T cell receptor (TCR) that targets the minor histocompatibility antigen HA-1

Abstract

Provided herein are T cell receptors (TCRs) or antigen-binding fragments thereof, such as those that recognize or bind hematopoietically restricted minor histocompatibility antigens, such as HA-1. In particular, the disclosure relates to TCRs that bind or recognize specific HA-1 peptides in the context of major histocompatibility complex (MHC) molecules. The disclosure further relates to nucleic acids encoding such TCRs, engineered cells comprising such TCRs, methods of isolating such TCRs, and their uses, e.g., in cell therapy.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 183,515, filed May 3, 2021, and U.S. Provisional Patent Application No. 63 / 251,261, filed October 1, 2021, each of which is incorporated herein by reference.

[0002] Sequence Listing The sequence listing set forth in file 578238_SeqListing_ST25.txt is 709 kilobytes in size, was created on April 28, 2022, and is incorporated herein by reference.

[0003] The present disclosure, in some embodiments, relates to T cell receptors (TCRs) or antigen-binding fragments thereof, such as those that recognize or bind hematopoietic-restricted minor histocompatibility antigens, such as HA-1. In particular, the present disclosure relates to TCRs that bind or recognize specific HA-1 peptides in the context of major histocompatibility complex (MHC) molecules. The present disclosure further relates to nucleic acids encoding such TCRs, engineered cells comprising such TCRs, methods for isolating such TCRs, and their uses, e.g., in cell therapy. [Background technology]

[0004] Allogeneic hematopoietic stem cell transplantation (alloSCT) can be used to treat diseases or conditions such as hematologic malignancies and other non-malignant conditions. Some subjects may relapse after alloSCT. Improved therapies are needed to achieve optimal treatment outcomes. Embodiments are provided that meet such needs. Summary of the Invention

[0005] Provided herein is a TCR or antigen-binding fragment thereof comprising: an alpha chain comprising a variable alpha (Vα) region and a beta chain comprising a variable beta (Vβ) region; or a gamma chain comprising a variable gamma (Vγ) region and a delta chain comprising a variable delta (Vδ) region, wherein the Vα or Vγ region comprises a complementarity determining region 3 (CDR-3) comprising SEQ ID NO: 3, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 11; or the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 21, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 22. the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 37, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 43; the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 51, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 57; the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 65, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 57; the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 78, and the Vβ whether the Vα region or Vδ region comprises a CDR-3 comprising SEQ ID NO:84; whether the Vα region or Vγ region comprises a CDR-3 comprising SEQ ID NO:92, and the Vβ region or Vδ region comprises a CDR-3 comprising SEQ ID NO:98; whether the Vα region or Vγ region comprises a CDR-3 comprising SEQ ID NO:106, and the Vβ region or Vδ region comprises a CDR-3 comprising SEQ ID NO:112; whether the Vα region or Vγ region comprises a CDR-3 comprising SEQ ID NO:120, and the Vβ region or Vδ region comprises a CDR-3 comprising SEQ ID NO:126; whether the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 152 and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 158; whether the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 166 and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 172; whether the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 180 and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 186;Whether the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 194, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 200; whether the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 208, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 214; whether the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 224, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 230; or whether the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 238 3, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 244; the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 252, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 258; the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 268, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 158; the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 278, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 284. or the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 359, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 363; or the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 369, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 373; or the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 379, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 383; or the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 389 and the Vβ region or Vδ region comprises a CDR-3 comprising SEQ ID NO: 393; or the Vα region or Vγ region comprises a CDR-3 comprising SEQ ID NO: 399, and the Vβ region or Vδ region comprises a CDR-3 comprising SEQ ID NO: 403; or the Vα region or Vγ region comprises a CDR-3 comprising SEQ ID NO: 409, and the Vβ region or Vδ region comprises a CDR-3 comprising SEQ ID NO: 413; or the Vα region or Vγ region comprises a CDR-3 comprising SEQ ID NO: 419, and the Vβ region or Vδ region comprises a CDR-3 comprising SEQ ID NO: 423;the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 429, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 433; the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 439, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 443; the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 449, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 453; or the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 480, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 484;

[0006] Provided herein is a TCR or antigen-binding fragment thereof comprising an alpha chain comprising a variable alpha (Vα) region and a beta chain comprising a variable beta (Vβ) region; or a gamma chain comprising a variable gamma (Vγ) region and a delta chain comprising a variable delta (Vδ) region, wherein the Vα region or the Vγ region is selected from the group consisting of AVRX, ... A X B Complementarity-determining region 3 (CDR-3) containing RTSGTYKYI (SEQ ID NO: 476), and the Vβ or Vδ region contains ASSX C X D X E GX F X G QF (SEQ ID NO: 478), wherein X A , X B , X C , X D , X E , X F , X G Each of X can be any amino acid. A can be an aliphatic amino acid (i.e., Ala, Ile, Leu, Val, or Pro), glycine, a sulfur-containing amino acid (i.e., Cys or Met), a hydroxyl amino acid (i.e., Ser or Thr), or an acidic residue (i.e., Asp or Glu). In some embodiments, X A can be Ala, Gly, Cys, Ser, Thr, Val, Asp, or Glu. Bmay be a cyclic imino group-containing amino acid or a hydroxyl amino acid. B can be Pro, Ser, or Thr. In some embodiments, X C can be an aliphatic amino acid or an aromatic amino acid (i.e., Phe, Tyr, or Trp). C can be Leu or Phe. D may be an aliphatic amino acid. D can be Val or Leu. E can be a hydroxyl amino acid, an aliphatic amino acid, or an amide amino acid (i.e., Asn or Gln). E can be Ser, Ala, Gln, or Asn. F may be an acidic amino acid or an amide amino acid. F can be Glu or Asn. G can be an acidic amino acid or a hydroxyl amino acid. G may be Glu or Thr. The Vα or Vγ region CDR-3 of any of the described TCRs may be replaced with a CDR-3 comprising SEQ ID NO: 476. The Vβ or Vδ region CDR-3 of any of the described TCRs may be replaced with a CDR-3 comprising SEQ ID NO: 478. For any of the described TCRs, the Vα or Vγ region CDR-3 may be replaced with a CDR-3 comprising SEQ ID NO: 476, and the Vβ or Vδ region CDR-3 may be replaced with a CDR-3 comprising SEQ ID NO: 478.

[0007] Provided herein is a TCR or antigen-binding fragment thereof comprising an alpha chain comprising a variable alpha (Vα) region and a beta chain comprising a variable beta (Vβ) region; or a gamma chain comprising a variable gamma (Vγ) region and a delta chain comprising a variable delta (Vδ) region, wherein the Vα or Vγ region comprises a complementarity-determining region 3 (CDR-3) comprising SEQ ID NO: 459, 460, 461, 462, 463, 464, 476, or 477, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 465, 466, 467, 468, 469, 478, or 479. In some embodiments, the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 459, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 465, 466, 467, 468, 469, 478, or 479; the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 460, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 465, 466, 467, 468, 469, 478, or 479; the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 461, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 465, 466, 467, 468, 469, 478, or 479; the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 462, and the Vβ or V the delta region comprises a CDR-3 comprising SEQ ID NO: 465, 466, 467, 468, 469, 478, or 479; the Va region or Vgamma region comprises a CDR-3 comprising SEQ ID NO: 463, and the Vβ region or Vδ region comprises a CDR-3 comprising SEQ ID NO: 465, 466, 467, 468, 469, 478, or 479; the Va region or Vgamma region comprises a CDR-3 comprising SEQ ID NO: 464, and the Vβ region or Vδ region comprises a CDR-3 comprising SEQ ID NO: 465, 466, 467, 468, 469, 478, or 479; the Va region or Vgamma region comprises a CDR-3 comprising SEQ ID NO: 459, 460, 461, 462, 463, 464, 476, or 477, and the Vβ region or Vδ region comprises a CDR-3 comprising SEQ ID NO: 465;The Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 459, 460, 461, 462, 463, 464, 476, or 477, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 466; the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 459, 460, 461, 462, 463, 464, 476, or 477, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 467; or the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 459, 460, 461, 462, 463, 464, 476, or 477, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 468; or the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 459, 460, 461, 462, 463, 464, 476, or 477, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 469. In some embodiments, the TCR or antigen-binding fragment thereof, the Vα or Vγ region contains a CDR-3 comprising SEQ ID NO: 463, and the Vβ or Vδ region contains a CDR-3 comprising SEQ ID NO: 469. In some embodiments, the Vα region or Vγ region comprises: a complementarity determining region 1 (CDR-1) comprising SEQ ID NO: 1, and a complementarity determining region 2 (CDR-2) comprising SEQ ID NO: 2; a CDR-1 comprising SEQ ID NO: 19, and a CDR-2 comprising SEQ ID NO: 20; a CDR-1 comprising SEQ ID NO: 35, and a CDR-2 comprising SEQ ID NO: 36; a CDR-1 comprising SEQ ID NO: 76, and a CDR-2 comprising SEQ ID NO: 77; a CDR-1 comprising SEQ ID NO: 134, and a CDR-2 comprising SEQ ID NO: 135; a CDR-1 comprising SEQ ID NO: 150, and a CDR-2 comprising SEQ ID NO: 151; a CDR-1 comprising SEQ ID NO: 222, and a CDR-2 comprising SEQ ID NO: 223; or a CDR-1 comprising SEQ ID NO: 266, and a CDR-2 comprising SEQ ID NO: 267;and the Vβ region or Vδ region comprises a CDR-1 comprising SEQ ID NO:9 and a CDR-2 comprising SEQ ID NO:10. In some embodiments, the TCRs or antigen-binding fragments thereof provided herein have the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule. The Vα or Vγ region CDR-3 of any of the described TCRs may be replaced with a CDR-3 comprising SEQ ID NO:459, 460, 461, 462, 463, 464, 476, or 477. The Vβ or Vδ region CDR-3 of any of the described TCRs may be replaced with a CDR-3 comprising SEQ ID NO:465, 466, 467, 468, 469, 478, or 479. For any of the TCRs described, the Vα or Vγ region CDR-3 may be replaced with a CDR-3 comprising SEQ ID NO: 459, 460, 461, 462, 463, 464, 476, or 477, and the Vβ or Vδ region CDR-3 may be replaced with a CDR-3 comprising SEQ ID NO: 465, 466, 467, 468, 469, 478, or 479;

[0008] Provided herein is a TCR, or antigen-binding fragment thereof, comprising: an alpha chain comprising a Vα region and a beta chain comprising a Vβ region; or a gamma chain comprising a Vγ region and a delta chain comprising a Vδ region, wherein the Vα region or Vγ region comprises a CDR-3 comprising SEQ ID NO: 470, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 57; the Vα region or Vγ region comprises a CDR-3 comprising SEQ ID NO: 471, and the Vβ region or Vδ region comprises a CDR-3 comprising SEQ ID NO: 57; the Vα region or Vγ region comprises a CDR-3 comprising SEQ ID NO: 472, and the Vβ region or Vδ region comprises a CDR-3 comprising SEQ ID NO: 57; the Vα region or Vγ region comprises a CDR-3 comprising SEQ ID NO: 473, and the Vβ region or Vδ region comprises a CDR-3 comprising SEQ ID NO: 57; or the Vα region or Vγ region comprises a CDR-3 comprising SEQ ID NO: 474, and the Vβ region or Vδ region comprises a CDR-3 comprising SEQ ID NO: 475. In some embodiments, the Vα or Vγ region comprises: a complementarity determining region 1 (CDR-1) comprising SEQ ID NO: 1, and a complementarity determining region 2 (CDR-2) comprising SEQ ID NO: 2; a CDR-1 comprising SEQ ID NO: 19, and a CDR-2 comprising SEQ ID NO: 20; a CDR-1 comprising SEQ ID NO: 35, and a CDR-2 comprising SEQ ID NO: 36; a CDR-1 comprising SEQ ID NO: 76, and a CDR-2 comprising SEQ ID NO: 77; a CDR-1 comprising SEQ ID NO: 134, and a CDR-2 comprising SEQ ID NO: 135; a CDR-1 comprising SEQ ID NO: 150, and a CDR-2 comprising SEQ ID NO: 151; a CDR-1 comprising SEQ ID NO: 222, and a CDR-2 comprising SEQ ID NO: 223; or a CDR-1 comprising SEQ ID NO: 266, and a CDR-2 comprising SEQ ID NO: 267; and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9, and a CDR-2 comprising SEQ ID NO: 10. In some embodiments, the TCRs or antigen-binding fragments thereof provided herein have the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule. In some embodiments, the Vα or Vγ region CDR-3 of TCR D can be replaced with a CDR-3 comprising SEQ ID NO: 470, 471, 472, 473, or 474.In some embodiments, the Vβ or Vδ region CDR-3 of TCR D may be replaced with a CDR-3 comprising SEQ ID NO: 475. In some embodiments, the Vα or Vγ region CDR-3 of TCR D may be replaced with a CDR-3 comprising SEQ ID NO: 470, 471, 472, 473, or 474, and the Vβ or Vδ region CDR-3 may be replaced with a CDR-3 comprising SEQ ID NO: 475.

[0009] In some of any of the embodiments provided herein, the Vα or Vγ region comprises a complementarity determining region 1 (CDR-1) comprising SEQ ID NO: 1 and a complementarity determining region 2 (CDR-2) comprising SEQ ID NO: 2, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9 and a CDR-2 comprising SEQ ID NO: 10; the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 19 and a CDR-2 comprising SEQ ID NO: 20, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9 and a CDR-2 comprising SEQ ID NO: 10; the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 35 and a CDR-2 comprising SEQ ID NO: 36, and the Vβ region or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9 and a CDR-2 comprising SEQ ID NO: 10; the Vα region or Vγ region comprises a CDR-1 comprising SEQ ID NO: 1 and a CDR-2 comprising SEQ ID NO: 2, and the Vβ region or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9 and a CDR-2 comprising SEQ ID NO: 10; the Vα region or Vγ region comprises a CDR-1 comprising SEQ ID NO: 1 and a CDR-2 comprising SEQ ID NO: 2, and the Vβ region or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9 and a CDR-2 comprising SEQ ID NO: 10 the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:76 and a CDR-2 comprising SEQ ID NO:77, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9 and a CDR-2 comprising SEQ ID NO:10; the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:19 and a CDR-2 comprising SEQ ID NO:20, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9 and a CDR-2 comprising SEQ ID NO:10; the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:76 and a CDR-2 comprising SEQ ID NO:77 the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 35 and a CDR-2 comprising SEQ ID NO: 36, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9 and a CDR-2 comprising SEQ ID NO: 10; the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 134 and a CDR-2 comprising SEQ ID NO: 135, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9 and a CDR-2 comprising SEQ ID NO: 10;the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 150 and a CDR-2 comprising SEQ ID NO: 151, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9 and a CDR-2 comprising SEQ ID NO: 10; the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 35 and a CDR-2 comprising SEQ ID NO: 36, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9 and a CDR-2 comprising SEQ ID NO: 10; the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 35 and a CDR-2 comprising SEQ ID NO: 36, or and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9 and a CDR-2 comprising SEQ ID NO:10; or the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:76 and a CDR-2 comprising SEQ ID NO:77, ... the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 222 and a CDR-2 comprising SEQ ID NO: 223, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9 and a CDR-2 comprising SEQ ID NO: 10; the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 76 and a CDR-2 comprising SEQ ID NO: 77, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9 and a CDR-2 comprising SEQ ID NO: 10; the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 19 and a CDR-2 comprising SEQ ID NO: 20, and the V the beta or Vδ region comprises a CDR-1 comprising SEQ ID NO:9 and a CDR-2 comprising SEQ ID NO:10; the Va region or Vγ region comprises a CDR-1 comprising SEQ ID NO:266 and a CDR-2 comprising SEQ ID NO:267, and the Vβ region or Vδ region comprises a CDR-1 comprising SEQ ID NO:9 and a CDR-2 comprising SEQ ID NO:10; or the Va region or Vγ region comprises a CDR-1 comprising SEQ ID NO:19 and a CDR-2 comprising SEQ ID NO:20, and the Vβ region or Vδ region comprises a CDR-1 comprising SEQ ID NO:9 and a CDR-2 comprising SEQ ID NO:10;

[0010] Also provided herein is a TCR or antigen-binding fragment thereof comprising: an alpha chain comprising a Vα region and a beta chain comprising a Vβ region; or a gamma chain comprising a Vγ region and a delta chain comprising a Vδ region, wherein the Vα region or Vγ region comprises CDR-1 comprising SEQ ID NO: 1, CDR-2 comprising SEQ ID NO: 2, and CDR-3 comprising SEQ ID NO: 3, and the Vβ region or Vδ region comprises CDR-1 comprising SEQ ID NO: 9, CDR-2 comprising SEQ ID NO: 10, and CDR-3 comprising SEQ ID NO: 11; the Vα or Vγ region comprises CDR-1 comprising SEQ ID NO: 35, CDR-2 comprising SEQ ID NO: 36, and CDR-3 comprising SEQ ID NO: 37, and the Vβ or Vδ region comprises CDR-1 comprising SEQ ID NO: 9, CDR-2 comprising SEQ ID NO: 10, and CDR-3 comprising SEQ ID NO: 43; ... the Vα region or Vγ region comprises CDR-1 comprising SEQ ID NO: 1, CDR-2 comprising SEQ ID NO: 2, and CDR-3 comprising SEQ ID NO: 51, and the Vβ region or Vδ region comprises CDR-1 comprising SEQ ID NO: 9, CDR-2 comprising SEQ ID NO: 10, and CDR-3 comprising SEQ ID NO: 57; the Vα region or Vγ region comprises CDR-1 comprising SEQ ID NO: 1, CDR-2 comprising SEQ ID NO: 2, and CDR-3 comprising SEQ ID NO: 65 ... the Vα or Vγ region comprises CDR-1 comprising SEQ ID NO: 19, CDR-2 comprising SEQ ID NO: 20, and CDR-3 comprising SEQ ID NO: 92, and the Vβ or Vδ region comprises CDR-1 comprising SEQ ID NO: 9, CDR-2 comprising SEQ ID NO: 10, and CDR-3 comprising SEQ ID NO: 98;The Vα or Vγ region comprises CDR-1 comprising SEQ ID NO:76, CDR-2 comprising SEQ ID NO:77, and CDR-3 comprising SEQ ID NO:106, and the Vβ or Vδ region comprises CDR-1 comprising SEQ ID NO:9, CDR-2 comprising SEQ ID NO:10, and CDR-3 comprising SEQ ID NO:112; the Vα or Vγ region comprises CDR-1 comprising SEQ ID NO:35, CDR-2 comprising SEQ ID NO:36, and CDR-3 comprising SEQ ID NO:120, and the Vβ or Vδ region comprises CDR-1 comprising SEQ ID NO:9, CDR-2 comprising SEQ ID NO:10, and CDR-3 comprising SEQ ID NO:112. the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 134, a CDR-2 comprising SEQ ID NO: 135, and a CDR-3 comprising SEQ ID NO: 136, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 142; or the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 150, a CDR-2 comprising SEQ ID NO: 151, and a CDR-3 comprising SEQ ID NO: 152, and the Vβ the Vα or Vγ region comprises CDR-1 comprising SEQ ID NO: 35, CDR-2 comprising SEQ ID NO: 36, and CDR-3 comprising SEQ ID NO: 166, and the Vβ or Vδ region comprises CDR-1 comprising SEQ ID NO: 9, CDR-2 comprising SEQ ID NO: 10, and CDR-3 comprising SEQ ID NO: 172; ... or the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:76, a CDR-2 comprising SEQ ID NO:77, and a CDR-3 comprising SEQ ID NO:194, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:200;the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:76, a CDR-2 comprising SEQ ID NO:77, and a CDR-3 comprising SEQ ID NO:208, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:214; the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:222, a CDR-2 comprising SEQ ID NO:223, and a CDR-3 comprising SEQ ID NO:224, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:230; the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:76, a CDR-2 comprising SEQ ID NO:77, and a CDR-3 comprising SEQ ID NO:238, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:244 or the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 19, a CDR-2 comprising SEQ ID NO: 20, and a CDR-3 comprising SEQ ID NO: 252, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 258; or the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 266, a CDR-2 comprising SEQ ID NO: 267, and a CDR-3 comprising SEQ ID NO: 268, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and SEQ ID NO: 158; or the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO: 19, a CDR-2 comprising SEQ ID NO: 20, and a CDR-3 comprising SEQ ID NO: 278, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 284.

[0011] Also provided herein is a TCR or antigen-binding fragment thereof comprising: an alpha chain comprising a Vα region and a beta chain comprising a Vβ region; or a gamma chain comprising a Vγ region and a delta chain comprising a Vδ region, wherein the Vα region or Vγ region comprises a CDR-3 that comprises a CDR-3 contained within the Vα region or Vγ region sequence of SEQ ID NO:4, and the Vβ region or Vδ region comprises a CDR-3 that comprises a CDR-3 contained within the Vβ region or Vδ region sequence of SEQ ID NO:12; the Vα or Vγ region comprises a CDR-3 that comprises a CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO:2, and the Vβ or Vδ region comprises a CDR-3 that comprises a CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO:28; the Vα or Vγ region comprises a CDR-3 that comprises a CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO:38, and the Vβ or Vδ region comprises a CDR-3 that comprises a CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO:44; the Vα or Vγ region comprises a CDR-3 that comprises a CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO:44 the Vα region or Vγ region comprises a CDR-3 that comprises a CDR-3 contained within the Vα region or Vγ region sequence of SEQ ID NO: 52, and the Vβ region or Vδ region comprises a CDR-3 that comprises a CDR-3 contained within the Vβ region or Vδ region sequence of SEQ ID NO: 58; the Vα region or Vγ region comprises a CDR-3 that comprises a CDR-3 contained within the Vα region or Vγ region sequence of SEQ ID NO: 66, and the Vβ region or Vδ region comprises a CDR-3 that comprises a CDR-3 contained within the Vβ region or Vδ region sequence of SEQ ID NO: 58; the Vα region or the Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα region or Vγ region sequence of SEQ ID NO:79, and the Vβ region or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ region or Vδ region sequence of SEQ ID NO:85; the Vα region or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα region or Vγ region sequence of SEQ ID NO:93, and the Vβ region or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ region or Vδ region sequence of SEQ ID NO:99;the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 107, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO: 113; the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 121, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO: 127; the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 137, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO: 143; the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 153, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO: 159; the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 167, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO: 173; the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 181, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO: 187; the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 195, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO: 201; the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 209, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO: 215;The Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 225, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO: 231; or the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 239, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ region sequence of SEQ ID NO: 245. the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within a Vα or Vγ region sequence of SEQ ID NO: 253, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within a Vβ or Vδ region sequence of SEQ ID NO: 259; the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within a Vα or Vγ region sequence of SEQ ID NO: 269, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO: 159; the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 279, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO: 285; the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα region sequence of SEQ ID NO: 360 the Vα or Vγ region comprises a CDR-3 that comprises a CDR-3 contained within a Vα or Vγ region sequence of SEQ ID NO: 370, and the Vβ or Vδ region comprises a CDR-3 that comprises a CDR-3 contained within a Vβ or Vδ region sequence of SEQ ID NO: 374;the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 380, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO: 384; or the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 390, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ region sequence of SEQ ID NO: 394 or the Vα or Vγ region comprises a CDR-3 that comprises a CDR-3 contained within a Vδ region sequence; the Vα or Vγ region comprises a CDR-3 that comprises a CDR-3 contained within a Vα or Vγ region sequence of SEQ ID NO: 400, and the Vβ or Vδ region comprises a CDR-3 that comprises a CDR-3 contained within a Vβ or Vδ region sequence of SEQ ID NO: 404; the Vα or Vγ region comprises a CDR-3 that comprises a CDR-3 contained within a Vα or Vγ region sequence of SEQ ID NO: 410; and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ region or Vδ region sequence of SEQ ID NO: 414; the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα region or Vγ region sequence of SEQ ID NO: 420, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ region or Vδ region sequence of SEQ ID NO: 424; or the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα region sequence or Vγ region sequence of SEQ ID NO: 430 the Vα or Vγ region comprises a CDR-3 that comprises a CDR-3 contained within a Vα or Vγ region sequence of SEQ ID NO: 440, and the Vβ or Vδ region comprises a CDR-3 that comprises a CDR-3 contained within a Vβ or Vδ region sequence of SEQ ID NO: 444;the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 450, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO: 454; or the Vα or Vγ region comprises a CDR-3 that comprises the CDR-3 contained within the Vα or Vγ region sequence of SEQ ID NO: 481, and the Vβ or Vδ region comprises a CDR-3 that comprises the CDR-3 contained within the Vβ or Vδ region sequence of SEQ ID NO: 485;

[0012] In some of any of the embodiments provided herein, the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO:4, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO:12; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO:22. and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:28; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO:38, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:44. the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO:52, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO:58; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO:66. -2, and the Vβ region or Vδ region comprises CDR-1 and CDR-2 that comprise the CDR-1 and CDR-2, respectively, contained within the Vβ region sequence or Vδ region sequence of SEQ ID NO:58; the Vα region or Vγ region comprises CDR-1 and CDR-2 that comprise the CDR-1 and CDR-2, respectively, contained within the Vα region sequence or Vγ region sequence of SEQ ID NO:79, and the Vβ region or Vδ region comprises CDR-1 and CDR-2 that comprise the CDR-1 and CDR-2, respectively, contained within the Vβ region sequence or Vδ region sequence of SEQ ID NO:85;the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO:93, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO:99; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO:107, and The Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 113; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO: 121, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 127; the α or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO: 137, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 143; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO: 153; the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 159; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO: 167, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 173;the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO: 181, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 187; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO: 195, and the Vβ region or the Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ region sequence or Vδ region sequence of SEQ ID NO: 201; the Vα region or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα region sequence or Vγ region sequence of SEQ ID NO: 209, and the Vβ region or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ region sequence or Vδ region sequence of SEQ ID NO: 215; the Vα region or Vγ region the Vα region or Vγ region comprises CDR-1 and CDR-2, respectively, that are contained within the Vα region or Vγ region sequence of SEQ ID NO: 225, and the Vβ region or Vδ region comprises CDR-1 and CDR-2, respectively, that are contained within the Vβ region or Vδ region sequence of SEQ ID NO: 231; the Vα region or Vγ region comprises CDR-1 and CDR-2, respectively, that are contained within the Vα region or Vγ region sequence of SEQ ID NO: 239, and the Vβ region or or the Vδ region comprises CDR-1 and CDR-2 that comprise the CDR-1 and CDR-2, respectively, contained within the Vβ region sequence or Vδ region sequence of SEQ ID NO: 245; the Vα region or Vγ region comprises CDR-1 and CDR-2 that comprise the CDR-1 and CDR-2, respectively, contained within the Vα region sequence or Vγ region sequence of SEQ ID NO: 253, and the Vβ region or Vδ region comprises CDR-1 and CDR-2 that comprise the CDR-1 and CDR-2, respectively, contained within the Vβ region sequence or Vδ region sequence of SEQ ID NO: 259;the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO:269, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO:159; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO:279; or wherein the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 285; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO: 360, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 364; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO: 370, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 374; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO: 380; the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 384; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO: 390, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 394;the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO:400, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO:404; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO:410; the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 414; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO: 420, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 424; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO:430, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO:434; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO:440; the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 444; the Vα or Vγ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vα or Vγ region sequence of SEQ ID NO: 450, and the Vβ or Vδ region comprises CDR-1 and CDR-2, respectively, that comprise the CDR-1 and CDR-2 contained within the Vβ or Vδ region sequence of SEQ ID NO: 454;or the Vα or Vγ region comprises CDR-1 and CDR-2 that comprise the CDR-1 and CDR-2, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO: 481, and the Vβ or Vδ region comprises CDR-1 and CDR-2 that comprise the CDR-1 and CDR-2, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO: 485;

[0013] Also provided is a TCR or antigen-binding fragment thereof comprising an alpha chain comprising a Vα region and a beta chain comprising a Vβ region; or a gamma chain comprising a Vγ region and a delta chain comprising a Vδ region, wherein the Vα region or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα region or Vγ region sequence of SEQ ID NO: 4, and the Vβ region or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ region or Vδ region sequence of SEQ ID NO: 12. the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO:22, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO:28; the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO:38. the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ region or Vδ region sequence of SEQ ID NO: 44; the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 52, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ region or Vδ region sequence of SEQ ID NO: 58 the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO:66, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO:58;The Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO:79, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO:85; the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO:93. the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO:99; the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO:107; The β or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 113; the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 121; and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 127. , CDR-2, and CDR-3, respectively, that are contained within the Vα region or Vγ region sequence of SEQ ID NO: 137; and the Vβ region or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ region or Vδ region sequence of SEQ ID NO: 143;The Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 153, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 159; the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 167. the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 173; the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 181; or the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO: 187; the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO: 195; and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO: 201. the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO:209, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO:215;The Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 225, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 231; or the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 239. the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 245; or the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 253; and The Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 259; the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 269, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 159. the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO:279, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO:285;The Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 360, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 364; or the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 370. the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 374; or the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 380; or wherein the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 384; the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 390; and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 394. the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO:400, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO:404;the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO:410, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:414; The Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 420, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 424; or the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 430. the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 434; or the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 440; and The Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 444; the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vα or Vγ region sequence of SEQ ID NO: 450, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3, respectively, that are contained within the Vβ or Vδ region sequence of SEQ ID NO: 454. or the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3 that comprise CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO:481, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3 that comprise CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:485.

