Anti-Vβ17 / anti-CD123 dual-specific antibody

Abstract

Anti-Vβ17 antibodies or antigen-binding fragments thereof are described. Nucleic acids encoding the antibodies, compositions comprising the antibodies, methods of producing the antibodies, and methods of using the antibodies are also described.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 484,143, filed February 9, 2023, U.S. Provisional Patent Application No. 63 / 391,676, filed July 22, 2022, and U.S. Provisional Patent Application No. 63 / 534,373, filed August 24, 2023, the contents of which are incorporated herein by reference in their entireties.

[0002] Incorporation by Reference All publications, patents, and patent applications herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event of a conflict between a term in this specification and a term in an incorporated reference, the term in this specification shall control.

[0003] The present invention relates to monoclonal anti-Vβ17 antibodies, nucleic acids and expression vectors encoding the antibodies, recombinant cells containing the vectors, and compositions comprising the antibodies. Methods of making the antibodies and using the antibodies to kill cancer cells are also provided.

[0004] Reference to an electronically submitted sequence listing This application contains a Sequence Listing that has been submitted electronically in XML file format with the filename "PRD4260WOPCT1 Sequence Listing", a creation date of January 25, 2024, and a size of 420,374 bytes. The electronically submitted Sequence Listing is a part of the present specification and is incorporated herein by reference in its entirety. [Background technology]

[0005] Cytotoxic T cells (e.g., CD8-positive T cells) can be used to directly kill cancer cells. By finding a way to direct cytotoxic T cells to cancer cells, it can result in the killing of such cells and the inhibition of cancer cell growth. It has been demonstrated that cytotoxic T cells can be activated against cancer cells that express cancer-associated antigens by using a bispecific antibody that binds to both cytotoxic T cells and cancer cells, and by bringing the cytotoxic T cells into close proximity with the cancer cells for a long period of time. This approach to killing cancer cells has various potential problems, such as selecting T cells and cancer cell antigens that mediate T cell activation, selecting parent antibodies with sufficient affinity to mediate binding in the context of bispecific antibodies, and selecting cancer cell antigens that activate T cells to specifically act against cancer cells rather than inducing nonspecific T cell activation. These problems are only exacerbated in situations where T cells are activated to destroy cancer cells in animal subjects. Summary of the Invention

[0006] Provided herein is an antibody capable of binding to Vβ17, an antigen associated with T cells. Also provided herein is an antibody capable of binding to Vβ17 and a second antigen associated with cancer cells, the second antigen being selected from the group consisting of CD123, kallikrein-related peptidase 2 (KLK2), prostate-specific membrane antigen (PSMA), and B-cell maturation antigen (BCMA). Cytotoxic T cells express T cell receptors consisting of α and β chains, such as Vβ17. It is hypothesized that bispecific antibodies that bind to Vβ17 and cancer-associated antigens, such as CD123, KLK2, PSMA, or BMCA, can direct cytotoxic T cells to antigen-expressing cancer cells. This type of bispecific antibody can be used to recruit or redirect cytotoxic T cells to antigen-expressing cancer cells, allowing T cells to kill cancer cells.

[0007] In one aspect, the present disclosure relates to an isolated bispecific antibody, or antigen-binding fragment thereof, that binds to any one of Vβ17 and CD123; Vβ17 and KLK2; Vβ17 and PSMA; and Vβ17 and BCMA.

[0008] Provided herein is an isolated Vβ17 bispecific antibody or antigen-binding fragment thereof. The isolated Vβ17 bispecific antibody or antigen-binding fragment thereof comprises: a. a first heavy chain (HC1); and b. a second heavy chain (HC2); and c. the first light chain (LC1); d. second light chain (LC2) and Including, HC1 associates with LC1, HC2 associates with LC2, HC1 comprises a heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NO:45, SEQ ID NO:46, and SEQ ID NO:47, respectively, and LC1 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NO:60, SEQ ID NO:61, and SEQ ID NO:62, respectively, forming a binding site for a first antigen, and HC2 and LC2 form a binding site for a second antigen. In certain embodiments, the binding site for the first antigen binds to Vβ17 on the surface of CD8-positive or CD4-positive T cells. In certain embodiments, the binding site for the second antigen binds to a tumor antigen present on the surface of cancer cells. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 48, 49, and 50, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 63, 64, and 65, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 51, 52, and 53, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 66, 67, and 68, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 54, 55, and 56, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 69, KVS, and SEQ ID NO: 71, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 57, 58, and 59, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 72, 73, and 74, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 77, 78, and 79, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 92, 93, and 94, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 80, 81, and 82, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 95, 96, and 97, respectively.In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 83, 84, and 85, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 98, 99, and 100, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 86, 87, and 88, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 101, KVS, and SEQ ID NO: 103, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 89, 90, and 91, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 104, 105, and 106, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 109, 110, and 111, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 124, 125, and 126, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 112, 113, and 114, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 127, 128, and 129, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 115, 116, and 117, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 130, 131, and 132, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 118, 119, and 120, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 133, KVS, and SEQ ID NO: 135, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 121, 122, and 123, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 136, 137, and 138, respectively.In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 141, 142, and 143, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 156, 157, and 158, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 144, 145, and 146, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 159, 160, and 161, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 147, 148, and 149, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 162, 163, and 164, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 150, 151, and 152, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 165, KVS, and SEQ ID NO: 167, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 153, 154, and 155, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 168, 169, and 170, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 173, 174, and 175, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 188, 189, and 190, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 176, 177, and 178, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 191, 192, and 193, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 179, 180, and 181, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 194, 195, and 196, respectively.In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 182, 183, and 184, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 197, KVS, and SEQ ID NO: 199, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 185, 186, and 187, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 200, 201, and 202, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 205, 206, and 207, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 220, 221, and 222, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 208, 209, and 210, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 223, 224, and 225, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 211, 212, and 213, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 226, 227, and 228, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 214, 215, and 216, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 229, KVS, and SEQ ID NO: 231, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 217, 218, and 219, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 232, 233, and 234, respectively.

[0009] In certain embodiments, binding of the bispecific antibody to Vβ17 present on the surface of CD8-positive or CD4-positive T cells and to a tumor antigen present on the surface of cancer cells results in the killing of the cancer cells.

[0010] In one embodiment, the isolated Vβ17 bispecific antibody or antigen-binding fragment thereof is an isolated anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof. In one embodiment, the isolated Vβ17 bispecific antibody or antigen-binding fragment thereof is an isolated anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof. In one embodiment, the isolated Vβ17 bispecific antibody or antigen-binding fragment thereof is an isolated anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof. In one embodiment, the isolated Vβ17 bispecific antibody or antigen-binding fragment thereof is an isolated anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof. In certain embodiments, HC2 and LC2 bind to CD123. In certain embodiments, HC2 and LC2 bind to KLK2. In certain embodiments, HC2 and LC2 bind to PSMA. In certain embodiments, HC2 and LC2 bind to BCMA. In one embodiment, HC2 comprises heavy chain complementarity determining region 1 (HCDR1-2), heavy chain complementarity determining region 2 (HCDR2-2), and heavy chain complementarity determining region 3 (HCDR3-2) comprising the amino acid sequences of SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, respectively, and LC2 comprises light chain complementarity determining region 1 (LCDR1-2), light chain complementarity determining region 2 (LCDR2-2), and light chain complementarity determining region 3 (LCDR3-2) comprising the amino acid sequences of SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 237, 238, and 239, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 252, 253, and 254, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 240, 241, and 242, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 255, 256, and 257, respectively.In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 243, 244, and 245, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 258, 259, and 260, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 246, 247, and 248, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 261, AAS, and SEQ ID NO: 263, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 249, 250, and 251, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 264, 265, and 266, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 269, 270, and 271, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 284, 285, and 286, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 272, 273, and 274, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 287, 288, and 289, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 275, 276, and 277, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 290, 291, and 292, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 278, 279, and 280, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 293, DNN, and SEQ ID NO: 295, respectively.In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 281, 282, and 283, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 296, 297, and 298, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 301, 302, and 303, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 316, 317, and 318, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 304, 305, and 306, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 319, 320, and 321, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 307, 308, and 309, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 322, 323, and 324, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 310, 311, and 312, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 325, GAS, and SEQ ID NO: 327, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 313, 314, and 315, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 328, 329, and 330, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 333, 334, and 335, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 348, 349, and 350, respectively.In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 336, 337, and 338, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 351, 352, and 353, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 339, 340, and 341, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 354, 355, and 356, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 342, 343, and 344, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 357, DNN, and SEQ ID NO: 359, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 345, 346, and 347, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 360, 361, and 362, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 365, 366, and 367, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 380, 381, and 382, ​​respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 368, 369, and 370, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 383, 384, and 385, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 371, 372, and 373, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 386, 387, and 388, respectively.In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 374, 375, and 376, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 389, DNN, and SEQ ID NO: 391, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 377, 378, and 379, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 392, 393, and 394, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 397, 398, and 399, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 412, 413, and 414, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 400, 401, and 402, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 415, 416, and 417, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 403, 404, and 405, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 418, 419, and 420, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 404, 405, and 406, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 421, KAS, and SEQ ID NO: 423, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 407, 408, and 409, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 424, 425, and 426, respectively. In certain embodiments, Vβ17 is present on the surface of CD8-positive or CD4-positive T cells. In certain embodiments, CD123 is present on the surface of cancer cells.In certain embodiments, KLK2 is present on the surface of cancer cells. In certain embodiments, PSMA is present on the surface of cancer cells. In certain embodiments, BCMA is present on the surface of cancer cells.

[0011] In certain embodiments, the bispecific antibody or antigen-binding fragment thereof is an IgG isotype, for example, IgG4 or IgG1.

[0012] In certain embodiments, the bispecific antibody or antigen-binding fragment thereof has an EC50 of less than about 0.2 picomolar (pM). 50 Induce CD8- or CD4-positive T cell-dependent cytotoxicity of cancer cells in vitro.

[0013] In certain embodiments, the anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof is chimeric, partially humanized, or fully humanized.

[0014] In certain embodiments, the anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof is chimeric, partially humanized, or fully humanized.

[0015] In certain embodiments, the anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof is chimeric, partially humanized, or fully humanized.

[0016] In certain embodiments, the anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof is chimeric, partially humanized, or fully humanized.

[0017] Also provided is an isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof. In one embodiment, the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof can comprise an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 28. In a particular embodiment, the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 28. In some embodiments, the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof can comprise a heavy chain (HC) having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 429, 432, 435, 438, 441, 444, 447, and 450. In some embodiments, the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof can comprise a heavy chain (HC) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 429, 432, 435, 438, 441, 444, 447, and 450. In some embodiments, the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof can comprise a light chain (LC) having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 431, 434, 437, 439, 443, 445, 449, and 452. In some embodiments, the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof can comprise a light chain (LC) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 431, 434, 437, 439, 443, 445, 449, and 452. In some embodiments, the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof can comprise a heavy chain (HC) having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 429, 432, 435, 438, 441, 444, 447, and 450, and a light chain (LC) having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 431, 434, 437, 439, 443, 445, 449, and 452.

[0018] Also provided are isolated nucleic acids encoding the monoclonal antibodies or antigen-binding fragments thereof and bispecific antibodies or antigen-binding fragments thereof disclosed herein.

[0019] Also provided are vectors comprising isolated nucleic acids encoding the monoclonal antibodies or antigen-binding fragments thereof and bispecific antibodies or antigen-binding fragments thereof disclosed herein.

[0020] Also provided are host cells comprising vectors that include the isolated nucleic acids disclosed herein.

[0021] Also provided are methods for homing Vβ17-expressing CD8-positive or CD4-positive T cells to cancer cells. In some embodiments, the methods comprise contacting Vβ17-expressing CD8-positive or CD4-positive T cells with an anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof disclosed herein, whereby contacting the Vβ17-expressing CD8-positive or CD4-positive T cells with the anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof can homing the Vβ17-expressing CD8-positive or CD4-positive T cells to cancer cells. In some embodiments, the methods comprise contacting Vβ17-expressing CD8-positive or CD4-positive T cells with an anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof disclosed herein, whereby contacting the Vβ17-expressing CD8-positive or CD4-positive T cells with the anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof can homing the Vβ17-expressing CD8-positive or CD4-positive T cells to cancer cells. In some embodiments, the method comprises contacting Vβ17-expressing CD8-positive or CD4-positive T cells with an anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof disclosed herein, whereby contacting the Vβ17-expressing CD8-positive or CD4-positive T cells with the anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof can homing the Vβ17-expressing CD8-positive or CD4-positive T cells to cancer cells. In some embodiments, the method comprises contacting Vβ17-expressing CD8-positive or CD4-positive T cells with an anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof disclosed herein, whereby contacting the Vβ17-expressing CD8-positive or CD4-positive T cells with the anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof can homing the Vβ17-expressing CD8-positive or CD4-positive T cells to cancer cells.

[0022] Also provided is a method for inhibiting the growth or proliferation of cancer cells. The method comprises contacting cancer cells with the bispecific antibodies disclosed herein. Contacting cancer cells with the described antibodies can, for example, inhibit the growth or proliferation of cancer cells or promote T cell-mediated killing of cancer cells.

[0023] Also provided is a method for producing the bispecific antibody or antigen-binding fragment thereof disclosed herein. The method includes culturing cells containing nucleic acids encoding one heavy and light chain pair of the bispecific antibody under conditions that produce the heavy and light chains or antigen-binding fragments thereof, and recovering the heavy and light chains or antigen-binding fragments thereof of the bispecific antibody from the cells or culture. After recovering the heavy and light chains of both arms of the bispecific antibody, the heavy and light chain pairs are mixed under conditions appropriate to allow self-assembly, and then the self-assembled bispecific antibody is recovered.

[0024] Also provided are methods of producing compositions, such as buffered or purified compositions, comprising the bispecific antibodies or antigen-binding fragments disclosed herein. For example, the methods can include combining the bispecific antibody or antigen-binding fragment thereof with an acceptable buffer for storage and use of the bispecific antibody.

[0025] Kits comprising the bispecific antibodies or antigen-binding fragments thereof disclosed herein and packaging materials therefor are also provided.

[0026] Also provided are, for example, monospecific and multispecific antibodies comprising one or more CDRs or combinations of CDRs disclosed throughout.

