TCR-VBETA-specific therapeutic molecules and uses thereof

Abstract

The present disclosure provides compositions and uses for binding a chimeric antigen receptor (CAR) or an antibody or antigen-binding fragment to the Vβ region of a T cell receptor. It also provides a method for treating diseases such as cancer or an autoimmune disease using a Vβ region-targeting molecule. The present disclosure provides a chimeric antigen receptor (CAR) comprising: (i) an antigen-binding molecule that specifically binds to a TCR Vβ region; (ii) an extracellular domain; (iii) a transmembrane domain; (iv) a costimulatory domain; and (v) an activation domain, wherein the antigen-binding molecule is a single-chain variable fragment (scFv) comprising a variable heavy chain (VH) set forth in any one of SEQ ID NOs: 45 to 131 and 534 to 544 and / or a variable light chain (VL) set forth in any one of SEQ ID NOs: 132 to 227 and 545 to 558.

Description

[Technical Field]

[0001] Reference to sequence listings submitted electronically via EFS-WEB The Sequence Listing filed and submitted electronically with this application (Name: 2681_136PC02_Seqlisting_ST26.xml; Size: 858,459 bytes; Creation Date: December 26, 2023) is hereby incorporated by reference in its entirety.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 477,365, filed December 27, 2022, and U.S. Provisional Application No. 63 / 484,916, filed February 14, 2023, which are incorporated by reference in their entireties.

[0003] According to various aspects, the present disclosure relates to chimeric antigen receptors (CARs) or antibodies or antigen-binding fragments comprising a domain that binds to the Vβ region of a T cell receptor. The present disclosure also relates to methods of treating disease in a subject using such binding molecules. [Background technology]

[0004] Autoimmune diseases are caused by T cell dysfunction (Haroon N et al., Arthritis Rheum. 2013 October;65(10):2645-54, Duarte J. et al., PloS One 2010 May 10;5(5):e10558; Konig M. et al., Front Immunol 2016 Jan. 25;7:11). T cell dysfunction afflicts a larger population than those affected solely by autoimmune diseases, including individuals with cancer and related T cell malignancies. Most lymphocytic malignancies, which lead to lymphocytic leukemia and lymphoma, can be divided into those derived from either T cells or B cells. T-cell malignancies are a clinically and biologically heterogeneous group of disorders that collectively comprise 10-20% of non-Hodgkin's lymphomas and 20% of acute leukemias (see, e.g., https: / / www.cancer.org / cancer / non-hodgkin-lymphoma / about / t-cell-lymphoma.html).

[0005] A challenge in developing treatments for T cell disorders and T cell malignancies is the significant overlap in marker expression between clonal and conventional T cells, preventing a single antigen from unambiguously identifying the clonal (malignant) cells. Chimeric antigen receptor (CAR) T cell therapy has shown efficacy in B cell leukemia and lymphoma. However, targeting T cell lymphoproliferative disorders has been challenging due to the difficulty in identifying appropriate antigens for CAR cell therapy. Furthermore, there are no satisfactory methods for mitigating T cell loss without depleting T cell numbers, which leads to undesirable toxicity and severe immunosuppression. There is a need for methods of treating T cell mediated diseases and T cell malignancies that exhibit high specificity and efficacy in eliminating abnormal T cells. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Haroon N et al., Arthritis Rheum. 2013 October;65(10):2645-54 [Non-patent document 2] Duarte J. et al., PloS One 2010 May 10;5(5):e10558 [Non-patent document 3] Konig M. et al., Front Immunol 2016 Jan. 25;7:11 Summary of the Invention [Means for solving the problem]

[0007] The present disclosure provides a chimeric antigen receptor (CAR) comprising: (i) an antigen-binding molecule that specifically binds to a TCR Vβ region; (ii) an extracellular domain; (iii) a transmembrane domain; (iv) a costimulatory domain; and (v) an activation domain, wherein the antigen-binding molecule is a single-chain variable fragment (scFv) comprising a variable heavy chain (VH) set forth in any one of SEQ ID NOs: 45 to 131 and 534 to 544, and / or a variable light chain (VL) set forth in any one of SEQ ID NOs: 132 to 227 and 545 to 558.

[0008] In some aspects, (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively, and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively, and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 418, or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 376, SEQ ID NO: 377, and SEQ ID NO: 378, respectively. 3, and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 424, SEQ ID NO: 425, and SEQ ID NO: 426, respectively; or the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 427, SEQ ID NO: 428, and SEQ ID NO: 429, respectively; or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​respectively. , SEQ ID NO: 383, and SEQ ID NO: 384, and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 430, SEQ ID NO: 431, and SEQ ID NO: 432, respectively; or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 433, SEQ ID NO: 434, and SEQ ID NO: 435, respectively.and CDR3, or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 388, SEQ ID NO: 389, and SEQ ID NO: 390, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 436, SEQ ID NO: 437, and SEQ ID NO: 438, respectively; or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 391, SEQ ID NO: 392, and SEQ ID NO: 393, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 436, SEQ ID NO: 437, and SEQ ID NO: 438, respectively. and (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 394, 395, and 396, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 442, 443, and 444, respectively; or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 397, 398, and 399, respectively. and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; or (i) the variable and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 451, SEQ ID NO: 452, SEQ ID NO: 453, respectively; or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455,or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 456; or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 412, SEQ ID NO: 413, and SEQ ID NO: 414, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 460, SEQ ID NO: 461, and SEQ ID NO: 462, respectively; or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 415, SEQ ID NO: 416, and SEQ ID NO: 417, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 463, SEQ ID NO: 464, and SEQ ID NO: 465, respectively; or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 584, SEQ ID NO: 585, SEQ ID NO: 586, SEQ ID NO: 587, SEQ ID NO: 589, SEQ ID NO: 590, SEQ ID NO: 600, SEQ ID NO: 601, SEQ ID NO: 602, SEQ ID NO: 603, SEQ ID NO: 604, SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, SEQ ID NO: 608, SEQ ID NO: 609, SEQ ID NO: 610, SEQ ID NO: 611, SEQ ID NO: 612, SEQ ID NO: 613, SEQ ID NO: 614, SEQ ID NO: 615, SEQ ID NO: 616, SEQ ID NO: 617, SEQ ID NO: 618, SEQ ID NO: 619, SEQ ID NO: 619, SEQ ID NO: 620, SEQ ID NO: 621, SEQ ID NO: and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 596, SEQ ID NO: 597, and SEQ ID NO: 598, respectively; or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 587, SEQ ID NO: 588, and SEQ ID NO: 589, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 599, SEQ ID NO: 600, and SEQ ID NO: 601, respectively. and CDR3, or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 591, and SEQ ID NO: 592, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively; and / or (ii) the variable light chain (VL) comprisesEach of them contains CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, or SEQ ID NO: 608, SEQ ID NO: 609, and SEQ ID NO: 610, respectively.

[0009] In some embodiments, the variable heavy chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 45-131, and 534-544.

[0010] In some embodiments, the variable light chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 132-227, and 545-558.

[0011] In some aspects, the TCR Vβ region is selected from the group consisting of Vβ1, Vβ2, Vβ3, Vβ4, Vβ5.1, Vβ5.3, Vβ7.1, Vβ7.2, Vβ8, Vβ9, Vβ11, Vβ12, Vβ13.1, Vβ13.2, Vβ13.6, Vβ14, Vβ16, Vβ17, Vβ18, Vβ20, and Vβ22. In some aspects, the TCR Vβ region is Vβ2.

[0012] In some embodiments, the antigen-binding domain is an scFv, which comprises the amino acid sequence set forth in any one of SEQ ID NOs: 14 to 44.

[0013] In some embodiments, the costimulatory domain comprises a 4-1BB costimulatory domain. In some embodiments, the 4-1BB costimulatory domain comprises the amino acid sequence set forth in SEQ ID NO:8.

[0014] In some embodiments, the transmembrane domain comprises an hCD28 transmembrane. In some embodiments, the transmembrane domain comprises an hCD28 amino acid sequence set forth in SEQ ID NO:7.

[0015] In some embodiments, the signaling domain comprises a CD247 signaling domain. In some embodiments, the signaling domain comprises the CD247 signaling domain amino acid sequence set forth in SEQ ID NO:9.

[0016] In some embodiments, the scFv comprises a CD28 signal peptide. In some embodiments, the scFv comprises a CD28 signal peptide and the amino acid sequence set forth in SEQ ID NO:3.

[0017] In some embodiments, the scFv comprises a linker peptide. In some embodiments, the scFv comprises a linker peptide set forth in SEQ ID NO:4.

[0018] The present disclosure also provides isolated polynucleotides comprising nucleic acid molecules encoding the VH of a chimeric antigen receptor described herein. In some embodiments, the isolated polynucleotides described herein further comprise a nucleic acid molecule encoding the VL of a chimeric antigen receptor described herein. The present disclosure also provides isolated polynucleotides comprising nucleic acid molecules encoding the VL of a chimeric antigen receptor described herein. In some embodiments, the isolated polynucleotides described herein further comprise a nucleic acid molecule encoding the VH of a chimeric antigen receptor.

[0019] The present disclosure also provides isolated polynucleotides comprising nucleic acid molecules that encode the chimeric antigen receptors described herein.

[0020] The present disclosure also provides a vector comprising the isolated polynucleotide disclosed herein, hi some aspects, the vector is selected from the group consisting of a retroviral vector, an adenoviral vector, a lentiviral vector, and an adeno-associated viral vector.

[0021] The present disclosure also provides an antibody or antigen-binding fragment thereof capable of specifically binding to a TCR Vβ region, comprising a heavy chain variable region (VH) having the amino acid sequence set forth in any of SEQ ID NOs: 228 to 295 and 559 to 569. In some embodiments, the VH comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any of SEQ ID NOs: 228 to 295 and 559 to 569.

[0022] In some embodiments, the antibody or antigen-binding fragment further comprises a light chain variable region (VL) having an amino acid sequence set forth in any of SEQ ID NOs: 296-369 and 570-583.

[0023] The present disclosure also provides an antibody or antigen-binding fragment thereof capable of specifically binding to a TCR Vβ region, comprising a light chain variable region (VL) having the amino acid sequence set forth in any of SEQ ID NOs: 296 to 369 and 570 to 583. In some embodiments described herein, the VL comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any of SEQ ID NOs: 296 to 369 and 570 to 583.

[0024] In some embodiments, the antibody or antigen-binding fragment further comprises a heavy chain variable region (VH) having an amino acid sequence set forth in any of SEQ ID NOs: 228-295 and 559-569.

[0025] In some embodiments, the antibody or antigen-binding fragment comprises (i) (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; or (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively; or (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively; or (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 376, SEQ ID NO: 377, and SEQ ID NO: 378, respectively. or (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively; or (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​SEQ ID NO: 383, and SEQ ID NO: 384, respectively; or (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; or (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 388, SEQ ID NO: 389, and SEQ ID NO: 390, respectively; or (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 391, respectively. , SEQ ID NO: 392, and CDR3 set forth in SEQ ID NO: 393; or (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively; or (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 397, SEQ ID NO: 398, and SEQ ID NO: 399, respectively; or (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; or (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 403, SEQ ID NO: 404, and SEQ ID NO: 405, respectively. or (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:406, SEQ ID NO:407, and SEQ ID NO:408, respectively; or (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:409, SEQ ID NO:410, and SEQ ID NO:411, respectively; or (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:412, SEQ ID NO:413, and SEQ ID NO:414, respectively; or (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:415, SEQ ID NO:416, and SEQ ID NO:417, respectively;or (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 584, SEQ ID NO: 585, and SEQ ID NO: 586, respectively; or (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 587, SEQ ID NO: 588, and SEQ ID NO: 589, respectively; or (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 591, and SEQ ID NO: 592, respectively; or (u) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively; and / or (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; or (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 418, SEQ ID NO: 419, and SEQ ID NO: 420, respectively; or (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; or (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 424, SEQ ID NO: 425, and SEQ ID NO: 426, respectively; or (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 42, respectively. or (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 430, 431, and 432, respectively; or (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 433, 434, and 435, respectively; or (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 436, 437, and 438, respectively; or (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 439, 440, and 441, respectively. or (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively; or (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; or (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; or (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 451, SEQ ID NO: 452, and SEQ ID NO: 453, respectively;or (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively; or (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; or (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 460, SEQ ID NO: 461, and SEQ ID NO: 462, respectively; or (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 463, SEQ ID NO: 464, and SEQ ID NO: 465, respectively; or (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 596 and SEQ ID NO: 597, respectively. or (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 599, SEQ ID NO: 601, and SEQ ID NO: 601, respectively; or (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (u) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, or SEQ ID NO: 608, SEQ ID NO: 609, and SEQ ID NO: 610, respectively;

[0026] In some embodiments described herein, the antibody or antigen-binding fragment thereof is human, humanized, or chimeric. In some embodiments, the antibody or antigen-binding fragment thereof is an IgG antibody. In some embodiments, the IgG antibody is an IgG1 antibody or an IgG4 antibody. In some embodiments, the IgG antibody is an IgG1 antibody. In some embodiments, the antibody is an antigen-binding fragment of an antibody. In some embodiments, the fragment is selected from the group consisting of Fab, F(ab')2, Fv, scFv, scFv-Fc, dsFv, and single domain molecules. In some embodiments, the fragment is an scFv. In some embodiments, the fragment is a Fab. In some embodiments, the fragment is an intrabody. In some embodiments, the antigen-binding fragment lacks the Fc region.

[0027] In some embodiments described herein, the antibodies or antigen-binding fragments described herein comprise a VH and a VL on the same polypeptide chain. In some embodiments described herein, the VH and VL are connected by a linker.

[0028] In some embodiments of the antibodies or antigen-binding fragments thereof described herein, the TCR Vβ region is selected from the group consisting of Vβ1, Vβ2, Vβ3, Vβ4, Vβ5.1, Vβ5.3, Vβ7.1, Vβ7.2, Vβ8, Vβ9, Vβ11, Vβ12, Vβ13.1, Vβ13.2, Vβ13.6, Vβ14, Vβ16, Vβ17, Vβ18, Vβ20, and Vβ22. In some embodiments, the TCR Vβ region is Vβ2.

[0029] The present disclosure also provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a T cell composition comprising a CAR, wherein the CAR comprises (i) an antigen-binding molecule that specifically binds to a TCR Vβ region, (ii) an extracellular domain, (iii) a transmembrane domain, (iv) a costimulatory domain, and (v) an activation domain, and the antigen-binding molecule is a single-chain variable fragment (scFv) comprising a variable heavy chain set forth in any one of SEQ ID NOs: 45 to 131 and 534 to 544, and / or a variable light chain set forth in any one of SEQ ID NOs: 132 to 227 and 545 to 558.

[0030] In some embodiments of the methods described herein, the chimeric antigen receptor comprises (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively. or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 373, 374, and 375, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 421, 422, and 423, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 376, 377, and 378, respectively. and / or (ii) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 424, SEQ ID NO: 425, and SEQ ID NO: 426, respectively, or a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 427, SEQ ID NO: 428, and SEQ ID NO: 429, respectively, or (i) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 3, 82, SEQ ID NO: 383, and SEQ ID NO: 384, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 430, SEQ ID NO: 431, and SEQ ID NO: 432, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 433, SEQ ID NO: 434, and SEQ ID NO: 435, respectively.and CDR3 set forth in SEQ ID NO: 388, SEQ ID NO: 389, and SEQ ID NO: 390, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 436, SEQ ID NO: 437, and SEQ ID NO: 438, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 391, SEQ ID NO: 392, and SEQ ID NO: 393, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 436, SEQ ID NO: 437, and SEQ ID NO: 438, respectively. a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 439, SEQ ID NO: 440, and SEQ ID NO: 441, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 397, SEQ ID NO: 398, and SEQ ID NO: 399, respectively, and and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 449, SEQ ID NO: 450, respectively; 03, SEQ ID NO: 404, and SEQ ID NO: 405, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 451, SEQ ID NO: 452, and SEQ ID NO: 453, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively.and CDR3 set forth in SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 412, SEQ ID NO: 413, and SEQ ID NO: 414, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively. 460, SEQ ID NO: 461, SEQ ID NO: 462, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 415, SEQ ID NO: 416, and SEQ ID NO: 417, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 463, SEQ ID NO: 464, and SEQ ID NO: 465, respectively, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 584, SEQ ID NO: 585, and SEQ ID NO: 586, respectively. and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 596, SEQ ID NO: 597, and SEQ ID NO: 598, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 587, SEQ ID NO: 588, and SEQ ID NO: 589, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 599, SEQ ID NO: 600, and SEQ ID NO: 601, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 59 1, and SEQ ID NO: 592, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, respectively, or SEQ ID NO: 608, SEQ ID NO: 609, respectively.and a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 610.

[0031] In some embodiments, the variable heavy chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 45-131, and 534-544. In some embodiments of the methods described herein, the variable light chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 132-227, and 545-558.

[0032] In some aspects of the methods described herein, the cancer is selected from the group consisting of T-cell lymphoma, T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma (PTCL), PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukemia / lymphoma (ATLL), hepatosplenic T-cell lymphoma (HSTL), subcutaneous pancreatitis-like T-cell lymphoma (SPTCL), T-cell acute lymphoblastic leukemia (T-ALL), T-cell chronic lymphocytic leukemia, large granular lymphocyte leukemia, T-cell prolymphocytic leukemia, lymphoma granulomatosis, small- to medium-sized pleomorphic T-cell lymphoma, mycosis fungoides, Sézary syndrome, and cytotoxic T-cell lymphoma.

[0033] In some aspects of the methods described herein, the composition is delivered intratumorally, intravenously, intraperitoneally, intramuscularly, intrathecally, transdermally, or subcutaneously, hi some aspects, the composition is delivered intravenously or intratumorally.

[0034] In some aspects of the methods described herein, the subject is a human.

[0035] The present disclosure also provides a method for treating cancer in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a composition comprising an antibody or antigen-binding fragment thereof capable of specifically binding to a TCR Vβ region, the antibody or antigen-binding fragment comprising: (i) a heavy chain variable region (VH) having an amino acid sequence set forth in any of SEQ ID NOs: 228 to 295 and 559 to 569, and / or (ii) a light chain variable region (VL) having an amino acid sequence set forth in any of SEQ ID NOs: 296 to 369 and 570 to 583.

[0036] In some embodiments of the methods described herein, the antibody or antigen-binding fragment comprises (i) (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; or (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively; or (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively; or (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 376, SEQ ID NO: 377, and SEQ ID NO: 378, respectively. or (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively; or (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​SEQ ID NO: 383, and SEQ ID NO: 384, respectively; or (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; or (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 388, SEQ ID NO: 389, and SEQ ID NO: 390, respectively; or (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO: 397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, SEQ ID NO: 406, SEQ ID NO: 407, SEQ ID NO: 408, SEQ ID NO: 409, SEQ ID NO: 410, SEQ ID NO: 411, SEQ ID NO: 412, SEQ ID NO: 413, SEQ ID NO: 414, SEQ ID NO: 415, SEQ ID NO: 416, SEQ ID NO: 417, SEQ ID NO: 418, SEQ ID NO (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively; or (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 397, SEQ ID NO: 398, and SEQ ID NO: 399, respectively; or (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; or (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 403, SEQ ID NO: 404, and SEQ ID NO: 4 or (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; or (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411, respectively; or (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 412, SEQ ID NO: 413, and SEQ ID NO: 414, respectively; or (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 415, SEQ ID NO: 416, and SEQ ID NO: 417, respectively;or (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 584, SEQ ID NO: 585, and SEQ ID NO: 586, respectively; or (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 587, SEQ ID NO: 588, and SEQ ID NO: 589, respectively; or (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 591, and SEQ ID NO: 592, respectively; or (u) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively; and / or (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; or (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 418, SEQ ID NO: 419, and SEQ ID NO: 420, respectively; or (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; or (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 424, SEQ ID NO: 425, and SEQ ID NO: 426, respectively; or (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 42, respectively. or (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 430, 431, and 432, respectively; or (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 433, 434, and 435, respectively; or (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 436, 437, and 438, respectively; or (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 439, 440, and 441, respectively. or (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively; or (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; or (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; or (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 451, SEQ ID NO: 452, and SEQ ID NO: 453, respectively;or (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively; or (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; or (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 460, SEQ ID NO: 461, and SEQ ID NO: 462, respectively; or (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 463, SEQ ID NO: 464, and SEQ ID NO: 465, respectively; or (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 596 and SEQ ID NO: 597, respectively. or (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 599, SEQ ID NO: 601, and SEQ ID NO: 601, respectively; or (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (u) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, or SEQ ID NO: 608, SEQ ID NO: 609, and SEQ ID NO: 610, respectively;

[0037] In some embodiments of the methods described herein, the variable heavy chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 228-295, and 559-569. In some embodiments, the antibody or antigen-binding fragment further comprises a light chain variable region (VL) having an amino acid sequence set forth in any of SEQ ID NOs: 296-369, and 570-583. In some embodiments, the variable light chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 296-369 and 570-583. In some embodiments of the methods described herein, the antibody or antigen-binding fragment further comprises a heavy chain variable region (VH) having an amino acid sequence set forth in any of SEQ ID NOs: 228-295 and 559-569.

[0038] In some aspects of the methods described herein, the TCR Vβ region is selected from the group consisting of Vβ1, Vβ2, Vβ3, Vβ4, Vβ5.1, Vβ5.3, Vβ7.1, Vβ7.2, Vβ8, Vβ9, Vβ11, Vβ12, Vβ13.1, Vβ13.2, Vβ13.6, Vβ14, Vβ16, Vβ17, Vβ18, Vβ20, and Vβ22.

[0039] In some embodiments, the TCR Vβ region is Vβ2.

[0040] In some aspects of the methods described herein, the composition is delivered intratumorally, intravenously, intraperitoneally, intramuscularly, intrathecally, transdermally, or subcutaneously. In some aspects, the composition is delivered intravenously. In some aspects, the composition is delivered intratumorally.

[0041] In some aspects of the methods described herein, the subject is a human.

[0042] In some aspects of the methods described herein, the cancer is selected from the group consisting of T-cell lymphoma, T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma (PTCL), PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukemia / lymphoma (ATLL), hepatosplenic T-cell lymphoma (HSTL), subcutaneous pancreatitis-like T-cell lymphoma (SPTCL), T-cell acute lymphoblastic leukemia (T-ALL), T-cell chronic lymphocytic leukemia, large granular lymphocyte leukemia, T-cell prolymphocytic leukemia, lymphoma granulomatosis, small- to medium-sized pleomorphic T-cell lymphoma, mycosis fungoides, Sézary syndrome, and cytotoxic T-cell lymphoma.

[0043] The present disclosure also provides a method for treating a T cell-mediated disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a T cell composition comprising a CAR, wherein the CAR comprises (i) an antigen-binding molecule that specifically binds to a TCR Vβ region, (ii) an extracellular domain, (iii) a transmembrane domain, (iv) a costimulatory domain, and (v) an activation domain, and the antigen-binding molecule is a single-chain variable fragment (scFv) comprising a variable heavy chain set forth in any one of SEQ ID NOs: 45 to 131 and 534 to 544, and / or a variable light chain set forth in any one of SEQ ID NOs: 132 to 227 and 545 to 558.

[0044] In some embodiments of the methods described herein, the chimeric antigen receptor comprises (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 418, respectively. or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 376, SEQ ID NO: 377, and SEQ ID NO: 378, respectively. and / or (ii) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 424, SEQ ID NO: 425, SEQ ID NO: 426, respectively, or CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 427, SEQ ID NO: 428, SEQ ID NO: 429, respectively, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​SEQ ID NO: 383, and SEQ ID NO: 384, respectively. a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 384, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 430, SEQ ID NO: 431, and SEQ ID NO: 432, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 433, SEQ ID NO: 434, and SEQ ID NO: 435, respectively;Alternatively, (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 388, 389, and 390, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 436, 437, and 438, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 391, 392, and 393, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 439, 440, and 441, respectively. 41, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 397, SEQ ID NO: 398, and SEQ ID NO: 399, respectively, and and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 403, SEQ ID NO: 404, and SEQ ID NO: 405, respectively. and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 451, SEQ ID NO: 452, and SEQ ID NO: 453, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively; or(i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 412, SEQ ID NO: 413, and SEQ ID NO: 414, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 460, SEQ ID NO: 461, and SEQ ID NO: 462, respectively. a variable light chain (VL) comprising CDR1, CDR2, and CDR3, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 415, SEQ ID NO: 416, and SEQ ID NO: 417, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 463, SEQ ID NO: 464, and SEQ ID NO: 465, respectively, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 584, SEQ ID NO: 585, and SEQ ID NO: 586, respectively, and / or (i (i) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 596, SEQ ID NO: 597, and SEQ ID NO: 598, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 587, SEQ ID NO: 588, and SEQ ID NO: 589, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 599, SEQ ID NO: 600, and SEQ ID NO: 601, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 591, and SEQ ID NO: 592, respectively. and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, or CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 608, SEQ ID NO: 609, and SEQ ID NO: 610, respectively;and a variable light chain (VL) comprising CDR3.

[0045] In some embodiments, the variable heavy chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 45-131, and 534-544. In some embodiments, the variable light chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 132-227, and 545-558.

[0046] In some embodiments of the methods described herein, the T cell mediated disease is selected from the group consisting of atherosclerosis, Parkinson's disease, Alzheimer's disease, type 1 diabetes, Graves' disease, Hashimoto's thyroiditis, Addison's disease, rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis, psoriatic arthritis, lichen planus, lichen planus pilaris, morphea, scleroderma, systemic sclerosis, acute or chronic graft-versus-host disease (GVHD), heart organ transplant rejection, lung organ transplant rejection, kidney organ transplant rejection, interstitial lung disease, scleroderma, alopecia areata, vitiligo, celiac disease (sprue), myasthenia gravis, pernicious anemia, Sjogren's syndrome, systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

[0047] In some aspects of the methods described herein, the composition is delivered intratumorally, intravenously, intraperitoneally, intramuscularly, intrathecally, transdermally, or subcutaneously, hi some aspects, the composition is delivered intravenously.

[0048] In some aspects of the methods described herein, the subject is a human.

[0049] The present disclosure also provides a method for treating a T cell-mediated disease in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a composition comprising an antibody or antigen-binding fragment thereof capable of specifically binding to a TCR Vβ region, the antibody or antigen-binding fragment comprising: (i) a heavy chain variable region (VH) having an amino acid sequence set forth in any of SEQ ID NOs: 228 to 295 and 559 to 569, and / or (ii) a light chain variable region (VL) having an amino acid sequence set forth in any of SEQ ID NOs: 296 to 369 and 570 to 583.

[0050] In some embodiments of the methods described herein, the antibody or antigen-binding fragment comprises (i) (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; or (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively; or (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively; or (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 376, SEQ ID NO: 377, and SEQ ID NO: 378, respectively. or (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively; or (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​SEQ ID NO: 383, and SEQ ID NO: 384, respectively; or (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; or (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 388, SEQ ID NO: 389, and SEQ ID NO: 390, respectively; or (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO: 397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, SEQ ID NO: 406, SEQ ID NO: 407, SEQ ID NO: 408, SEQ ID NO: 409, SEQ ID NO: 410, SEQ ID NO: 411, SEQ ID NO: 412, SEQ ID NO: 413, SEQ ID NO: 414, SEQ ID NO: 415, SEQ ID NO: 416, SEQ ID NO: 417, SEQ ID NO: 418, SEQ ID NO (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively; or (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 397, SEQ ID NO: 398, and SEQ ID NO: 399, respectively; or (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; or (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 403, SEQ ID NO: 404, and SEQ ID NO: 4 or (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; or (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411, respectively; or (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 412, SEQ ID NO: 413, and SEQ ID NO: 414, respectively; or (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 415, SEQ ID NO: 416, and SEQ ID NO: 417, respectively;or (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 584, SEQ ID NO: 585, and SEQ ID NO: 586, respectively; or (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 587, SEQ ID NO: 588, and SEQ ID NO: 589, respectively; or (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 591, and SEQ ID NO: 592, respectively; or (u) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively; and / or (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; or (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 418, SEQ ID NO: 419, and SEQ ID NO: 420, respectively; or (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; or (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 424, SEQ ID NO: 425, and SEQ ID NO: 426, respectively; or (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 42, respectively. or (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 430, 431, and 432, respectively; or (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 433, 434, and 435, respectively; or (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 436, 437, and 438, respectively; or (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 439, 440, and 441, respectively. or (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively; or (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; or (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; or (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 451, SEQ ID NO: 452, and SEQ ID NO: 453, respectively;or (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively; or (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; or (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 460, SEQ ID NO: 461, and SEQ ID NO: 462, respectively; or (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 463, SEQ ID NO: 464, and SEQ ID NO: 465, respectively; or (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 596 and SEQ ID NO: 597, respectively. or (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 599, SEQ ID NO: 601, and SEQ ID NO: 601, respectively; or (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (u) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, or SEQ ID NO: 608, SEQ ID NO: 609, and SEQ ID NO: 610, respectively;

[0051] In some embodiments, the variable heavy chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 228-295, and 559-569. In some embodiments, the antibody or antigen-binding fragment further comprises a light chain variable region (VL) having an amino acid sequence set forth in any of SEQ ID NOs: 296-369, and 570-583.