[0014] Also provided is a TCR or antigen-binding fragment thereof comprising an alpha chain comprising a Vα region and a beta chain comprising a Vβ region; or a gamma chain comprising a Vγ region and a delta chain comprising a Vδ region, wherein the Vα region or Vγ region comprises SEQ ID NO: 4, or a sequence having at least 90% sequence identity thereto, and the Vβ region or Vδ region comprises SEQ ID NO: 12, or a sequence having at least 90% sequence identity thereto; or the Vα region or Vγ region comprises SEQ ID NO: 22, or a sequence having at least 90% sequence identity thereto. the Vα or Vγ region comprises SEQ ID NO: 38, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 44, or a sequence having at least 90% sequence identity thereto; the Vα or Vγ region comprises SEQ ID NO: 52, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises the Vα or Vγ region comprises SEQ ID NO: 66, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 58, or a sequence having at least 90% sequence identity thereto; the Vα or Vγ region comprises SEQ ID NO: 79, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 85, or a sequence having at least 90% sequence identity thereto. the Vα or Vγ region comprises SEQ ID NO:93, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:99, or a sequence having at least 90% sequence identity thereto; the Vα or Vγ region comprises SEQ ID NO:107, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:113, or a sequence having at least 90% sequence identity thereto;whether the Vα or Vγ region comprises SEQ ID NO: 121, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 127, or a sequence having at least 90% sequence identity thereto; whether the Vα or Vγ region comprises SEQ ID NO: 137, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 143, or a sequence having at least 90% sequence identity thereto; whether the Vα or Vγ region comprises SEQ ID NO: 153, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 159, or a sequence having at least 90% sequence identity thereto; whether the Vα or Vγ region comprises SEQ ID NO: 167, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 173, or a sequence having at least 90% sequence identity thereto. the Vα or Vγ region comprises SEQ ID NO: 181, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 187, or a sequence having at least 90% sequence identity thereto; the Vα or Vγ region comprises SEQ ID NO: 195, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 201, or a sequence having at least 90% sequence identity thereto; the Vα or Vγ region comprises SEQ ID NO: 209, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 215, or a sequence having at least 90% sequence identity thereto; the Vα or Vγ region comprises SEQ ID NO: 225, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 231, or a sequence having at least 90% sequence identity thereto;whether the Vα or Vγ region comprises SEQ ID NO:239, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:245, or a sequence having at least 90% sequence identity thereto; whether the Vα or Vγ region comprises SEQ ID NO:253, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:259, or a sequence having at least 90% sequence identity thereto; whether the Vα or Vγ region comprises SEQ ID NO:269, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:159, or a sequence having at least 90% sequence identity thereto; whether the Vα or Vγ region comprises SEQ ID NO:279, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:285, or a sequence having at least 90% sequence identity thereto; whether the Vα or Vγ region comprises SEQ ID NO: 360, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 364, or a sequence having at least 90% sequence identity thereto; whether the Vα or Vγ region comprises SEQ ID NO: 370, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 374, or a sequence having at least 90% sequence identity thereto; whether the Vα or Vγ region comprises SEQ ID NO: 380, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 384, or a sequence having at least 90% sequence identity thereto; whether the Vα or Vγ region comprises SEQ ID NO: 390, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 394, or a sequence having at least 90% sequence identity thereto;the Vα or Vγ region comprises SEQ ID NO: 400, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 404, or a sequence having at least 90% sequence identity thereto; the Vα or Vγ region comprises SEQ ID NO: 410, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 414, or a sequence having at least 90% sequence identity thereto; the Vα or Vγ region comprises SEQ ID NO: 420, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 424, or a sequence having at least 90% sequence identity thereto; the Vα or Vγ region comprises SEQ ID NO: 430, or a sequence having at least 90% sequence identity thereto; the Vβ or Vδ region comprises SEQ ID NO: 434, or a sequence having at least 90% sequence identity thereto; the Vα or Vγ region comprises SEQ ID NO: 440, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 444, or a sequence having at least 90% sequence identity thereto; the Vα or Vγ region comprises SEQ ID NO: 450, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 454, or a sequence having at least 90% sequence identity thereto; or the Vα or Vγ region comprises SEQ ID NO: 481, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 485, or a sequence having at least 90% sequence identity thereto;

[0015] In some of any of the embodiments provided herein, the Vα or Vγ region comprises SEQ ID NO:4 and the Vβ or Vδ region comprises SEQ ID NO:12; the Vα or Vγ region comprises SEQ ID NO:22 and the Vβ or Vδ region comprises SEQ ID NO:28; the Vα or Vγ region comprises SEQ ID NO:38 and the Vβ or Vδ region comprises SEQ ID NO:44; the Vα or Vγ region comprises SEQ ID NO:52 and the Vβ or Vδ region comprises SEQ ID NO:58; or the Vα or Vγ region comprises SEQ ID NO:66. and the Vβ region or Vδ region comprises SEQ ID NO:58; or the Vα region or Vγ region comprises SEQ ID NO:79 and the Vβ region or Vδ region comprises SEQ ID NO:85; or the Vα region or Vγ region comprises SEQ ID NO:93 and the Vβ region or Vδ region comprises SEQ ID NO:99; or the Vα region or Vγ region comprises SEQ ID NO:107 and the Vβ region or Vδ region comprises SEQ ID NO:113; or the Vα region or Vγ region comprises SEQ ID NO:121 and the Vβ region or Vδ region comprises SEQ ID NO:127; or the Vα region or Vγ region comprises SEQ ID NO:1 37, and the Vβ region or Vδ region comprises SEQ ID NO: 143; or the Vα region or Vγ region comprises SEQ ID NO: 153, and the Vβ region or Vδ region comprises SEQ ID NO: 159; or the Vα region or Vγ region comprises SEQ ID NO: 167, and the Vβ region or Vδ region comprises SEQ ID NO: 173; or the Vα region or Vγ region comprises SEQ ID NO: 181, and the Vβ region or Vδ region comprises SEQ ID NO: 187; or the Vα region or Vγ region comprises SEQ ID NO: 195, and the Vβ region or Vδ region comprises SEQ ID NO: 201; or the Vα region or V whether the gamma region comprises SEQ ID NO: 209 and the Vβ or Vδ region comprises SEQ ID NO: 215; whether the Vα or Vγ region comprises SEQ ID NO: 225 and the Vβ or Vδ region comprises SEQ ID NO: 231; whether the Vα or Vγ region comprises SEQ ID NO: 239 and the Vβ or Vδ region comprises SEQ ID NO: 245; whether the Vα or Vγ region comprises SEQ ID NO: 253 and the Vβ or Vδ region comprises SEQ ID NO: 259; whether the Vα or Vγ region comprises SEQ ID NO: 269 and the Vβ or Vδ region comprises SEQ ID NO: 159;whether the Vα or Vγ region comprises SEQ ID NO: 279 and the Vβ or Vδ region comprises SEQ ID NO: 285; whether the Vα or Vγ region comprises SEQ ID NO: 360 and the Vβ or Vδ region comprises SEQ ID NO: 364; whether the Vα or Vγ region comprises SEQ ID NO: 370 and the Vβ or Vδ region comprises SEQ ID NO: 374; whether the Vα or Vγ region comprises SEQ ID NO: 380 and the Vβ or Vδ region comprises SEQ ID NO: 384; whether the Vα or Vγ region comprises SEQ ID NO: 390 and the Vβ or Vδ region comprises SEQ ID NO: 394; whether the Vα or Vγ region comprises SEQ ID NO: 400 and the Vβ or Vδ region comprises SEQ ID NO: 404 the Vα or Vγ region comprises SEQ ID NO: 410, and the Vβ or Vδ region comprises SEQ ID NO: 414; the Vα or Vγ region comprises SEQ ID NO: 420, and the Vβ or Vδ region comprises SEQ ID NO: 424; the Vα or Vγ region comprises SEQ ID NO: 430, and the Vβ or Vδ region comprises SEQ ID NO: 434; the Vα or Vγ region comprises SEQ ID NO: 440, and the Vβ or Vδ region comprises SEQ ID NO: 444; the Vα or Vγ region comprises SEQ ID NO: 450, and the Vβ or Vδ region comprises SEQ ID NO: 454; or the Vα or Vγ region comprises SEQ ID NO: 481, and the Vβ or Vδ region comprises SEQ ID NO: 485.

[0016] In some of any of the embodiments provided herein, the alpha chain further comprises an alpha constant (Cα) region, and the beta chain further comprises a beta constant (Cβ) region; or the gamma chain further comprises a gamma constant (Cγ) region, and the delta chain further comprises a delta constant (Cδ) region. In some of any of the embodiments provided herein, the Cα comprises SEQ ID NO: 294 or 296, and the Cβ comprises SEQ ID NO: 297 or 299.

[0017] In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:6, and the beta or delta chain comprises SEQ ID NO:14; the alpha or gamma chain comprises SEQ ID NO:24, and the beta or delta chain comprises SEQ ID NO:30; the alpha or gamma chain comprises SEQ ID NO:40, and the beta or delta chain comprises SEQ ID NO:46; the alpha or gamma chain comprises SEQ ID NO:54, and the beta or delta chain comprises SEQ ID NO:60; the alpha or gamma chain comprises SEQ ID NO:68, and the beta or delta chain comprises SEQ ID NO:71; the alpha or gamma chain comprises SEQ ID NO:81, and the beta or delta chain comprises SEQ ID NO:87; the alpha or gamma chain comprises SEQ ID NO:95, and the beta or delta chain comprises SEQ ID NO:101; the alpha or gamma chain comprises SEQ ID NO:109, and the beta or delta chain comprises SEQ ID NO:115; the alpha or gamma chain comprises SEQ ID NO:123, and the beta or delta chain comprises SEQ ID NO: 129; the alpha or gamma chain comprises SEQ ID NO: 139 and the beta or delta chain comprises SEQ ID NO: 145; the alpha or gamma chain comprises SEQ ID NO: 155 and the beta or delta chain comprises SEQ ID NO: 161; the alpha or gamma chain comprises SEQ ID NO: 169 and the beta or delta chain comprises SEQ ID NO: 175; the alpha or gamma chain comprises SEQ ID NO: 183 and the beta or delta chain comprises SEQ ID NO: 189; the alpha or gamma chain comprises SEQ ID NO: 197 whether the alpha or gamma chain comprises SEQ ID NO:211 and the beta or delta chain comprises SEQ ID NO:217; whether the alpha or gamma chain comprises SEQ ID NO:227 and the beta or delta chain comprises SEQ ID NO:233; whether the alpha or gamma chain comprises SEQ ID NO:241 and the beta or delta chain comprises SEQ ID NO:247; whether the alpha or gamma chain comprises SEQ ID NO:255 and the beta or delta chain comprises SEQ ID NO:261;whether the alpha or gamma chain comprises SEQ ID NO:271 and the beta or delta chain comprises SEQ ID NO:161; whether the alpha or gamma chain comprises SEQ ID NO:281 and the beta or delta chain comprises SEQ ID NO:287; whether the alpha or gamma chain comprises SEQ ID NO:362 and the beta or delta chain comprises SEQ ID NO:366; whether the alpha or gamma chain comprises SEQ ID NO:372 and the beta or delta chain comprises SEQ ID NO:376; whether the alpha or gamma chain comprises SEQ ID NO:382 and the beta or delta chain comprises SEQ ID NO:386; whether the alpha or gamma chain comprises SEQ ID NO:392 and the beta or delta chain comprises SEQ ID NO:396; whether the alpha or gamma chain comprises SEQ ID NO:402, and the beta or delta chain comprises SEQ ID NO:406; the alpha or gamma chain comprises SEQ ID NO:412 and the beta or delta chain comprises SEQ ID NO:416; the alpha or gamma chain comprises SEQ ID NO:422 and the beta or delta chain comprises SEQ ID NO:426; the alpha or gamma chain comprises SEQ ID NO:432 and the beta or delta chain comprises SEQ ID NO:436; the alpha or gamma chain comprises SEQ ID NO:442 and the beta or delta chain comprises SEQ ID NO:446; the alpha or gamma chain comprises SEQ ID NO:452 and the beta or delta chain comprises SEQ ID NO:456; or the alpha or gamma chain comprises SEQ ID NO:483 and the beta or delta chain comprises SEQ ID NO:487.

[0018] In some of any of the embodiments provided herein, the TCR or antigen-binding fragment thereof recognizes a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule. In some of any of the embodiments provided herein, the MHC molecule is a human leukocyte antigen (HLA)-A molecule. In some of any of the embodiments provided herein, the HLA-A molecule is of the serotype HLA-A * In some of the embodiments provided herein, the HLA-A molecule is of the serotype HLA-A* 02:06. In some of any of the embodiments provided herein, the peptide epitope of HA-1 is set forth in SEQ ID NO:354.

[0019] Also provided are polynucleotides that encode the TCRs provided herein or antigen-binding fragments thereof, or any of the alpha, beta, gamma, or delta chains thereof.

[0020] In some of any of the embodiments provided herein, the polynucleotide comprises a nucleotide sequence encoding a Vα region and a nucleotide sequence encoding a Vβ region; or a nucleotide sequence encoding a Vγ region and a nucleotide sequence encoding a Vδ region, wherein the nucleotide sequence encoding the Vα region or the Vγ region comprises SEQ ID NO:7, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region or the Vδ region comprises SEQ ID NO:15, or a sequence having at least 90% sequence identity thereto; wherein the nucleotide sequence encoding the Vα region or the Vγ region comprises SEQ ID NO:25, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region or the Vδ region comprises SEQ ID NO:31, or a sequence having at least 90% sequence identity thereto; or wherein the nucleotide sequence encoding the Vα region or the Vγ region comprises SEQ ID NO:41, or a sequence having at least 90% sequence identity thereto, and the Vβ region or the Vδ region comprises SEQ ID NO:15, or a sequence having at least 90% sequence identity thereto. whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:55, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:61, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:69, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:72, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:82, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:88, or a sequence having at least 90% sequence identity thereto;the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:96, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:102, or a sequence having at least 90% sequence identity thereto; the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:110, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:116, or a sequence having at least 90% sequence identity thereto; the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:124, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:130, or a sequence having at least 90% sequence identity thereto; the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:140, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 146, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 156, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 162, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 170, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 176, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 184, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 190, or a sequence having at least 90% sequence identity thereto;whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 198, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 204, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 212, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 218, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 228, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 234, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:242, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:248, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:256, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:262, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:272, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:274, or a sequence having at least 90% sequence identity thereto;or the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 282, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 288, or a sequence having at least 90% sequence identity thereto;

[0021] In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:8, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:16; the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:26, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:32; the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:42, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:48; the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:56, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:62; the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:70, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:73; the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:83, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: whether the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:97, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO:103; whether the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:111, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO:117; whether the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:125, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO:131; whether the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:141, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO:147; whether the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:157, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO:163; whether the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:171, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO:177;whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:185 and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:191; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:199 and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:205; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:213 and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:219; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:229 and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:235 the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 243, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 249; the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 257, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 263; the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 273, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 275; or the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 283, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 289. In some embodiments, the nucleotide sequence encoding the alpha or gamma chain and the nucleotide sequence encoding the beta or delta chain comprise the sequence present in SEQ ID NO: 368, 378, 388, 398, 408, 418, 428, 438, 448, 458, or 489. The P2A sequences encoding the alpha chain, 368, 378, 388, 398, 408, 418, 428, 438, 448, 458, and 489, and the beta chain are shown in Sequence Table 4.

[0022] In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 301, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 321; the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 302, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 322; the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 303, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 323; the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 304, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 324; the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 305, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 325; the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 306, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 326. whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 307, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 327; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 308, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 328; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 309, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 329; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 310, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 330; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 311, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 331; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 312, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 332;whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:313 and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:333; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:314 and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:334; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:315 and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:335; whether the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:316 and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:336 the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 317 and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 337; the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 318 and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 338; the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 319 and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 339; or the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 320 and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 340;

[0023] In some of any of the embodiments provided herein, the polynucleotide comprises a nucleotide sequence encoding an alpha chain and a nucleotide sequence encoding a beta chain; or a nucleotide sequence encoding a gamma chain and a nucleotide sequence encoding a delta chain, wherein the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:8, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO:16, or a sequence having at least 90% sequence identity thereto; the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:26, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO:32, or a sequence having at least 90% sequence identity thereto; or the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:42, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO: whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:56, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:62, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:70, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:73, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:83, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:89, or a sequence having at least 90% sequence identity thereto;whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:97, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:103, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:111, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:117, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:125, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:131, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 141, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 147, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 157, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 163, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 171, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 177, or a sequence having at least 90% sequence identity thereto;whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 185, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 191, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 199, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 205, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 213, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 219, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:229, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:235, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:243, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:249, or a sequence having at least 90% sequence identity thereto; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:257, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:263, or a sequence having at least 90% sequence identity thereto;The nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:273, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:275, or a sequence having at least 90% sequence identity thereto; or the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:283, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:289, or a sequence having at least 90% sequence identity thereto;

[0024] In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:8, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:16; the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:26, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:32; the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:42, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:48; the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:56, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:62; the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:70, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:73; the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:83, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: whether the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:97, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO:103; whether the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:111, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO:117; whether the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:125, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO:131; whether the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:141, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO:147; whether the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:157, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO:163; whether the nucleotide sequence encoding the alpha chain or the gamma chain comprises SEQ ID NO:171, and the nucleotide sequence encoding the beta chain or the delta chain comprises SEQ ID NO:177;whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:185 and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:191; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:199 and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:205; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:213 and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:219; whether the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:229 and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:235 the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:243 and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:249; the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:257 and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:263; the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:273 and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:275; or the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:283 and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:289;

[0025] In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha chain and the nucleotide sequence encoding the beta chain are separated by a peptide sequence that causes ribosome skipping. In some of any of the embodiments provided herein, the peptide that causes ribosome skipping is a P2A peptide. In some of any of the embodiments provided herein, the P2A peptide comprises SEQ ID NO: 352. In some of any of the embodiments provided herein, the sequence encoding the P2A peptide is set forth in SEQ ID NO: 351.

[0026] In some of any of the embodiments provided herein, the nucleotide sequence encodes SEQ ID NO: 18; the nucleotide sequence encodes SEQ ID NO: 34; the nucleotide sequence encodes SEQ ID NO: 50; the nucleotide sequence encodes SEQ ID NO: 64; the nucleotide sequence encodes SEQ ID NO: 75; the nucleotide sequence encodes SEQ ID NO: 91; the nucleotide sequence encodes SEQ ID NO: 105; the nucleotide sequence encodes SEQ ID NO: 119; the nucleotide sequence encodes SEQ ID NO: 133; the nucleotide sequence encodes SEQ ID NO: 149; the nucleotide sequence encodes SEQ ID NO: 165; the nucleotide sequence encodes SEQ ID NO: 179; the nucleotide sequence encodes SEQ ID NO: 193; the nucleotide sequence encodes SEQ ID NO: 207; the nucleotide sequence encodes SEQ ID NO: 221. or; the nucleotide sequence encodes SEQ ID NO: 237; the nucleotide sequence encodes SEQ ID NO: 251; the nucleotide sequence encodes SEQ ID NO: 265; the nucleotide sequence encodes SEQ ID NO: 277; the nucleotide sequence encodes SEQ ID NO: 291; the nucleotide sequence encodes SEQ ID NO: 367; the nucleotide sequence encodes SEQ ID NO: 377; the nucleotide sequence encodes SEQ ID NO: 387; the nucleotide sequence encodes SEQ ID NO: 397; the nucleotide sequence encodes SEQ ID NO: 407; the nucleotide sequence encodes SEQ ID NO: 417; the nucleotide sequence encodes SEQ ID NO: 427; the nucleotide sequence encodes SEQ ID NO: 437; the nucleotide sequence encodes SEQ ID NO: 447; the nucleotide sequence encodes SEQ ID NO: 457; or the nucleotide sequence encodes SEQ ID NO: 487.

[0027] In some of any of the embodiments provided herein, the nucleotide sequence comprises SEQ ID NO: 17; the nucleotide sequence comprises SEQ ID NO: 33; the nucleotide sequence comprises SEQ ID NO: 49; the nucleotide sequence comprises SEQ ID NO: 63; the nucleotide sequence comprises SEQ ID NO: 74; the nucleotide sequence comprises SEQ ID NO: 90; the nucleotide sequence comprises SEQ ID NO: 104; the nucleotide sequence comprises SEQ ID NO: 118; the nucleotide sequence comprises SEQ ID NO: 132; the nucleotide sequence comprises SEQ ID NO: 148; the nucleotide sequence comprises SEQ ID NO: 164; the nucleotide sequence comprises SEQ ID NO: 178; the nucleotide sequence comprises SEQ ID NO: 192; the nucleotide sequence comprises SEQ ID NO: 206; the nucleotide sequence comprises SEQ ID NO: 220 or; does the nucleotide sequence comprise SEQ ID NO: 236; does the nucleotide sequence comprise SEQ ID NO: 250; does the nucleotide sequence comprise SEQ ID NO: 264; does the nucleotide sequence comprise SEQ ID NO: 276; does the nucleotide sequence comprise SEQ ID NO: 290; does the nucleotide sequence comprise SEQ ID NO: 368; does the nucleotide sequence comprise SEQ ID NO: 378; does the nucleotide sequence comprise SEQ ID NO: 388; does the nucleotide sequence comprise SEQ ID NO: 398; does the nucleotide sequence comprise SEQ ID NO: 408; does the nucleotide sequence comprise SEQ ID NO: 418; does the nucleotide sequence comprise SEQ ID NO: 428; does the nucleotide sequence comprise SEQ ID NO: 438; does the nucleotide sequence comprise SEQ ID NO: 448; does the nucleotide sequence comprise SEQ ID NO: 458; or does the nucleotide sequence comprise SEQ ID NO: 487.

[0028] Also provided herein is a vector comprising any of the polynucleotides provided herein. In some of the embodiments provided herein, the vector is a viral vector. In some of the embodiments provided herein, the viral vector is a lentiviral vector.

[0029] Also provided herein are modified cells comprising any of the TCRs or antigen-binding fragments thereof provided herein. Also provided herein are modified cells comprising any of the polynucleotides provided herein or any of the vectors provided herein. In some of the embodiments provided herein, the TCR or antigen-binding fragment thereof is heterologous to the cell. In some of the embodiments provided herein, the modified cell is a cell line. In some of the embodiments provided herein, the modified cell is a primary cell obtained from a subject. In some of the embodiments provided herein, the modified cell is a T cell.

[0030] Also provided herein are methods for producing modified cells that involve introducing any of the polynucleotides provided herein, or any of the vectors provided herein, into a cell to form the modified cell.

