or stability. For example, the CLEC2D antigen may contain a mutation at H176C to introduce an additional disulfide crosslink at the Cys163 amino acid to improve the stability and uniformity of the expressed protein. 【0085】 In some embodiments, the antigen includes an epitope tag at either the N-terminus or C-terminus of the polypeptide. Exemplary tags include, but are not limited to, polyhistidine tags and FLAG tags. Any epitope tag well known in the art is considered to be within the scope of this disclosure. 【0086】 CLAX, also known as lectin-like transcript-1 (LLT1), and C-type lectin domain family 2 member D (CLEC2D), is a member of the natural killer cell receptor C-type lectin family. CLEC2D binds to killer cell lectin-like receptor B1 (KLRB1). KLRB1 is also known as CD161, CLEC5B, NKR, NKR-P1, NKR-P1A, NKRP1A, and hNKR-P1A. All orthologues and isoforms of CLEC2D and CD161 are considered to be within the scope of this disclosure. 【0087】 In some embodiments, any of the C-type lectin domain family 2 member D (CLEC2D) proteins or their aliases or homologs, whether derived from humans or other species, represent the target antigen of the antibody produced by the method described herein. 【0088】 In some embodiments, the antigen is a CLEC2D antigen having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to CLEC2D sequences isolated or derived from Homo sapiens, Mus musculus, Rattus norvegicus, Canis lupis familiaris, and Cynomolgus macaca fascicularis. 【0089】 In some embodiments, any of the CD161 protein or its aliases or homologs, whether derived from humans or other species, represents the target antigen of the antibody produced by the method described herein. 【0090】 In some embodiments, the CD161 antigen has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to CD161 sequences isolated or derived from Homo sapiens, Mus musculus, Rattus norvegicus, Canis lupis familiaris, and Cynomolgus macaca fascicularis. 【0091】 Exemplary antigens are shown in Table 1 below. [Table 1-1] [Table 1-2] Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 【0092】 Antibody In one embodiment, the term “antibody” means an immunoglobulin that may be derived in whole or in part from a natural source or that may be synthetically produced. The terms “antibody” and “immunoglobulin” are used synonymously throughout this specification unless otherwise specified. 【0093】 In one embodiment, the term “antibody” includes both polyclonal and monoclonal antibody preparations, and also includes chimeric antibody molecules, F(ab')2 fragments and F(ab) fragments, Fv molecules, single-chain Fv molecules (ScFv), dimeric antibody fragments and trimer antibody fragments, bispecific antibodies, minibodies, humanized monoclonal antibody molecules, human antibodies, the Fc region of antibodies, and fusion proteins containing any functional fragments arising from these molecules, wherein the derivative molecules retain the immunological function of the parent antibody molecule. The antibodies of this disclosure are human antibodies, humanized antibodies, chimeric antibodies, or antibodies that are further genetically modified insofar as the properties of this disclosure are retained. 【0094】 Natural antibodies and immunoglobulins are typically heterotetrameric glycoproteins of approximately 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to the heavy chain by a single covalent disulfide bond, and the number of disulfide bonds varies between heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (VH) at one end, followed by many constant domains. Each light chain has a variable domain (VL) at one end and a constant domain at the other, with the constant domain of the light chain aligned with the first constant domain of the heavy chain, and the variable domain of the light chain aligned with the variable domain of the heavy chain. It is thought that specific amino acid residues form the interface between the light chain variable domain and the heavy chain variable domain (Clothia et al., J.Mol.Biol.186:651(1985); Novotny and Haber, Proc.Natl.Acad.Sci.USA82:4592(1985)). 【0095】 The term "antigen-binding site" or "binding region" refers to a portion of the immunoglobulin molecule involved in antigen binding. The antigen-binding site is formed by amino acid residues in the N-terminal variable ("V") regions of the heavy ("H") and light ("L") chains. Three highly distinct stretches within the V regions of the heavy and light chains, called "hypervariable regions," are located between more conserved adjacent stretches known as "framework regions," or "FRs." Therefore, the term "FR" refers to the naturally occurring amino acid sequences between and adjacent to the hypervariable regions of immunoglobulins. Within the antibody molecule, the three hypervariable regions of the light chain and the three hypervariable regions of the heavy chain are arranged in three-dimensional space relative to each other to form the antigen-binding surface. The antigen-binding surface is complementary to the three-dimensional surface of the bound antigen, and the three hypervariable regions of the heavy and light chains are called "complementarity-determining regions," or "CDRs." 【0096】 The term "variable" refers to the fact that the sequences of specific parts of the variable domain differ significantly between antibodies, and that these specific parts are utilized for each individual antibody's binding and specificity to its particular antigen. However, variability is not uniformly distributed throughout the variable domain of an antibody. Variability is concentrated in three segments called complementarity-determining regions (CDRs) or hypervariable regions in both the light chain and heavy chain variable domains. The more highly conserved parts of the variable domain are called frameworks (FRs). The natural heavy chain and light chain variable domains each contain four FR regions that primarily take on a β-sheet structure, bound by three CDRs that form loops that bind to the β-sheet structure, and in some cases bound by three CDRs that form part of the β-sheet structure. The CDRs within each molecular chain are maintained in close proximity by the FR region and, together with the CDR of the other molecular chain, contribute to the formation of the antibody target binding site (see Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md. (1991)). The constant domain does not directly participate in antibody binding to the antigen, but exerts various effector functions, such as the antibody's involvement in antibody-dependent cytotoxicity. 【0097】 An “antibody fragment” comprises a portion of a full-length antibody, preferably its variable domain, or at least its antigen-binding site. For scFv antibodies, see, for example, Huston, JS, Methods in Enzymol. 203 (1991) 46-88. In one embodiment, the “antibody fragment” is a portion of a complete antibody that retains the ability to exhibit antigen-binding activity. In addition, the antibody fragment comprises a single-chain polypeptide that gives the antibody properties of the present disclosure by having a VH domain that binds to a corresponding antigen (i.e., can assemble with the VL domain) or a VL domain that can assemble with the VH domain, or by having a functional antigen-binding site. 【0098】 Papain digestion of the antibody yields two identical antigen-binding fragments called "Fab" fragments, each possessing one antigen-binding site, and the remaining "Fc" fragment (named because it is easily crystallizable). Pepsin treatment produces an F(ab')2 fragment, which still has two antigen-binding sites that can crosslink to the antigen. 【0099】 "Fv" is the smallest antibody fragment containing a complete antigen recognition and binding site. This region consists of a dimer of one tightly non-covalently bonded heavy chain variable domain and one light chain variable domain. In this structure, the three CDRs of each variable domain interact to define the antigen-binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of Fv containing only three antigen-specific CDRs) has the ability to recognize and bind to antigens, albeit with lower affinity compared to a complete binding site. 【0100】 Single-chain Fv ("scFv") polypeptide molecules are covalently linked VH:VL heterodimers that can be expressed from gene fusions containing VH-coding and VL-coding genes linked by peptide code linkers. Numerous methods have been described for identifying the chemical structure to convert naturally aggregated but chemically separated light and heavy polypeptide chains derived from the antibody V region into scFv molecules that fold into a three-dimensional structure substantially similar to the structure of the antigen-binding site. See, for example, U.S. Patents 5,091,513, 5,132,405, and 4,946,778. 【0101】 The Fab fragment also contains a constant domain of the light chain and a first constant domain (CH1) of the heavy chain. The Fab' fragment differs from the Fab fragment by the addition of several residues containing one or more cysteines, derived from the antibody hinge region, to the carboxyl terminus of the heavy chain CH1 domain. Fab'-SH is the name used herein for Fab' fragments in which the cysteine ​​residue(s) of the constant domain have a free thiol group. The F(ab')2 antibody fragment was originally constructed as a pair of Fab' fragments having hinge cysteines between them. Other chemical couplings of antibody fragments are also known. 【0102】 The "light chain" of an antibody (immunoglobulin) derived from any vertebrate species can be assigned to one of two distinct types, called kappa (k) and lambda (l), based on the amino acid sequence of its constant domain. 【0103】 As used herein, the terms "immunological binding" and "immunological binding properties" refer to the type of non-covalent binding interactions that occur between an immunoglobulin molecule and an antigen to which the immunoglobulin is specific. The strength or affinity of an immunological binding interaction can be expressed based on the dissociation constant (Kd) of the interaction, with a smaller Kd representing a higher affinity. The immunological binding properties of a selected polypeptide can be quantified using methods well known in the art. One such method requires measuring the rate of formation and dissociation of an antigen-binding site / antigen complex, which rates are determined by geometric parameters that equally affect the concentration of the complex partners, the affinity of the interaction, and the rates in both directions. Therefore, both the "on rate constant" (Kon) and the "off rate constant" (Koff) can be determined by calculating the concentration as well as the actual binding and dissociation rates. The ratio of Koff / Kon cancels out all parameters not related to affinity and corresponds to the dissociation constant Kd. In some embodiments, the antibodies of the present disclosure bind to CLEC2D with a Kd of ≤10 μM, preferably ≤1 μM, more preferably ≤100 nM, such as ≤90 nM, ≤80 nM, ≤70 nM, ≤60 nM, ≤50 nM, ≤40 nM, ≤30 nM, ≤20 nM, ≤10 nM, ≤5 nM, or ≤1 nM when measured using an assay, such as a radioligand binding assay or a similar assay well known to those skilled in the art. In some embodiments, the binding affinity of the antibodies of the present disclosure is within the range of 10 -5 M to 10 -12 M. For example, the binding affinity of the antibodies of the present disclosure is 10 -6 M to 10 -12 M, 10 -7 M to 10 -12 M, 10 -8 M to 10 -12 M, 10 -9 M to 10 -12 M, 10 -5 M to 10 -11 M, 10 -6 M to 10 -11 M, 10 -7 M to 10 -11 M, 10 -8 M to 10 -11 M, 10-9 M~10 -11 M、10 -10 M~10 -11 M、10 -5 M~10 -10 M、10 -6 M~10 -10 M、10 -7 M~10 -10 M、10 -8 M~10 -10 M、10 -9 M~10 -10 M、10 -5 M~10 -9 M、10 -6 M~10 -9 M、10 -7 M~10 -9 M、10 -8 M~10 -9 M、10 -5 M~10 -8 M、10 -6 M~10 -8 M、10 -7 M~10 -8 M、10 -5 M~10 -7 M、10 -6 M~10 -7 M、または10 -5 M~10 -6 Mである。 【0104】 This disclosure also features antibodies having a specific percentage of identity or similarity to the amino acid or nucleotide sequence of any of the CLEC2D antibodies described herein. For example, an antibody may have at least 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher percentage of identity when compared to any one specific region or full length of any of the CLEC2D antibodies described herein. Preferably, an antibody may have at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher percentage of identity when compared to any one specific region or full length of any of the CLEC2D antibodies described herein. More preferably, the antibody may have at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher percentage identity when compared to any one specific region or full length of any of the CLEC2D antibodies described herein. Even more preferably, the antibody may have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher percentage identity when compared to any one specific region or full length of any of the CLEC2D antibodies described herein. Sequence identity or similarity to the nucleic acids and proteins of this disclosure can be determined by sequence comparison and / or alignment using methods well known in the art. For example, percent sequence identity or similarity to the nucleic acids and proteins of this disclosure can be determined using sequence comparison algorithms (i.e., BLAST or BLAST 2.0), manual alignment, or visual inspection. 【0105】 Those skilled in the art will readily understand that, with respect to amino acid sequences, individual substitutions, deletions, or additions to nucleic acid, peptide, polypeptide, or protein sequences that alter, add, delete, or substitute a single amino acid or a small percentage of amino acids within the coding sequence are collectively referred to herein as “conservative modification variants.” In some embodiments, the alteration results in the substitution of an amino acid to a chemically similar amino acid. Tables of conservative substitutions that provide functionally similar amino acids are well known in the art. 【0106】 Immunoglobulins can be assigned to different classes depending on the amino acid sequence of the constant domain of the heavy chain. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM. Several of these can be further classified into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, ∂, ε, γ, and μ, respectively. The subunit structures and three-dimensional structures of different classes of immunoglobulins are well known. 【0107】 In one embodiment, humanized antibodies may be used in the compositions and methods provided herein. In some embodiments, the term “humanized antibody” or “humanized form of antibody” means an antibody in which the framework or “complementarity-determining region” (CDR) is modified to include CDRs of immunoglobulins with different specificity compared to the specificity of the parent immunoglobulin. In other embodiments, “humanized antibodies” are prepared by grafting VH and VL CDRs onto the framework region of a human antibody. See, for example, Riechmann, L., et al, Nature 332 (1988) 323-327; and Neuberger, MS, et al, Nature 314 (1985) 268-270. The heavy-chain variable framework region and the light-chain variable framework region can be derived from the same or different human antibody sequences. The human antibody sequence may be a sequence of a naturally occurring human antibody. Human heavy chain variable framework regions and human light chain variable framework regions are listed, for example, in Lefranc, M.