[0052] In some embodiments, the variable light chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 296-369, and 570-583.

[0053] In some embodiments, the antibody or antigen-binding fragment further comprises a heavy chain variable region (VH) having an amino acid sequence set forth in any of SEQ ID NOs: 228-295 and 559-569.

[0054] In some aspects of the methods described herein, the TCR Vβ region is selected from the group consisting of Vβ1, Vβ2, Vβ3, Vβ4, Vβ5.1, Vβ5.3, Vβ7.1, Vβ7.2, Vβ8, Vβ9, Vβ11, Vβ12, Vβ13.1, Vβ13.2, Vβ13.6, Vβ14, Vβ16, Vβ17, Vβ18, Vβ20, and Vβ22. In some aspects, the TCR Vβ region is Vβ2.

[0055] In some embodiments of the methods described herein, the T cell mediated disease is selected from the group consisting of atherosclerosis, Parkinson's disease, Alzheimer's disease, type 1 diabetes, Graves' disease, Hashimoto's thyroiditis, Addison's disease, rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis, psoriatic arthritis, lichen planus, lichen planus pilaris, morphea, scleroderma, systemic sclerosis, acute or chronic graft-versus-host disease (GVHD), heart organ transplant rejection, lung organ transplant rejection, kidney organ transplant rejection, interstitial lung disease, scleroderma, alopecia areata, vitiligo, celiac disease (sprue), myasthenia gravis, pernicious anemia, Sjogren's syndrome, systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

[0056] In some aspects of the methods described herein, the composition is delivered intratumorally, intravenously, intraperitoneally, intramuscularly, intrathecally, or subcutaneously.

[0057] In some embodiments, the composition is delivered intravenously.

[0058] In some aspects of the methods described herein, the subject is a human.

[0059] The present disclosure also provides for the use of (a) a CAR described herein, or (b) an antibody or antigen-binding fragment described herein, for the manufacture of a medicament for treating a T-cell mediated disease. In some embodiments, the T cell mediated disease is selected from the group consisting of atherosclerosis, Parkinson's disease, Alzheimer's disease, type 1 diabetes, Graves' disease, Hashimoto's thyroiditis, Addison's disease, rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis, psoriatic arthritis, lichen planus, lichen planus pilaris, morphea, scleroderma, systemic sclerosis, acute or chronic graft-versus-host disease (GVHD), heart organ transplant rejection, lung organ transplant rejection, kidney organ transplant rejection, interstitial lung disease, scleroderma, alopecia areata, vitiligo, celiac disease (sprue), myasthenia gravis, pernicious anemia, Sjogren's syndrome, systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

[0060] The present disclosure also provides the use of (a) a CAR described herein, or (b) an antibody or antigen-binding fragment described herein, for the manufacture of a medicament for treating cancer. In some aspects, the cancer is selected from the group consisting of T-cell lymphoma, T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma (PTCL), PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukemia / lymphoma (ATLL), hepatosplenic T-cell lymphoma (HSTL), subcutaneous pancreatitis-like T-cell lymphoma (SPTCL), T-cell acute lymphoblastic leukemia (T-ALL), T-cell chronic lymphocytic leukemia, large granular lymphocyte leukemia, T-cell prolymphocytic leukemia, lymphoma granulomatosis, small- to medium-sized pleomorphic T-cell lymphoma, mycosis fungoides, Sézary syndrome, and cytotoxic T-cell lymphoma.

[0061] The present disclosure also provides a kit of parts comprising at least one of (i) a variable heavy chain and / or (ii) a variable light chain of (a) a CAR disclosed herein, or (b) an antibody or antigen-binding fragment disclosed herein. In some aspects, the kit further comprises instructions for use.

[0062] The present disclosure also provides an adeno-associated virus (AAV) vector encoding a chimeric antigen receptor (CAR) comprising: (i) an antigen-binding molecule that specifically binds to a TCR Vβ region; (ii) an extracellular domain; (iii) a transmembrane domain; (iv) a costimulatory domain; and (v) an activation domain, wherein the antigen-binding molecule is a single-chain variable fragment (scFv) comprising a variable heavy chain set forth in any one of SEQ ID NOs: 45 to 131 and 534 to 544, or a variable light chain set forth in any one of SEQ ID NOs: 132 to 227 and 545 to 558.

[0063] In some embodiments of the AAV vectors described herein, the vector comprises: (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 418, respectively. or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 376, SEQ ID NO: 377, and SEQ ID NO: 378, respectively. and / or (ii) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 424, SEQ ID NO: 425, SEQ ID NO: 426, respectively, or CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 427, SEQ ID NO: 428, SEQ ID NO: 429, respectively, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​SEQ ID NO: 383, and SEQ ID NO: 384, respectively. a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 384, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 430, SEQ ID NO: 431, and SEQ ID NO: 432, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 433, SEQ ID NO: 434, and SEQ ID NO: 435, respectively;Alternatively, (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 388, 389, and 390, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 436, 437, and 438, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 391, 392, and 393, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 439, 440, and 441, respectively. 41, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 397, SEQ ID NO: 398, and SEQ ID NO: 399, respectively, and and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 403, SEQ ID NO: 404, and SEQ ID NO: 405, respectively. and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 451, SEQ ID NO: 452, and SEQ ID NO: 453, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively; or(i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 412, SEQ ID NO: 413, and SEQ ID NO: 414, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 460, SEQ ID NO: 461, and SEQ ID NO: 462, respectively. a variable light chain (VL) comprising CDR1, CDR2, and CDR3, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 415, SEQ ID NO: 416, and SEQ ID NO: 417, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 463, SEQ ID NO: 464, and SEQ ID NO: 465, respectively, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 584, SEQ ID NO: 585, and SEQ ID NO: 586, respectively, and / or (i (i) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 596, SEQ ID NO: 597, and SEQ ID NO: 598, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 587, SEQ ID NO: 588, and SEQ ID NO: 589, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 599, SEQ ID NO: 600, and SEQ ID NO: 601, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 591, and SEQ ID NO: 592, respectively. and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, or CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 608, SEQ ID NO: 609, and SEQ ID NO: 610, respectively;and a variable light chain (VL) comprising CDR3.

[0064] In some embodiments, the variable heavy chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 45-131, and 534-544. In some embodiments, the variable light chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 132-227, and 545-558.

[0065] In some embodiments of the AAV described herein, the TCR Vβ region is selected from the group consisting of Vβ1, Vβ2, Vβ3, Vβ4, Vβ5.1, Vβ5.3, Vβ7.1, Vβ7.2, Vβ8, Vβ9, Vβ11, Vβ12, Vβ13.1, Vβ13.2, Vβ13.6, Vβ14, Vβ16, Vβ17, Vβ18, Vβ20, and Vβ22. In some embodiments, the TCR Vβ region is Vβ2.

[0066] In some embodiments of the AAVs described herein, the antigen-binding domain is an scFv. In some embodiments, the scFv comprises the amino acid sequence set forth in any of SEQ ID NOs: 14 to 44.

[0067] In some embodiments of the AAVs described herein, the costimulatory domain comprises a 4-1BB costimulatory domain. In some embodiments, the 4-1BB costimulatory domain comprises the amino acid sequence set forth in SEQ ID NO:8.

[0068] In some embodiments of the AAV described herein, the transmembrane domain comprises an hCD28 transmembrane. In some embodiments, the transmembrane domain comprises the hCD28 amino acid sequence set forth in SEQ ID NO:7.

[0069] In some embodiments of the AAV described herein, the signaling domain comprises a CD247 signaling domain. In some embodiments, the signaling domain comprises the CD247 signaling domain amino acid sequence set forth in SEQ ID NO:9.

[0070] In some embodiments of the AAVs described herein, the scFv comprises a CD28 signal peptide. In some embodiments, the scFv comprises a CD28 signal peptide and the amino acid sequence set forth in SEQ ID NO:3.

[0071] In some embodiments of the AAVs described herein, the scFv comprises a linker peptide. In some embodiments, the scFv comprises a linker peptide as set forth in SEQ ID NO:4.

[0072] The present disclosure also provides methods further comprising determining the subject's TCR Vβ usage. In some embodiments, determining the subject's TCR Vβ usage comprises obtaining a sample from the subject, wherein the sample is a blood sample or a tissue sample. In some embodiments, the subject is administered (a) a CAR described herein, or (b) an antibody or antigen-binding fragment described herein, that corresponds to the subject's TCR Vβ usage.

[0073] In some embodiments of the antibodies described herein, the ADCC activity of the antibody composition is increased or decreased by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 125%, about 150%, about 175%, about 200%, about 1-fold, about 2-fold, about 3-fold, or about 4-fold, or by about 5% to about 400%.

[0074] In some embodiments of the antibodies described herein, the antigen or antigen-binding fragment has increased antibody-dependent cell-mediated cytotoxicity activity achieved by non-fucosylation.

[0075] In some aspects of the antibodies described herein, the antibody or antigen-binding fragment has increased antibody-dependent cell-mediated cytotoxicity activity achieved through glycosylation. [Brief explanation of the drawings]

[0076] [Figure 1] The chimeric antigen receptor expressing lentiviral vector plasmid contains an EF-1a core promoter, hCD28 signal peptide, variable heavy chain, linker, variable light chain, hCD8a hinge, hCD28 transmembrane, h4-1bb signal peptide, hCD247 signal peptide, P2A peptide, and EGFP. [Figure 2A] This chart shows the effective killing of Vβ2+ cutaneous T-cell lymphoma (CTCL), but not Vβ13+ CTCL cells, by mCAR-Vβ2 T cells without a knockout (KO) of the endogenous T-cell receptor alpha constant (TRAC) region, as quantified by flow cytometry. [Figure 2B] This is a chart quantified by flow cytometry showing the effective killing of Vβ2+ CTCL cells, but not Vβ13+ CTCL cells, by mCAR-Vβ2 T cells with KO of the endogenous TRAC region. [Figure 2C] 1 is a chart quantified by flow cytometry showing specific targeting / killing of Vβ2+ CTCL cells while sparing Vβ2-negative conventional T cells and non-T cells in two different patient samples. [Figure 2D] 1 is a chart quantified by flow cytometry showing specific targeting / killing of Vβ2+ CTCL cells while sparing Vβ2-negative conventional T cells and non-T cells in two different patient samples. [Figure 2E]1 is a chart quantified by flow cytometry showing the killing specificity of mCAR-Vβ2 TRAC KO effector T cells in healthy control cultured peripheral blood mononuclear cells (PBMCs). [Figure 2F] 10 is a chart quantified by flow cytometry showing the killing specificity of mCAR-Vβ2 TRAC KO effector T cells in healthy controls cultured with purified pan-T. [Figure 3] FIG. 1 is a schematic diagram of the mouse model used to investigate in vivo Vβ2+ T lymphoma killing by allogeneic TCR-KO mCAR-Vβ2 T cells derived from healthy donors. [Figure 4] A-C are flow cytometric charts showing the number of CTCLs in spleen, bone marrow, and blood samples, respectively, between non-CAR-treated controls (NC) and mCAR-Vβ2-treated patient-derived CTCL-engrafted immunodeficient NSG mice. [Figure 5] A-C are flow cytometrically quantified charts showing the number of Vβ2+-negative CD4+ T cells in spleen, bone marrow, and blood samples, respectively, between non-CAR-treated controls (NC) and mCAR-Vβ2-treated patient-derived CTCL-transplanted immunodeficient NSG mice. [Figure 6] A-C are flow cytometric charts showing mCAR-Vβ2 numbers in spleen, bone marrow, and blood samples, respectively, between non-CAR-treated controls (NC) and mCAR-Vβ2-treated patient-derived CTCL-transplanted immunodeficient NSG mice. [Figure 7] This is a chart quantified by flow cytometry showing bone marrow-derived Jurkat-Vβ2 numbers between non-CAR-treated controls and mCAR-Vβ2-treated Jurkat-Vβ2 cell-transplanted immunodeficient NSG mice after 10 days. [Figure 8] This is a chart quantified by flow cytometry showing bone marrow-derived mCAR-Vβ2 numbers between non-CAR-treated controls and mCAR-Vβ2-treated Jurkat-Vβ2 cell-transplanted immunodeficient NSG mice after 10 days. [Figure 9A] 1 is a chart quantified by flow cytometry showing effective killing of Vβ2+ CTCL cells by humanized CAR-Vβ2 T cells with KO of the endogenous TRAC region. [Figure 9B] 1 is a chart quantified by flow cytometry showing effective killing of Vβ2+ CTCL cells by humanized CAR-Vβ2 T cells with KO of the endogenous TRAC region. [Figure 9C] 1 is a chart quantified by flow cytometry showing effective killing of Vβ2+ CTCL cells by humanized CAR-Vβ2 T cells with KO of the endogenous TRAC region. [Figure 9D] 1 is a chart quantified by flow cytometry showing effective killing of Vβ2+ CTCL cells by humanized CAR-Vβ2 T cells with KO of the endogenous TRAC region. [Figure 10A] 1 is a chart quantified by single-cell RNA sequencing and T cell receptor (TCR) sequencing to identify and quantify T cell clones in CTCL patients and healthy controls. [Figure 10B] 1 is a chart showing the frequency of different Vβ usage by malignant cells across CTCL patients, quantified by anti-Vβ antibody staining and flow cytometry. [Figure 11] 1 is a chart quantified by flow cytometry showing the efficiency of TCR alpha constant region knockout (TRAC KO) in mCAR-Vβ T cells and the purity of TRAC KO mCAR-Vβ2 T cells after magnetic bead removal of remaining CD3+ cells. [Figure 12] The percentage of CD4+ and CD8+ T cells during in vitro expansion of CAR cells (center) and the lentiviral transduction efficiency of each subtype (left: CD4+, right: CD8+) are shown, as measured by flow cytometry. [Figure 13A]Figure 1 shows reduced MHC class I protein expression by mCAR Vβ2 T cells after knockout of beta-2-microglobulin (B2M KO) compared to non-knockout control (NC). [Figure 13B] Figure 1 shows reduced MHC class II protein expression by mCAR-Vβ2 T cells following knockout of class II major histocompatibility complex transactivator (CIITA KO) compared to non-knockout control (NC). [Figure 14] A and B are flow cytometric charts showing the number of Vβ2+ CTCLs in bone marrow and spleen samples, respectively, between non-CAR-treated controls (NC) and immunodeficient NSG mice transplanted with CTCL cells from CAR-CD19-treated and mCAR-Vβ2-treated patients. [Figure 15] A and B are flow cytometric charts showing the number of Vβ2-negative T cells in bone marrow and spleen samples, respectively, between non-CAR-treated controls (NC) and immunodeficient NSG mice transplanted with CTCL cells from CAR-CD19-treated and mCAR-Vβ2-treated patients. [Figure 16] A and B are flow cytometric charts showing CD8+ CAR numbers in bone marrow and spleen samples, respectively, between non-CAR-treated controls (NC) and immunodeficient NSG mice transplanted with CTCL cells from CAR-CD19-treated and mCAR-Vβ2-treated patients. [Figure 17] A and B are flow cytometric charts showing CD4+ CAR numbers in bone marrow and spleen samples, respectively, between non-CAR-treated controls (NC) and immunodeficient NSG mice transplanted with CTCL cells from CAR-CD19- and mCAR-Vβ2-treated patients. [Figure 18]This is an adeno-associated virus (AAV) vector plasmid expressing a chimeric antigen receptor (CAR). The AAV vector plasmid contains the left homology arm (LHA) of the human TRAC region, T2A in-frame with the TRAC coding sequence, CAR-Vb2, P2A peptide, EGFP, bGH polyA signal, and the right homology arm (RHA) of the human TRAC region. [Figure 19A] 10 is a chart quantified by flow cytometry showing CD3 and HLA-A / B / C expression on pan T cells before and after CD3+ cell depletion using CD3+ microbeads, after TRAC / B2M / CIITA triple KO and AAV-CAR delivery. [Figure 19B] Chart quantified by flow cytometry showing expression of GFP as a CAR expression reporter in CD3-HLA-A / B / CT cells after TRAC / B2M / CIITA triple KO and AAV-CAR-Vβ2 transduction at 2 days (left) and 10 days (right) post-transduction. [Figure 20] Figure 10 is a flow cytometry quantified chart showing effective killing of CTCL cells by mCAR Vβ2+ using the TRAC / B2M / CIITA triple KO and AAV-CAR strategies. [Figure 21] FIG. 24 is a chart showing the reference arrays for identifying each of the CAR constructs represented in the charts in each of FIGS. 22-23. [Figure 22] The immunogenicity results of various allogeneic CAR constructs are shown according to the alignment shown in Figure 21. The figure is quantified by flow cytometry detecting anti-allogeneic cell IgM and assay of serum from healthy control 1 (HC1). [Figure 23] The immunogenicity results of various allogeneic CAR constructs are shown according to the alignment shown in Figure 21. The figure is quantified by flow cytometry detecting anti-allogeneic cell IgM and assay of serum from healthy control 2 (HC2). [Figure 24]The immunogenicity results of various allogeneic CAR constructs are shown according to the alignment shown in Figure 21. The figure is quantified by flow cytometry detecting anti-allogeneic cell IgM and assay of serum from healthy control 3 (HC3). [Figure 25] The immunogenicity results of various allogeneic CAR constructs are shown according to the alignment shown in Figure 21. The figure is quantified by flow cytometry detecting anti-allogeneic cell IgM and Vβ1 assays of patient-derived sera. [Figure 26] The immunogenicity results of various allogeneic CAR constructs are shown according to the alignment shown in Figure 21. The figure is quantified by flow cytometry detecting anti-allogeneic cell IgM and Vβ2 assays of patient-derived sera. [Figure 27] The immunogenicity results of various allogeneic CAR constructs are shown according to the alignment shown in Figure 21. The figure is quantified by flow cytometry detecting anti-allogeneic cell IgM and Vβ13.2 assays of patient-derived sera. [Figure 28] The immunogenicity results of various allogeneic CAR constructs are shown according to the alignment shown in Figure 21. The figure is quantified by flow cytometry detecting anti-allogeneic cell IgG and assay of serum from healthy control 1 (HC1). [Figure 29] The immunogenicity results of various allogeneic CAR constructs are shown according to the alignment shown in Figure 21. The figure is quantified by flow cytometry detecting anti-allogeneic cell IgG and assay of serum from healthy control 2 (HC2). [Figure 30] The immunogenicity results of various allogeneic CAR constructs are shown according to the alignment shown in Figure 21. The figure is quantified by flow cytometry detecting anti-allogeneic cell IgG and assay of serum from healthy control 3 (HC3). [Figure 31]The immunogenicity results of various allogeneic CAR constructs are shown according to the alignment shown in Figure 21. The figure is quantified by flow cytometry detecting anti-allogeneic cell IgG and Vβ1 assay of patient-derived sera. [Figure 32] The immunogenicity results of various allogeneic CAR constructs are shown according to the alignment shown in Figure 21. The figure is quantified by flow cytometry detecting anti-allogeneic cell IgG and Vβ2 assays of patient-derived sera. [Figure 33] The immunogenicity results of various allogeneic CAR constructs are shown according to the alignment shown in Figure 21. The figure is quantified by flow cytometry detecting anti-allogeneic cell IgG and Vβ13.2 assays of patient-derived sera. [Figure 34A] 1 shows the results of in vivo imaging system (IVIS) imaging in prone position in untreated immunodeficient NSG mice (NC), mice administered with Jurkat-Vβ2+ cells, mice administered with luciferase-expressing Jurkat-Vβ2+ cells, and mice administered with luciferase-expressing Jurkat-Vβ2+ cells and hCAR-Vβ2 T cells. [Figure 34B] 1 is a bar graph showing the results of luciferin signaling from regions of interest (ROIs) by IVIS imaging in untreated immunodeficient NSG mice (NC), mice administered Jurkat-Vβ2+ cells, mice administered luciferase-expressing Jurkat-Vβ2+ cells, and mice administered luciferase-expressing Jurkat-Vβ2+ cells and hCAR-Vβ2 T cells. [Figure 35A] 1 shows the results of in vivo imaging system (IVIS) imaging in supine untreated immunodeficient NSG mice (NC), mice administered with Jurkat-Vβ2+ cells, mice administered with luciferase-expressing Jurkat-Vβ2+ cells, and mice administered with luciferase-expressing Jurkat-Vβ2+ cells and hCAR-Vβ2 T cells. [Figure 35B] 1 is a bar graph showing the results of luciferin signaling from regions of interest (ROIs) by IVIS imaging in untreated immunodeficient NSG mice (NC), mice administered Jurkat-Vβ2+ cells, mice administered luciferase-expressing Jurkat-Vβ2+ cells, and mice administered luciferase-expressing Jurkat-Vβ2+ cells and hCAR-Vβ2 T cells. [Figure 36A] Shown are CD3 purity, percentages of CD4 and CD8 populations, and CAR expression of AAV-dependent allogeneic hCAR-Vβ2 T cells (see bottom row) compared to lentivirus-dependent allogeneic CAR-CD19 T cells (see top row), as quantified by flow cytometry. [Figure 36B] 10 is a chart quantified by flow cytometry showing effective killing of Vβ2+ cutaneous T-cell lymphoma (CTCL) by AAV hCAR-Vβ2 T cells compared to CAR-CD19 in cells obtained from Vβ2+ Patient 1 (see chart on the left) and Vβ2+ Patient 1 (see chart on the right). [Figure 36C] 10 is a flow cytometry quantification chart showing the number of live Jurkat-TRBV20-1 (Vβ2L, see chart on the left) or Jurkat-TRBV6-2 (Vβ13.2+, see chart on the right) cells after overnight in vitro culture with allogeneic lentiCAR-CD19 T cells or AAV-hCAR-Vβ2 T cells at various E:T ratios. [Figure 37] 10 is a flow cytometry quantification chart showing CD3 purity, CD4, and CD8 population percentages, and green fluorescent protein (GFP) expression as a chimeric antigen receptor (CAR) reporter in lentivirally delivered CAR-CD19 (see top row), lenti-hCAR-Vβ2 (see middle row), and AAV-hCAR-Vβ2 T cells (see bottom row). [Figure 38A] Results are shown for total CD4 T cells isolated from a Vβ2+ PTCL patient, adoptively transferred into groups of NSG mice, and then treated with allogeneic triple KO AAV-hCAR-Vβ2 (AAV hCAR-Vβ2) or lentiCAR-CD19 (CAR-CD19) generated from healthy donor pan T cells compared to an optional untreated control (NC). Results were quantified by flow cytometry using Vβ2+ CTCL cells derived from spleen samples 3 days after treatment. [Figure 38B] Results are shown for total CD4 T cells isolated from a Vβ2+ PTCL patient, adoptively transferred into groups of NSG mice, and then treated with allogeneic triple KO AAV-hCAR-Vβ2 (AAV hCAR-Vβ2) or lentiCAR-CD19 (CAR-CD19) generated from healthy donor pan T cells compared to an optional untreated control (NC). Results were quantified by flow cytometry using Vβ2 conventional T cells derived from spleen samples 3 days after treatment. [Figure 38C] Figure 1 shows the results of total CD4 T cells isolated from a Vβ2+ PTCL patient, adoptively transferred into groups of NSG mice, and then treated with allogeneic triple KO AAV-hCAR-Vβ2 (AAV hCAR-Vβ2) or lentiCAR-CD19 (CAR-CD19) generated from healthy donor pan T cells compared to an optional untreated control (NC). Results were quantified by flow cytometry using the percentage of CD69+ among CD8 CAR-T cells from spleen samples 3 days after treatment. [Figure 38D] Figure 1 shows the results of total CD4 T cells isolated from a Vβ2+ PTCL patient, adoptively transferred into groups of NSG mice, and then treated with allogeneic triple KO AAV-hCAR-Vβ2 (AAV hCAR-Vβ2) or lentiCAR-CD19 (CAR-CD19) generated from healthy donor pan-T cells compared to an optional untreated control (NC). Results were quantified by flow cytometry using the percentage of CD69+ among CD4 CAR-T cells from spleen samples 3 days after treatment. [Figure 38E]Results are shown for total CD4 T cells isolated from a Vβ2+ PTCL patient, adoptively transferred into groups of NSG mice, and then treated with allogeneic triple KO AAV-hCAR-Vβ2 (AAV hCAR-Vβ2) or lentiCAR-CD19 (CAR-CD19) generated from healthy donor pan T cells compared to an optional untreated control (NC). Results were quantified by flow cytometry using bone marrow (BM)-derived Vβ2+ CTCL cells. [Figure 38F] Results are shown for total CD4 T cells isolated from a Vβ2+ PTCL patient, adoptively transferred into groups of NSG mice, and then treated with allogeneic triple KO AAV-hCAR-Vβ2 (AAV hCAR-Vβ2) or lentiCAR-CD19 (CAR-CD19) generated from healthy donor pan-T cells compared to an optional untreated control (NC). The percentage of CD69+ among bone marrow (BM)-derived CD8 CAR-T cells was used to quantitate results by flow cytometry. [Figure 38G] Results are shown for total CD4 T cells isolated from a Vβ2+ PTCL patient, adoptively transferred into groups of NSG mice, and then treated with allogeneic triple KO AAV-hCAR-Vβ2 (AAV hCAR-Vβ2) or lentiCAR-CD19 (CAR-CD19) generated from healthy donor pan-T cells compared to an optional untreated control (NC). The percentage of CD69+ among bone marrow (BM)-derived CD4 CAR-T cells was used to quantitate results by flow cytometry. [Figure 39A] FIG. 1 shows long-term monitoring of NSG mice bearing Jurkat-TRBV20-1 lucifer cells by IVIS (luciferin bioluminescence signal) over periods of 2, 10, 16, 23, and 30 days after a single treatment with no treatment (NC) mice (see top row), CAR-CD19 T cells (see second row from the top), lenti-hCAR-Vβ2 T cells (see second row from the bottom), and AAV-hCAR-Vβ2 T cells (see bottom row) in the prone position. [Figure 39B]Figure 1 shows long-term monitoring of NSG mice bearing Jurkat-TRBV20-1 lucifer cells by IVIS (luciferin bioluminescence signal) over periods of 2, 10, 16, 23, and 30 days after a single treatment with no treatment (NC) mice (see top row), CAR-CD19 T cells (see second row from the top), lenti-hCAR-Vβ2 T cells (see second row from the bottom), and AAV-hCAR-Vβ2 T cells (see bottom row) in the supine position. [Figure 39C] 10 is a chart showing bioluminescence of NSG mice bearing Jurkat-TRBV20-1 Lucifer cells by IVIS (luciferin bioluminescence signal) from days 0 to 30 among no treatment (NC) mice, mice treated with CAR-CD19 T cells, lenti-hCAR-Vβ2 T cells, and mice treated with AAV-hCAR-Vβ T cells in the prone position. [Figure 39D] 10 is a chart showing bioluminescence of NSG mice bearing Jurkat-TRBV20-1 Lucifer cells by IVIS (luciferin bioluminescence signal) from days 0 to 30 among no treatment (NC) mice, mice treated with CAR-CD19 T cells, lenti-hCAR-Vβ2 T cells, and AAV-hCAR-Vβ T cells in the supine position. [Figure 40] A shows the body weight of the same NSG mice as in Figures 39A-39D after treatment with no treatment (NC), CAR-CD19 T cells, lenti-hCAR-Vβ2 T cells, and AAV-hCAR-Vβ T cells, and after treatment with Jurkat-TRBV20-1-Lucifer cells. B shows the survival rate (%) of the same NSG mice as in Figures 39A-39D after treatment with no treatment (NC), CAR-CD19 T cells, lenti-hCAR-Vβ2 T cells, and AAV-hCAR-Vβ T cells, and after treatment with Jurkat-TRBV20-1-Lucifer cells. [Figure 41] FIG. 1 is an exemplary schematic diagram of various cytokine combinations used to expand hCAR-Vβ2 T cells in vitro. [Figure 42]1 is a chart showing the number of viable CD3-hCAR-Vβ2 T cells at days 0, 7, and 12 under various cytokine combination conditions. [Figure 43] A is a chart showing the number of viable Jurkat-TRBV20-1 cells after 0-4 days of culture by repeat Jurkat-TRBV20-1 killing assay (see Figure 41), as quantified by trypan blue cell counting and flow cytometry. B is a chart showing the number of viable CD3-hCAR-Vβ2 T cells after 0-4 days of culture by repeat Jurkat-TRBV20-1 killing assay (see Figure 41), as quantified by trypan blue cell counting and flow cytometry. [Figure 44A] 1 is a chart showing the mean fluorescence intensity (MFI) of CD45RA+CD45RO+ % of CD8+CD3- hCAR-Vβ2 T cells expressing CD45RA+CD45RO+ as quantified by flow cytometry. [Figure 44B] 1 is a chart showing the mean fluorescence intensity (MFI) of Tim3 on CD8+CD3- hCAR-Vβ2 T cells expressed as quantified by flow cytometry. [Figure 44C] 1 is a chart showing the percentage of IFNγ+ cytokine-expanded CD8+CD3− hCAR-Vβ2 T cells at 7 days after 6 hours of Jurkat-TRBV20-1 stimulation in vitro, as quantified by flow cytometry. [Figure 45A] 10 is a chart showing the percentage of IFNγ+ cytokine proliferation-rested CD8+CD3− hCAR-Vβ2 T cells over 12 days as quantified by flow cytometry. [Figure 45B] 10 is a chart showing the percentage of CD45RA+CD45RO+ cytokine proliferation-rested CD8+CD3- hCAR-Vβ2 T cells quantified by flow cytometry for 7 and 12 days. [Figure 46] 1 is an exemplary depiction of optimal cytokine combinations that promote CAR-T growth in vitro. [Figure 47]Figure 1 shows charts depicting the expression of Lens Culinaris Agglutinin (LCA) on the surface of parental expiCHO antibody-producing cells (see chart on the left), pre-sorted expiCHO cells after Fut8 knockout (KO) (see chart in the middle), and sorted (purified) expiCHO cells after Fut8 KO (see chart on the right), as quantified by flow cytometry. [Figure 48] 1 is a chart showing an anti-Vβ2 antibody competition assay between 1.25 βg / mL mouse and humanized anti-Vβ2-FITC antibodies quantified by flow cytometry. [Figure 49] 1 is a chart showing functional antibody-dependent cellular cytotoxicity (ADCC) assays of humanized and murine anti-Vβ2 antibodies. [Figure 50] 1 is a chart showing the number of viable Jurkat-TRBV20-1 target cells measured by flow cytometry after overnight co-culture with effector NK cells from healthy donors at various E:T ratios with no antibody, 100 ng / mL mouse anti-Vβ2 antibody, and humanized anti-Vβ2 antibody. [Figure 51] (A) is a chart showing the number of viable CTCL cells measured by flow cytometry in PBMCs from Vβ2+ CTCL patient 1 after overnight culture with NK effector cells from a healthy donor at various E:T ratios without added antibody, without added mouse anti-Vβ2 antibody, and with added humanized anti-Vβ2 antibody. (B) is a chart showing the number of viable CTCL cells measured by flow cytometry in PBMCs from Vβ2+ CTCL patient 2 after overnight culture with NK effector cells from a healthy donor at various E:T ratios without added antibody, without added mouse anti-Vβ2 antibody, and with added humanized anti-Vβ2 antibody. [Figure 52](A) is a chart showing the number of live Vβ2-negative T cells quantified by flow cytometry from PBMCs of Vβ2+ CTCL patient 1, cultured overnight with natural killer (NK) effector cells from a healthy donor at various E:T ratios without, with, or with a mouse anti-Vβ2 antibody, and with a humanized anti-Vβ2 antibody. (B) is a chart showing the number of live Vβ2-negative T cells quantified by flow cytometry from Vβ2+ CTCL patient 2, cultured overnight with natural killer (NK) effector cells from a healthy donor at various E:T ratios without, with, or with a mouse anti-Vβ2 antibody, and with a humanized anti-Vβ2 antibody. [Figure 53] (A) is a chart showing the results of viable non-T cell counts quantified by flow cytometry from PBMCs of Vβ2+ CTCL patient 1 cultured overnight with NK effector cells from a healthy donor at various E:T ratios without, with, and with humanized anti-Vβ2 antibodies. (B) is a chart showing the results of viable non-T cell counts quantified by flow cytometry from Vβ2+ CTCL patient 2 (FIG. 52B) cultured overnight with NK effector cells from a healthy donor at various E:T ratios without, with, and with humanized anti-Vβ2 antibodies. [Figure 54] 16A-16C are images showing successful treatment of T-cell lymphoma with anti-Vβ2 humanized therapeutic antibody treatment in NSG mice over 7, 14, and 16 days, with a comparison between control antibody and NK cells (see top row), followed by anti-Vβ2 antibody and NK cells (see middle row), and with anti-Vβ2 antibody administration alone (see bottom row). [Figure 55A] Graph showing that anti-Vβ1 CAR has specificity for Vβ1 over Vβ3, Vβ7.1, and non-Vβ-expressing Jurkat effector cells. [Figure 55B] 1 is a table showing the percentage area under "CD69 activation" for anti-Vβ1 CARs on Vβ1, Vβ3, Vβ7.1, and non-Vβ-expressing Jurkat effector cells. [Figure 56A] Graph showing that anti-Vβ7.2 CAR has specificity for Vβ7.2 over Vβ13.1, Vβ13.6, and non-Vβ-expressing Jurkat effector cells. [Figure 56B] 1 is a table showing the percentage area under "CD69 activation" of anti-Vβ7.2 CARs on Vβ7.2, Vβ13.1, Vβ13.6, and non-Vβ-expressing Jurkat effector cells. [Figure 57A] Graph showing that anti-Vβ13.6 CAR has specificity for Vβ13.6 over Vβ13.1, Vβ17, and non-Vβ-expressing Jurkat effector cells. [Figure 57B] 1 is a table showing the percentage area under "CD69 activation" for anti-Vβ13.6 CARs on Vβ13.6, Vβ13.1, Vβ17, and non-Vβ-expressing Jurkat effector cells. DETAILED DESCRIPTION OF THE INVENTION