[0031] Also provided herein are compositions comprising any of the TCRs or antigen-binding fragments thereof provided herein, any of the polynucleotides provided herein, any of the vectors provided herein, or any of the modified cells provided herein. In some of any of the embodiments provided herein, the composition also comprises a pharmaceutically acceptable excipient.

[0032] Also provided herein is a method for identifying a TCR that targets a hematopoietic-restricted minor histocompatibility antigen (miHA), which involves identifying a functional TCR that recognizes a hematopoietic-restricted miHA from among a plurality of functional TCRs, wherein the plurality of functional TCRs are encoded by a plurality of functional TCR-encoding nucleic acid vectors produced by a high-throughput nucleic acid amplification and assembly method using nucleic acid obtained from a single T cell among the plurality of T cells; the plurality of T cells is derived from a human female donor who is or was pregnant with a fetus having a mismatched or immunogenic hematopoietic-restricted miHA.

[0033] Also provided herein is a method for identifying a TCR that targets a hematopoietic-restricted miHA, comprising: (i) producing a plurality of functional TCR-encoding nucleic acid vectors by a high-throughput nucleic acid amplification and assembly method using nucleic acid obtained from a single T cell among a plurality of T cells, wherein the T cell is derived from a human female donor who is or was pregnant with a fetus having a mismatched or immunogenic hematopoietic-restricted miHA; and (ii) identifying a functional TCR that recognizes the hematopoietic-restricted miHA from among the plurality of functional TCRs encoded by the plurality of functional TCR-encoding nucleic acid vectors.

[0034] In some of any of the embodiments provided herein, the hematopoietic-restricted miHA is the minor histocompatibility antigen HA-1. In some of any of the embodiments provided herein, the identified functional TCR recognizes a peptide epitope of the minor histocompatibility antigen HA-1 in association with an MHC molecule. In some of any of the embodiments provided herein, the MHC molecule is a human leukocyte antigen (HLA)-A molecule. In some of any of the embodiments provided herein, the HLA-A molecule is of the serotype HLA-A * In some of the embodiments provided herein, the HLA-A molecule is of the serotype HLA-A * 02:06. In some of any of the embodiments provided herein, the peptide epitope of HA-1 is set forth in SEQ ID NO:354.

[0035] In some of any of the embodiments provided herein, T cells from a human female donor are cultured under conditions for cell expansion of the T cells prior to production of a plurality of functional TCR-encoding nucleic acid vectors.

[0036] In some of any of the embodiments provided herein, the T cells from the human female donor are not cultured under conditions for cell expansion of the T cells prior to production of the plurality of functional TCR-encoding nucleic acid vectors.

[0037] In some of any of the embodiments provided herein, high-throughput nucleic acid amplification and assembly includes: (1) amplifying a first amplification product and a second amplification product from complementary DNA (cDNA) produced from RNA obtained from a single T cell from the plurality of T cells sorted into each of a plurality of distinct locations on a device, wherein the first amplification product comprises a nucleotide sequence encoding a full-length Vα region or a full-length Vγ region of a TCR, and the second amplification product comprises a nucleotide sequence encoding a full-length Vβ region or a full-length Vδ region of a TCR; and (2) assembling the first amplification product and the second amplification product from each of the plurality of distinct locations into a nucleic acid vector to obtain an assembled nucleic acid vector comprising a nucleotide sequence encoding a functional TCR for each of the plurality of distinct locations, wherein the functional TCR comprises (i) a full-length Vα region and a full-length Vβ region derived from the single T cell, or (ii) a full-length Vγ region and a full-length Vδ region derived from the single T cell.

[0038] Also provided herein are modified cells comprising a TCR identified by any of the methods described herein. Also provided herein are compositions comprising any of the modified cells provided herein. In some of any of the embodiments provided herein, the composition also comprises a pharmaceutically acceptable excipient.

[0039] Also provided herein are therapeutic methods involving administering any of the TCRs or antigen-binding fragments thereof provided herein, any of the polynucleotides provided herein, any of the vectors provided herein, any of the modified cells provided herein, or any of the compositions provided herein to a subject with a disease or disorder. Also provided herein are any of the TCRs or antigen-binding fragments thereof provided herein, any of the polynucleotides provided herein, any of the vectors provided herein, any of the modified cells provided herein, or any of the compositions provided herein for use in treating a disease or disorder in a subject. Also provided herein is the use of any of the TCRs or antigen-binding fragments thereof provided herein, any of the polynucleotides provided herein, any of the vectors provided herein, any of the modified cells provided herein, or any of the compositions provided herein in the manufacture of a medicament for the treatment of a disease or disorder in a subject. Also provided herein is the use of any of the TCRs or antigen-binding fragments thereof provided herein, any of the polynucleotides provided herein, any of the vectors provided herein, any of the modified cells provided herein, or any of the compositions provided herein for the treatment of a disease or disorder in a subject.

[0040] In some of any of the embodiments provided herein, the subject is eligible for or will undergo allogeneic hematopoietic stem cell transplantation (HSCT). In some of any of the embodiments provided herein, the subject has or has been diagnosed with a malignant hematologic disorder. In some of any of the embodiments provided herein, the subject has been diagnosed with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or acute lymphoblastic leukemia (ALL). In some of any of the embodiments provided herein, the subject has or has been diagnosed with a liquid tumor, hematopoietic tumor, lymphoma, or chronic myeloid leukemia (CML). In some of any of the embodiments provided herein, administration of the modified cells or compositions induces or enhances cell death of cells associated with a malignant hematologic injury or induces or enhances a graft versus leukemia effect (GVL) in a subject. [Brief explanation of the drawings]

[0041] [Figure 1] FACS analysis of expanded donor cells, PBMCs alone (left panel), or PBMCs cocultured with B cells from the same donor (B-APC; right panel) double-stained with miHA-1 dextramers labeled with either FITC or APC is shown. [Figure 2] Figure 1 shows a FACS plot analysis of the controls used to screen for miHA-1-specific TCRs. Empty vector and non-HA-1-specific TCRs served as negative controls, and an exemplary HA-1-targeting TCR was used as a positive control. [Figure 3]Figure 1 shows plots of % TRAV, TRBV expression, and CD3 as assessed by FACS in 701 TCR clones transiently expressed in HEK293 cells. Clones that exhibited higher surface TCR expression than the positive control are shown in blue, clones that exhibited lower surface TCR expression than the negative control are shown in yellow, and clones that fall between the two controls are shown in green. [Figure 4A] FIG. 1 shows FACS-based assessment of individual TCRs expressed in HEK293 cells to determine transfection efficiency as indicated by mCherry and IP26 staining. [Figure 4B] FACS analysis of individual TCRs expressed in HEK293 stained with HA-1 "H" dextramer is shown. [Figure 5] Figure 1 shows TCR expression for beta chain variants (TRBV) after sequencing of TRBV amplified in a screen of 704 receptors. [Figure 6] The distribution of non-singleton clones between non-expanded and expanded cultures, including those grown in the presence of naked HA-1 peptide or HA-1 presented by donor B cells, is shown. [Figure 7] The percentage of CD3 cells that stained positive for HA-1 "H" dextramer among 704 clones obtained from parous women and re-expressed in reporter cells is shown. [Figure 8] EC50 estimates from CD69 activation studies of reporter cells expressing one of 16 exemplary anti-HA-1 TCRs are shown. [Figure 9] Assessment of TCR binding in the presence of either the HA-1 "H" peptide or the HA-1 "R" peptide is shown. [Figure 10] An IL-2 secretion assay is shown in which the functionality of Jurkat T cells transduced with HA-1-targeting TCR was assessed in the presence of APCs presenting the target "H" peptide. [Figure 11]1 shows an IL-2 secretion assay that assessed the functionality of Jurkat T cells transduced with HA-1-targeting TCRs in response to APCs presenting either the HA-1 "H" or HA-1 "R" peptide. [Figure 12] 1 shows the results of EC50 evaluation from a CD69 activation study of Jurkat T cells expressing various TCR candidates after overnight incubation with A*0201 LCL and increasing concentrations of HA-1 "H" peptide. [Figure 13A] A representative EC50 assessment is shown in which Jurkat T cells expressing an exemplary HA-1 specific TCR were assessed for CD69 activation in response to increasing concentrations of HA-1 peptide. [Figure 13B] 1 shows the results of an experiment to determine the EC50 of an exemplary TCR in the presence of increasing concentrations of HA-1. [Figure 14] A comparison of the EC50 determined for an exemplary TCR with CD69 activation data reconstructed from known HA-1 specific TCRs is shown. [Figure 15] 1 shows CD69 activation of exemplary anti-HA-1 TCR-expressing cells in response to different HA-1 peptide alleles presented by HLA-A*02:01 and non-HLA-A*02:01 LCLs. [Figure 16] 1 shows A*0201 / HA-1 dextramer staining of an exemplary HA-1 TCR expressed on human primary T cells. [Figure 17] Flow cytometry plots of cell populations in a cell killing assay are shown, in which LCLs loaded with HA-1 "H" or "R" were labeled with CFSE to demonstrate killing and target specificity by the HA-1-specific TCR expressed on primary human cells. [Figure 18A] Cell numbers of HA-1 "H" and HA-1 "R" loaded LCLs are shown after exposure to untransduced T cells at increasing effector to target (E:T) ratios. [Figure 18B]Shown are the cell numbers of HA-1 "H"- and HA-1 "R"-loaded LCLs after exposure to HA-1-specific TCR expressed on human primary T cells at increasing effector-to-target (E:T) ratios. DETAILED DESCRIPTION OF THE INVENTION

[0042] Provided herein are TCRs, such as recombinant TCRs, including those that bind to or recognize peptide epitopes associated with hematopoietic-restricted minor histocompatibility antigens, e.g., HA-1, such as peptide epitopes expressed on the surface of cells in the context of MHC molecules. Among the provided embodiments are approaches useful in the treatment of such diseases and conditions and / or for targeting cell types, such as cancer cells or cells associated with hematological ailments. In some embodiments, the provided TCRs and antigen-binding fragments thereof bind to or recognize peptide epitopes of HA-1 in the context of MHC molecules.

[0043] Also provided herein are nucleic acid molecules encoding TCRs, engineered cells containing TCRs, compositions containing TCRs or cells, and methods of treatment or use, such as therapeutic applications, involving administering such TCRs, engineered cells, or compositions, as well as uses of such TCRs, cells, or compositions. In some embodiments, engineered cells expressing the provided TCRs or antigen-binding fragments thereof exhibit cytotoxic activity against target cells expressing the peptide epitope, such as cancer cells or cells associated with a hematologic disorder. Also provided herein are methods for identifying TCRs that target hematopoietic-restricted miHAs.

[0044] Allogeneic stem cell transplantation (Allo-SCT) can be a curative treatment for patients with hematologic malignancies as well as for patients with nonmalignant but medically serious conditions, such as hemoglobinopathies, thalassemias, and autoimmune diseases. Allo-SCT can also be used to create tolerance to transplanted solid organs. Mature αβ T cells contained in the donor allograft play a key role and can be considered in two broad classes. One class promotes the reconstitution of anti-pathogen immunity, particularly through the transfer of memory T cells. The second class of T cells, called alloreactive T cells, recognizes the patient as "non-self." When allo-SCT is used to treat hematologic malignancies, alloreactive donor T cells can kill malignant cells, thereby mediating the graft-versus-host leukemia (GVL) effect. However, they can also cause graft-versus-host disease (GVHD), in which alloreactive T cells attack healthy host tissues, including, for example, the skin, gut, and liver.

[0045] In human leukocyte antigen (HLA)-matched alloSCT, alloreactive T cells target miHA, a peptide product of a coding polymorphism that distinguishes the recipient from the donor. Importantly, alloreactive CD8+ T cells targeting miHA, which has expression restricted to hematopoietic cells, are less likely to cause GVHD. Administration of anti-miHA T cells, among other strategies, could minimize the risk of extensive toxicity without compromising therapeutic efficacy, either in the context of boosting alloSCT or as a stand-alone therapy.

[0046] Cell therapies (including those involving the administration of cells expressing recombinant receptors or TCRs specific for a disease or disorder of interest, such as recombinant TCRs and / or other recombinant antigen receptors), as well as other adoptive immune cell and adoptive T cell therapies, can be effective in treating diseases and disorders. In certain circumstances, available approaches to adoptive cell therapy may not always be entirely satisfactory. In some situations, optimal effectiveness may depend on the ability of the administered cells to express the recombinant receptor and the ability of the recombinant receptor to recognize and bind to a target antigen within the subject, such as a peptide epitope of HA-1, based, for example, on the affinity of the antigen-binding domain of the TCR for that target antigen. In some cases, the consistency and / or efficiency of expression of the recombinant receptor, as well as the activity of the receptor, limit the availability of certain cells or certain cell populations to certain therapeutic approaches.

[0047] In some embodiments, the development of humanized and / or fully human recombinant TCRs presents technical challenges. For example, in some embodiments, humanized and / or fully human recombinant TCRs, when engineered into human T cells, can compete with endogenous TCR complexes and / or form mispairs with endogenous TCR chains, which, in certain embodiments, can reduce recombinant TCR signaling, activity, and / or expression and ultimately result in reduced activity of the engineered cell. For example, in some cases, suboptimal expression of an engineered or recombinant TCR can result from competition with endogenous TCRs and / or TCRs with mispaired chains for signaling molecules and / or domains involved in enabling expression of the complex on the cell surface, such as the invariant CD3 signaling molecule (e.g., availability of co-expressed CD3 delta, epsilon, gamma, and / or zeta chains). In some embodiments, available CD3 molecules can limit TCR expression and function within the cell.

[0048] In some aspects, provided embodiments are based on the observation of improved affinity, expression, or activity of exemplary fully human recombinant TCRs, such as certain provided TCRs specific for HA-1, even at low effector-to-target (E:T) ratios. The activity, e.g., cytokine secretion and / or cytolytic activity, of engineered T cells expressing the recombinant TCRs can, in some cases, be limited when fewer engineered T cells are present compared to target cells. In some aspects, such improved activity at low E:T ratios and with fully human sequences is advantageous for improving the efficacy of therapies.

[0049] In some cases, certain available approaches for obtaining antigen-specific recombinant receptors, such as recombinant TCRs, may result in recombinant receptors that exhibit cross-reactivity to different non-target antigens (see, e.g., Cameron et al. (2013) Science Translational Medicine 5(197):197ra103). In some aspects, provided embodiments may be used in combination with other antigen-specific recombinant receptors, such as those targeting HLA subtypes A, B, C, D, E, E, F, F, HLA subtypes B, E, F, F, HLA subtypes C, E, F, F, HLA subtypes D, E, F, F, HLA subtypes ... * This is based on the observation that certain provided TCRs specific for particular immunogenic HA-1 peptides presented by 0201 do not exhibit cross-reactivity to cells expressing other peptide antigens or alloreactivity to other subtypes. Thus, the provided TCRs exhibit improved expression and activity while minimizing the risk of cross-reactivity to other antigens, such as non-target antigens or peptide epitopes presented via non-target HLA subtypes, that may be present in the subject.

[0050] In some aspects, therapeutic approaches using such TCRs, e.g., adoptive cell therapy with engineered human T cells expressing the provided recombinant TCRs, may ultimately result in increased efficacy, e.g., by improving the GVL effect. In some situations, the provided embodiments, including TCRs, polynucleotides encoding such TCRs, modified cells, and cell compositions, may offer various advantages over available TCR-based therapies, improving the activity of the recombinant receptors and response to adoptive cell therapy targeting cancer cells and cells associated with hematological diseases.

[0051] All publications, including patent documents, scientific articles, and databases, referenced in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. To the extent that a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in a patent, application, published application, or other publication incorporated herein by reference, the definition set forth herein takes precedence over the definition incorporated herein by reference.

[0052] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0053] I. T cell receptor targeting histocompatibility antigen 1 (HA-1) As used herein, TCRs are those that bind to or recognize peptide epitopes associated with hematopoietic-restricted miHAs, such as peptide epitopes expressed on the surface of cancer cells and / or cells associated with hematologic disorders in the context of an MHC molecule. In some embodiments, the provided TCRs bind to or recognize peptide epitopes of miHA HA-1 in the context of an MHC molecule. Such TCRs and antigen-binding fragments exhibit antigen specificity that binds to or recognizes such peptide epitopes. In some embodiments, nucleic acid molecules encoding TCRs, engineered cells expressing TCRs, compositions, and therapeutic methods involving administering such TCRs, engineered cells, or compositions are also provided. In some aspects, engineered cells expressing the provided TCRs or antigen-binding fragments exhibit cytotoxic activity against target cells expressing the peptide epitope, such as cancer cells or cells associated with a hematologic disorder.

[0054] A. Allogeneic stem cell transplantation AlloSCT is a curative treatment option for patients with hematological malignancies. In alloSCT, patients undergo a pre-transplant regimen consisting of chemotherapy, sometimes with radiation therapy, which facilitates engraftment by killing any remaining malignant cells, creating space in the recipient's bone marrow for donor stem cell engraftment, and by killing the patient's immune cells that can mediate donor allograft rejection.

[0055] Mature alpha / beta donor T cells contained in the donor graft play important roles and can be considered in two broad classes. One class promotes the reconstitution of anti-pathogen immunity, particularly through the transfer of memory T cells. The second class of T cells recognizes the patient as "non-self." These so-called "allo-reactive" T cells have both positive and detrimental effects. An important advantage of these cells is their ability to kill recipient malignant cells that mediate the GVL effect. Alloreactive T cells can also kill normal patient or host hematopoietic and immune cells, both of which create space for cell engraftment and reduce immunological rejection of donor cells. However, donor T cells can also attack normal recipient tissues, causing GVHD. Therefore, all patients undergo some form of systemic immunosuppression to reduce the frequency and severity of GVHD.

[0056] Despite the GVL effect, recurrent malignancies are the single largest cause of treatment failure and death in recipients of alloSCT for the treatment of hematologic neoplasms. There is good reason to believe that engineering more effective alloreactive T cell responses could reduce relapse. GVHD and the consequences of systemic immunosuppression (e.g., infection) are other major causes of morbidity and mortality. These, too, could be mitigated if allogeneic responses were better engineered to focus on hematopoietic cells rather than normal host tissues. Despite these limitations, alloSCT remains the global standard of care for patients with intermediate- to high-risk hematologic malignancies, supported by data from multiple sources supporting higher survival rates than without transplantation.

[0057] During HLA-matched alloSCT, alloreactive donor T cells target miHAs expressed in the recipient. MiHAs are peptide products of coding polymorphisms that distinguish recipients from donors. These polymorphisms exist at stable, known frequencies in the population and are inherited by Mendelian genetics. Some miHA-encoding genes are expressed in a wide range of tissues, whereas others are relatively restricted to hematopoietic cells. As currently practiced, there is no control over which miHAs are targeted in alloSCT. Because T cell responses against miHAs expressed on normal tissues almost always occur, severe GVHD is a major risk, thus necessitating immunosuppression. In contrast, miHAs, which are expressed relatively restricted to hematopoietic cells, are considered ideal targets for immunotherapy with donor-derived CD8+ T cells in combination with alloSCT. CD8+ T cells targeting such antigens can kill recipient malignant blood cells, mediating the GVL effect. T cells targeting hematopoietic-restricted antigens can mediate graft-versus-host leukemia and promote engraftment with a reduced risk of graft-versus-host disease. They can also kill non-malignant recipient hematopoietic cells, including immune cells, thereby promoting engraftment and reducing the risk of immune rejection. Interestingly, CD8+ T cells targeting hematopoietic-restricted miHAs have a reduced risk of causing GVHD.

[0058] CD8+ T cells recognize their targets through their antigen receptors (TCRs). The process of producing these receptors creates a highly diverse repertoire of unique TCRs, and each person has approximately 10 7 It is estimated that TCRs contain T cells that express more than 100 unique receptors. This diversity allows individuals to respond to a wide range of pathogens as well as miHAs. Unlike antibodies, which bind intact proteins, TCRs recognize short peptides, usually about 8-12 amino acids long, embedded on the surface of MHC molecules expressed on the surface of cells.

[0059] The advantage of this system of antigen detection is that T cells can recognize peptides derived from any protein, even those not expressed on the cell surface. Throughout evolution, MHC molecules have diversified in populations, with most of the variation occurring in the portion of the MHC molecule that binds and displays or presents peptides to the TCR. This allows for a large diversity of peptides that can be presented to T cells by MHC molecules, with the preference or restriction of certain peptides to specific MHC molecules. The result of this is that each miHA is generally restricted to a single MHC type. Importantly, over the past few decades, over 50 relatively hematopoietically restricted miHAs have been identified, a number sufficient to ensure that nearly all donor / recipient combinations, regardless of MHC type, have targetable hematopoietically restricted miHAs.

[0060] B. Histocompatibility antigen 1 (HA-1) HA-1 is a hematopoietic-restricted miHA found on Hofbauer and trophoblast cells in the human placenta and is important for bone marrow transplantation outcomes. The antigenic peptide derived from HA-1 results from a single nucleotide difference between a non-immunogenic peptide ("R peptide") containing the amino acid sequence VLRDDLLEA (SEQ ID NO: 355) and an immunogenic peptide ("H peptide") containing the amino acid sequence VLHDDLLEA (SEQ ID NO: 354). The immunogenic peptide binds to HLA-A. * 0201, A * 0206, B * 60, and B * It can be presented in the context of at least four different class I MHC molecules, including HLA-A 40012. As a result of immunogenic single nucleotide polymorphisms (SNPs), HLA-A 40012 can be expressed on antigen-presenting cells (APCs). * 0201 peptide-binding groove, thus increasing the binding affinity of the HA-1H peptide to HLA-A * This results in immunogenic peptides that can be recognized by 0201-restricted T cells.

[0061] The difference in immunogenicity of these peptides may be due to various factors. For example, the proteasomal cleavage and TAP-mediated transport of the two peptides into the endoplasmic reticulum are similar, and both variants can bind to HLA-restricted alleles. However, the R peptide does not bind to HLA-A. * HLA-A is a nucleotide sequence that is likely related to the relatively large size of the arginine residue, which provides steric and electrostatic hindrance with the D-pocket residues. * It has lower affinity and less stable binding to 0201. Differences in both MHC molecule and TCR binding may explain the immunogenicity of the HA-1 H peptide.

[0062] In some instances, the miHA HA-1 H peptide (VLHDDLLEA; SEQ ID NO: 354) is targeted, while the non-immunogenic R peptide (VLRDDLLEA; SEQ ID NO: 355) is not. HA-1 is ideal in that its expression is restricted to hematopoietic cells, is presented (or "restricted") by the most common human HLA types, and has an allele frequency of approximately 50%. See de Bueger et al. (1992) J Immunol Baltim Md 1950 149(5):1788-1794 and Wilke et al. (2003) Hematol J. 4(5):315-320.

[0063] In some embodiments, the TCR recognizes or binds to the HA-1 epitope in the context of an MHC molecule, such as an MHC class I molecule. In some embodiments, the MHC class I molecule is any one or more subtypes thereof, e.g., HLA-A * 0201, * 0202, * 0203, * 0206, or * 0207. In some cases, there may be differences in the frequency of subtypes between different populations. For example, in some embodiments, more than 95% of the HLA-A2 positive Caucasian population is HLA-A2. * In the Chinese population, the frequency is approximately 23% HLA-A* 0201, 45% HLA-A * 0207, 8% HLA-A * 0206, and 23% HLA-A * 0203. In some embodiments, the MHC molecule is HLA-A * The time is 0201.

[0064] In some embodiments, the provided TCRs or antigen-binding fragments thereof recognize or bind to an immunogenic (e.g., mismatched between the donor and recipient of alloSCT) epitope or domain of HA-1, such as the immunogenic H peptide comprising the amino acid sequence VLHDDLLEA (SEQ ID NO: 354). In some embodiments, the provided TCRs or antigen-binding fragments thereof recognize or bind to a non-immunogenic epitope or domain of HA-1, such as the non-immunogenic R peptide comprising the amino acid sequence VLRDDLLEA (SEQ ID NO: 355).

[0065] In some embodiments, the TCR or antigen-binding fragment thereof is isolated or purified, or recombinant. In certain embodiments, any of the provided TCRs or antigen-binding fragments thereof is recombinant. In some aspects, the TCR or antigen-binding fragment thereof is human. In some aspects, the TCR is a single chain. In other embodiments, the TCR contains two chains. In some embodiments, the TCR or antigen-binding fragment thereof is expressed on the surface of a cell (e.g., a T cell, such as a T cell engineered to lack expression of an endogenous TCR).

[0066] In some embodiments, the provided TCRs have one or more specified functional characteristics, such as a binding characteristic including binding to a particular epitope, and / or a particular binding affinity, e.g., as described herein. In some embodiments, engineered cells, such as T cells, expressing a provided TCR have one or more specified functional characteristics, such as a binding characteristic including binding to a particular epitope, a particular binding affinity, activation or stimulation of cell signaling, such as T cell signaling or TCR signaling, secretion of cytokines, and / or killing of target cells expressing or presenting an antigen, e.g., as described herein.

[0067] In some embodiments, the provided binding molecule is a TCR or an antigen-binding fragment thereof. In some embodiments, the TCR is an alpha chain comprising a Vα region and a beta chain comprising a Vβ region (also known as TCRα and TCRβ, respectively), or a gamma chain comprising a Vγ region and a delta chain comprising a Vδ region (also known as TCRγ and TCRδ, respectively), or a molecule containing an antigen-binding portion thereof, which can specifically bind to an antigen, e.g., a peptide antigen or peptide epitope bound to an MHC molecule. In some embodiments, the TCR is in the αβ form (e.g., an αβ TCR). In some embodiments, the TCR is in the γδ form (e.g., a γδ TCR). Typically, TCRs present in the αβ or γδ form are generally structurally similar, although T cells expressing them may have different anatomical locations or functions. TCRs can be found on the surface of cells or in a soluble form. Generally, TCRs are found on the surface of T cells, where they are responsible for recognizing antigens, typically peptides bound to MHC molecules.