[0027] The foregoing summary, as well as the following detailed description of preferred embodiments of the present application, will be better understood when read in conjunction with the accompanying drawings. It should be understood, however, that the application is not limited to the precise embodiments shown in the drawings. [Brief explanation of the drawings]

[0028] [Figure 1] FIG. 1 shows a schematic demonstrating anti-Vβ17 / anti-tumor antigen bispecific antibody binding to recruit T cells to cancer cells and induce cancer cell death. [Figure 2] Figure 2 shows that Vβ17+CD8+ T cells are present in healthy subjects and can be expanded in vitro when cultured with M1 peptide. Figure 2A shows FACS histograms of peripheral blood mononuclear cells (PBMCs) gated for CD8+ T cells expressing Vβ17 on the cell surface (Vβ17+) from a healthy subject. Figure 2B shows the HLA subtypes of various donors and the percentage of Vβ17+CD8+ T cells identified on day 0 and after 14 days of in vitro expansion with M1 peptide (day 14). [Figure 3] Figure 1 shows that Vβ17+CD8+ T cells have characteristics of killer cytotoxic cells. The bar graph shows the expression of CD107a, CD69, granzyme B (Gzb), and interferon-γ (IFNγ) on gated PBMCs for CD8+ T cells expressing Vβ17 on the cell surface (Vβ17+) on day 0 (without M1) and day 14 of stimulation with M1 peptide (+M1). [Figure 4] Figure 1 shows binding of VB11 [anti-Vβ17 / anti-CD123] bispecific antibody and VB13 [Vβ17 null control bispecific] antibody to CD8+ T cells. Data are presented from CD8+ T cells isolated from PBMCs from three different donors (D203517, HPU09381, and HPU08694). The table below each graph shows the EC50 values ​​for binding in nanomolar (nM). [Figure 5] Figure 1 shows the binding of Vβ17 and CD123 bispecific (VB11) and Vβ17 null control bispecific (VB13) antibodies to AML cancer cell lines. The data presented show the binding of the bispecific antibodies to the Kasumi3 AML cell line. The table below the graph shows the EC50 values ​​for binding in nM. [Figure 6]Figure 1 shows the tropism of Vβ17-positive T cells by bispecific antibodies that induce efficient killing of AML cancer cells. Data in the left graph show killing of Kasumi3 cancer cells and bispecific antibody dose titration at an effector-to-target (E:T) ratio of 0.5:1. Data in the middle graph show killing of Kasumi3 cancer cells and bispecific antibody dose titration at an E:T ratio of 1:1. Data in the right graph show killing of Kasumi3 cancer cells and bispecific antibody dose titration at an E:T ratio of 5:1. The table below the graphs shows the EC50 values ​​calculated from the graphs in picomolar (pM) units. [Figure 7] Figure 7 shows the specific binding of anti-Vβ17 / anti-CD123 bispecific antibody (VB11) and Vβ17 null bispecific antibody (VB13) to CD8-positive T cells isolated from PBMCs. Figure 7A shows FACS histograms of gated PBMCs for CD8-positive T cells expressing Vβ17 on the cell surface (Vβ17 positive) from a healthy subject (left graph, no Vβ17 depletion) and PBMCs depleted of Vβ17-positive T cells using negative selection (right graph, Vβ17 depletion). Figure 7B shows the specific binding of anti-Vβ17 / anti-CD123 bispecific antibody (VB11) and Vβ17 null bispecific antibody (VB13) to CD8-positive T cells from Figure 7A. The dose response of the bispecific antibodies is shown in the figure. The table below the graph shows the EC50 values ​​for binding calculated from the graph in nM. [Figure 8]Figure 1 shows the specific recruitment of Vβ17 T cells by a Vβ17 bispecific antibody to kill Kasumi3 cancer cells. The left panel shows the killing of Kasumi3 AML cell line when effector cells were isolated from PBMCs (untouched CD8 T cells) containing CD8 T cells expressing Vβ17 on their cell surface (Vβ17+). The inset shows the presence of 10.1% Vβ17+ CD8 T cells in the effector cell population. The right panel shows the killing of Kasumi3 AML cell line when effector CD8+ T cells were isolated from PBMCs but depleted of Vβ17+ T cells by negative selection. The inset shows the presence of a small number (0.086%) of Vβ17+ CD8+ T cells in the effector cell population. [Figure 9-1] Figure 9A shows the lack of T cell pan-activation when Vβ17 bispecific antibodies are used. Figure 9A shows a FACS plot of CD8-positive T cells gated on Vβ17-positive and Vβ17-negative. When T cells were activated with Vβ17 bispecific antibodies, CD69 expression was significantly elevated on Vβ17-positive T cells (62.5%) compared to Vβ17-negative CD8-positive T cells (1.80%). Figure 9B shows a bar graph of elevated CD69 expression on CD8-positive T cells gated on Vβ17-positive and Vβ17-negative T cells activated with Vβ17 bispecific antibodies. [Figure 9-2] Same as above [Figure 10] Figure 1 shows that Vβ17-positive T cells from HLA A2-negative donors are also effector killer cells, and pre-stimulation of Vβ17-positive cells is not required. Efficient cytotoxicity mediated by Vβ17 bispecific antibodies against Kasumi3 cancer cells is demonstrated from PBMCs containing Vβ17-positive T cells from an HLA A2-negative donor (HPU09381). [Figure 11]1 shows the VH and VL amino acid sequences of parental, LH spFv, and HL spFv versions of (1) a Vβ17 binder with the N33S mutation, and (2) a Vβ17 binder with the G34R mutation. The VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 sequences of the two Vβ17 binders are also shown. DETAILED DESCRIPTION OF THE INVENTION

[0029] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing a context for the present invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any invention disclosed or claimed.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Otherwise, certain terms used herein have the meanings described herein.

[0031] Unless otherwise specified, any numerical values, such as concentrations or concentration ranges described herein, should be understood in all instances to be modified by the term "about." Thus, numerical values ​​typically include ±10% of the recited value. For example, a concentration of 1 mg / mL includes 0.9 mg / mL to 1.1 mg / mL. Similarly, a concentration range of 1% to 10% (w / v) includes 0.9% (w / v) to 11% (w / v). As used herein, the use of numerical ranges explicitly includes all possible subranges, all individual numerical values ​​within such ranges, including integers and fractions of values ​​within such ranges, unless the context clearly indicates otherwise.

[0032] Unless otherwise indicated, the term "at least" preceding a series of elements should be understood to refer to every element of the series. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by this invention.

[0033] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0034] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," or "containing," or any other variation thereof, are understood to mean the inclusion of a stated integer or group of integers, but not the exclusion of any other integer or group of integers, and are intended to be non-exclusive or open-ended. For example, a composition, mixture, process, method, article, or device that includes a list of elements is not necessarily limited to only those elements and may include other elements not expressly listed or inherent in such composition, mixture, process, method, article, or device. Further, unless expressly stated to the contrary, "or" refers to an inclusive "or," not an exclusive "or." For example, condition A or B is satisfied by any one of the following: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist).

[0035] As used herein, the connective term "and / or" between multiple listed elements is understood to encompass both individual and combined options. For example, when two elements are joined by "and / or," the first option refers to applying the first element without the second element. The second option refers to applying the second element without the first element. The third option refers to applying the first element and the second element together. Any one of these options is understood to be within the meaning and thus meets the requirements of the term "and / or" as used herein. Applying two or more of the options together is also understood to be within the meaning and therefore meets the requirements of the term "and / or."

[0036] It should also be understood that the terms "about," "approximately," "generally," "substantially," and similar terms used herein when referring to dimensions or characteristics of components of the preferred invention indicate that the described dimensions / characteristics are not precise boundaries or parameters, but do not exclude minor variations therefrom that are functionally the same or similar, as would be understood by one of ordinary skill in the art. At a minimum, such references involving numerical parameters include variations within the least significant digit using mathematical and industrial principles accepted in the art (e.g., rounding, measurement or other systematic errors, manufacturing tolerances, etc.).

[0037] The terms "identical" or percent "identity" in the context of two or more nucleic acid or polypeptide sequences (e.g., anti-Vβ17 / anti-CD123 bispecific antibodies and the polynucleotides encoding them, Vβ17 polypeptides and the Vβ17 polynucleotides encoding them, CD123 polypeptides and the CD123 polynucleotides encoding them) refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same, when compared and aligned for maximum correspondence, as determined using one of the following sequence comparison algorithms or by visual inspection.

[0038] For sequence comparison, typically, one sequence acts as reference sequence, and test sequence is compared with it.When using sequence comparison algorithm, test sequence and reference sequence are input into computer, and if necessary, partial sequence coordinate is designated, and sequence algorithm program parameter is designated.Then, sequence comparison algorithm calculates the sequence identity percentage for test sequence with reference sequence based on designated program parameter.

[0039] Optimal alignment of sequences for comparison can be determined, for example, by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the similarity search method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computer implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by visual inspection (generally, Current Protocols in Molecular Biology, F.M. Ausubel et al., eds., Current Protocols, Greene Publishing Associates, Inc. and John This can be done by a joint venture of Wiley & Sons, Inc. (1995 Acquisition) (see Ausubel).

[0040] Examples of algorithms suitable for determining percent sequence identity and percent sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1990) J. Mol. Biol. 215: 403-410 and Altschul et al. (1997) Nucleic Acids Res. 25: 3389-3402, respectively. Software for performing BLAST analysis is publicly available through the National Center for Biotechnology Information. This algorithm involves first identifying high-scoring sequence pairs (HSPs) by identifying short words of length W in a query sequence that, when aligned with words of the same length in a database sequence, match or meet some positive threshold score T. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are then extended in both directions along each sequence for as far as the cumulative alignment score can be increased.

[0041] Cumulative scores are calculated using the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0) for nucleotide sequences. For amino acid sequences, a scoring matrix is ​​used to calculate the cumulative score. Extension of word hits in each direction is stopped when the cumulative alignment score falls by an amount X from its maximum achieved value; when the cumulative score falls below 0 due to the accumulation of one or more negative-scoring residue alignments; or when the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) of 10, M=5, N=-4, and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89:10915 (1989)).

[0042] In addition to calculating percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, for example, Karlin & Altschul, Proc. Nat'l. Acad. Sci. USA 90:5873-5787 (1993)). One measure of similarity provided by the BLAST algorithm is the minimum sum probability (P(N)), which provides an indication of the probability that a match between two nucleotide or amino acid sequences will occur by chance. For example, a nucleic acid is considered to be similar to a reference sequence when the minimum sum probability is less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001, when comparing the test nucleic acid with the reference nucleic acid.

[0043] Another indicator that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid shows immunological cross-reactivity with the polypeptide encoded by the second nucleic acid, as described below.Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, when the two peptides differ only by conservative substitutions.Another indicator that two nucleic acid sequences are substantially identical is that the two molecules hybridize with each other under stringent conditions.

[0044] antibody

[0045] Described herein are isolated anti-Vβ17 bispecific antibodies or antigen-binding fragments thereof, nucleic acids and expression vectors encoding the antibodies, recombinant cells containing the vectors, and compositions comprising the antibodies. In one aspect, the invention relates to isolated anti-Vβ17 / anti-CD123 bispecific antibodies or antigen-binding fragments thereof, nucleic acids and expression vectors encoding the antibodies, recombinant cells containing the vectors, and compositions comprising the bispecific antibodies. In one aspect, the invention relates to isolated anti-Vβ17 / anti-KLK2 bispecific antibodies or antigen-binding fragments thereof, nucleic acids and expression vectors encoding the antibodies, recombinant cells containing the vectors, and compositions comprising the bispecific antibodies. In one aspect, the invention relates to isolated anti-Vβ17 / anti-PSMA bispecific antibodies or antigen-binding fragments thereof, nucleic acids and expression vectors encoding the antibodies, recombinant cells containing the vectors, and compositions comprising the bispecific antibodies. In one aspect, the invention relates to isolated anti-Vβ17 / anti-BCMA bispecific antibodies or antigen-binding fragments thereof, nucleic acids and expression vectors encoding the antibodies, recombinant cells containing the vectors, and compositions comprising the bispecific antibodies. Methods of making the antibodies and using the antibodies to treat diseases, including cancer, are also provided herein. The antibodies disclosed herein possess one or more desirable functional properties including, but not limited to, high affinity binding to Vβ17 and / or CD123, high specificity for Vβ17 and / or CD123, high affinity binding to Vβ17 and / or KLK2, high specificity for Vβ17 and / or KLK2, high affinity binding to Vβ17 and / or PSMA, high specificity for Vβ17 and / or PSMA, high affinity binding to Vβ17 and / or BCMA, high specificity for Vβ17 and / or BCMA, and the ability to treat or prevent cancer when administered alone or in combination with other anti-cancer therapies.

[0046] As used herein, the term "antibody" is used broadly to encompass immunoglobulin or antibody molecules, including human, humanized, composite, and chimeric antibodies, as well as antibody fragments, whether monoclonal or polyclonal. Generally, antibodies are proteins or peptide chains that exhibit binding specificity to a specific antigen. The structure of antibodies is well known. Immunoglobulins can be assigned to five major classes (i.e., IgA, IgD, IgE, IgG, and IgM) depending on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subclassified into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Antibody light chains of vertebrate species can be assigned to one of two clearly distinct types, kappa and lambda, based on the amino acid sequence of their constant domains. Thus, antibodies of the present invention can contain kappa or lambda light chain constant domains. According to certain embodiments, the antibodies disclosed herein comprise heavy and / or light chain constant regions derived from murine or human antibodies. In addition to heavy and light chain constant domains, antibodies contain an antigen-binding region composed of a light chain variable region and a heavy chain variable region, each of which contains three domains (i.e., complementarity-determining regions 1-3; CDR1, CDR2, and CDR3). The light chain variable region domains are alternatively referred to as LCDR1, LCDR2, and LCDR3, and the heavy chain variable region domains are alternatively referred to as HCDR1, HCDR2, and HCDR3.

[0047] As used herein, the term "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds Vβ17 is substantially free of antibodies that do not bind Vβ17; an isolated antibody that specifically binds CD123 is substantially free of antibodies that do not bind CD123; an isolated antibody that specifically binds KLK2 is substantially free of antibodies that do not bind KLK2; an isolated antibody that specifically binds PSMA is substantially free of antibodies that do not bind PSMA; and / or an isolated antibody that specifically binds BCMA is substantially free of antibodies that do not bind BCMA). Furthermore, an isolated antibody is substantially free of other cellular material and / or chemicals.

[0048] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for minor amounts of naturally occurring mutations. The monoclonal antibodies disclosed herein can be produced by hybridoma methods, phage display technology, single lymphocyte gene cloning technology, or recombinant DNA methods. For example, monoclonal antibodies can be produced by hybridomas containing B cells obtained from transgenic non-human animals, such as transgenic mice or rats, whose genomes contain human heavy chain transgenes and light chain transgenes.

[0049] As used herein, the term "antigen-binding fragment" refers to an antibody fragment, such as, for example, a diabody, Fab, Fab', F(ab'), Fv fragment, disulfide-stabilized Fv fragment (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabody (dsdiabody), single-chain antibody molecule (scFv), single-domain antibody (sdab), scFv dimer (bivalent diabody), multispecific antibody formed from a portion of an antibody comprising one or more CDRs, camelized single-domain antibody, nanobody, domain antibody, bivalent domain antibody, or any other antibody fragment that binds to an antigen but does not comprise the complete antibody structure. An antigen-binding fragment can bind to the same antigen to which the parent antibody or parent antibody fragment binds. According to certain embodiments, the antigen-binding fragment comprises a light chain variable region, a light chain constant region, and the Fd segment of a heavy chain. According to other specific embodiments, the antigen-binding fragment comprises Fab and F(ab').

[0050] As used herein, the term "humanized antibody" refers to a non-human antibody that has been modified to increase its sequence homology with that of a human antibody, such that the antigen-binding properties of the antibody are retained but its antigenicity in humans is reduced.

[0051] As used herein, the term "multispecific antibody" refers to an antibody comprising multiple immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope. In one embodiment, the first and second epitopes do not overlap or substantially do not overlap. In one embodiment, the first and second epitopes are present on different antigens, e.g., different proteins (or different subunits of a multimeric protein). In one embodiment, the multispecific antibody comprises a third, fourth, or fifth immunoglobulin variable domain. In one embodiment, the multispecific antibody is a bispecific, trispecific, or tetraspecific antibody molecule.

[0052] As used herein, the term "bispecific antibody" refers to a multispecific antibody that binds to no more than two epitopes or no more than two antigens. A bispecific antibody is characterized by a first immunoglobulin heavy and light chain pair that has binding specificity for a first epitope (e.g., an epitope on the Vβ17 antigen) and a second immunoglobulin heavy and light chain pair that has binding specificity for a second epitope (e.g., an epitope on the CD123 antigen, an epitope on the KLK2 antigen, an epitope on the PSMA antigen, or an epitope on the BCMA antigen). In one embodiment, the first and second epitopes are present on different antigens, e.g., different proteins (or different subunits of a multimeric protein). In one embodiment, a bispecific antibody comprises heavy and light chain variable domain sequences that have binding specificity for a first epitope and heavy and light chain variable domain sequences that have binding specificity for a second epitope. In one embodiment, a bispecific antibody comprises a half antibody or fragment thereof having binding specificity for a first epitope and a half antibody or fragment thereof having binding specificity for a second epitope. In one embodiment, a bispecific antibody comprises an scFv or fragment thereof having binding specificity for a first epitope and an scFv or fragment thereof having binding specificity for a second epitope. In one embodiment, the first epitope is located on Vβ17 and the second epitope is located on CD123. In one embodiment, the first epitope is located on Vβ17 and the second epitope is located on KLK2. In one embodiment, the first epitope is located on Vβ17 and the second epitope is located on PSMA. In one embodiment, the first epitope is located on Vβ17 and the second epitope is located on BCMA. In one embodiment, the first epitope is located on Vβ17 and the second epitope is located on PD-1, PD-L1, CTLA-4, EGFR, HER-2, CD19, CD20, CD3 and / or other tumor-associated immunosuppressive factors or surface antigens.