[0077] definition 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 disclosure belongs. In case of conflict, the present application, including definitions, will control. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. All publications, patents, and other references mentioned herein are incorporated by reference in their entirety, as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0078] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting. Other features and advantages of the present disclosure will be apparent from the detailed description, and from the claims.

[0079] In order to further define this disclosure, the following terms and definitions are provided.

[0080] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as "one or more," and "at least one," can be used interchangeably herein. As used herein, the term "a" or "an" means "one." As disclosed herein, the term "a" or "an" includes "two or more" or "plurality."

[0081] The term "about" is used herein to mean approximately, roughly, around, or within a range thereof. When the term "about" is used in conjunction with a numerical range, the term modifies that range by extending its boundaries above and below the numerical values ​​set forth. In general, the term "about" is used herein to modify a numerical value by plus or minus 10 percent (above or below) the set forth value.

[0082] As disclosed herein, the word "comprising" comprises similar aspects otherwise disclosed with the terms "consisting of" and / or "consisting essentially of."

[0083] Throughout this disclosure, various aspects of the present disclosure are presented in a range format. The description in range format should be understood merely for convenience and simplicity and should not be construed as an inflexible limitation on the scope of the present disclosure. Accordingly, the description of a range should be considered to specifically disclose all possible subranges and individual numerical values ​​within that range. For example, a description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. Numerical ranges described include the numerical boundaries defining the range and include each integer within the defined range.

[0084] Units, prefixes, and symbols are indicated in their accepted form in the International System of Units (SI). Numerical ranges are intended to be inclusive of the numbers defining the range. When a range of values ​​is recited, it is understood that each intervening integer and each fractional part between the recited upper and lower limits of that range is also expressly disclosed, along with each subrange between such values. The upper and lower limits of any range may independently be included or excluded from the range, and each range including either, neither, or both of the upper and lower limits is also encompassed within the present disclosure. Thus, ranges recited herein are understood to be shorthand for all values ​​within the range, including the recited endpoints. For example, a range of 1 to 10 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0085] When a value is explicitly recited, it should be understood that values ​​that are approximately the same number or amount as the recited value are also within the scope of the disclosure. Thus, any value recited herein includes the exact value and values ​​that are approximately the same as the exact value. When a combination is disclosed, each subcombination of the elements of that combination is also specifically disclosed and is within the scope of the disclosure. Conversely, when different elements or groups of elements are individually disclosed, combinations thereof are also disclosed. When any element of the disclosure is disclosed as having multiple alternatives, examples of the disclosure in which each alternative is excluded, alone or in any combination with other alternatives, are also disclosed herein; more than one element of the disclosure may have such an exclusion, and all combinations of elements with such exclusions are disclosed herein.

[0086] As used herein, the term "and / or" should be considered a specific disclosure of each of the two specified features or components, whether or not the other is present. Thus, the term "and / or" used herein in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0087] As used herein, the term "effective amount" or "pharmaceutically effective amount" or "therapeutically effective amount" refers to the amount or content of a therapeutic agent described herein that is sufficient to elicit the necessary or desired therapeutic response; in other words, the amount is sufficient to induce a measurable biological response when administered to a patient.

[0088] As used herein, the term "unit dosage form" or "unit dose composition" refers to a device containing a measured amount of a therapeutic agent as described herein, wherein said amount is such that one or more predetermined units can be provided as a single therapeutic administration.

[0089] As used herein, the term "administration" refers to administration to a subject. Administration to an animal subject (e.g., a human) can be by any appropriate route. "Administering" refers to physically introducing a composition containing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those of skill in the art. In some aspects of the present disclosure, administration can be enteral administration (including oral and transoral administration), administration via an endoscopic delivery system, administration via a nasogastric tube, administration via a nasojejunal tube, administration via an upper gastrointestinal endoscope, administration via colonoscopy, or administration via a retention enema, parenteral administration (e.g., intramuscular, subdermal, subcutaneous, intravenous, and intradermal injection), or administration via any other suitable route of administration known to those of skill in the art, or any combination thereof. Administration can also be, for example, single, multiple, and / or over one or more extended periods of time.

[0090] As used herein, the terms "treat," "treated," and "treating" refer to both therapeutic and prophylactic treatments or preventative measures aimed at reversing, alleviating, mitigating, reducing, inhibiting, or delaying the progression, onset, severity, or recurrence of undesirable symptoms, complications, conditions, or biochemical indicators of a disorder or disease, or achieving beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; reduction in the extent of a condition, disorder, or disease; a stabilized condition, disorder, or disease (i.e., not worsening); a delay in the onset or slowing of progression of a condition, disorder, or disease; an improvement or remission (whether partial or complete) of a condition, disorder, or disease state, whether detectable or undetectable; an improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or an improvement or amelioration of a condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. In some cases, treatment includes prolonging survival as compared to expected survival if not receiving treatment.

[0091] A "complete response" or "complete remission" is defined for any given cancer type as the absence of cancer cells detectable by imaging or molecular methods conventionally used to detect that type of cancer. A "complete response" does not necessarily mean that all cancer cells are eliminated from the patient. For cancers for which multiple conventional imaging or molecular methods are conventionally used for detection, the absence of detectable cancer cells using any one of such methods is sufficient to indicate a "complete response" for purposes of this disclosure.

[0092] For cancers for which multiple conventional imaging or molecular methods are traditionally used for detection, a 50% reduction in cancer cells detectable using any one of such methods is sufficient to indicate a "partial response" for purposes of this disclosure. A "partial response" or "partial remission" is defined for any given cancer repair as at least a 50% reduction in the estimated number of cancer cells or tumor burden detectable by an imaging or molecular method traditionally used to detect that type of cancer.

[0093] An "inadequate response" is any response to treatment with a CAR or antibody or antigen-binding fragment, or composition of the present disclosure that is not a "complete response" or a "partial response." An inadequate response can include an increase in cancer cells or tumor mass that is detectable using conventional imaging or molecular methods for detecting that type of cancer. An inadequate response can also include a minimal decrease in cancer cells that is still not sufficient to be considered a "partial remission."

[0094] As used herein, "CAR" or "CAR-T" toxicity refers to early responses to CAR or antibody or antigen-binding fragment treatment, including cytokine release syndrome and neurotoxicity. Although CAR-T toxicity is often considered a rejection reaction, it is also a likely efficacy indicator of CAR T cell therapy because it results from T cell activity.

[0095] As used herein, "cytokine release syndrome" or "CRS" refers to a condition characterized by high fever, myalgia, fatigue, respiratory failure, hypotension-related perfusion instability and capillary leak, tachycardia, hypoxia, respiratory rate, hemophagocytic lymphohistiocytosis / macrophage activation syndrome, or other organ toxicity associated with elevated serum cytokine concentrations. Increased cytokines and related molecules include interferon (IFN)-γ, IL-2, soluble IL-2Ra, IL-6, soluble IL-6R, granulocyte-macrophage colony-stimulating factor (GM-CSF), and other cytokines secreted primarily by monocytes and / or macrophages, such as IL-1, IL-6, IL-8, IL-10, IL-12, tumor necrosis factor (TNF)-α, IFN-α, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP) 1α. CRS usually occurs within days of receiving the genetically modified T cells.

[0096] As used herein, "neurotoxicity" associated with CAR therapy is characterized by encephalopathy, headache, delirium, anxiety, tremors, aphasia, decreased level of consciousness, obtundation, seizures, or cerebral edema. Neurotoxicity may be associated with elevated serum concentrations of IL-6, IFN-γ, and TNF-α.

[0097] As used herein, the term "amelioration" or "ameliorating" refers to a reduction in the severity of at least one indicator of a condition or disease. As used herein, the term "preventing" or "prevention" refers to delaying or forestalling the onset, occurrence, or progression of a condition or disease for a period of time, e.g., weeks, months, or years. As used herein, the term "prophylactic" (e.g., "prophylactic agent," "prophylactic treatment," "prophylactically effective amount") refers to any complete or partial prevention of a disease or its symptoms, and / or can be therapeutic in terms of a partial or complete cure of the disease and / or adverse reactions and / or symptoms resulting from the disease.

[0098] A "disease" is a state of health of an animal or subject in which the subject is unable to maintain homeostasis (e.g., cancer and autoimmune diseases, T cell-mediated diseases, etc.) and in which the subject's health continues to deteriorate if the disease is not improved. In contrast, a "disease" of a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject's health is less favorable than in the absence of the disease. If left untreated, a disease does not necessarily cause a further decline in the subject's health.

[0099] As used herein, "cancer" can encompass any type of oncogenic process and / or cancerous growth. In this disclosure, cancer can include, but is not limited to, primary tumors, as well as metastatic tissues or malignantly transformed cells, tissues, or organs. Cancer can encompass the histopathology and stage of cancer, e.g., invasive / severe status. Cancer can encompass recurrent and / or treatment-resistant cancers. The terms "cancer" and "tumor" can be used interchangeably. For example, both terms encompass solid tumors and liquid tumors. As used herein, the term "cancer" or "tumor" includes pre-cancer and malignant cancers and tumors.

[0100] Exemplary T-cell-related cancers, or T-cell malignancies, include, but are not limited to, T-cell lymphoma, T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma (PTCL), PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukemia / lymphoma (ATLL), hepatosplenic T-cell lymphoma (HSTL), subcutaneous pancreatitis-like T-cell lymphoma (SPTCL), T-cell acute lymphoblastic leukemia (T-ALL), T-cell chronic lymphocytic leukemia, large granular lymphocyte leukemia, T-cell prolymphocytic leukemia, lymphoma granulomatosis, small- to medium-sized pleomorphic T-cell lymphoma, mycosis fungoides, Sézary syndrome, and cytotoxic T-cell lymphoma.

[0101] The term "autoimmunity" in relation to a TCR means that such a TCR is involved in the development of an autoimmune disease.

[0102] As used herein, the term "autoimmune disease" is defined as a disorder resulting from, for example, an autoimmune response. Autoimmune diseases can result from both insufficient and excessive responses to self-antigens. Exemplary treatable autoimmune diseases include, but are not limited to, type 1 diabetes, Graves' disease, Hashimoto's thyroiditis, Addison's disease, rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis, psoriatic arthritis, lichen planus, lichen planus pilaris, morphea, scleroderma, systemic sclerosis, acute or chronic graft-versus-host disease (GVHD), heart organ transplant rejection, lung organ transplant rejection, kidney organ transplant rejection, interstitial lung disease, stiff-man syndrome, scleroderma, alopecia areata, vitiligo, celiac disease (sprue), myasthenia gravis, pernicious anemia, Sjögren's syndrome, systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, inflammatory bowel disease, Crohn's disease, and ulcerative colitis. Additionally, there are other inflammatory diseases in which reactive T cells are essential drivers of inflammation in disease pathogenesis, even though they may not have historically been considered autoimmune. Indeed, chronic inflammatory diseases are recognized today as the most significant cause of death worldwide, with over 50% of all deaths attributed to inflammation-related conditions, including ischemic heart disease, stroke, cancer, diabetes mellitus, chronic kidney disease, nonalcoholic liver disease (NAFLD), and autoimmune and neurodegenerative conditions [GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1736-1788 (2018)]. These include atherosclerosis and resulting cardiovascular diseases, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, and chronic obstructive pulmonary disease, all of which are encompassed under the term "autoimmune diseases."

[0103] As used herein, "plasma cells" refer to a type of white blood cell that can produce and secrete antibodies. Plasma cells are also called plasmocytes, plasma cells, or effector B cells.

[0104] As used herein, the terms "therapeutically effective amount," "therapeutically effective," "effective amount," or "in an effective amount" are used interchangeably herein and refer to an amount of a compound, preparation, substance, or composition that is effective to achieve a particular biological result described herein, including, but not limited to, treating or reducing the number of cancers or tumors, or alleviating or ameliorating an autoimmune disease.

[0105] As used herein, the terms "subject" and "patient" are used interchangeably. A subject can be an animal. A subject can be a mammal, such as a non-human animal (e.g., a cow, pig, horse, cat, dog, rat, mouse, monkey or other primate, etc.). A subject can be a human.

[0106] As used herein, the term "cytotoxicity" refers to an unintended or undesired alteration in the normal state of a cell. The normal state of a cell can refer to the state that appears or exists before the cell is exposed to a cytotoxic composition, agent, and / or condition. Generally, a cell in a normal state is a cell in a homeostatic state. An unintended or undesired alteration in the normal state of a cell can be manifested in the form of, for example, cell death (e.g., programmed cell death), reduced replicative capacity, reduced cellular integrity such as membrane integrity, reduced metabolic activity, reduced developmental capacity, or any of the cytotoxic effects disclosed herein.

[0107] The phrases "reducing cytotoxicity" or "reducing cytotoxicity" refer to a reduction in the degree or frequency of unintended or undesired changes in the normal state of a cell upon exposure to a cytotoxic composition, agent, and / or condition. The phrases can refer to reducing the degree of cytotoxicity in an individual cell exposed to a cytotoxic composition, agent, and / or condition, or to reducing the number of cells in a population that exhibit cytotoxicity when the cell population is exposed to a cytotoxic composition, agent, and / or condition.

[0108] As used herein, the phrase "disrupt" and its grammatical equivalents can refer to the process of changing a gene, for example, by deletion, insertion, mutation, rearrangement, or any combination thereof. For example, a gene can be disrupted by "knockout" (KO). Disrupting a gene can partially reduce or completely suppress the expression of the gene. Disrupting a gene can also cause the activation of a different gene, for example, a downstream gene. As described herein, exemplary KO of endogenous TCR in T cells strongly eliminated alloreactivity compared to TCR-expressing T cells (Stenger, D., et al., Blood 136(12):1407-1418, September 2020).

[0109] As used herein, the term "nucleic acid" or "polynucleotide" refers to nucleotides and / or polynucleotides, such as deoxyribonucleic acid or ribonucleic acid (RNA), oligonucleotides, fragments produced by polymerase chain reaction (PCR), and fragments produced by ligation, degradation, endonuclease action, and exonuclease action.

[0110] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. Polymers may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. These terms also encompass amino acid polymers that have been modified, naturally or by intervention, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. The definition also includes, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids), as well as other modifications known in the art.

[0111] As used herein, the term "conservative sequence modification" is intended to mean an amino acid modification that does not significantly affect or alter the binding properties of the antibody or CAR containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into the antibodies of the present disclosure by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. A conservative amino acid substitution is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains are defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, for example, one or more amino acid residues within the extracellular region of a CAR of the present disclosure can be replaced with other amino acid residues having a similar side chain or charge, and the ability of the altered CAR to bind to its target can be tested using the functional assays described herein.

[0112] The term "variant" refers to a polypeptide having an amino acid sequence substantially identical to a reference amino acid sequence or encoded by a substantially identical nucleotide sequence. In aspects described herein, the variant can be a functional variant. The term "functional variant" refers to a polypeptide having an amino acid sequence substantially identical to a reference amino acid sequence or encoded by a substantially identical nucleotide sequence, and capable of possessing one or more activities of the reference amino acid sequence.

[0113] An "isolated" polypeptide, antibody, polynucleotide, vector, cell, or composition refers to a polypeptide, antibody, polynucleotide, vector, cell, or composition in a form not found in nature. Isolated polypeptides, antibodies, polynucleotides, vectors, cells, or compositions include those that have been purified to the extent that they are no longer in a form found in nature.

[0114] As disclosed herein, an isolated antibody, polynucleotide, vector, cell, or composition is substantially pure. As used herein, "substantially pure" refers to material that is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.

[0115] "Percent identity" refers to the degree of identity between two sequences (e.g., amino acid sequences or nucleic acid sequences). Percent identity can be determined by aligning two sequences while introducing gaps that maximize the identity between the sequences. Alignment can be generated using programs known in the art. For non-limiting purposes herein, alignment of nucleotide sequences can be performed using the blastn program set to default parameters, and alignment of amino acid sequences can be performed using the blastp program set to default parameters (see the National Center for Biotechnology Information (NCBI) on the World Wide Web at ncbi.nlm.nih.gov).

[0116] The human "T cell receptor," also called "TCR" or "T receptor," is a heterodimeric protein complex found on the surface of T lymphocytes. T receptors are present only on T lymphocytes. The primary function of the TCR is to specifically recognize processed antigens bound to molecules of the major histocompatibility complex (HLA). Human TCRs contain two subunits: α and β chains or γ and δ chains, connected by disulfide bonds and docked to the cell membrane. Each TCR chain has a constant (C) domain connected to an N-terminal variable (V) domain, a connecting domain, and a transmembrane domain that anchors the receptor in the T lymphocyte plasma membrane. T receptors interact with MHC / antigen complexes through six regions that determine their complementarity (CDRs): three α chain regions and three β chain regions.

[0117] A small proportion of T lymphocytes have gamma / delta type T receptors. These are arranged similarly to alpha / beta receptors, but differ in their primary structure in that they possess many functional characteristics. They exhibit much lower variability (limited clonal specificity) and recognize antigens in complexes with "non-classical" (non-MHC) antigen-presenting molecules, or even in free antigen.

[0118] As used herein, the terms "T cell receptor beta variable chain," "TCR Vβ," "TCR Vb," and "TCR βV" are used interchangeably and refer to the extracellular region of the T cell receptor β chain that contains the antigen recognition domain of the T cell receptor. The terms "VB," "Vβ," "variable beta," "variable β," and "v beta," and grammatical equivalents, are used interchangeably and refer to the variable beta chain of the T cell receptor. The term "TCR Vβ" or "TCR βV" includes isoforms; mammalian, e.g., human TCR βV; human species homologs; and analogs that share at least one epitope in common with TCR βV. Isoforms of TCR Vβ can be identified by integers or letters of the alphabet, e.g., 1, 2, 3, 4, or A, B, C. Human TCRβV comprises a gene family that comprises a subfamily, including, but not limited to, the TCRβ V1 subfamily, TCRβ V2 subfamily, TCRβ V3 subfamily, TCRβ V4 subfamily, TCRβ V5 subfamily, TCRβ V6 subfamily, TCRβ V7 subfamily, TCRβ V8 subfamily, TCRβ V9 subfamily, TCRβ V10 subfamily, TCRβ V11 subfamily, TCRβ V12 subfamily, TCRβ V13 subfamily, TCRβ V14 subfamily, TCRβ V15 subfamily, TCRβ V16 subfamily, TCRβ V17 subfamily, TCRβ V18 subfamily, TCRβ V19 subfamily, TCRβ V20 subfamily, TCRβ V21 subfamily, TCRβ V22 subfamily, TCRβ V23 subfamily, TCRβ V24 subfamily, or TCRβ V25 subfamily. An exemplary list of TCRVβ and subfamilies is shown in Table 1 (below). [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0119] The term "accession number" or "accession code," and all grammatical equivalents, means an identifiable or searchable number or code that references a peptide or nucleotide sequence. Searching for an accession number can be accomplished in a number of ways, including, but not limited to, IMGT (www.imgt.org), GenBank (www.ncbi.nlm.nih.gov / genbank), and The Kabat Database (G. Johnson and TTWu, 2002; http: / / www.kabatdatabase.com).

[0120] The term "antibody" refers to an immunoglobulin molecule that recognizes and binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination thereof, through at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term "antibody" includes intact polyclonal antibodies, intact monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antibody, and any other modified immunoglobulin molecule provided that the antibody exhibits the desired biological activity.

[0121] Antibodies can be any of five major immunoglobulin classes: IgA, IgD, IgE, IgG, and IgM, or their subclasses (isotypes, e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the identity and constant region of their heavy chains, called alpha, delta, epsilon, gamma, and mu, respectively. Immunoglobulins of different classes have different and well-known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated to other molecules, such as toxins, radioisotopes, etc.

[0122] The term "antibody fragment" refers to a portion of an intact antibody. An "antigen-binding fragment," "antigen-binding domain," or "antigen-binding region" refers to a portion of an intact antibody that binds to an antigen. An antigen-binding fragment can contain the antigen recognition site of the intact antibody (e.g., a complementarity-determining region (CDR) sufficient to bind to the antigen). Examples of antigen-binding fragments of antibodies include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, and single-chain antibodies. Antigen-binding fragments of antibodies can be derived from any animal, such as rodents (e.g., mice, rats, or hamsters) and humans, or can be artificially generated.

[0123] The term "intrabody" refers to an antibody or antibody-binding fragment that acts inside a cell to bind to an intracellular protein.

[0124] As used herein, "antigen" (Ag) refers to a molecule capable of eliciting an immune response, e.g., involving the activation of certain immune cells and / or antibody genes. Any natural or synthetic immunogenic substance, including but not limited to haptens, or any macromolecule, including but not limited to almost any protein or peptide, can be an antigen. Antigens can also be derived from genomic recombinants or DNA. For example, any DNA containing a nucleotide sequence or partial nucleotide sequence encoding a protein capable of eliciting an immune response encodes an "antigen." An antigen need not be encoded solely by the full-length nucleotide sequence of a gene, nor need it be encoded by a gene at all. Antigens can be synthesized or derived from biological samples, e.g., tissue samples, tumor samples, cells, or fluids containing other biological components. As used herein, "tumor antigen" or, interchangeably, "cancer antigen" includes any molecule present in or associated with cancer, e.g., cancer cells, or the tumor microenvironment, capable of eliciting an immune response. As used herein, an "immune cell antigen" includes any molecule present on or associated with an immune cell that is capable of eliciting an immune response.

[0125] As used herein, "immune cell" refers to any of a variety of cells that function in the immune system, for example, to defend against infections and foreign agents. This term includes white blood cells, such as neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Innate white blood cells include phagocytes (e.g., macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. Innate white blood cells identify and eliminate larger pathogens, either by attacking them on contact or by engulfing and then killing the microorganisms, and are mediators in the activation of the adaptive immune response. Cells of the adaptive immune system are specialized types of white blood cells, called lymphocytes. B cells and T cells are important types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, while T cells are involved in the cellular immune response. The term "immune cell" includes immune effector cells.

[0126] As used herein, the term "specifically binds to" refers to an antigen-binding molecule that recognizes and binds to a binding partner protein (such as a variable β region) present in a sample, but does not substantially recognize or bind to other molecules in the sample.