[0068] In some embodiments, the TCRs provided herein can be intact or full-length TCRs, such as TCRs containing a full-length α chain and a full-length β chain, or a TCR containing a full-length γ chain and a full-length δ chain. In some embodiments, the antigen-binding portion of a TCR provided herein can be less than a full-length TCR, but binds to a specific peptide bound to an MHC molecule, such as binding to an MHC-peptide complex. In some cases, the antigen-binding portion or fragment of a TCR can contain only a portion of the structural domain of a full-length or intact TCR, but can still bind to a peptide epitope, such as an MHC-peptide complex, to which a full-length TCR binds. In some cases, the antigen-binding portion contains a variable domain of a TCR, such as the Vα and Vβ regions of a TCR provided herein or the Vγ and Vδ regions of a TCR, but is sufficient to form a binding site for the antigen-binding portion to bind to a specific MHC-peptide complex.

[0069] In some embodiments, the variable domain of a TCR generally contains the CDRs, which contribute to the antigen recognition and binding capacity and specificity of peptides, MHC molecules, and / or MHC-peptide complexes. In some embodiments, the CDRs of a TCR, or combinations thereof, form all or substantially all of the antigen-binding site of a given TCR molecule. The various CDRs within the variable region of a TCR chain are generally separated by framework regions (FRs), which generally show less variability among TCRs compared to the CDRs (see, e.g., Jores et al., Proc. Nat'l Acad. Sci. USA 87:9138 (1990); Chothia et al., EMBO J. 7:3745 (1988); see also Lefranc et al., Dev. Comp. Immunol. 27:55 (2003)). In some embodiments, CDR-3 is the primary CDR responsible for antigen binding or specificity, or the most important of the three CDRs on a given TCR variable region for antigen recognition and / or interaction with the processed peptide portion of a peptide-MHC complex. In some circumstances, CDR-1 of the alpha chain can interact with the N-terminal portion of a particular antigenic peptide. In some circumstances, CDR-1 of the beta chain can interact with the C-terminal portion of a peptide. In some circumstances, CDR-2 is the most strongly contributing or primary CDR responsible for interaction with or recognition of the MHC portion of an MHC-peptide complex. In some embodiments, the variable region of the beta chain can contain an additional hypervariable region (e.g., CDR4 or HVR4), which is generally involved in superantigen binding and not antigen recognition (Kotb (1995) Clinical Microbiology Reviews 8:411-426).

[0070] In some embodiments, the α and / or β chains of the TCR, or the γ and / or δ chains of the TCR, may also contain a constant domain, a transmembrane domain, and / or a short cytoplasmic tail (see, e.g., Janeway et al., "Immunobiology: The Immune System in Health and Disease," 3rd ed., Current Biology Publications, 4:33, 1997). In some aspects, each chain (e.g., alpha or beta) of the TCR may have one N-terminal immunoglobulin variable domain, one immunoglobulin constant domain, a transmembrane region, and a short C-terminal cytoplasmic tail. In some embodiments, the TCR associates, e.g., via the cytoplasmic tail, with the invariant protein of the CD3 complex, which is involved in mediating signal transduction. In some cases, the structure allows the TCR to associate with other molecules, such as CD3 and its subunits. For example, a constant domain-containing TCR with a transmembrane region may anchor the protein to the cell membrane and associate with the invariant subunit of the CD3 signaling apparatus or complex. The intracellular tails of the CD3 signaling subunits (e.g., CD3γ, CD3δ, CD3ε, and CD3ζ chains) contain one or more immunoreceptor tyrosine-based activation motifs or ITAMs and are generally involved in the signaling capabilities of the TCR complex.

[0071] Various domains or regions of the TCR can be identified. In some cases, the exact location of a domain or region may vary depending on the particular structural or homology modeling or other characteristics used to describe a particular domain. It is understood that reference to amino acids, including particular sequences described as SEQ ID NOs, used to describe the domain organization of a TCR is for illustrative purposes and is not meant to limit the scope of the provided embodiments. In some cases, a particular domain (e.g., a variable domain or a constant domain) may be longer or shorter than a few amino acids (such as 1, 2, 3, or 4). In some embodiments, the residues of a TCR are known or can be identified according to the International Immunogenetics Information System (IMGT) numbering system (see, e.g., www.imgt.org; see also, Lefranc et al. (2003), Developmental and Comparative Immunology, Vol. 27(I); pp. 55-77; and The T Cell Factsbook, 2nd ed., Lefranc and LeFranc Academic Press, 2001). Using this system, the CDR-1 sequence within the TCR Vα and / or Vβ region optionally corresponds to amino acids located between residues 27-38 (inclusive), the CDR-2 sequence within the TCR Vα and / or Vβ region optionally corresponds to amino acids located between residues 56-65 (inclusive), and the CDR-3 sequence within the TCR Vα and / or Vβ region optionally corresponds to amino acids located between residues 105-117 (inclusive).

[0072] In some embodiments, some TCRs or antigen-binding fragments thereof provided herein bind to or recognize a hematopoietic-restricted minor histocompatibility antigen, such as HA-1, in the context of an MHC molecule. In some embodiments, some TCRs or antigen-binding fragments thereof provided herein recognize or bind an immunogenic (e.g., mismatched between the donor and recipient of an alloSCT) epitope or domain of HA-1, such as the immunogenic H peptide comprising the amino acid sequence VLHDDLLEA (SEQ ID NO: 354). In some embodiments, some TCRs or antigen-binding fragments thereof provided herein do not recognize or bind a non-immunogenic epitope or domain of HA-1, such as the non-immunogenic R peptide comprising the amino acid sequence VLRDDLLEA (SEQ ID NO: 355). In some embodiments, some TCRs or antigen-binding fragments thereof provided herein preferentially or selectively recognize or bind immunogenic (e.g., mismatched between donor and recipient of alloSCT) epitopes or domains of HA-1, such as the immunogenic H peptide comprising the amino acid sequence VLHDDLLEA (SEQ ID NO: 354), and some do not recognize or bind non-immunogenic epitopes or domains of HA-1, such as the non-immunogenic R peptide comprising the amino acid sequence VLRDDLLEA (SEQ ID NO: 355), or exhibit reduced affinity or selectivity for binding to non-immunogenic epitopes.

[0073] In some aspects, some of the TCRs or antigen-binding fragments thereof provided herein are HLA-A * Some TCRs or antigen-binding fragments thereof provided herein bind to or recognize an epitope of HA-1 complexed with an MHC molecule of a specific HLA type, such as 02:01, e.g., an immunogenic H peptide comprising the amino acid sequence VLHDDLLEA (SEQ ID NO: 354). * 02:06 or B *Some bind to or recognize epitopes of HA-1 complexed with MHC molecules of specific HLA types, such as 40:01.

[0074] In some embodiments, the TCRs provided herein are full-length TCRs. In some embodiments, the TCRs provided herein are dimeric TCRs (dTCRs). In some embodiments, the TCRs provided herein are single-chain TCRs (sc-TCRs). The TCRs provided herein can be in cell-associated or soluble form. In some embodiments, the TCRs provided herein are cell-associated forms that are expressed on the surface of a cell (e.g., a T cell, such as a T cell engineered to lack expression of an endogenous TCR).

[0075] In some embodiments, the TCRs provided herein are scTCRs, which are single-chain amino acids containing an α chain and a β chain capable of binding to an MHC-peptide complex. Typically, scTCRs can be produced as described elsewhere. See, e.g., WO 96 / 13593, WO 96 / 18105, WO 99 / 18129, WO 04 / 033685, WO 2006 / 037960, WO 2011 / 044186; U.S. Patent No. 7,569,664; and Schlueter, CJ et al., J. Mol. Biol. 256:859 (1996).

[0076] C. Exemplary Variable Domains Provided herein are TCRs or antigen-binding fragments thereof that recognize or bind, in the context of an MHC molecule, an epitope or region of a hematopoietic-restricted minor histocompatibility antigen, such as HA-1. In some embodiments, the HA-1 peptide is an immunogenic peptide (an allele of HA-1 that is mismatched between the donor and recipient of alloSCT). Exemplary sequences of HA-1-specific TCRs (e.g., CDRs, Vα and / or Vβ, or Vγ and / or Vδ, and constant region sequences) are provided.

[0077] In some embodiments, the TCRs or antigen-binding fragments thereof provided herein bind to or recognize an immunogenic HA-1 allele displayed on the surface of leukemia cells in an alloSCT recipient. In some aspects, the cytotoxic activity of T cells expressing an anti-HA-1 TCR is stimulated upon contact of the T cells with a target cell that presents or expresses an antigen, such as an immunogenic HA-1 peptide. In some embodiments, some of the provided TCRs or antigen-binding fragments thereof provided herein bind to or recognize a peptide epitope of HA-1 (e.g., a peptide epitope of an immunogenic allele of HA-1) in the context of an MHC, such as a particular MHC or a particular HLA subtype.

[0078] Among such TCRs or antigen-binding fragments thereof are TCRs or antigen-binding fragments thereof that contain either the Vα and Vβ regions, or the Vγ and Vδ regions, the sequences individually described, or a sufficient antigen-binding portion of such a sequence. In some embodiments, the provided TCRs or antigen-binding fragments thereof (e.g., anti-HA-1 TCRs) contain a Vα region sequence or a Vγ region sequence, or a sufficient antigen-binding portion thereof, that contains CDR-1, CDR-2, and / or CDR-3 described herein. In some embodiments, the provided TCRs or antigen-binding fragments thereof (e.g., anti-HA-1 TCRs) contain a Vβ region sequence or a Vδ region sequence, or a sufficient antigen-binding portion thereof, that contains CDR-1, CDR-2, and / or CDR-3 described herein. In some embodiments, the TCR or antigen-binding fragment thereof (e.g., an anti-HA-1 TCR) contains a Vα or Vγ region sequence containing CDR-1, CDR-2, and / or CDR-3 described herein, and contains a Vβ or Vδ region sequence containing CDR-1, CDR-2, and / or CDR-3 described herein. Also provided are TCRs having sequences that are at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to such sequences.

[0079] In some embodiments, the TCRs or antigen-binding fragments thereof provided herein are selected from the group consisting of SEQ ID NOs: 3, 21, 37, 51, 65, 78, 92, 106, 120, 136, 152, 166, 180, 194, 208, 224, 238, 252, 268, 278, 359, 369, 379, 389, 399, 409, 419, 429, 439, 449, 459, 460, 461 , 462, 463, 464, 470, 471, 472, 473, 474, 476, 477, and 480, or a sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such a sequence. In some aspects, the TCRs or antigen-binding fragments thereof provided herein contain a Vα or Vγ region that contains a CDR-3 comprising an amino acid sequence set forth in any of SEQ ID NOs: 4, 22, 38, 52, 66, 79, 93, 107, 121, 137, 153, 167, 181, 195, 209, 225, 239, 253, 269, 279, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, and 481, or a sequence that is at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to such a sequence.

[0080] In some embodiments, the Vα or Vγ region contains a CDR-1 comprising an amino acid sequence set forth in any of SEQ ID NOs: 1, 19, 35, 76, 134, 150, 222, and 266, or a sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such a sequence. In some embodiments, the Vα or Vγ region contains a CDR-1 contained within an amino acid sequence set forth in any of SEQ ID NOs: 4, 22, 38, 52, 66, 79, 93, 107, 121, 137, 153, 167, 181, 195, 209, 225, 239, 253, 269, 279, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, and 481, or a sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such a sequence. In some embodiments, the Vα or Vγ region contains a CDR-2 comprising an amino acid sequence set forth in any of SEQ ID NOs: 2, 20, 36, 77, 135, 151, 223, and 267, or a sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such a sequence. In some embodiments, the Vα or Vγ region contains a CDR-2 contained within an amino acid sequence set forth in any of SEQ ID NOs: 4, 22, 38, 52, 66, 79, 93, 107, 121, 137, 153, 167, 181, 195, 209, 225, 239, 253, 269, 279, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, and 481, or a sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such a sequence.

[0081] In some examples, the TCRs or antigen-binding fragments thereof provided herein contain a Vβ region or Vδ region that contains a CDR-3 comprising an amino acid sequence set forth in any of SEQ ID NOs: 11, 27, 43, 57, 84, 98, 112, 126, 142, 158, 172, 186, 200, 214, 230, 244, 258, 284, 363, 373, 383, 393, 403, 413, 423, 433, 443, 453, 465, 466, 467, 468, 469, 475, 478, 479, and 484, or a sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such a sequence. In some embodiments, the TCRs or antigen-binding fragments thereof provided herein contain a Vβ or Vδ region that contains a CDR-3 contained within an amino acid sequence set forth in any of SEQ ID NOs: 12, 28, 44, 58, 85, 99, 113, 127, 143, 159, 173, 187, 201, 215, 231, 245, 259, 285, 364, 374, 384, 394, 404, 414, 424, 434, 444, 454, and 485, or a sequence that is at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to such a sequence.

[0082] In some examples, the Vβ region or Vδ region contains a CDR-1 comprising the amino acid sequence set forth in SEQ ID NO: 9, or a sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such a sequence. In some embodiments, the Vβ or Vδ region contains a CDR-1 contained within an amino acid sequence set forth in any of SEQ ID NOs: 12, 28, 44, 58, 85, 99, 113, 127, 143, 159, 173, 187, 201, 215, 231, 245, 259, 285, 364, 374, 384, 394, 404, 414, 424, 434, 444, 454, and 485, or a sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such a sequence. In some embodiments, the Vβ or Vδ region contains a CDR-2 comprising the amino acid sequence set forth in SEQ ID NO: 10, or a sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such a sequence. In some embodiments, the Vβ or Vδ region contains a CDR-2 contained within an amino acid sequence set forth in any of SEQ ID NOs: 12, 28, 44, 58, 85, 99, 113, 127, 143, 159, 173, 187, 201, 215, 231, 245, 259, 285, 364, 374, 384, 394, 404, 414, 424, 434, 444, 454, and 485, or a sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such a sequence.

[0083] In some embodiments, the Vα or Vγ region contains SEQ ID NO: 4, 22, 38, 52, 66, 79, 93, 107, 121, 137, 153, 167, 181, 195, 209, 225, 239, 253, 269, 279, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, and 481, or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some examples, the Vβ or Vδ region contains SEQ ID NOs: 12, 28, 44, 58, 85, 99, 113, 127, 143, 159, 173, 187, 201, 215, 231, 245, 259, 285, 364, 374, 384, 394, 404, 414, 424, 434, 444, 454, and 485, or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the TCR contains an alpha chain comprising either such a Vα or Vγ region sequence and either such a Vβ or Vδ region sequence.

[0084] In one embodiment, a TCR or antigen-binding fragment thereof provided herein having the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise an alpha chain (or gamma chain) having a CDR-1 having the amino acid sequence set forth in SEQ ID NO: 1 (or a variant of SEQ ID NO: 1 with one or two amino acid modifications), a CDR-2 having the amino acid sequence set forth in SEQ ID NO: 2 (or a variant of SEQ ID NO: 2 with one or two amino acid modifications), and a CDR-3 having the amino acid sequence set forth in SEQ ID NO: 3 (or a variant of SEQ ID NO: 3 with one or two amino acid modifications); and a beta chain (or delta chain) having a CDR-1 having the amino acid sequence set forth in SEQ ID NO: 9 (or a variant of SEQ ID NO: 9 with one or two amino acid modifications), a CDR-2 having the amino acid sequence set forth in SEQ ID NO: 10 (or a variant of SEQ ID NO: 10 with one or two amino acid modifications), and a CDR-3 having the amino acid sequence set forth in SEQ ID NO: 11 (or a variant of SEQ ID NO: 11 with one or two amino acid modifications). Examples of such TCRs that have these CDRs in the context of an MHC molecule and are capable of binding to a peptide epitope of the minor histocompatibility antigen HA-1 include, but are not limited to, TCR A.

[0085] In some cases, an alpha chain (or gamma chain) having the ability to bind, in the context of an MHC molecule, to a peptide epitope of the minor histocompatibility antigen HA-1 and having a CDR-1 having the amino acid sequence set forth in SEQ ID NO: 1 (or a variant of SEQ ID NO: 1 with one or two amino acid modifications), a CDR-2 having the amino acid sequence set forth in SEQ ID NO: 2 (or a variant of SEQ ID NO: 2 with one or two amino acid modifications), and a CDR-3 having the amino acid sequence set forth in SEQ ID NO: 3 (or a variant of SEQ ID NO: 3 with one or two amino acid modifications). The TCRs or antigen-binding fragments thereof provided herein having a beta chain (or delta chain) having a CDR-1 having the amino acid sequence set forth in SEQ ID NO:9 (or a variant of SEQ ID NO:9 with one or two amino acid modifications), a CDR-2 having the amino acid sequence set forth in SEQ ID NO:10 (or a variant of SEQ ID NO:10 with one or two amino acid modifications), and a CDR-3 having the amino acid sequence set forth in SEQ ID NO:11 (or a variant of SEQ ID NO:11 with one or two amino acid modifications) may comprise any suitable framework region.For example, such a TCR or antigen-binding fragment thereof may comprise: framework region 1 having the entire amino acid sequence set forth in SEQ ID NO:4 upstream of the amino acid sequence of SEQ ID NO:1 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications); framework region 2 having the entire amino acid sequence set forth in SEQ ID NO:4 between the amino acid sequence of SEQ ID NO:1 and SEQ ID NO:2 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications); framework region 3 having the entire amino acid sequence set forth in SEQ ID NO:4 between the amino acid sequence of SEQ ID NO:2 and SEQ ID NO:3 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications); and framework region 4 having the entire amino acid sequence set forth in SEQ ID NO:4 downstream of the amino acid sequence of SEQ ID NO:3 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications). and a beta strand comprising: a lufa strand; and a beta strand comprising: a framework region 1 having the entire amino acid sequence set forth in SEQ ID NO: 12 upstream of the amino acid sequence of SEQ ID NO: 9 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid modifications); a framework region 2 having the entire amino acid sequence set forth in SEQ ID NO: 12 between the amino acid sequence of SEQ ID NO: 9 and SEQ ID NO: 10 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid modifications); a framework region 3 having the entire amino acid sequence set forth in SEQ ID NO: 12 between the amino acid sequence of SEQ ID NO: 10 and SEQ ID NO: 11 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid modifications); and a framework region 4 having the entire amino acid sequence set forth in SEQ ID NO: 12 downstream of the amino acid sequence of SEQ ID NO: 11 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid modifications).

[0086] In some cases, a TCR or antigen-binding fragment thereof provided herein that has the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise an alpha chain comprising an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 4, and a beta chain comprising an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 12. For example, a TCR or antigen-binding fragment thereof provided herein can comprise an alpha chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 4, and a beta chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 12. In some cases, a TCR or antigen-binding fragment thereof provided herein can comprise (a) an alpha chain comprising an amino acid sequence having 100 percent identity to the amino acid sequence set forth in SEQ ID NO:4, and (b) a beta chain comprising an amino acid sequence having 100 percent identity to the amino acid sequence set forth in SEQ ID NO:12.

[0087] In some cases, a TCR or antigen-binding fragment thereof provided herein that has the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise: (a) an alpha chain comprising an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:4 (with the proviso that the alpha chain comprises the amino acid sequences set forth in SEQ ID NOs:1, 2, and 3); and (b) a beta chain comprising an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO:12 (with the proviso that the beta chain comprises the amino acid sequences set forth in SEQ ID NOs:9, 10, and 11). For example, a TCR or antigen-binding fragment thereof provided herein can include (a) an alpha chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO:4 (with the proviso that the alpha chain comprises the amino acid sequence set forth in SEQ ID NOs:1, 2, and 3); and (b) a beta chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identity to the amino acid sequence set forth in SEQ ID NO:12 (with the proviso that the beta chain comprises the amino acid sequence set forth in SEQ ID NOs:9, 10, and 11).

[0088] In some cases, a TCR or antigen-binding fragment thereof provided herein that has the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise (a) an alpha chain having the amino acid sequence set forth in SEQ ID NO: 4, or the amino acid sequence set forth in SEQ ID NO: 4 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions); and (b) a beta chain having the amino acid sequence set forth in SEQ ID NO: 12, or the amino acid sequence set forth in SEQ ID NO: 12 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions). For example, a TCR or antigen-binding fragment thereof provided herein can (a) have the ability to bind, in the context of an MHC molecule, to a peptide epitope of the minor histocompatibility antigen HA-1; (b) can comprise an alpha chain having the amino acid sequence set forth in SEQ ID NO:4 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions), provided that the alpha chain includes the amino acid sequences set forth in SEQ ID NOs:1, 2, and 3; and (c) a beta chain having the amino acid sequence set forth in SEQ ID NO:12 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions), provided that the beta chain includes the amino acid sequences set forth in SEQ ID NOs:9, 10, and 11.

[0089] In one embodiment, a TCR or antigen-binding fragment thereof provided herein having the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise an alpha chain (or gamma chain) having a CDR-1 having the amino acid sequence set forth in SEQ ID NO: 19 (or a variant of SEQ ID NO: 19 with one or two amino acid modifications), a CDR-2 having the amino acid sequence set forth in SEQ ID NO: 20 (or a variant of SEQ ID NO: 20 with one or two amino acid modifications), and a CDR-3 having the amino acid sequence set forth in SEQ ID NO: 21 (or a variant of SEQ ID NO: 21 with one or two amino acid modifications); and a beta chain (or delta chain) having a CDR-1 having the amino acid sequence set forth in SEQ ID NO: 9 (or a variant of SEQ ID NO: 9 with one or two amino acid modifications), a CDR-2 having the amino acid sequence set forth in SEQ ID NO: 10 (or a variant of SEQ ID NO: 10 with one or two amino acid modifications), and a CDR-3 having the amino acid sequence set forth in SEQ ID NO: 27 (or a variant of SEQ ID NO: 27 with one or two amino acid modifications). Examples of such TCRs that have these CDRs in the context of an MHC molecule and are capable of binding to a peptide epitope of the minor histocompatibility antigen HA-1 include, but are not limited to, TCR B.

[0090] In some cases, the alpha chain (or gamma chain) has the ability to bind, in the context of an MHC molecule, to a peptide epitope of the minor histocompatibility antigen HA-1 and has a CDR-1 having the amino acid sequence set forth in SEQ ID NO: 19 (or a variant of SEQ ID NO: 19 with one or two amino acid modifications), a CDR-2 having the amino acid sequence set forth in SEQ ID NO: 20 (or a variant of SEQ ID NO: 20 with one or two amino acid modifications), and a CDR-3 having the amino acid sequence set forth in SEQ ID NO: 21 (or a variant of SEQ ID NO: 21 with one or two amino acid modifications). The TCRs or antigen-binding fragments thereof provided herein having a beta chain (or delta chain) having CDR-1 having the amino acid sequence set forth in SEQ ID NO:9 (or a variant of SEQ ID NO:9 with one or two amino acid modifications), CDR-2 having the amino acid sequence set forth in SEQ ID NO:10 (or a variant of SEQ ID NO:10 with one or two amino acid modifications), and CDR-3 having the amino acid sequence set forth in SEQ ID NO:27 (or a variant of SEQ ID NO:27 with one or two amino acid modifications) may comprise any suitable framework region.For example, such a TCR or antigen-binding fragment thereof may have a framework region 1 having the entire amino acid sequence set forth in SEQ ID NO:22 upstream of the amino acid sequence of SEQ ID NO:19 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid modifications), a framework region 2 having the entire amino acid sequence set forth in SEQ ID NO:22 between the amino acid sequences of SEQ ID NO:19 and SEQ ID NO:20 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid modifications). framework region 2 having the entire amino acid sequence set forth in SEQ ID NO:22 located between the amino acid sequences of SEQ ID NO:20 and SEQ ID NO:21 (or variants of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid modifications); framework region 3 having the entire amino acid sequence set forth in SEQ ID NO:22 located downstream of the amino acid sequence of SEQ ID NO:21 (or variants of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid modifications); and framework region 4 having the entire amino acid sequence set forth in SEQ ID NO:22 located downstream of the amino acid sequence of SEQ ID NO:21 (or variants of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid modifications). an alpha chain comprising: a framework region 1 having the entire amino acid sequence set forth in SEQ ID NO:28 upstream of the amino acid sequence of SEQ ID NO:9 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications); a framework region 2 having the entire amino acid sequence set forth in SEQ ID NO:28 between the amino acid sequences of SEQ ID NO:9 and SEQ ID NO:10 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications); and a beta strand comprising framework region 3 having the entire amino acid sequence set forth in SEQ ID NO:28 between the amino acid sequence of SEQ ID NO:27 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications), and framework region 4 having the entire amino acid sequence set forth in SEQ ID NO:28 downstream of the amino acid sequence of SEQ ID NO:27 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications).

[0091] In some cases, a TCR or antigen-binding fragment thereof provided herein that has the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise an alpha chain comprising an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 22, and a beta chain comprising an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 28. For example, a TCR or antigen-binding fragment thereof provided herein can comprise an alpha chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 22, and a beta chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 28. In some cases, a TCR or antigen-binding fragment thereof provided herein can comprise (a) an alpha chain comprising an amino acid sequence having 100 percent identity to the amino acid sequence set forth in SEQ ID NO: 22, and (b) a beta chain comprising an amino acid sequence having 100 percent identity to the amino acid sequence set forth in SEQ ID NO: 28.

[0092] In some cases, a TCR or antigen-binding fragment thereof provided herein that has the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise: (a) an alpha chain comprising an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 22 (with the proviso that the alpha chain comprises the amino acid sequences set forth in SEQ ID NOs: 19, 20, and 21); and (b) a beta chain comprising an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 28 (with the proviso that the beta chain comprises the amino acid sequences set forth in SEQ ID NOs: 9, 10, and 27). For example, a TCR or antigen-binding fragment thereof provided herein can include (a) an alpha chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 22 (with the proviso that the alpha chain comprises the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21); and (b) a beta chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 28 (with the proviso that the beta chain comprises the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 27).