-P., Current Protocols in Immunology (2000) - Appendix IP A.1P.1-A.1P.37 and are available via IMGT, the international ImMunoGeneTics information system® (http: / / imgt.cines.fr) or http: / / vbase.mrc-cpe.cam.ac.uk. Optionally, the framework regions may be modified by further mutations. Particularly preferred CDRs correspond to CDRs representing sequences that recognize the above-mentioned antigens against chimeric antibodies. The term “humanized antibody” also, as used herein, includes antibodies in which the constant region has been modified, for example, by “class switching,” i.e., by a change or mutation of the Fc portion (e.g., a mutation from IgG1 to IgG4 and / or IgG1 / IgG4 mutation), to produce the characteristics of the disclosure, particularly with respect to C1q binding and / or FcR binding. As used herein, the term "human antibody" means an antibody having a variable region and a constant region derived from a human germline immunoglobulin sequence.Human antibodies are well known in current technology (van Dijk, MA, and van de Winkel, JG, Curr. Opin. Chem. Biol. 5 (2001) 368-374). Human antibodies can also be produced using transgenic animals (e.g., mice) that can produce a complete repertoire or selection of human antibodies without producing endogenous immunoglobulins when immunized. By introducing a human germline immunoglobulin gene array into such germline mutant mice, the production of human antibodies can be induced upon antigen induction (e.g., Jakobovits, A., et al, Proc. Natl. Acad. Sci. USA 90 (1993) 2551-2555; Jakobovits, A., et al, Nature). See 362(1993)255-258; Brueggemann,MD,et al.,Year Immunol.7(1993)33-40). Human antibodies can also be prepared using phage display libraries (Hoogenboom,HR,and Winter,G.,J.Mol.Biol.227(1992)381-388; Marks,JD,et al.,J.Mol.Biol.222(1991)581-597). The techniques of Cole,A.,et al. and Boerner,P.,et al. are also available for the preparation of human monoclonal antibodies (Cole,A.,et al.,Monoclonal Antibodies and Cancer Therapy, Liss, AL, p.77 (1985); and Boerner, P., et al, J. Immunol. 147 (1991) 86-95). As already mentioned in the humanized antibodies of this disclosure, the term “human antibody” also, as used herein, includes antibodies whose constant region has been modified to produce the characteristics of this disclosure. 【0108】 In one embodiment, the term “monoclonal antibody” means an antibody composition having a homogeneous antibody population. The antibody is not limited by the species or source of the antibody, or by the method of antibody production. In another embodiment, the term includes, in addition to complete immunoglobulin, fragments such as Fab, F(ab')2, Fv, and other fragments, as well as chimeric homogeneous antibody populations and humanized homogeneous antibody populations exhibiting immunological binding properties to the parent monoclonal antibody molecule. In another embodiment, the term “monoclonal antibody” or “monoclonal antibody composition” means, as used herein, a preparation of an antibody molecule having a single amino acid composition. In another embodiment, the term “Fab” or “ScFv” is used as the antibody fragment specifically mentioned. 【0109】 In some embodiments, chimeric antibodies may be used in the compositions and methods provided herein. In one embodiment, the term “chimeric antibody” generally means a monoclonal antibody prepared using recombinant DNA technology, comprising at least a portion of a variable region, i.e., a binding region, derived from one species (e.g., mouse or rat), and a constant region derived from a different source or species (e.g., human). Chimeric antibodies comprising a mouse variable region and a human constant region are particularly preferred. Such a chimeric antibody is an expression product of an immunoglobulin gene comprising a DNA segment encoding an immunoglobulin variable region derived from one species and a DNA segment encoding an immunoglobulin constant region of a different species. Other forms of “chimeric antibody” as encompassed in this disclosure are chimeric antibodies in which the class or subclass is changed or altered from the class or subclass of the original antibody. Such “chimeric” antibodies are also called “class-switched antibodies.” Methods for producing chimeric antibodies include conventional recombinant DNA technology and gene transfection technology, which are currently well known in the art. For example, see Morrison, SL, et al, Proc. Natl. Acad Sci. USA 81(1984) 6851-6855; US5, 202, 238, and US5, 204, 244. 【0110】 In one embodiment, “antibody display library” means a platform(s) on which antibodies are expressed on the surface of cells or cell-free cells suitable for a screening method against a target antigen. In this specification, phage display libraries and yeast display libraries are used in their respective specifications unless otherwise specified. 【0111】 In one embodiment, the term “naive library” means a collection of nucleic acid sequences encoding a natural VH repertoire derived from a non-immunized source. 【0112】 In one embodiment, the term "VH" refers to a single heavy chain variable domain of an antibody of a type that may naturally exist in mammals lacking a light chain or part of a light chain, and naive VH can be understood as appropriate. 【0113】 In one embodiment, the term "VL" refers to a single light chain variable domain of an antibody, which exists in two types based on the constant domain sequence: Vk (kappa constant region) and Vl (lambda constant region), as appropriate. 【0114】 In one embodiment, the term "CDR" refers to the complementarity-determining region of the antibody structure. 【0115】 In one embodiment, the term "repertoire" means a collection, representing genetic diversity. 【0116】 In one embodiment, the term “framework region” is used herein to mean the nucleic acid sequence region of an antibody molecule that encodes a structural element of the molecule. 【0117】 In another embodiment, the term “vector” means DNA associated with a cloning or expression system for supplying an antibody gene to a specific restriction site. Phagemid vectors (applicable to phage display systems), yeast vectors (applicable to yeast display systems), or mammalian expression vectors (applicable to mammalian expression systems) are understood as appropriate. 【0118】 This disclosure provides antibodies and antibody fragments that bind to the CLEC2D antigen of this disclosure. 【0119】 This disclosure provides the VH domain and VL domain of an antibody or antibody fragment that binds to the CLEC2D antigen or CLEC2D epitope described herein. 【0120】 This disclosure provides sequences of CDR1, CDR2, and CDR3 of the VH domain and CDR1, CDR2, and CDR3 of the VL domain of antibodies that bind to the CLEC2D antigen or epitope of CLEC2D described herein. 【0121】 Any combination of the VH and VL sequences in this disclosure shall be deemed to be within the scope of this disclosure. Any combination of the CDR1, CDR2, and CDR3 sequences of the VH domain, or the CDR1, CDR2, and CDR3 sequences of the VL domain, shall be deemed to be within the scope of this disclosure. 【0122】 Those skilled in the art will understand that if a monoclonal antibody has the same specificity as the monoclonal antibody of this disclosure, it is possible to measure this without excessive experimentation by confirming whether the former inhibits the latter from binding to CLEC2D. If the monoclonal antibody being tested competes with the monoclonal antibody of this disclosure, as indicated by the reduced binding by the monoclonal antibody of this disclosure, it is likely that the two monoclonal antibodies will bind to the same epitope or closely related epitopes. 【0123】 Another method for determining whether a monoclonal antibody has the specificity of the monoclonal antibody of this disclosure is to pre-culture the monoclonal antibody of this disclosure with the CLEC2D protein, and if the reaction is normal, add the monoclonal antibody of test to see if its ability to bind to CLEC2D is inhibited. If the monoclonal antibody of test is inhibited, it is very likely that the monoclonal antibody has the same or functionally equivalent epitope specificity as the monoclonal antibody of this disclosure. Screening of the monoclonal antibody of this disclosure can also be performed by using CLEC2D to see if the monoclonal antibody of test is capable of neutralizing CLEC2D. 【0124】 Various methods known in the art may be used to produce polyclonal or monoclonal antibodies toward the proteins or their derivatives, fragments, analogs, homologs, or orthologues described herein. (See, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY). 【0125】 Antibodies may be purified using well-known techniques, such as affinity chromatography using protein A or protein G, which primarily yields the IgG fraction of the immunoserum. Subsequently, or alternatively, immuno-specific antibodies may be purified by immobilizing the specific antigen or epitope that is the target of the immunoglobulin being sought on a column using immunoaffinity chromatography. For example, D. Wilkinson discusses the purification of immunoglobulins (The Scientist, Vol. 14, No. 8 (April 17, 2000), pp. 25-28, published by The Scientist, Inc., Philadelphia PA). 【0126】 Monoclonal antibodies can be prepared using hybridoma methods, such as those described in Kohler and Milstein, Nature, 256:495 (1975). Hybridoma methods typically involve immunizing mice, hamsters, or other suitable host animals with an immunizing agent to induce lymphocytes that produce or are capable of producing antibodies that specifically bind to the immunizing agent. Alternatively, lymphocytes may be immunized in vitro. 【0127】 Immunotherapeutic agents generally contain protein antigens, their fragments, or fusion proteins. Generally, if human-derived cells are desired, peripheral blood lymphocytes are used, or if a non-human mammalian source is desired, spleen cells or lymph node cells are used. Next, the lymphocytes are fused with the immortalized cell line using a suitable fusion agent, such as polyethylene glycol, to form hybridoma cells (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103). The immortalized cell line is usually transformed mammalian cell, in particular myeloma cells of rodent, bovine, and human origin. Typically, rat or mouse myeloma cells are employed. The hybridoma cells may be cultured in a suitable medium which preferably contains one or more substances that inhibit the proliferation or survival of unfused immortalized cells. For example, if the parent cells lack the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT or HPRT), the culture medium for hybridomas typically contains hypoxanthine, aminopterin, and thymidine ("HAT medium"), and these substances inhibit the proliferation of HGPRT-deficient cells. 【0128】 Preferred immortalized cell lines are those that efficiently fuse, maintain stable high levels of antibody expression by selected antibody-producing cells, and are susceptible to the influence of culture media such as HAT medium. More preferred immortalized cell lines are, for example, mouse myeloma cells obtainable from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Manassas, Virginia. Human myeloma cell lines and mouse-human xenomyeloma cell lines have also been described for the production of human monoclonal antibodies. (See Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63). 【0129】 Next, the culture medium for hybridoma cells may be assayed for the presence of monoclonal antibodies targeting the antigen. Preferably, the binding specificity of the monoclonal antibodies produced by hybridoma cells is measured by immunoprecipitation or an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques and assays are well known in the art. The binding affinity of monoclonal antibodies can be measured, for example, using scatchard analysis as described in Munson and Pollard, Anal. Biochem., 107:220 (1980). Furthermore, in the therapeutic application of monoclonal antibodies, it is important to identify antibodies that have a high degree of specificity and high binding affinity to the target antigen. 【0130】 After identifying the desired hybridoma cells, the clones may be subcloned using the limiting dilution method and propagated using standard methods. (Goding, Monoclonal Antibodies: Principles and Practice, Academic) See Press, (1986) pp. 59-103). Suitable media for this purpose include, for example, Dulbecco's Modified Eagle Medium and RPMI-1640 Medium. Alternatively, hybridoma cells may be grown in vivo in mammalian ascites fluid. 【0131】 Monoclonal antibodies secreted by subclones may be isolated or purified from culture media or ascites fluid using conventional immunoglobulin purification methods, such as protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. 【0132】 Monoclonal antibodies can also be produced using recombinant DNA methods, such as the recombinant DNA method described in U.S. Patent No. 4,816,567. The DNA encoding the monoclonal antibodies of this disclosure can be easily isolated and sequenced using conventional methods (e.g., by using oligonucleotide probes that can specifically bind to the genes encoding the heavy and light chains of the mouse antibody). In some embodiments, the hybridoma cells of this disclosure serve as a source of such DNA. In some embodiments, the antibody gene sequence is isolated and cloned using the methods of this disclosure (e.g., phage library display and yeast library display), but the antibody gene sequence serves as a source of such DNA. After isolation, the DNA may be placed in an expression vector, and the expression vector may be transfected into host cells that would otherwise not produce immunoglobulin proteins, such as ape COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells, to obtain synthesis of the monoclonal antibody in recombinant host cells. DNA may also be modified, for example, by substituting the coding sequence with human heavy and light chain constant domains instead of homologous mouse sequences (see U.S. Patent No. 4,816,567; Morrison, Nature 368,812-13 (1994)), or by covalently linking all or part of the coding sequence of a non-immunoglobulin polypeptide to an immunoglobulin coding sequence. Such a non-immunoglobulin polypeptide may be substituted with the constant domain of the antibody of this disclosure, or with the variable domain of one antigen-binding site of the antibody of this disclosure, in order to produce a chimeric bivalent antibody. 【0133】 All cell lines suitable for the expression and purification of antibodies or antibody fragments are considered to be within the scope of this disclosure. In some embodiments, the cell lines are mammalian cell lines. Cell lines may be isolated or induced from any source, including humans, mice, and hamsters. Suitable cell lines include Chinese hamster ovary (CHO) cells, HEK 293 cells, HEK293T cells, BHK21 cells, NSO cells, PER.C6 cells, B cells, and HEK Examples include, but are not limited to, 293-6E cells, Sp2 / 0-Ag14 cells, and DG44 cells. In some embodiments, the cell line is a hybridoma cell line. 【0134】 The antibody may be expressed using a vector containing a DNA segment encoding the single-chain antibody described herein. 