[0053] The term "half antibody," as used herein, refers to one immunoglobulin heavy chain associated with one immunoglobulin light chain. An exemplary half antibody is set forth in SEQ ID NO: 28. Those skilled in the art will readily appreciate that half antibodies can encompass fragments thereof and can also have an antigen-binding domain consisting of a single variable domain, for example, derived from Camelidae.

[0054] As used herein, the term "Vβ17" refers to a T cell receptor expressed in response to the immune response of cytotoxic T cells. Vβ17-expressing CD8-positive T cells are generally produced in response to influenza A virus exposure in a subject. Vβ17-expressing CD8-positive T cells show an excellent memory response in response to influenza exposure in a subject. The term "Vβ17" includes any Vβ17 variant, isoform, and species homolog that can be naturally expressed by cells (including T cells) or expressed on cells transfected with a gene or cDNA encoding the polypeptide. Unless otherwise specified, preferably, Vβ17 is human Vβ17. The human Vβ17 amino acid sequence is provided by GenBank accession number AAB49730.1.

[0055] The term "CD123" refers to a molecule found on cells that helps transmit the signal of interleukin-3, a soluble cytokine important in the immune system. CD123 may also be referred to as the "interleukin-3 receptor." This receptor belongs to the type I cytokine receptor family and is a heterodimer with a unique α chain paired with a common β subunit (βc or CD131). The CD123 receptor can be found on multipotent progenitor cells, induces tyrosine phosphorylation within cells, and promotes proliferation and differentiation within hematopoietic cell lines. CD123 can also be expressed in acute myeloid leukemia (AML) subtypes. The term "CD123" includes any CD123 variants, isoforms, and species homologs that can be naturally expressed by cells (including T cells) or expressed on cells transfected with genes or cDNAs encoding these polypeptides. Unless otherwise specified, "CD123" preferably refers to human CD123. The human CD123 amino acid sequence is provided by GenBank accession number AY789109.1.

[0056] The term "KLK2" refers to kallikrein-related peptidase-2, a serine protease present in prostate tissue and semen. KLK2 can also be referred to as hK2 or human glandular kallikrein 1. KLK2 is abnormally expressed in various human cancer types, including prostate cancer. The term "KLK2" includes any KLK2 variant, isoform, and species homolog that can be naturally expressed by cells (including T cells) or expressed on cells transfected with genes or cDNAs encoding these polypeptides. Unless otherwise specified, "KLK2" is preferably human KLK2. The human KLK2 amino acid sequence is provided by accession number P20151.

[0057] The term "PSMA" refers to prostate-specific membrane antigen. PMSA is encoded by FOLH1, is highly expressed in the prostate, and is upregulated in cancerous prostate cells compared to non-cancerous prostate cells. PMSA is also a molecular target for the diagnosis and treatment of prostate cancer by positron emission tomography (PET) scanning. PSMA can also be referred to as glutamic acid carboxypeptidase II, N-acetyl-L-aspartyl-L-glutamic acid peptidase I (NAALADase I), or NAAG peptidase. The term "PSMA" includes any PSMA variant, isoform, and species homolog that can be naturally expressed by cells (including T cells) or expressed on cells transfected with genes or cDNAs encoding these polypeptides. Unless otherwise specified, "PSMA" preferably refers to human PSMA. The human KLK2 amino acid sequence is provided by accession number NP_004467.1.

[0058] The term "BCMA" refers to B-cell maturation antigen, a cell surface receptor of the tumor necrosis factor receptor family that is preferentially expressed in mature B lymphocytes. BCMA is also highly expressed in multiple myeloma. BCMA may also be referred to as BCM or tumor necrosis factor receptor superfamily member 17 (TNFRSF17). The term "BCMA" includes any BCMA variant, isoform, and species homolog that can be naturally expressed by cells (including T cells) or expressed on cells transfected with genes or cDNAs encoding these polypeptides. Unless otherwise specified, "BCMA" is preferably human PSMA. The human BCMA amino acid sequence is provided by accession number Q02223.

[0059] As used herein, an antibody that "specifically binds to Vβ17" is defined as an antibody that specifically binds to Vβ17. -7 M or less, preferably 1 × 10 -8 M or less, preferably 5×10 -9 M or less, 1×10 -9 M or less, 5×10-10 M or less, or 1 x 10 -10 "KD" refers to an antibody that binds to Vβ17, preferably human Vβ17, with a KD of M or less. The term "KD" refers to the dissociation constant, which is obtained from the ratio of Kd to Ka (i.e., Kd / Ka) and is expressed as a molar concentration (M). The KD value of an antibody can be determined using methods in the art in light of the present disclosure. For example, the KD of an antibody can be determined by using surface plasmon resonance, e.g., by using a biosensor system, e.g., a Biacore® system, or by using biolayer interferometry technology, e.g., an Octet RED96 system.

[0060] As used herein, an antibody that "specifically binds to CD123" is an antibody that specifically binds to CD123, and is present in an amount of 1×10 -7 M or less, preferably 1 × 10 -8 M or less, preferably 5×10 -9 M or less, 1×10 -9 M or less, 5×10 -10 M or less, or 1 x 10 -10 As used herein, an antibody that "specifically binds to KLK2" refers to an antibody that binds to CD123, preferably human CD123, with a KD of 1 x 10 M or less. -7 M or less, preferably 1 × 10 -8 M or less, preferably 5×10 -9 M or less, 1×10 -9 M or less, 5×10 -10 M or less, or 1 x 10 -10 As used herein, an antibody that "specifically binds to PSMA" refers to an antibody that binds to KLK2, preferably human KLK2, with a KD of 1 x 10 M or less. -7 M or less, preferably 1 × 10 -8 M or less, preferably 5×10 -9 M or less, 1×10 -9 M or less, 5×10 -10 M or less, or 1 x 10 -10 As used herein, an antibody that "specifically binds BCMA" refers to an antibody that binds to PSMA, preferably human PSMA, with a KD of 1 x 10 M or less.-7 M or less, preferably 1 × 10 -8 M or less, preferably 5×10 -9 M or less, 1×10 -9 M or less, 5×10 -10 M or less, or 1 x 10 -10 "KD" refers to an antibody that binds to BCMA, preferably human BCMA, with a KD of M or less. The term "KD" refers to the dissociation constant, which is obtained from the ratio of Kd to Ka (i.e., Kd / Ka) and is expressed as a molar concentration (M). The KD value of an antibody can be determined using methods in the art in light of the present disclosure. For example, the KD of an antibody can be determined by using surface plasmon resonance, e.g., by using a biosensor system, e.g., a Biacore® system, or by using biolayer interferometry technology, e.g., an Octet RED96 system.

[0061] The smaller the KD value of an antibody, the higher the affinity with which the antibody binds to its target antigen.

[0062] In one aspect, the present invention relates to an isolated Vβ17 bispecific antibody or antigen-binding fragment thereof, comprising: (a) a first heavy chain (HC1); (b) a second heavy chain (HC2); (c) a first light chain (LC1); and (d) a second light chain (LC2). HC1 can associate with LC1, and HC2 can associate with LC2. HC1 can comprise heavy chain complementarity-determining region 1 (HCDR1), HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NO:45, SEQ ID NO:46, and SEQ ID NO:47, respectively, and LC1 can comprise light chain complementarity-determining region 1 (LCDR1), LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NO:60, SEQ ID NO:61, and SEQ ID NO:62, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 48, 49, and 50, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 63, 64, and 65, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 51, 52, and 53, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 66, 67, and 68, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 54, 55, and 56, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 69, KVS, and SEQ ID NO: 71, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 57, 58, and 59, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 72, 73, and 74, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 77, 78, and 79, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 92, 93, and 94, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 80, 81, and 82, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 95, 96, and 97, respectively.In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 83, 84, and 85, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 98, 99, and 100, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 86, 87, and 88, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 101, KVS, and SEQ ID NO: 103, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 89, 90, and 91, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 104, 105, and 106, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 109, 110, and 111, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 124, 125, and 126, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 112, 113, and 114, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 127, 128, and 129, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 115, 116, and 117, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 130, 131, and 132, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 118, 119, and 120, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 133, KVS, and SEQ ID NO: 135, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 121, 122, and 123, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 136, 137, and 138, respectively.In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 141, 142, and 143, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 156, 157, and 158, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 144, 145, and 146, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 159, 160, and 161, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 147, 148, and 149, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 162, 163, and 164, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 150, 151, and 152, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 165, KVS, and SEQ ID NO: 167, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 153, 154, and 155, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 168, 169, and 170, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 173, 174, and 175, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 188, 189, and 190, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 176, 177, and 178, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 191, 192, and 193, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 179, 180, and 181, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 194, 195, and 196, respectively.In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 182, 183, and 184, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 197, KVS, and SEQ ID NO: 199, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 185, 186, and 187, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 200, 201, and 202, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 205, 206, and 207, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 220, 221, and 222, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 208, 209, and 210, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 223, 224, and 225, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 211, 212, and 213, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 226, 227, and 228, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 214, 215, and 216, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 229, KVS, and SEQ ID NO: 231, respectively. In one embodiment, HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 217, 218, and 219, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 232, 233, and 234, respectively.

[0063] In certain embodiments, HC1 and LC1 form a binding site for a first antigen, and HC2 and LC2 form a binding site for a second antigen. For example, the binding site for the first antigen can bind to Vβ17 on CD8-positive or CD4-positive T cells, and the binding site for the second antigen can bind to, for example, a tumor antigen present on the surface of a cancer cell. When a Vβ17 bispecific antibody binds to Vβ17 present on the surface of CD8-positive or CD4-positive T cells and a tumor antigen present on the surface of a cancer cell, it can, for example, result in the death of the cancer cell.

[0064] In one embodiment, the isolated Vβ17 bispecific antibody or antigen-binding fragment thereof is an isolated anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof. In one embodiment, it is an isolated anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof. In one embodiment, it is an isolated anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof. In one embodiment, it is an isolated anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof. In certain embodiments, HC2 and LC2 bind to CD123. In certain embodiments, HC2 and LC2 bind to KLK2. In certain embodiments, HC2 and LC2 bind to PSMA. In certain embodiments, HC2 and LC2 bind to BCMA. In one embodiment, HC2 comprises heavy chain complementarity determining region 1 (HCDR1-2), heavy chain complementarity determining region 2 (HCDR2-2), and heavy chain complementarity determining region 3 (HCDR3-2) comprising the amino acid sequences of SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, respectively, and LC2 comprises light chain complementarity determining region 1 (LCDR1-2), light chain complementarity determining region 2 (LCDR2-2), and light chain complementarity determining region 3 (LCDR3-2) comprising the amino acid sequences of SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 237, 238, and 239, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 252, 253, and 254, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 240, 241, and 242, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 255, 256, and 257, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 243, 244, and 245, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 258, 259, and 260, respectively.In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 246, 247, and 248, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 261, AAS, and SEQ ID NO: 263, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 249, 250, and 251, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 264, 265, and 266, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 269, 270, and 271, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 284, 285, and 286, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 272, 273, and 274, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 287, 288, and 289, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 275, 276, and 277, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 290, 291, and 292, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 278, 279, and 280, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 293, DNN, and SEQ ID NO: 295, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 281, 282, and 283, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 296, 297, and 298, respectively.In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 301, 302, and 303, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 316, 317, and 318, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 304, 305, and 306, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 319, 320, and 321, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 307, 308, and 309, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 322, 323, and 324, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 310, 311, and 312, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 325, GAS, and SEQ ID NO: 327, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 313, 314, and 315, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 328, 329, and 330, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 333, 334, and 335, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 348, 349, and 350, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 336, 337, and 338, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 351, 352, and 353, respectively.In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 339, 340, and 341, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 354, 355, and 356, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 342, 343, and 344, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 357, DNN, and SEQ ID NO: 359, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 345, 346, and 347, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 360, 361, and 362, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 365, 366, and 367, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 380, 381, and 382, ​​respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 368, 369, and 370, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 383, 384, and 385, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 371, 372, and 373, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 386, 387, and 388, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 374, 375, and 376, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 389, DNN, and SEQ ID NO: 391, respectively.In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 377, 378, and 379, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 392, 393, and 394, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 397, 398, and 399, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 412, 413, and 414, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 400, 401, and 402, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 415, 416, and 417, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 403, 404, and 405, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 418, 419, and 420, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 404, 405, and 406, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 421, KAS, and SEQ ID NO: 423, respectively. In one embodiment, HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 407, 408, and 409, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 424, 425, and 426, respectively. In certain embodiments, Vβ17 is present on the surface of CD8-positive or CD4-positive T cells. In certain embodiments, CD123 is present on the surface of cancer cells. In certain embodiments, KLK2 is present on the surface of cancer cells. In certain embodiments, PSMA is present on the surface of cancer cells. In certain embodiments, BCMA is present on the surface of cancer cells.

[0065] In certain embodiments, Vβ17 is present on the surface of CD8-positive or CD4-positive T cells. In certain embodiments, CD123 is present on the surface of cancer cells (e.g., leukemia cells).

[0066] In some embodiments, the bispecific antibodies disclosed herein can take the form of diabodies, crossbodies, or bispecific antibodies obtained via controlled Fab arm exchange as described herein.

[0067] In some embodiments, bispecific antibodies include IgG-like molecules with complementary CH3 domains that promote heterodimerization; recombinant IgG-like dual-targeting molecules, in which the two halves of the molecule each contain an Fab fragment or portion of an Fab fragment of at least two different antibodies; IgG fusion molecules, in which a full-length IgG antibody is fused to an extra Fab fragment or portion of an Fab fragment; Fc fusion molecules, in which a single-chain Fv molecule or stabilized diabody is fused to a heavy-chain constant domain, Fc region, or portion thereof; Fab fusion molecules, in which different Fab fragments are fused together; ScFv- and diabody-based heavy-chain antibodies (e.g., domain antibodies, nanobodies), in which different single-chain Fv molecules or different diabodies or different heavy-chain antibodies (e.g., domain antibodies, nanobodies) are fused to each other or to another protein or carrier molecule.

[0068] In some embodiments, IgG-like molecules with complementary CH3 domain molecules include Triomab / Quadroma (Trion Pharma / Fresenius Biotech), Knobs-into-Holes (Genentech), CrossMAbs (Roche) and electrostatically matched molecules (Amgen), LUZ-Y (Genentech), Strand Exchange Engineered Domain body (SEEDbody) (EMD Serono), Biclonic (Merus), and DuoBody (Genmab A / S).

[0069] In some embodiments, recombinant IgG-like dual targeting molecules include Dual Targeting (DT)-Ig (GSK / Domantis), Two-in-one Antibody (Genentech), Cross-linked Mab (Karmanos Cancer Center), mAb2 (F-Star), and CovX-body (CovX / Pfizer).

[0070] In some embodiments, IgG fusion molecules include Dual Variable Domain (DVD)-Ig (Abbott), IgG-like Bispecific (InnClone / Eli Lilly), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche).

[0071] In some embodiments, Fc fusion molecules can include ScFv / Fc Fusion (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS), Dual Affinity Retargeting Technology (Fc-DART) (MacroGenics), and Dual(ScFv)2-Fab (National Research Center for Antibody Medicine-China).

[0072] In some embodiments, Fab-fused bispecific antibodies include F(ab)2 (Medarex / AMGEN), Dual-Action or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), Bivalent Bispecific (Biotecnol), and Fab-Fv (UCB-Celltech). ScFv, diabody-based, and domain antibodies include, but are not limited to, Bispecific T Cell Engager (BiTE) (Micromet), Tandem Diabody (Tandab) (Affimed), Dual Affinity Retargeting Technology (DART) (MacroGenics), Single-chain Diabody (Academic), TCR-like antibody (AIT, ReceptorLogics), Human Serum Albumin ScFv Fusion (Merrimack) and COMBODY (Epigen Biotech), dual-targeting nanobodies (Ablynx), and dual-targeting heavy chain-only domain antibodies.