[0093] In some cases, a TCR or antigen-binding fragment thereof provided herein that has the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise (a) an alpha chain having the amino acid sequence set forth in SEQ ID NO: 22, or the amino acid sequence set forth in SEQ ID NO: 22 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions); and (b) a beta chain having the amino acid sequence set forth in SEQ ID NO: 28, or the amino acid sequence set forth in SEQ ID NO: 28 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions). For example, a TCR or antigen-binding fragment thereof provided herein can (a) have the ability to bind, in the context of an MHC molecule, to a peptide epitope of the minor histocompatibility antigen HA-1; (b) can comprise an alpha chain having the amino acid sequence set forth in SEQ ID NO: 22 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions), with the proviso that the alpha chain includes the amino acid sequences set forth in SEQ ID NOs: 19, 20, and 21; and (c) a beta chain having the amino acid sequence set forth in SEQ ID NO: 28 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions), with the proviso that the beta chain includes the amino acid sequences set forth in SEQ ID NOs: 9, 10, and 27.

[0094] In one embodiment, a TCR or antigen-binding fragment thereof provided herein having the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise an alpha chain (or gamma chain) having a CDR-1 having the amino acid sequence set forth in SEQ ID NO: 35 (or a variant of SEQ ID NO: 35 with one or two amino acid modifications), a CDR-2 having the amino acid sequence set forth in SEQ ID NO: 36 (or a variant of SEQ ID NO: 36 with one or two amino acid modifications), and a CDR-3 having the amino acid sequence set forth in SEQ ID NO: 37 (or a variant of SEQ ID NO: 37 with one or two amino acid modifications); and a beta chain (or delta chain) having a CDR-1 having the amino acid sequence set forth in SEQ ID NO: 9 (or a variant of SEQ ID NO: 9 with one or two amino acid modifications), a CDR-2 having the amino acid sequence set forth in SEQ ID NO: 10 (or a variant of SEQ ID NO: 10 with one or two amino acid modifications), and a CDR-3 having the amino acid sequence set forth in SEQ ID NO: 43 (or a variant of SEQ ID NO: 43 with one or two amino acid modifications). Examples of such TCRs that have these CDRs in the context of an MHC molecule and are capable of binding to a peptide epitope of the minor histocompatibility antigen HA-1 include, but are not limited to, TCR C.

[0095] In some cases, the alpha chain (or gamma chain) has the ability to bind, in the context of an MHC molecule, to a peptide epitope of the minor histocompatibility antigen HA-1 and has a CDR-1 having the amino acid sequence set forth in SEQ ID NO: 35 (or a variant of SEQ ID NO: 35 with one or two amino acid modifications), a CDR-2 having the amino acid sequence set forth in SEQ ID NO: 36 (or a variant of SEQ ID NO: 36 with one or two amino acid modifications), and a CDR-3 having the amino acid sequence set forth in SEQ ID NO: 37 (or a variant of SEQ ID NO: 37 with one or two amino acid modifications). The TCRs or antigen-binding fragments thereof provided herein having a beta chain (or delta chain) having CDR-1 having the amino acid sequence set forth in SEQ ID NO:9 (or a variant of SEQ ID NO:9 with one or two amino acid modifications), CDR-2 having the amino acid sequence set forth in SEQ ID NO:10 (or a variant of SEQ ID NO:10 with one or two amino acid modifications), and CDR-3 having the amino acid sequence set forth in SEQ ID NO:43 (or a variant of SEQ ID NO:43 with one or two amino acid modifications) may comprise any suitable framework region.For example, such a TCR or antigen-binding fragment thereof may have a framework region 1 having the entire amino acid sequence set forth in SEQ ID NO: 38 upstream of the amino acid sequence of SEQ ID NO: 35 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid modifications), a framework region 2 having the entire amino acid sequence set forth in SEQ ID NO: 38 between the amino acid sequences of SEQ ID NO: 35 and SEQ ID NO: 36 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid modifications). framework region 2 having the entire amino acid sequence set forth in SEQ ID NO: 38 located between the amino acid sequences of SEQ ID NO: 36 and SEQ ID NO: 37 (or variants of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid modifications); and framework region 4 having the entire amino acid sequence set forth in SEQ ID NO: 38 located downstream of the amino acid sequence of SEQ ID NO: 37 (or variants of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid modifications). an alpha chain comprising: a framework region 1 having the entire amino acid sequence set forth in SEQ ID NO: 44 upstream of the amino acid sequence of SEQ ID NO: 9 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications); a framework region 2 having the entire amino acid sequence set forth in SEQ ID NO: 44 between the amino acid sequences of SEQ ID NO: 9 and SEQ ID NO: 10 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications); and a beta strand comprising framework region 3 having the entire amino acid sequence set forth in SEQ ID NO: 44 between the amino acid sequence of SEQ ID NO: 43 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications), and framework region 4 having the entire amino acid sequence set forth in SEQ ID NO: 44 downstream of the amino acid sequence of SEQ ID NO: 43 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications).

[0096] In some cases, a TCR or antigen-binding fragment thereof provided herein that has the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise an alpha chain comprising an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 38, and a beta chain comprising an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 44. For example, a TCR or antigen-binding fragment thereof provided herein can comprise an alpha chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 38, and a beta chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 44. In some cases, a TCR or antigen-binding fragment thereof provided herein can comprise (a) an alpha chain comprising an amino acid sequence having 100 percent identity to the amino acid sequence set forth in SEQ ID NO: 38, and (b) a beta chain comprising an amino acid sequence having 100 percent identity to the amino acid sequence set forth in SEQ ID NO: 44.

[0097] In some cases, a TCR or antigen-binding fragment thereof provided herein that has the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise: (a) an alpha chain comprising an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 38 (with the proviso that the alpha chain comprises the amino acid sequences set forth in SEQ ID NOs: 35, 36, and 37); and (b) a beta chain comprising an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 44 (with the proviso that the beta chain comprises the amino acid sequences set forth in SEQ ID NOs: 9, 10, and 43). For example, a TCR or antigen-binding fragment thereof provided herein can include (a) an alpha chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 38 (with the proviso that the alpha chain comprises the amino acid sequence set forth in SEQ ID NOs: 35, 36, and 37); and (b) a beta chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 44 (with the proviso that the beta chain comprises the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 43).

[0098] In some cases, a TCR or antigen-binding fragment thereof provided herein having the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise (a) an alpha chain having the amino acid sequence set forth in SEQ ID NO: 38, or the amino acid sequence set forth in SEQ ID NO: 38 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions); and (b) a beta chain having the amino acid sequence set forth in SEQ ID NO: 44, or the amino acid sequence set forth in SEQ ID NO: 44 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions). For example, a TCR or antigen-binding fragment thereof provided herein can (a) have the ability to bind, in the context of an MHC molecule, to a peptide epitope of the minor histocompatibility antigen HA-1; (b) can comprise an alpha chain having the amino acid sequence set forth in SEQ ID NO: 38 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions), with the proviso that the alpha chain includes the amino acid sequences set forth in SEQ ID NOs: 35, 36, and 37; and (c) a beta chain having the amino acid sequence set forth in SEQ ID NO: 44 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions), with the proviso that the beta chain includes the amino acid sequences set forth in SEQ ID NOs: 9, 10, and 43.

[0099] In one embodiment, a TCR or antigen-binding fragment thereof provided herein having the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise an alpha chain (or gamma chain) having a CDR-1 having the amino acid sequence set forth in SEQ ID NO: 1 (or a variant of SEQ ID NO: 1 with one or two amino acid modifications), a CDR-2 having the amino acid sequence set forth in SEQ ID NO: 2 (or a variant of SEQ ID NO: 2 with one or two amino acid modifications), and a CDR-3 having the amino acid sequence set forth in SEQ ID NO: 51 (or a variant of SEQ ID NO: 51 with one or two amino acid modifications); and a beta chain (or delta chain) having a CDR-1 having the amino acid sequence set forth in SEQ ID NO: 9 (or a variant of SEQ ID NO: 9 with one or two amino acid modifications), a CDR-2 having the amino acid sequence set forth in SEQ ID NO: 10 (or a variant of SEQ ID NO: 10 with one or two amino acid modifications), and a CDR-3 having the amino acid sequence set forth in SEQ ID NO: 57 (or a variant of SEQ ID NO: 57 with one or two amino acid modifications). Examples of such TCRs that have these CDRs in the context of an MHC molecule and are capable of binding to a peptide epitope of the minor histocompatibility antigen HA-1 include, but are not limited to, TCR D.

[0100] In some cases, an alpha chain (or gamma chain) that has the ability to bind, in the context of an MHC molecule, to a peptide epitope of the minor histocompatibility antigen HA-1 and has a CDR-1 having the amino acid sequence set forth in SEQ ID NO: 1 (or a variant of SEQ ID NO: 1 with one or two amino acid modifications), a CDR-2 having the amino acid sequence set forth in SEQ ID NO: 2 (or a variant of SEQ ID NO: 2 with one or two amino acid modifications), and a CDR-3 having the amino acid sequence set forth in SEQ ID NO: 51 (or a variant of SEQ ID NO: 51 with one or two amino acid modifications). and a beta chain (or delta chain) having CDR-1 having the amino acid sequence set forth in SEQ ID NO:9 (or a variant of SEQ ID NO:9 with one or two amino acid modifications), CDR-2 having the amino acid sequence set forth in SEQ ID NO:10 (or a variant of SEQ ID NO:10 with one or two amino acid modifications), and CDR-3 having the amino acid sequence set forth in SEQ ID NO:57 (or a variant of SEQ ID NO:57 with one or two amino acid modifications), may comprise any suitable framework region.For example, such a TCR or antigen-binding fragment thereof comprises: framework region 1 having the entire amino acid sequence set forth in SEQ ID NO:52 upstream of the amino acid sequence of SEQ ID NO:1 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications); framework region 2 having the entire amino acid sequence set forth in SEQ ID NO:52 between the amino acid sequence of SEQ ID NO:1 and SEQ ID NO:2 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications); framework region 3 having the entire amino acid sequence set forth in SEQ ID NO:52 between the amino acid sequence of SEQ ID NO:2 and SEQ ID NO:51 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications); and framework region 4 having the entire amino acid sequence set forth in SEQ ID NO:52 downstream of the amino acid sequence of SEQ ID NO:51 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications). alpha chain and framework region 1 having the entire amino acid sequence set forth in SEQ ID NO:58 upstream of the amino acid sequence of SEQ ID NO:9 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications); framework region 2 having the entire amino acid sequence set forth in SEQ ID NO:58 between the amino acid sequences of SEQ ID NO:9 and SEQ ID NO:10 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications); and a beta strand comprising framework region 3 having the entire amino acid sequence set forth in SEQ ID NO: 58 located between the amino acid sequence of SEQ ID NO: 57 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications), and framework region 4 having the entire amino acid sequence set forth in SEQ ID NO: 58 located downstream of the amino acid sequence of SEQ ID NO: 57 (or a variant of that sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications).

[0101] In some cases, a TCR or antigen-binding fragment thereof provided herein that has the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise an alpha chain comprising an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 52, and a beta chain comprising an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 58. For example, a TCR or antigen-binding fragment thereof provided herein can comprise an alpha chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 52, and a beta chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 58. In some cases, a TCR or antigen-binding fragment thereof provided herein can comprise (a) an alpha chain comprising an amino acid sequence having 100 percent identity to the amino acid sequence set forth in SEQ ID NO: 52, and (b) a beta chain comprising an amino acid sequence having 100 percent identity to the amino acid sequence set forth in SEQ ID NO: 58.

[0102] In some cases, a TCR or antigen-binding fragment thereof provided herein that has the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise: (a) an alpha chain comprising an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 52 (wherein the alpha chain comprises the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 51); and (b) a beta chain comprising an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 58 (wherein the beta chain comprises the amino acid sequences set forth in SEQ ID NOs: 9, 10, and 57). For example, a TCR or antigen-binding fragment thereof provided herein can include (a) an alpha chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 52 (with the proviso that the alpha chain comprises the amino acid sequence set forth in SEQ ID NOs: 1, 2, and 51); and (b) a beta chain comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 58 (with the proviso that the beta chain comprises the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 57).

[0103] In some cases, a TCR or antigen-binding fragment thereof provided herein that has the ability to bind to a peptide epitope of the minor histocompatibility antigen HA-1 in the context of an MHC molecule can comprise (a) an alpha chain having the amino acid sequence set forth in SEQ ID NO: 52, or the amino acid sequence set forth in SEQ ID NO: 52 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions); and (b) a beta chain having the amino acid sequence set forth in SEQ ID NO: 58, or the amino acid sequence set forth in SEQ ID NO: 58 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions). For example, a TCR or antigen-binding fragment thereof provided herein can (a) have the ability to bind, in the context of an MHC molecule, to a peptide epitope of the minor histocompatibility antigen HA-1; (b) can comprise an alpha chain having the amino acid sequence set forth in SEQ ID NO: 52 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions), provided that the alpha chain includes the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 51; and (c) a beta chain having the amino acid sequence set forth in SEQ ID NO: 58 with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications (e.g., amino acid substitutions, amino acid deletions, and / or amino acid additions), provided that the beta chain includes the amino acid sequences set forth in SEQ ID NOs: 9, 10, and 57.

[0104] In some embodiments, the TCRs or antigen-binding fragments thereof provided herein comprise CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 1, 2, and 3, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 19, 20, and 21, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 35, 36, and 37, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 1, 2, and 51, respectively; and CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 1, 2, and 65, respectively. CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 76, 77, and 78, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 19, 20, and 92, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 76, 77, and 106, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 35, 36, and 120, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 134, 135, and 136, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 150, 151, and 152, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 35, 36, and 166, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 35, 36, and 180, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 76, 77, and 194, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 76, 77, and 208, respectively; and CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 222, 223, and 224. 4, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 76, 77, and 238, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 19, 20, and 252, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 266, 267, and 268, respectively; or Vα or Vγ regions containing CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 19, 20, and 278, respectively.In some embodiments, the TCRs or antigen-binding fragments thereof provided herein comprise CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 9, 10, 11, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, 27, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, 43, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, 57, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, and 84, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, and 98, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, and 112, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, and 126, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, and 142, respectively. CDR-3; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, and 158, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, and 172, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, and 186, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, and 200, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, and 214, respectively; SEQ ID NOs: 9, 10, and 2 or Vβ or Vδ regions containing CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, and 244, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, and 258, respectively; CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, and 158, respectively; or CDR-1, CDR-2, and CDR-3 comprising SEQ ID NOs: 9, 10, and 284, respectively. Also provided are TCRs having sequences that are at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to such sequences.

[0105] In some embodiments, a TCR or antigen-binding fragment thereof provided herein comprises a Vα region or Vγ region containing CDR-1, CDR-2, and CDR-3, comprising the CDR-1, CDR-2, and CDR-3 amino acid sequences respectively set forth in Table 1, such as in each row therein, and a Vβ region or Vδ region containing CDR-1, CDR-2, and CDR-3, comprising the CDR-1, CDR-2, and CDR-3 amino acid sequences respectively set forth in Table 1, such as in each row therein. In some embodiments, the TCRs or antigen-binding fragments thereof provided herein comprise a Vα or Vγ region containing CDR-1, CDR-2, and CDR-3, which include the CDR-1, CDR-2, and CDR-3 amino acid sequences contained within the Vα or Vγ region amino acid sequences, respectively, set forth in Table 1, e.g., in the individual rows therein, and a Vβ or Vδ region containing CDR-1, CDR-2, and CDR-3, which include the CDR-1, CDR-2, and CDR-3 amino acid sequences contained within the Vα or Vγ region amino acid sequences, respectively, set forth in Table 1, e.g., in the individual rows therein. Also provided are TCRs containing sequences that are at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to such sequences. Exemplary TCRs containing such CDRs, or modified versions thereof described elsewhere herein, are also set forth in Table 1, e.g., in the individual rows therein.

[0106] [Table 1]

[0107] In some examples, the TCRs or antigen-binding fragments thereof provided herein comprise an alpha chain (or gamma chain) comprising a set of three CDRs (e.g., CDR-1, CDR-2, and CDR-3) as described in Table 1 (e.g., SEQ ID NOs: 1-3; SEQ ID NOs: 19-21; SEQ ID NOs: 35-37; SEQ ID NOs: 1, 2, and 51; SEQ ID NOs: 1, 2, and 65; SEQ ID NOs: 76-78; SEQ ID NOs: 19, 20, and 92; SEQ ID NO: 7). SEQ ID NOs: 6, 77, and 106; SEQ ID NOs: 35, 36, and 120; SEQ ID NOs: 134 to 136; SEQ ID NOs: 150 to 152; SEQ ID NOs: 35, 36, and 166; SEQ ID NOs: 35, 36, and 180; SEQ ID NOs: 76, 77, and 194; SEQ ID NOs: 76, 77, and 208; SEQ ID NOs: 222 to 224; SEQ ID NOs: 76, 77, and 238; SEQ ID NOs: 19, 20, and 252; SEQ ID NOs: 266 to 268; or SEQ ID NOs: 19, 20, and 278) The antibody fragments are designed to include a β chain (or δ chain) containing a set of three CDRs (e.g., CDR-1, CDR-2, and CDR-3) as described in Table 1, and a beta chain (or delta chain) containing a set of CDRs (e.g., CDR-1, CDR-2, and CDR-3) as described in Table 1 (e.g., SEQ ID NOs: 9-10; SEQ ID NOs: 9, 10, and 27; SEQ ID NOs: 9, 10, and 43; SEQ ID NOs: 9, 10, and 57; SEQ ID NOs: 9, 10, and 84; SEQ ID NOs: 9, 10, and 98; SEQ ID NOs: 9, 10, and 10). 12; SEQ ID NOs: 9, 10, and 126; SEQ ID NOs: 9, 10, and 142; SEQ ID NOs: 9, 10, and 158; SEQ ID NOs: 9, 10, and 172; SEQ ID NOs: 9, 10, and 186; SEQ ID NOs: 9, 10, and 200; SEQ ID NOs: 9, 10, and 214; SEQ ID NOs: 9, 10, and 230; SEQ ID NOs: 9, 10, and 244; SEQ ID NOs: 9, 10, and 258; or SEQ ID NOs: 9, 10, and 284).

[0108] In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO: 1, a CDR-2 comprising SEQ ID NO: 2, and a CDR-3 comprising SEQ ID NO: 3, and the Vβ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 11. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO: 19, a CDR-2 comprising SEQ ID NO: 20, and a CDR-3 comprising SEQ ID NO: 21, and the Vβ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 27. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO: 35, a CDR-2 comprising SEQ ID NO: 36, and a CDR-3 comprising SEQ ID NO: 37, and the Vβ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 43. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO: 1, a CDR-2 comprising SEQ ID NO: 2, and a CDR-3 comprising SEQ ID NO: 51, and the Vβ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 57. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO: 1, a CDR-2 comprising SEQ ID NO: 2, and a CDR-3 comprising SEQ ID NO: 65, and the Vβ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 57. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO: 76, a CDR-2 comprising SEQ ID NO: 77, and a CDR-3 comprising SEQ ID NO: 78, and the Vβ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 84. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO: 19, a CDR-2 comprising SEQ ID NO: 20, and a CDR-3 comprising SEQ ID NO: 92, and the Vβ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 98.In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO:76, a CDR-2 comprising SEQ ID NO:77, and a CDR-3 comprising SEQ ID NO:106, and the Vβ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:112. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO:35, a CDR-2 comprising SEQ ID NO:36, and a CDR-3 comprising SEQ ID NO:120, and the Vβ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:126. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO:134, a CDR-2 comprising SEQ ID NO:135, and a CDR-3 comprising SEQ ID NO:136, and the Vβ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:142. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO: 150, a CDR-2 comprising SEQ ID NO: 151, and a CDR-3 comprising SEQ ID NO: 152, and the Vβ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 158. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO: 35, a CDR-2 comprising SEQ ID NO: 36, and a CDR-3 comprising SEQ ID NO: 166, and the Vβ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 172. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO: 35, a CDR-2 comprising SEQ ID NO: 36, and a CDR-3 comprising SEQ ID NO: 180, and the Vβ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 186. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO: 76, a CDR-2 comprising SEQ ID NO: 77, and a CDR-3 comprising SEQ ID NO: 194, and the Vβ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 200.In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO:76, a CDR-2 comprising SEQ ID NO:77, and a CDR-3 comprising SEQ ID NO:208, and the Vβ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:214. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO:222, a CDR-2 comprising SEQ ID NO:223, and a CDR-3 comprising SEQ ID NO:224, and the Vβ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:230. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO:76, a CDR-2 comprising SEQ ID NO:77, and a CDR-3 comprising SEQ ID NO:238, and the Vβ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:244. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO: 19, a CDR-2 comprising SEQ ID NO: 20, and a CDR-3 comprising SEQ ID NO: 252, and the Vβ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 258. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO: 266, a CDR-2 comprising SEQ ID NO: 267, and a CDR-3 comprising SEQ ID NO: 268, and the Vβ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 158. In some of any of the embodiments provided herein, the Vα region comprises a CDR-1 comprising SEQ ID NO: 19, a CDR-2 comprising SEQ ID NO: 20, and a CDR-3 comprising SEQ ID NO: 278, and the Vβ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 284.

[0109] In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO:4, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO:12. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO:22, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO:28. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 38, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 44. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 52, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 58. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3, each comprising the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 66, and the Vβ region comprises CDR-1, CDR-2, and CDR-3, each comprising the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 58.In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO:79, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO:85. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO:93, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO:99. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 107, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 113. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 121, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 127. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3, each comprising the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 137, and the Vβ region comprises CDR-1, CDR-2, and CDR-3, each comprising the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 143.In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 153, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 159. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 167, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 173. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 181, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 187. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 195, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 201. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3, each comprising the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 209, and the Vβ region comprises CDR-1, CDR-2, and CDR-3, each comprising the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 215.In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 225, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 231. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 239, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 245. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 253, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 259. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 269, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 159. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3, each comprising the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 279, and the Vβ region comprises CDR-1, CDR-2, and CDR-3, each comprising the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 285.In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 360, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 364. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 370, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 374. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 380, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 384. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 390, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 394. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3, each comprising the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 400, and the Vβ region comprises CDR-1, CDR-2, and CDR-3, each comprising the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 404.In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 410, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 414. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 420, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 424. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 430, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 434. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 440, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 444. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 450, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 454. In some of any of the embodiments provided herein, the Vα region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vα region sequence of SEQ ID NO: 481, and the Vβ region comprises CDR-1, CDR-2, and CDR-3 that respectively comprise the CDR-1, CDR-2, and CDR-3 contained within the Vβ region sequence of SEQ ID NO: 485.

[0110] In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO:4, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO:12, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO:22, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO:28, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO:38, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO:44, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO:52, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO:58, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO:66, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO:58, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO:79, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO:85, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO:93, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO:99, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO:107, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO:113, or a sequence having at least 90% sequence identity thereto.In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 121, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 127, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 137, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 143, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 153, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 159, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 167, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 173, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 181, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 187, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 195, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 201, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 209, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 215, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 225, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 231, or a sequence having at least 90% sequence identity thereto.In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO:239, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO:245, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO:253, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO:259, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO:269, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO:159, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO:279, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO:285, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 360, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 364, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 370, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 374, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 380, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 384, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 390, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 394, or a sequence having at least 90% sequence identity thereto.In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 400, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 404, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 410, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 414, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 420, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 424, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 430, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 434, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 440, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 444, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 450, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 454, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the Vα region comprises SEQ ID NO: 481, or a sequence having at least 90% sequence identity thereto, and the Vβ region comprises SEQ ID NO: 485, or a sequence having at least 90% sequence identity thereto.

[0111] In some of the embodiments provided herein, the Vα region comprises SEQ ID NO:4 and the Vβ region comprises SEQ ID NO:12. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO:22 and the Vβ region comprises SEQ ID NO:28. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO:38 and the Vβ region comprises SEQ ID NO:44. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO:52 and the Vβ region comprises SEQ ID NO:58. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO:66 and the Vβ region comprises SEQ ID NO:58. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO:79 and the Vβ region comprises SEQ ID NO:85. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO:93 and the Vβ region comprises SEQ ID NO:99. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO:107 and the Vβ region comprises SEQ ID NO:113. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 121 and the Vβ region comprises SEQ ID NO: 127. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 137 and the Vβ region comprises SEQ ID NO: 143. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 153 and the Vβ region comprises SEQ ID NO: 159. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 167 and the Vβ region comprises SEQ ID NO: 173. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 181 and the Vβ region comprises SEQ ID NO: 187. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 195 and the Vβ region comprises SEQ ID NO: 201. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 209 and the Vβ region comprises SEQ ID NO: 215. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 225 and the Vβ region comprises SEQ ID NO: 231.In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 239 and the Vβ region comprises SEQ ID NO: 245. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 253 and the Vβ region comprises SEQ ID NO: 259. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 269 and the Vβ region comprises SEQ ID NO: 159. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 279 and the Vβ region comprises SEQ ID NO: 285. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 360 and the Vβ region comprises SEQ ID NO: 364. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 370 and the Vβ region comprises SEQ ID NO: 374. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 380 and the Vβ region comprises SEQ ID NO: 384. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 390 and the Vβ region comprises SEQ ID NO: 394. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 400 and the Vβ region comprises SEQ ID NO: 404. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 410 and the Vβ region comprises SEQ ID NO: 414. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 420 and the Vβ region comprises SEQ ID NO: 424. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 430 and the Vβ region comprises SEQ ID NO: 434. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 440 and the Vβ region comprises SEQ ID NO: 444. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 450 and the Vβ region comprises SEQ ID NO: 454. In some of the embodiments provided herein, the Vα region comprises SEQ ID NO: 481 and the Vβ region comprises SEQ ID NO: 485.