【0135】 These include vectors, liposomes, naked DNA, adjuvant-assisted DNA, gene guns, and catheters. Examples of vectors include chemical conjugates such as those described in WO93 / 64701, having a targeting moiety (e.g., a ligand for a cell surface receptor) and a nucleic acid-binding moiety (e.g., polylysine), viral vectors (e.g., DNA viral vectors or RNA viral vectors), fusion proteins such as those described in PCT / US95 / 02140 (WO95 / 22618), plasmids, and phages, which contain a targeting moiety (e.g., an antibody specific to a target cell) and a nucleic acid-binding moiety (e.g., protamine). Vectors may be chromosomal, non-chromosomal, or synthetic. 【0136】 Preferred vectors include viral vectors, fusion proteins, and chemical conjugates. A retroviral vector is Moloney's mouse leukemia virus. DNA viral vectors are preferred. These vectors include pox vectors, such as orthopox vectors or tripox vectors; herpesvirus vectors, such as herpes simplex virus type 1 (HSV) vectors (see Geller, AI et al., J. Neurochem, 64:487 (1995); Lim, F., et al., in DNA Cloning: Mammalian Systems, D. Glover, Ed. (Oxford Univ. Press, Oxford England) (1995); Geller, AI et al., Proc Natl. Acad. Sci.: USA 90:7603 (1993); Geller, AI, et al., Proc Natl. Acad. Sci USA 87:1149 (1990)); and adenovirus vectors (see LeGal LaSalle et al., Science, 259:988 (1993); Davidson, et al., Nat. Genet 3:219 (1993); Yang, et Examples include al., J. Virol. 69:2004 (1995), and adeno-associated virus vectors (see Kaplitt, MG. et al., Nat. Genet. 8:148 (1994)). 【0137】 Poxvirus vectors introduce genes into the cytoplasm of cells. Tripoxvirus vectors result in only short-term expression of nucleic acids. Adenovirus vectors, adeno-associated virus vectors, and herpes simplex virus (HSV) vectors are preferred for introducing nucleic acids into nerve cells. Adenovirus vectors result in a shorter period of expression (about 2 months) compared to adeno-associated virus (about 4 months), which is even shorter than that of HSV vectors. The specific vector to choose depends on the target cells and the symptoms to be treated. Introduction may be by standard techniques, such as infection, transfection, transduction, or transformation. Examples of gene introduction methods include, for example, naked DNA, CaPO4 precipitation, DEAE dextran, electroporation, plasma fusion, lipofection, cell microinjection, and viral vectors. 【0138】 Table 2 below shows exemplary VH amino acid sequences of the CLEC2D antibody of this disclosure. VH amino acid sequences having at least 50% identity, at least 55% identity, at least 60% identity, at least 65% identity, at least 70% identity, at least 75% identity, at least 80% identity, at least 85% identity, at least 90% identity, at least 91% identity, at least 92% identity, at least 93% identity, at least 94% identity, at least 95% identity, at least 96% identity, at least 97% identity, at least 98% identity, at least 99% identity, at least 99.5% identity, at least 99.8% identity, at least 99.9% identity, or 100% identity to the sequences listed in Table 2 are considered to be within the scope of this disclosure. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] 【0139】 The VH amino acid sequence of this disclosure may be encoded by the polynucleotides shown in Table 3 below. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18 Table 3-19 Table 3-20 Table 3-21 Table 3-22 Table 3-23 Table 3-24 Table 3-25 【0140】 Table 4 below shows exemplary VL amino acid sequences of the CLEC2D antibody of this disclosure. VL amino acid sequences having 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, at least 99.9%, or 100% identity to the sequences listed in Table 4 are considered to be within the scope of this disclosure. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] 【0141】 The VL amino acid sequences of this disclosure may be encoded by the polynucleotides shown in Table 5 below. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Table 5-12] [Table 5-13] [Table 5-14] [Table 5-15] [Table 5-16] [Table 5-17] [Table 5-18] [Table 5-19] [Table 5-20] [Table 5-21] 【0142】 An exemplary CDR amino acid sequence of the CLEC2D antibody disclosed herein is shown in Table 6 below. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] Table 6-12 Table 6-13 Table 7-1 Table 7-2 Table 7-3 Table 7-4 Table 7-5 Table 7-6 Table 7-7 Table 7-8 Table 7-9 Table 7-10 Table 7-11 Table 7-12 Table 7-13 Table 7-14 Table 7-15 Table 7-16 Table 7-17 Table 7-18 Table 7-19 Table 8-1 Table 8-2 Table 8-3 Table 8-4 Table 8-5 Table 8-6 Table 8-7 Table 8-8 Table 8-9 Table 8-10 Table 8-11 Table 8-12 Table 8-13 [Table 8-14] [Table 8-15] [Table 8-16] [Table 8-17] [Table 8-18] 【0143】 In some embodiments, the nucleotide sequences encoding the antibodies, antibody fragments, VH domains, VL domains, or CDRs of the Disclosure are wild-type sequences. In some embodiments, the nucleotide sequences are codon-optimized for expression in mammalian cells. In some embodiments, the nucleotide sequences are codon-optimized for expression in human cells. 【0144】 In some embodiments, the present invention relates to an antibody that is capable of binding to CLEC2D and blocks the interaction between CLEC2D and CD161 (Figure 1). In some embodiments, the anti-CLEC2D antibody disclosed herein is a monoclonal antibody. In some embodiments, the anti-CLEC2D antibody disclosed herein is a polyclonal antibody. 【0145】 In some embodiments, the present invention relates to an antibody that can bind to CLEC2D and eliminate CLEC2D-expressing cells by blocking the interaction between CLEC2D and CD161, thereby enabling antibody-dependent cell-mediated cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC). In some embodiments, the present invention relates to an antibody that can bind to CLEC2D and promote cytokine production and NK cell-mediated cytotoxicity by blocking the interaction between CLEC2D and CD161. 【0146】 In some embodiments, the anti-CLEC2D antibody disclosed herein is a humanized antibody. In some embodiments, the anti-CLEC2D antibody disclosed herein is human IgG1, IgG1 The anti-CLEC2D antibody is an N296A, IgG2, IgG3, or IgG4 isotype. In some embodiments, the anti-CLEC2D antibody is a mouse IgG1, IgG2a, IgG2b, or IgG3 isotype. 【0147】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises a variable heavy chain (VH) having 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, at least 99.9%, or 100% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 108. 【0148】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises a variable light chain (VL) having 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, at least 99.9%, or 100% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 217 to 324. 【0149】 In some embodiments, the anti-CLEC2D antibody disclosed herein has at least 50% identity, at least 55% identity, at least 60% identity, at least 65% identity, at least 70% identity, at least 75% identity, at least 80% identity, at least 85% identity, at least 90% identity, at least 91% identity, at least 92% identity, at least 93% identity, at least 94% identity, at least 95% identity, at least 96% identity, at least 97% identity, at least 98% identity, at least 99% identity, at least 99.5% identity, at least 99.8% identity, at least 99.9% identity, or 100% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 108. The invention comprises a variable heavy chain (VH) and a variable light chain (VL) containing an amino acid sequence that has 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, at least 99.9%, or 100% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 217-324. 【0150】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises a variable heavy chain (VH) containing an amino acid sequence encoded by a nucleic acid selected from the group consisting of SEQ ID NOs: 109 to 216. 【0151】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises a variable light chain (VL) containing an amino acid sequence encoded by a nucleic acid selected from the group consisting of SEQ ID NOs: 325 to 432. 【0152】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises a variable heavy chain (VH) containing an amino acid sequence encoded by a nucleic acid selected from the group consisting of SEQ ID NOs: 109 to 216, and a variable light chain (VL) containing an amino acid sequence encoded by a nucleic acid selected from the group consisting of SEQ ID NOs: 325 to 432. 【0153】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises a variable heavy chain (VH) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 108. 【0154】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises a variable light chain (VL) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 217 to 324. 【0155】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises a variable heavy chain (VH) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 108, and a variable light chain (VL) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 217 to 324. 【0156】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises VH, which contains the amino acid sequence described in SEQ ID NO: 44, and VL, which contains the amino acid sequence described in SEQ ID NO: 260. 【0157】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises VH, which contains the amino acid sequence described in SEQ ID NO: 45, and VL, which contains the amino acid sequence described in SEQ ID NO: 261. 【0158】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises VH, which contains the amino acid sequence described in SEQ ID NO: 42, and VL, which contains the amino acid sequence described in SEQ ID NO: 258. 【0159】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises VH, which contains the amino acid sequence described in SEQ ID NO: 1, and VL, which contains the amino acid sequence described in SEQ ID NO: 217. 【0160】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises VH, which contains the amino acid sequence described in SEQ ID NO: 73, and VL, which contains the amino acid sequence described in SEQ ID NO: 289. 【0161】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises VH, which contains the amino acid sequence described in SEQ ID NO: 21, and VL, which contains the amino acid sequence described in SEQ ID NO: 237. 【0162】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises VH, which contains the amino acid sequence described in SEQ ID NO: 35, and VL, which contains the amino acid sequence described in SEQ ID NO: 251. 【0163】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises VH, which contains the amino acid sequence described in SEQ ID NO: 58, and VL, which contains the amino acid sequence described in SEQ ID NO: 274. 【0164】 In some embodiments, the anti-CLEC2D antibody disclosed herein comprises VH, which contains the amino acid sequence described in SEQ ID NO: 7, and VL, which contains the amino acid sequence described in SEQ ID NO: 223. 【0165】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes a variable heavy chain (VH) complementarity-determining region 1 (CDR1) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 433 to 485. 【0166】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes a variable heavy chain (VH) complementarity-determining region 2 (CDR2) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 486 to 546. 【0167】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes a variable heavy chain (VH) complementarity-determining region 3 (CDR3) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 547 to 653. 【0168】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes a variable light chain (VL) complementarity-determining region 1 (CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 654 to 726. 【0169】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes a variable light chain (VL) complementarity-determining region 2 (CDR2) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 727 to 783. 【0170】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes a variable light chain (VL) complementarity-determining region 3 (CDR3) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 784 to 885. 【0171】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes a variable heavy chain (VH) complementarity determination region 1 (CDR1) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 433 to 485, a VH complementarity determination region 2 (CDR2) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 486 to 546, and a VH complementarity determination region 3 (CDR3) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 547 to 653. 【0172】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes a variable light chain (VL) complementarity determination region 1 (CDR1) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 654 to 726, a VL complementarity determination region 2 (CDR2) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 727 to 783, and a VL complementarity determination region 3 (CDR3) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 784 to 885. 【0173】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes a variable heavy chain (VH) complementarity determination region 1 (CDR1) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 433 to 485, a VH complementarity determination region 2 (CDR2) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 486 to 546, and a VH complementarity determination region 3 (CDR3) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 547 to 653; and a variable light chain (VL) complementarity determination region 1 (CDR1) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 654 to 726, a VL complementarity determination region 2 (CDR2) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 727 to 783, and a VL complementarity determination region 3 (CDR3) containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 784 to 885. 【0174】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include VH CDR1 containing the amino acid sequence described in SEQ ID NO: 439, VH CDR2 containing the amino acids described in SEQ ID NO: 492, and VH CDR3 containing the amino acid sequence described in SEQ ID NO: 589, as well as VL CDR1 containing the amino acid sequence described in SEQ ID NO: 687, VL CDR2 containing the amino acid sequence described in SEQ ID NO: 729, and VL CDR3 containing the amino acid sequence described in SEQ ID NO: 827. 【0175】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include VH CDR1 containing the amino acid sequence described in SEQ ID NO: 439, VH CDR2 containing the amino acids described in SEQ ID NO: 492, and VH CDR3 containing the amino acid sequence described in SEQ ID NO: 590, as well as VL CDR1 containing the amino acid sequence described in SEQ ID NO: 688, VL CDR2 containing the amino acid sequence described in SEQ ID NO: 755, and VL CDR3 containing the amino acid sequence described in SEQ ID NO: 828. 【0176】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include VH CDR1 containing the amino acid sequence described in SEQ ID NO: 473, VH CDR2 containing the amino acids described in SEQ ID NO: 495, and VH CDR3 containing the amino acid sequence described in SEQ ID NO: 587, as well as VL CDR1 containing the amino acid sequence described in SEQ ID NO: 655, VL CDR2 containing the amino acid sequence described in SEQ ID NO: 732, and VL CDR3 containing the amino acid sequence described in SEQ ID NO: 825. 