[0073] The full-length bispecific antibodies disclosed herein can be generated, for example, by using Fab arm exchange (or half molecule exchange) between two monospecific bivalent antibodies, introducing substitutions into the heavy chain CH3 interface in each half molecule to support heterodimerization of two antibody half molecules with distinct specificities in a cell-free environment in vitro or using coexpression. The Fab arm exchange reaction is the result of disulfide bond isomerization and dissociation-association of the CH3 domains. The heavy chain disulfide bonds in the hinge region of the parent monospecific antibodies are reduced. A free cysteine ​​from one of the parent monospecific antibodies forms an inter-heavy chain disulfide bond with a cysteine ​​residue in the second parent monospecific antibody molecule, while the CH3 domain of the parent antibody is released and reformed by dissociation-association. The CH3 domain of the Fab arm can be engineered to favor heterodimerization over homodimerization. The resulting product is a bispecific antibody with two Fab arms or half molecules, each binding to a different epitope, ie, an epitope on Vβ17 and an epitope on a tumor antigen.

[0074] "Homodimerization," as used herein, refers to the interaction of two heavy chains with identical CH3 amino acid sequences. "Homodimer," as used herein, refers to an antibody having two heavy chains with identical CH3 amino acid sequences.

[0075] "Heterodimerization," as used herein, refers to the interaction of two heavy chains with non-identical CH3 amino acid sequences. "Heterodimer," as used herein, refers to an antibody having two heavy chains with non-identical CH3 amino acid sequences.

[0076] A "knob-in-hole" strategy (see, e.g., PCT International Publication No. 2006 / 028936) can be used to produce full-length bispecific antibodies. Briefly, selected amino acids that form the interface of the CH3 domain in human IgG can be mutated at positions that affect CH3 domain interactions to promote heterodimer formation. An amino acid with a small side chain (hole) is introduced into the heavy chain of an antibody that specifically binds to a first antigen, and an amino acid with a large side chain (knob) is introduced into the heavy chain of an antibody that specifically binds to a second antigen. After co-expression of the two antibodies, a heterodimer is formed as a result of preferential interaction between the heavy chain with the "hole" and the heavy chain with the "knob." Exemplary CH3 substitution pairs that form knobs and holes are (expressed as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V.

[0077] Other strategies can be used, such as promoting heavy chain heterodimerization using electrostatic interactions by substituting positively charged residues on one CH3 surface and negatively charged residues on the second CH3 surface, as described in U.S. Patent Application Publication Nos. 2010 / 0015133; 2009 / 0182127; 2010 / 028637; or 2011 / 0123532. In other strategies, heterodimerization can be achieved using the following substitutions (expressed as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): L351Y_F405AY407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V K409F, as described in U.S. Patent Application Publication No. 2012 / 0149876 or U.S. Patent Application Publication No. 2013 / 0195849. It can be promoted by Y407A / T366A_K409F, or T350V_L351Y_F405A Y407V / T350V_T366L_K392L_T394W.

[0078] In addition to the above methods, the bispecific antibodies disclosed herein can be produced in vitro in a cell-free environment by introducing asymmetric mutations into the CH3 regions of two monospecific homodimeric antibodies and forming a bispecific heterodimeric antibody from the two parent monospecific homodimeric antibodies under reducing conditions that allow disulfide bond isomerization, according to the method described in WO 2011 / 131746. In this method, a first monospecific bivalent antibody (e.g., an anti-CD33 antibody) and a second monospecific bivalent antibody (e.g., an anti-CD3 antibody) are engineered to have specific substitutions in the CH3 domains that promote heterodimer stability, and the antibodies are incubated together under reducing conditions sufficient to allow cysteines in the hinge regions to undergo disulfide bond isomerization, thereby producing a bispecific antibody by Fab arm exchange. The incubation conditions can optionally be returned to non-reducing conditions. Exemplary reducing agents that can be used include 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine, and β-mercaptoethanol. Preferably, the reducing agent is selected from the group consisting of 2-mercaptoethylamine, dithiothreitol, and tris(2-carboxyethyl)phosphine. For example, incubation in the presence of at least 25 mM 2-MEA or at least 0.5 mM dithiothreitol, at a pH of 5-8, e.g., pH 7.0 or 7.4, at a temperature of at least 20°C, for at least 90 minutes can be used.

[0079] In certain embodiments, the anti-Vβ17 bispecific antibody or antigen-binding fragment thereof a. heavy chain 1 (HC1) having the amino acid sequence of SEQ ID NO: 429, heavy chain 2 (HC2) having the amino acid sequence of SEQ ID NO: 430, and light chain 2 (LC2) having the amino acid sequence of SEQ ID NO: 431, or b. HC1, HC2, and LC2 having the amino acid sequences of SEQ ID NOs: 432, 433, and 434, respectively; or c. HC1, HC2, and LC2 having the amino acid sequences of SEQ ID NOs: 435, 436, and 437, respectively; or d. HC1, light chain 1 (LC1), and HC2 having the amino acid sequences of SEQ ID NOs: 438, 439, and 440, respectively; or e. HC1, HC2, and LC2 having the amino acid sequences of SEQ ID NOs: 441, 442, and 443, respectively; or f. HC1, LC1, and HC2 having the amino acid sequences of SEQ ID NOs: 444, 445, and 446, respectively; or g. HC1, HC2, and LC2 having the amino acid sequences of SEQ ID NOs: 447, 448, and 449, respectively; or These include HC1, HC2, and LC2, which have the amino acid sequences of SEQ ID NOs: 450, 451, and 452, respectively.

[0080] In another specific aspect, the present invention relates to an isolated anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof that induces antibody-dependent cell-mediated cytotoxicity (ADCC). The anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof can induce ADCC, for example, in vitro. The bispecific antibody or antigen-binding fragment thereof has an EC 50 In certain embodiments, ADCC can be induced by EC 50is less than about 1 pM, less than about 0.9 pM, less than about 0.8 pM, less than about 0.7 pM, less than about 0.6 pM, less than about 0.5 pM, less than about 0.4 pM, less than about 0.300 pM, less than about 0.2 pM, less than about 0.19 pM, less than about 0.18 pM, less than about 0.17 pM, less than about 0.16 pM, less than about 0.15 pM, less than about 0.14 pM

[0023] The antibody has an IgG1, IgG2, IgG3, or IgG4 backbone. In one such embodiment, the anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof has an antibody backbone of the IgG4 isotype. In another such embodiment, the anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof has an antibody backbone of the IgG1 isotype.

[0081] In another specific aspect, the present invention relates to an isolated anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof that induces antibody-dependent cell-mediated cytotoxicity (ADCC). The anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof can induce ADCC, for example, in vitro. The bispecific antibody or antigen-binding fragment thereof has an EC 50 In certain embodiments, ADCC can be induced by EC 50is less than about 1 pM, less than about 0.9 pM, less than about 0.8 pM, less than about 0.7 pM, less than about 0.6 pM, less than about 0.5 pM, less than about 0.4 pM, less than about 0.300 pM, less than about 0.2 pM, less than about 0.19 pM, less than about 0.18 pM, less than about 0.17 pM, less than about 0.16 pM, less than about 0.15 pM, less than about 0.14 pM

[0023] The antibody has an IgG1, IgG2, IgG3, or IgG4 backbone. In one such embodiment, the anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof has an IgG4 isotype backbone. In another such embodiment, the anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof has an IgG1 isotype backbone.

[0082] In another specific aspect, the present invention relates to an isolated anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof that induces antibody-dependent cell-mediated cytotoxicity (ADCC). The anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof can induce ADCC, for example, in vitro. The bispecific antibody or antigen-binding fragment thereof has an EC 50 In certain embodiments, ADCC can be induced by EC 50is less than about 1 pM, less than about 0.9 pM, less than about 0.8 pM, less than about 0.7 pM, less than about 0.6 pM, less than about 0.5 pM, less than about 0.4 pM, less than about 0.300 pM, less than about 0.2 pM, less than about 0.19 pM, less than about 0.18 pM, less than about 0.17 pM, less than about 0.16 pM, less than about 0.15 pM, less than about 0.14 pM

[0023] The antibody has an IgG1, IgG2, IgG3, or IgG4 backbone. In one such embodiment, the anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof has an IgG4 isotype backbone. In another such embodiment, the anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof has an IgG1 isotype backbone.

[0083] In another specific aspect, the present invention relates to an isolated anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof that induces antibody-dependent cell-mediated cytotoxicity (ADCC). The anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof can induce ADCC, for example, in vitro. The bispecific antibody or antigen-binding fragment thereof has an EC 50 In certain embodiments, ADCC can be induced by EC 50is less than about 1 pM, less than about 0.9 pM, less than about 0.8 pM, less than about 0.7 pM, less than about 0.6 pM, less than about 0.5 pM, less than about 0.4 pM, less than about 0.300 pM, less than about 0.2 pM, less than about 0.19 pM, less than about 0.18 pM, less than about 0.17 pM, less than about 0.16 pM, less than about 0.15 pM, less than about 0.14 pM

[0023] The antibody has an IgG1 / IgG2 backbone of about 0.01 pM, about 0.13 pM, about 0.12 pM, about 0.11 pM, about 0.1 pM, about 0.09 pM, about 0.08 pM, about 0.07 pM, about 0.06 pM, about 0.05 pM, about 0.04 pM, about 0.03 pM, about 0.02 pM, or about 0.01 pM. In certain embodiments, the anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof comprises an IgG1, IgG2, IgG3, or IgG4 backbone. In one such embodiment, the anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof has an antibody backbone of the IgG4 isotype. In another such embodiment, the anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof has an antibody backbone of the IgG1 isotype.

[0084] In some embodiments described herein, the immune effector properties of the anti-Vβ17 / anti-CD123 bispecific antibodies provided herein, the anti-Vβ17 / anti-KLK2 bispecific antibodies provided herein, the anti-Vβ17 / anti-PSMA bispecific antibodies provided herein, and / or the anti-Vβ17 / anti-BCMA bispecific antibodies provided herein can be enhanced or silenced through Fc modification by techniques known to those skilled in the art. For example, Fc effector functions such as C1q binding, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and downregulation of cell surface receptors (e.g., B cell receptors; BCRs) can be provided and / or controlled by modifying residues in the Fc involved in these activities.

[0085] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a cell-mediated reaction in which nonspecific cytotoxic cells that express Fc receptors (FcRs) (e.g., natural killer (NK) cells, neutrophils, and macrophages) recognize bound antibody on target cells and subsequently cause lysis of the target cells.

[0086] The ability of antibodies to induce ADCC can be enhanced by engineering their oligosaccharide components. Human IgG1 or IgG3 is N-glycosylated at Asn297, with the majority of glycans being of the well-known biantennary G0, G0F, G1, G1F, G2, or G2F forms. Antibodies produced by unengineered CHO cells typically have a glycan fucose content of at least about 85%. Removal of core fucose from biantennary complex oligosaccharides attached to the Fc region enhances the ADCC of antibodies through improved FcγRIIIa binding without altering antigen binding or CDC activity. These Abs have been used in a variety of applications, including controlling culture osmolarity (Konno et al., Cytotechnology 64:249-65, 2012), using the variant CHO cell line Lec13 as a host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), using the variant CHO cell line EB66 as a host cell line (Olivier et al., MAbs; 2(4), 2010; Epub ahead of publication; PMID:20562582), using the rat hybridoma cell line YB2 / 0 as a host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, 2003), and introducing small interfering RNA specific for the α-1,6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng 88:901-908, It has been reported that relatively highly defucosylated antibodies with biantennary complex Fc oligosaccharides can be expressed using different methods, such as co-expression of β-1,4-N-acetylglucosaminyltransferase III and Golgi α-mannosidase II or the potent α-mannosidase I inhibitor kifunensin (Ferrara et al., J Biol Chem 281:5032-5036, 2006; Ferrara et al., Biotechnol Bioeng 93:851-861, 2006; Xhou et al., Biotechnol Bioeng 99:652-65, 2008).

[0087] In some embodiments described herein, the ADCC elicited by the anti-Vβ17 / anti-CD123 bispecific antibodies provided herein, the anti-Vβ17 / anti-KLK2 bispecific antibodies provided herein, the anti-Vβ17 / anti-PSMA bispecific antibodies provided herein, and / or the anti-Vβ17 / anti-BCMA bispecific antibodies provided herein can also be enhanced by certain substitutions in the antibody Fc. Exemplary substitutions include substitutions at amino acid positions 256, 290, 298, 312, 356, 330, 333, 334, 360, 378, or 430 (residue numbering according to the EU index), as described, for example, in U.S. Patent No. 6,737,056.

[0088] In another particular aspect, the present invention relates to an isolated anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof capable of inducing T cell-dependent cytotoxicity in Vβ17-expressing cells and / or CD123-expressing cells. The bispecific antibody or antigen-binding fragment thereof has, for example, an EC 50 In certain embodiments, EC 50 is less than about 2.0 nM, less than about 1.9 nM, less than about 1.8 nM, less than about 1.7 nM, less than about 1.6 nM, less than about 1.5 nM, less than about 1.4 nM, less than about 1.3 nM, less than about 1.2 nM, less than about 1.1 nM, less than about 1.0 nM, less than about 0.9 nM, less than about 0.8 nM, less than about 0.7 nM, less than about 0.6 nM, less than about 0.5 nM, less than about 0.4 nM, less than about 0.3 nM, less than about 0.2 nM, and less than about 0.1 nM.

[0089] In another specific aspect, the present invention relates to an isolated anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof capable of inducing T cell-dependent cytotoxicity in Vβ17-expressing cells and / or KLK2-expressing cells. The bispecific antibody or antigen-binding fragment thereof has, for example, an EC 50In certain embodiments, EC 50 is less than about 2.0 nM, less than about 1.9 nM, less than about 1.8 nM, less than about 1.7 nM, less than about 1.6 nM, less than about 1.5 nM, less than about 1.4 nM, less than about 1.3 nM, less than about 1.2 nM, less than about 1.1 nM, less than about 1.0 nM, less than about 0.9 nM, less than about 0.8 nM, less than about 0.7 nM, less than about 0.6 nM, less than about 0.5 nM, less than about 0.4 nM, less than about 0.3 nM, less than about 0.2 nM, and less than about 0.1 nM.

[0090] In another particular aspect, the present invention relates to an isolated anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof capable of inducing T cell-dependent cytotoxicity in Vβ17-expressing cells and / or PSMA-expressing cells. The bispecific antibody or antigen-binding fragment thereof has, for example, an EC 50 In certain embodiments, EC 50 is less than about 2.0 nM, less than about 1.9 nM, less than about 1.8 nM, less than about 1.7 nM, less than about 1.6 nM, less than about 1.5 nM, less than about 1.4 nM, less than about 1.3 nM, less than about 1.2 nM, less than about 1.1 nM, less than about 1.0 nM, less than about 0.9 nM, less than about 0.8 nM, less than about 0.7 nM, less than about 0.6 nM, less than about 0.5 nM, less than about 0.4 nM, less than about 0.3 nM, less than about 0.2 nM, and less than about 0.1 nM.

[0091] In another particular aspect, the present invention relates to an isolated anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof capable of inducing T cell-dependent cytotoxicity in Vβ17-expressing cells and / or BCMA-expressing cells. The bispecific antibody or antigen-binding fragment thereof may, for example, have an EC 50 In certain embodiments, EC50 is less than about 2.0 nM, less than about 1.9 nM, less than about 1.8 nM, less than about 1.7 nM, less than about 1.6 nM, less than about 1.5 nM, less than about 1.4 nM, less than about 1.3 nM, less than about 1.2 nM, less than about 1.1 nM, less than about 1.0 nM, less than about 0.9 nM, less than about 0.8 nM, less than about 0.7 nM, less than about 0.6 nM, less than about 0.5 nM, less than about 0.4 nM, less than about 0.3 nM, less than about 0.2 nM, and less than about 0.1 nM.