[0112] D. Exemplary Constant Domains In some embodiments, the alpha chain of a TCR or antigen-binding fragment thereof provided herein further comprises an alpha constant (Cα) region or a portion thereof. In some aspects, the beta chain further comprises a beta constant (Cβ) region or a portion thereof. Thus, in some embodiments, a TCR provided herein (e.g., an anti-HA-1 TCR provided herein) or antigen-binding fragment thereof comprises an alpha chain comprising a Vα region and a Cα domain or a portion thereof, and / or a beta chain comprising a Vβ region and a Cβ domain or a portion thereof. In some embodiments, the gamma chain of a TCR or antigen-binding fragment thereof provided herein further comprises a gamma constant (Cγ) region or a portion thereof. In some aspects, the delta chain further comprises a delta constant (Cδ) region or a portion thereof. Thus, in some embodiments, a TCR provided herein (e.g., an anti-HA-1 TCR provided herein) or antigen-binding fragment thereof comprises a gamma chain comprising a Vγ region and a Cγ domain or a portion thereof, and / or a delta chain comprising a Vδ region and a Cδ domain or a portion thereof.

[0113] In some embodiments, the α and β chains, or the γ and δ chains, of the TCRs provided herein each further contain a constant domain. In some embodiments, the Cα and Cβ domains, or the Cγ and Cδ domains, are individually mammalian (e.g., human or mouse constant domains). In some embodiments, the constant domains are adjacent to the cell membrane. For example, in some cases, the extracellular portion of the TCR formed by the two chains contains two membrane-proximal constant domains and two membrane-distal variable domains, each of which contains a CDR.

[0114] In some aspects, provided herein are TCRs that contain human constant domains, such as an alpha chain containing a human Cα domain and a beta chain containing a human Cβ domain, or a gamma chain containing a human Cγ domain and a delta chain containing a human Cδ domain. In some embodiments, the provided TCRs are fully human. Among the TCRs provided are TCRs that contain human constant domains, e.g., fully human TCRs, whose expression and / or activity is unaffected or substantially unaffected by the presence of endogenous human TCRs, e.g., when expressed in human cells, e.g., human T cells, such as primary human T cells.

[0115] In some embodiments, each of the Cα and Cβ domains, or each of the Cγ and Cδ domains, is human. In some embodiments, Cα is encoded by the TRAC gene (IMGT nomenclature) or a variant thereof. In some embodiments, Cβ is encoded by the TRBC1 gene or the TRBC2 gene (IMGT nomenclature) or a variant thereof. In some embodiments, Cγ is encoded by the TRGC1 gene or the TRGC2 gene (IMGT nomenclature) or a variant thereof. In some embodiments, Cδ is encoded by the TRDC gene (IMGT nomenclature) or a variant thereof.

[0116] In some embodiments, the Cα domain or variant thereof has or comprises a sequence of amino acids set forth in SEQ ID NO: 294 or 296, or an amino acid sequence exhibiting at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 294 or 296. In some embodiments, the Cα domain has or comprises a sequence of amino acids set forth in SEQ ID NO: 294. In some embodiments, the Cα domain has or comprises a sequence of amino acids set forth in SEQ ID NO: 296. In some embodiments, the Cβ domain or variant thereof has or comprises a sequence of amino acids set forth in SEQ ID NO: 298 or 300, or a sequence of amino acids exhibiting at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 298 or 300. In some embodiments, the Cβ domain has or comprises a sequence of amino acids set forth in SEQ ID NO: 298. In some embodiments, the Cβ domain has or comprises a sequence of amino acids set forth in SEQ ID NO: 300. In some embodiments, the TCR comprises a Cα domain and a Cβ domain set forth in SEQ ID NOs: 294 and 298, respectively. In some embodiments, the TCR comprises a Cα domain and a Cβ domain set forth in SEQ ID NOs: 296 and 298, respectively. In some embodiments, the TCR comprises a Cα domain and a Cβ domain set forth in SEQ ID NOs: 294 and 300, respectively. In some embodiments, the TCR comprises the Cα and Cβ domains set forth in SEQ ID NOs: 296 and 300, respectively.

[0117] In some embodiments, the Cγ domain or variant thereof has or comprises a sequence of amino acids set forth in SEQ ID NO: 356 or 358, or an amino acid sequence exhibiting at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 356 or 357. In some embodiments, the Cγ domain has or comprises a sequence of amino acids set forth in SEQ ID NO: 356. In some embodiments, the Cγ domain has or comprises a sequence of amino acids set forth in SEQ ID NO: 357. In some embodiments, the Cδ domain or variant thereof has or comprises a sequence of amino acids set forth in SEQ ID NO: 358, or a sequence of amino acids exhibiting at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 358. In some embodiments, the TCR comprises a Cγ domain and a Cδ domain set forth in SEQ ID NOs: 356 and 358, respectively. In some embodiments, the TCR comprises a Cγ domain and a Cδ domain set forth in SEQ ID NOs: 357 and 358, respectively.

[0118] In some embodiments, variants of the Cα domain contain at least one non-native cysteine ​​replacement, such as any of the replacements described herein. In some embodiments, variants of the Cβ domain contain at least one non-native cysteine ​​replacement, such as any of the replacements described herein.

[0119] In some embodiments, any of the provided TCRs or antigen-binding fragments thereof can be human / mouse chimeric TCRs. In some cases, the TCRs or antigen-binding fragments thereof provided herein comprise an alpha chain and / or a beta chain, or a gamma chain and / or a delta chain, comprising a mouse constant domain. In some embodiments, the Cα domain and / or Cβ domain, or the Cγ domain and / or Cδ domain, is a mouse Cα domain and / or a mouse Cβ domain, or a mouse Cγ domain and / or a mouse Cδ domain. In some embodiments, the Cα domain and / or Cβ domain, or the Cγ domain and / or Cδ domain is or comprises any of the Cα domain and / or Cβ domain, or the Cγ domain and / or Cδ domain described in WO2015 / 184228, WO2015 / 009604, and WO2015 / 009606.

[0120] In some embodiments, the TCRs or antigen-binding fragments thereof provided herein comprise variants of the alpha and / or beta chain, or the gamma and / or delta chain. In some embodiments, the variants comprise the amino acid sequences of any of the TCRs described herein, with one, two, three, or four or more amino acid substitution(s) in the constant domain of the alpha or beta chain. In some embodiments, a TCR (or functional portion thereof) comprising a substituted amino acid sequence(s) advantageously provides one or more of reduced mispairing with endogenous TCR chain(s), increased expression by host cells, increased recognition of the HA-1 target, and increased anti-tumor activity, compared to a parent TCR comprising an unsubstituted amino acid sequence.

[0121] In some embodiments, the constant domain contains substituted amino acid sequences of mouse constant domains of the TCR α and β chains or TCR γ and δ chains corresponding to all or part of the unsubstituted mouse Cα and Cβ domains or the mouse Cγ and Cδ domains. In some embodiments, the TCR may be a heterodimer of α and β chains or γ and δ chains linked by one disulfide bond or multiple disulfide bonds, etc. In some embodiments, the constant domain of the TCR may contain a short linking sequence in which cysteine ​​residues form disulfide bonds, thereby linking the two chains of the TCR. In some embodiments, the TCR may have additional cysteine ​​residues in each of the α and β chains or the γ and δ chains such that the TCR contains two disulfide bonds in the constant domain. In some embodiments, the constant domain and the variable domain each contain disulfide bonds formed by cysteine ​​residues.

[0122] In some embodiments, the TCRs provided herein may contain an introduced disulfide bond or multiple disulfide bonds. In some embodiments, native disulfide bonds are absent. In some embodiments, one or more of the native cysteines (e.g., in the α and β, or γ and δ, chain constant domains) that form native interchain disulfide bonds are substituted with another residue, such as serine or alanine. In some embodiments, the introduced disulfide bond can be formed by mutating non-cysteine ​​residues on the alpha and beta chains, such as the α and β or γ and δ, chain constant domains, to cysteine. Opposing cysteines in the TCR α and β or TCR γ and δ chains link the TCR α and β, or TCR γ and δ, chain constant domains of the substituted TCRs to each other, providing a disulfide bond that is not present in TCRs comprising unsubstituted constant domains where native disulfide bonds exist, such as unsubstituted native human constant domains or unsubstituted native mouse constant domains. In some embodiments, the presence of non-native cysteine ​​residues in a recombinant TCR (e.g., resulting in one or more non-native disulfide bonds) may favor production of the desired recombinant TCR in a cell into which it is introduced over expression of a mismatched TCR pair containing native TCR chains.

[0123] Exemplary non-native disulfide bonds in TCRs are described in published International PCT Patent Applications Nos. 2006 / 000830 and 2006 / 037960. In some embodiments, cysteines may be introduced or substituted at residues corresponding to Thr48 of the Cα domain and Ser57 of the Cβ domain, Thr45 of the Cα domain and Ser77 of the Cβ domain, Tyr10 of the Cα domain and Ser17 of the Cβ domain, Thr45 of the Cα domain and Asp59 of the Cβ domain, and / or Ser15 of the Cα domain and Glu15 of the Cβ domain.

[0124] In some embodiments, any of the provided cysteine ​​mutations can be made at a corresponding position in another sequence, for example, the sequence of the human or mouse Cα and / or Cβ domains, or the Cγ and / or Cδ domains described above. The term "corresponding" with respect to a protein position, such as a statement that an amino acid position in a disclosed sequence, as set forth in the Sequence Listing, is a "corresponding" amino acid position, refers to an amino acid position identified upon alignment with the disclosed sequence based on a structural sequence alignment or using a standard alignment algorithm, such as the GAP algorithm. For example, corresponding residues can be determined by aligning a reference sequence with either the Cα sequence set forth in SEQ ID NO: 294 or 296 or the Cβ sequence set forth in SEQ ID NO: 298 or 300, using structural alignment methods as described herein. By aligning the sequences, corresponding residues can be identified, for example, using conserved and identical amino acid residues as a guide.

[0125] In some embodiments, the TCRs or antigen-binding fragments thereof provided herein are a sequence of amino acids set forth in any of SEQ ID NOs: 6, 24, 40, 54, 68, 81, 95, 109, 123, 139, 155, 169, 183, 197, 211, 227, 241, 255, 271, 281, 362, 372, 382, ​​392, 402, 412, 422, 432, 442, 452, and 483, or a sequence having at least 90% sequence identity thereto (e.g., a sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto). and / or a beta or delta chain that is or comprises a sequence of amino acids set forth in SEQ ID NOs: 14, 30, 46, 60, 71, 87, 101, 115, 129, 145, 161, 175, 189, 203, 217, 233, 247, 261, 161, 287, 366, 376, 386, 396, 406, 416, 426, 436, 446, 456, and 487, or a sequence having at least 90% sequence identity thereto (e.g., a sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such a sequence).

[0126] Exemplary TCRs or antigen-binding fragments include those set forth in Table 2, such as in each row therein. In some embodiments, the Vα and Vβ regions, or the Vγ and Vδ regions, contain amino acid sequences corresponding to a SEQ ID NO: set forth in Table 2, such as in each row therein. In some embodiments, the Vα and Vβ regions, or the Vγ and Vδ regions, contain CDR-1, CDR-2, and CDR-3 sequences contained within the Vα and Vβ regions or the Vγ and Vδ regions set forth in Table 2, such as in each row therein. In some aspects, the TCRs contain constant alpha and constant beta domain sequences, such as those corresponding to a SEQ ID NO: set forth in Table 2, such as in each row therein. In some cases, the TCRs contain complete sequences including variable and constant domains, such as sequences corresponding to a SEQ ID NO: set forth in Table 2 ("complete"), such as in each row therein. Also among the provided TCRs are those that contain sequences that are at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to such sequences. Exemplary TCRs containing such sequences, or modified versions thereof as described elsewhere herein, are also respectively set forth in Table 2, e.g., in individual rows therein. In some aspects, the exemplary TCRs provided comprise, when expressed as mature proteins, mature Vα and / or Vβ regions, or mature Vγ and / or Vδ mature regions that, when fully processed and expressed, do not include a signal sequence (e.g., from cleavage of a signal sequence).

[0127] [Table 2]

[0128] In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:6, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO:14, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:24, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO:30, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:40, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO:46, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:54, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO:60, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:68, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO:71, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:81, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO:87, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 95, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 101, or a sequence having at least 90% sequence identity thereto.In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 109, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 115, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 123, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 129, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 139, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 145, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 155, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 161, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 169, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 175, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 183, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 189, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 197, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 203, or a sequence having at least 90% sequence identity thereto.In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:211, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO:217, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:227, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO:233, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:241, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO:247, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:255, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO:261, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:271, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO:161, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:281, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO:287, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 362, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 366, or a sequence having at least 90% sequence identity thereto.In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 372, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 376, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 382, ​​or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 386, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 392, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 396, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 402, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 406, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 412, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 416, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 422, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 426, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 432, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 436, or a sequence having at least 90% sequence identity thereto.In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 442, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 446, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 452, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 456, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 483, or a sequence having at least 90% sequence identity thereto, and the beta or delta chain comprises SEQ ID NO: 487, or a sequence having at least 90% sequence identity thereto.

[0129] In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO:6 and the beta chain comprises SEQ ID NO:14. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO:24 and the beta chain comprises SEQ ID NO:30. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO:40 and the beta chain comprises SEQ ID NO:46. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO:54 and the beta chain comprises SEQ ID NO:60. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO:68 and the beta chain comprises SEQ ID NO:71. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO:81 and the beta chain comprises SEQ ID NO:87. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO:95 and the beta chain comprises SEQ ID NO:101. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO:109 and the beta chain comprises SEQ ID NO:115. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO:123 and the beta chain comprises SEQ ID NO:129. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO: 139 and the beta chain comprises SEQ ID NO: 145. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO: 155 and the beta chain comprises SEQ ID NO: 161. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO: 169 and the beta chain comprises SEQ ID NO: 175. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO: 183 and the beta chain comprises SEQ ID NO: 189. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO: 197 and the beta chain comprises SEQ ID NO: 203. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO: 211 and the beta chain comprises SEQ ID NO: 217. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO: 227 and the beta chain comprises SEQ ID NO: 233.In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO:241 and the beta chain comprises SEQ ID NO:247. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO:255 and the beta chain comprises SEQ ID NO:261. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO:271 and the beta chain comprises SEQ ID NO:161. In some of the embodiments provided herein, the alpha chain comprises SEQ ID NO:281 and the beta chain comprises SEQ ID NO:287. In some of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:362 and the beta or delta chain comprises SEQ ID NO:366. In some of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:372 and the beta or delta chain comprises SEQ ID NO:376. In some of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:382 and the beta or delta chain comprises SEQ ID NO:386. In some of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 392, and the beta or delta chain comprises SEQ ID NO: 396. In some of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 402, and the beta or delta chain comprises SEQ ID NO: 406. In some of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 412, and the beta or delta chain comprises SEQ ID NO: 416. In some of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 422, and the beta or delta chain comprises SEQ ID NO: 426. In some of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 432, and the beta or delta chain comprises SEQ ID NO: 436. In some of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 442, and the beta or delta chain comprises SEQ ID NO: 446. In some of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO: 452, and the beta or delta chain comprises SEQ ID NO: 456.In some of any of the embodiments provided herein, the alpha or gamma chain comprises SEQ ID NO:483 and the beta or delta chain comprises SEQ ID NO:487.

[0130] II. Nucleic Acids Encoding TCRs Also provided herein are nucleic acids, such as polynucleotides or nucleic acid molecules, that encode any of the provided TCRs or antigen-binding fragments thereof. Nucleic acids can include those that contain natural and / or non-natural nucleotides and bases, including, for example, those with backbone modifications. The terms "nucleic acid molecule," "nucleic acid," and "polynucleotide" may be used interchangeably and refer to a polymer of nucleotides. Such polymers of nucleotides may contain natural and / or non-natural nucleotides and include, but are not limited to, DNA, RNA, and PNA. A "nucleic acid sequence" refers to a linear sequence of nucleotides that comprises a nucleic acid molecule or polynucleotide.

[0131] In some embodiments, the TCRs or antigen-binding portions thereof provided herein may be recombinantly produced native proteins or mutant forms thereof that have altered one or more properties, such as binding characteristics. In some aspects, the nucleic acid is synthetic. In some cases, the nucleic acid is or contains cDNA. In some aspects, the polynucleotide can be modified for use in the constructs described herein, such as for codon optimization. In some cases, the sequence can be designed to contain terminal restriction site sequences for purposes of cloning into a vector.

[0132] In some embodiments, the TCRs or antigen-binding portions thereof provided herein can be produced synthetically from knowledge of the sequence of the TCR.

[0133] In some embodiments, the polynucleotide contains a nucleic acid sequence encoding an alpha chain and / or a nucleotide sequence encoding a beta chain, hi some embodiments, the polynucleotide contains a nucleic acid sequence encoding a gamma chain and / or a nucleotide sequence encoding a delta chain.

[0134] In some embodiments, the nucleotide sequence encoding the alpha or gamma chain, and / or the nucleotide sequence encoding the beta or delta chain, or any domain, region, or portion thereof, is codon-optimized. Typically, codon optimization involves balancing the proportion of selected codons with the published abundance of human transfer RNA to avoid overloading or limiting codons. This may be necessary in some cases because most amino acids are encoded by more than one codon and codon usage varies between organisms. Differences in codon usage between the transfected gene and the host cell can affect protein expression and the immunogenicity of the nucleic acid construct. Generally, for codon optimization, codons are selected to select codons that are balanced with human usage. Typically, the codon redundancy for an amino acid is such that different codons encode one amino acid. In some embodiments, when selecting a codon for replacement, it may be desirable for the resulting mutation to be silent, so that the codon change does not affect the amino acid sequence. Generally, the last nucleotide of a codon can be changed without affecting the amino acid sequence.

[0135] In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO:7, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO:15, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO:25, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO:31, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO:41, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO:47, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO:55, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO:61, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO:69, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO:72, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO:82, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO:88, or a sequence having at least 90% sequence identity thereto.In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO:96, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO:102, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO:110, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO:116, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO:124, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO:130, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 140, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 146, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 156, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 162, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 170, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 176, or a sequence having at least 90% sequence identity thereto.In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 184, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 190, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 198, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 204, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 212, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 218, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 228, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 234, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 242, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 248, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 256, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 262, or a sequence having at least 90% sequence identity thereto.In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 272, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 274, or a sequence having at least 90% sequence identity thereto. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 282, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 288, or a sequence having at least 90% sequence identity thereto.

[0136] In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:8, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:16. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:26, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:32. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:42, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:48. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:56, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:62. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:70, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:73. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 83, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 89. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 97, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 103. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 111, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 117. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 125, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 131.In some of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 141, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 147. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 157, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 163. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 171, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 177. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 185, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 191. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 199, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 205. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 213, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 219. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 229, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 235. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 243, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 249. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 257, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 263.In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 273, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 275. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO: 283, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO: 289.

[0137] In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 301, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 321. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 302, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 322. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 303, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 323. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 304, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 324. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 305, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 325. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 306, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 326. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 307, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 327. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 308, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 328. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 309, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 329. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 310, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 330.In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 311, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 331. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 312, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 332. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 313, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 333. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 314, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 334. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 315, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 335. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 316, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 336. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 317, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 337. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 318, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 338. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 319, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 339. In some of any of the embodiments provided herein, the nucleotide sequence encoding the Vα region comprises SEQ ID NO: 320, and the nucleotide sequence encoding the Vβ region comprises SEQ ID NO: 340.

[0138] In some embodiments, the nucleic acid sequence encoding the alpha chain or gamma chain comprises one of the following: SEQ ID NOs: 8, 26, 42, 56, 70, 83, 97, 111, 125, 141, 157, 171, 185, 199, 213, 229, 243, 257, 273, or 283, a degenerate sequence thereof, or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto. In some embodiments, the nucleotide sequence encoding the beta or delta chain comprises one of the following: SEQ ID NOs: 16, 32, 48, 62, 73, 89, 103, 117, 131, 147, 163, 177, 191, 205, 219, 235, 249, 263, 275, or 289, or a degenerate sequence thereof, or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto.

[0139] In some of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO:8, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO:16. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO:26, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO:32. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO:42, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO:48. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO:56, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO:62. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO:70, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO:73. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO:83, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO:89. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO:97, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO:103. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO: 111, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO: 117. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO: 125, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO: 131. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO: 141, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO: 147.In some of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO: 157, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO: 163. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO: 171, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO: 177. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO: 185, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO: 191. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO: 199, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO: 205. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO: 213, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO: 219. In some of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO: 229, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO: 235. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO: 243, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO: 249. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO: 257, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO: 263. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO: 273, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO: 275. In some of any of the embodiments provided herein, the nucleotide sequence encoding the alpha chain comprises SEQ ID NO: 283, and the nucleotide sequence encoding the beta chain comprises SEQ ID NO: 289.Also provided herein are nucleic acid(s) or polynucleotides that contain sequences that are at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to such sequences. Also provided are embodiments of one or more chains (e.g., alpha or gamma and / or beta or delta chains) of a TCR or binding fragment thereof encoded by any of such polynucleotides.

[0140] In some embodiments, the alpha or gamma and / or beta or delta chains of a TCR are encoded by a sequence of nucleotides that includes a signal peptide (also referred to as a leader sequence). A non-limiting example of such a signal peptide is a signal peptide having or comprising the sequence of amino acids set forth in any of SEQ ID NOs: 341-350.

[0141] In some embodiments, the nucleic acid encoding the alpha or gamma chain and the nucleic acid encoding the beta or delta chain may be connected via a linker, such as those optionally described elsewhere herein.

[0142] In some embodiments, the nucleic acid encoding the alpha or gamma chain and the nucleic acid encoding the beta or delta chain may be connected via a cleavable linker sequence or a peptide that causes ribosome skipping (e.g., T2A or P2A), such as those optionally described elsewhere herein.

[0143] Also provided herein are vectors or constructs containing such nucleotide sequences. In some embodiments, the vectors or constructs contain one or more promoters operably linked to nucleotides encoding the alpha or gamma chain and / or the beta or delta chain. In some embodiments, the promoter is operably linked to one or more nucleotide sequences.

[0144] In some embodiments, a vector or construct can contain a single promoter driving expression of one or more nucleotide sequences. In some embodiments, such a promoter can be multicistronic (e.g., bicistronic or tricistronic; see, e.g., U.S. Pat. No. 6,060,273). For example, in some embodiments, a transcription unit can be engineered as a bicistronic unit containing an IRES (internal ribosome entry site), allowing for simultaneous expression of gene products (e.g., encoding the alpha or gamma and / or beta or delta chains of a TCR) by messages from a single promoter. Alternatively, in some cases, a single promoter can direct expression of RNA containing two or three genes (e.g., encoding the alpha or gamma and / or beta or delta chains of a TCR) in a single open reading frame (ORF), separated from each other by sequences encoding a self-cleaving peptide (e.g., P2A) or a protease recognition site (e.g., furin). Thus, the ORF encodes a single polyprotein that is cleaved into individual proteins either during translation (in the case of 2A, e.g., P2A) or post-translationally. In some cases, peptides such as P2A can cause the ribosome to skip synthesis of the peptide bond at the C-terminus of the 2A element (ribosomal skipping), resulting in separation between the end of the 2A sequence and the next downstream peptide (see, e.g., de Felipe, Genetic Vaccines and Ther. 2:13 (2004) and de Felipe et al., Traffic 5:616-626 (2004)).Examples of 2A cleavage peptides, including those capable of inducing ribosome skipping, are 2A sequences from Thosea asigna virus (T2A), porcine teschovirus-1 (P2A, e.g., SEQ ID NO: 352), equine rhinitis A virus (E2A), and foot-and-mouth disease virus (F2A), as described in U.S. Patent Publication No. 2007 / 0116690. In some such examples, the peptide that causes ribosome skipping is a P2A peptide and / or contains the sequence of amino acids set forth in SEQ ID NO: 352.

[0145] In some embodiments, the nucleic acid sequence encoding the alpha or gamma chain and the nucleotide sequence encoding the beta or delta chain are present in any order, separated by a nucleotide sequence encoding a peptide sequence that causes ribosome skipping. For example, in some embodiments, the nucleotide sequence comprises, in that order, a nucleic acid sequence encoding a beta or delta chain, a nucleic acid sequence encoding a peptide sequence that causes ribosome skipping, such as a P2A sequence described herein, and a nucleic acid sequence encoding an alpha or gamma chain. In other embodiments, the nucleotide sequence contains, in that order, a nucleic acid sequence encoding an alpha or gamma chain, a nucleic acid sequence encoding a peptide sequence that causes ribosome skipping (e.g., a P2A sequence as described herein), and a nucleic acid sequence encoding a beta or delta chain.

[0146] In some embodiments, the nucleotide sequences encoding the TCR alpha or gamma and / or beta or delta chains comprise nucleic acid sequences corresponding to SEQ ID NOs set forth in Table 3. Also among the provided nucleotide sequences encoding TCRs are those containing sequences that are at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to such sequences. Also provided are any of the mature TCR alpha or gamma chains encoded by any of the sequences set forth in Table 3, e.g., in each row therein. Also provided are any of the mature TCR beta or delta chains encoded by any of the sequences set forth in Table 3, e.g., in each row therein. Also provided are any of the mature TCR alpha and beta chains, or mature gamma and delta chains, encoded by any of the sequences set forth in Table 3, e.g., in each row therein. In some aspects, the nucleotide sequence contains a sequence encoding a signal sequence, and the encoded exemplary TCR, when expressed as a mature protein, includes, e.g., a mature Vα region and / or mature Vβ region, or a mature Vγ region and / or Vδ mature region that, when fully processed and expressed, does not include the signal sequence (e.g., from cleavage of the signal sequence).

[0147] In some embodiments, the nucleotide sequence encodes a polypeptide containing an amino acid sequence set forth in Table 3, such as in each row therein, or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the nucleotide sequence encodes a mature polypeptide set forth herein, e.g., in Table 3, such as in each row therein, or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0148] [Table 3]

[0149] The nucleic acid may encode an amino acid sequence comprising the Vα region of a TCR. In some cases, the nucleic acid encodes an amino acid sequence comprising the Vβ region of a TCR. In further embodiments, one or more vectors (e.g., expression vectors) comprising such nucleic acids are provided.