【0177】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include VH CDR1 containing the amino acid sequence described in SEQ ID NO: 433, VH CDR2 containing the amino acids described in SEQ ID NO: 486, and VH CDR3 containing the amino acid sequence described in SEQ ID NO: 547, as well as VL CDR1 containing the amino acid sequence described in SEQ ID NO: 654, VL CDR2 containing the amino acid sequence described in SEQ ID NO: 727, and VL CDR3 containing the amino acid sequence described in SEQ ID NO: 784. 【0178】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include VH CDR1 containing the amino acid sequence described in SEQ ID NO: 439, VH CDR2 containing the amino acids described in SEQ ID NO: 492, and VH CDR3 containing the amino acid sequence described in SEQ ID NO: 618, as well as VL CDR1 containing the amino acid sequence described in SEQ ID NO: 678, VL CDR2 containing the amino acid sequence described in SEQ ID NO: 730, and VL CDR3 containing the amino acid sequence described in SEQ ID NO: 852. 【0179】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include VH CDR1 containing the amino acid sequence described in SEQ ID NO: 446, VH CDR2 containing the amino acids described in SEQ ID NO: 501, and VH CDR3 containing the amino acid sequence described in SEQ ID NO: 567, as well as VL CDR1 containing the amino acid sequence described in SEQ ID NO: 655, VL CDR2 containing the amino acid sequence described in SEQ ID NO: 735, and VL CDR3 containing the amino acid sequence described in SEQ ID NO: 804. 【0180】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include VH CDR1 containing the amino acid sequence described in SEQ ID NO: 435, VH CDR2 containing the amino acids described in SEQ ID NO: 488, and VH CDR3 containing the amino acid sequence described in SEQ ID NO: 581, as well as VL CDR1 containing the amino acid sequence described in SEQ ID NO: 680, VL CDR2 containing the amino acid sequence described in SEQ ID NO: 782, and VL CDR3 containing the amino acid sequence described in SEQ ID NO: 818. 【0181】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include VH CDR1 containing the amino acid sequence described in SEQ ID NO: 466, VH CDR2 containing the amino acids described in SEQ ID NO: 521, and VH CDR3 containing the amino acid sequence described in SEQ ID NO: 603, as well as VL CDR1 containing the amino acid sequence described in SEQ ID NO: 662, VL CDR2 containing the amino acid sequence described in SEQ ID NO: 732, and VL CDR3 containing the amino acid sequence described in SEQ ID NO: 814. 【0182】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include VH CDR1 containing the amino acid sequence described in SEQ ID NO: 439, VH CDR2 containing the amino acids described in SEQ ID NO: 492, and VH CDR3 containing the amino acid sequence described in SEQ ID NO: 553, as well as VL CDR1 containing the amino acid sequence described in SEQ ID NO: 660, VL CDR2 containing the amino acid sequence described in SEQ ID NO: 733, and VL CDR3 containing the amino acid sequence described in SEQ ID NO: 790. 【0183】 This disclosure provides an antibody library containing at least about 108 unique monoclonal antibody clones, of which at least about 80% are detectable and specifically bind to the CLEC2D antigen. Various anti-CLEC2D antibodies having specific combinations of heavy chain, light chain, heavy chain CDR1-3 (i.e., CDRH1, CDRH2, and CDRH3), and light chain CDR1-3 (i.e., CDRL1, CDRL2, and CDRL3) are listed in Table 9A. [Table 9A-1] [Table 9A-2] [Table 9A-3] [Table 9A-4] [Table 9B] [Table 9C] 【0184】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number A1 disclosed in Table 9A, and the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibody disclosed herein includes the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number A1 disclosed in Table 9A. In some embodiments, anti-CLEC2D antibody number A1 disclosed in Table 9B includes a variable heavy chain having framework region sequences of the germ cell gene families: IGHV4, IGHD3, and IGHJ2. In some embodiments, anti-CLEC2D antibody number A1 disclosed in Table 9B includes a variable light chain having framework region sequences of the germ cell families: IGKV3 and IGKJ4. 【0185】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number B1 disclosed in Table 9A, and the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibody disclosed herein includes the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number B1 disclosed in Table 9A. In some embodiments, anti-CLEC2D antibody number B1 disclosed in Table 9B includes a variable heavy chain having framework region sequences of the germ cell gene families: IGHV4, IGHD3, and IGHJ5. In some embodiments, anti-CLEC2D antibody number B1 disclosed in Table 9B includes a variable light chain having framework region sequences of the germ cell families: IGKV1 and IGKJ1. 【0186】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number C1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number C1 disclosed in Table 9A. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number C1 disclosed in Table 9A. 【0187】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number D1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number D1 disclosed in Table 9A. 【0188】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number: E1 disclosed in Table 9A, and the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibody disclosed herein includes the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number: E1 disclosed in Table 9A. In some embodiments, anti-CLEC2D antibody number: E1 disclosed in Table 9B includes a variable heavy chain having framework region sequences of the germ cell gene families: IGHV3, IGHD5, and IGHJ4. In some embodiments, anti-CLEC2D antibody number: E1 disclosed in Table 9B includes a variable light chain having framework region sequences of the germ cell families: IGKV3 and IGKJ5. 【0189】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number F1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3, and the combinations of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number F1 disclosed in Table 9A. 【0190】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number G1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number G1 disclosed in Table 9A. 【0191】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number H1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number H1 disclosed in Table 9A. 【0192】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number I1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number I1 disclosed in Table 9A. 【0193】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number J1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number J1 disclosed in Table 9A. 【0194】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number K1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number K1 disclosed in Table 9A. 【0195】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number L1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3, and the combinations of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number L1 disclosed in Table 9A. 【0196】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number M1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number M1 disclosed in Table 9A. 【0197】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number N1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number N1 disclosed in Table 9A. 【0198】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number O1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3, and the combinations of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number O1 disclosed in Table 9A. 【0199】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number P1 disclosed in Table 9A, and the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibody disclosed herein includes the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number P1 disclosed in Table 9A. In some embodiments, anti-CLEC2D antibody number P1 disclosed in Table 9B includes a variable heavy chain having framework region sequences of the germ cell gene families: IGHV1, IGHD6, and IGHJ4. In some embodiments, anti-CLEC2D antibody number P1 disclosed in Table 9B includes a variable light chain having framework region sequences of the germ cell families: IGKV3 and IGKJ5. 【0200】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number Q1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number Q1 disclosed in Table 9A. 【0201】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number R1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3, and the combinations of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number R1 disclosed in Table 9A. 【0202】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number S1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3, and the combinations of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number S1 disclosed in Table 9A. 【0203】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number T1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number T1 disclosed in Table 9A. 【0204】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number U1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibody disclosed herein includes the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number U1 disclosed in Table 9A. In some embodiments, anti-CLEC2D antibody number U1 disclosed in Table 9B includes a variable heavy chain having framework region sequences of the germ cell gene families: IGHV4, IGHD1, and IGHJ4. In some embodiments, anti-CLEC2D antibody number U1 disclosed in Table 9B includes a variable light chain having framework region sequences of the germ cell families: IGKV4 and IGKJ4. 【0205】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number V1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number V1 disclosed in Table 9A. 【0206】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number W1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number W1 disclosed in Table 9A. 【0207】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number X1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3, and the combinations of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number X1 disclosed in Table 9A. 【0208】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number: Y1 disclosed in Table 9A, and the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibody disclosed herein includes the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number: Y1 disclosed in Table 9A. In some embodiments, anti-CLEC2D antibody number: Y1 disclosed in Table 9B includes a variable heavy chain having framework region sequences of the germ cell gene families: IGHV5, IGHD5, and IGHJ4. In some embodiments, anti-CLEC2D antibody number: Y1 disclosed in Table 9B includes a variable light chain having framework region sequences of the germ cell families: IGKV3 and IGKJ4. 【0209】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number Z1 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number Z1 disclosed in Table 9A. 【0210】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number A2 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number A2 disclosed in Table 9A. 【0211】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number B2 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3, and the combinations of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number B2 disclosed in Table 9A. 【0212】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number C2 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3, and the combinations of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number C2 disclosed in Table 9A. 【0213】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number D2 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number D2 disclosed in Table 9A. 【0214】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number E2 disclosed in Table 9A, and the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibody disclosed herein includes the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number E2 disclosed in Table 9A. In some embodiments, anti-CLEC2D antibody number E2 disclosed in Table 9B includes a variable heavy chain having framework region sequences of the germ cell gene families: IGHV1, IGHD5, and IGHJ4. In some embodiments, anti-CLEC2D antibody number E2 disclosed in Table 9B includes a variable light chain having framework region sequences of the germ cell families: IGKV1 and IGKJ1. 【0215】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number F2 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number F2 disclosed in Table 9A. 【0216】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number G2 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3, and the combinations of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number G2 disclosed in Table 9A. 【0217】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number H2 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3, and the combinations of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number H2 disclosed in Table 9A. 【0218】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number I2 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibody disclosed herein includes the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number I2 disclosed in Table 9A. In some embodiments, anti-CLEC2D antibody number I2 disclosed in Table 9B includes a variable heavy chain having framework region sequences of the germ cell gene families: IGHV6, IGHD1, and IGHJ4. In some embodiments, anti-CLEC2D antibody number I2 disclosed in Table 9B includes a variable light chain having framework region sequences of the germ cell families: IGKV3 and IGKJ1. 【0219】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number J2 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number J2 disclosed in Table 9A. 【0220】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number K2 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3, and the combinations of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number K2 disclosed in Table 9A. 【0221】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number: L2 disclosed in Table 9A, and the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the light chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibody disclosed herein includes the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number: L2 disclosed in Table 9A. In some embodiments, anti-CLEC2D antibody number: L2 disclosed in Table 9B includes a variable heavy chain having framework region sequences of the germ cell gene families: IGHV4, IGHD3, and IGHJ4. In some embodiments, anti-CLEC2D antibody number: L2 disclosed in Table 9B includes a variable light chain having framework region sequences of the germ cell families: IGKV1 and IGKJ3. 【0222】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain CDR1, 2, and 3 of anti-CLEC2D antibody number M2 disclosed in Table 9A, as well as combinations of the heavy chain CDR1, 2, and 3 and light chain CDR1, 2, and 3 as described in the amino acid sequences of the heavy chain CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include combinations of the heavy chain and light chain as described in the amino acid sequences of the heavy chain and light chain of anti-CLEC2D antibody number M2 disclosed in Table 9A. 