[0092] In one aspect, the present invention relates to an isolated anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof, wherein the anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof is chimeric. In one aspect, the present invention relates to an isolated anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof, wherein the anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof is chimeric. In one aspect, the present invention relates to an isolated anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof, wherein the anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof is chimeric. In one aspect, the present invention relates to an isolated anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof, wherein the anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof is chimeric.

[0093] In one aspect, the present invention relates to an isolated anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof, wherein the anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof is human or humanized. In one aspect, the present invention relates to an isolated anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof, wherein the anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof is humanized. In one aspect, the present invention relates to an isolated anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof, wherein the anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof is humanized. In one aspect, the present invention relates to an isolated anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof, wherein the anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof is humanized.

[0094] In another general aspect, the present invention relates to an isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 85%, preferably 90%, more preferably 95% or more, e.g., 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 28. In specific embodiments, the humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 28. In some embodiments, the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 429, 432, 435, 438, 441, 444, 447, and 450. In some embodiments, the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof can comprise a heavy chain (HC) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 429, 432, 435, 438, 441, 444, 447, and 450. In some embodiments, the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof can comprise a light chain (LC) having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 431, 434, 437, 439, 443, 445, 449, and 452. In some embodiments, the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof can comprise a light chain (LC) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 431, 434, 437, 439, 443, 445, 449, and 452. In some embodiments, the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof can comprise a heavy chain (HC) having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 429, 432, 435, 438, 441, 444, 447, and 450, and a light chain (LC) having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 431, 434, 437, 439, 443, 445, 449, and 452.In some embodiments, the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof can comprise a heavy chain (HC) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 429, 432, 435, 438, 441, 444, 447, and 450, and a light chain (LC) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 431, 434, 437, 439, 443, 445, 449, and 452.

[0095] In another general aspect, the present invention relates to isolated nucleic acids encoding the monoclonal antibodies or antigen-binding fragments thereof disclosed herein. In another general aspect, the present invention relates to isolated nucleic acids encoding the bispecific antibodies or antigen-binding fragments thereof disclosed herein. It will be understood by those skilled in the art that the coding sequence for a protein can be altered (e.g., substituted, deleted, inserted, etc.) without changing the amino acid sequence of the protein. Thus, it will be understood by those skilled in the art that the nucleic acid sequences encoding the monoclonal and / or bispecific antibodies disclosed herein can be modified without changing the amino acid sequence of the protein.

[0096] In another general aspect, the present invention relates to a vector comprising an isolated nucleic acid disclosed herein. Any vector known to one of skill in the art in light of the present disclosure can be used, such as a plasmid, cosmid, phage vector, or viral vector. In some embodiments, the vector is a recombinant expression vector such as a plasmid. The vector can include any elements for establishing the conventional functions of an expression vector, such as a promoter, a ribosome binding element, a terminator, an enhancer, a selection marker, and an origin of replication. The promoter can be a constitutive, inducible, or repressible promoter. Several expression vectors capable of delivering nucleic acids into cells are known in the art and can be used herein to produce antibodies or antigen-binding fragments thereof in cells. Conventional cloning techniques or artificial gene synthesis can be used to generate recombinant expression vectors according to embodiments disclosed herein. Such techniques are well known to one of skill in the art in light of the present disclosure.

[0097] In another general aspect, the present invention relates to a host cell comprising an isolated nucleic acid encoding the monoclonal and / or bispecific antibodies, or antigen-binding fragments thereof, disclosed herein. Any host cell known to one of skill in the art in light of the present disclosure can be used for recombinant expression of the antibodies, or antigen-binding fragments thereof, disclosed herein. In some embodiments, the host cell is Escherichia coli (E. coli) TG1 or BL21 cell (e.g., for expression of scFv or Fab antibodies), CHO-DG44 or CHO-K1 cell, or HEK293 cell (e.g., for expression of full-length IgG antibodies). According to certain embodiments, the recombinant expression vector is transformed into the host cell by conventional methods, such as chemical transfection, heat shock, or electroporation, and stably integrated into the host cell genome for efficient expression of the recombinant nucleic acid.

[0098] In another general aspect, the present invention relates to a method of producing a bispecific antibody or antigen-binding fragment thereof disclosed herein. The method comprises culturing cells containing nucleic acid encoding the bispecific antibody or antigen-binding fragment thereof under conditions to produce the bispecific antibody or antigen-binding fragment thereof disclosed herein, and recovering the antibody or antigen-binding fragment thereof from the cells or cell culture (e.g., from the supernatant). The expressed antibody or antigen-binding fragment thereof can be recovered from the cells and purified according to conventional techniques known in the art and as described herein.

[0099] How to use In a general aspect, the present invention relates to a method for targeting CD123 on the surface of cancer cells, the method comprising exposing the cancer cells to an anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof. In a general aspect, the present invention relates to a method for targeting KLK2 on the surface of cancer cells, the method comprising exposing the cancer cells to an anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof. In a general aspect, the present invention relates to a method for targeting PSMA on the surface of cancer cells, the method comprising exposing the cancer cells to an anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof. In a general aspect, the present invention relates to a method for targeting BCMA on the surface of cancer cells, the method comprising exposing the cancer cells to an anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof.

[0100] The functional activity of bispecific antibodies and their antigen-binding fragments that bind to Vβ17 and / or CD123 can be characterized by methods known in the art and described herein. Methods for characterizing antibodies and their antigen-binding fragments that bind to Vβ17 and / or CD123 include, but are not limited to, affinity and specificity assays, including Biacore, ELISA, and OctetRed analysis; binding assays for detecting the binding of antibodies to CD123 on cancer cells by FACS; binding assays for detecting the binding of antibodies to Vβ17 on CD8-positive or CD4-positive T cells. According to certain embodiments, methods for characterizing antibodies and their antigen-binding fragments that bind to Vβ17 and / or CD123 include those described below.

[0101] The functional activity of the bispecific antibody and its antigen-binding fragment that binds to Vβ17 and / or KLK2 can be characterized by methods known in the art and described herein.Methods for characterizing the antibody and its antigen-binding fragment that binds to Vβ17 and / or KLK2 include, but are not limited to, affinity and specificity assays, including Biacore, ELISA, and OctetRed analysis; binding assays for detecting the binding of the antibody to KLK2 on cancer cells by FACS; binding assays for detecting the binding of the antibody to Vβ17 on CD8+ or CD4+ T cells.According to certain embodiments, the methods for characterizing the antibody and its antigen-binding fragment that binds to Vβ17 and / or KLK2 include those described below.

[0102] The functional activity of the bispecific antibody and its antigen-binding fragment that binds to Vβ17 and / or PSMA can be characterized by methods known in the art and described herein.Methods for characterizing the antibody and its antigen-binding fragment that binds to Vβ17 and / or PSMA include, but are not limited to, affinity and specificity assays, including Biacore, ELISA, and OctetRed analysis; binding assays for detecting the binding of the antibody to PSMA on cancer cells by FACS; binding assays for detecting the binding of the antibody to Vβ17 on CD8+ or CD4+ T cells.According to certain embodiments, the methods for characterizing the antibody and its antigen-binding fragment that binds to Vβ17 and / or PSMA include those described below.

[0103] The functional activity of bispecific antibodies and antigen-binding fragments thereof that bind to Vβ17 and / or BCMA can be characterized by methods known in the art and described herein. Methods for characterizing antibodies and antigen-binding fragments thereof that bind to Vβ17 and / or BCMA include, but are not limited to, affinity and specificity assays, including Biacore, ELISA, and OctetRed analysis; binding assays for detecting antibody binding to BCMA on cancer cells by FACS; and binding assays for detecting antibody binding to Vβ17 on CD8-positive or CD4-positive T cells. According to certain embodiments, methods for characterizing antibodies and antigen-binding fragments thereof that bind to Vβ17 and / or BCMA include those described below.

[0104] In one aspect, the present invention relates to a method for directing Vβ17-expressing CD8-positive or CD4-positive T cells to cancer cells. In some embodiments, the method comprises contacting Vβ17-expressing CD8-positive or CD4-positive T cells with an anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof, wherein the antibody or antibody fragment directs the Vβ17-expressing CD8-positive or CD4-positive T cells to cancer cells that have CD123 on their surface. In some embodiments, the method comprises contacting Vβ17-expressing CD8-positive or CD4-positive T cells with an anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof, wherein the antibody or antibody fragment directs the Vβ17-expressing CD8-positive or CD4-positive T cells to cancer cells that have KLK2 on their surface. In some embodiments, the methods comprise contacting Vβ17-expressing CD8+ or CD4+ T cells with an anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof, wherein the antibody or antibody fragment directs the Vβ17-expressing CD8+ or CD4+ T cells to cancer cells that have PSMA on their surface. In some embodiments, the methods comprise contacting Vβ17-expressing CD8+ or CD4+ T cells with an anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof, wherein the antibody or antibody fragment directs the Vβ17-expressing CD8+ or CD4+ T cells to cancer cells that have BCMA on their surface.

[0105] In one aspect, the present invention relates to a method for inhibiting the growth or proliferation of cancer cells. In some embodiments, the method comprises contacting Vβ17-expressing CD8-positive T cells with an anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof, whereby contacting the cancer cells with the antibody or antibody fragment inhibits the growth or proliferation of the cancer cells. In some embodiments, the method comprises contacting Vβ17-expressing CD8-positive T cells with an anti-Vβ17 / anti-KLK2 bispecific antibody or antigen-binding fragment thereof, whereby contacting the cancer cells with the antibody or antibody fragment inhibits the growth or proliferation of the cancer cells. In some embodiments, the method comprises contacting Vβ17-expressing CD8-positive T cells with an anti-Vβ17 / anti-PSMA bispecific antibody or antigen-binding fragment thereof, whereby contacting the cancer cells with the antibody or antibody fragment inhibits the growth or proliferation of the cancer cells. In some embodiments, the method comprises contacting Vβ17-expressing CD8-positive T cells with an anti-Vβ17 / anti-BCMA bispecific antibody or antigen-binding fragment thereof, whereby contacting the cancer cells with the antibody or antibody fragment inhibits the growth or proliferation of the cancer cells.

[0106] According to embodiments of the present invention, the described anti-Vβ17 / anti-CD123 bispecific antibodies or antigen-binding fragments thereof can be provided in a buffer composition for storage or use. Buffers suitable for storing the described anti-Vβ17 / anti-CD123 bispecific antibodies or antigen-binding fragments thereof help maintain the stability of the antibody or antibody fragment by minimizing degradation during storage, not promoting aggregation of the antibody or antibody fragment, or minimizing adhesion to the storage container.

[0107] According to embodiments of the present invention, the described anti-Vβ17 / anti-KLK2 bispecific antibodies or antigen-binding fragments thereof can be provided in a buffer composition for storage or use. Buffers suitable for storing the described anti-Vβ17 / anti-KLK2 bispecific antibodies or antigen-binding fragments thereof help maintain the stability of the antibodies or antibody fragments by minimizing deterioration during storage, not promoting aggregation of the antibodies or antibody fragments, or minimizing adhesion to storage containers.

[0108] According to embodiments of the present invention, the described anti-Vβ17 / anti-PSMA bispecific antibodies or antigen-binding fragments thereof can be provided in a buffer composition for storage or use. Buffers suitable for storing the described anti-Vβ17 / anti-PSMA bispecific antibodies or antigen-binding fragments thereof help maintain the stability of the antibody or antibody fragment by minimizing degradation during storage, not promoting aggregation of the antibody or antibody fragment, or minimizing adhesion to the storage container.

[0109] According to embodiments of the present invention, the described anti-Vβ17 / anti-BCMA bispecific antibodies or antigen-binding fragments thereof can be provided in a buffer composition for storage or use. Buffers suitable for storage of the described anti-Vβ17 / anti-BCMA bispecific antibodies or antigen-binding fragments thereof help to maintain the stability of the antibody or antibody fragment by minimizing degradation during storage, not promoting aggregation of the antibody or antibody fragment, or minimizing adhesion to the storage container.

[0110] According to embodiments of the present invention, the described anti-Vβ17 antibodies or antigen-binding fragments thereof can be provided in a buffer composition for storage or use. Buffers suitable for storing the described anti-Vβ17 antibodies or antigen-binding fragments thereof help maintain the stability of the antibodies or antibody fragments by minimizing deterioration during storage, not promoting aggregation of the antibodies or antibody fragments, or minimizing adhesion to storage containers.

[0111] Embodiment The present invention provides the following non-limiting embodiments.

[0112] Embodiment 1 is a. a first heavy chain (HC1); and b. a second heavy chain (HC2); and c. the first light chain (LC1); d. second light chain (LC2) and 1. A Vβ17 bispecific antibody or antigen-binding fragment thereof comprising: HC1 associates with LC1 to form a binding site for a first antigen, HC2 associates with LC2 to form a binding site for a second antigen, HC1 comprises heavy chain complementarity determining region 1 (HCDR1), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3), LC1 comprises light chain complementarity determining region 1 (LCDR1), light chain complementarity determining region 2 (LCDR2), and light chain complementarity determining region 3 (LCDR3), i. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 45, 46, and 47, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 60, 61, and 62, respectively; or ii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 48, 49, and 50, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 63, 64, and 65, respectively; or iii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 51, 52, and 53, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 66, 67, and 68, respectively; or iv. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 54, 55, and 56, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 69, KVS, and SEQ ID NO: 71, respectively; or v. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 57, 58, and 59, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 72, 73, and 74, respectively; or vi. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 77, 78, and 79, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 92, 93, and 94, respectively; or vii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 80, 81, and 82, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 95, 96, and 97, respectively; or viii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 83, 84, and 85, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 98, 99, and 100, respectively; or ix. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 86, 87, and 88, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 101, KVS, and SEQ ID NO: 103, respectively; or x. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 89, 90, and 91, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 104, 105, and 106, respectively; or xi. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 109, 110, and 111, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 124, 125, and 126, respectively; or xii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 112, 113, and 114, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 127, 128, and 129, respectively; or xiii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 115, 116, and 117, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 130, 131, and 132, respectively; or xiv. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 118, 119, and 120, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 133, KVS, and SEQ ID NO: 135, respectively; or xv. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 121, 122, and 123, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 136, 137, and 138, respectively; or xvi. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 141, 142, and 143, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 156, 157, and 158, respectively; or xvii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 144, 145, and 146, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 159, 160, and 161, respectively; or xviii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 147, 148, and 149, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 162, 163, and 164, respectively; or xix. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 150, 151, and 152, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 165, KVS, and SEQ ID NO: 167, respectively; or xx. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 153, 154, and 155, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 168, 169, and 170, respectively; or xxi. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 173, 174, and 175, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 188, 189, and 190, respectively; or xxii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 176, 177, and 178, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 191, 192, and 193, respectively; or xxiii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 179, 180, and 181, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 194, 195, and 196, respectively; or xxiv. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 182, 183, and 184, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 197, KVS, and SEQ ID NO: 199, respectively; or xxv. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 185, 186, and 187, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 200, 201, and 202, respectively; or xxvi. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 205, 206, and 207, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 220, 221, and 222, respectively; or xxvii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 208, 209, and 210, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 223, 224, and 225, respectively; or xxviii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 211, 212, and 213, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 226, 227, and 228, respectively; or xxix. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 214, 215, and 216, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 229, KVS, and SEQ ID NO: 231, respectively; or xxx. A Vβ17 bispecific antibody or antigen-binding fragment thereof, wherein HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 217, 218, and 219, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 232, 233, and 234, respectively.

[0113] Embodiment 2 is the Vβ17 bispecific antibody or antigen-binding fragment thereof of Embodiment 1, wherein the binding site for the first antigen binds to Vβ17 on CD8-positive or CD4-positive T cells.

[0114] Embodiment 3 is the Vβ17 bispecific antibody or antigen-binding fragment thereof of Embodiment 1 or 2, wherein the binding site for the second antigen binds to a tumor antigen present on the surface of a cancer cell.

[0115] Embodiment 4 is a Vβ17 bispecific antibody or antigen-binding fragment of any one of embodiments 1 to 3, wherein HC1 and LC1 are humanized.