[0127] As used herein, the term "high affinity" refers to high specificity of a molecule in binding to, interacting with, or attracting a target molecule.

[0128] As used herein, the terms "variable region" and "variable domain" are used interchangeably and are common in the art. A variable region typically refers to a portion of an antibody, generally a portion of either the light or heavy chain, typically the amino-terminal 100-120 or 110-125 amino acids in a mature heavy chain and approximately 90-115 amino acids in a mature light chain, which differ in sequence between antibodies and are used to determine the binding and specificity of a particular antibody for its particular antigen. While sequence variability is concentrated in these regions, called complementarity-determining regions (CDRs), the more highly conserved regions within variable domains are called framework regions (FRs). While not wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction of the antibody with and specificity for the antigen.

[0129] The terms "VH" and "VH domain" are used interchangeably and refer to the heavy chain variable region of an antibody or antigen-binding fragment thereof.

[0130] The terms "VL" and "VL domain" are used interchangeably and refer to the light chain variable region of an antibody or antigen-binding fragment thereof.

[0131] The hypervariable regions in each chain are held in close proximity to the hypervariable regions of the other chain by FRs and contribute to the formation of the antigen-binding site of antibodies (see Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 1992). As used herein, the term "hypervariable region" refers to the amino acid residues of an antibody that are responsible for antigen binding. Hypervariable regions generally contain amino acid residues from "complementarity-determining regions" or "CDRs," the latter of which exhibit the highest sequence variability and / or are involved in antigen recognition. Many CDR definitions are in use and are included herein. Kabat's definition is based on sequence variability and is the most commonly used (Kabat EA et al., supra). Meanwhile, Chothia refers to the location of structural loops (Chothia C & Lesk AM (1987) J. Mol. Biol. 196: 901-917). The AbM definition is a compromise between the Kabat and Chothia definitions and is used in Oxford Molecular's AbM antibody modeling software (Martin AC R et al., (1989) Proc. Natl. Acad. Sci. USA, 86:9268-72; Martin AC R et al., (1991) Methods Enzymol. 203:121-153; Pedersen JT et al., (1992) Immunomethods, 1:126-136; Rees AR et al., (1996) In Sternberg MJE (ed.), Protein Structure Prediction. Oxford University Press, Oxford, 141-172). A contact definition has been recently introduced (Maccallum RM et al., (1996) J. Mol. Biol. 262: 732-745) and is based on the analysis of complex structures available in the Protein Databank.The CDR definitions according to MGT®, the international ImMunoGeneTics information System® (http: / / www.imgt.org), are based on the IMGT numbering for all immunoglobulin and T-cell receptor V-regions of all species (IMGT®, the international ImMunoGeneTics information System®; Lefranc MP et al., (1991) Nucleic Acids Res. 27(1):209-12; Ruiz M et al., (2000) Nucleic Acids Res. 28(1):219-21; Lefranc MP (2001) Nucleic Acids Res. 29(1):207-9; Lefranc MP (2003) Nucleic Acids Res. 31(1):307-10; Lefranc MP et al., (2005) Dev. Comp. Immunol. 29(3):185-203; Kaas Q et al., (2007) Briefings in Functional Genomics & Proteomics, 6(4):253-64).

[0132] The complementarity determining regions (CDRs) disclosed herein can be defined according to IMGT®. CDRs can be defined according to Chothia. CDRs can be defined according to Kabat. For example, for the light chain, the variable domain residues for each of the CDRs can be LCDR1: 27-32, LCDR2: 50-52, and LCDR3: 89-97 (numbering according to Kabat EA, et al., supra). As used herein, the "non-CDR regions" of the VL region include the amino acid sequences: 1-26 (FR1), 33-49 (FR2), 53-88 (FR3), and 98 to approximately 107 (FR4). For the heavy chain, the variable domain residues for each of the three CDRs can be HCDR1: 26-35, HCDR2: 51-57, and HCDR3: 93-102.

[0133] Various software can be used to generate alternative CDR sequences for variable region framework sequences with various CDR sequences obtained using various software programs. The use of alternative CDR sequences can improve the binding affinity of the antibody to at least one antigen. Alternative CDR sequences are used to optimize the affinity of one or both antigen-binding sites of an antibody according to the present disclosure. Alternative CDRs are defined according to the annotations of Kabat, Chothia, Paratome, AbM, Contact, and / or IMGT. CDRs are defined according to two or more annotations.

[0134] As used herein, the term "Fab region" refers to the VH and CHI domains of the heavy chain (a "Fab heavy chain") or the VL and CL domains of the light chain (a "Fab light chain") of an immunoglobulin.

[0135] As used herein, the term "scFv" or "single-chain antibody fragment" refers to a single chain consisting of an antibody heavy chain variable region and a light chain variable region linearly linked to each other by a linker (e.g., a short peptide of 10 to 25 amino acids), and exhibits specific binding to an antigen. scFv can refer to a single chain comprising a signal peptide and an antibody heavy chain variable region and a light chain variable region linearly linked to each other by a linker.

[0136] As used herein, the terms "constant region" and "constant domain" are interchangeable and have their common meanings in the art. The constant region is the portion of an antibody, e.g., the carboxyl-terminal portion of the light and / or heavy chain, that is not directly involved in binding to an antigen but can exhibit various effector functions, such as interaction with Fc receptors. The constant region of an immunoglobulin molecule generally has a more conserved amino acid sequence compared to the immunoglobulin variable domain.

[0137] As used herein, the term "heavy chain" when used in reference to an antibody can refer to any of the different types, e.g., alpha (a), delta (d), epsilon (e), gamma (g), and mu (m), based on the amino acid sequence of the constant domain, which give rise to antibodies of the IgA, IgD, IgE, IgG, and IgM classes, respectively, which include the subclasses of IgG, e.g., IgG1, IgG2, IgG3, and IgG4. The heavy chain can be a human heavy chain.

[0138] As used herein, the term "light chain" when used in reference to an antibody can refer to any unique type, e.g., kappa (K) or lambda (1), based on the amino acid sequence of the constant domain. Light chain amino acid sequences are well known in the art. The light chain can be a human light chain.

[0139] The term "chimeric" antibody, or antigen-binding fragment thereof, refers to an antibody or antigen-binding fragment thereof whose amino acid sequences are derived from two or more species. Typically, the variable regions of both the light and heavy chains correspond to the variable regions of an antibody or antigen-binding fragment thereof from one species of mammal (e.g., mouse, rat, rabbit, etc.) having the desired specificity, affinity, and function, while the constant regions are homologous to the sequences of an antibody or antigen-binding fragment thereof from another species (usually human) to avoid eliciting an immune response in that species.

[0140] The term "humanized" antibody or antigen-binding fragment thereof refers to a non-human (e.g., murine) antibody or antigen-binding fragment that is a specific immunoglobulin chain, chimeric immunoglobulin, or fragment thereof that contains minimal non-human (e.g., murine) sequence. Typically, a humanized antibody or antigen-binding fragment thereof is a human immunoglobulin in which residues from its complementarity-determining regions (CDRs) have been replaced with residues from CDRs of a non-human species (e.g., mouse, rat, rabbit, hamster) having the desired specificity, affinity, and function ("CDR grafting") (Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239:1534-1536 (1988)). In some cases, the Fv framework regions (FRs) of a human immunoglobulin are replaced with corresponding residues in an antibody or fragment from a non-human species having the desired specificity, affinity, and function. Humanized antibodies or antigen-binding fragments thereof can be further modified by substitution of additional residues within the Fv framework regions and / or non-human CDRs to improve and optimize the specificity, affinity, and / or function of the antibody or antigen-binding fragment. Generally, humanized antibodies or antigen-binding fragments thereof comprise substantially all of at least one, and usually two or three, variable domains, including all or substantially all of the CDR regions corresponding to a non-human immunoglobulin, while all or substantially all of the FR regions are those of a human immunoglobulin consensus region. Humanized antibodies or antigen-binding fragments thereof can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Patent No. 5,225,539, Roguska et al., Proc. Natl. Acad. Sci., USA, 91(3):969-973 (1994), and Roguska et al., Protein Eng. 9(10):895-904 (1996). A "humanized antibody" can be a resurfaced antibody.

[0141] The term "human antibody," or antigen-binding fragment thereof, means an antibody or antigen-binding fragment thereof having an amino acid sequence derived from a human immunoglobulin gene locus, and such antibodies or antigen-binding fragments are made using any technique known in the art. This definition of a human antibody or antigen-binding fragment thereof includes intact, or full-length, antibodies and fragments thereof.

[0142] As used herein, the term "ADCC" or "antibody-dependent cellular cytotoxicity" refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing FcγR recognize bound antibodies on target cells and subsequently cause lysis of the target cells. ADCC correlates with binding to FcγRIIIa, and increased binding to FcγRIIIa results in increased ADCC activity.

[0143] As used herein, the term "ADCP" or antibody-dependent cell-mediated phagocytosis refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing FcγR recognize bound antibody on a target cell and subsequently cause phagocytosis of the target cell.

[0144] In some embodiments, the humanized antibody heavy chain Fc region with ADCC-enhancing mutations includes, but is not limited to, one or more of the following mutations: H268F, S324T, S239D, and I332E, and any combination thereof.

[0145] In vitro and / or in vivo cytotoxicity assays can be performed to confirm reduced / depleted CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to ensure that the antibody lacks FcγR binding (and thus likely lacks ADCC activity) but retains FcRn binding ability. Primary cells for mediating ADCC, NK cells, express only FcγRIII, whereas monocytes express FcγRI and FcγRII. FcγRIII FcR expression in hematopoietic cells is summarized in Table 3, p. 464, of Ravetch, JV, and Kinet, JP, Annu. Rev. Immunol. 9 (1991) 457-492. Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest are described in U.S. Pat. No. 5,500,362 (see, e.g., Hellstrom, I. et al., Proc. Natl. Acad. Sci. USA 83 (1986) 7059-7063; and Hellstrom, I. et al., Proc. Natl. Acad. Sci. USA 82 (1985) 1499-1502); U.S. Pat. No. 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166 (1987) 1351-1361). Alternatively, non-radioactive assay methods can be used (see, e.g., ACTI™ Non-Radioactive Cytotoxicity Assay for Flow Cytometry (CellTechnology, Inc. Mountain View, Calif.; and CytoTox 96® Non-Radioactive Cytotoxicity Assay (Promega, Madison, Wis.)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells.

[0146] Alternatively, or additionally, the ADCC activity of the molecule of interest can be investigated in vivo, e.g., in an animal model such as that disclosed in Clynes, R. et al., Proc Natl Acad Sci USA 95, (1998) 652-656. C1q binding assays may also be performed to confirm that the antibody is unable to bind C1q and thus lacks CDC activity. See, e.g., the C1q and C3c binding ELISAs in WO2006 / 029879 and WO2005 / 100402. To investigate complement activation, a CDC assay may be performed (see, e.g., Gazzano-Santoro, H. et al., J. Immunol. Methods 202 (1996) 163-171; Cragg, MS et al., Blood 101 (2003) 1045-1052; and Cragg, MS and MJ Glennie, Blood 103 (2004) 2738-274). FcRn binding and in vivo clearance / half-life measurements can also be performed using methods well known in the art (see, e.g., Petkova, SB et al., Int. Immunol. 18 (2006) 1759-1769).

[0147] Antibodies with reduced effector function include those with substitutions at one or more of Fc region residues 238, 265, 269, 270, 297, 327, and 329 (U.S. Patent No. 6,737,056). Such Fc variants include Fc variants with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc mutant with substitutions of residues 265 and 297 to alanine (U.S. Patent No. 7,332,581).

[0148] As used herein, "effector function" refers to a biochemical event that results from the interaction of an antibody Fc region with an Fc receptor or ligand. Effector functions include, but are not limited to, ADCC, ADCP, and CDC.

[0149] Certain antibody variants with improved or reduced binding to FcRs are described, for example, in U.S. Pat. No. 6,737,056; WO 2004 / 056312; and Shields, RL et al., J. Biol. Chem. 276 (2001) 6591-6604.

[0150] In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that improve ADCC, for example, substitutions at positions 298, 333, and / or 334 (EU residue numbering) of the Fc region.

[0151] "Binding affinity" generally refers to the strength of the sum of non-covalent interactions between a molecule (e.g., a single binding site of an antibody or antigen-binding fragment thereof) and its binding partner (e.g., an antigen). Unless otherwise indicated, "binding affinity," as used herein, refers to the intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an antibody or antigen-binding fragment thereof). The affinity of a molecule X for its partner Y can generally be represented by a dissociation constant (KD). Affinity can be measured and / or expressed in a number of ways known in the art, including, but not limited to, the equilibrium dissociation constant (KD) and the equilibrium association rate constant (KA). KD is determined by the k off / k on KA is calculated from the quotient of k on / k off It is calculated from the quotient of k on refers to the association rate constant of, for example, an antibody or antigen-binding fragment thereof to an antigen, and k off refers to, for example, the dissociation of an antibody or antigen-binding fragment thereof from an antigen. on and k off can be measured by techniques known to those skilled in the art, such as BIAcore® or KinExA.

[0152] As used herein, "epitope" is a term used in the art and refers to a localized region of an antigen to which an antibody or antigen-binding fragment thereof can specifically bind. An epitope can be, for example, consecutive amino acids of a polypeptide (a linear or continuous epitope), or an epitope can be derived, for example, from two or more non-contiguous regions of a polypeptide or polypeptide together (a structural, non-linear, discontinuous, or discontinuous epitope).

[0153] The epitope bound by an antibody or antigen-binding fragment thereof can be determined, for example, by NMR spectroscopy, X-ray diffraction crystallography, ELISA assays, hydrogen / deuterium exchange coupled with mass spectrometry (e.g., liquid chromatography electrospray mass spectrometry), array-based oligopeptide scanning assays, and / or mutagenesis mapping (e.g., site-directed mutagenesis mapping).

[0154] As used herein, an antibody "competitively inhibits" the binding of a reference antibody to a given epitope if it preferentially binds to that epitope, or an overlapping epitope, to the extent that it blocks the reference antibody from binding to that epitope to some extent. Competitive inhibition can be measured by any method known in the art, for example, by competitive ELISA assay. An antibody can be said to competitively inhibit the binding of the reference antibody to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0155] As used herein, the term "promoter / regulatory sequence" refers to a nucleic acid sequence necessary to express a gene product operably linked to the promoter / regulatory sequence. The term "constitutive" promoter refers to a nucleotide sequence that, when operably linked to a polynucleotide encoding or specifying a gene product, results in the production of the gene product in a cell under most or all physiological conditions of the cell. The term "inducible" promoter means that, when operably linked to a polynucleotide encoding a particular gene product, it essentially results in the production of the gene in a cell only when the inducer corresponding to the promoter is present in the cell.

[0156] As used herein, the term "expression" refers to the process by which a gene produces a biochemical, e.g., a polypeptide. This process includes any manifestation of the functional presence of a gene in a cell, including, but not limited to, gene knockdown and both transient and stable expression. This includes, but is not limited to, gene transcription into messenger RNA (mRNA) and translation of such mRNA into polypeptide(s). Expression of a gene results in a "gene product." As used herein, a gene product can be a nucleic acid, e.g., a messenger RNA produced by transcription of a gene, or a polypeptide translated from a transcript. Gene products described herein further include nucleic acids with post-transcriptional modifications (e.g., polyadenylation) or polypeptides with post-translational modifications (e.g., methylation, glycosylation, addition of lipids, association with other protein subunits, proteolytic cleavage, etc.).

[0157] Nucleic acid molecules can be cloned into any number of different types of vectors. For example, nucleic acid molecules can be cloned into vectors including, but not limited to, plasmids, phagemids, phage derivatives, animal viruses, and cosmids. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.

[0158] As used herein, the term "vector" includes, but is not limited to, a viral vector, a plasmid, an RNA vector, or a linear or circular DNA or RNA molecule which may contain chromosomal, non-chromosomal, semisynthetic, or synthetic nucleic acid. In some cases, vectors are capable of autonomous replication (episomal vectors) and / or expression of nucleic acids to which they are linked (expression vectors). Many suitable vectors are known to those of skill in the art and are commercially available. Viral vectors include negative-strand RNA viruses such as retroviruses, adenoviruses, parvoviruses (e.g., adeno-associated viruses), coronaviruses, and orthomyxoviruses (e.g., influenza viruses), positive-strand RNA viruses such as rhabdoviruses (e.g., rabies and vesicular stomatitis viruses), paramyxoviruses (e.g., measles and Sendai viruses), picornaviruses, and alphaviruses, as well as double-stranded DNA viruses, including adenoviruses, herpesviruses (e.g., herpes simplex viruses 1 and 2, Epstein-Barr virus, cytomegalovirus), and poxviruses (e.g., vaccinia, fowlpox, and canarypox). Other viruses include, for example, Norwalk virus, togavirus, flavivirus, reovirus, papovavirus, hepadnavirus, and hepatitis virus. Examples of retroviruses include avian leukemia sarcoma virus, mammalian types C, B, and D viruses, the HTLV-BLV complex, and lentiviruses.

[0159] As used herein, the term "expression vector" refers to a vector containing a recombinant polynucleotide comprising expression control sequences operably linked to a nucleotide sequence to be expressed. An expression vector contains sufficient cis-acting elements for expression; other elements for expression can be provided by the host cell or in an in vitro expression system. Expression vectors include those known in the art, including cosmids, plasmids (e.g., naked or contained in cosmids), and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate a recombinant polynucleotide.

[0160] The expression vector can be provided to cells in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Sambrook et al., 2012, MOLECULAR CLONING: A LABORATORY MANUAL, volumes 1-4, Cold Spring Harbor Press, NY, and other virology and molecular biology manuals. Viruses useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. In general, suitable vectors contain a replication origin functional in at least one organism, a promoter sequence, a convenient restriction endonuclease, and one or more selectable markers (e.g., WO 01 / 96584; WO 01 / 29058; and U.S. Patent No. 6,326,193).

[0161] Additional promoter elements, e.g., enhancers, control the frequency of transcription initiation. While these are typically located in the region 30–110 bp upstream of the start site, many promoters have recently been shown to contain functional elements in the start site granule as well. Spacing between promoter elements is often flexible, so that promoter function is preserved when elements are inverted or moved relative to one another. In the thymidine kinase (tk) promoter, spacing between promoter elements can be increased to as much as 50 bp apart before activity begins to decline. Depending on the promoter, individual elements can function either cooperatively or independently to activate transcription.

[0162] As used herein, the term "transcription vector" refers to a composition containing an isolated nucleic acid and a substance that can be used to deliver the isolated nucleic acid into a cell. Many vectors are known in the art, including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses. Thus, a transcription vector can include a self-replicating plasmid or virus. The term "transcription vector" should also be interpreted to include non-plasmid and non-viral compounds that facilitate the transfer of nucleic acids into cells, such as polylysine compounds, liposomes, etc. Examples of viral transfer vectors include, but are not limited to, adenoviral vectors, adeno-associated viral vectors, retroviral vectors, lentiviral vectors, etc.

[0163] As used herein, " lentivirus " refers to a genus of the Retroviridae family. Lentivirus is unique among retroviruses in that it can infect non-dividing cells, and can deliver significant amounts of genetic information into the DNA of host cells, making it one of the most efficient gene delivery vectors. HIV, SIV, and FIV are all examples of lentivirus. Lentivirus-derived vectors provide a means to achieve significant levels of gene transfer in vivo.

[0164] As used herein, the term "operably linked" or "transcriptional control" refers to the functional association of a regulatory sequence with a heterologous nucleic acid sequence, resulting in expression of the heterologous nucleic acid sequence. For example, a first nucleic acid sequence and a second nucleic acid sequence are operably linked when they are placed in a functional relationship. For example, a promoter is operably linked to a coding sequence if it effects the transcription or expression of the coding sequence. Operably linked DNA sequences can be contiguous with each other, e.g., when linking two protein-coding regions is required, the DNA sequences are in the same reading frame.

[0165] Methods for introducing and expressing genes in cells are known in the art. In the context of expression vectors, the vectors can be easily introduced into host cells, such as mammalian, bacterial, yeast, or insect cells, by any method known in the art. For example, the expression vector can be transferred into the host cell by physical, chemical, or biological means.

[0166] As used herein, the term "host cell" can be any cell type, e.g., a primary cell, a cell in culture, or a cell from a cell line. The term "host cell" refers to a cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. The progeny of such a cell may not be identical to the parent cell transfected with the nucleic acid molecule due, for example, to mutations or environmental influences that may occur in subsequent generations, or to integration of the nucleic acid molecule into the host cell genome.

[0167] Physical methods for introducing polynucleotides into host cells include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, etc. Methods for producing cells containing vectors and / or exogenous nucleic acids are well known in the art. See, for example, Sambrook et al., 2012, MOLECULAR CLONING: A LABORATORY MANUAL, volumes 1-4, Cold Spring Harbor Press, NY.

[0168] Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors. RNA vectors include vectors having an RNA promoter and / or other associated domains for producing RNA transcripts. Viral vectors, and in particular retroviral vectors, are the most widely used method for inserting genes into mammalian cells, such as human cells. Other viral vectors can be derived from lentiviruses, poxviruses, herpes simplex viruses, adenoviruses, and adeno-associated viruses, etc. See, for example, U.S. Patent Nos. 5,350,674 and 5,585,362.

[0169] Chemical means for introducing polynucleotides into host cells include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system for use as an in vitro and in vivo delivery vehicle is a liposome (e.g., artificial membrane vesicle). When a non-viral delivery system is used, an exemplary delivery vehicle is a liposome. The use of lipid formulations for the introduction of nucleic acids into host cells (e.g., in vitro, ex vivo, or in vivo) is contemplated. In another embodiment, the nucleic acid can be associated with a lipid. Lipid-associated nucleic acids can be encapsulated within the aqueous interior of liposomes, interspersed within the lipid bilayer of liposomes, bound to liposomes via linker molecules associated with both the liposomes and the oligonucleotides, entrapped in liposomes, complexed with liposomes, dispersed in a solution containing lipids, mixed with lipids, combined with lipids, contained as a suspension in lipids, contained in or complexed with micelles, or otherwise associated with lipids. Lipid, lipid / DNA, or lipid / expression vector-associated compositions are not limited to any particular structure in solution. For example, they can exist in bilayer structures, as micelles, or with "collapsed" structures. They can also simply be interspersed in solution, sometimes forming aggregates that are not uniform in size or shape. Lipids are aliphatic substances, and can be naturally occurring or synthetic lipids. For example, lipids include the aliphatic droplets that occur naturally in the cytoplasm, as well as a class of compounds that contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, aminoalcohols, and aldehydes.

[0170] The terms "AAV," "AAV construct," or "recombinant AAV" or "AAV" refer to adeno-associated viruses of any known serotype, including AAV-1, AAV-2, AAV-3, AAV-4, AAV-5, AAV-6, AAV-7, AAV-8, AAV-9, AAV-10, AAV-11, or AAV-12, scAAV, rh10, chimeric, or hybrid AAV, or any combination, derivative, or variant thereof. AAVs are small, non-enveloped, single-stranded DNA viruses. They are non-pathogenic parvoviruses and may require helper viruses, such as adenovirus, herpes simplex virus, vaccinia virus, and CMV, for replication. Wild-type AAVs are common throughout the population and are not associated with any known pathologies. Hybrid AAVs are AAVs that contain capsid proteins from one serotype and genomic material from another AAV serotype. A chimeric AAV comprises genetic and / or protein sequences derived from two or more AAV serotypes and may contain mutations made to the genetic sequences of these two or more AAV serotypes. Exemplary chimeric AAVs include chimeric AAV capsids, e.g., capsid proteins containing one or more regions of amino acids derived from two or more AAV serotypes. An AAV variant is an AAV that contains one or more amino acid mutations in its genome or protein compared to its parent AAV, e.g., one or more amino acid mutations in the capsid protein compared to its parent AAV. As used herein, AAV includes avian AAV, bovine AAV, canine AAV, equine AAV, primate AAV, non-primate AAV, and ovine AAV, where primate AAV refers to AAV that infects non-primates, and non-primate AAV refers to AAV that infects non-primate animals, e.g., avian AAV that infects avian animals. In some cases, wild-type AAV contains the rep and cap genes, where the rep gene is required for viral replication and the cap gene is required for synthesis of capsid proteins. As used herein, the terms "recombinant AAV" and "rAAV" are used interchangeably.

[0171] The terms "recombinant AAV vector," "AAV vector," or "AAV vector" refer to vectors derived from any of the AAV serotypes described above. In some cases, AAV vectors can contain one or more AAV wild-type genes, such as the rep and / or cap genes, deleted in whole or in part, but contain functional elements necessary for packaging and use of AAV viruses for gene therapy. For example, functional inverted terminal repeat (ITR) sequences flanking the open reading frame or foreign sequence to be cloned are known to be important for replication and packaging of AAV virions, but ITR sequences can be modified from the wild-type nucleotide sequence, including nucleotide insertions, deletions, or substitutions, making AAV suitable for use in the disclosures described herein, such as gene therapy or gene transfer systems. Gene therapy can include, for example, AAV DNA coding sequences for in vivo delivery via intradermal, intramuscular, intravenous, intralymphatic (lymph node), intratumoral, or other injection into a patient, such that therapeutic CAR or antibody formation can be performed in vivo using the patient's own cells.

[0172] In some embodiments, self-complementary vectors (sc) can be used, such as self-complementary AAV vectors, which can bypass the requirement for viral double-stranded DNA synthesis and result in higher levels of transgene protein expression, as described in Wu, Hum Gene Ther. 2007, 18(2):171-82, incorporated herein by reference. In some embodiments, AAV vectors can be generated to allow for selection of the optimal serotype, promoter, and transgene. In some cases, the vector can be a targeted vector or a modified vector that selectively binds to or infects immune cells.

[0173] The term "AAV virion" or "AAV virion" refers to a viral particle comprising a capsid that includes at least one AAV capsid protein that encapsidates an AAV vector described herein; in some embodiments, the vector can further comprise a heterologous polynucleotide sequence or transgene.

[0174] Modified adeno-associated viral vectors can be useful for treating a variety of indications, including cancer or T cell-mediated autoimmune diseases in subjects. For example, autologous peripheral blood lymphocytes (PBLs) can be modified using adeno-associated viral methods to express foreign cellular receptors that recognize unique epitopes, mutations, or neoantigens on cancer cells, and can be used in the disclosed compositions and methods for intracellular genome transplantation. These compositions utilizing mutant and chimeric adeno-associated viral vectors, as well as methods using the above-described AAV vectors for intracellular genome transplantation, can provide therapies with many advantages. For example, they can result in highly efficient gene transfer, expression, increased cell viability, efficient introduction of recombination-induced double-strand breaks, a process that favors homology-directed repair (HDR) over non-homologous end joining (NHEJ), and efficient recovery and propagation of homologous recombinants. In some embodiments of both lentiviral and AAV vectors, P2A and GFP can be removed or replaced with P2A human CD47 to reduce or decrease the host-versus-graft (HVG) effect, and AmpR can be replaced with a kanamycin resistance gene. In some embodiments of both lentiviral and AAV vectors, P2A can be removed or replaced with P2A human CD47 to reduce or decrease the host-versus-graft (HVG) effect, and AmpR can be replaced with a kanamycin resistance gene. In some embodiments of both lentiviral and AAV vectors, GFP can be removed or replaced with P2A human CD47 to reduce or decrease the host-versus-graft (HVG) effect, and AmpR can be replaced with a kanamycin resistance gene.

[0175] As used herein, the term "autologous" refers to any material that originates from an individual and is later reintroduced into the same individual.

[0176] Intracellular genome transfer can be a method of genetically modifying cells and nucleic acids for therapeutic applications. The compositions and methods described herein can improve existing viral delivery mechanisms using mature and chimeric adeno-associated viral vectors. Effective adoptive cell transfer-based immunotherapy (ACT) can be useful for treating various indications in subjects. For example, autologous peripheral blood lymphocytes (PBLs) can be modified using modified adeno-associated viral vectors with mutations in at least a portion of the capsid protein, or adeno-associated viral vectors with capsid proteins derived from at least two different serologies.

[0177] At the cellular level, AAVs can undergo five steps before achieving gene expression: 1) binding or attachment to cell surface receptors, 2) endocytosis, 3) trafficking to the nucleus, 4) viral uncoating to release the genome, and 5) conversion of the genome from single-stranded to double-stranded DNA as a template for transcription within the nucleus. The cumulative efficiency with which AAVs can successfully execute each individual step may determine the overall transduction efficiency. Rate-limiting steps in AAV transduction can include the absence or insufficiency of cell surface receptors required for viral attachment and internalization, inefficient endosomal escape resulting in lysosomal degradation, and slow conversion of single-stranded to double-stranded DNA templates. Therefore, vectors containing modifications to the genome and / or capsid can be designed to facilitate more efficient or more specific transduction of cells or tissues for gene therapy.