【0223】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chains CDR1, 2, and 3 of anti-CLEC2D antibody number N2 disclosed in Table 9A, as well as the combinations of the heavy chains CDR1, 2, and 3 and the light chains CDR1, 2, and 3 as described in the amino acid sequences of the heavy chains CDR1, 2, and 3. In some embodiments, the anti-CLEC2D antibodies disclosed herein include the combinations of the heavy chains and light chains as described in the amino acid sequences of the heavy chains and light chains of anti-CLEC2D antibody number N2 disclosed in Table 9A. 【0224】 In some embodiments, one or all of the anti-CLEC2D antibodies disclosed herein (for example, one or all of the antibody numbers disclosed in Tables 9A and 9B: A1, B1, E1, P1, U1, Y1, E2, I2, and L2) include a human IgG1 Fc region or backbone. In some embodiments, one or all of the anti-CLEC2D antibodies disclosed herein (for example, one or all of the antibody numbers disclosed in Tables 9A and 9B: A1, B1, E1, P1, U1, Y1, E2, I2, and L2) include a human IgG4 Fc region or backbone. In some embodiments, one or all of the anti-CLEC2D antibodies disclosed herein (e.g., one or all of the antibody numbers disclosed in Tables 9A and 9B: A1, B1, E1, P1, U1, Y1, E2, I2, and L2) include the human IgG1 N~A Fc region or backbone. In some embodiments, one or all of the anti-CLEC2D antibodies disclosed herein (e.g., one or all of the antibody numbers disclosed in Tables 9A and 9B: A1, B1, E1, P1, U1, Y1, E2, I2, and L2) include the human IgG2 Fc region or backbone. In some embodiments, one or all of the anti-CLEC2D antibodies disclosed herein (e.g., one or all of the antibody numbers disclosed in Table 9: A1, B1, E1, P1, U1, Y1, E2, I2, and L2) are afucosylated. In some embodiments, one or all of the anti-CLEC2D antibodies disclosed herein (for example, one or all of the antibody numbers disclosed in Table 9: A1, B1, E1, P1, U1, Y1, E2, I2, and L2) include an afucosylated antibody region. 【0225】 In some embodiments, one or all of the anti-CLEC2D antibodies selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A and 9B include the human IgG1 Fc region or backbone. In some embodiments, one or all of the anti-CLEC2D antibodies selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Table 9C include the human IgG4 Fc region or backbone. In some embodiments, one or all of the anti-CLEC2D antibodies selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A and 9B include the human IgG1 N~A Fc region or backbone. In some embodiments, one or all of the anti-CLEC2D antibodies selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Table 9C include a human IgG2 Fc region or main chain. 【0226】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain and light chain combinations described in the heavy chain and light chain amino acid sequences of IgG1 format anti-CLEC2D antibody number: A1 disclosed in Table 9C. 【0227】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain and light chain combinations described in the heavy chain and light chain amino acid sequences of IgG1 format anti-CLEC2D antibody number: B1 disclosed in Table 9C. 【0228】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain and light chain combinations described in the heavy chain and light chain amino acid sequences of IgG1 format anti-CLEC2D antibody number: E1 disclosed in Table 9C. 【0229】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain and light chain combinations described in the heavy chain and light chain amino acid sequences of IgG1 format anti-CLEC2D antibody number: P1 disclosed in Table 9C. 【0230】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain and light chain combinations described in the heavy chain and light chain amino acid sequences of IgG1 format anti-CLEC2D antibody number:U1 disclosed in Table 9C. 【0231】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain and light chain combinations described in the heavy chain and light chain amino acid sequences of IgG1 format anti-CLEC2D antibody number:Y1 disclosed in Table 9C. 【0232】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain and light chain combinations described in the heavy chain and light chain amino acid sequences of IgG1 format anti-CLEC2D antibody number: E2 disclosed in Table 9C. 【0233】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain and light chain combinations described in the heavy chain and light chain amino acid sequences of IgG1 format anti-CLEC2D antibody number: I2 disclosed in Table 9C. 【0234】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain and light chain combinations described in the heavy chain and light chain amino acid sequences of IgG1 format anti-CLEC2D antibody number: L2 disclosed in Table 9C. 【0235】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chain described in the amino acid sequence of the heavy chain of IgG4 format anti-CLEC2D antibody number: A1 disclosed in Table 9C. 【0236】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chain described in the amino acid sequence of the heavy chain of IgG4 format anti-CLEC2D antibody number B1 disclosed in Table 9C. 【0237】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG4 format anti-CLEC2D antibody number: E1 disclosed in Table 9C. 【0238】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG4 format anti-CLEC2D antibody number: P1 disclosed in Table 9C. 【0239】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG4 format anti-CLEC2D antibody number:U1 disclosed in Table 9C. 【0240】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chain described in the amino acid sequence of the heavy chain of IgG4 format anti-CLEC2D antibody number:Y1 disclosed in Table 9C. 【0241】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chain described in the amino acid sequence of the heavy chain of IgG4 format anti-CLEC2D antibody number: E2 disclosed in Table 9C. 【0242】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chain described in the amino acid sequence of the heavy chain of IgG4 format anti-CLEC2D antibody number: I2 disclosed in Table 9C. 【0243】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG4 format anti-CLEC2D antibody number: L2 disclosed in Table 9C. 【0244】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the IgG N2A sequence described in the heavy chain amino acid sequence of IgG4 format anti-CLEC2D antibody number: L2 disclosed in Table 9C. 【0245】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chain described in the amino acid sequence of the heavy chain of IgG2 format anti-CLEC2D antibody number A1 disclosed in Table 9C. 【0246】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chain described in the amino acid sequence of the heavy chain of IgG2 format anti-CLEC2D antibody number B1 disclosed in Table 9C. 【0247】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chain described in the amino acid sequence of the heavy chain of IgG2 format anti-CLEC2D antibody number: E1 disclosed in Table 9C. 【0248】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG2-format anti-CLEC2D antibody number: P1 disclosed in Table 9C. 【0249】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chain described in the amino acid sequence of the heavy chain of IgG2-format anti-CLEC2D antibody number U1 disclosed in Table 9C. 【0250】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chain described in the amino acid sequence of the heavy chain of IgG2-format anti-CLEC2D antibody number:Y1 disclosed in Table 9C. 【0251】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chain described in the amino acid sequence of the heavy chain of IgG2 format anti-CLEC2D antibody number: E2 disclosed in Table 9C. 【0252】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG2-format anti-CLEC2D antibody number: I2 disclosed in Table 9C. 【0253】 In some embodiments, the anti-CLEC2D antibody disclosed herein includes the heavy chain described in the amino acid sequence of the heavy chain of IgG2 format anti-CLEC2D antibody number: L2 disclosed in Table 9C. 【0254】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the IgG N2A sequence described in the heavy chain amino acid sequence of IgG2 format anti-CLEC2D antibody number: L2 disclosed in Table 9C. 【0255】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG N2A format anti-CLEC2D antibody number: A1 disclosed in Table 9C. 【0256】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG N2A format anti-CLEC2D antibody number B1 disclosed in Table 9C. 【0257】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG N2A format anti-CLEC2D antibody number: E1 disclosed in Table 9C. 【0258】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG N2A format anti-CLEC2D antibody number: P1 disclosed in Table 9C. 【0259】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG N2A format anti-CLEC2D antibody number: U1 disclosed in Table 9C. 【0260】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG N2A format anti-CLEC2D antibody number: Y1 disclosed in Table 9C. 【0261】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG N2A format anti-CLEC2D antibody number: E2 disclosed in Table 9C. 【0262】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG N2A format anti-CLEC2D antibody number: I2 disclosed in Table 9C. 【0263】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the heavy chain described in the amino acid sequence of the heavy chain of IgG N2A format anti-CLEC2D antibody number: L2 disclosed in Table 9C. 【0264】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include the IgG N2A sequence described in the heavy chain amino acid sequence of IgG N2A format anti-CLEC2D antibody number: L2 disclosed in Table 9C. 【0265】 In some embodiments, one or all of the anti-CLEC2D antibodies selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C are afucosylated. In some embodiments, one or all of the anti-CLEC2D antibodies selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C include an afucosylated antibody region. 【0266】 In some embodiments, an anti-CLEC2D antibody selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C includes a variable heavy chain sequence and a variable light chain sequence that recognize and bind to a human CLEC2D protein having an amino acid sequence described in at least one of SEQ ID NOs: 886-920 and SEQ ID NOs: 930-1003. 【0267】 In some embodiments, an anti-CLEC2D antibody selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C includes a variable heavy chain sequence and a variable light chain sequence that recognize and bind to a human CLEC2D protein having an amino acid sequence described in at least one of SEQ ID NOs: 886 to 909. In some embodiments, an anti-CLEC2D antibody or antibody fragment disclosed herein includes a variable heavy chain sequence and a variable light chain sequence that recognize and bind to a human CLEC2D protein having an amino acid sequence described in at least one of SEQ ID NOs: 930 to 1003. 【0268】 In some embodiments, anti-CLEC2D antibodies selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C include a variable heavy chain sequence and a variable light chain sequence that recognize and bind to a structural epitope of the CLEC2D antigen, and consist of amino acid sites that either overlap with and / or do not overlap with CD161 receptor interacting amino acid residues. 【0269】 In some embodiments, an anti-CLEC2D antibody selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C comprises a variable heavy chain sequence and a variable light chain sequence that inhibit, repress, or compete with another antibody that recognizes and binds to a structural epitope of the CLEC2D antigen, and consists of amino acid sites that either overlap with and / or do not overlap with CD161 receptor interacting amino acid residues. 【0270】 In some embodiments, anti-CLEC2D antibodies selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C include variable heavy chain sequences and variable light chain sequences that bind to the structural epitopes of the CLEC2D antigen, including any of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, ASN95, or any combination thereof. 【0271】 In some embodiments, anti-CLEC2D antibodies selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C include variable heavy chain sequences and variable light chain sequences that inhibit, suppress, or compete with the binding of another antibody to a structural epitope of the CLEC2D antigen, including any of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, ASN95, or any combination thereof. 【0272】 In some embodiments, the anti-CLEC2D antibody selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C is the amino acid site ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP at sequence numbers 886-920 and 930-1003. The molecule comprises a variable heavy chain sequence and a variable light chain sequence that bind to a structural epitope of the CLEC2D antigen, which includes at least one of 92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming a nonlinear scaffold for CD161 receptor interacting amino acid residues. 【0273】 In some embodiments, the anti-CLEC2D antibody selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C is the amino acid site ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP at sequence numbers 886-909 and 930-1003. The molecule comprises a variable heavy chain sequence and a variable light chain sequence that bind to a structural epitope of the CLEC2D antigen, which includes at least one of 92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming a nonlinear scaffold for CD161 receptor interacting amino acid residues. 【0274】 In some embodiments, the anti-CLEC2D antibody selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C is the amino acid site ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, TH The present invention comprises a variable heavy chain sequence and a variable light chain sequence that bind to a structural epitope of the CLEC2D antigen, which includes at least one of R93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming a nonlinear scaffold for CD161 receptor interacting amino acid residues. 【0275】 In some embodiments, the anti-CLEC2D antibody selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C is the amino acid site ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, TH at sequence numbers 886-920 and 930-1003. The invention comprises a variable heavy chain sequence and a variable light chain sequence that bind to a structural epitope of the CLEC2D antigen, which includes at least one of R93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming an allosteric and nonlinear scaffold for CD161 receptor non-interacting amino acid residues. 【0276】 In some embodiments, the anti-CLEC2D antibody selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C is the amino acid site ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, TH at sequence numbers 886-909 and 930-1003. The invention comprises a variable heavy chain sequence and a variable light chain sequence that bind to a structural epitope of the CLEC2D antigen, which includes at least one of R93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming an allosteric and nonlinear scaffold for CD161 receptor non-interacting amino acid residues. 【0277】 In some embodiments, the anti-CLEC2D antibody selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C is the amino acid site ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, L The present invention comprises a variable heavy chain sequence and a variable light chain sequence that bind to a structural epitope of the CLEC2D antigen, which includes at least one of YS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming an allosteric and nonlinear scaffold for CD161 receptor non-interacting amino acid residues. 