[0116] Embodiment 5 is a Vβ17 bispecific antibody or antigen-binding fragment thereof according to any one of embodiments 1 to 4, wherein the binding site for the second antigen binds to CD123, kallikrein-related peptidase 2 (KLK2), prostate-specific membrane antigen (PSMA), or B-cell maturation antigen (BCMA).

[0117] Embodiment 6 is a Vβ17 bispecific antibody or antigen-binding fragment thereof according to any one of embodiments 1 to 5, wherein HC2 and LC2 bind to CD123, kallikrein-related peptidase 2 (KLK2), prostate-specific membrane antigen (PSMA), or B-cell maturation antigen (BCMA).

[0118] Embodiment 7 is a fragment of a HC2 antibody, wherein HC2 comprises heavy chain complementarity determining region 1 (HCDR1-2), heavy chain complementarity determining region 2 (HCDR2-2), and heavy chain complementarity determining region 3 (HCDR3-2); LC2 comprises light chain complementarity determining region 1 (LCDR1-2), light chain complementarity determining region 2 (LCDR2-2), and light chain complementarity determining region 3 (LCDR3-2); i. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 34, 35, and 36, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 37, 38, and 39, respectively; or ii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 237, 238, and 239, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 252, 253, and 254, respectively; or iii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 240, 241, and 242, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 255, 256, and 257, respectively; or iv. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 243, 244, and 245, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 258, 259, and 260, respectively; or v. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 246, 247, and 248, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 261, AAS, and SEQ ID NO: 263, respectively; or vi. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 249, 250, and 251, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 264, 265, and 266, respectively; or vii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 269, 270, and 271, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 284, 285, and 286, respectively; or viii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 272, 273, and 274, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 287, 288, and 289, respectively; or ix. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 275, 276, and 277, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 290, 291, and 292, respectively; or x. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 278, 279, and 280, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 293, DNN, and SEQ ID NO: 295, respectively; or xi. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 281, 282, and 283, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 296, 297, and 298, respectively; or xii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 301, 302, and 303, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 316, 317, and 318, respectively; or xiii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 304, 305, and 306, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 319, 320, and 321, respectively; or xiv. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 307, 308, and 309, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 322, 323, and 324, respectively; or xv. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 310, 311, and 312, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 325, GAS, and SEQ ID NO: 327, respectively; or xvi. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 313, 314, and 315, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 328, 329, and 330, respectively; or xvii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 333, 334, and 335, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 348, 349, and 350, respectively; or xviii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 336, 337, and 338, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 351, 352, and 353, respectively; or xix. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 339, 340, and 341, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 354, 355, and 356, respectively; or xx. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 342, 343, and 344, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 357, DNN, and SEQ ID NO: 359, respectively; or xxi. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 345, 346, and 347, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 360, 361, and 362, respectively; or xxii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 365, 366, and 367, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 380, 381, and 382, ​​respectively; or xxiii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 368, 369, and 370, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 383, 384, and 385, respectively; or xxiv. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 371, 372, and 373, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 386, 387, and 388, respectively; or xxv. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 374, 375, and 376, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 389, DNN, and SEQ ID NO: 391, respectively; or xxvi. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 377, 378, and 379, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 392, 393, and 394, respectively; or xxvii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 397, 398, and 399, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 412, 413, and 414, respectively; or xxviii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 400, 401, and 402, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 415, 416, and 417, respectively; or xxix. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 403, 404, and 405, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 418, 419, and 420, respectively; or xxx. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 404, 405, and 406, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 421, KAS, and SEQ ID NO: 423, respectively; or xxxi. The Vβ17 bispecific antibody or antigen-binding fragment thereof according to any one of embodiments 1 to 6, wherein HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 407, 408, and 409, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 424, 425, and 426, respectively.

[0119] Embodiment 8 is a Vβ17 bispecific antibody or antigen-binding fragment thereof according to any one of embodiments 1 to 7, which is of the IgG isotype.

[0120] Embodiment 9 is a Vβ17 bispecific antibody or antigen-binding fragment thereof according to any one of embodiments 1 to 8, which is of the IgG4 isotype.

[0121] Embodiment 10 is a Vβ17 bispecific antibody or antigen-binding fragment thereof according to any one of embodiments 1 to 8, which is of the IgG1 isotype.

[0122] Embodiment 11 is a method for treating a cancer having an EC of less than about 0.2 picomolar (pM). 50 11. The Vβ17 bispecific antibody or antigen-binding fragment thereof according to any one of embodiments 1 to 10, which induces CD8-positive or CD4-positive T cell-dependent cytotoxicity of cancer cells in vitro.

[0123] Embodiment 12 is an isolated nucleic acid encoding the HC1 and LC1 of the Vβ17 bispecific antibody or antigen-binding fragment thereof of any one of embodiments 1 to 11.

[0124] Embodiment 13 is an isolated nucleic acid encoding the HC2 and LC2 of the Vβ17 bispecific antibody or antigen-binding fragment thereof of any one of embodiments 1 to 11.

[0125] Embodiment 14 is a vector comprising the isolated nucleic acid of embodiment 12 or embodiment 13.

[0126] Embodiment 15 is a host cell comprising the vector of embodiment 14.

[0127] Embodiment 16 is a buffer composition comprising the Vβ17 bispecific antibody or antigen-binding fragment thereof of any one of embodiments 1 to 11 and a buffer solution.

[0128] Embodiment 17 is a. a first heavy chain (HC1); and b. a second heavy chain (HC2); and c. the first light chain (LC1); d. second light chain (LC2) and Including, HC1 associates with LC1, HC2 associates with LC2, HC1 comprises a heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, LC1 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively, and form a binding site for a first antigen that specifically binds to Vβ17, and HC2 comprises a heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, and form a binding site for a first antigen that specifically binds to Vβ17, and HC2 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively, and form a binding site for a first antigen that specifically binds to Vβ17, and An isolated anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof, comprising a heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, and a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively, forming a binding site for a second antigen that specifically binds to CD123.

[0129] Embodiment 18 is the isolated anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment of embodiment 17, wherein HC1 comprises the amino acid sequence of SEQ ID NO: 13, LC1 comprises the amino acid sequence of SEQ ID NO: 14, HC2 comprises the amino acid sequence of SEQ ID NO: 15, and LC2 comprises the amino acid sequence of SEQ ID NO: 16.

[0130] Embodiment 19 is the isolated anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof of embodiment 17 or embodiment 18, wherein Vβ17 is present on the surface of CD8-positive or CD4-positive T cells.

[0131] Embodiment 20 is an isolated anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof according to any one of embodiments 17 to 19, wherein CD123 is present on the surface of a cancer cell.

[0132] Embodiment 21 is a method for treating a rheumatoid arthritis, comprising administering to a subject an EC50 inhibitor or rheumatoid arthritis patient having ... 50 21. The isolated anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof of any one of embodiments 17 to 20, which induces CD8-positive or CD4-positive T cell-dependent cytotoxicity of cancer cells in vitro.

[0133] Embodiment 22 is an isolated nucleic acid encoding the HC1 and LC1 of the anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof of any one of Embodiments 17 to 21.

[0134] Embodiment 23 is an isolated nucleic acid encoding the HC2 and LC2 of the anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof of any one of Embodiments 17 to 21.

[0135] Embodiment 24 is a vector comprising the isolated nucleic acid of embodiment 22 or embodiment 23.

[0136] Embodiment 25 is a host cell comprising the vector of embodiment 24.

[0137] Embodiment 26 is a buffer composition comprising the isolated anti-Vβ17 / anti-CD123 bispecific antibody or antigen-binding fragment thereof of any one of Embodiments 17 to 21 and a buffer solution.

[0138] Embodiment 27 is a method for directing Vβ17-expressing CD8-positive or CD4-positive T cells to cancer cells, comprising contacting Vβ17-expressing CD8-positive or CD4-positive T cells with the Vβ17 bispecific antibody or antigen-binding fragment thereof described in any one of embodiments 1 to 9, wherein contacting the Vβ17-expressing CD8-positive or CD4-positive T cells with the Vβ17 bispecific antibody or antigen-binding fragment thereof directs the Vβ17-expressing CD8-positive or CD4-positive T cells to cancer cells that have a second antigen on their cell surface.

[0139] Embodiment 28 is the method of embodiment 27, wherein the second antigen is selected from the group consisting of CD123, kallikrein-related peptidase 2 (KLK2), prostate-specific membrane antigen (PSMA), or B-cell maturation antigen (BCMA).

[0140] Embodiment 29(a) is the method of embodiment 27 or 28, wherein Vβ17-expressing CD8-positive or CD4-positive T cells are contacted with a Vβ17 bispecific antibody of any one of embodiments 1 to 9.

[0141] Embodiment 29(b) is a method according to embodiment 27 or 28, wherein Vβ17-expressing CD8-positive or CD4-positive T cells are contacted with a Vβ17 bispecific antibody fragment according to any one of embodiments 1 to 9.

[0142] Embodiment 30 is a method for inhibiting the growth or proliferation of cancer cells, comprising contacting cancer cells with a Vβ17 bispecific antibody or fragment thereof of embodiments 1 to 9, whereby contacting the cancer cells with the antibody or antibody fragment inhibits the growth or proliferation of cancer cells.

[0143] Embodiment 31(a) is the method of embodiment 30, wherein the cancer cells are contacted with the Vβ17 bispecific antibody or fragment thereof in the presence of Vβ17-expressing CD8-positive T cells.

[0144] Embodiment 31(b) is the method of embodiment 30 or 31(a), wherein the cancer cells are contacted with the Vβ17 bispecific antibody of any one of embodiments 1 to 9.

[0145] Embodiment 32 is a kit comprising the Vβ17 bispecific antibody or antigen-binding fragment thereof of any one of Embodiments 1 to 9 and packaging material thereof.

[0146] Embodiment 33 is a kit comprising the Vβ17 bispecific antibody or antigen-binding fragment thereof of any one of embodiments 1 to 9 and instructions for use.

[0147] Embodiment 34 is a method of producing a Vβ17 bispecific antibody or antigen-binding fragment thereof, comprising culturing the host cell of embodiment 15 under conditions to produce the Vβ17 bispecific antibody or antigen-binding fragment thereof, and recovering the Vβ17 bispecific antibody or antigen-binding fragment thereof from the cell or culture.

[0148] Embodiment 35 is an isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof, comprising a heavy chain (HC) having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 429, 432, 435, 438, 441, 444, 447, and 450.

[0149] Embodiment 36 is an isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof according to embodiment 35, wherein the heavy chain (HC) sequence is selected from the group consisting of SEQ ID NOs: 429, 432, 435, 438, 441, 444, 447, and 450.

[0150] Embodiment 37 is an isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof according to embodiment 35 or 36, further comprising a light chain (LC) having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 431, 434, 437, 439, 443, 445, 449, and 452.

[0151] Embodiment 38 is an isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof described in any one of embodiments 35 to 37, wherein the light chain (LC) sequence is selected from the group consisting of SEQ ID NOs: 431, 434, 437, 439, 443, 445, 449, and 452.

[0152] Embodiment 39 is an isolated nucleic acid encoding the humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof of any one of embodiments 35 to 38.

[0153] Embodiment 40 is a vector comprising the isolated nucleic acid of any one of embodiments 35 to 39.

[0154] Embodiment 41 is a host cell comprising the vector of embodiment 40.

[0155] Embodiment 42 is a buffer composition comprising the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof of any one of embodiments 35 to 39.

[0156] Embodiment 42 is a Vβ17 antibody or antigen-binding fragment thereof, comprising: a first heavy chain (HC1) having a heavy chain complementarity-determining region 1 (HCDR1), a heavy chain complementarity-determining region 2 (HCDR2), and a heavy chain complementarity-determining region 3 (HCDR3); and a first light chain (LC1) having a light chain complementarity-determining region 1 (LCDR1), a light chain complementarity-determining region 2 (LCDR2), and a light chain complementarity-determining region 3 (LCDR3); i. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 45, 46, and 47, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 60, 61, and 62, respectively; or ii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 48, 49, and 50, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 63, 64, and 65, respectively; or iii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 51, 52, and 53, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 66, 67, and 68, respectively; or iv. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 54, 55, and 56, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 69, KVS, and SEQ ID NO: 71, respectively; or v. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 57, 58, and 59, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 72, 73, and 74, respectively; or vi. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 77, 78, and 79, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 92, 93, and 94, respectively; or vii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 80, 81, and 82, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 95, 96, and 97, respectively; or viii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 83, 84, and 85, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 98, 99, and 100, respectively; or ix. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 86, 87, and 88, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 101, KVS, and SEQ ID NO: 103, respectively; or x. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 89, 90, and 91, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 104, 105, and 106, respectively; or xi. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 109, 110, and 111, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 124, 125, and 126, respectively; or xii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 112, 113, and 114, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 127, 128, and 129, respectively; or xiii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 115, 116, and 117, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 130, 131, and 132, respectively; or xiv. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 118, 119, and 120, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 133, KVS, and SEQ ID NO: 135, respectively; or xv. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 121, 122, and 123, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 136, 137, and 138, respectively; or xvi. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 141, 142, and 143, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 156, 157, and 158, respectively; or xvii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 144, 145, and 146, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 159, 160, and 161, respectively; or xviii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 147, 148, and 149, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 162, 163, and 164, respectively; or xix. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 150, 151, and 152, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 165, KVS, and SEQ ID NO: 167, respectively; or xx. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 153, 154, and 155, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 168, 169, and 170, respectively; or xxi. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 173, 174, and 175, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 188, 189, and 190, respectively; or xxii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 176, 177, and 178, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 191, 192, and 193, respectively; or xxiii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 179, 180, and 181, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 194, 195, and 196, respectively; or xxiv. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 182, 183, and 184, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 197, KVS, and SEQ ID NO: 199, respectively; or xxv. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 185, 186, and 187, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 200, 201, and 202, respectively; or xxvi. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 205, 206, and 207, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 220, 221, and 222, respectively; or xxvii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 208, 209, and 210, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 223, 224, and 225, respectively; or xxviii. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 211, 212, and 213, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 226, 227, and 228, respectively; or xxix. HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 214, 215, and 216, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 229, KVS, and SEQ ID NO: 231, respectively; or xxx. A Vβ17 antibody or antigen-binding fragment thereof, wherein HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 217, 218, and 219, respectively, and LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 232, 233, and 234, respectively.

[0157] Embodiment 43 is an antibody or antigen-binding fragment thereof, comprising: a second heavy chain (HC2) having heavy chain complementarity determining region 1 (HCDR1-2), heavy chain complementarity determining region 2 (HCDR2-2), and heavy chain complementarity determining region 3 (HCDR3-2); and a second light chain (LC2) having light chain complementarity determining region 1 (LCDR1-2), light chain complementarity determining region 2 (LCDR2-2), and light chain complementarity determining region 3 (LCDR3-2), i. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 34, 35, and 36, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 37, 38, and 39, respectively; or ii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 237, 238, and 239, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 252, 253, and 254, respectively; or iii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 240, 241, and 242, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 255, 256, and 257, respectively; or iv. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 243, 244, and 245, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 258, 259, and 260, respectively; or v. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 246, 247, and 248, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 261, AAS, and SEQ ID NO: 263, respectively; or vi. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 249, 250, and 251, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 264, 265, and 266, respectively; or vii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 269, 270, and 271, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 284, 285, and 286, respectively; or viii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 272, 273, and 274, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 287, 288, and 289, respectively; or ix. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 275, 276, and 277, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 290, 291, and 292, respectively; or x. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 278, 279, and 280, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 293, DNN, and SEQ ID NO: 295, respectively; or xi. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 281, 282, and 283, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 296, 297, and 298, respectively; or xii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 301, 302, and 303, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 316, 317, and 318, respectively; or xiii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 304, 305, and 306, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 319, 320, and 321, respectively; or xiv. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 307, 308, and 309, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 322, 323, and 324, respectively; or xv. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 310, 311, and 312, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 325, GAS, and SEQ ID NO: 327, respectively; or xvi. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 313, 314, and 315, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 328, 329, and 330, respectively; or xvii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 333, 334, and 335, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 348, 349, and 350, respectively; or xviii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 336, 337, and 338, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 351, 352, and 353, respectively; or xix. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 339, 340, and 341, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 354, 355, and 356, respectively; or xx. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 342, 343, and 344, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 357, DNN, and SEQ ID NO: 359, respectively; or xxi. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 345, 346, and 347, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 360, 361, and 362, respectively; or xxii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 365, 366, and 367, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 380, 381, and 382, ​​respectively; or xxiii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 368, 369, and 370, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 383, 384, and 385, respectively; or xxiv. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 371, 372, and 373, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 386, 387, and 388, respectively; or xxv. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 374, 375, and 376, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 389, DNN, and SEQ ID NO: 391, respectively; or xxvi. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 377, 378, and 379, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 392, 393, and 394, respectively; or xxvii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 397, 398, and 399, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 412, 413, and 414, respectively; or xxviii. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 400, 401, and 402, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 415, 416, and 417, respectively; or xxix. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 403, 404, and 405, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 418, 419, and 420, respectively; or xxx. HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 404, 405, and 406, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 421, KAS, and SEQ ID NO: 423, respectively; or xxxi. An antibody or antigen-binding fragment thereof, wherein HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 407, 408, and 409, respectively, and LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 424, 425, and 426, respectively. [Example]

[0158] The following example is based on the premise that influenza virus-derived peptide M1 can expand a select set of T cells. These cells express the TCR-haplotype Vβ17, and the majority of these cells exhibit efficient cytotoxicity against tumor target cells. This ability is then exploited using a bispecific antibody designed so that one arm binds to the Vβ17 structure and the other arm binds to an antigen expressed by cancer cells. Thus, the bispecific antibody crosslinks effector and target cells, resulting in the death of the cancer cells. This mechanism of action is shown diagrammatically in Figure 1.