[0150] Also provided herein are vectors, such as vectors containing any of the nucleic acids described herein. In some embodiments, a nucleic acid or nucleic acids encoding one or both chains of a TCR are cloned or assembled into a suitable expression vector or vectors. The expression vector may be any suitable recombinant expression vector and may be used to transform or transfect any suitable host. Suitable vectors include vectors designed for propagation and expansion, or for expression, or both, such as plasmids and viruses. In some embodiments, the vector is an expression vector.

[0151] III. Methods for Isolating, Characterizing, and Identifying T Cell Receptors In some aspects, provided herein are methods for isolating multiple nucleic acid sequences encoding provided TCRs specific for minor histocompatibility antigens. In some aspects, provided HA-1-specific TCRs are identified based on the methods described herein. In some aspects, the methods also include isolating the nucleic acid sequences, assembling the nucleic acid sequences into a vector, assessing TCR expression and / or activity, and optionally using high-throughput methods to screen and identify specific TCRs of interest.

[0152] The methods described herein also relate to determining the binding activity and functional capacity of the candidate TCRs.

[0153] A. Donor criteria and methods for isolating miHA-specific T cell candidates Alloreactive T cells have been isolated from patients who have undergone alloSCT. However, such patients may have few circulating T cells, undergo immunosuppressive treatment, and have other alloSCT-related diseases that may compromise donor candidate aspects, including timely blood collection. To improve elements of the blood collection process and the quality of donor samples, alternative donor sources have been explored. Parous women, including multiparous women, may be naturally immunized against paternal miHA during pregnancy and delivery. In some cases, miHA-reactive T cells are expanded as a result of pregnancy. See Lee et al. (2019) Biol Blood Marrow Transpl. 25(4):625-638. In some embodiments, T cells are obtained from naive male PBMCs.

[0154] In some embodiments, whole-exome sequencing is used to classify parous volunteers for their HLA repertoire and for polymorphisms encoding HA-1 miHA or non-immunogenic variants. For subjects with the appropriate HLA type lacking HA-1, the offspring child(ren) or father(s) are then classified to determine whether they express the desired HA-1. If so, the mother may be immunized during pregnancy / delivery. Suitable parous women are recruited for blood collection. Anti-HA-1 reactive T cells from the parous women are identified based on their binding to HLA multimers folded with HA-1 peptides. These cells are single-cell sorted and their TCRs are screened for anti-HA-1 reactivity.

[0155] B. High-throughput isolation, amplification, and assembly of TCR-encoding nucleic acid sequences In some embodiments, nucleic acid molecules encoding TCRs can be obtained or identified from a variety of sources. In some embodiments, TCRs can be obtained or identified using high-throughput TCR isolation and screening methods. Examples of such methods that can be used include, for example, those described in WO 2018 / 102473, which is incorporated by reference in its entirety. In some embodiments, high-throughput TCR isolation and screening methods involve amplifying nucleic acids encoding TCR alpha and / or beta chains or TCR gamma and / or delta chains from a plurality of different cells, such as T cells isolated from a donor. Also provided herein are methods related to isolating or screening a plurality of different TCRs to obtain TCRs specific for hematopoietic-restricted minor histocompatibility antigens, such as HA-1 peptides.

[0156] In some embodiments, nucleic acid molecules encoding TCRs can be obtained from a variety of sources, such as by polymerase chain reaction (PCR) amplification of encoding nucleic acids within or isolated from a given cell or cells. In some embodiments, TCRs are obtained from biological sources, such as cells such as T cells (e.g., cytotoxic T cells), T cell hybridomas, or other publicly available sources. In some embodiments, TCRs can be derived from one of a variety of animal species, such as human, mouse, rat, or other mammals. In some embodiments, T cells can be obtained from cells isolated in vivo, such as from a normal (or healthy) or diseased subject, including T cells present in peripheral blood mononuclear cells (PBMCs) or tumor-infiltrating lymphocytes (TILs). In some embodiments, T cells can be cultured T cell hybridomas or clones. For example, in some embodiments, to produce a vector encoding a TCR, the alpha and beta chains can be PCR amplified from total cDNA isolated from a T cell clone expressing the TCR of interest and cloned into an expression vector. In some embodiments, the alpha and beta chains can be produced synthetically. In some embodiments, the alpha and beta chains are cloned into the same vector.

[0157] As described herein, the methods and materials provided herein may enable users to successfully capture most, if not all, functional TCRs from a sorted T cell population. For example, an amplification (e.g., a nested amplification procedure such as nested PCR) procedure may involve using a primer collection designed to amplify all known functional V segments of the two variable chains of a particular mammalian (e.g., human) TCR (e.g., any known functional V segments of the α and β variable chains of a particular αβ TCR, or any known functional V segments of the γ and δ variable chains of a particular γδ TCR). For humans, the amplification procedure may include a primer collection designed to amplify all 45 V segments of the α chain currently known to be functional and all 48 V segments of the β chain currently known to be functional. When referring to a TCR V segment of the α chain herein, the abbreviation TRAV may be used. Similarly, when referring to a TCR V segment of the β chain herein, the abbreviation TRBV may be used. The same is true for the TCR V-segments of the gamma and delta chains, which can be referred to as TRGV and TRDV, respectively.

[0158] In some aspects, this document provides methods and materials involved in cloning a functional TCR from a single T cell. For example, in some aspects, this document provides methods and materials for obtaining nucleic acid encoding a TCR from a single T cell and arranging the nucleic acid to form a nucleic acid vector successfully designed to express a TCR (e.g., a fully intact TCR, such as a fully intact TCR with the variable chain combination present in the single T cell), kits for obtaining nucleic acid encoding a TCR from a single T cell and arranging the nucleic acid to form a nucleic acid vector successfully designed to express a TCR (e.g., a fully intact TCR, such as a fully intact TCR with the variable chain combination present in the single T cell), and methods for making such kits. A cloned αβ TCR with a variable chain combination as present in the single T cell used to clone the TCR can include a VJα segment combination as present in the single T cell, a VDJβ segment combination as present in the single T cell, the nucleotide sequence of the entire α variable region as present in the single T cell, and the nucleotide sequence of the entire β variable region as present in the single T cell. Similarly, a cloned γδ TCR having a variable chain combination as present in the single T cell used to clone the TCR may comprise a VJγ segment combination as present in the single T cell, a VDJδ segment combination as present in the single T cell, the nucleotide sequence of the entire gamma variable region as present in the single T cell, and the nucleotide sequence of the entire delta variable region as present in the single T cell.

[0159] In some aspects, this document provides collections of nucleic acid primers designed to amplify the entire coding sequence of both variable regions (e.g., the α and β variable regions, or the γ and δ variable regions) of each expressed V-segment (e.g., each expressed α and β V-segment, or each expressed γ and δ V-segment) of a functional αβ or γδ TCR of a particular mammalian species (e.g., mouse or human), methods of using such collections of nucleic acid primers to clone functional TCRs from single T cells, and kits containing such collections of nucleic acid primers for cloning functional TCRs from single T cells.

[0160] In some aspects, the methods and materials provided herein may allow for highly multiplexed reactions to be performed, allowing for the cloning of many different TCRs (e.g., hundreds to thousands, or more, different TCRs) rapidly (e.g., in some cases simultaneously) directly from a single T cell, and in a manner that misses few, if any, α / β variable chain combinations (or γ / δ variable chain combinations). For example, the methods and materials provided herein can be used to clone many different αβ TCRs (e.g., hundreds to thousands or more different αβ TCRs) directly from a single αβ T-cell in a manner that loses less than 10 percent (e.g., less than 9 percent, less than 8 percent, less than 7 percent, less than 6 percent, less than 5 percent, less than 4 percent, less than 3 percent, less than 2 percent, or less than 1 percent) of the α variable chains and less than 10 percent (e.g., less than 9 percent, less than 8 percent, less than 7 percent, less than 6 percent, less than 5 percent, less than 4 percent, less than 3 percent, less than 2 percent, or less than 1 percent) of the β variable chains possible for a species (e.g., a mouse or human species). Similarly, the methods and materials provided herein can be used to clone many different γδ TCRs (e.g., hundreds to thousands or more different γδ TCRs) directly from a single γδ T cell in a manner that loses less than 10 percent (e.g., less than 9 percent, less than 8 percent, less than 7 percent, less than 6 percent, less than 5 percent, less than 4 percent, less than 3 percent, less than 2 percent, or less than 1 percent) of the gamma variable chains and less than 10 percent (e.g., less than 9 percent, less than 8 percent, less than 7 percent, less than 6 percent, less than 5 percent, less than 4 percent, less than 3 percent, less than 2 percent, or less than 1 percent) of the delta variable chains possible for a species (e.g., a mouse or human species). In some cases, the methods and materials provided herein involve (a) obtaining a sample of T cells; (b) sorting those T cells into isolated locations (e.g., wells) so that most, if not all, of the isolated locations (e.g., each well) contain a single T cell; and(c) lysing (e.g., simultaneously lysing) single T cells located in separate isolated locations (e.g., separate wells) to release the RNA of each single T cell; (d) performing (e.g., simultaneously performing) reverse transcription using the released RNA as a template, appropriate primers for cDNA synthesis from the RNA, and reverse transcriptase to produce cDNA within each isolated location (e.g., each well) (cDNA representative of the RNA expressed by a single T cell located in that isolated location (e.g., well)); and (e) for each isolated location, performing (e.g., simultaneously performing) reverse transcription of the isolated T cells. A first round amplification reaction (e.g., a first round polymerase chain reaction (PCR)) of an amplification procedure (e.g., a nested amplification procedure such as nested PCR) using cDNA as a template, a first round primer collection (e.g., a first round PCR primer collection), and a polymerase (e.g., Tap Polymerase) to generate at least an amplification product containing the nucleic acid sequence of the α variable chain (or γ variable chain) of the TCR of the single T cell at the same isolated location, and an amplification product containing the nucleic acid sequence of the β variable chain (or δ variable chain) of the TCR of the same single T cell at the same isolated location. (f) performing (e.g., simultaneously) a second round of amplification reaction (e.g., a second round of PCR) of a nested amplification procedure (e.g., a nested PCR procedure) using the amplification product of the first round of amplification reaction as a template to generate, for each isolated location, at least a first amplification product containing the nucleic acid sequence of the α variable chain (or γ variable chain) of the TCR of the single T cell at that isolated location and a second amplification product containing the nucleic acid sequence of the β variable chain (or δ variable chain) of the TCR of that same single T cell at that same isolated location. (e.g., simultaneously) performing round-one primer collection (e.g., second-round PCR primer collection) and polymerase (e.g., Tap polymerase); and (g) for each isolated locus, cloning the first and second amplification products into an expression vector designed to express a functional TCR having an α / β or γ / δ variable chain combination (or a portion thereof, such as a V segment of an α / β or γ / δ variable chain combination) as was present in the single T cell used to generate the amplification product.

[0161] The resulting expression vector can be introduced into cells so that the cells express the cloned TCR. Such cells, and / or the TCRs they express from the introduced expression vector, can be screened to identify TCRs with desired capabilities. For example, cells expressing a cloned TCR that recognizes a particular antigen (e.g., a peptide derived from a tumor polypeptide) can be identified, and those cells, the TCR expression vectors they contain, or the cloned TCR constructs can be used for further analysis or therapeutic applications.

[0162] In some cases, once the signaling machinery of a functional TCR is engaged, expression of the cloned TCR on its surface and expression of a functional TCR can be assessed by introducing an expression vector into TCR-negative reporter cells engineered to express a measurable marker signal or marker polypeptide. In these cases, functional TCRs can be screened using antibodies (e.g., anti-CD3 antibodies) designed to nonspecifically activate the TCR. In some cases, cloned TCRs can be screened for antigen specificity. For example, reporter cells expressing the cloned TCR can be screened for recognition of a specific antigen (e.g., a peptide derived from a tumor polypeptide). In some cases, primary T cells (e.g., human primary T cells) can be transfected with the expression vector and screened for antigen specificity via a T cell proliferation assay.

[0163] The methods and materials provided herein may enable clinicians, medical professionals, laboratory personnel, and researchers to use a collection of T cells with different TCRs to produce a collection of expression vectors that express functional versions of the different TCRs with the same variable chain combinations or portions thereof (e.g., the same α / β variable chain combinations or the same γ / δ variable chain combinations) that were present in the original T cells used to produce the collection. Such collections of expression vectors can be obtained quickly, efficiently, inexpensively, and effectively. For example, in some cases, using the methods and materials provided herein, collection of expression vectors expressing functional versions of many different TCRs with authentic variable chain combinations as found in T cells obtained from a mammal (e.g., a human) can be achieved in less than 12 days (e.g., 4-11 days, 5-11 days, 6-11 days, 7-11 days, 8-11 days, 4-10 days, 5-10 days, 6-10 days, 7-10 days, 8-10 days, 4-9 days, 5-9 days, 6-9 days, 7-9 days, 4-8 days, 5-8 days, TCRs can be produced within 6-8 days (or 7-8 days) using fewer than 12 steps (e.g., 5-11 steps, 6-11 steps, 7-11 steps, 8-11 steps, 5-10 steps, 6-10 steps, 7-10 steps, 8-10 steps, 5-9 steps, 6-9 steps, 7-9 steps, or 8-9 steps), for less than about $10 per TCR, and with greater than about 80 percent (e.g., greater than about 85, 90, or 95 percent) efficiency (based on sorting a single T cell into each of 384 wells of a 384-well plate). In some cases, the methods and materials provided herein can be performed without nucleic acid sequencing, without a restriction endonuclease cleavage step, without other steps or techniques described herein, and / or without the use of certain reagents or materials described herein.

[0164] The methods and materials provided herein may also enable users to successfully capture most, if not all, functional TCRs from a sorted T cell population. For example, in some cases, the methods and materials provided herein may include a nested amplification procedure (e.g., a nested PCR procedure) that includes a collection of primers designed to amplify all known functional V segments of the two variable chains of a particular mammalian (e.g., human) TCR (e.g., any known functional V segments of the α and β variable chains of a particular αβ TCR, or any known functional V segments of the γ and δ variable chains of a particular γδ TCR). Having the ability to clone most, if not all, functional TCRs from a sorted T cell population may enable users to identify specific TCRs, including rare TCRs, that might otherwise be overlooked. It is these rare TCRs that may be overlooked that can provide a rich source of newly cloned TCRs for effective therapies, such as cancer treatments, involving the delivery of effective T cells.

[0165] In some cases, the methods and materials provided herein may enable users to obtain additional information about single T cells from which functional TCR clones are generated. In some cases, the flow cytometry techniques used for single-cell sorting described herein can be used to distinguish activated and experienced T cells from naive T cells by staining the cells for activation markers. When applying the methods and materials provided herein in methods for treating certain diseases (e.g., cancer), T cells can be isolated from a patient, and the T cells have already been activated and expanded within the patient. Once these T cells are isolated and cDNA is produced from single-cell RNA, an additional level of selection can be applied. For example, in addition to using cDNA generated from the RNA of a single T cell to amplify and clone the variable chain (or portion thereof) of the TCR of that T cell, the cDNA can also be used to assess RNA expression and / or RNA expression levels within that T cell.

[0166] CD8 + In the case of T cells, TCRs associated with multifunctional (e.g., multi-cytokine producing) effector cells or TCRs associated with resting or exhausted long-lived memory cells can be identified by examining the relative mRNA levels of expression of transcription factors such as Eomesodermin and T-bet (McLane et al., J. Immunol. 190(7):3207-3215 (2013); and Buggert et al., PLoS Pathog. 10(7):e1004251 (2014)).

[0167] In some cases, T cells can be stimulated (e.g., in vitro) before sorting, and RNA expression can then be assessed (e.g., via qPCR) to determine which T cells responded to the stimulation. Any suitable type of stimulation can be used, including, but not limited to, nonspecific stimulation, such as with concanavalin A, phytohemagglutinin-P, phorbol ester plus ionomycin, phorbol myristate acetate plus calcium ionophore, or an antibody capable of cross-linking the TCR (e.g., an anti-CD3 antibody plus an anti-CD28 antibody, or an anti-TCRβ antibody), or antigen-specific stimulation, such as with one or more specific antigens as described elsewhere (Downward et al., Nature 346:719-23 (1990); and Dasgupta et al., Proc. Natl. Acad. Sci. USA 84:1094-8 (1987)). In some cases, cytokine expression levels, such as TNF-α, IFN-γ, IL-2, IL-4, IL-5, IL-10, IL-13, or IL-17 expression levels, can be determined and compared with unstimulated populations. Once single T cells are sorted, the methods provided herein can be used to determine which T cells were producing specific cytokines in response to stimulation (e.g., in response to a peptide antigen used to stimulate the T cells). In these cases, antigen-specific T cells can be determined without the tedious method of expanding reactive T cells or the destructive method of paraformaldehyde fixation and intracellular cytokine staining, which can reduce the ability to effectively clone TCRs. In such cases, specific TCRs produced from activated and antigen-specific T cells can be rapidly identified, as opposed to inactive bystander T cells.

[0168] In some cases, cytokine expression levels, such as TNF-α, IFN-γ, IL-2, IL-4, IL-5, IL-10, IL-13, or IL-17 expression levels, can be determined for a single T cell used to clone a functional TCR, thereby allowing for identification of a particular TCR based on the particular phenotype (e.g., elevated IFN-γ expression) of the T cell that donated the variable chain (or portion thereof) of the particular TCR. In such cases, specific TCRs produced from active, rather than inactive, T cells can be rapidly identified. In some cases, specific TCRs produced from inactive, rather than active, T cells can be rapidly identified.

[0169] In some cases, the absence of cytokine production by a T cell does not necessarily reflect the absence of TCR specificity. Signals initiated by the TCR can be disrupted and / or suppressed by a number of inhibitory co-receptors (Sheppard et al., FEBS Lett. 574(1-3):37-41 (2004); and Yokosuka et al., J. Exp. Med. 209(6):1201-1217 (2012)). In some cases, TCRs can be obtained using T cells that are refractory to stimulation, and the specificity of the cloned TCR can be tested or screened in cells in which canonical TCR signaling is not suppressed.

[0170] In some cases, MHC-peptide complexes (or HLA-peptide complexes) can be used to identify cloned TCRs that recognize such complexes. In these cases, it is possible that clonal exclusion and / or lack of antigen priming during the immune response can result in TCRs with this specificity not being present in the activated and / or expanded TCR pool. In such cases, the methods and materials provided herein can be used to clone naive or inactivated TCRs that recognize such complexes, although in some cases only a single T cell needs to be present. In some cases, a pool of naive T cells can be stained with MHC-peptide tetramers (or HLA-peptide tetramers), and any MHC-peptide (or HLA-peptide)-reactive TCRs in the naive T cells can be used to clone these TCRs using the methods and materials provided herein.

[0171] In some aspects, methods provided herein include methods for obtaining a plurality of nucleic acid vectors containing nucleic acids encoding functional T cell receptors, the method comprising, or consisting essentially of: (a) obtaining a device including a plurality of distinct locations, wherein each distinct location contains cDNA produced from RNA obtained from a single T cell sorted to the distinct location; (b) performing a nested amplification procedure using the cDNA at each of the plurality of distinct locations as a template to obtain a first amplification product and a second amplification product for each cDNA at the plurality of distinct locations, wherein the first amplification product comprises a nucleic acid encoding a Vα segment or a Vγ segment, and the second amplification product comprises a nucleic acid encoding a Vβ segment or a Vδ segment; and (c) assembling the first amplification product and the second amplification product for each cDNA at the plurality of distinct locations into a nucleic acid vector to obtain an assembled nucleic acid vector for each cDNA at the plurality of distinct locations, wherein the assembled nucleic acid vector for each cDNA at the plurality of distinct locations comprises a nucleic acid encoding a functional T cell receptor. The plurality can be greater than 50. The plurality can be greater than 500. The plurality can be greater than 5000. The plurality of nucleic acid vectors can be a plurality of nucleic acid expression vectors. The device can comprise a multiwell plate. The multiwell plate can be a 96-well plate, a 384-well plate, or a 1536-well plate. The cDNA produced from RNA obtained from a single T cell can comprise cDNA produced from RNA obtained from a single human T cell. The first amplification product can comprise a nucleic acid encoding the L sequence of a Vα or Vγ segment. The first amplification product can comprise a nucleic acid encoding a Jα or Jγ segment. The first amplification product can comprise a nucleic acid encoding a 5' portion of a Cα or Cγ region. The first amplification product can comprise a nucleic acid encoding the L sequence of a Vα or Vγ segment, a Jα or Jγ segment, and a 5' portion of a Cα or Cγ region. The second amplification product can comprise a nucleic acid encoding the L sequence of a Vβ or Vδ segment.The second amplification product may include a nucleic acid encoding a Dβ segment or a Dδ segment. The second amplification product may include a nucleic acid encoding a Jβ segment or a Jδ segment. The second amplification product may include a nucleic acid encoding a 5' portion of a Cβ or Cδ region. The second amplification product may include a nucleic acid encoding a Vβ or Vδ segment, a Dβ or Dδ segment, a Jβ or Jδ segment, and an L sequence in the 5' portion of a Cβ or Cδ region. The first amplification product may include an adapter sequence added to the cDNA amplification template sequence via the second round of amplification in the nested amplification procedure. The second amplification product may include an adapter sequence added to the cDNA amplification template sequence via the second round of amplification in the nested amplification procedure. The first amplification product may include a first adapter sequence added to the cDNA amplification template sequence via a second round of amplification in a nested amplification procedure, and the second amplification product may include a second adapter sequence added to the cDNA amplification template sequence via a second round of amplification in a nested amplification procedure, wherein the first adapter sequence and the second adapter sequence are different. Each functional T cell receptor of the assembled nucleic acid vector may include a Vα / Vβ combination or a Vγ / Vδ combination as present in a single T cell originating from RNA. Each functional T cell receptor of the assembled nucleic acid vector may include (a) a full-length α variable region and a full-length β variable region, or (b) a full-length γ variable region and a full-length δ variable region. Each functional T cell receptor of the assembled nucleic acid vector may include (a) a full-length α variable region and a full-length β variable region as present in a single T cell originating from RNA, or (b) a full-length γ variable region and a full-length δ variable region as present in a single T cell originating from RNA. The functional T cell receptor of each assembled nucleic acid vector can include (a) a full-length alpha constant region and a full-length beta constant region, or (b) a full-length gamma constant region and a full-length delta constant region. Each assembled nucleic acid vector can include a nucleic acid sequence encoding a self-cleaving peptide or an internal ribosome entry site (IRES). The method can include sorting single T cells into distinct locations.The method may include performing a reverse transcription reaction to obtain cDNA. The assembling step may include seamless cloning. Each assembled nucleic acid vector may be obtained without performing nucleic acid sequencing. Each assembled nucleic acid vector may be obtained without performing a restriction endonuclease cleavage reaction.

[0172] C. Assessment of Minor Histocompatibility Antigen-Specific T Cell Receptor Expression, Activity, and Function Exemplary assays can be used to assess the activity, expression, and / or function of the TCRs and antigen-binding fragments described herein. The assays described herein should not be construed as limiting and can be used to assess the functional capabilities of candidate miHA-specific TCRs.

[0173] Functional characterization of TCRs is performed either by binding assays utilizing fluorescently labeled MHC molecules bearing specific target peptides (tetramers / pentamers / dextramers) or by activation assays by co-culturing TCR-expressing cells with antigen-presenting cells (APCs) presenting the corresponding MHC / peptide complexes.

[0174] Cytokine release assays can assess the ability of candidate TCRs to produce the cytokines IL-2 and / or IFN-γ after exposure to cells presenting the target antigen. T cells were incubated with T2 cells loaded with the target HA-1 "H" peptide (HA-1 (陰性) / HLA-A * :02:01 (陽性) As a control, T2 cells are loaded with the non-targeting HA-1 "R" peptide or an irrelevant peptide control. T cell IL-2 and / or IFN-γ responses are followed by intracellular cytokine staining and analysis by FACS.

[0175] The T cell activation / degranulation marker assay can assess the ability of candidate TCRs to express the surface marker CD107a after exposure to cells presenting a target antigen. CD107a is a marker for T cell degranulation, which is part of the cell killing response. T cells are incubated with T2 cells loaded with the target HA-1 "H" peptide. As a control, T2 cells are loaded with the non-target HA-1 "R" peptide or an irrelevant peptide control. The degranulation response is tracked on T cells by CD107a surface staining and analysis by FACS.

[0176] Killing assays can evaluate the ability of candidate TCRs to lyse cells presenting target antigens. T cells are incubated with a mixture of fluorescently tagged T2 cells differentially loaded with target and control peptides, allowing on-target and off-target cytotoxicity to be tested within a single test sample. Fluorescent cell counting beads are included as a normalization / counting control. Fluorescently tagged T2 cells are loaded with the target HA-1 "H" peptide. As a control, T2 cells labeled with a different fluorescent tag are loaded with the non-target HA-1 "R" peptide or an irrelevant peptide control. Gated cell counts of HA-1 "H" peptide-loaded T2 cells and control peptide-loaded T2 cells remaining after incubation with T cells are tracked by FACS.

[0177] The CD34 marker can be used as a surrogate potency measure. See Philip et al. (2014) Blood 124(8):1277-1287. Detection of CD34, a marker of transduction efficiency, can be correlated with the functional potency measures described herein.

[0178] In some embodiments, the expansion screening and non-expansion sc...