【0278】 In some embodiments, anti-CLEC2D antibodies selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C bind to CLEC2D selected from SEQ ID NOs: 886-920 and 930-1003, with amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, and GLU1 The molecule comprises a variable heavy chain sequence and a variable light chain sequence that bind to at least one of the following: 50, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, and induce tumor killing or cytotoxicity, either alone or in combination. In some embodiments, the antibodies or antigen-binding fragments disclosed herein induce cytotoxicity in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, 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%, or at least 95% of the total number of cells treated with the antibodies or antigen-binding fragments. 【0279】 In some embodiments, anti-CLEC2D antibodies selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C bind to CLEC2D selected from SEQ ID NOs: 886-909 and 930-1003, with amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, and GLU1 The molecule comprises a variable heavy chain sequence and a variable light chain sequence that bind to at least one of the following: 50, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, and induce tumor killing or cytotoxicity, either alone or in combination. In some embodiments, the antibodies or antigen-binding fragments disclosed herein induce cytotoxicity in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, 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%, or at least 95% of the total number of cells treated with the antibodies or antigen-binding fragments. 【0280】 In some embodiments, anti-CLEC2D antibodies selected from the group consisting of antibody numbers A1, B1, E1, P1, U1, Y1, E2, I2, and L2 disclosed in Tables 9A, 9B, and 9C bind to CLEC2D selected from SEQ ID NOs: 886-890, at amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GL The present invention comprises variable heavy chain sequences and variable light chain sequences that bind to at least one of the following: N154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, and induce tumor killing or cytotoxicity, either alone or in combination. In some embodiments, the antibodies or antigen-binding fragments disclosed herein induce cytotoxicity in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, 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%, or at least 95% of the total number of cells treated with the antibodies or antigen-binding fragments. 【0281】 In some embodiments, the anti-CLEC2D antibody disclosed herein is deglycosylated. In some embodiments, the deglycosylated anti-CLEC2D antibody disclosed herein exhibits higher cytotoxicity to host cells compared to the glycosylated form of the same anti-CLEC2D antibody. In some embodiments, the anti-CLEC2D antibody disclosed herein includes N-linked glycosylation. 【0282】 In some embodiments, the anti-CLEC2D antibody disclosed herein is afucosylated. In some embodiments, the afucosylated anti-CLEC2D antibody disclosed herein exhibits higher cytotoxicity to host cells compared to the fucosylated form of the same anti-CLEC2D antibody. 【0283】 In some embodiments, the anti-CLEC2D antibody disclosed herein is sialylated. In some embodiments, the sialylated anti-CLEC2D antibody disclosed herein exhibits higher cytotoxicity to host cells compared to the non-sialylated form of the same anti-CLEC2D antibody. 【0284】 In some embodiments, the anti-CLEC2D antibodies disclosed herein are highly galactosylated. In some embodiments, the highly galactosylated anti-CLEC2D antibodies disclosed herein exhibit higher cytotoxicity to host cells compared to the non-galactosylated or low-galactosylated forms of the same anti-CLEC2D antibody. 【0285】 In some embodiments, the anti-CLEC2D antibodies disclosed herein are highly mannosylated. In some embodiments, the highly mannosylated anti-CLEC2D antibodies disclosed herein exhibit higher cytotoxicity to host cells compared to the non-galactosylated or low-mannosylated forms of the same anti-CLEC2D antibody. 【0286】 In some embodiments, the present invention disclosed herein relates to nucleic acid sequences encoding amino acid sequences of any heavy chain CDR1, 2, and 3 of the anti-CLEC2D antibodies disclosed herein. In some embodiments, the present invention disclosed herein relates to nucleic acid sequences encoding amino acid sequences of any light chain CDR1, 2, and 3 of the anti-CLEC2D antibodies disclosed herein. 【0287】 In some embodiments, the present invention disclosed herein relates to a nucleic acid sequence encoding the amino acid sequence of a variable heavy chain among the anti-CLEC2D antibodies disclosed herein. In some embodiments, the present invention disclosed herein relates to a nucleic acid sequence encoding the amino acid sequence of a light chain among the anti-CLEC2D antibodies disclosed herein. 【0288】 In some embodiments, the present invention as disclosed herein relates to nucleic acid sequences encoding amino acid sequences of any of the variable heavy chains CDR1, 2, and 3 among the anti-CLEC2D antibodies disclosed in Table 9A. In some embodiments, the present invention as disclosed herein relates to nucleic acid sequences encoding amino acid sequences of any of the variable light chains CDR1, 2, and 3 among the anti-CLEC2D antibodies disclosed in Table 9A. 【0289】 In some embodiments, the present invention disclosed herein relates to nucleic acid sequences encoding the amino acid sequence of a variable heavy chain among the anti-CLEC2D antibodies disclosed in Table 9A. In some embodiments, the present invention disclosed herein relates to nucleic acid sequences encoding the amino acid sequence of a variable light chain among the anti-CLEC2D antibodies disclosed in Table 9A. 【0290】 In some embodiments, the present invention as disclosed herein relates to nucleic acid sequences encoding amino acid sequences of any of the variable heavy chains CDR1, 2, and 3 among the anti-CLEC2D antibodies disclosed in Table 9A. 【0291】 In some embodiments, the present invention disclosed herein relates to nucleic acid sequences encoding amino acid sequences of any variable light chain CDR1, 2, and 3 among the anti-CLEC2D antibodies disclosed in Table 9A. 【0292】 In some embodiments, the present invention disclosed herein relates to nucleic acid sequences encoding the amino acid sequence of the heavy chain of an anti-CLEC2D antibody disclosed in Table 9A, having a framework region sequence of the germline family disclosed herein. In some embodiments, the present invention disclosed herein relates to nucleic acid sequences encoding the amino acid sequence of the light chain of an anti-CLEC2D antibody disclosed in Table 9A, having a framework region sequence of the germline family disclosed herein. 【0293】 In some embodiments, the anti-CLEC2D antibody or antibody fragment disclosed herein may contain a framework region sequence derived from or being derived from the human, mouse, rodent, rabbit, horse, cattle, bird, goat, pig, fish, dog, or feline framework germline family. In some embodiments, the anti-CLEC2D antibody or antibody fragment disclosed herein may contain a framework region sequence derived from or being derived from the human framework germline family. 【0294】 In some embodiments, the present invention disclosed herein relates to a vector carrying nucleic acids encoding the amino acid sequences of the anti-CLEC2D antibodies disclosed herein. In some embodiments, the present invention disclosed herein relates to a vector carrying any one or all of the nucleic acid sequences encoding the amino acid sequences of the anti-CLEC2D antibodies disclosed in Table 9A. 【0295】 In some embodiments, the present invention disclosed herein relates to host cells transfected with a vector carrying a nucleic acid encoding the amino acid sequence of the anti-CLEC2D antibody disclosed herein. In some embodiments, the present invention disclosed herein relates to host cells transfected with a vector carrying a nucleic acid sequence encoding the amino acid sequence of the anti-CLEC2D antibody disclosed in Table 9A. 【0296】 In some embodiments, the anti-CLEC2D antibody or antibody fragment disclosed herein may be conjugated to a drug, chemical, or small molecule. In some embodiments, the drug is a therapeutic agent. In some embodiments, the therapeutic agent is a chemotherapeutic agent. In some embodiments, the therapeutic agent is a cytotoxic agent or drug. In some embodiments, the therapeutic agent is a radioisotope. In some embodiments, the drug is a diagnostic agent. In some embodiments, the diagnostic agent may be, but is not limited to, a fluorescent, chemiluminescent, or radioisotope dye or drug. 【0297】 Epitope Recognition Generally, the term “epitope” refers to an area or region on an antigen to which an antibody specifically binds; that is, an “epitope” is an area or region that is in physical contact with the antibody. Protein epitopes may include amino acid residues within the antigen that are directly involved in binding to the antibody (also called the major antigenic component of the epitope), and other amino acid residues that are not directly involved in binding. In some embodiments, the term “epitope” as used herein includes both types of binding sites, any specific region in CLEC2D that specifically binds to the anti-CLEC2D antibody of this disclosure or another CLEC2D-specific substance, unless otherwise specified (for example, in some circumstances, this disclosure relates to an antibody that directly binds to a specific amino acid residue). More detailed epitope mapping of individual anti-CLEC2D antibodies can be obtained by alanine scanning. 【0298】 In some embodiments, the anti-CLEC2D antibody or antibody fragment disclosed herein includes a variable heavy chain sequence and a variable light chain sequence that recognize and bind to a human CLEC2D protein having an amino acid sequence described in at least one of SEQ ID NOs: 886-920 and 930-1003. 【0299】 In some embodiments, the anti-CLEC2D antibody or antibody fragment disclosed herein includes a variable heavy chain sequence and a variable light chain sequence that recognize and bind to a human CLEC2D protein having an amino acid sequence described in at least one of SEQ ID NOs: 886 to 909. In some embodiments, the anti-CLEC2D antibody or antibody fragment disclosed herein includes a variable heavy chain sequence and a variable light chain sequence that recognize and bind to a human CLEC2D protein having an amino acid sequence described in at least one of SEQ ID NOs: 930 to 1003. 【0300】 In some embodiments, the anti-CLEC2D antibody or antibody fragment disclosed herein comprises a variable heavy chain sequence and a variable light chain sequence that recognize and bind to a structural epitope of the CLEC2D antigen, and consists of amino acid sites that either overlap with and / or do not overlap with CD161 receptor interacting amino acid residues. 【0301】 In some embodiments, the anti-CLEC2D antibody or antibody fragment disclosed herein comprises a variable heavy chain sequence and a variable light chain sequence that inhibit, repress, or compete with another antibody that recognizes and binds to a structural epitope of the CLEC2D antigen, and consists of amino acid sites that either overlap with and / or do not overlap with CD161 receptor interacting amino acid residues. 【0302】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that bind to a structural epitope of the CLEC2D antigen, including any of the following amino acid sites: ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, ASN95, or any combination thereof. 【0303】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that inhibit, suppress, or compete with the binding of another antibody to a structural epitope of the CLEC2D antigen, including any of the following amino acid sites: ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, ASN95, or any combination thereof. 【0304】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that bind to a structural epitope of the CLEC2D antigen, which includes at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95 of SEQ ID NOs: 886-920 and 930-1003, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming a nonlinear scaffold for the CD161 receptor interacting amino acid residues. 【0305】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that bind to a structural epitope of the CLEC2D antigen, which includes at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95 of SEQ ID NOs: 886-909 and 930-1003, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming a nonlinear scaffold for the CD161 receptor-interacting amino acid residues. 【0306】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that bind to a structural epitope of the CLEC2D antigen, which includes at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95 of SEQ ID NOs: 886-890, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming a nonlinear scaffold for the CD161 receptor-interacting amino acid residues. 【0307】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that bind to a structural epitope of the CLEC2D antigen, which includes at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95 of SEQ ID NOs: 886-920 and 930-1003, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming an allosteric and nonlinear scaffold for CD161 receptor non-interacting amino acid residues. 【0308】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that bind to a structural epitope of the CLEC2D antigen, which includes at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95 of SEQ ID NOs: 886-909 and 930-1003, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming an allosteric and nonlinear scaffold for CD161 receptor non-interacting amino acid residues. 【0309】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that bind to a structural epitope of the CLEC2D antigen, which includes at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95 of SEQ ID NOs: 886-890, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming an allosteric and nonlinear scaffold for CD161 receptor non-interacting amino acid residues. 【0310】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that, upon binding to CLEC2D selected from SEQ ID NOs: 886-920 and 930-1003, bind to at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, either alone or in combination, induce tumor killing or cytotoxicity. In some embodiments, the antibodies or antigen-binding fragments disclosed herein induce cytotoxicity in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, 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%, or at least 95% of the total number of cells treated with the antibodies or antigen-binding fragments. 【0311】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that, upon binding to CLEC2D selected from SEQ ID NOs: 886-909 and 930-1003, bind to at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, either alone or in combination, induce tumor killing or cytotoxicity. In some embodiments, the antibodies or antigen-binding fragments disclosed herein induce cytotoxicity in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, 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%, or at least 95% of the total number of cells treated with the antibodies or antigen-binding fragments. 