[0178] As used herein, the terms "transfection" and "transduction" refer to the process by which an exogenous nucleic acid sequence is introduced into a host cell. The nucleic acid can be integrated into the host cell DNA or maintained extrachromosomally. The nucleic acid can be transiently maintained or stably introduced. Transfection can be achieved by various means known in the art, including, but not limited to, calcium phosphate-DNA co-precipitation, DEAE-dextran-mediated transfection, polybrene-mediated transfection, electroporation, microinjection, liposome fusion, lipofection, protoplast fusion, retroviral infection, and biolistics. Transduction refers to the delivery of a gene(s) using a viral or retroviral vector by viral infection rather than transfection. In some embodiments, retroviral vectors are transduced by packaging the vector into virions prior to contacting the cell. For example, a nucleic acid encoding a TCR Vβ CAR carried by a retroviral vector can be transduced into a cell by infection and proviral integration.

[0179] The term "chimeric antigen receptor" (CAR) refers to a chimeric molecule comprising a binding domain that binds to a component (e.g., a ligand) present on a target cell (e.g., the binding domain can comprise an antibody or antigen-binding fragment thereof (e.g., the Vβ region of a TCR) specific for a desired antigen), and a T cell receptor activation intracellular domain. CARs exhibit specific anti-target cell immune activity. CARs can comprise an extracellular ligand-binding domain (e.g., a single-chain antibody binding domain (scFv)) fused to an intracellular signaling domain of the zeta chain of the T cell antigen receptor complex. CARs can comprise an extracellular ligand-binding domain, a hinge, a transmembrane domain, and a cytoplasmic domain. The cytoplasmic domain can comprise a costimulatory domain (e.g., 4-1BB) and a signaling domain (e.g., CD3ζ). When expressed in T cells, CARs can redirect antigen recognition based on the specificity of the antibody.

[0180] Expression of a natural or synthetic nucleic acid molecule encoding a CAR or antibody or antigen-binding fragment is typically achieved by operably linking the nucleic acid encoding the CAR polypeptide or antibody or antigen-binding fragment polypeptide(s) or a portion thereof to a promoter (e.g., the EF1 alpha promoter) and incorporating the construct into an expression vector. Vectors are generally capable of replicating in mammalian cells and / or are also capable of integrating into the mammalian cell genome. Typical vectors contain transcription and translation terminators, initiation sequences, and promoters useful for controlling the expression of the desired nucleic acid sequence.

[0181] A "costimulatory domain" or "costimulatory molecule" refers to a cognate binding partner on a T cell that specifically binds to a costimulatory ligand, thereby mediating a costimulatory response (e.g., a proliferative response) by the cell. Costimulatory molecules include, but are not limited to, MHC class I molecules, BTLA, and Toll ligand receptors. Examples of costimulatory molecules include ligands that specifically bind to CD27, CD28, CD8, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and CD83. A costimulatory molecule can be a cell surface molecule, other than an antigen receptor or its ligand, that promotes an efficient immune response.

[0182] "Costimulatory ligand" refers to a molecule on an antigen-presenting cell that specifically binds to a cognate costimulatory molecule on a T cell.

[0183] Costimulatory ligands include, but are not limited to, CD7, B7-1 (CD80), B7-2 (CD86), PD-L1, PD-L2, 4-1BBL, OX40L, inducible costimulatory ligand (ICOS-L), intercellular adhesion molecule (ICAM), CD30L, CD40, CD70, CD83, HLA-G, MICA, M1CB, HVEM, lymphotoxin beta receptor, 3 / TR6, ILT3, ILT4, agonists or antibodies that bind to Toll ligand receptors, and ligands that specifically bind to B7-H3.

[0184] As used herein, the term "extracellular ligand-binding domain" or "extracellular domain" refers to an oligopeptide or polypeptide capable of binding to a ligand, e.g., a cell surface molecule. For example, the extracellular ligand-binding domain can be selected to recognize a ligand that functions as a cell surface marker on target cells associated with a particular disease state (e.g., cancer, or T-cell-mediated autoimmune disease). Examples of cell surface markers that can function as ligands include those associated with viral, bacterial, and parasitic infections, autoimmune diseases, and cancer cells.

[0185] As used herein with respect to CARs, a "signal transduction domain," or "signaling domain," is responsible for intracellular signal transduction after the extracellular ligand-binding domain binds to its target. The signaling domain used in a CAR results in the activation of immune cells and immune responses. In other words, the signal transduction domain can be responsible for activating at least one of the normal effector functions of the immune cell in which the CAR is expressed. For example, the effector function of a T cell can be cytolytic activity or helper activity, including cytokine secretion. Thus, a signal transduction domain refers to a portion of a protein that transduces effector function signals and instructs the cell to perform a specialized function. Examples of signal transduction domains for use in CARs can be the cytoplasmic sequences of T cell receptors and coreceptors, which jointly initiate signal transduction after antigen receptor engagement, as well as any derivatives or variants of these sequences and systemic sequences with the same functional capabilities. In some cases, the signaling domain includes two different classes of cytoplasmic signaling sequences: those that initiate antigen-dependent primary activation and those that function independently of the antigen to provide secondary or costimulatory signals. The primary cytoplasmic signaling sequence can contain signaling motifs known as immunoreceptor tyrosine-based activation motifs (ITAMs).

[0186] "ITAM" refers to a signaling motif found in the cytoplasmic tails of various receptors that function as binding sites for the syk / zap70 class tyrosine kinase. Exemplary ITAMs include those derived from TCRζ, FcRγ, FcRbeta, FcRε, CD3γ, CD3δ, CD3ε, CD3ζ, CD5, CD22, CD79a, CD79b, and CD66d. The signaling domain of a CAR can comprise a CD3ζ signaling domain.

[0187] As used herein, a "transmembrane region" or "transmembrane domain" is the portion of a CAR that anchors the extracellular binding moiety to the plasma membrane of an immune effector cell and facilitates binding of the binding domain to a target antigen. In some embodiments, the transmembrane domain can be a CD3ζ transmembrane domain, although other transmembrane domains that can be used include those obtained from CD8α, CD4, CD28, CD45, CD9, CD16, CD22, CD33, CD64, CD80, CD86, CD134, CD137, or CD154.

[0188] The binding domain of a CAR can be followed by a "spacer" or "hinge," which refers to a region that separates or displaces the antigen-binding domain from the effector cell. In some embodiments, the hinge allows for cell-cell contact, antigen binding, and activation (Patel et al., Gene Therapy, 1999;6:412-419). The hinge region in a CAR can be between the transmembrane (TM) and the binding domain. In some embodiments, the hinge region is an immunoglobulin hinge region, and can be a wild-type immunoglobulin hinge region or a modified wild-type immunoglobulin hinge region. Other exemplary hinge regions used in the CARs disclosed herein can include hinge regions derived from the extracellular regions of type 1 membrane proteins, such as CD8α, CD4, CD28, and CD7, which can be the wild-type hinge region from the molecule or can be modified. In some embodiments, the hinge region comprises a CD8α hinge.

[0189] It should be understood that the headings are provided for ease of reading only and are not intended to be limiting: aspects disclosed under one or more headings may be applicable to or combinable with aspects disclosed under one or more other headings.

[0190] It is further noted that the claims may be drafted to exclude any element. Accordingly, this statement is intended to serve as a guidepost for use of exclusive terminology such as "solely," "only," or "negative" limitations in connection with the recitation of claim elements.

[0191] I. Chimeric Antigen Receptor T Cells (CAR) Chimeric antigen receptors (CARs) redirect the specificity of T cells to antibody-recognized antigens expressed on the cell surface (e.g., the variable β region of the TCR).

[0192] In some embodiments described herein, the present disclosure includes a chimeric antigen receptor (CAR) specific for the Vβ region of a TCR. In some embodiments described herein, the CAR comprises, for example, an extracellular domain, a transmembrane domain, an intracellular signaling domain (such as a signaling domain derived from CD3ζ or FCRγ), and / or one or more costimulatory signaling domains derived from costimulatory molecules, including, but not limited to, 4-1BB. In some embodiments, the CAR comprises a hinge or spacer region between the extracellular binding domain and the transmembrane domain, e.g., a CD8α hinge.

[0193] In some embodiments described herein, the costimulatory domain comprises a 4-1BB costimulatory domain. In some embodiments described herein, the 4-1BB costimulatory domain comprises the amino acid sequence set forth in SEQ ID NO:8.

[0194] In some embodiments described herein, the transmembrane domain comprises an hCD28 transmembrane. In some embodiments described herein, the transmembrane domain comprises an hCD28 amino acid sequence set forth in SEQ ID NO:3.

[0195] In some embodiments described herein, the signaling domain comprises a CD247 signaling domain. In some embodiments described herein, the signaling domain comprises the CD247 signaling domain amino acid sequence set forth in SEQ ID NO:9.

[0196] In some embodiments described herein, the scFv comprises a CD28 signal peptide. In some embodiments described herein, the scFv comprises a CD28 signal peptide and the amino acid sequence set forth in SEQ ID NO:7.

[0197] In some embodiments, the binding domain or extracellular domain of a CAR, for example, confers on the CAR the ability to bind to a target antigen of interest. A binding domain (e.g., a ligand-binding domain or an antigen-binding domain) can be any protein, polypeptide, oligopeptide, or peptide capable of specifically recognizing and binding to, for example, a biomolecule (e.g., a cell surface receptor or tumor protein, or a component thereof, or the variable beta chain of a T cell receptor). A binding domain can include any naturally occurring, synthetic, semi-synthetic, or recombinantly produced binding partner for a biomolecule of interest. For example, and as further disclosed herein, the binding domain can be antibody light and heavy chain variable regions, or the light and heavy chain variable regions linked together in either orientation in a single chain (e.g., VL-VH, or VH-VL).

[0198] In some embodiments described herein, the chimeric antigen receptor (CAR) comprises (i) an antigen-binding molecule that specifically binds to a TCR Vβ region, (ii) an extracellular domain, (iii) a transmembrane domain, (iv) a costimulatory domain, and (v) an activation domain, and the antigen-binding molecule is a single-chain variable fragment (scFv) comprising a variable heavy chain (VH) set forth in any one of SEQ ID NOs: 45 to 131 and 534 to 544, or a variable light chain (VL) set forth in any one of SEQ ID NOs: 132 to 227 and 545 to 558.

[0199] In some embodiments described herein, the CAR comprises (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 418, SEQ ID NO: 420, SEQ ID NO: 422, SEQ ID NO: 423, SEQ ID NO: 424, SEQ ID NO: 425, SEQ ID NO: 426, SEQ ID NO: 427, SEQ ID NO: 428, SEQ ID NO: 429, SEQ ID NO: 430, SEQ ID NO: 431, SEQ ID NO: 432, SEQ ID NO: 433, SEQ ID NO: 434, SEQ ID NO: 435, SEQ ID NO: 436, SEQ ID NO: 437, SEQ ID NO: 438, SEQ ID NO: 439, SEQ ID NO: 440, SEQ ID NO: 441, SEQ ID NO: 442, SEQ ID NO: 443, SEQ ID NO: 444, SEQ ID NO: 445, SEQ ID NO: 446, SEQ ID NO: 447, SEQ ID NO: 448, SEQ ID a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 419 and SEQ ID NO: 420, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 376, SEQ ID NO: 377, and SEQ ID NO: 378, respectively. and / or (ii) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 424, SEQ ID NO: 425, SEQ ID NO: 426, respectively, or CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 427, SEQ ID NO: 428, SEQ ID NO: 429, respectively, or (i) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​SEQ ID NO: 383, and SEQ ID NO: 384, respectively. a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 384, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 430, SEQ ID NO: 431, and SEQ ID NO: 432, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 433, SEQ ID NO: 434, and SEQ ID NO: 435, respectively;Alternatively, (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 388, 389, and 390, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 436, 437, and 438, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 391, 392, and 393, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 439, 440, and 441, respectively. 41, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 397, SEQ ID NO: 398, and SEQ ID NO: 399, respectively, and and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 403, SEQ ID NO: 404, and SEQ ID NO: 405, respectively. and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 451, SEQ ID NO: 452, and SEQ ID NO: 453, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively; or(i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 412, SEQ ID NO: 413, and SEQ ID NO: 414, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 460, SEQ ID NO: 461, and SEQ ID NO: 462, respectively. a variable light chain (VL) comprising CDR1, CDR2, and CDR3, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 415, SEQ ID NO: 416, and SEQ ID NO: 417, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 463, SEQ ID NO: 464, and SEQ ID NO: 465, respectively, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 584, SEQ ID NO: 585, and SEQ ID NO: 586, respectively, and / or (i (i) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 596, SEQ ID NO: 597, and SEQ ID NO: 598, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 587, SEQ ID NO: 588, and SEQ ID NO: 589, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 599, SEQ ID NO: 600, and SEQ ID NO: 601, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 591, and SEQ ID NO: 592, respectively. and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, or CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 608, SEQ ID NO: 609, and SEQ ID NO: 610, respectively;and a variable light chain (VL) comprising CDR3.

[0200] In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 85% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 86% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 87% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 88% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 89% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 91% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 92% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 93% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 94% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 45-131, and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 96% sequence identity to any one of SEQ ID NOs: 45-131, and 534-544.In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 97% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 98% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 99% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 45-131 and 534-544.

[0201] In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 85% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 86% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 87% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 88% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 89% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 91% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 92% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 93% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 94% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some aspects described herein, the variable light chain comprises an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 132-227, and 545-558. In some aspects described herein, the variable light chain comprises an amino acid sequence having at least 96% sequence identity to any one of SEQ ID NOs: 132-227, and 545-558.In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 97% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 98% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 99% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 132-227 and 545-558.

[0202] In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having any of the above-mentioned percent identities to any one of SEQ ID NOs: 45-131 and 534-544, and the variable light chain comprises an amino acid sequence having any of the above-mentioned percent identities to any one of SEQ ID NOs: 132-227 and 545-558. Specifically, non-limiting examples of variable heavy and light chain pairings include a variable heavy chain comprising an amino acid sequence having at least 88% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544, and a variable light chain comprising an amino acid sequence having at least 93% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In other aspects described herein, the pairing of variable heavy chains and light chains includes a variable heavy chain comprising an amino acid sequence having any of the above-mentioned percent identities to any one of SEQ ID NOs: 45 to 131 and 534 to 544, and a variable light chain comprising an amino acid sequence set forth in any one of SEQ ID NOs: 132 to 227 and 545 to 558. In other aspects described herein, the pairing of variable heavy chains and light chains includes a variable heavy chain comprising an amino acid sequence set forth in any one of SEQ ID NOs: 45 to 131 and 534 to 544, and a variable light chain comprising an amino acid sequence having any of the above-mentioned percent identities to any one of SEQ ID NOs: 132 to 227 and 545 to 558. Specifically, non-limiting examples of pairings of variable heavy and light chains include a variable heavy chain comprising an amino acid sequence having at least 92% sequence identity to any one of SEQ ID NOs: 45 to 226, and a variable light chain comprising an amino acid sequence set forth in any one of SEQ ID NOs: 132 to 227 and 545 to 558. In yet another aspect described herein, the variable heavy chain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 45 to 131 and 534 to 544, and the variable light chain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 132 to 227 and 545 to 558.

[0203] In some embodiments described herein, the CAR comprises (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 418, SEQ ID NO: 420, SEQ ID NO: 422, SEQ ID NO: 423, SEQ ID NO: 424, SEQ ID NO: 425, SEQ ID NO: 426, SEQ ID NO: 427, SEQ ID NO: 428, SEQ ID NO: 429, SEQ ID NO: 430, SEQ ID NO: 431, SEQ ID NO: 432, SEQ ID NO: 433, SEQ ID NO: 434, SEQ ID NO: 435, SEQ ID NO: 436, SEQ ID NO: 437, SEQ ID NO: 438, SEQ ID NO: 439, SEQ ID NO: 440, SEQ ID NO: 441, SEQ ID NO: 442, SEQ ID NO: 443, SEQ ID NO: 444, SEQ ID NO: 445, SEQ ID NO: 446, SEQ ID NO: 447, SEQ ID NO: 448, SEQ ID a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 419 and SEQ ID NO: 420, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 376, SEQ ID NO: 377, and SEQ ID NO: 378, respectively. and / or (ii) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 424, SEQ ID NO: 425, SEQ ID NO: 426, respectively, or CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 427, SEQ ID NO: 428, SEQ ID NO: 429, respectively, or (i) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​SEQ ID NO: 383, and SEQ ID NO: 384, respectively. a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 384, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 430, SEQ ID NO: 431, and SEQ ID NO: 432, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 433, SEQ ID NO: 434, and SEQ ID NO: 435, respectively;Alternatively, (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 388, 389, and 390, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 436, 437, and 438, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 391, 392, and 393, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 439, 440, and 441, respectively. 41, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 397, SEQ ID NO: 398, and SEQ ID NO: 399, respectively, and and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 403, SEQ ID NO: 404, and SEQ ID NO: 405, respectively. and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 451, SEQ ID NO: 452, and SEQ ID NO: 453, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively; or(i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 412, SEQ ID NO: 413, and SEQ ID NO: 414, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 460, SEQ ID NO: 461, and SEQ ID NO: 462, respectively. a variable light chain (VL) comprising CDR1, CDR2, and CDR3, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 415, SEQ ID NO: 416, and SEQ ID NO: 417, respectively, and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 463, SEQ ID NO: 464, and SEQ ID NO: 465, respectively, or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 584, SEQ ID NO: 585, and SEQ ID NO: 586, respectively, and / or (i (i) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 596, SEQ ID NO: 597, and SEQ ID NO: 598, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 587, SEQ ID NO: 588, and SEQ ID NO: 589, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 599, SEQ ID NO: 600, and SEQ ID NO: 601, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 591, and SEQ ID NO: 592, respectively. and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (i) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively; and / or (ii) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, or CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 608, SEQ ID NO: 609, and SEQ ID NO: 610, respectively;and a variable light chain (VL) comprising CDR3.

[0204] In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 85% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 86% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 87% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 88% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 89% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 91% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 92% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 93% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 94% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 45-131, and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 96% sequence identity to any one of SEQ ID NOs: 45-131, and 534-544.In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 97% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 98% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 99% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 45-131 and 534-544.

[0205] In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 85% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 86% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 87% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 88% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 89% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 91% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 92% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 93% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 94% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some aspects described herein, the variable light chain comprises an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 132-227, and 545-558. In some aspects described herein, the variable light chain comprises an amino acid sequence having at least 96% sequence identity to any one of SEQ ID NOs: 132-227, and 545-558.In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 97% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 98% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 99% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In some embodiments described herein, the variable light chain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 132-227 and 545-558.

[0206] In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having any of the above-mentioned percent identities to any one of SEQ ID NOs: 45-131 and 534-544, and the variable light chain comprises an amino acid sequence having any of the above-mentioned percent identities to any one of SEQ ID NOs: 132-227 and 545-558. Specifically, non-limiting examples of variable heavy and light chain pairings include a variable heavy chain comprising an amino acid sequence having at least 88% sequence identity to any one of SEQ ID NOs: 45-131 and 534-544, and a variable light chain comprising an amino acid sequence having at least 93% sequence identity to any one of SEQ ID NOs: 132-227 and 545-558. In other aspects described herein, the pairing of variable heavy chains and light chains includes a variable heavy chain comprising an amino acid sequence having any of the above-mentioned percent identities to any one of SEQ ID NOs: 45 to 131 and 534 to 544, and a variable light chain comprising an amino acid sequence set forth in any one of SEQ ID NOs: 132 to 227 and 545 to 558. In other aspects described herein, the pairing of variable heavy chains and light chains includes a variable heavy chain comprising an amino acid sequence set forth in any one of SEQ ID NOs: 45 to 131 and 534 to 544, and a variable light chain comprising an amino acid sequence having any of the above-mentioned percent identities to any one of SEQ ID NOs: 132 to 227 and 545 to 558. Specifically, non-limiting examples of pairings of variable heavy and light chains include a variable heavy chain comprising an amino acid sequence having at least 92% sequence identity to any one of SEQ ID NOs: 45 to 226, and a variable light chain comprising an amino acid sequence set forth in any one of SEQ ID NOs: 132 to 227 and 545 to 558. In yet another aspect described herein, the variable heavy chain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 45 to 131 and 534 to 544, and the variable light chain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 132 to 227 and 545 to 558.

[0207] In some embodiments described herein, the CAR is capable of specifically binding to Vβ2, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ2 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:45, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:132; SEQ ID NO:133; SEQ ID NO:134; SEQ ID NO:135; SEQ ID NO:136; SEQ ID NO:137; SEQ ID NO:138; SEQ ID NO:139; SEQ ID NO:140; SEQ ID NO:141; SEQ ID NO:142; SEQ ID NO:143; SEQ ID NO:144; SEQ ID NO:145; SEQ ID NO:146; SEQ ID NO:147; SEQ ID NO:148; SEQ ID NO:149; SEQ ID NO:150; SEQ ID NO:151; SEQ ID NO:152; SEQ ID NO:153; SEQ ID NO:154; SEQ ID NO:155; SEQ ID NO:156; SEQ ID NO:157; SEQ ID NO:158; or SEQ ID NO:159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 46, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 47, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159.In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 48, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 49, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 50, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159.In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 51, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 52, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 53, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 54, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 55, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159.In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 56, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 57, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 58, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159.In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 59, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 60, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 61, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159.In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 62, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 63, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 64, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 65, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 66, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159.In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 67, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 68, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 69, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159.In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 70, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 71, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159. In some aspects, the Vβ2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 72, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155; SEQ ID NO: 156; SEQ ID NO: 157; SEQ ID NO: 158; or SEQ ID NO: 159.In some embodiments, the VH and VL described above comprise an amino acid sequence having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0208] In some embodiments, the CAR is capable of specifically binding to Vβ7.2, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ7.2 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:73, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:160; SEQ ID NO:161; SEQ ID NO:162; or SEQ ID NO:163. In some embodiments, the Vβ7.2 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:74, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:160; SEQ ID NO:161; SEQ ID NO:162; or SEQ ID NO:163. In some embodiments, the Vβ7.2 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:75, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:160; SEQ ID NO:161; SEQ ID NO:162; or SEQ ID NO:163. In some embodiments, the VH and VL described above comprise an amino acid sequence having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0209] In some embodiments described herein, the CAR is capable of specifically binding to Vβ4, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ4 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 76, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 164; SEQ ID NO: 165; SEQ ID NO: 166; or SEQ ID NO: 167. In some embodiments, the Vβ4 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 77, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 164; SEQ ID NO: 165; SEQ ID NO: 166; or SEQ ID NO: 167. In some embodiments, the Vβ4 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 78, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 164; SEQ ID NO: 165; SEQ ID NO: 166; or SEQ ID NO: 167. In some embodiments, a Vβ4 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 79, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 164; SEQ ID NO: 165; SEQ ID NO: 166; or SEQ ID NO: 167. In some embodiments, a Vβ4 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 80, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 164; SEQ ID NO: 165; SEQ ID NO: 166; or SEQ ID NO: 167. In some embodiments, the VH and VL described above comprise amino acid sequences having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0210] In some embodiments described herein, the CAR is capable of specifically binding to Vβ13.2, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ13.2 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:81 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:168; SEQ ID NO:169; SEQ ID NO:170; SEQ ID NO:171; SEQ ID NO:172; SEQ ID NO:173; SEQ ID NO:174; or SEQ ID NO:175. In some embodiments, the Vβ13.2 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:82 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:168; SEQ ID NO:169; SEQ ID NO:170; SEQ ID NO:171; SEQ ID NO:172; SEQ ID NO:173; SEQ ID NO:174; or SEQ ID NO:175. In some embodiments, the Vβ13.2 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 83, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 168; SEQ ID NO: 169; SEQ ID NO: 170; SEQ ID NO: 171; SEQ ID NO: 172; SEQ ID NO: 173; SEQ ID NO: 174; or SEQ ID NO: 175. In some embodiments, the Vβ13.2 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 84, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 168; SEQ ID NO: 169; SEQ ID NO: 170; SEQ ID NO: 171; SEQ ID NO: 172; SEQ ID NO: 173; SEQ ID NO: 174; or SEQ ID NO: 175. In some embodiments, the Vβ13.2 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 85, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 168; SEQ ID NO: 169; SEQ ID NO: 170; SEQ ID NO: 171; SEQ ID NO: 172; SEQ ID NO: 173; SEQ ID NO: 174; or SEQ ID NO: 175. In some embodiments, the Vβ13.2 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 86, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 168; SEQ ID NO: 169; SEQ ID NO: 170; SEQ ID NO: 171; SEQ ID NO: 172; SEQ ID NO: 173; SEQ ID NO: 174; or SEQ ID NO: 175.In some embodiments, the Vβ13.2 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 87, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 168; SEQ ID NO: 169; SEQ ID NO: 170; SEQ ID NO: 171; SEQ ID NO: 172; SEQ ID NO: 173; SEQ ID NO: 174; or SEQ ID NO: 175. In some embodiments, the VH and VL comprise amino acid sequences having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0211] In some embodiments described herein, the CAR is capable of specifically binding Vβ14, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ14 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 88, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 176; SEQ ID NO: 177; SEQ ID NO: 178; SEQ ID NO: 179; SEQ ID NO: 180; or SEQ ID NO: 181. In some embodiments, the Vβ14 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 89, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 176; SEQ ID NO: 177; SEQ ID NO: 178; SEQ ID NO: 179; SEQ ID NO: 180; or SEQ ID NO: 181. In some embodiments, a Vβ14 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 90, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 176; SEQ ID NO: 177; SEQ ID NO: 178; SEQ ID NO: 179; SEQ ID NO: 180; or SEQ ID NO: 181. In some embodiments, a Vβ14 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 91, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 176; SEQ ID NO: 177; SEQ ID NO: 178; SEQ ID NO: 179; SEQ ID NO: 180; or SEQ ID NO: 181. In some embodiments, the VH and VL described above comprise amino acid sequences having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0212] In some embodiments described herein, the CAR is capable of specifically binding to Vβ22, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ22 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:92, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:182; SEQ ID NO:183; SEQ ID NO:184; or SEQ ID NO:185. In some embodiments, the Vβ22 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:93, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:182; SEQ ID NO:183; SEQ ID NO:184; or SEQ ID NO:185. In some embodiments, the Vβ22 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:94, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:182; SEQ ID NO:183; SEQ ID NO:184; or SEQ ID NO:185. In some embodiments, a Vβ22 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 95, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 182; SEQ ID NO: 183; SEQ ID NO: 184; or SEQ ID NO: 185. In some embodiments, the VH and VL described above comprise amino acid sequences having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0213] In some embodiments described herein, the CAR is capable of specifically binding to Vβ11, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ11 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 96, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 186; SEQ ID NO: 187; SEQ ID NO: 188; or SEQ ID NO: 189. In some embodiments, the Vβ11 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 97, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 186; SEQ ID NO: 187; SEQ ID NO: 188; or SEQ ID NO: 189. In some embodiments, the VH and VL described above comprise an amino acid sequence having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0214] In some embodiments described herein, the CAR is capable of specifically binding to Vβ1, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ1 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 98, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 190; SEQ ID NO: 191; SEQ ID NO: 192; SEQ ID NO: 193; or SEQ ID NO: 194. In some embodiments, the Vβ1 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 99, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 190; SEQ ID NO: 191; SEQ ID NO: 192; SEQ ID NO: 193; or SEQ ID NO: 194. In some embodiments, the VH and VL described above comprise an amino acid sequence having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0215] In some embodiments described herein, the CAR is capable of specifically binding Vβ12, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ12 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 100, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 195; SEQ ID NO: 196; SEQ ID NO: 197; SEQ ID NO: 198; or SEQ ID NO: 199. In some embodiments, the Vβ12 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 101, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 195; SEQ ID NO: 196; SEQ ID NO: 197; SEQ ID NO: 198; or SEQ ID NO: 199. In some embodiments, a Vβ12 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 102, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 195; SEQ ID NO: 196; SEQ ID NO: 197; SEQ ID NO: 198; or SEQ ID NO: 199. In some embodiments, a Vβ12 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 103, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 195; SEQ ID NO: 196; SEQ ID NO: 197; SEQ ID NO: 198; or SEQ ID NO: 199. In some embodiments, the VH and VL described above comprise amino acid sequences having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0216] In some embodiments described herein, the CAR is capable of specifically binding to Vβ8, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ8 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 104 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 200; SEQ ID NO: 201; or SEQ ID NO: 202. In some embodiments, the Vβ8 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 105 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 200; SEQ ID NO: 201; or SEQ ID NO: 202. In some embodiments, the Vβ8 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 106 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 200; SEQ ID NO: 201; or SEQ ID NO: 202. In some embodiments, the VH and VL described above comprise an amino acid sequence having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0217] In some embodiments described herein, the CAR is capable of specifically binding to Vβ13.1, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ13.1 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 107, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 203; SEQ ID NO: 204; or SEQ ID NO: 205. In some embodiments, the Vβ13.1 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 108, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 203; SEQ ID NO: 204; or SEQ ID NO: 205. In some embodiments, the Vβ13.1 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 109, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 203; SEQ ID NO: 204; or SEQ ID NO: 205. In some embodiments, the Vβ13.1 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 110, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 203; SEQ ID NO: 204; or SEQ ID NO: 205. In some embodiments, the VH and VL described above comprise amino acid sequences having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0218] In some embodiments described herein, the CAR is capable of specifically binding to Vβ5.1, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ5.1 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 111 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 206; SEQ ID NO: 207; or SEQ ID NO: 208. In some embodiments, the Vβ5.1 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 112 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 206; SEQ ID NO: 207; or SEQ ID NO: 208. In some embodiments, the Vβ5.1 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 113 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 206; SEQ ID NO: 207; or SEQ ID NO: 208. In some embodiments, a Vβ5.1 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 114, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 206; SEQ ID NO: 207; or SEQ ID NO: 208. In some embodiments, a Vβ5.1 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 115, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 206; SEQ ID NO: 207; or SEQ ID NO: 208. In some embodiments, the VH and VL described above comprise amino acid sequences having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0219] In some embodiments described herein, the CAR is capable of specifically binding to Vβ9, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ9 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 116, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 209; SEQ ID NO: 210; SEQ ID NO: 211; or SEQ ID NO: 212. In some embodiments, the Vβ9 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 117, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 209; SEQ ID NO: 210; SEQ ID NO: 211; or SEQ ID NO: 212. In some embodiments, the Vβ9 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 118, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 209; SEQ ID NO: 210; SEQ ID NO: 211; or SEQ ID NO: 212. In some embodiments, the Vβ9 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 119, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 209; SEQ ID NO: 210; SEQ ID NO: 211; or SEQ ID NO: 212. In some embodiments, the VH and VL described above comprise amino acid sequences having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0220] In some embodiments described herein, the CAR is capable of specifically binding to Vβ17, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ17 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 120 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 213; SEQ ID NO: 214; or SEQ ID NO: 215. In some embodiments, the Vβ17 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 121 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 213; SEQ ID NO: 214; or SEQ ID NO: 215. In some embodiments, the Vβ17 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 122 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 213; SEQ ID NO: 214; or SEQ ID NO: 215. In some embodiments, the VH and VL described above comprise an amino acid sequence having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0221] In some embodiments described herein, the CAR is capable of specifically binding to Vβ3, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ3 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 123, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 216; SEQ ID NO: 217; or SEQ ID NO: 218. In some embodiments, the Vβ3 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 124, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 216; SEQ ID NO: 217; or SEQ ID NO: 218. In some embodiments, the Vβ3 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 125, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 216; SEQ ID NO: 217; or SEQ ID NO: 218. In some embodiments, the VH and VL described above comprise an amino acid sequence having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0222] In some embodiments described herein, the CAR is capable of specifically binding to Vβ7.1, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ7.1 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 126, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 219; SEQ ID NO: 220; SEQ ID NO: 221; SEQ ID NO: 222; SEQ ID NO: 223; or SEQ ID NO: 224. In some embodiments, the Vβ7.1 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 127, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 219; SEQ ID NO: 220; SEQ ID NO: 221; SEQ ID NO: 222; SEQ ID NO: 223; or SEQ ID NO: 224. In some embodiments, the Vβ7.1 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 128, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 219; SEQ ID NO: 220; SEQ ID NO: 221; SEQ ID NO: 222; SEQ ID NO: 223; or SEQ ID NO: 224. In some embodiments, the Vβ7.1 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 129, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 219; SEQ ID NO: 220; SEQ ID NO: 221; SEQ ID NO: 222; SEQ ID NO: 223; or SEQ ID NO: 224. In some embodiments, the VH and VL described above comprise an amino acid sequence having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0223] In some embodiments described herein, the CAR is capable of specifically binding to Vβ5.3, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ5.3 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 130, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 225; SEQ ID NO: 226; or SEQ ID NO: 227. In some embodiments, the Vβ5.3 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 131, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 225; SEQ ID NO: 226; or SEQ ID NO: 227. In some embodiments, the VH and VL described above comprise an amino acid sequence having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0224] In some embodiments described herein, the CAR is capable of specifically binding to Vβ20, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ20 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:534, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:545; SEQ ID NO:546; or SEQ ID NO:547. In some embodiments, the Vβ20 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:535, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:545; SEQ ID NO:546; or SEQ ID NO:547. In some embodiments, the Vβ20 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:536, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:545; SEQ ID NO:546; or SEQ ID NO:547. In some embodiments, the VH and VL described above comprise an amino acid sequence having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0225] In some embodiments described herein, the CAR is capable of specifically binding to Vβ18, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ18 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:537 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:548; SEQ ID NO:549; or SEQ ID NO:550. In some embodiments, the Vβ18 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:538 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:548; SEQ ID NO:549; or SEQ ID NO:550. In some embodiments, the Vβ18 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:539 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:548; SEQ ID NO:549; or SEQ ID NO:550. In some embodiments, the VH and VL described above comprise an amino acid sequence having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0226] In some embodiments described herein, the CAR is capable of specifically binding to Vβ13.6, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ13.6 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 540 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 551 or SEQ ID NO: 552. In some embodiments, the Vβ13.6 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 541 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 551 or SEQ ID NO: 552. In some embodiments, the VH and VL described above comprise an amino acid sequence having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0227] In some embodiments described herein, the CAR is capable of specifically binding to Vβ16, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ16 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:542, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:553; SEQ ID NO:554; SEQ ID NO:555; SEQ ID NO:556; SEQ ID NO:557; or SEQ ID NO:558. In some embodiments, the Vβ16 CAR comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:543, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:553; SEQ ID NO:554; SEQ ID NO:555; SEQ ID NO:556; SEQ ID NO:557; or SEQ ID NO:558. In some embodiments, the Vβ16 CAR comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 544, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 553; SEQ ID NO: 554; SEQ ID NO: 555; SEQ ID NO: 556; SEQ ID NO: 557; or SEQ ID NO: 558. In some embodiments, the VH and VL described above comprise amino acid sequences having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0228] Various assays are known for identifying binding domains of the present disclosure that specifically bind to a particular target, including Western blot, ELISA, flow cytometry, or surface plasmon resonance analysis (e.g., using BIACORE analysis). The target can be an antigen of clinical interest for which it is desirable to trigger an effector immune response that leads to tumor killing. In some embodiments described herein, the target antigen of the binding domain of a chimeric antigen receptor can be, for example, the Vβ region of a TCR.