[0159] The examples that follow can be divided into the following categories: (1) production of bispecific antibodies capable of binding to the Vβ17 arm of the T cell receptor (TCR) on CTLs (Examples 1 and 2); and (2) evidence showing bispecific antibody-enabled target cell killing by in vitro expanded CTLs (Example 3).

[0160] [Example 1] Human framework adaptation of anti-Vβ17 mAb E17.5F Mouse IgG1 anti-human T cell receptor Vβ17 clone E17.5F was obtained from BeckmanCoulter, Inc. (Brea, CA). Sample preparation and LC / MSMS analysis were performed at Protea Bioscience Inc. (Morgantown, WV). The sample was reduced, alkylated, divided into seven aliquots, and proteolytically digested with trypsin / LysC, chymotrypsin, LysC, pepsin, and AspN, elastase, and proteinase K enzymes. The resulting peptides were desalted using ZipTip C18 Pipette Tips and separated online using reversed-phase chromatography. Mass spectrometry was performed on a Thermo Q-Exactive spectrometer using HCD fragmentation. MS datasets were analyzed using PEAKS software by matching de novo sequence tags to an IMGT-based antibody sequence database. Gaps in the sequence were assigned using contig sequence assembly of the de novo identified peptides. All CDRs and hypermutations were confirmed by examining the MS / MS spectra.

[0161] The sequences obtained are shown in Tables 1 and 2.

[0162] [Table 1]

[0163] [Table 2]

[0164] The sequence was modified to prepare the bispecific antibody (Table 3). Changes included: (1) the framework mutation Asn1 in the heavy chain was not conserved, so the sequence was altered to have the DVQLW sequence; (2) another mutation identified in the Fc, K337Y, was considered atypical, so a construct was synthesized without this mutation; and (3) a potential secondary glycosylation site on the heavy chain was observed, so two versions of this mAb were synthesized, with and without an N-linked site (N82a based on Chothia numbering).

[0165] [Table 3]

[0166] Two antibodies (B17B1 and B17B2) were expressed in HEK293Expi cells. The supernatants (B17B1 and B17B2) were tested for Vβ17 binding, and only B17B1 showed binding. Therefore, B17B1 was expressed with an IgG4 constant region with Fc substitutions.

[0167] The anti-human TCR Vβ17 murine mAb B17B1 was humanized using the human framework adaptation (HFA) method (Fransson J, et al. J. Mol. Biol. 2010; 398:214-231). To find the best combination of humanized heavy and light chains, several human V region sequences were selected for testing (Table 4). The selection of human germline sequences was based solely on overall sequence similarity to mouse antibodies in the framework (FR) regions. Neither the CDR sequences nor their length or canonical structure were considered in this selection.

[0168] The CDR definitions used in HFA are described in (Fransson J, et al. J. Mol. Biol. 2010; 398:214-231) and correspond to Martin's definition (Abhinandan KR and Martin AC. Mol. Immunol. 2008; 45:3832-3839). The CDRs (Table 1) were defined as follows (using the Chothia numbering scheme [Chothia C, and Lesk AJ Mol. Biol. 1987; 196:901-917]): HCDR1 (SEQ ID NO: 1) 26-35 HCDR2 (SEQ ID NO: 2) 50-58 HCDR3 (SEQ ID NO: 3) 95-102 LCDR1 (SEQ ID NO: 4) 24-34 LCDR2 (SEQ ID NO: 5) 50-56 LCDR3 (SEQ ID NO: 6) 89-97

[0169] Selected human germlines are shown in Table 4 (IMGT notation).

[0170] [Table 4] CDR1 to 3 are underlined

[0171] "Back mutations" in some variants were introduced at FR positions known to be important for VL / VH pairing and CDR conformation. Selected human germlines are shown in Table 5 (in IMGT notation), and the back mutations are listed.

[0172] [Table 5]

[0173] The amino acid sequences of all nine combinations of three heavy and three light chain pairs were reverse-translated into DNA, and cDNA was prepared using gene synthesis techniques (U.S. Patent Nos. 6,670,127; 6,521,427). Using standard molecular biology techniques, the heavy chain (HC) variable region was subcloned onto the human IgG4 constant region using an in-house expression vector with a CMV promoter. Using standard molecular biology techniques, the light chain (LC) variable region was subcloned onto the human lambda (λ) constant region using an in-house expression vector with a CMV promoter. The resulting plasmid was transfected into HEK EXPI cells (LifeTechnologies; Carlsbad, CA), and the mAb was expressed. Purification was performed by standard methods using a Protein A column (hiTrap MAbSelect SuRe column). After elution, the pool was dialyzed into D-PBS, pH 7.2.

[0174] [Table 6]

[0175] Humanized antibodies were screened for binding to the TCR-Vβ17 (SEQ ID NO: 27) / Va10.2-Fc (SEQ ID NO: 44) fusion protein by ELISA. Biotinylated TCR-Vβ17 / Va10.2-Fc fusion protein was added to a streptavidin-coated ELISA plate. Unbound protein was washed away, and mAb was added at a range of concentrations (0.01-10 μg / mL). The plate was washed, and an anti-kappa:HRP detection antibody was added. The plate was washed, chemiluminescent detection reagent was added, and the plate was read for luminescence on a Perkin Elmer EnVision plate reader. B17B20 and B17B21 showed strong binding to the TCR-Vβ17 protein. B17B22 showed weak binding to this protein. These antibodies were then purified as described above for further testing. B17B21 showed the best binding ability to recombinant TCR-Vβ17 protein and M1-stimulated T cells and was therefore selected as a target molecule for further functional studies aimed at T cell-directed altered cancer cell killing, especially as a bispecific antibody.

[0176] Therefore, the variable region sequences of B17B21 (anti-Vβ17) and I3RB217 (anti-CD123 antibody) were used to generate a bispecific antibody to test for T cell-directed altered killing of acute myeloid leukemia (AML) cells.

[0177] [Example 2] Preparation of anti-Vβ17 / anti-CD123 bispecific antibody The VB11 (anti-Vβ17 / anti-CD123) and VB13 (Vβ17 × null) bispecific antibodies were produced as full-length antibodies in a knob-in-hole format as human IgG4, as previously described (Atwell et al. J. Mol. Biol. 270: 26-35, 1997). The nucleic acid sequences encoding the variable regions were subcloned into a custom mammalian expression vector containing the constant region of an IgG4 expression cassette using standard PCR-based restriction enzyme-based cloning techniques. The bispecific antibodies were expressed by transient transfection in a Chinese hamster ovary cell line. The antibodies were first purified using a Mab Select SuRe Protein A column (GE Healthcare, Piscataway, New Jersey) (Brown, Bottomley et al. 1998). The column was equilibrated with phosphate-buffered saline (PBS), pH 7.2, and the fermentation supernatant was loaded at a flow rate of 2 mL / min. After loading, the column was washed with PBS (4 column volumes) and subsequently eluted in 30 mM sodium acetate, pH 3.5. Fractions containing the protein peak, monitored by absorbance at 280 nm on an Äkta Explorer (GE Healthcare), were pooled together and neutralized to pH 9.0 by adding 1% 3 M sodium acetate, pH 5.0. For the polishing step, the antibody was purified by preparative size-exclusion chromatography (SEC) using a Superdex 200 column (GE Healthcare). Sample integrity was assessed by endotoxin measurement and SDS-polyacrylamide gel electrophoresis under reducing and non-reducing conditions. The final protein concentrations were 0.48 mg / mL for anti-Vβ17 / anti-CD123 and 0.24 mg / mL for Vβ17×Null. Based on these protein concentrations, the final EU levels for anti-Vβ17 / anti-CD123 and Vβ17×Null were 2.053 EU / mg and 4.219 EU / mg, respectively.

[0178] [Table 7-1]

[0179] [Table 7-2]

[0180] [Table 7-3]

[0181] [Table 7-4]

[0182] [Table 8-1]

[0183] [Table 8-2]

[0184] [Example 3] Evaluation of binding and cytotoxicity of anti-Vβ17 / anti-CD123 bispecific antibodies using Kasumi-3 cells and human CD8+ T cells Stimulation and proliferation of Vβ17-positive CD8-positive T cells from total PBMCs

[0185] To expand Vβ17-positive CD8-positive T cells, total PBMCs from an HLA-A2 donor (HPU-08694) were stimulated with 1 μg / mL of FLU MP 58 peptide (in DMSO). The frequency of Vβ17-positive cells among total CD8-positive T cells was determined on days 8 and 14 of the culture period. To count the frequency of Vβ17-positive cells among total CD8-positive T cells, total viable PBMCs were first gated, doublets were removed, total CD8-positive T cells were gated, and then Vβ17-positive cells were gated (Figure 3A). Substantial expansion of Vβ17-positive cells was observed on day 8 of the culture period compared with the frequency of Vβ17-positive cells among total CD8-positive T cells on day 0 (Figure 3B). In this donor, the proportion of Vβ17-positive cells among CD8-positive T cells on day 8 was higher (Figure 3B).

[0186] Anti-Vβ17 / anti-CD123 bispecific antibody binding assay

[0187] On Kasumi-3 cells

[0188] To understand the binding kinetics of the anti-Vβ17 / anti-CD123 bispecific antibody, Kasumi-3 cells were incubated with various concentrations of the anti-Vβ17 / anti-CD123 bispecific antibody (ranging from 5 μg / mL to 0 μg / mL) and a Vβ17×NULL arm control. Cell-bound bispecific antibody was detected with a mouse anti-human IgG4 Fc-PE secondary antibody. Table 9 shows the frequency of Kasumi-3 cells positive for PE (secondary antibody) when treated with different concentrations of the bispecific antibody. EC values ​​of anti-Vβ17 / anti-CD123 and NULL×CD123. 50 were determined to be 6 nM and 42.7 nM, respectively (Table 9).

[0189] [Table 9]

[0190] The binding affinity of the bispecific antibodies to Kasumi-3 cells was determined by flow cytometry. The half maximal effective concentration (EC 50) values ​​were calculated as the bispecific concentration resulting in 50% of maximum binding (PE-positive cells). ND: Not determined.

[0191] On enriched CD8+ T cells

[0192] Concentrated FLU MP 58 peptide-stimulated CD8+ T cells (from day 14 culture) were incubated with various concentrations of anti-Vβ17 / anti-CD123 bispecific antibody and Vβ17×NULL arm control antibody. The bispecific antibody was detected using a mouse anti-human IgG4 Fc-PE secondary antibody. Table 10 shows the frequency of CD8+ T cells positive for PE (secondary antibody) when treated with different concentrations of bispecific antibody. EC of anti-Vβ17 / anti-CD123, Vβ17×NULL 50 were determined to be 9.0 nm and 18.7 nm, respectively (Table 10).

[0193] [Table 10]

[0194] Bispecific antibody binding affinity to CD8-positive T cells was determined by flow cytometry. 50 ) values ​​were calculated as the antibody concentration that resulted in 50% of maximum binding (PE-positive cells). ND: Not determined

[0195] Bispecific-mediated cytotoxicity assay

[0196] To analyze the efficacy of anti-Vβ17 / anti-CD123 bispecific antibody-mediated cytotoxicity, CFSE-labeled target (Kasumi-3) cells were co-cultured with stimulated CD8+ T cells (effectors) from day 14 of culture at effector-to-target (ET) ratios of 0.5:1, 1:1, and 5:1 for 14 and 24 hours, with various concentrations of anti-Vβ17 / anti-CD123 bispecific antibody and Vβ17 × NULL arm control antibody. CD123 expression on target Kasumi-3 cells was confirmed using a commercially available anti-CD123 antibody. Target cells (Kasumi-3) were labeled with CFSE and identified as CFSE-positive during flow cytometry analysis. After the co-culture period, 7-AAD was added, and the percentage of 7-AAD-positive / CFSE-positive cells was analyzed as a measure of cytotoxicity. The basal cytotoxicity observed in the absence of the bispecific antibody was subtracted to obtain the specific cytotoxicity in response to the bispecific antibody. The assay was performed once with a single donor (HPU-08694). EC values ​​for anti-Vβ17 / anti-CD123 bispecific antibodies at ET ratios of 0.5:1, 1:1, and 5:1 at 14 hours were calculated. 50 were 3.7 pM, 0.1 pM and 0.133 pM, respectively (Table 11).

[0197] [Table 11]

[0198] EC of anti-Vβ17 / anti-CD123 bispecific at ET ratios of 0.5:1, 1:1, and 5:1 at 24 hours 50 were 0.4 pM, 0.2 pM, and 1.0 pM, respectively (Table 12).

[0199] [Table 12]

[0200] Similarly, anti-Vβ17 / anti-CD123 bispecific-mediated cytotoxicity of unstimulated CD8+ T cells was tested at ET ratios of 0.5:1, 1:1, and 5:1 for 14 hours (Table 13) and 24 hours (Table 14). At an anti-Vβ17 / anti-CD123 bispecific concentration of 5 ng / ml and the 14-hour time point, unstimulated CD8+ T cells at ET ratios of 0.5:1 and 1:1 demonstrated 2.8% and 9.8% target cell cytotoxicity, respectively, compared with 77% and 73% cytotoxicity by stimulated CD8+ T cells (Table 13). At an ET ratio of 5:1, unstimulated CD8+ T cells demonstrated 31.65% target cytotoxicity, compared with 70.9% by stimulated CD8+ T cells. Similar results were obtained at the 24-hour time point (Tables 12, 15, 16, and 17). At the highest concentration of anti-Vβ17 / anti-CD123 bispecific tested (5 ng / ml), unstimulated CD8+ T cells exhibited higher cytotoxicity against target cells with a higher ET ratio.

[0201] [Table 13]

[0202] [Table 14]

[0203] [Table 15]

[0204] Median effective concentration (EC 50 ) values ​​were calculated as the antibody concentration that produced 50% of the maximum cytotoxic (CFSE-positive 7AAD-positive) cells. ND: Not determined.

[0205] [Table 16]

[0206] Median effective concentration (EC 50) values ​​were calculated as the antibody concentration that produced 50% of the maximum cytotoxicity (CFSE-positive 7AAD-positive) cells. ND: Not determined

[0207] [Table 17]

[0208] Median effective concentration (EC 50 ) values ​​were calculated as the antibody concentration that produced 50% of the maximum cytotoxicity (CFSE-positive 7AAD-positive) cells. UD: Undetectable

[0209] Those skilled in the art will appreciate that changes could be made to the above-described embodiments without departing from the broad inventive concept thereof. It is therefore understood that the invention is not limited to the particular embodiments disclosed, but that it is intended to cover modifications within the spirit and scope of the invention as defined by this description.