【0312】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that, upon binding to CLEC2D selected from SEQ ID NOs: 886-890, bind to at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, either alone or in combination, induce tumor killing or cytotoxicity. In some embodiments, the antibodies or antigen-binding fragments disclosed herein induce cytotoxicity in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, 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%, or at least 95% of the total number of cells treated with the antibodies or antigen-binding fragments. 【0313】 In some embodiments, the anti-CLEC2D antibodies disclosed herein are the amino acid residues in human CLEC2D of the amino acid sequences described in SEQ ID NOs: 886, 889, 894, 899, 903, 905, 906, or 907: THR178, ASN95, ARG137, GLU179, TYR177, SER98, GLU162, GRN139, ARG101, ALA160, TRP96, CYS176, GLU138, ARG175, GLY140, SER136, ASP104, ASP92, THR97, LYS94, GLU150, THR149, GLY148, GLN141, PRO142, LYS144, THR152, TRP151, A SN147, ARG153, TRP143, ILE157, CYS163, SER129, THR93, LYS181, ASP91, ARG180, SER187, LYS194, TYR165, ALA174, L EU110, ASN167, ASP168, ILE146, SER172, GLY161, SER173, LEU135, ASP130, GLN100, PHE155, GLY159, PRO156, LEU158 , GLN117, SER115, GLU114, GLN154, ASN120, PHE116, PHE102, GLN106, SER105, ASP107, LYS186, ASP109, GLN112, VAL1 It includes variable heavy chain sequences and variable light chain sequences that recognize and bind to 91, TRP145, LYS169, GLY127, PRO128, GLN83, LYS85, GLU77, GLY170, LEU119, LEU123, TRP182, SER90, ALA108, TYR88, HIS190, ILE189, ALA73, ARG84, SER78, TRP79, PRO76, PHE82, ALA171, ASP188, and CYS75. 【0314】 In some embodiments, the anti-CLEC2D antibodies disclosed herein include variable heavy chain sequences and variable light chain sequences that recognize and bind to amino acid residues ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95 in human CLEC2D, as described in SEQ ID NOs: 886, 889, 894, 899, 903, 905, 906, or 907. 【0315】 In some embodiments, the anti-CLEC2D antibody or antibody fragment disclosed herein includes variable heavy chain sequences and variable light chain sequences of SEQ ID NO: 42 and SEQ ID NO: 258 that recognize and bind to a human CLEC2D protein having an amino acid sequence described in at least one of SEQ ID NOs: 886 to 909. In some embodiments, the anti-CLEC2D antibody or antibody fragment disclosed herein includes variable heavy chain sequences and variable light chain sequences of SEQ ID NOs: 42 and SEQ ID NO: 258 that recognize and bind to a human CLEC2D protein having an amino acid sequence described in at least one of SEQ ID NOs: 921 to 909. 【0316】 In some embodiments, the anti-CLEC2D antibody or antibody fragment disclosed herein comprises a variable heavy chain sequence and a variable light chain sequence that recognize and bind to a structural epitope of the CLEC2D antigen, and consists of amino acid sites that either overlap with and / or do not overlap with CD161 receptor interacting amino acid residues. 【0317】 In some embodiments, the anti-CLEC2D antibody or antibody fragment disclosed herein comprises a variable heavy chain sequence and a variable light chain sequence that inhibit, repress, or compete with another antibody that recognizes and binds to a structural epitope of the CLEC2D antigen, and consists of amino acid sites that either overlap with and / or do not overlap with CD161 receptor interacting amino acid residues. 【0318】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that bind to a structural epitope of the CLEC2D antigen, including any of the following amino acid sites: ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, ASN95, or any combination thereof. 【0319】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that inhibit, suppress, or compete with the binding of another antibody to a structural epitope of the CLEC2D antigen, including any of the following amino acid sites: ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, ASN95, or any combination thereof. 【0320】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that bind to a structural epitope of the CLEC2D antigen, which includes at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95 of SEQ ID NOs: 886-920 and 930-1003, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming a nonlinear scaffold for the CD161 receptor interacting amino acid residues. 【0321】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that bind to a structural epitope of the CLEC2D antigen, which includes at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95 of SEQ ID NOs: 886-909 and 930-1003, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming a nonlinear scaffold for the CD161 receptor-interacting amino acid residues. 【0322】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that bind to a structural epitope of the CLEC2D antigen, which includes at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95 of SEQ ID NOs: 886-890, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming a nonlinear scaffold for the CD161 receptor-interacting amino acid residues. 【0323】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that bind to a structural epitope of the CLEC2D antigen, which includes at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95 of SEQ ID NOs: 886-920 and 930-1003, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming an allosteric and nonlinear scaffold for CD161 receptor non-interacting amino acid residues. 【0324】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that bind to a structural epitope of the CLEC2D antigen, which includes at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95 of SEQ ID NOs: 886-909 and 930-1003, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming an allosteric and nonlinear scaffold for CD161 receptor non-interacting amino acid residues. 【0325】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that bind to a structural epitope of the CLEC2D antigen, which includes at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95 of SEQ ID NOs: 886-890, thereby blocking the interaction between the CLEC2D receptor and the CD161 receptor by forming an allosteric and nonlinear scaffold for CD161 receptor non-interacting amino acid residues. 【0326】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that, upon binding to CLEC2D selected from SEQ ID NOs: 886-920 and 930-1003, bind to at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, either alone or in combination, induce tumor killing or cytotoxicity. In some embodiments, the antibodies or antigen-binding fragments disclosed herein induce cytotoxicity in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, 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%, or at least 95% of the total number of cells treated with the antibodies or antigen-binding fragments. 【0327】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that, upon binding to CLEC2D selected from SEQ ID NOs: 886-909 and 930-1003, bind to at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, either alone or in combination, induce tumor killing or cytotoxicity. In some embodiments, the antibodies or antigen-binding fragments disclosed herein induce cytotoxicity in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, 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%, or at least 95% of the total number of cells treated with the antibodies or antigen-binding fragments. 【0328】 In some embodiments, the antibodies or antigen-binding fragments disclosed herein include variable heavy chain sequences and variable light chain sequences that, upon binding to CLEC2D selected from SEQ ID NOs: 886-890, bind to at least one of the amino acid sites ARG175, TYR177, GLU179, ARG153, ARG84, HIS190, ARG101, GLU150, GLN154, THR152, GLN141, SER105, ASP107, ASP92, THR93, LYS94, LYS144, GLU138, CYS176, GLN139, ARG180, SER187, LYS181, PHE116, and ASN95, either alone or in combination, induce tumor killing or cytotoxicity. In some embodiments, the antibodies or antigen-binding fragments disclosed herein induce cytotoxicity in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, 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%, or at least 95% of the total number of cells treated with the antibodies or antigen-binding fragments. 【0329】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 42 and SEQ ID NO: 258, include variable heavy chain sequences and variable light chain sequences that recognize and bind to the amino acids ARG175-XAA176-TYR177-XAA178-GLU179, ARG153, ARG84, and HIS190. 【0330】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 44 and SEQ ID NO: 260, include variable heavy chain sequences and variable light chain sequences that recognize and bind to the amino acids ARG101, GLU150-XAA151-THR152-ARG153-GLN154, and ARG175-XAA176-TYR177-XAA178-GLU179. 【0331】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 45 and SEQ ID NO: 261, include a variable heavy chain sequence and a variable light chain sequence that recognize and bind to the amino acids GLN141, ARG101-XAA102-XAA-103-XAA104-SER105-XAA106-ASP107, and HIS190. 【0332】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 1 and SEQ ID NO: 217, include a variable heavy chain sequence and a variable light chain sequence that recognize and bind to the amino acids GRN141, ARG153, ASP92-THR93-LYS94, and HIS190. 【0333】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 58 and SEQ ID NO: 274, include a variable heavy chain sequence and a variable light chain sequence that recognize and bind to the amino acids GLU138-XAA139-XAA140-GLN141-XAA142-XAA143-LYS144 and CYS176. 【0334】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 35 and SEQ ID NO: 251, include variable heavy chain sequences and variable light chain sequences that recognize and bind to the amino acids GLU138-GLN139-XAA140-GLN141, ARG175-XAA176-TYR177-XAA178-XAA179-ARG180, and SER187. 【0335】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 21 and SEQ ID NO: 237, include a variable heavy chain sequence and a variable light chain sequence that recognize and bind to the amino acids ASP92, TYR177-XAA179-XAA180-LYS181, and THR152-ARG153-GLN154. 【0336】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 7 and SEQ ID NO: 223, include variable heavy chain sequences and variable light chain sequences that recognize and bind to the amino acids THR93-XAA94-ASN95, ARG101, GLN139, PHE116, and ARG153. 【0337】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 73 and SEQ ID NO: 289, include variable heavy chain sequences and variable light chain sequences that recognize and bind to the amino acids THR93-LYS94, ARG101, GLN141, and TYR177-XAA178-GLU179. 【0338】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 73 and SEQ ID NO: 289, are SEQ ID NO: 2561~2567 The amino acids listed below one of the following It includes a variable heavy chain sequence and a variable light chain sequence that recognize and bind to it. 【0339】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 73 and SEQ ID NO: 289, include a variable heavy chain sequence and a variable light chain sequence that recognize and bind to the amino acid described in SEQ ID NO: 2561. 【0340】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 73 and SEQ ID NO: 289, include a variable heavy chain sequence and a variable light chain sequence that recognize and bind to the amino acids described in SEQ ID NO: 2562. 【0341】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 73 and SEQ ID NO: 289, include a variable heavy chain sequence and a variable light chain sequence that recognize and bind to the amino acid described in SEQ ID NO: 2563. 【0342】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 73 and SEQ ID NO: 289, include a variable heavy chain sequence and a variable light chain sequence that recognize and bind to the amino acid described in SEQ ID NO: 2564. 【0343】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 73 and SEQ ID NO: 289, include a variable heavy chain sequence and a variable light chain sequence that recognize and bind to the amino acid described in SEQ ID NO: 2565. 【0344】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 73 and SEQ ID NO: 289, include a variable heavy chain sequence and a variable light chain sequence that recognize and bind to the amino acid described in SEQ ID NO: 2566. 【0345】 In some embodiments, the anti-CLEC2D antibodies disclosed herein, SEQ ID NO: 73 and SEQ ID NO: 289, include a variable heavy chain sequence and a variable light chain sequence that recognize and bind to the amino acid described in SEQ ID NO: 2567. 【0346】 Library screening While not limited to any particular technology, antibodies that bind to the antigens of this disclosure can be identified and characterized using the methods described below. 【0347】 This specification provides a naive antibody library as a source of therapeutic agents for treating diseases including cancer, rheumatoid arthritis, neurological disorders, infectious diseases, and metabolic disorders, or any combination thereof. Antibodies identified using the methods of this disclosure may be used as diagnostic tools, prognostic tools, for research purposes, target discovery, functional genomics, or any application using antibodies or antibody derivatives. 【0348】 In one embodiment, the term "panning" refers to affinity selection techniques for selecting a binding substance for a specific target / antigen. 【0349】 In some embodiments, a method for screening a naive antibody gene expression library involves sequentially investigating the expression profiles of a pool of gene clones by utilizing two independent scanning tools: 1) phage display technology and 2) yeast display technology (Figure 3). Using a yeast system for antibody gene expression is advantageous for the translation, processing, and proper folding of antibody products on the cell surface of eukaryotic cell proteins. Furthermore, yeast expression enables highly specific and appropriate interactions with antigenic targets. 【0350】 In some embodiments, the methods disclosed herein maintain diversity in the library, enabling the identification of specific molecules for various antigenic targets. 【0351】 In some embodiments of the methods of the present disclosure, the methods also include a strategy of moving and exploring diversity between two platforms as various recombinant antibody formats, including but not limited to chimeric antibody molecules, Fv, Fav, F(ab')2, Fab', dsFv, scFv, sc(Fv)2, scFv-CH3, scFv-Fc, ScFab, dimeric antibody fragments and trimer antibody fragments, minibodies, humanized monoclonal antibody molecules, human antibodies, bispecific antibodies, fusion proteins containing the Fc region of an antibody and any functional fragments arising from these molecules (the derivative molecules retain the immunological function of the parent antibody molecule), and all other antibody formats. 