[0229] Exemplary ligand-binding domains include antigen-binding proteins, e.g., antigen-binding fragments of antibodies, such as scFv; extracellular domains of receptors; ligands for cell surface molecules / receptors; or receptor-binding domains thereof; and tumor-binding proteins. In some embodiments described herein, for example, the antigen-binding domain included in a CAR of the present disclosure can be a variable region (Fv), CDR, Fab, scFv, VH, or VL.

[0230] In some embodiments described herein, the binding domain of the CAR is the Vβ region of a TCR single-chain antibody (scFv), which can be a murine, chimeric, human, or humanized scFv. Single-chain antibodies can be cloned from the V region genes of hybridomas specific for a desired target. Techniques that can be used to clone the variable heavy (VH) and variable light (VL) chains are disclosed, for example, in Orlandi et al., PNAS, 1989;86:3833-3837. Thus, in some embodiments, the binding domain includes an antibody-derived binding domain, but can also be a non-antibody-derived binding domain. An antibody-derived binding domain can be an antibody fragment or a recombinant product of one or more antibody fragments, where the fragment is responsible for binding to the antigen.

[0231] In some aspects described herein, the TCR Vβ region is selected from the group consisting of Vβ1, Vβ2, Vβ3, Vβ4, Vβ5.1, Vβ5.3, Vβ6, Vβ7.1, Vβ7.2, Vβ8, Vβ9, Vβ10, Vβ11, Vβ12, Vβ13.1, Vβ13.2, Vβ14, Vβ15, Vβ16, Vβ17, Vβ18, Vβ19, Vβ20, Vβ21, Vβ22, Vβ23, Vβ24, Vβ25, Vβ26, Vβ27, Vβ28, Vβ29, Vβ30, VβA, VβB, and VβC. It will be appreciated that combinations of variable heavy and light chains described herein that specifically bind to the same TCR Vβ region may provide increased in vitro and / or in vivo activity compared to combinations of variable heavy and light chains described herein that specifically bind to different TCR Vβ regions.

[0232] In some aspects described herein, the TCR Vβ region is selected from the group consisting of Vβ1, Vβ2, Vβ3, Vβ4, Vβ5.1, Vβ5.3, Vβ7.1, Vβ7.2, Vβ8, Vβ9, Vβ11, Vβ12, Vβ13.1, Vβ13.2, Vβ14, Vβ17, and Vβ22.

[0233] In some embodiments described herein, the TCR Vβ region is Vβ2.

[0234] In some embodiments described herein, the antigen-binding domain is an scFv. In some embodiments described herein, the scFv comprises, for example, the amino acid sequence set forth in any one of SEQ ID NOs: 16 to 44.

[0235] In some embodiments, a CAR of the present disclosure can include a linker between one or more domains, e.g., added for proper spacing and conformation of the molecule. For example, in some embodiments, a linker can be present between the VH or VL binding domains. In some embodiments, the linker can be 1 to 10 amino acids in length. In some embodiments, the linker between any of the domains of the chimeric antigen receptor can be 1 to 20 amino acids in length, or 20 amino acids in length. In this regard, the linker can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids in length. In some embodiments, the linker can be 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids in length. Linkers ranging in length from 10 to 30 amino acids inclusive, including the numbers described herein, are also encompassed herein.

[0236] In some embodiments, linkers suitable for use in the CARs disclosed herein are flexible linkers. Suitable linkers can be readily selected and can be of any of a variety of suitable lengths, such as 1 amino acid (e.g., Gly) to 20 amino acids, 2 to 15 amino acids, 3 to 12 amino acids, including 4 to 10 amino acids, 5 to 9 amino acids, 6 to 8 amino acids, or 7 to 8 amino acids, and can be 1, 2, 3, 4, 5, 6, or 7 amino acids.

[0237] Exemplary flexible linkers include glycine polymers (G)n (where n is an integer of at least 1), glycine-serine polymers, glycine-alanine polymers, alanine-serine polymers, and other flexible linkers known in the art. Because glycine and glycine-serine polymers are relatively unstructured, they can serve as neutral tethers between domains of fusion proteins such as the CARs disclosed herein. Glycine has significantly more access to phi-psi space than alanine and is less restricted than residues with longer side chains (see Scheraga, Rev. Computational Chem. 11173-142 (1992)). Those skilled in the art will recognize that CAR designs can include fully or partially flexible linkers, whereby the linker can include a flexible linker and one or more moieties that impart less flexible structure to yield the desired CAR structure.

[0238] In some embodiments described herein, the scFv comprises a linker peptide. In some embodiments described herein, the scFv comprises a linker peptide set forth in SEQ ID NO:4.

[0239] Signals generated through the T cell receptor alone are usually insufficient to fully activate T cells; therefore, costimulatory signals or signaling domains are present to activate T cells. Examples of signal transduction domains for use in CARs can be the cytoplasmic sequences of T cell receptors and coreceptors, which jointly initiate signal transduction after antigen receptor engagement, as well as any derivatives or variants of these sequences and systemic sequences with the same functional capabilities. In some cases, the signaling domains include two different classes of cytoplasmic signaling sequences: those that initiate antigen-dependent primary activation and those that function independently of antigen to provide secondary or costimulatory signals. Primary cytoplasmic signaling sequences can contain signaling motifs known as immunoreceptor tyrosine-based activation motifs (ITAMs). ITAMs can be found in the cytoplasmic tails of various receptors, where they function as binding sites for the syk / zap70 class tyrosine kinases.

[0240] In some embodiments described herein, ITAMs can include, for example, those derived from TCRζ, FcRγ, FcRbeta, FcRε, CD3γ, CD3δ, CD3ε, CD3ζ, CD5, CD22, CD79a, CD79b, and CD66d. In some embodiments, the signal transduction domain of the CAR can comprise a CD3ζ / CD247 signaling domain.

[0241] In some embodiments, the CARs disclosed herein can include a costimulatory domain, e.g., derived from a costimulatory molecule. Costimulatory molecules can include, but are not limited to, MHC class I molecules, BTLA, and Toll ligand receptors. Examples of costimulatory molecules include, for example, ligands that specifically bind to CD27, CD28, CD8, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and CD83. Costimulatory molecules can be cell surface molecules other than antigen receptors or their ligands that can contribute to an efficient immune response.

[0242] Thus, while the present disclosure provides an exemplary costimulatory domain derived from 4-1BB, other costimulatory domains are contemplated for use with the CARs disclosed herein. The inclusion of one or more costimulatory signaling domains can improve the efficacy and proliferation of T cells expressing the CAR receptors disclosed herein. The intracellular signaling and costimulatory signaling domains can be attached in any order in tandem with the carboxyl terminus of the transmembrane domain.

[0243] Although scFv-based CARs engineered to include signaling domains from CD3 or FcRγ have been shown to deliver potent signals for T cell activation and effector function, they are not sufficient to induce signals that promote T cell survival and proliferation in the absence of concomitant costimulatory signals. Other CARs containing a signaling domain from CD3ζ or FcRγ along with a binding domain, hinge, transmembrane, and one or more costimulatory signal domains (e.g., intracellular costimulatory domains from CD28, CD137, CD134, and CD278) can direct more efficient anti-tumor activity in vitro and in animal models and cancer patients, as well as increased cytokine secretion, lysis, survival, and proliferation in CAR-expressing T cells (Milone et al., Molecular Therapy, 2009;17:1453-1464; Zhong et al., Molecular Therapy, 2010;18:413-420; Carpenito et al., PNAS, 2009;106:3360-3365).

[0244] In some aspects, the Vβ region of a TCR-binding CAR of the present disclosure comprises: (a) an anti-Vβ region of a TCR scFv as a binding domain (e.g., an scFv having a binding region (e.g., a CDR or variable domain) derived from the anti-Vβ region of a TCR antibody or antigen-binding fragment thereof disclosed herein); (b) a hinge region (e.g., derived from human CD8α); (c) a transmembrane domain (e.g., a human CD28α transmembrane domain); and (d) a signaling domain (e.g., a human T cell receptor CD3ζ chain signaling domain), and optionally one or more costimulatory signal domains, e.g., a 4-1BB costimulatory domain.

[0245] In some aspects, the various protein domains are arranged from amino terminus to carboxyl terminus in the following order: binding domain, hinge, and transmembrane domain. The intracellular signaling domain and any costimulatory signaling domain are attached in tandem, in any order, to the transmembrane carboxy terminus to form a single-chain chimeric polypeptide.

[0246] In some embodiments, the nucleic acid construct encoding the Vβ region of the TCR binding CAR is a chimeric nucleic acid molecule that includes various coding sequences, for example (from 5' to 3') the coding sequence of the human anti-Vβ region of the TCR scFv, a human CD8α hinge region, a human CD28α transmembrane domain, and a CD247 signaling domain. In some embodiments, the nucleic acid construct encoding the Vβ region of the TCR binding CAR is a chimeric nucleic acid molecule that includes various coding sequences, for example (from 5' to 3') the coding sequence of the human anti-Vβ region of the TCR scFv, a human CD8α hinge, a human CD28α transmembrane domain, a 4-1BB costimulatory domain, and a CD247 signaling domain.

[0247] In some embodiments described herein, a polynucleotide encodes a CAR disclosed herein and is inserted into a vector. In some embodiments, a vector, as used herein, refers to a vehicle into which a polynucleotide encoding a protein can be covalently inserted to result in expression of the protein and / or cloning of the polynucleotide. An isolated polynucleotide can be inserted into a vector using methods known in the art. For example, but not limited to, a vector can be digested with an appropriate restriction enzyme and then ligated to an isolated polynucleotide having matching restriction ends. In some embodiments, an expression vector is capable of incorporating and expressing a heterologous or modified nucleic acid sequence that encodes at least a portion of a gene product that can be transcribed intracellularly. In most cases, the RNA molecule is then translated into a protein. Expression vectors can contain various control sequences, and "control sequences" refers to nucleic acid sequences for directing the transcription, and optionally translation, of an operably linked coding sequence in a particular host organism. In addition to regulatory sequences that govern transcription and translation, vectors and expression vectors can contain nucleic acid sequences that perform other functions, which are discussed below. Expression vectors can include additional elements. For example, an expression vector can have two replication systems, allowing it to be maintained in two organisms, for example, in human cells for expression and in a prokaryotic host for cloning and amplification.

[0248] The expression vector can have 5' upstream and 3' downstream regulatory elements, such as a promoter sequence (e.g., CMV, PGK, or EF1 alpha promoter), a ribosome recognition and binding TATA box, and a 3' UTR AAUAAA transcription termination sequence, for efficient gene transcription and translation in corresponding host cells. Other suitable promoters include the constitutive promoter of Simian Virus 40 (SV40 early promoter), mouse mammary tumor virus (MMTV), HIV LTR promoter, MoMuLV promoter, avian leukosis virus promoter, EBV immediate early promoter, and Rous sarcoma virus promoter. Human gene promoters, including but not limited to, actin promoter, myosin promoter, hemoglobin promoter, and creatine kinase promoter, can also be used. In some embodiments, an inducible promoter is also contemplated as part of a vector expressing a chimeric antigen receptor. This provides a molecular switch that can turn on or off expression of a polynucleotide sequence of interest. Examples of inducible promoters include, but are not limited to, a metallothionine promoter, a glucocorticoid promoter, a progesterone promoter, or a tetracycline promoter.

[0249] Expression vectors can have additional sequences, such as hexa-histidine, c-Myc, and FLAG tags, that are incorporated into the expressed CAR. Thus, expression vectors can be modified to contain 5' and 3' untranslated regulatory sequences, which can optionally function as enhancer sequences; promoter regions and / or terminator sequences, which can facilitate or improve efficient transcription of the nucleic acid(s) carried by the expression vector. Expression vectors can also be engineered for replication and / or expression functionality (e.g., transcription and translation) in specific cell types, cell locations, or tissue types. Expression vectors can include selectable markers for maintenance of the vector in host or recipient cells.

[0250] In some embodiments, vectors are plasmids, autonomously replicating sequences, and transposable elements. Further exemplary vectors include, but are not limited to, plasmids; phagemids; cosmids; artificial chromosomes, such as yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), or P1-derived artificial chromosomes (PACs); bacteriophages, such as lambda phage or M13 phage; and animal viruses. Examples of animal virus categories that are useful as vectors include, but are not limited to, retroviruses (including lentiviruses), adenoviruses, adeno-associated viruses, herpesviruses (e.g., herpes simplex viruses), poxviruses, baculoviruses, papillomaviruses, and papovaviruses (e.g., SV40). Examples of expression vectors are the Lenti-X™ Bicistronic Expression System (Neo) vector (Clontrch), the pClneo vector (Promega) for expression in mammalian cells, and pLenti4 / V5-DEST™, pLenti6 / V5-DEST™, and pLenti6.2N5-GW / lacZ (Invitrogen) for lentivirus-mediated gene transfer and expression in mammalian cells. The coding sequence of the CAR disclosed herein can be ligated into an expression vector for expression of the chimeric protein in mammalian cells.

[0251] In some embodiments, for expression of the Vβ region of a TCR-binding CAR, a vector can be introduced into a host cell and the polypeptide can be expressed in the host cell. Expression vectors can contain various elements for controlling expression, including, but not limited to, promoter sequences, transcription initiation sequences, enhancer sequences, selectable markers, and signal sequences. These elements can be appropriately selected by those skilled in the art, as disclosed herein. For example, a promoter sequence can be selected to promote transcription of a polynucleotide within the vector. Suitable promoter sequences include, but are not limited to, T7 promoter, T3 promoter, SP6 promoter, β-actin promoter, EF1a promoter, CMV promoter, and SV40 promoter. An enhancer sequence can be selected to improve transcription of a polynucleotide. A selectable marker can be selected to enable selection of host cells that are inserted with a vector not native to the host cell; for example, a selectable marker can be a gene that confers antibiotic resistance. A signal sequence can be selected to transport the expressed polypeptide outside the host cell.

[0252] Some aspects described herein disclose nucleic acid molecules encoding chimeric antigen receptor VHs. In the aspects described herein, the nucleic acid molecules encode polypeptides comprising the chimeric antigen receptor VHs set forth in any of SEQ ID NOS: 45 to 131 and 534 to 544.

[0253] Some embodiments described herein disclose nucleic acid molecules encoding the VL of a chimeric antigen receptor. In the embodiments described herein, the nucleic acid molecule encodes a polypeptide comprising the VL of a chimeric antigen receptor set forth in any of SEQ ID NOs: 132 to 227 and 545 to 558.

[0254] Some embodiments described herein disclose nucleic acid molecules encoding chimeric antigen receptors. In the embodiments described herein, the nucleic acid molecules encode the chimeric antigen receptors set forth in any of SEQ ID NOS: 16 to 44.

[0255] In some aspects described herein, a vector comprising the isolated polynucleotide is disclosed, in some aspects described herein, the vector is selected from the group consisting of a retroviral vector, an adenoviral vector, a lentiviral vector, and an adeno-associated viral vector.

[0256] For cloning a polynucleotide, a vector is introduced into a host cell (isolated host cell) to allow the vector to replicate, thereby amplifying copies of the polynucleotide contained in the vector. Cloning vectors generally contain sequence components, including, but not limited to, an origin of replication, a promoter sequence, a transcription initiation sequence, an enhancer sequence, and a selectable marker. These elements can be appropriately selected by those skilled in the art. For example, an origin of replication can be selected to promote autonomous replication of the vector in the host cell.

[0257] In some aspects, the present disclosure provides isolated host cells containing the vectors provided herein. Host cells containing the vectors can be useful for expressing or cloning polynucleotides contained in the vectors. Suitable host cells can include, but are not limited to, prokaryotic cells, fungal cells, yeast cells, or higher eukaryotic cells, such as mammalian cells. Suitable prokaryotic cells for this purpose include, but are not limited to, eubacteria, e.g., gram-negative or gram-positive organisms, e.g., Enterobacteriaceae, such as Escherichia, e.g., E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans and Shigella, Bacilli, e.g., B. subtilis and B. licheniformis, Pseudomonas, e.g., P. aeruginosa, and Streptomyces.

[0258] The CAR of the present disclosure can be introduced into host cells using transfection and / or transduction techniques known in the art. As used herein, the terms "transfection" and "transduction" refer to the process by which an exogenous nucleic acid sequence is introduced into a host cell. The nucleic acid can be integrated into the host cell DNA or can be maintained extrachromosomally. The nucleic acid can be maintained transiently or can be stably introduced. Transfection can be achieved by various means known in the art, including, but not limited to, calcium phosphate-DNA co-precipitation, DEAE-dextran-mediated transfection, polybrene-mediated transfection, electroporation, microinjection, liposome fusion, lipofection, protoplast fusion, retroviral infection, and biolistics. Transduction refers to the delivery of a gene(s) using a viral or retroviral vector by viral infection rather than transfection. In some embodiments, retroviral vectors are transduced by packaging the vector into virions before contacting the cell. For example, nucleic acids encoding the Vβ regions of a TCR CAR, carried by a retroviral vector, can be transduced into cells by infection and by proviral integration.

[0259] Immune effector cells, such as T cells, can be genetically modified after isolation using known methods, or immune effector cells can be activated and expanded (or differentiated, if progenitor) in vitro prior to genetic modification. In another aspect, immune effector cells, such as T cells, are genetically modified with a chimeric antigen receptor disclosed herein (e.g., transduced with a viral vector comprising a nucleic acid encoding a CAR) and then activated and expanded in vitro. Methods for activating and expanding T cells are known in the art and are disclosed, for example, in U.S. Pat. Nos. 6,905,874, 6,867,041, 6,797,514, and WO2012079000. Generally, such methods include contacting PBMCs or isolated T cells with stimulatory and costimulatory agents, such as anti-CD3 and anti-CD28 antibodies, typically bound to beads or other surfaces, in a medium containing appropriate cytokines, such as IL-2.

[0260] Anti-CD3 and anti-CD28 antibodies bound to the same bead function as "surrogate" antigen-presenting cells (APCs). In some embodiments, T cells can be activated and stimulated to proliferate with feeder cells and appropriate antibodies and cytokines using methods such as those disclosed in U.S. Patent Nos. 6,040,177, 5,827,642, and WO2012129514.

[0261] CAR-expressing immune effector cells prepared as disclosed herein can be utilized in methods and compositions for adoptive immunotherapy according to known techniques, or variations thereof that will be apparent to those skilled in the art based on this disclosure. See, e.g., U.S. Patent Application Publication No. 2003 / 0170238 (Gruenberg et al.). See also U.S. Patent No. 4,690,915 (Rosenberg).

[0262] In some embodiments, cells are formulated by first harvesting them from the culture medium, then washing the cells and concentrating them in a therapeutically effective amount in a medium and container system suitable for administration (a "pharmaceutically acceptable" carrier). A suitable infusion medium can be any isotonic medium formulation, typically saline, Normosol R (Abbott), or Plasma-Lyte A (Baxter), although 5% dextrose in water or lactated Ringer's solution can also be utilized. The infusion medium may be supplemented with human serum albumin.

[0263] The cells can be autologous or xenogeneic to the patient undergoing therapy. If desired, the treatment can also include a mitogen (e.g., PHA) or lymphokines, cytokines, and / or chemokines (e.g., IFN-γ, IL-2, IL-12, TNF-α, IL-18, and TNF-β, GM-CSF, IL-4, IL-13, Flt3-L, RANTES, MIP1α, etc.) disclosed herein to enhance induction of an immune response.

[0264] The present disclosure provides methods for producing immune effector cells that express a CAR disclosed herein. In some embodiments, immune effector cells are isolated from an individual and genetically modified without further in vitro manipulation. Such cells can then be directly readministered to the individual. In some embodiments, immune effector cells are first activated and stimulated to expand in vitro before being genetically modified to express a CAR. In this regard, immune effector cells can be cultured (i.e., transduced or transfected to express a CAR disclosed herein) before or after being genetically modified.

[0265] Prior to in vitro manipulation or genetic modification of the immune effector cells disclosed herein, a source of cells can be obtained from a subject. In particular, immune effector cells for use with the CARs disclosed herein include T cells. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from the site of infection, ascites, pleural effusion, spleen tissue, and tumors. In some embodiments, T cells can be obtained from a blood unit collected from a subject using any number of techniques known to those skilled in the art, such as, for example, Ficoll separation. In some embodiments, cells from an individual's circulating blood are obtained by apheresis. The apheresis product typically includes lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets.

[0266] In some embodiments, cells collected by apheresis can be washed to remove the plasma fraction and place the cells in a buffer or medium appropriate for subsequent processing. In some embodiments, the cells are washed with PBS. In some embodiments, the washed solution lacks medium, may lack magnesium, or may lack many, but not all, divalent cations. As will be appreciated by those skilled in the art, washing steps can be accomplished by methods known to those skilled in the art, such as using a semi-automated flow-through centrifuge. After washing, the cells can be resuspended in various biocompatible buffers or other saline solutions, with or without buffers. In some embodiments, undesirable components of the apheresis sample are removed and the cells can be resuspended directly in culture medium.