[0210] [Table 18-1]

[0211] [Table 18-2]

[0212] [Table 18-3]

[0213] [Table 18-4]

[0214] [Table 18-5]

[0215] [Table 18-6]

[0216] Table 18-7

[0217] Table 18-8

[0218] Table 18-9

[0219] Table 18-10

[0220] Table 18-11

[0221] Table 18-12

[0222] Table 18-13

[0223] Table 18-14

[0224] Table 18-15

[0225] Table 18-16

[0226] Table 18-17

[0227] Table 18-18

[0228] Table 18-19

[0229] Table 18-20

[0230] Table 18-21

[0231] Table 18-22

[0232] Table 18-23

[0233] Table 18-24

[0234] Table 18-25

[0235] Table 18-26

[0236] Table 18-27

[0237] Table 18-28

[0238] Table 18-29

[0239] Table 18-30

[0240] Table 18-31

[0241] Table 18-32

[0242] Table 18-33

[0243] Table 18-34

[0244] Table 18-35

[0245] Table 18-36

Claims

1. a. a first heavy chain (HC1); and b. the first light chain (LC1); c. a second heavy chain (HC2); and d. the second light chain (LC2) and 1. A Vβ17 bispecific antibody or antigen-binding fragment thereof comprising: HC1 associates with LC1 to form a binding site for a first antigen, and HC2 associates with LC2 to form a binding site for a second antigen; HC1 comprises heavy chain complementarity determining region 1 (HCDR1), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3); LC1 comprises light chain complementarity determining region 1 (LCDR1), light chain complementarity determining region 2 (LCDR2), and light chain complementarity determining region 3 (LCDR3); i. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 45, 46, and 47, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 60, 61, and 62, respectively; or ii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 48, 49, and 50, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 63, 64, and 65, respectively; or iii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 51, 52, and 53, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 66, 67, and 68, respectively; or iv. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 54, 55, and 56, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 69, KVS, and 71, respectively; or v. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 57, 58, and 59, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 72, 73, and 74, respectively; or vi. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 77, 78, and 79, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 92, 93, and 94, respectively; or vii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 80, 81, and 82, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 95, 96, and 97, respectively; or viii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 83, 84, and 85, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 98, 99, and 100, respectively; or ix. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 86, 87, and 88, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 101, KVS, and 103, respectively; or x. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 89, 90, and 91, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 104, 105, and 106, respectively; or xi. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 109, 110, and 111, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 124, 125, and 126, respectively; or xii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 112, 113, and 114, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 127, 128, and 129, respectively; or xiii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 115, 116, and 117, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 130, 131, and 132, respectively; or xiv. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 118, 119, and 120, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 133, KVS, and 135, respectively; or xv. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 121, 122, and 123, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 136, 137, and 138, respectively; or xvi. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 141, 142, and 143, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 156, 157, and 158, respectively; or xvii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 144, 145, and 146, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 159, 160, and 161, respectively; or xviii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 147, 148, and 149, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 162, 163, and 164, respectively; or xix. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 150, 151, and 152, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 165, KVS, and 167, respectively; or xx. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 153, 154, and 155, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 168, 169, and 170, respectively; or xxi. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 173, 174, and 175, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 188, 189, and 190, respectively; or xxii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 176, 177, and 178, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 191, 192, and 193, respectively; or xxiii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 179, 180, and 181, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 194, 195, and 196, respectively; or xxiv. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 182, 183, and 184, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 197, KVS, and 199, respectively; or xxv. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 185, 186, and 187, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 200, 201, and 202, respectively; or xxvi. The HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 205, 206, and 207, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 220, 221, and 222, respectively; or xxvii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 208, 209, and 210, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 223, 224, and 225, respectively; or xxviii. The HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 211, 212, and 213, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 226, 227, and 228, respectively; or xxix. The HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 214, 215, and 216, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 229, KVS, and 231, respectively; or xxx. A Vβ17 bispecific antibody or antigen-binding fragment thereof, wherein the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 217, 218, and 219, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 232, 233, and 234, respectively.

2. 2. The Vβ17 bispecific antibody or antigen-binding fragment thereof of claim 1, wherein the binding site for the first antigen binds to Vβ17 on CD8-positive or CD4-positive T cells.

3. 3. The Vβ17 bispecific antibody or antigen-binding fragment thereof of claim 1 or 2, wherein the binding site for the second antigen binds to a tumor antigen present on the surface of a cancer cell.

4. 4. The Vβ17 bispecific antibody or antigen-binding fragment of claim 1 , wherein HC1 and LC1 are humanized.

5. 5. The Vβ17 bispecific antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, wherein the binding site for the second antigen binds to CD123, kallikrein-related peptidase 2 (KLK2), prostate-specific membrane antigen (PSMA), or B-cell maturation antigen (BCMA).

6. the HC2 comprises a heavy chain complementarity determining region 1 (HCDR1-2), a heavy chain complementarity determining region 2 (HCDR2-2), and a heavy chain complementarity determining region 3 (HCDR3-2); the LC2 comprises a light chain complementarity determining region 1 (LCDR1-2), a light chain complementarity determining region 2 (LCDR2-2), and a light chain complementarity determining region 3 (LCDR3-2); i. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 34, 35, and 36, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 37, 38, and 39, respectively; or ii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 237, 238, and 239, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 252, 253, and 254, respectively; or iii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 240, 241, and 242, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 255, 256, and 257, respectively; or iv. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 243, 244, and 245, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 258, 259, and 260, respectively; or v. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs:246, 247, and 248, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs:261, AAS, and 263, respectively; or vi. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 249, 250, and 251, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 264, 265, and 266, respectively; or vii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 269, 270, and 271, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 284, 285, and 286, respectively; or viii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 272, 273, and 274, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 287, 288, and 289, respectively; or ix. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 275, 276, and 277, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 290, 291, and 292, respectively; or x. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 278, 279, and 280, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 293, DNN, and 295, respectively; or xi. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 281, 282, and 283, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 296, 297, and 298, respectively; or xii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 301, 302, and 303, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 316, 317, and 318, respectively; or xiii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 304, 305, and 306, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 319, 320, and 321, respectively; or xiv. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 307, 308, and 309, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 322, 323, and 324, respectively; or xv. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 310, 311, and 312, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 325, GAS, and 327, respectively; or xvi. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 313, 314, and 315, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 328, 329, and 330, respectively; or xvii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 333, 334, and 335, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 348, 349, and 350, respectively; or xviii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 336, 337, and 338, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 351, 352, and 353, respectively; or xix. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 339, 340, and 341, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 354, 355, and 356, respectively; or xx. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 342, 343, and 344, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 357, DNN, and 359, respectively; or xxi. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 345, 346, and 347, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 360, 361, and 362, respectively; or xxii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 365, 366, and 367, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 380, 381, and 382, ​​respectively; or xxiii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 368, 369, and 370, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 383, 384, and 385, respectively; or xxiv. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 371, 372, and 373, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 386, 387, and 388, respectively; or xxv. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 374, 375, and 376, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 389, DNN, and 391, respectively; or xxvi. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 377, 378, and 379, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 392, 393, and 394, respectively; or xxvii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 397, 398, and 399, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 412, 413, and 414, respectively; or xxviii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 400, 401, and 402, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 415, 416, and 417, respectively; or xxix. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 403, 404, and 405, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 418, 419, and 420, respectively; or xxx. The HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 404, 405, and 406, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 421, KAS, and 423, respectively; or xxxi. The Vβ17 bispecific antibody or antigen-binding fragment thereof of any one of claims 1 to 5, wherein the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 407, 408, and 409, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 424, 425, and 426, respectively.

7. 7. A Vβ17 bispecific antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, which is of an IgG isotype, for example IgG4 or IgG1.

8. An isolated polynucleotide comprising a polynucleotide encoding HC1 and LC1 of a Vβ17 bispecific antibody or antigen-binding fragment thereof according to any one of claims 1 to 7.

9. An isolated polynucleotide comprising a polynucleotide encoding HC2 and LC2 of a Vβ17 bispecific antibody or antigen-binding fragment thereof described in any one of claims 1 to 7.

10. A vector comprising the isolated polynucleotide of claim 8 and / or claim 9.

11. A host cell comprising the vector of claim 10.

12. 8. A method for inhibiting the growth or proliferation of cancer cells, comprising contacting the cancer cells with a Vβ17 bispecific antibody or antigen-binding fragment thereof described in any one of claims 1 to 7, wherein said contacting the cancer cells with the Vβ17 bispecific antibody or antigen-binding fragment thereof inhibits the growth or proliferation of the cancer cells.

13. 13. The method of claim 12, wherein the cancer cells are CD123-expressing cancer cells, kallikrein-related peptidase 2 (KLK2)-expressing cancer cells, prostate-specific membrane antigen (PSMA)-expressing cancer cells, or B-cell maturation antigen (BCMA)-expressing cancer cells.

14. A kit comprising a Vβ17 bispecific antibody or antigen-binding fragment thereof according to any one of claims 1 to 7 and instructions for use.

15. 1. A method for producing a Vβ17 bispecific antibody or antigen-binding fragment thereof, comprising: (a) culturing the host cell of claim 11 to produce a Vβ17 bispecific antibody or antigen-binding fragment thereof; (b) recovering the Vβ17 bispecific antibody or antigen-binding fragment thereof from the cell or culture; A method comprising:

16. An isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof, comprising a heavy chain (HC) having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 429, 432, 435, 438, 441, 444, 447, and 450.

17. 17. The isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment of claim 16, wherein the heavy chain (HC) sequence is selected from the group consisting of SEQ ID NOs: 429, 432, 435, 438, 441, 444, 447, and 450.

18. An isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof described in claim 16 or 17, further comprising a light chain (LC) having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 431, 434, 437, 439, 443, 445, 449, and 452.

19. 19. An isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof according to any one of claims 16 to 18, wherein the light chain (LC) sequence is selected from the group consisting of SEQ ID NOs: 431, 434, 437, 439, 443, 445, 449, and 452.

20. 20. An isolated nucleic acid encoding the isolated humanized Vβ17 monoclonal antibody or antigen-binding fragment thereof of any one of claims 16 to 19.

21. A vector comprising the isolated nucleic acid of claim 20.

22. A host cell comprising the vector of claim 21.

23. A Vβ17 antibody or antigen-binding fragment thereof, comprising: a first heavy chain (HC1) having a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2), and a heavy chain complementarity determining region 3 (HCDR3); and a first light chain (LC1) having a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2), and a light chain complementarity determining region 3 (LCDR3), i. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 45, 46, and 47, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 60, 61, and 62, respectively; or ii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 48, 49, and 50, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 63, 64, and 65, respectively; or iii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 51, 52, and 53, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 66, 67, and 68, respectively; or iv. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 54, 55, and 56, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 69, KVS, and 71, respectively; or v. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 57, 58, and 59, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 72, 73, and 74, respectively; or vi. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 77, 78, and 79, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 92, 93, and 94, respectively; or vii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 80, 81, and 82, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 95, 96, and 97, respectively; or viii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 83, 84, and 85, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 98, 99, and 100, respectively; or ix. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 86, 87, and 88, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 101, KVS, and 103, respectively; or x. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 89, 90, and 91, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 104, 105, and 106, respectively; or xi. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 109, 110, and 111, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 124, 125, and 126, respectively; or xii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 112, 113, and 114, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 127, 128, and 129, respectively; or xiii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 115, 116, and 117, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 130, 131, and 132, respectively; or xiv. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 118, 119, and 120, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 133, KVS, and 135, respectively; or xv. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 121, 122, and 123, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 136, 137, and 138, respectively; or xvi. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 141, 142, and 143, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 156, 157, and 158, respectively; or xvii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 144, 145, and 146, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 159, 160, and 161, respectively; or xviii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 147, 148, and 149, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 162, 163, and 164, respectively; or xix. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 150, 151, and 152, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 165, KVS, and 167, respectively; or xx. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 153, 154, and 155, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 168, 169, and 170, respectively; or xxi. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 173, 174, and 175, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 188, 189, and 190, respectively; or xxii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 176, 177, and 178, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 191, 192, and 193, respectively; or xxiii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 179, 180, and 181, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 194, 195, and 196, respectively; or xxiv. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 182, 183, and 184, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 197, KVS, and 199, respectively; or xxv. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 185, 186, and 187, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 200, 201, and 202, respectively; or xxvi. The HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 205, 206, and 207, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 220, 221, and 222, respectively; or xxvii. the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 208, 209, and 210, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 223, 224, and 225, respectively; or xxviii. The HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 211, 212, and 213, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 226, 227, and 228, respectively; or xxix. The HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 214, 215, and 216, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 229, KVS, and 231, respectively; or xxx. A Vβ17 antibody or antigen-binding fragment thereof, wherein the HCDR1, HCDR2, and HCDR3 comprise the amino acid sequences of SEQ ID NOs: 217, 218, and 219, respectively, and the LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 232, 233, and 234, respectively.

24. an antibody or antigen-binding fragment comprising a second heavy chain (HC2) having heavy chain complementarity determining region 1 (HCDR1-2), heavy chain complementarity determining region 2 (HCDR2-2), and heavy chain complementarity determining region 3 (HCDR3-2); and a second light chain (LC2) having light chain complementarity determining region 1 (LCDR1-2), light chain complementarity determining region 2 (LCDR2-2), and light chain complementarity determining region 3 (LCDR3-2); i. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 34, 35, and 36, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 37, 38, and 39, respectively; or ii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 237, 238, and 239, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 252, 253, and 254, respectively; or iii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 240, 241, and 242, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 255, 256, and 257, respectively; or iv. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 243, 244, and 245, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 258, 259, and 260, respectively; or v. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs:246, 247, and 248, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs:261, AAS, and 263, respectively; or vi. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 249, 250, and 251, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 264, 265, and 266, respectively; or vii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 269, 270, and 271, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 284, 285, and 286, respectively; or viii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 272, 273, and 274, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 287, 288, and 289, respectively; or ix. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 275, 276, and 277, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 290, 291, and 292, respectively; or x. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 278, 279, and 280, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 293, DNN, and 295, respectively; or xi. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 281, 282, and 283, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 296, 297, and 298, respectively; or xii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 301, 302, and 303, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 316, 317, and 318, respectively; or xiii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 304, 305, and 306, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 319, 320, and 321, respectively; or xiv. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 307, 308, and 309, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 322, 323, and 324, respectively; or xv. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 310, 311, and 312, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 325, GAS, and 327, respectively; or xvi. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 313, 314, and 315, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 328, 329, and 330, respectively; or xvii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 333, 334, and 335, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 348, 349, and 350, respectively; or xviii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 336, 337, and 338, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 351, 352, and 353, respectively; or xix. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 339, 340, and 341, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 354, 355, and 356, respectively; or xx. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 342, 343, and 344, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 357, DNN, and 359, respectively; or xxi. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 345, 346, and 347, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 360, 361, and 362, respectively; or xxii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 365, 366, and 367, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 380, 381, and 382, ​​respectively; or xxiii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 368, 369, and 370, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 383, 384, and 385, respectively; or xxiv. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 371, 372, and 373, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 386, 387, and 388, respectively; or xxv. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 374, 375, and 376, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 389, DNN, and 391, respectively; or xxvi. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 377, 378, and 379, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 392, 393, and 394, respectively; or xxvii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 397, 398, and 399, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 412, 413, and 414, respectively; or xxviii. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 400, 401, and 402, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 415, 416, and 417, respectively; or xxix. the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 403, 404, and 405, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 418, 419, and 420, respectively; or xxx. The HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 404, 405, and 406, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 421, KAS, and 423, respectively; or xxxi. An antibody or antigen-binding fragment, wherein the HCDR1-2, HCDR2-2, and HCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 407, 408, and 409, respectively, and the LCDR1-2, LCDR2-2, and LCDR3-2 comprise the amino acid sequences of SEQ ID NOs: 424, 425, and 426, respectively.

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