【0352】 In some embodiments, candidate antibody molecules obtained by this method are further optimized by rational design guided by structure-function testing of antibody-antigen interactions. The requirements for success in the manufacturability of monoclonal antibody drugs depend on various biological and / or correlated properties, such as solubility, aggregation, antigenicity, and stability. For example, rational, evidence-based, and more rapid structure-based drug design has been highly beneficial, particularly in the fields of cancer chemotherapy, drug-resistant infections, and neurological diseases. The results obtained by these methods are employed in this disclosure to improve the manufacturability of antibody libraries and selected molecules. 【0353】 In some embodiments, the term “isolated” refers to novel and unique molecules comprising two protein chains or fragments thereof that are not part of a biological membrane. More specifically, the isolated molecules of this disclosure are soluble and linked either directly or indirectly via a linker molecule by covalent or non-covalent bonds. Examples of such molecules include monoclonal antibodies or polyclonal antibodies, which can be readily obtained according to methods well known to those skilled in the art. 【0354】 In some embodiments, affinity tags may be incorporated into the antigens or antibodies disclosed herein for isolation or detection purposes. Affinity tags are well known in the art and are used to bind to targets and to detect or isolate targets using molecules that bind to the affinity tag. Primarily, any peptide or protein from which antibodies or other specific binding agents can be obtained can be used as affinity tags. Examples of affinity tags suitable for use include, but are not limited to, monocyte adapter protein (MONA) binding peptides, T7 binding peptides, V5 tags, streptavidin binding peptides, polyhistidine tracts, protein A (Nilsson et al., EMBO J.4:1075 (1985); Nilsson et al., Methods Enzymol. 198:3 (1991)), glutathione S transferase (Smith and Johnson, Gene 67:31 (1988)), Glu-Glu affinity tags (Grussenmeyer et al., Proc. Natl. Acad. Sci. USA 82:7952 (1985)), substance P, FLAG peptide (Hopp et al., Biotechnology 6:1204 (1988)), or other antigenic epitopes or binding domains. For general information, see Ford et al., Protein Expression and Purification 2:95 (1991). In one embodiment, the His6 tag is used in the method disclosed herein. In another embodiment, the FLAG tag is used in the method disclosed herein. In yet another embodiment, the V5 tag is used in the method and composition disclosed herein. DNA molecules encoding affinity tags are commercially available from commercial suppliers (e.g., Pharmacia Biotech, Piscataway, NJ). 【0355】 In summary, the methods described herein focus on identifying, confirming, characterizing, and developing novel monoclonal antibodies against CLEC2D antigenic targets. These novel monoclonal antibodies are being developed for use in therapeutic, diagnostic, and prognostic products applicable to a variety of diseases, including cancer. 【0356】 In some embodiments, the antibody library, which may be a naive antibody library, allows for the isolation of specific antibody molecules having desired functional properties against a particular therapeutic target, i.e., an antigen, such as the CLEC2D protein disclosed herein or any fragment thereof. 【0357】 By combining diverse libraries with appropriate and compatible display platforms, rapid selection and production of therapeutic antibodies with higher affinity and superior functionality for specific antigen molecules becomes possible. Standard screening of targeted therapeutic antibody molecules involves selecting molecules from diverse and large antibody libraries against target antigens using display platforms with smaller antibody fragments, and then constructing full-length antibody molecules for expression in mammalian cell lines. After expression, several functional assays are performed to verify the purification process. Further enhancement of the development of selected lead antibodies is achieved by optimizing parameters such as epitope identification, formulation, stability testing, and in vivo efficacy. 【0358】 In exemplary embodiments of this disclosure, a method for screening, isolating, and developing monoclonal antibodies against the CLEC2D antigen from a human naive antibody library includes the following: designing and constructing various CLEC2D antigen constructs, i.e., soluble extradomains of wild-type and mutant full-length CLEC2D proteins, using vectors appropriately optimized / customized for expression in a mammalian system, and then purifying them using affinity chromatography until homogeneous. 【0359】 In some embodiments, a library of molecules is screened by phage panning with the CLEC2D antigen for approximately 1–3 rounds. During each round, specific binding agents are selected from the library by removing unbound substances. With or without randomization of selection diversity, the selected molecule pool screened using the phage display platform is introduced into a yeast surface display platform. This avoids any PCR-based steps and thereby maintains the selected molecule pool against the CLEC2D antigen. The yeast display platform includes expressing various antibody moieties in different formats. Presentation fragments are screened against a specific antigenic target, and then specific populations showing higher affinity for the target antigen are isolated. The antigen specificity of these selected pools is further tested. Finally, individual clones are isolated, and the clonal population is used for sequencing individual antibody clones. 【0360】 Methods for phage panning against antigens are well known in the art. For example, magnetic beads may be used. Antigens may be prepared coated on magnetic Dynabeads, and a phage antibody library may be panned against the antigen-coated beads to separate phage particles expressing the desired antibody clone. 【0361】 Next, the purified DNA may be digested and ligated into a suitable yeast expression vector to produce antibodies in the desired format, such as Fab or ScFv. Antibody expression may be confirmed after transforming the yeast cells using standard methods. Antibody surface expression may be analyzed using multiple types of tags for heavy and light chains and immunohistochemistry, such as FLAG tags, c-Myc tags, and (His)6 tags, as well as V5 tags. Yeast cells expressing antibody sequences that show specific antigen binding may be isolated using flow cytometry. Flow cytometry sorting of the yeast cell population may be repeated at least 1×, at least 2×, at least 3×, at least 4×, or at least 5× to enrich antibody clones with higher affinity for the labeled antigen. 【0362】 Individual yeast clones are sequenced using standard methods in the relevant field, and then the antibody sequences are further cloned into a suitable mammalian gene expression vector. 【0363】 This disclosure provides a method for screening a highly diverse antibody gene library with antibodies that bind to the CLEC2D antigen. In some embodiments, the method includes transforming phages by inserting a library of antibody genes into phage protein genes using a vector to produce a phage library containing the highly diverse antibody gene library. The phages in the phage library present the library of antibody genes on their surface. Next, an enriched phage library is produced by panning this phage library with the CLEC2D antigen against individual phages that bind to the CLEC2D antigen, thereby enriching the antibody genes encoding antibodies that bind to the CLEC2D antigen. This panning can be carried out, for example, by conjugating the antigen onto magnetic beads, which can then be used to isolate phages that bind to the antigen on the beads. The panning step may be repeated at least once, at least twice, or more times to enrich phages expressing antibodies or antibody fragments that bind to the antigen. 【0364】 Next, the gene for the antibody or antibody fragment derived from the enriched phage library is introduced into a yeast surface display library. In some embodiments, this introduction is carried out by cloning the gene for the antibody or antibody fragment into a suitable yeast transformation vector and then transforming yeast cells using methods standard in the art. Next, yeast cells expressing the antibody or antibody fragment that binds to the CLEC2D antigen are isolated. In some embodiments, this isolation is carried out using flow cytometry to sort the yeast cells. In some embodiments, the method further includes enriching yeast cells expressing the antibody or antibody fragment that binds to the antigen by repeating the flow cytometry isolation at least 1×, at least 2×, at least 3×, at least 4×, or at least 5×, or more times. In some embodiments, the meth...

Claims

[Claim 1] A pharmaceutical composition for treating a disease, wherein the pharmaceutical composition comprises an isolated anti-CLEC2D antibody or its antigen-binding fragment, which includes a heavy chain variable domain (VH) and a light chain variable domain (VL), and the antibody or its antigen-binding fragment is a) VH containing complementarity determination regions (CDRs) 1, 486, and 547 respectively, and VL containing CDRs 1, 727, and 784 respectively, b) VH containing CDR1, CDR2, and CDR3 of sequence numbers 439, 492, and 590 respectively, and VL containing CDR1, CDR2, and CDR3 of sequence numbers 688, 755, and 828 respectively, c) VH containing CDR1, CDR2, and CDR3 of sequence numbers 439, 492, and 589 respectively, and VL containing CDR1, CDR2, and CDR3 of sequence numbers 687, 729, and 827 respectively, d) VH containing CDR1, CDR2, and CDR3 of sequence numbers 466, 521, and 603 respectively, and VL containing CDR1, CDR2, and CDR3 of sequence numbers 662, 732, and 814 respectively, or e) VH containing CDR1, CDR2, and CDR3 of sequence numbers 439, 492, and 553 respectively, and VL containing CDR1, CDR2, and CDR3 of sequence numbers 660, 733, and 790 respectively, A pharmaceutical composition intended for use in combination with an immune checkpoint inhibitor. [Claim 2] The pharmaceutical composition according to claim 1, wherein the antibody comprises the VH amino acid sequence of SEQ ID NO: 1 and the VL amino acid sequence of SEQ ID NO: 217, and is for use in combination with an immune checkpoint inhibitor. [Claim 3] The pharmaceutical composition according to claim 1, wherein the antibody comprises the VH amino acid sequence of SEQ ID NO: 45 and the VL amino acid sequence of SEQ ID NO: 261, and is for use in combination with an immune checkpoint inhibitor. [Claim 4] The pharmaceutical composition according to claim 1, wherein the antibody comprises the VH amino acid sequence of SEQ ID NO: 44 and the VL amino acid sequence of SEQ ID NO: 260, and is for use in combination with an immune checkpoint inhibitor. [Claim 5] The pharmaceutical composition according to claim 1, wherein the antibody comprises the VH amino acid sequence of SEQ ID NO: 58 and the VL amino acid sequence of SEQ ID NO: 274, and is for use in combination with an immune checkpoint inhibitor. [Claim 6] The pharmaceutical composition according to claim 1, wherein the antibody comprises the VH amino acid sequence of SEQ ID NO: 7 and the VL amino acid sequence of SEQ ID NO: 223, and is for use in combination with an immune checkpoint inhibitor. [Claim 7] The pharmaceutical composition according to any one of claims 1 to 6, wherein the immune checkpoint inhibitor is selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, TIM-3 inhibitors, and LAG-3 inhibitors. [Claim 8] The pharmaceutical composition according to claim 7, wherein the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, and semiprimab. [Claim 9] The pharmaceutical composition according to claim 7, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, and durvalumab. [Claim 10] The pharmaceutical composition according to claim 7, wherein the CTLA-4 inhibitor is ipilimumab. [Claim 11] The pharmaceutical composition according to any one of claims 1 to 6, wherein the antibody is a bispecific antibody having a first specificity for CLEC2D and a second specificity for an immune checkpoint protein, for the treatment of cancer. [Claim 12] The pharmaceutical composition according to claim 11, wherein the immune checkpoint protein is PD-1, PD-L1, CTLA-4, TIM-3, LAG-3, TIGIT, OX40, CD137, or GITR. [Claim 13] The pharmaceutical composition according to claim 11 or 12, for use in combination with a adoptive cell therapy agent comprising CAR-T cells or CAR-NK cells directed toward the second antigen. [Claim 14] The pharmaceutical composition according to any one of claims 1 to 13, wherein the disease is cancer. [Claim 15] The pharmaceutical composition according to claim 14, wherein the cancer is selected from the group consisting of non-small cell lung cancer, melanoma, breast cancer, gastric cancer, prostate cancer, renal cell carcinoma, colorectal cancer, pancreatic cancer, lymphoma, urothelial carcinoma, or head and neck squamous cell carcinoma. [Claim 16] A pharmaceutical composition according to any one of claims 1 to 15, for use in combination with at least one additional anti-cancer therapy selected from the group consisting of chemotherapeutic agents, targeted small molecules, cancer vaccines, adoptive cell therapy agents, and tumor lysis viruses. [Claim 17] The pharmaceutical composition according to claim 16, wherein the chemotherapeutic agent is selected from the group consisting of taxanes, platinum-based drugs, antimetabolites, and alkylating agents. [Claim 18] A pharmaceutical composition according to any one of claims 1 to 13, for use in combination with an immune checkpoint inhibitor for the treatment of an autoimmune disorder or inflammatory disorder. [Claim 19] The pharmaceutical composition according to claim 18, wherein the immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a TIM-3 inhibitor, or a LAG-3 inhibitor. [Claim 20] The pharmaceutical composition according to claim 18 or 19, wherein the autoimmune or inflammatory disorder is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, ankylosing spondylitis, Sjögren's syndrome, type 1 diabetes mellitus, autoimmune uveitis, and autoimmune thyroiditis. [Claim 21] A pharmaceutical composition comprising an isolated anti-CLEC2D antibody or its antigen-binding fragment comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), and an immune checkpoint inhibitor, wherein the antibody or its antigen-binding fragment a) VH containing complementarity determination regions (CDRs) 1, 486, and 547 respectively, and VL containing CDRs 1, 727, and 784 respectively, b) VH containing CDR1, CDR2, and CDR3 of sequence numbers 439, 492, and 590 respectively, and VL containing CDR1, CDR2, and CDR3 of sequence numbers 688, 755, and 828 respectively, c) VH containing CDR1, CDR2, and CDR3 of sequence numbers 439, 492, and 589 respectively, and VL containing CDR1, CDR2, and CDR3 of sequence numbers 687, 729, and 827 respectively, d) VH containing CDR1, CDR2, and CDR3 of sequence numbers 466, 521, and 603 respectively, and VL containing CDR1, CDR2, and CDR3 of sequence numbers 662, 732, and 814 respectively, or e) A pharmaceutical composition comprising VH containing CDR1, CDR2, and CDR3 of SEQ ID NOs: 439, 492, and 553, respectively, and VL containing CDR1, CDR2, and CDR3 of SEQ ID NOs: 660, 733, and 790, respectively, wherein the pharmaceutical composition is for the treatment of autoimmune disorders or inflammatory disorders.

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