Claims

1. A nucleic acid encoding a T cell receptor (TCR) or an antigen-binding fragment thereof that recognizes a minor histocompatibility antigen HA-1 peptide having the sequence VLHDDLLEA (SEQ ID NO:354), wherein the pair of nucleic acids comprises a sequence encoding: an alpha chain comprising a variable alpha (Vα) region and a beta chain comprising a variable beta (Vβ) region; or a gamma chain comprising a variable gamma (Vγ) region and a delta chain comprising a variable delta (Vδ) region, The nucleic acid is provided as either: (i) a polynucleotide encoding a T cell receptor (TCR) or an antigen-binding fragment thereof; or (ii) a pair of nucleic acid molecules, wherein a first nucleic acid molecule of the pair of nucleic acid molecules encodes an alpha chain and a second nucleic acid molecule of the pair of nucleic acid molecules encodes a beta chain, or wherein a first nucleic acid molecule of the pair of nucleic acid molecules encodes a gamma chain and a second nucleic acid molecule of the pair of nucleic acid molecules encodes a delta chain. (a) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO:51, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO:57; (b) the Vα or Vγ region comprises a complementarity determining region 3 (CDR-3) comprising SEQ ID NO:3, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO:11; (c) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO:21, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO:27; (d) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO:37, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO:43; (e) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO:65, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO:57; (f) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:78, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:84; (g) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:92, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:98; (h) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO:106, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO:112; (i) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO:120, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO:126; (j) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO:136, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO:142; (k) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO:152, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO:158; (l) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO:166, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO:172; (m) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:180, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:186; (n) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO:194, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO:200; (o) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:208, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:214; (p) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO:224, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO:230; (q) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:238, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:244; (r) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:252, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:258; (s) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:268, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:158; (t) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:278, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:284; (u) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:359, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:363; (v) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:369, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:373; (w) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:379, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:383; (x) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:389, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:393; (y) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO:399, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO:403; (z) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:409, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:413; (aa) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:419, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:423; (ab) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:429, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:433; (ac) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:439, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:443; (ad) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:449, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:453; (ae) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:480, and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:484; (af) the Vα or Vγ region comprises a complementarity determining region 3 (CDR-3) comprising SEQ ID NO: 459, 460, 461, 462, 463, 464, 476, or 477, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 465, 466, 467, 468, 469, 478, or 479; (ag) the Vα or Vγ region comprises a CDR-3 that comprises SEQ ID NO:463 and the Vβ or Vδ region comprises a CDR-3 that comprises SEQ ID NO:469; (ah) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 470, 471, 472, 473, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO: 57; or (ai) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO:474, and the Vβ or Vδ region comprises a CDR-3 comprising SEQ ID NO:475; Nucleic acid.

2. The T cell receptor (TCR) or antigen-binding fragment thereof, (a) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:1, a CDR-2 comprising SEQ ID NO:2, and a CDR-3 comprising SEQ ID NO:51, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:57; (b) the Vα or Vγ region comprises a complementarity determining region 1 (CDR-1) comprising SEQ ID NO:1, a complementarity determining region 2 (CDR-2) comprising SEQ ID NO:2, and a complementarity determining region 3 (CDR-3) comprising SEQ ID NO:3, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:11; (c) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:19, a CDR-2 comprising SEQ ID NO:20, and a CDR-3 comprising SEQ ID NO:21, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:27; (d) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:35, a CDR-2 comprising SEQ ID NO:36, and a CDR-3 comprising SEQ ID NO:37, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:43; (e) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:1, a CDR-2 comprising SEQ ID NO:2, and a CDR-3 comprising SEQ ID NO:65, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:57; (f) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:76, a CDR-2 comprising SEQ ID NO:77, and a CDR-3 comprising SEQ ID NO:78, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:84; (g) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:19, a CDR-2 comprising SEQ ID NO:20, and a CDR-3 comprising SEQ ID NO:92, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:98; (h) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:76, a CDR-2 comprising SEQ ID NO:77, and a CDR-3 comprising SEQ ID NO:106, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:112; (i) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:35, a CDR-2 comprising SEQ ID NO:36, and a CDR-3 comprising SEQ ID NO:120, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:126; (j) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:134, a CDR-2 comprising SEQ ID NO:135, and a CDR-3 comprising SEQ ID NO:136, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:142; (k) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:150, a CDR-2 comprising SEQ ID NO:151, and a CDR-3 comprising SEQ ID NO:152, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:158; (l) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:35, a CDR-2 comprising SEQ ID NO:36, and a CDR-3 comprising SEQ ID NO:166, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:172; (m) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:35, a CDR-2 comprising SEQ ID NO:36, and a CDR-3 comprising SEQ ID NO:180, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:186; (n) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:76, a CDR-2 comprising SEQ ID NO:77, and a CDR-3 comprising SEQ ID NO:194, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:200; (o) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:76, a CDR-2 comprising SEQ ID NO:77, and a CDR-3 comprising SEQ ID NO:208, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:214; (p) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:222, a CDR-2 comprising SEQ ID NO:223, and a CDR-3 comprising SEQ ID NO:224, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:230; (q) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:76, a CDR-2 comprising SEQ ID NO:77, and a CDR-3 comprising SEQ ID NO:238, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:244; (r) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:19, a CDR-2 comprising SEQ ID NO:20, and a CDR-3 comprising SEQ ID NO:252, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:258; (s) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:266, a CDR-2 comprising SEQ ID NO:267, and a CDR-3 comprising SEQ ID NO:268, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:158; (t) the Vα or Vγ region comprises a CDR-1 comprising SEQ ID NO:19, a CDR-2 comprising SEQ ID NO:20, and a CDR-3 comprising SEQ ID NO:278, and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO:9, a CDR-2 comprising SEQ ID NO:10, and a CDR-3 comprising SEQ ID NO:284; (u) the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO:360, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:364; (v) the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO:370, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:374; (w) the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO:380, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:384; (x) the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO:390, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:394; (y) the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO:400, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:404; (z) the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO:410, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:414; (aa) the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO:420, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:424; (ab) the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO:430, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:434; (ac) the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO:440, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:444; (ad) the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO:450, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:454; (ae) the Vα or Vγ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vα or Vγ region sequence of SEQ ID NO:481, and the Vβ or Vδ region comprises CDR-1, CDR-2, and CDR-3 that comprise the CDR-1, CDR-2, and CDR-3, respectively, contained within the Vβ or Vδ region sequence of SEQ ID NO:485; or (af) the Vα or Vγ region comprises a CDR-3 comprising SEQ ID NO: 459, 460, 461, 462, 463, 464, 476, or 477, and (i) a CDR-1 comprising SEQ ID NO:1, and a CDR-2 comprising SEQ ID NO:2; (ii) CDR-1 comprising SEQ ID NO:19, and CDR-2 comprising SEQ ID NO:20; (iii) CDR-1 comprising SEQ ID NO:35, and CDR-2 comprising SEQ ID NO:36; (iv) CDR-1 comprising SEQ ID NO:76, and CDR-2 comprising SEQ ID NO:77; (v) CDR-1 comprising SEQ ID NO: 134, and CDR-2 comprising SEQ ID NO: 135; (vi) CDR-1 comprising SEQ ID NO: 150, and CDR-2 comprising SEQ ID NO: 151; (vii) CDR-1 comprising SEQ ID NO: 222 and CDR-2 comprising SEQ ID NO: 223; or (viii) CDR-1 comprising SEQ ID NO:266, and CDR-2 comprising SEQ ID NO:267; and the Vβ or Vδ region comprises a CDR-1 comprising SEQ ID NO: 9, a CDR-2 comprising SEQ ID NO: 10, and a CDR-3 comprising SEQ ID NO: 465, 466, 467, 468, 469, 478, or 479; The nucleic acid of claim 1.

3. The following: (a) the Vα or Vγ region comprises SEQ ID NO:52, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:58, or a sequence having at least 90% sequence identity thereto; (b) the Vα or Vγ region comprises SEQ ID NO:4, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:12, or a sequence having at least 90% sequence identity thereto; (c) the Vα or Vγ region comprises SEQ ID NO:22, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:28, or a sequence having at least 90% sequence identity thereto; (d) the Vα or Vγ region comprises SEQ ID NO:38, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:44, or a sequence having at least 90% sequence identity thereto; (e) the Vα or Vγ region comprises SEQ ID NO:66, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:58, or a sequence having at least 90% sequence identity thereto; (f) the Vα or Vγ region comprises SEQ ID NO:79, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:85, or a sequence having at least 90% sequence identity thereto; (g) the Vα or Vγ region comprises SEQ ID NO:93, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:99, or a sequence having at least 90% sequence identity thereto; (h) the Vα or Vγ region comprises SEQ ID NO: 107, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 113, or a sequence having at least 90% sequence identity thereto; (i) the Vα or Vγ region comprises SEQ ID NO: 121, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 127, or a sequence having at least 90% sequence identity thereto; (j) the Vα or Vγ region comprises SEQ ID NO: 137, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 143, or a sequence having at least 90% sequence identity thereto; (k) the Vα or Vγ region comprises SEQ ID NO: 153, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 159, or a sequence having at least 90% sequence identity thereto; (l) the Vα or Vγ region comprises SEQ ID NO: 167, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 173, or a sequence having at least 90% sequence identity thereto; (m) the Vα or Vγ region comprises SEQ ID NO:181, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:187, or a sequence having at least 90% sequence identity thereto; (n) the Vα or Vγ region comprises SEQ ID NO: 195, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO: 201, or a sequence having at least 90% sequence identity thereto; (o) the Vα or Vγ region comprises SEQ ID NO:209, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:215, or a sequence having at least 90% sequence identity thereto; (p) the Vα or Vγ region comprises SEQ ID NO:225, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:231, or a sequence having at least 90% sequence identity thereto; (q) the Vα or Vγ region comprises SEQ ID NO:239, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:245, or a sequence having at least 90% sequence identity thereto; (r) the Vα or Vγ region comprises SEQ ID NO:253, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:259, or a sequence having at least 90% sequence identity thereto; (s) the Vα or Vγ region comprises SEQ ID NO:269, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:159, or a sequence having at least 90% sequence identity thereto; (t) the Vα or Vγ region comprises SEQ ID NO:279, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:285, or a sequence having at least 90% sequence identity thereto; (u) the Vα or Vγ region comprises SEQ ID NO:360, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:364, or a sequence having at least 90% sequence identity thereto; (v) the Vα or Vγ region comprises SEQ ID NO:370, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:374, or a sequence having at least 90% sequence identity thereto; (w) the Vα or Vγ region comprises SEQ ID NO:380, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:384, or a sequence having at least 90% sequence identity thereto; (x) the Vα or Vγ region comprises SEQ ID NO:390, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:394, or a sequence having at least 90% sequence identity thereto; (y) the Vα or Vγ region comprises SEQ ID NO:400, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:404, or a sequence having at least 90% sequence identity thereto; (z) the Vα or Vγ region comprises SEQ ID NO:410, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:414, or a sequence having at least 90% sequence identity thereto; (aa) the Vα or Vγ region comprises SEQ ID NO:420, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:424, or a sequence having at least 90% sequence identity thereto; (ab) the Vα or Vγ region comprises SEQ ID NO:430, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:434, or a sequence having at least 90% sequence identity thereto; (ac) the Vα or Vγ region comprises SEQ ID NO:440, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:444, or a sequence having at least 90% sequence identity thereto; (ad) the Vα or Vγ region comprises SEQ ID NO:450, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:454, or a sequence having at least 90% sequence identity thereto; or (ae) the Vα or Vγ region comprises SEQ ID NO:481, or a sequence having at least 90% sequence identity thereto, and the Vβ or Vδ region comprises SEQ ID NO:485, or a sequence having at least 90% sequence identity thereto; The nucleic acid of claim 1.

4. the alpha chain further comprises an alpha constant (Cα) region and the beta chain further comprises a beta constant (Cβ) region; or The gamma chain further comprises a gamma constant (Cγ) region and the delta chain further comprises a delta constant (Cδ) region. The nucleic acid of claim 1.

5. 5. The nucleic acid of claim 4, wherein the Cα comprises SEQ ID NO:294 or SEQ ID NO:296 and the Cβ comprises SEQ ID NO:297 or SEQ ID NO:

299.

6. (a) the alpha or gamma chain comprises SEQ ID NO:54 and the beta or delta chain comprises SEQ ID NO:60; (b) the alpha or gamma chain comprises SEQ ID NO:6 and the beta or delta chain comprises SEQ ID NO:14; (c) the alpha or gamma chain comprises SEQ ID NO:24 and the beta or delta chain comprises SEQ ID NO:30; (d) the alpha or gamma chain comprises SEQ ID NO:40 and the beta or delta chain comprises SEQ ID NO:46; (e) the alpha or gamma chain comprises SEQ ID NO:68 and the beta or delta chain comprises SEQ ID NO:71; (f) the alpha or gamma chain comprises SEQ ID NO:81 and the beta or delta chain comprises SEQ ID NO:87; (g) the alpha or gamma chain comprises SEQ ID NO:95 and the beta or delta chain comprises SEQ ID NO:101; (h) the alpha or gamma chain comprises SEQ ID NO: 109 and the beta or delta chain comprises SEQ ID NO: 115; (i) the alpha or gamma chain comprises SEQ ID NO:123 and the beta or delta chain comprises SEQ ID NO:129; (j) the alpha or gamma chain comprises SEQ ID NO: 139 and the beta or delta chain comprises SEQ ID NO: 145; (k) the alpha or gamma chain comprises SEQ ID NO:155 and the beta or delta chain comprises SEQ ID NO:161; (l) the alpha or gamma chain comprises SEQ ID NO:169 and the beta or delta chain comprises SEQ ID NO:175; (m) the alpha or gamma chain comprises SEQ ID NO:183 and the beta or delta chain comprises SEQ ID NO:189; (n) the alpha or gamma chain comprises SEQ ID NO: 197 and the beta or delta chain comprises SEQ ID NO: 203; (o) the alpha or gamma chain comprises SEQ ID NO:211 and the beta or delta chain comprises SEQ ID NO:217; (p) the alpha or gamma chain comprises SEQ ID NO:227 and the beta or delta chain comprises SEQ ID NO:233; (q) the alpha or gamma chain comprises SEQ ID NO:241 and the beta or delta chain comprises SEQ ID NO:247; (r) the alpha or gamma chain comprises SEQ ID NO:255 and the beta or delta chain comprises SEQ ID NO:261; (s) the alpha or gamma chain comprises SEQ ID NO:271 and the beta or delta chain comprises SEQ ID NO:161; (t) the alpha or gamma chain comprises SEQ ID NO:281 and the beta or delta chain comprises SEQ ID NO:287; (u) the alpha or gamma chain comprises SEQ ID NO:362 and the beta or delta chain comprises SEQ ID NO:366; (v) the alpha or gamma chain comprises SEQ ID NO:372 and the beta or delta chain comprises SEQ ID NO:376; (w) the alpha or gamma chain comprises SEQ ID NO:382 and the beta or delta chain comprises SEQ ID NO:386; (x) the alpha or gamma chain comprises SEQ ID NO:392 and the beta or delta chain comprises SEQ ID NO:396; (y) the alpha or gamma chain comprises SEQ ID NO:402 and the beta or delta chain comprises SEQ ID NO:406; (z) the alpha or gamma chain comprises SEQ ID NO:412 and the beta or delta chain comprises SEQ ID NO:416; (aa) the alpha or gamma chain comprises SEQ ID NO:422 and the beta or delta chain comprises SEQ ID NO:426; (ab) the alpha or gamma chain comprises SEQ ID NO:432 and the beta or delta chain comprises SEQ ID NO:436; (ac) the alpha or gamma chain comprises SEQ ID NO:442 and the beta or delta chain comprises SEQ ID NO:446; (ad) the alpha or gamma chain comprises SEQ ID NO:452 and the beta or delta chain comprises SEQ ID NO:456; or (ae) the alpha or gamma chain comprises SEQ ID NO: 483, and the beta or delta chain comprises SEQ ID NO: 487; The nucleic acid according to claim 4.

7. The nucleic acid described in claim 1, wherein the encoded TCR or antigen-binding fragment thereof recognizes HA-1 in association with a human leukocyte antigen (HLA)-A molecule of serotype HLA-A*02:01 or serotype HLA-A*02:

06.

8. The nucleic acid of claim 1, wherein the encoded TCR or antigen-binding fragment thereof recognizes a peptide having the sequence VLHDDLLEA (SEQ ID NO:354) with higher affinity than a peptide having the sequence VLRDDLLEA (SEQ ID NO:355).

9. The nucleic acid comprising: (a) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:55, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:61, or a sequence having at least 90% sequence identity thereto; (b) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:7, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:15, or a sequence having at least 90% sequence identity thereto; (c) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:25, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:31, or a sequence having at least 90% sequence identity thereto; (d) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:41, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:47, or a sequence having at least 90% sequence identity thereto; (e) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:69, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:72, or a sequence having at least 90% sequence identity thereto; (f) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:82, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:88, or a sequence having at least 90% sequence identity thereto; (g) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:96, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:102, or a sequence having at least 90% sequence identity thereto; (h) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:110, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:116, or a sequence having at least 90% sequence identity thereto; (i) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 124, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 130, or a sequence having at least 90% sequence identity thereto; (j) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:140, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:146, or a sequence having at least 90% sequence identity thereto; (k) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 156, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 162, or a sequence having at least 90% sequence identity thereto; (l) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 170, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 176, or a sequence having at least 90% sequence identity thereto; (m) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:184, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:190, or a sequence having at least 90% sequence identity thereto; (n) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:198, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:204, or a sequence having at least 90% sequence identity thereto; (o) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:212, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:218, or a sequence having at least 90% sequence identity thereto; (p) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:228, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:234, or a sequence having at least 90% sequence identity thereto; (q) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:242, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:248, or a sequence having at least 90% sequence identity thereto; (r) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:256, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:262, or a sequence having at least 90% sequence identity thereto; (s) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:272, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:274, or a sequence having at least 90% sequence identity thereto; (t) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:282, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:288, or a sequence having at least 90% sequence identity thereto; (u) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:301, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:321; (v) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:302, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:322; (w) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:303, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:323; (x) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:304, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:324; (y) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:305, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:325; (z) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:306, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:326; (aa) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:307, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:327; (ab) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:308, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:328; (ac) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:309, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:329; (ad) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:310, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:330; (ae) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:311, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:331; (af) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:312, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:332; (ag) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:313, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:333; (ah) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:314, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:334; (ai) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:315, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:335; (aj) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:316, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:336; (ak) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:317, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:337; (al) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:318, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:338; (am) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO:319, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO:339; or (an) the nucleotide sequence encoding the Vα or Vγ region comprises SEQ ID NO: 320, and the nucleotide sequence encoding the Vβ or Vδ region comprises SEQ ID NO: 340; The nucleic acid of claim 1.

10. The nucleic acid comprising: (a) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:56, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:62, or a sequence having at least 90% sequence identity thereto; (b) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:8, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:16, or a sequence having at least 90% sequence identity thereto; (c) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:26, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:32, or a sequence having at least 90% sequence identity thereto; (d) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:42, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:48, or a sequence having at least 90% sequence identity thereto; (e) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:70, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:73, or a sequence having at least 90% sequence identity thereto; (f) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:83, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:89, or a sequence having at least 90% sequence identity thereto; (g) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:97, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:103, or a sequence having at least 90% sequence identity thereto; (h) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:111, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:117, or a sequence having at least 90% sequence identity thereto; (i) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:125, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:131, or a sequence having at least 90% sequence identity thereto; (j) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:141, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:147, or a sequence having at least 90% sequence identity thereto; (k) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:157, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:163, or a sequence having at least 90% sequence identity thereto; (l) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:171, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:177, or a sequence having at least 90% sequence identity thereto; (m) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:185, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:191, or a sequence having at least 90% sequence identity thereto; (n) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:199, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:205, or a sequence having at least 90% sequence identity thereto; (o) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:213, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:219, or a sequence having at least 90% sequence identity thereto; (p) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:229, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:235, or a sequence having at least 90% sequence identity thereto; (q) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:243, or a sequence with at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:249, or a sequence with at least 90% sequence identity thereto; (r) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:257, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:263, or a sequence having at least 90% sequence identity thereto; (s) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:273, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:275, or a sequence having at least 90% sequence identity thereto; (t) the nucleotide sequence encoding the alpha or gamma chain comprises SEQ ID NO:283, or a sequence having at least 90% sequence identity thereto, and the nucleotide sequence encoding the beta or delta chain comprises SEQ ID NO:289, or a sequence having at least 90% sequence identity thereto; The nucleic acid of claim 1.

11. The nucleic acid of claim 10, wherein the nucleotide sequence encoding the alpha chain and the nucleotide sequence encoding the beta chain are provided in a single open reading frame and are separated by a nucleic acid sequence encoding a peptide sequence that causes ribosome skipping.

12. the peptide that causes ribosome skipping comprises a P2A peptide; Optionally, the P2A peptide comprises SEQ ID NO:352, The P2A peptide is encoded by a sequence comprising SEQ ID NO:

351. The nucleic acid of claim 11.

13. (a) the single open reading frame encodes SEQ ID NO:64; (b) the single open reading frame encodes SEQ ID NO:18; (c) the single open reading frame encodes SEQ ID NO:34; (d) the single open reading frame encodes SEQ ID NO:50; (e) the single open reading frame encodes SEQ ID NO:75; (f) the single open reading frame encodes SEQ ID NO:91; (g) the single open reading frame encodes SEQ ID NO:105; (h) the single open reading frame encodes SEQ ID NO:119; (i) the single open reading frame encodes SEQ ID NO:133; (j) the single open reading frame encodes SEQ ID NO:149; (k) the single open reading frame encodes SEQ ID NO: 165; (l) the single open reading frame encodes SEQ ID NO:179; (m) the single open reading frame encodes SEQ ID NO:193; (n) the single open reading frame encodes SEQ ID NO:207; (o) the single open reading frame encodes SEQ ID NO:221; (p) the single open reading frame encodes SEQ ID NO:237; (q) the single open reading frame encodes SEQ ID NO:251; (r) the single open reading frame encodes SEQ ID NO:265; (s) the single open reading frame encodes SEQ ID NO:277; (t) the single open reading frame encodes SEQ ID NO:291; (u) the single open reading frame encodes SEQ ID NO:367; (v) the single open reading frame encodes SEQ ID NO:377; (w) the single open reading frame encodes SEQ ID NO:387; (x) the single open reading frame encodes SEQ ID NO:397; (y) the single open reading frame encodes SEQ ID NO:407; (z) the single open reading frame encodes SEQ ID NO:417; (aa) the single open reading frame encodes SEQ ID NO:427; (ab) the single open reading frame encodes SEQ ID NO:437; (ac) the single open reading frame encodes SEQ ID NO:447; (ad) the single open reading frame encodes SEQ ID NO:457; or (ae) the single open reading frame encodes SEQ ID NO:488; The nucleic acid of claim 12.

14. The single open reading frame comprises: (a) the nucleotide sequence of SEQ ID NO:63; (b) the nucleotide sequence of SEQ ID NO:17; (c) the nucleotide sequence of SEQ ID NO:33; (d) the nucleotide sequence of SEQ ID NO:49; (e) the nucleotide sequence of SEQ ID NO:74; (f) the nucleotide sequence of SEQ ID NO:90; (g) the nucleotide sequence of SEQ ID NO: 104; (h) the nucleotide sequence of SEQ ID NO: 118; (i) the nucleotide sequence of SEQ ID NO: 132; (j) the nucleotide sequence of SEQ ID NO: 148; (k) the nucleotide sequence of SEQ ID NO: 164; (l) the nucleotide sequence of SEQ ID NO: 178; (m) the nucleotide sequence of SEQ ID NO: 192; (n) the nucleotide sequence of SEQ ID NO: 206; (o) the nucleotide sequence of SEQ ID NO: 220; (p) the nucleotide sequence of SEQ ID NO: 236; (q) the nucleotide sequence of SEQ ID NO: 250; (r) the nucleotide sequence of SEQ ID NO: 264; (s) the nucleotide sequence of SEQ ID NO: 276; (t) the nucleotide sequence of SEQ ID NO: 290; (u) the nucleotide sequence of SEQ ID NO: 368; (v) the nucleotide sequence of SEQ ID NO: 378; (w) the nucleotide sequence of SEQ ID NO: 388; (x) the nucleotide sequence of SEQ ID NO: 398; (y) the nucleotide sequence of SEQ ID NO: 408; (z) the nucleotide sequence of SEQ ID NO:418; (aa) the nucleotide sequence of SEQ ID NO: 428; (ab) the nucleotide sequence of SEQ ID NO: 438; (ac) the nucleotide sequence of SEQ ID NO:448; (ad) the nucleotide sequence of SEQ ID NO: 458; or (ae) the nucleotide sequence of SEQ ID NO: 489 The nucleic acid of claim 13 .

15. 15. A vector comprising the nucleic acid of any one of claims 1 to 14, optionally wherein the vector is a viral vector, optionally wherein the viral vector is a lentiviral vector.

16. 15. A modified cell comprising the nucleic acid of any one of claims 1 to 14, optionally wherein the modified cell is a primary cell obtained from a subject.

17. The modified cell of claim 16, wherein the modified cell is a T cell.

18. 20. A composition comprising the modified cell of claim 17, optionally further comprising a pharma- ceutically acceptable excipient.

19. A pharmaceutical composition comprising the modified cells of claim 16 for use in treating a malignant blood injury in a subject.

20. 20. The pharmaceutical composition of claim 19, wherein the subject is eligible for or is scheduled to undergo allogeneic hematopoietic stem cell transplantation (HSCT).

21. 20. The pharmaceutical composition of claim 19, wherein the subject has or has been diagnosed with a liquid tumor, a hematopoietic tumor, a lymphoma, a chronic myelogenous leukemia, an acute myelogenous leukemia (AML), a myelodysplastic syndrome (MDS), or an acute lymphoblastic leukemia (ALL).

22. A pharmaceutical composition for use in treating a malignant blood disorder in a subject, comprising a TCR or an antigen-binding fragment thereof encoded by a nucleic acid described in any one of claims 1 to 14.

23. The pharmaceutical composition of claim 22, wherein the subject is eligible for or is scheduled to undergo allogeneic hematopoietic stem cell transplantation (HSCT).

24. The pharmaceutical composition of claim 22, wherein the subject has a liquid tumor, a hematopoietic tumor, lymphoma, chronic myeloid leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or acute lymphoblastic leukemia (ALL), or has been diagnosed with a liquid tumor, a hematopoietic tumor, lymphoma, chronic myeloid leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or acute lymphoblastic leukemia (ALL).

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