Antigen binding proteins targeting a common antigen

Abstract

Provided herein are HLA-peptide targets and antigen binding proteins that bind HLA- peptide targets. Also disclosed herein are methods of identifying the HLA-peptide targets and identifying one or more antigen binding proteins that bind a given HLA-peptide target.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 547,146, filed August 18, 2017, and U.S. Provisional Application No. 62 / 581,368, filed November 3, 2017, which are incorporated by reference herein in their entireties for all purposes.

[0003] SEQUENCE LISTING

[0004] The instant application contains a Sequence Listing which has been filed electronically in ASCII format and which is incorporated by reference herein in its entirety. The ASCII copy, created on August 16, 2018, is named 40698PCT_CRF_sequencelisting.txt and is 1,591,443 bytes in size. BACKGROUND

[0005] To provide antigen-specific protection against pathogens, the immune system employs two types of immune responses, the humoral immune response and the cellular immune response, which are mediated by B lymphocytes and T lymphocytes, respectively, that specifically recognize pathogen antigens.

[0006] Since T lymphocytes are the antigen-specific effectors of cellular immunity, T lymphocytes play a central role in the body's defense against diseases mediated by intracellular pathogens, such as viruses, intracellular bacteria, mycoplasmas, and intracellular parasites, by directly cytolysing cells infected by such pathogens. The specificity of the T lymphocyte response is conferred by and activated by the T cell receptor (TCR). The T cell receptor is an antigen-specific receptor that is clonally distributed among individual T lymphocytes, and its antigen-specific repertoire is generated via somatic gene rearrangement mechanisms similar to those involved in generating the repertoire of antibody genes. The T cell receptor comprises a heterodimer of transmembrane molecules, the major type of which is composed of a-β polypeptide dimers and a smaller subset of γ-δ polypeptide dimers. The T lymphocyte receptor subunits include variable and constant regions similar to immunoglobulins in the extracellular domain, a short hinge region with cysteines that facilitate pairing of the a and β chains, a transmembrane, and a short cytoplasmic region. TCR-triggered signal transduction is indirectly mediated by CD3-ζ, an associated multi-subunit complex that includes signal transducing subunits.

[0007] The T lymphocyte receptor does not normally recognize native antigens, but rather recognizes complexes displayed on the surface of cells, including fragments of intracellularly processed antigens associated with major histocompatibility complex (MHC) molecules used to present peptide antigens. Major histocompatibility complex genes are highly polymorphic within a species population, including multiple common alleles of each individual gene.

[0008] Major histocompatibility complex class I molecules are expressed on the surface of almost all nucleated cells in the body and are dimeric molecules comprising a transmembrane heavy chain (including a peptide antigen binding groove) and a smaller extracellular chain called β2-microglobulin. The peptides presented by MHC class I molecules are derived from cytosolic proteins degraded by the proteasome, a multi-unit structure in the cytoplasm (Niedermann G., 2002 Curr Top Microbiol Immunol 268:91-136; for processing of bacterial antigens, see Wick MJ and Ljunggren HG, 1999 Immunol Rev. 172:153-62). The cleaved peptides are transported by TAP to the lumen of the endoplasmic reticulum (ER) and bind to the groove of the class I assembly molecule, which then transports the resulting MHC / peptide complex to the cell membrane, enabling the antigen to be presented to T lymphocytes (Yewdell JW., 2001. Trends Cell Biol. 11:294-7; Yewdell JW and Bennink JR., 2001. Curr Opin Immunol. 13:13-8). Alternatively, cleaved peptides can be loaded onto MHC class I molecules in a TAP-independent manner, and proteins of extracellular origin can also be presented by the process of cross-presentation. In this way, once the identity of the complex (peptide sequence and MHC subtype) is determined, a specific MHC / peptide complex presents a novel protein structure on the cell surface that can be targeted by novel antigen-binding proteins (e.g., antibodies or TCRs).

[0009] Tumor cells can express antigens, and such antigens can be displayed on the surface of tumor cells. Such tumor-associated antigens can be used to develop novel immunotherapeutic reagents to specifically target tumor cells. For example, tumor-associated antigens can be used to identify therapeutic antigen-binding proteins, e.g., TCRs, antibodies, or antigen-binding fragments. Such tumor-associated antigens can also be used in pharmaceutical compositions, e.g., vaccines. SUMMARY

[0010] In an aspect, provided herein is an isolated antigen binding protein (ABP) that specifically binds to a human leukocyte antigen (HLA)-peptide target, wherein the HLA-peptide target comprises an HLA-restricted peptide complexed with an HLA class I molecule, wherein the HLA-restricted peptide is located in a peptide binding groove of an alpha 1 / alpha 2 heterodimer portion of the HLA class I molecule, and wherein: the HLA class I molecule is HLA subtype A*02:01 and the HLA-restricted peptide comprises the sequence LLASSILCA; the HLA class I molecule is HLA subtype A*01:01 and the HLA-restricted peptide comprises the sequence EVDPIGHLY; the HLA class I molecule is HLA subtype B*44:02 and the HLA-restricted peptide comprises the sequence GEMSSNSTAL; the HLA class I molecule is HLA subtype A*02:01 and HLA-restricted peptide comprises the sequence GVYDGEEHSV; the HLA class I molecule is HLA subtype *01:01 and the HLA-restricted peptide comprises the sequence EVDPIGHVY; or the HLA class I molecule is HLA subtype HLA-A*01:01 and the HLA-restricted peptide comprises the sequence NTDNNLAVY.