[0267] In some embodiments, T cells are isolated from peripheral blood mononuclear cells (PBMCs) by lysing red blood cells and depleting monocytes, for example, by centrifugation through a PERCOLL™ gradient. Specific subpopulations of T cells, such as CD28+, CD4+, CD8+, CD45RA+, and CD45RO+ T cells, can be further isolated by positive or negative selection techniques. For example, enrichment of a T cell population by negative selection can be achieved using a combination of antibodies directed against surface markers unique to the negatively selected cells. One method for use herein is cell sorting and / or selection by negative magnetic immunoadhesion or flow cytometry using a cocktail of monoclonal antibodies directed against cell surface markers present on the negatively selected cells. For example, to enrich CD4+ cells by negative selection, the cocktail of monoclonal antibodies typically includes antibodies against CD14, CD20, CD1b, CD16, HLA-DR, and CD8. Flow cytometry and cell sorting can also be used to isolate cell populations of interest for use in the present disclosure.

[0268] PBMCs can be directly used for genetic modification with CARs using the methods disclosed herein. In some embodiments, after isolating PBMCs, T lymphocytes are further isolated, and in some embodiments, both cytotoxic and helper T lymphocytes can be sorted into naive, memory, and effector cell subpopulations either before or after genetic modification and / or expansion. CD8+ cells can be obtained using standard methods. In some embodiments, CD8+ cells are further sorted into naive, central memory, and effector cells by identifying cell surface antigens associated with each of these types of CD8+ cells.

[0269] The CAR-expressing immune effector cells of the present disclosure can be administered alone or as a pharmaceutical composition in combination with other components or cell populations, such as diluents and / or IL-2 or other cytokines. Briefly, the pharmaceutical compositions of the present disclosure can include the CAR-expressing immune effector cells, such as T cells, disclosed herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents, or excipients. Such compositions include a buffer, such as neutral buffered saline, phosphate buffered saline, or the like; a carbohydrate, such as glucose, mannose, sucrose, or dextran, mannitol; a protein; an amino acid, such as a polypeptide or glycine; an antioxidant; a chelating agent, such as EDTA or glutathione; an adjuvant (e.g., aluminum hydroxide); and a preservative. The compositions of the present disclosure can be formulated for intravenous administration.

[0270] Humoral immune response can be induced, which is mainly mediated by helper T cells that can activate B cells, thereby resulting in antibody production. To analyze the type of immune response induced by the composition of the present disclosure, various techniques can be used, which are well-disclosed in the art; for example, Current Protocols in Immunology, Edited by: John E. Coligan, Ada M. Kruisbeek, David H. Margulies, Ethan M. Shevach, Warren Strober (2001) John Wiley & Sons, NY, NY.

[0271] Methods of administering the cell compositions disclosed herein include any method effective to result in the ex vivo reintroduction in a subject of genetically modified immune effector cells that either directly express a CAR of the present disclosure, or genetically modified progenitors of immune effector cells that, upon introduction into a subject, differentiate into mature immune effector cells that express a CAR. One method involves transducing peripheral blood T cells ex vivo with a nucleic acid construct according to the present disclosure and returning the transduced cells to the subject.

[0272] The present disclosure also provides a vector into which a nucleic acid molecule encoding a CAR of the present disclosure is inserted.Vectors, including those derived from retroviruses such as lentiviruses, are suitable tools for achieving long-term gene transfer because they allow long-term stable integration of the transgene and its propagation in daughter cells.Lentiviral vectors have an additional advantage over vectors derived from oncogenic retroviruses such as murine leukemia viruses in that they can transduce non-proliferating cells such as hepatocytes.Lentiviral vectors also have the additional advantage of being less immunogenic in subjects into which they are introduced.

[0273] Prior to in vitro manipulation or genetic modification of the immune effector cells disclosed herein, a source of cells can be obtained from a subject. In particular, immune effector cells for use with the CARs disclosed herein include T cells. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from the site of infection, ascites, pleural effusion, spleen tissue, and tumors.

[0274] II. Anti-TCRVβ Antibodies and Antigen-Binding Fragments Thereof In some aspects, provided herein are antibodies (e.g., monoclonal antibodies) and antigen-binding fragments thereof that specifically bind to a Vβ region of a TCR (e.g., a human Vβ region of a TCR).

[0275] In some embodiments described herein, the antibody or antigen-binding fragment comprises, for example, (i) (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; or (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively; or (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively; or (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 376, SEQ ID NO: 377, and SEQ ID NO: 378, respectively. or (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively; or (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​SEQ ID NO: 383, and SEQ ID NO: 384, respectively; or (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; or (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 388, SEQ ID NO: 389, and SEQ ID NO: 390, respectively; or (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO: 397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, SEQ ID NO: 406, SEQ ID NO: 407, SEQ ID NO: 408, SEQ ID NO: 409, SEQ ID NO: 410, SEQ ID NO: 411, SEQ ID NO: 412, SEQ ID NO: 413, SEQ ID NO: 414, SEQ ID NO: 415, SEQ ID NO: 416, SEQ ID NO: 417, SEQ ID NO: 418, SEQ ID NO (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively; or (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 397, SEQ ID NO: 398, and SEQ ID NO: 399, respectively; or (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; or (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 403, SEQ ID NO: 404, and SEQ ID NO: 4 or (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; or (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411, respectively; or (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 412, SEQ ID NO: 413, and SEQ ID NO: 414, respectively; or (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 415, SEQ ID NO: 416, and SEQ ID NO: 417, respectively;or (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 584, SEQ ID NO: 585, and SEQ ID NO: 586, respectively; or (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 587, SEQ ID NO: 588, and SEQ ID NO: 589, respectively; or (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 591, and SEQ ID NO: 592, respectively; or (u) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively; and / or (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; or (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 418, SEQ ID NO: 419, and SEQ ID NO: 420, respectively; or (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; or (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 424, SEQ ID NO: 425, and SEQ ID NO: 426, respectively; or (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 42, respectively. or (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 430, 431, and 432, respectively; or (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 433, 434, and 435, respectively; or (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 436, 437, and 438, respectively; or (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 439, 440, and 441, respectively. or (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively; or (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; or (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; or (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 451, SEQ ID NO: 452, and SEQ ID NO: 453, respectively;or (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively; or (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; or (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 460, SEQ ID NO: 461, and SEQ ID NO: 462, respectively; or (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 463, SEQ ID NO: 464, and SEQ ID NO: 465, respectively; or (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 596 and SEQ ID NO: 597, respectively. or (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 599, SEQ ID NO: 601, and SEQ ID NO: 601, respectively; or (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (u) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, or SEQ ID NO: 608, SEQ ID NO: 609, and SEQ ID NO: 610, respectively;

[0276] In some embodiments described herein, the antibody or antigen-binding fragment thereof is capable of specifically binding to a TCR Vβ region comprising a heavy chain variable region (VH) having an amino acid sequence set forth in any one of SEQ ID NOs: 228-295 and 559-569. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 85% sequence identity to any one of SEQ ID NOs: 228-295 and 559-569. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 86% sequence identity to any one of SEQ ID NOs: 228-295 and 559-569. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 87% sequence identity to any one of SEQ ID NOs: 228-295 and 559-569. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 88% sequence identity to any one of SEQ ID NOs: 228-295 and 559-569. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 89% sequence identity to any one of SEQ ID NOs: 228-295 and 559-569. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 228-295 and 559-569. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 91% sequence identity to any one of SEQ ID NOs: 228-295 and 559-569. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 92% sequence identity to any one of SEQ ID NOs: 228-295 and 559-569. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 93% sequence identity to any one of SEQ ID NOs: 228-295, and 559-569. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 94% sequence identity to any one of SEQ ID NOs: 228-295, and 559-569.In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 228-295 and 559-569. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 96% sequence identity to any one of SEQ ID NOs: 228-295 and 559-569. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 97% sequence identity to any one of SEQ ID NOs: 228-295 and 559-569. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 98% sequence identity to any one of SEQ ID NOs: 228-295 and 559-569. In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having at least 99% sequence identity to any one of SEQ ID NOs: 228-295 and 559-569. In some embodiments described herein, the variable heavy chain comprises the amino acid sequence set forth in any one of SEQ ID NOs: 228-295 and 559-569.

[0277] In some embodiments described herein, the antibody or antigen-binding fragment comprising the above-described heavy chain variable region (VH) further comprises a light chain variable region (VL) having an amino acid sequence set forth in any of SEQ ID NOs: 296 to 369 and 570 to 583.

[0278] In some embodiments described herein, the antibody or antigen-binding fragment thereof is capable of specifically binding to a TCR Vβ region comprising a light chain variable region (VL) having the amino acid sequence set forth in any one of SEQ ID NOs: 296-369 and 570-583. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 85% sequence identity to any one of SEQ ID NOs: 296-369 and 570-583. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 86% sequence identity to any one of SEQ ID NOs: 296-369 and 570-583. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 87% sequence identity to any one of SEQ ID NOs: 296-369 and 570-583. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 88% sequence identity to any one of SEQ ID NOs: 296-369 and 570-583. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 89% sequence identity to any one of SEQ ID NOs: 296-369 and 570-583. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 296-369 and 570-583. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 91% sequence identity to any one of SEQ ID NOs: 296-369 and 570-583. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 92% sequence identity to any one of SEQ ID NOs: 296-369 and 570-583. In some aspects described herein, the variable light chain comprises an amino acid sequence having at least 93% sequence identity to any one of SEQ ID NOs: 296-369, and 570-583. In some aspects described herein, the variable light chain comprises an amino acid sequence having at least 94% sequence identity to any one of SEQ ID NOs: 296-369, and 570-583.In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 296-369 and 570-583. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 96% sequence identity to any one of SEQ ID NOs: 296-369 and 570-583. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 97% sequence identity to any one of SEQ ID NOs: 296-369 and 570-583. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 98% sequence identity to any one of SEQ ID NOs: 296-369 and 570-583. In some embodiments described herein, the variable light chain comprises an amino acid sequence having at least 99% sequence identity to any one of SEQ ID NOs: 296-369 and 570-583. In some aspects described herein, the variable light chain comprises the amino acid sequence set forth in any one of SEQ ID NOs: 296-369 and 570-583.

[0279] In some embodiments described herein, the antibody or antigen-binding fragment comprising the above-described light chain variable region (VL) further comprises a heavy chain variable region (VH) having an amino acid sequence set forth in any of SEQ ID NOs: 228 to 295 and 559 to 569.

[0280] In some embodiments described herein, the variable heavy chain comprises an amino acid sequence having any of the above-mentioned percent identities to any one of SEQ ID NOs: 296-369 and 570-583, and the variable light chain comprises an amino acid sequence having any of the above-mentioned percent identities to any one of SEQ ID NOs: 296-369 and 570-583. Specifically, non-limiting examples of variable heavy and light chain pairings include a variable heavy chain comprising an amino acid sequence having at least 88% sequence identity to any one of SEQ ID NOs: 228-295 and 559-569, and a variable light chain comprising an amino acid sequence having at least 93% sequence identity to any one of SEQ ID NOs: 269-369 and 570-583. In other aspects described herein, the pairing of variable heavy chains and light chains includes a variable heavy chain comprising an amino acid sequence having any of the above-mentioned percent identities to any one of SEQ ID NOs: 228 to 295 and 559 to 569, and a variable light chain comprising an amino acid sequence set forth in any one of SEQ ID NOs: 269 to 369 and 570 to 583. In other aspects described herein, the pairing of variable heavy chains and light chains includes a variable heavy chain comprising an amino acid sequence set forth in any one of SEQ ID NOs: 228 to 295 and 559 to 569, and a variable light chain comprising an amino acid sequence having any of the above-mentioned percent identities to any one of SEQ ID NOs: 269 to 369 and 570 to 583. Specifically, non-limiting examples of variable heavy and light chain pairings include a variable heavy chain comprising an amino acid sequence having at least 92% sequence identity to any one of SEQ ID NOs: 228 to 295 and 559 to 569, and a variable light chain comprising an amino acid sequence set forth in any one of SEQ ID NOs: 269 to 369 and 570 to 583. In yet another aspect described herein, the variable heavy chain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 228 to 295 and 559 to 569, and the variable light chain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 269 to 369 and 570 to 583.

[0281] In some embodiments described herein, the antibody or antigen-binding fragment thereof is capable of specifically binding to TCR Vβ2, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ2 antibody or antigen-binding fragment comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:228, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:296; SEQ ID NO:297; SEQ ID NO:298; SEQ ID NO:299; SEQ ID NO:300; SEQ ID NO:301; SEQ ID NO:302; or SEQ ID NO:303. In some embodiments, the Vβ2 antibody or antigen-binding fragment comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:229, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:296; SEQ ID NO:297; SEQ ID NO:298; SEQ ID NO:299; SEQ ID NO:300; SEQ ID NO:301; SEQ ID NO:302; or SEQ ID NO:303. In some embodiments, the Vβ2 antibody or antigen-binding fragment comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 230, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 296; SEQ ID NO: 297; SEQ ID NO: 298; SEQ ID NO: 299; SEQ ID NO: 300; SEQ ID NO: 301; SEQ ID NO: 302; or SEQ ID NO: 303. In some embodiments, the Vβ2 antibody or antigen-binding fragment comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 231, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 296; SEQ ID NO: 297; SEQ ID NO: 298; SEQ ID NO: 299; SEQ ID NO: 300; SEQ ID NO: 301; SEQ ID NO: 302; or SEQ ID NO: 303. In some embodiments, the Vβ2 antibody or antigen-binding fragment comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 232, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 296; SEQ ID NO: 297; SEQ ID NO: 298; SEQ ID NO: 299; SEQ ID NO: 300; SEQ ID NO: 301; SEQ ID NO: 302; or SEQ ID NO: 303. In some embodiments, the Vβ2 antibody or antigen-binding fragment comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 233, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 296; SEQ ID NO: 297; SEQ ID NO: 298; SEQ ID NO: 299; SEQ ID NO: 300; SEQ ID NO: 301; SEQ ID NO: 302; or SEQ ID NO: 303.In some embodiments, the Vβ2 antibody or antigen-binding fragment comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 234, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 296; SEQ ID NO: 297; SEQ ID NO: 298; SEQ ID NO: 299; SEQ ID NO: 300; SEQ ID NO: 301; SEQ ID NO: 302; or SEQ ID NO: 303. In some embodiments, the Vβ2 antibody or antigen-binding fragment comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 235, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 296; SEQ ID NO: 297; SEQ ID NO: 298; SEQ ID NO: 299; SEQ ID NO: 300; SEQ ID NO: 301; SEQ ID NO: 302; or SEQ ID NO: 303. In some embodiments, the VH and VL described above comprise an amino acid sequence having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0282] In some embodiments described herein, the antibody or antigen-binding fragment thereof can specifically bind to Vβ7.2, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ7.2 antibody or antigen-binding fragment comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:236 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:304; SEQ ID NO:305; SEQ ID NO:306; or SEQ ID NO:307. In some embodiments, the Vβ7.2 antibody or antigen-binding fragment comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO:237 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:304; SEQ ID NO:305; SEQ ID NO:306; or SEQ ID NO:307. In some embodiments, the Vβ7.2 antibody or antigen-binding fragment comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 238, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 304; SEQ ID NO: 305; SEQ ID NO: 306; or SEQ ID NO: 307. In some embodiments, the VH and VL comprise amino acid sequences having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0283] In some embodiments described herein, the antibody or antigen-binding fragment thereof is capable of specifically binding to Vβ4, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments, the Vβ4 antibody or antigen-binding fragment comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 239 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 308 or SEQ ID NO: 309. In some embodiments, the Vβ4 antibody or antigen-binding fragment comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 240 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 308 or SEQ ID NO: 309. In some embodiments, the Vβ4 antibody or antigen-binding fragment comprises, e.g., (i) a variable heavy chain (VH) set forth in SEQ ID NO: 241 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 308 or SEQ ID NO: 309. In some embodiments, the Vβ4 antibody or antigen-binding fragment comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 242 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 308 or SEQ ID NO: 309. In some embodiments, the Vβ4 antibody or antigen-binding fragment comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO: 243 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO: 308 or SEQ ID NO: 309. In some embodiments, the VH and VL described above comprise amino acid sequences having a percent identity of at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% to any one of the above SEQ ID NOs.

[0284] In some embodiments described herein, the antibody or antigen-binding fragment thereof is capable of specifically binding to Vβ13.2, e.g., comprises (i) a variable heavy chain (VH) and / or a variable light chain (VL). In some embodiments described herein, the antibody or antigen-binding fragment thereof is capable of specifically binding to Vβ13.2, e.g., comprises (i) a variable heavy chain (VH) set forth in SEQ ID NO:244 and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:310; SEQ ID NO:311; SEQ ID NO:312; SEQ ID NO:313; SEQ ID NO:314; SEQ ID NO:315; SEQ ID NO:316; or SEQ ID NO:317. In some embodiments, the Vβ13.2 antibody or antigen-binding fragment comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO:245, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:310; SEQ ID NO:311; SEQ ID NO:312; SEQ ID NO:313; SEQ ID NO:314; SEQ ID NO:315; SEQ ID NO:316; or SEQ ID NO:317. In some embodiments, the Vβ13.2 antibody or antigen-binding fragment comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO:246, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:310; SEQ ID NO:311; SEQ ID NO:312; SEQ ID NO:313; SEQ ID NO:314; SEQ ID NO:315; SEQ ID NO:316; or SEQ ID NO:317. In some embodiments, the Vβ13.2 antibody or antigen-binding fragment comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO:247, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:310; SEQ ID NO:311; SEQ ID NO:312; SEQ ID NO:313; SEQ ID NO:314; SEQ ID NO:315; SEQ ID NO:316; or SEQ ID NO:317. In some embodiments, the Vβ13.2 antibody or antigen-binding fragment comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO:248, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:310; SEQ ID NO:311; SEQ ID NO:312; SEQ ID NO:313; SEQ ID NO:314; SEQ ID NO:315; SEQ ID NO:316; or SEQ ID NO:317.In some embodiments, the Vβ13.2 antibody or antigen-binding fragment comprises, for example, (i) a variable heavy chain (VH) set forth in SEQ ID NO:249, and / or (ii) a variable light chain (VL) set forth in SEQ ID NO:310; SEQ ID NO:311; SEQ ID NO:312; SEQ ID NO:313; SEQ ID NO:314; SEQ ID NO:315; ...

Claims

1. A chimeric antigen receptor (CAR) comprising: (i) an antigen-binding molecule that specifically binds to a TCR Vβ region; (ii) an extracellular domain; (iii) a transmembrane domain; (iv) a costimulatory domain; and (v) an activation domain, The antigen-binding molecule (a) a variable heavy chain (VH) set forth in any one of SEQ ID NOs: 45-131, and 534-544; and / or (b) The chimeric antigen receptor, which is a single-chain variable fragment (scFv), comprising a variable light chain (VL) set forth in any one of SEQ ID NOs: 132 to 227 and 545 to 558.

2. (a) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; (b) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 418, SEQ ID NO: 419, and SEQ ID NO: 420, respectively; (c) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; (d) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:376, SEQ ID NO:377, and SEQ ID NO:378, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:424, SEQ ID NO:425, and SEQ ID NO:426, respectively; (e) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:379, SEQ ID NO:380, and SEQ ID NO:381, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:427, SEQ ID NO:428, and SEQ ID NO:429, respectively; (f) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​SEQ ID NO: 383, and SEQ ID NO: 384, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 430, SEQ ID NO: 431, and SEQ ID NO: 432, respectively; (g) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 433, SEQ ID NO: 434, and SEQ ID NO: 435, respectively; (h) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 388, SEQ ID NO: 389, and SEQ ID NO: 390, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 436, SEQ ID NO: 437, and SEQ ID NO: 438, respectively; (i) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 391, SEQ ID NO: 392, and SEQ ID NO: 393, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 439, SEQ ID NO: 440, and SEQ ID NO: 441, respectively; (j) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively; (k) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:397, SEQ ID NO:398, and SEQ ID NO:399, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:445, SEQ ID NO:446, and SEQ ID NO:447, respectively; (l) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; (m) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:403, SEQ ID NO:404, and SEQ ID NO:405, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:451, SEQ ID NO:452, and SEQ ID NO:453, respectively; (n) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively; (o) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:409, SEQ ID NO:410, and SEQ ID NO:411, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:457, SEQ ID NO:458, and SEQ ID NO:459, respectively; (p) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:412, SEQ ID NO:413, and SEQ ID NO:414, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:460, SEQ ID NO:461, and SEQ ID NO:462, respectively; (q) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:415, SEQ ID NO:416, and SEQ ID NO:417, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:463, SEQ ID NO:464, and SEQ ID NO:465, respectively; (r) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:584, SEQ ID NO:585, and SEQ ID NO:586, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:596, SEQ ID NO:597, and SEQ ID NO:598, respectively; (s) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:587, SEQ ID NO:588, and SEQ ID NO:589, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:599, SEQ ID NO:600, and SEQ ID NO:601, respectively; (t) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:590, SEQ ID NO:591, and SEQ ID NO:592, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:602, SEQ ID NO:603, and SEQ ID NO:604, respectively; or (u) The chimeric antigen receptor of claim 1, wherein (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 593, 594, and 595, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 605, 606, 607, respectively, or SEQ ID NOs: 608, 609, and 610, respectively.

3. 3. The chimeric antigen receptor of claim 1 or 2, wherein the variable heavy chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 45-131, and 534-544.

4. 3. The chimeric antigen receptor of claim 1 or 2, wherein the variable light chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 132-227, and 545-558.

5. The chimeric antigen receptor of any one of claims 1 to 4, wherein the TCR Vβ region is selected from the group consisting of Vβ1, Vβ2, Vβ3, Vβ4, Vβ5.1, Vβ5.3, Vβ7.1, Vβ7.2, Vβ8, Vβ9, Vβ11, Vβ12, Vβ13.1, Vβ13.2, Vβ13.6, Vβ14, Vβ16, Vβ17, Vβ18, Vβ20, and Vβ22.

6. The chimeric antigen receptor of claim 5, wherein the TCR Vβ region is Vβ2.

7. The chimeric antigen receptor of claim 1 , wherein the antigen-binding domain is an scFv.

8. The chimeric antigen receptor of claim 7, wherein the scFv comprises an amino acid sequence set forth in any one of SEQ ID NOs: 14 to 44.

9. The chimeric antigen receptor of any one of claims 1 to 8, wherein the costimulatory domain comprises a 4-1BB costimulatory domain.

10. The chimeric antigen receptor of claim 9, wherein the 4-1BB costimulatory domain comprises the amino acid sequence set forth in SEQ ID NO:

8.

11. The chimeric antigen receptor according to any one of claims 1 to 10, wherein the transmembrane domain comprises a hCD28 transmembrane domain.

12. The chimeric antigen receptor of claim 11, wherein the transmembrane domain comprises the hCD28 amino acid sequence set forth in SEQ ID NO:

7.

13. The chimeric antigen receptor of any one of claims 1 to 12, wherein the signaling domain comprises a CD247 signaling domain.

14. The chimeric antigen receptor of claim 13, wherein the signaling domain comprises the CD247 signaling domain amino acid sequence set forth in SEQ ID NO:

9.

15. The chimeric antigen receptor according to any one of claims 1 to 14, wherein the scFv comprises a CD28 signal peptide.

16. The chimeric antigen receptor of claim 15, wherein the scFv comprises a CD28 signal peptide and the amino acid sequence set forth in SEQ ID NO:

3.

17. The chimeric antigen receptor according to any one of claims 1 to 16, wherein the scFv comprises a linker peptide.

18. The chimeric antigen receptor of claim 17, wherein the scFv comprises a linker peptide set forth in SEQ ID NO:

4.

19. An isolated polynucleotide comprising a nucleic acid molecule encoding the VH of the chimeric antigen receptor of any one of claims 1 to 18.

20. 20. The isolated polynucleotide of claim 19, further comprising a nucleic acid molecule encoding the VL of the chimeric antigen receptor of any one of claims 1 to 18.

21. An isolated polynucleotide comprising a nucleic acid molecule encoding the VL of the chimeric antigen receptor of any one of claims 1 to 18.

22. 22. The isolated polynucleotide of claim 21, further comprising a nucleic acid molecule encoding the VH of the chimeric antigen receptor of any one of claims 1 to 18.

23. An isolated polynucleotide comprising a nucleic acid molecule encoding the chimeric antigen receptor of any one of claims 1 to 18.

24. A vector comprising the isolated polynucleotide of claim 23.

25. 25. The vector of claim 24, wherein the vector is selected from the group consisting of a retroviral vector, an adenoviral vector, a lentiviral vector, and an adeno-associated viral vector.

26. An antibody or antigen-binding fragment thereof capable of specifically binding to a TCR Vβ region, comprising a heavy chain variable region (VH) having an amino acid sequence set forth in any of SEQ ID NOs: 228 to 295 and 559 to 569.

27. An antibody or antigen-binding fragment thereof capable of specifically binding to a TCR Vβ region, comprising a light chain variable region (VL) having an amino acid sequence set forth in any of SEQ ID NOs: 296 to 369 and 570 to 583.

28. 27. The antibody or antigen-binding fragment of claim 26, wherein the VH comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any of SEQ ID NOs: 228-295 and 559-569.

29. 28. The antibody or antigen-binding fragment of claim 27, wherein the VL comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any of SEQ ID NOs: 228-295, and 559-569.

30. The antibody or antigen-binding fragment of claim 26, further comprising a light chain variable region (VL) having an amino acid sequence set forth in any of SEQ ID NOs: 296-369 and 570-583.

31. The antibody or antigen-binding fragment of claim 27, further comprising a heavy chain variable region (VH) having an amino acid sequence set forth in any of SEQ ID NOs: 228-295 and 559-569.

32. The antibody or antigen-binding fragment of any one of claims 26 to 31, wherein the antibody or antigen-binding fragment is human, humanized, or chimeric.

33. The antibody or antigen-binding fragment of any one of claims 26 to 32, wherein the antibody or antigen-binding fragment is an IgG antibody.

34. 34. The antibody or antigen-binding fragment of claim 33, wherein the IgG antibody is an IgG1 antibody or an IgG4 antibody.

35. The antibody or antigen-binding fragment of any one of claims 26 to 34, wherein the antibody is an antigen-binding fragment of an antibody.

36. 36. The antibody or antigen-binding fragment of claim 35, wherein the fragment is selected from the group consisting of Fab, F(ab')2, Fv, scFv, scFv-Fc, dsFv, and single domain molecules.

37. 37. The antibody or antigen-binding fragment of claim 35 or 36, wherein the fragment is an scFv.

38. 37. The antibody or antigen-binding fragment of claim 35 or 36, wherein the fragment is a Fab.

39. 37. The antibody or antigen-binding fragment of claim 35 or 36, wherein the fragment is an intracellular antibody.

40. 40. The antibody or antigen-binding fragment of any one of claims 26 to 39, wherein the antigen-binding fragment lacks the Fc region.

41. The antibody or antigen-binding fragment of any one of claims 26 to 40, comprising a VH and a VL in the same polypeptide chain.

42. The antibody or antigen-binding fragment of any one of claims 26 to 41, wherein the VH and VL are connected by a linker.

43. 43. The antibody or antigen-binding fragment of any one of claims 26 to 42, wherein the TCR Vβ region is selected from the group consisting of Vβ1, Vβ2, Vβ3, Vβ4, Vβ5.1, Vβ5.3, Vβ7.1, Vβ7.2, Vβ8, Vβ9, Vβ11, Vβ12, Vβ13.1, Vβ13.2, Vβ13.6, Vβ14, Vβ16, Vβ17, Vβ18, Vβ20, and Vβ22.

44. 44. The antibody or antigen-binding fragment of claim 43, wherein the TCR Vβ region is Vβ2.

45. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a T cell composition comprising a CAR, the CAR comprising: (i) an antigen-binding molecule that specifically binds to a TCR Vβ region, (ii) an extracellular domain, (iii) a transmembrane domain, (iv) a costimulatory domain, and (v) an activation domain; The antigen-binding molecule (a) a variable heavy chain according to any one of SEQ ID NOs: 45-131, and 534-544, and / or (b) a variable light chain set forth in any one of SEQ ID NOs: 132-227, and 545-558. The method of any one of claims 1 to 4, wherein the fragment is a single-chain variable fragment (scFv) comprising:

46. The chimeric antigen receptor (a) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; (b) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 418, SEQ ID NO: 419, and SEQ ID NO: 420, respectively; (c) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; (d) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:376, SEQ ID NO:377, and SEQ ID NO:378, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:424, SEQ ID NO:425, and SEQ ID NO:426, respectively; (e) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:379, SEQ ID NO:380, and SEQ ID NO:381, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:427, SEQ ID NO:428, and SEQ ID NO:429, respectively; (f) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​SEQ ID NO: 383, and SEQ ID NO: 384, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 430, SEQ ID NO: 431, and SEQ ID NO: 432, respectively; (g) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 433, SEQ ID NO: 434, and SEQ ID NO: 435, respectively; (h) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 388, SEQ ID NO: 389, and SEQ ID NO: 390, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 436, SEQ ID NO: 437, and SEQ ID NO: 438, respectively; (i) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 391, SEQ ID NO: 392, and SEQ ID NO: 393, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 439, SEQ ID NO: 440, and SEQ ID NO: 441, respectively; (j) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively; (k) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:397, SEQ ID NO:398, and SEQ ID NO:399, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:445, SEQ ID NO:446, and SEQ ID NO:447, respectively; (l) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; (m) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:403, SEQ ID NO:404, and SEQ ID NO:405, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:451, SEQ ID NO:452, and SEQ ID NO:453, respectively; (n) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively; (o) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:409, SEQ ID NO:410, and SEQ ID NO:411, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:457, SEQ ID NO:458, and SEQ ID NO:459, respectively; (p) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:412, SEQ ID NO:413, and SEQ ID NO:414, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:460, SEQ ID NO:461, and SEQ ID NO:462, respectively; (q) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:415, SEQ ID NO:416, and SEQ ID NO:417, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:463, SEQ ID NO:464, and SEQ ID NO:465, respectively; (r) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:584, SEQ ID NO:585, and SEQ ID NO:586, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:596, SEQ ID NO:597, and SEQ ID NO:598, respectively; (s) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:587, SEQ ID NO:588, and SEQ ID NO:589, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:599, SEQ ID NO:600, and SEQ ID NO:601, respectively; (t) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:590, SEQ ID NO:591, and SEQ ID NO:592, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO:602, SEQ ID NO:603, and SEQ ID NO:604, respectively; or (u) The method of claim 45, wherein (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively, and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, respectively, or SEQ ID NO: 608, SEQ ID NO: 609, SEQ ID NO: 610, respectively.

47. 47. The method of claim 45 or 46, wherein the variable heavy chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 45-131, and 534-544.

48. 47. The method of claim 45 or 46, wherein the variable light chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 132-227, and 545-558.

49. 49. The method of any one of claims 45 to 48, wherein the TCR Vβ region is selected from the group consisting of Vβ1, Vβ2, Vβ3, Vβ4, Vβ5.1, Vβ5.3, Vβ7.1, Vβ7.2, Vβ8, Vβ9, Vβ11, Vβ12, Vβ13.1, Vβ13.2, Vβ13.6, Vβ14, Vβ16, Vβ17, Vβ18, Vβ20, and Vβ22.

50. 50. The method of claim 49, wherein the TCR Vβ region is Vβ2.

51. 51. The method of any one of claims 45 to 50, wherein the cancer is selected from the group consisting of T-cell lymphoma, T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma (PTCL), PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukemia / lymphoma (ATLL), hepatosplenic T-cell lymphoma (HSTL), subcutaneous pancreatitis-like T-cell lymphoma (SPTCL), T-cell acute lymphoblastic leukemia (T-ALL), T-cell chronic lymphocytic leukemia, large granular lymphocyte leukemia, T-cell prolymphocytic leukemia, lymphoma granulomatosis, small to medium pleomorphic T-cell lymphoma, mycosis fungoides, Sézary syndrome, and cytotoxic T-cell lymphoma.

52. 52. The method of any one of claims 45 to 51, wherein the composition is delivered intratumorally, intravenously, intraperitoneally, intramuscularly, intrathecally, transdermally, or subcutaneously.

53. 53. The method of claim 52, wherein the composition is delivered intravenously or intratumorally.

54. The method of any one of claims 45 to 53, wherein the subject is a human.

55. 1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of: (i) a heavy chain variable region (VH) having an amino acid sequence set forth in any one of SEQ ID NOs: 228 to 295 and 559 to 569; or (ii) a light chain variable region (VL) having an amino acid sequence set forth in any one of SEQ ID NOs: 296 to 369 and 570 to 583 The method comprises administering a composition comprising an antibody or antigen-binding fragment thereof capable of specifically binding to a TCR Vβ region, comprising:

56. The antibody or antigen-binding fragment (i) (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively; (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively; (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:376, SEQ ID NO:377, and SEQ ID NO:378, respectively; (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively; (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​SEQ ID NO: 383, and SEQ ID NO: 384, respectively; (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 388, SEQ ID NO: 389, and SEQ ID NO: 390, respectively; (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 391, SEQ ID NO: 392, and SEQ ID NO: 393, respectively; (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively; (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 397, SEQ ID NO: 398, and SEQ ID NO: 399, respectively; (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 403, SEQ ID NO: 404, and SEQ ID NO: 405, respectively; (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411, respectively; (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:412, SEQ ID NO:413, and SEQ ID NO:414, respectively; (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:415, SEQ ID NO:416, and SEQ ID NO:417, respectively; (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:584, SEQ ID NO:585, and SEQ ID NO:586, respectively; (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:587, SEQ ID NO:588, and SEQ ID NO:589, respectively; (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 591, and SEQ ID NO: 592, respectively; or (u) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively; and / or (ii) (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15; (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:418, SEQ ID NO:419, and SEQ ID NO:420, respectively; (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:424, SEQ ID NO:425, and SEQ ID NO:426, respectively; (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 427, SEQ ID NO: 428, and SEQ ID NO: 429, respectively; (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 430, SEQ ID NO: 431, and SEQ ID NO: 432, respectively; (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 433, SEQ ID NO: 434, and SEQ ID NO: 435, respectively; (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 436, 437, and 438, respectively; (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 439, SEQ ID NO: 440, and SEQ ID NO: 441, respectively; (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively; (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 451, SEQ ID NO: 452, and SEQ ID NO: 453, respectively; (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively; (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 460, SEQ ID NO: 461, and SEQ ID NO: 462, respectively; (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 463, SEQ ID NO: 464, and SEQ ID NO: 465, respectively; (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:596, SEQ ID NO:597, and SEQ ID NO:598, respectively; (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:599, SEQ ID NO:601, and SEQ ID NO:601, respectively; (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (u) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, or SEQ ID NO: 608, SEQ ID NO: 609, SEQ ID NO: 610, respectively.

56. The method of claim 55, comprising:

57. 57. The method of claim 55 or 56, wherein the variable heavy chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 228-295, and 559-569.

58. 57. The method of claim 55 or 56, wherein the variable light chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 296-369, and 570-583.

59. 56. The antibody or antigen-binding fragment of claim 55, further comprising a light chain variable region (VL) having an amino acid sequence set forth in any of SEQ ID NOs: 296-369 and 570-583.

60. The antibody or antigen-binding fragment of claim 55, further comprising a heavy chain variable region (VH) having an amino acid sequence set forth in any of SEQ ID NOs: 228-295 and 534-544.

61. 61. The method of any one of claims 55-60, wherein the TCR Vβ region is selected from the group consisting of Vβ1, Vβ2, Vβ3, Vβ4, Vβ5.1, Vβ5.3, Vβ7.1, Vβ7.2, Vβ8, Vβ9, Vβ11, Vβ12, Vβ13.1, Vβ13.2, Vβ13.6, Vβ14, Vβ16, Vβ17, Vβ18, Vβ20, and Vβ22.

62. 62. The method of claim 61, wherein the TCR Vβ region is Vβ2.

63. 63. The method of any one of claims 55 to 62, wherein the cancer is selected from the group consisting of T-cell lymphoma, T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma (PTCL), PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukemia / lymphoma (ATLL), hepatosplenic T-cell lymphoma (HSTL), subcutaneous pancreatitis-like T-cell lymphoma (SPTCL), T-cell acute lymphoblastic leukemia (T-ALL), T-cell chronic lymphocytic leukemia, large granular lymphocyte leukemia, T-cell prolymphocytic leukemia, lymphoma granulomatosis, small to medium pleomorphic T-cell lymphoma, mycosis fungoides, Sézary syndrome, and cytotoxic T-cell lymphoma.

64. 64. The method of any one of claims 55-63, wherein the composition is delivered intratumorally, intravenously, intraperitoneally, intramuscularly, intrathecally, transdermally, or subcutaneously.

65. 65. The method of claim 64, wherein the composition is delivered intravenously.

66. 65. The method of claim 64, wherein the composition is delivered intratumorally.

67. 67. The method of any one of claims 55 to 66, wherein the subject is a human.

68. 1. A method for treating a T cell-mediated disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a T cell composition comprising a CAR, the CAR comprising: (i) an antigen-binding molecule that specifically binds to a TCR Vβ region, (ii) an extracellular domain, (iii) a transmembrane domain, (iv) a costimulatory domain, and (v) an activation domain; The antigen-binding molecule (a) a variable heavy chain according to any one of SEQ ID NOs: 45-131, and 534-544, and / or (b) the variable light chain comprises any one of SEQ ID NOs: 132-227, and 545-558.

69. The chimeric antigen receptor (a) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; (b) (i) the variable heavy chain (VH) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 370, 371, and 372, respectively; and / or (ii) the variable light chain (VL) comprises CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 418, 419, and 420, respectively; (c) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 373, 374, and 375, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 421, 422, and 423, respectively; (d) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 376, 377, and 378, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 424, 425, and 426, respectively; (e) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 427, SEQ ID NO: 428, and SEQ ID NO: 429, respectively; (f) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 382, ​​383, and 384, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 430, 431, and 432, respectively; (g) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 433, SEQ ID NO: 434, and SEQ ID NO: 435, respectively; (h) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 388, SEQ ID NO: 389, and SEQ ID NO: 390, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 436, SEQ ID NO: 437, and SEQ ID NO: 438, respectively; (i) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 391, SEQ ID NO: 392, and SEQ ID NO: 393, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 439, SEQ ID NO: 440, and SEQ ID NO: 441, respectively; (j) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 394, 395, and 396, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 442, 443, and 444, respectively; (k) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 397, SEQ ID NO: 398, and SEQ ID NO: 399, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; (l) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; (m) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 403, 404, and 405, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 451, 452, and 453, respectively; (n) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 406, 407, and 408, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 454, 455, and 456, respectively; (o) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; (p) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 412, 413, and 414, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 460, 461, and 462, respectively; (q) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 415, 416, and 417, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 463, 464, and 465, respectively; (r) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 584, SEQ ID NO: 585, and SEQ ID NO: 586, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 596, SEQ ID NO: 597, and SEQ ID NO: 598, respectively; (s) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO:587, SEQ ID NO:588, and SEQ ID NO:589, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO:599, SEQ ID NO:601, and SEQ ID NO:601, respectively; (t) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 591, and SEQ ID NO: 592, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (u) (i) the variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 593, 594, and 595, respectively; and / or (ii) the variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 605, 606, 607, respectively, or SEQ ID NOs: 608, 609, and 610, respectively.

69. The method of claim 68, comprising:

70. 70. The method of claim 68 or 69, wherein the variable heavy chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 45-131, and 534-544.

71. 70. The method of claim 68 or 69, wherein the variable light chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 132-227, and 545-558.

72. 72. The method of any one of claims 68-71, wherein the TCR Vβ region is selected from the group consisting of Vβ1, Vβ2, Vβ3, Vβ4, Vβ5.1, Vβ5.3, Vβ7.1, Vβ7.2, Vβ8, Vβ9, Vβ11, Vβ12, Vβ13.1, Vβ13.2, Vβ13.6, Vβ14, Vβ16, Vβ17, Vβ18, Vβ20, and Vβ22.

73. 73. The method of claim 72, wherein the TCR Vβ region is Vβ2.

74. 70. The method of any one of claims 68 or 69, wherein the T cell mediated disease is selected from the group consisting of atherosclerosis, Parkinson's disease, Alzheimer's disease, type 1 diabetes, Graves' disease, Hashimoto's thyroiditis, Addison's disease, rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis, psoriatic arthritis, lichen planus, lichen planus pilaris, morphea, scleroderma, systemic sclerosis, acute or chronic graft-versus-host disease (GVHD), heart organ transplant rejection, lung organ transplant rejection, kidney organ transplant rejection, interstitial lung disease, scleroderma, alopecia areata, vitiligo, celiac disease (sprue), myasthenia gravis, pernicious anemia, Sjogren's syndrome, systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

75. 75. The method of any one of claims 68-74, wherein the composition is delivered intratumorally, intravenously, intraperitoneally, intramuscularly, intrathecally, transdermally, or subcutaneously.

76. 76. The method of claim 75, wherein the composition is delivered intravenously.

77. 77. The method of any one of claims 68 to 76, wherein the subject is a human.

78. 1. A method of treating a T cell mediated disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of: (i) a heavy chain variable region (VH) having an amino acid sequence set forth in any one of SEQ ID NOs: 228 to 295 and 559 to 569; and / or (ii) a light chain variable region (VL) having an amino acid sequence set forth in any one of SEQ ID NOs: 296 to 369 and 570 to 583 The method comprises administering a composition comprising an antibody or antigen-binding fragment thereof capable of specifically binding to a TCR Vβ region, the ...

79. The antibody or antigen-binding fragment (i) (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively; (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively; (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:376, SEQ ID NO:377, and SEQ ID NO:378, respectively; (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively; (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​SEQ ID NO: 383, and SEQ ID NO: 384, respectively; (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 388, SEQ ID NO: 389, and SEQ ID NO: 390, respectively; (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 391, SEQ ID NO: 392, and SEQ ID NO: 393, respectively; (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively; (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 397, SEQ ID NO: 398, and SEQ ID NO: 399, respectively; (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 403, SEQ ID NO: 404, and SEQ ID NO: 405, respectively; (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411, respectively; (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:412, SEQ ID NO:413, and SEQ ID NO:414, respectively; (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:415, SEQ ID NO:416, and SEQ ID NO:417, respectively; (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:584, SEQ ID NO:585, and SEQ ID NO:586, respectively; (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:587, SEQ ID NO:588, and SEQ ID NO:589, respectively; (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 591, and SEQ ID NO: 592, respectively; or (u) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively; and / or (ii) (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15; (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:418, SEQ ID NO:419, and SEQ ID NO:420, respectively; (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:424, SEQ ID NO:425, and SEQ ID NO:426, respectively; (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 427, SEQ ID NO: 428, and SEQ ID NO: 429, respectively; (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 430, SEQ ID NO: 431, and SEQ ID NO: 432, respectively; (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 433, SEQ ID NO: 434, and SEQ ID NO: 435, respectively; (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 436, 437, and 438, respectively; (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 439, SEQ ID NO: 440, and SEQ ID NO: 441, respectively; (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively; (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 451, SEQ ID NO: 452, and SEQ ID NO: 453, respectively; (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively; (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 460, SEQ ID NO: 461, and SEQ ID NO: 462, respectively; (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 463, SEQ ID NO: 464, and SEQ ID NO: 465, respectively; (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:596, SEQ ID NO:597, and SEQ ID NO:598, respectively; (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:599, SEQ ID NO:601, and SEQ ID NO:601, respectively; (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (u) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, or SEQ ID NO: 608, SEQ ID NO: 609, SEQ ID NO: 610, respectively.

79. The method of claim 78, comprising:

80. 80. The method of claim 78 or 79, wherein the variable heavy chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 228-295, and 559-569.

81. 80. The method of claim 78 or 79, wherein the variable light chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 296-369, and 570-583.

82. The antibody or antigen-binding fragment of claim 78, further comprising a light chain variable region (VL) having an amino acid sequence set forth in any of SEQ ID NOs: 296-369 and 570-583.

83. The antibody or antigen-binding fragment of claim 78, further comprising a heavy chain variable region (VH) having an amino acid sequence set forth in any of SEQ ID NOs: 228-295 and 559-569.

84. 84. The method of any one of claims 78-83, wherein the TCR Vβ region is selected from the group consisting of Vβ1, Vβ2, Vβ3, Vβ4, Vβ5.1, Vβ5.3, Vβ7.1, Vβ7.2, Vβ8, Vβ9, Vβ11, Vβ12, Vβ13.1, Vβ13.2, Vβ13.6, Vβ14, Vβ16, Vβ17, Vβ18, Vβ20, and Vβ22.

85. 85. The method of claim 84, wherein the TCR Vβ region is Vβ2.

86. 86. The method of any one of claims 78 to 85, wherein the T cell mediated disease is selected from the group consisting of atherosclerosis, Parkinson's disease, Alzheimer's disease, type 1 diabetes, Graves' disease, Hashimoto's thyroiditis, Addison's disease, rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis, psoriatic arthritis, lichen planus, lichen planus pilaris, morphea, scleroderma, systemic sclerosis, acute or chronic graft-versus-host disease (GVHD), heart organ transplant rejection, lung organ transplant rejection, kidney organ transplant rejection, interstitial lung disease, scleroderma, alopecia areata, vitiligo, celiac disease (sprue), myasthenia gravis, pernicious anemia, Sjogren's syndrome, systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

87. 87. The method of any one of claims 78-86, wherein the composition is delivered intratumorally, intravenously, intraperitoneally, intramuscularly, intrathecally, or subcutaneously.

88. 88. The method of claim 87, wherein the composition is delivered intravenously.

89. 89. The method of any one of claims 78 to 88, wherein the subject is a human.

90. Use of (a) the CAR of any one of claims 1 to 18, or (b) the antibody or antigen-binding fragment of any one of claims 26 to 44, for the manufacture of a medicament for treating a T-cell mediated disease.

91. 91. The use of claim 90, wherein the T cell mediated disease is selected from the group consisting of atherosclerosis, Parkinson's disease, Alzheimer's disease, type 1 diabetes, Graves' disease, Hashimoto's thyroiditis, Addison's disease, rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis, psoriatic arthritis, lichen planus, lichen planus pilaris, morphea, scleroderma, systemic sclerosis, acute or chronic graft-versus-host disease (GVHD), heart organ transplant rejection, lung organ transplant rejection, kidney organ transplant rejection, interstitial lung disease, scleroderma, alopecia areata, vitiligo, celiac disease (sprue), myasthenia gravis, pernicious anemia, Sjogren's syndrome, systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

92. Use of (a) the CAR of any one of claims 1 to 18, or (b) the antibody or antigen-binding fragment of any one of claims 26 to 44, for the manufacture of a medicament for treating cancer.

93. 93. The use of claim 92, wherein the cancer is selected from the group consisting of T-cell lymphoma, T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma (PTCL), PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukemia / lymphoma (ATLL), hepatosplenic T-cell lymphoma (HSTL), subcutaneous pancreatitis-like T-cell lymphoma (SPTCL), T-cell acute lymphoblastic leukemia (T-ALL), T-cell chronic lymphocytic leukemia, large granular lymphocyte leukemia, T-cell prolymphocytic leukemia, lymphoma granulomatosis, small- to medium-sized pleomorphic T-cell lymphoma, mycosis fungoides, Sézary syndrome, and cytotoxic T-cell lymphoma.

94. (a) the CAR according to any one of claims 1 to 18, or (b) the antibody or antigen-binding fragment according to any one of claims 26 to 44; a kit of parts comprising at least one of (i) the variable heavy chain, and / or (ii) the variable light chain of

95. 95. The kit of claim 94, wherein the kit further comprises instructions for use.

96. An adeno-associated virus (AAV) vector encoding a chimeric antigen receptor (CAR) comprising: (i) an antigen-binding molecule that specifically binds to a TCR Vβ region; (ii) an extracellular domain; (iii) a transmembrane domain; (iv) a costimulatory domain; and (v) an activation domain; The antigen-binding molecule (a) a variable heavy chain according to any one of SEQ ID NOs: 45-131, and 534-544, and / or (b) a variable light chain set forth in any one of SEQ ID NOs: 132-227, and 545-558. The AAV vector is a single-chain variable fragment (scFv) comprising:

97. (i) (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively; (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively; (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:376, SEQ ID NO:377, and SEQ ID NO:378, respectively; (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively; (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​SEQ ID NO: 383, and SEQ ID NO: 384, respectively; (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 388, SEQ ID NO: 389, and SEQ ID NO: 390, respectively; (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 391, SEQ ID NO: 392, and SEQ ID NO: 393, respectively; (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively; (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 397, SEQ ID NO: 398, and SEQ ID NO: 399, respectively; (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 403, SEQ ID NO: 404, and SEQ ID NO: 405, respectively; (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411, respectively; (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:412, SEQ ID NO:413, and SEQ ID NO:414, respectively; (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:415, SEQ ID NO:416, and SEQ ID NO:417, respectively; (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:584, SEQ ID NO:585, and SEQ ID NO:586, respectively; (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:587, SEQ ID NO:588, and SEQ ID NO:589, respectively; (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 591, and SEQ ID NO: 592, respectively; or (u) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively; and / or (ii) (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15; (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:418, SEQ ID NO:419, and SEQ ID NO:420, respectively; (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:424, SEQ ID NO:425, and SEQ ID NO:426, respectively; (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 427, SEQ ID NO: 428, and SEQ ID NO: 429, respectively; (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 430, SEQ ID NO: 431, and SEQ ID NO: 432, respectively; (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 433, SEQ ID NO: 434, and SEQ ID NO: 435, respectively; (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 436, 437, and 438, respectively; (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 439, SEQ ID NO: 440, and SEQ ID NO: 441, respectively; (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively; (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 451, SEQ ID NO: 452, and SEQ ID NO: 453, respectively; (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively; (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 460, SEQ ID NO: 461, and SEQ ID NO: 462, respectively; (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 463, SEQ ID NO: 464, and SEQ ID NO: 465, respectively; (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:596, SEQ ID NO:597, and SEQ ID NO:598, respectively; (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:599, SEQ ID NO:601, and SEQ ID NO:601, respectively; (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (u) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, or SEQ ID NO: 608, SEQ ID NO: 609, SEQ ID NO: 610, respectively.

97. The AAV vector of claim 96, comprising:

98. 98. The AAV vector of claim 96 or 97, wherein the variable heavy chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 45-131, and 534-544.

99. 98. The AAV vector of claim 96 or 97, wherein the variable light chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% sequence identity to any one of SEQ ID NOs: 132-227, and 545-558.

100. The AAV vector of any one of claims 96 to 99, wherein the TCR Vβ region is selected from the group consisting of Vβ1, Vβ2, Vβ3, Vβ4, Vβ5.1, Vβ5.3, Vβ7.1, Vβ7.2, Vβ8, Vβ9, Vβ11, Vβ12, Vβ13.1, Vβ13.2, Vβ13.6, Vβ14, Vβ16, Vβ17, Vβ18, Vβ20, and Vβ22.

101. The AAV vector of claim 100, wherein the TCR Vβ region is Vβ2.

102. 97. The AAV vector of claim 96, wherein the antigen-binding domain is an scFv.

103. The AAV vector of claim 102, wherein the scFv comprises an amino acid sequence set forth in any one of SEQ ID NOs: 14 to 44.

104. The AAV vector of any one of claims 96 to 103, wherein the costimulatory domain comprises a 4-1BB costimulatory domain.

105. The AAV vector of claim 104, wherein the 4-1BB costimulatory domain comprises the amino acid sequence set forth in SEQ ID NO:

8.

106. The AAV vector of any one of claims 96 to 105, wherein the transmembrane domain comprises a hCD28 transmembrane.

107. The AAV vector of claim 106, wherein the transmembrane domain comprises the hCD28 amino acid sequence set forth in SEQ ID NO:

7.

108. The AAV vector of any one of claims 96 to 107, wherein the signaling domain comprises a CD247 signaling domain.

109. The AAV vector of claim 108, wherein the signaling domain comprises the CD247 signaling domain amino acid sequence set forth in SEQ ID NO:

9.

110. The AAV vector of any one of claims 96 to 109, wherein the scFv comprises a CD28 signal peptide.

111. The AAV vector of claim 110, wherein the scFv comprises a CD28 signal peptide and the amino acid sequence set forth in SEQ ID NO:

3.

112. The AAV vector of any one of claims 96 to 111, wherein the scFv comprises a linker peptide.

113. The AAV vector of claim 112, wherein the scFv comprises a linker peptide set forth in SEQ ID NO:

4.

114. 90. The method of any one of claims 45 to 89, further comprising measuring TCR Vβ usage in said subject.

115. 115. The method of claim 114, wherein determining the subject's TCR Vβ usage comprises obtaining a sample from the subject, wherein the sample is a blood sample or a tissue sample.

116. The method of claim 114 or 115, wherein the subject is administered (a) a CAR of any one of claims 1 to 18, or (b) an antibody or antigen-binding fragment of any one of claims 26 to 44, that corresponds to the subject's TCR Vβ usage.

117. The antibody or antigen-binding fragment (i) (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 370, SEQ ID NO: 371, and SEQ ID NO: 372, respectively; (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375, respectively; (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:376, SEQ ID NO:377, and SEQ ID NO:378, respectively; (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381, respectively; (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 382, ​​SEQ ID NO: 383, and SEQ ID NO: 384, respectively; (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 385, SEQ ID NO: 386, and SEQ ID NO: 387, respectively; (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 388, SEQ ID NO: 389, and SEQ ID NO: 390, respectively; (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 391, SEQ ID NO: 392, and SEQ ID NO: 393, respectively; (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 394, SEQ ID NO: 395, and SEQ ID NO: 396, respectively; (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 397, SEQ ID NO: 398, and SEQ ID NO: 399, respectively; (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 400, SEQ ID NO: 401, and SEQ ID NO: 402, respectively; (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 403, SEQ ID NO: 404, and SEQ ID NO: 405, respectively; (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408, respectively; (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411, respectively; (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:412, SEQ ID NO:413, and SEQ ID NO:414, respectively; (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:415, SEQ ID NO:416, and SEQ ID NO:417, respectively; (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:584, SEQ ID NO:585, and SEQ ID NO:586, respectively; (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:587, SEQ ID NO:588, and SEQ ID NO:589, respectively; (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 590, SEQ ID NO: 591, and SEQ ID NO: 592, respectively; or (u) a variable heavy chain (VH) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 593, SEQ ID NO: 594, and SEQ ID NO: 595, respectively; and / or (ii) (a) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; (b) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:418, SEQ ID NO:419, and SEQ ID NO:420, respectively; (c) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 421, SEQ ID NO: 422, and SEQ ID NO: 423, respectively; (d) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:424, SEQ ID NO:425, and SEQ ID NO:426, respectively; (e) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 427, SEQ ID NO: 428, and SEQ ID NO: 429, respectively; (f) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 430, SEQ ID NO: 431, and SEQ ID NO: 432, respectively; (g) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 433, SEQ ID NO: 434, and SEQ ID NO: 435, respectively; (h) CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 436, 437, and 438, respectively; (i) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 439, SEQ ID NO: 440, and SEQ ID NO: 441, respectively; (j) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 442, SEQ ID NO: 443, and SEQ ID NO: 444, respectively; (k) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 445, SEQ ID NO: 446, and SEQ ID NO: 447, respectively; (l) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 448, SEQ ID NO: 449, and SEQ ID NO: 450, respectively; (m) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 451, SEQ ID NO: 452, and SEQ ID NO: 453, respectively; (n) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 454, SEQ ID NO: 455, and SEQ ID NO: 456, respectively; (o) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 457, SEQ ID NO: 458, and SEQ ID NO: 459, respectively; (p) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 460, SEQ ID NO: 461, and SEQ ID NO: 462, respectively; (q) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 463, SEQ ID NO: 464, and SEQ ID NO: 465, respectively; (r) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:596, SEQ ID NO:597, and SEQ ID NO:598, respectively; (s) CDR1, CDR2, and CDR3 set forth in SEQ ID NO:599, SEQ ID NO:601, and SEQ ID NO:601, respectively; (t) CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 602, SEQ ID NO: 603, and SEQ ID NO: 604, respectively; or (u) a variable light chain (VL) comprising CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, or SEQ ID NO: 608, SEQ ID NO: 609, SEQ ID NO: 610, respectively.

28. The antibody or antigen-binding fragment of claim 26 or 27, comprising:

118. 80. The antibody or antigen-binding fragment of any one of claims 26, 27, 56, or 78, wherein the ADCC activity of the antibody composition is increased or decreased by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 125%, about 150%, about 175%, about 200%, about 1-fold, about 2-fold, about 3-fold, or about 4-fold, or is increased or decreased by about 5% to about 400%.

119. The antibody or antigen-binding fragment of claim 118, wherein the antibody or antigen-binding fragment has increased antibody-dependent cell-mediated cytotoxicity activity achieved by non-fucosylation.

120. The antibody or antigen-binding fragment of claim 119, wherein the antibody or antigen-binding fragment has increased antibody-dependent cell-mediated cytotoxicity activity achieved by glycosylation.

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