[0011] In some embodiments, the HLA class I molecule is HLA subtype A*02:01 and the HLA-restricted peptide consists of the sequence LLASSILCA; the HLA class I molecule is HLA subtype A*01:01 and the HLA-restricted peptide consists of the sequence EVDPIGHLY; the HLA class I molecule is HLA subtype B*44:02 and the HLA-restricted peptide consists of the sequence GEMSSNSTAL; the HLA class I molecule is HLA subtype A*02:01 and the HLA-restricted peptide consists of the sequence GVYDGEEHSV; the HLA class I molecule is HLA subtype *01:01 and the HLA-restricted peptide consists of the sequence EVDPIGHVY; or the HLA class I molecule is HLA subtype HLA-A*01:01 and the HLA-restricted peptide consists of the sequence NTDNNLAVY.

[0012] In some embodiments, the HLA-restricted peptide is between about 5 and 15 amino acids in length. In some embodiments, the HLA-restricted peptide is between about 8 and 12 amino acids in length.

[0013] In an aspect, the ABP comprises an antibody or antigen binding fragment thereof.

[0014] In some embodiments, the HLA Class I molecule is HLA subtype A*02:01, and the HLA- restricted peptide comprises the sequence LLASSILCA. In some embodiments, the ABP comprises a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOS: 3025-3032. In some embodiments, the ABP comprises a CDR-L3 comprising the sequence set forth in any one of SEQ ID NOS: 3043-3050. In some embodiments, the ABP comprises a CDR-H3 and a CDR-L3 from an scFv designated G7R3-P1C6, G7R3-P1G10, 1-G7R3-P1B4, 2-G7R4-P2C2, 3-G7R4-P1A3, 4-G7R4-B5-P2E9, 5-G7R4-B10-P1F8, or B7 (G7R3-P3A9). In some embodiments, the ABP comprises all three heavy chain CDRs and all three light chain CDRs from an scFv designated G7R3-P1C6, G7R3-P1G10, 1-G7R3-P1B4, 2-G7R4-P2C2, 3-G7R4-P1A3, 4-G7R4-B5-P2E9, 5-G7R4-B10-P1F8, or B7 (G7R3-P3A9). In some embodiments, the ABP comprises a VH sequence selected from SEQ ID NOS: 2994-3001. In some embodiments, the ABP comprises a VL sequence selected from SEQ ID NOS: 3002-3009. In some embodiments, the ABP comprises a VH sequence and a VL sequence from an scFv designated G7R3-P1C6, G7R3-P1G10, 1-G7R3-P1B4, 2-G7R4-P2C2, 3-G7R4-P1A3, 4-G7R4-B5-P2E9, 5-G7R4-B10-P1F8, or B7 (G7R3-P3A9). In some embodiments, the ABP binds to the HLA- peptide target via any one or more of residues 1-5 of the restricting peptide LLASSILCA.

[0015] In some embodiments, the HLA Class I molecule is HLA subtype HLA-A*01:01, and the HLA-restricted peptide comprises the sequence NTDNNLAVY. In some embodiments, the ABP comprises a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 2902-2933. In some embodiments, the ABP comprises a CDR-L3 comprising the sequence set forth in any one of SEQ ID NOs: 2971-2993. In some embodiments, the ABP comprises a CDR-H3 and a CDR-L3 from an scFv designated G2-P2E07, G2-P2E03, G2-P2A11, G2-P2C06, G2-P1G01, G2-P1C02, G2-P1H01, G2-P1B12, G2-P1B06, G2-P2H10, G2-P1H10, G2-P2C11, G2-P1C09, G2-P1A10, G2-P1B10, G2-P1D07, G2-P1E05, G2-P1D03, G2-P1G12, G2-P2H11, G2-P1C03, G2-P1G07, G2-P1F12, G2-P1G03, G2-P2B08, G2-P2A10, G2-P2D04, G2-P1C06, G2-P2A09, G2-P1B08, G2-P1E03, G2-P2A03, G2-P2F01, G2-P1H11, or G2-P1D06. In some embodiments, the ABP comprises all three heavy chain CDRs and all three light chain CDRs from an scFv designated G2-P2E07, G2-P2E03, G2-P2A11, G2-P2C06, G2-P1G01, G2-P1C02, G2-P1H01, G2-P1B12, G2-P1B06, G2-P2H10, G2-P1H10, G2-P2C11, G2-P1C09, G2-P1A10, G2-P1B10, G2-P1D07, G2-P1E05, G2-P1D03, G2-P1G12, G2-P2H11, G2-P1C03, G2-P1G07, G2-P1F12, G2-P1G03, G2-P2B08, G2-P2A10, G2-P2D04, G2-P1C06, G2-P2A09, G2-P1B08, G2-P1E03, G2-P2A03, G2-P2F01, G2-P1H11, or G2-P1D06. In some embodiments, the ABP comprises a VH sequence selected from SEQ ID NOs: 2781-2815. In some embodiments, the ABP comprises a VL sequence selected from SEQ ID NOs: 2816-2850.In some embodiments, the ABP comprises a VH sequence and a VL sequence from an scFv designated G2-P2E07, G2-P2E03, G2-P2A11, G2-P2C06, G2-P1G01, G2-P1C02, G2-P1H01, G2-P1B12, G2-P1B06, G2-P2H10, G2-P1H10, G2-P2C11, G2-P1C09, G2-P1A10, G2-P1B10, G2-P1D07, G2-P1E05, G2-P1D03, G2-P1G12, G2-P2H11, G2-P1C03, G2-P1G07, G2-P1F12, G2-P1G03, G2-P2B08, G2-P2A10, G2-P2D04, G2-P1C06, G2-P2A09, G2-P1B08, G2-P1E03, G2-P2A03, G2-P2F01, G2-P1H11, or G2-P1D06. In some embodiments, the ABP binds to an HLA-peptide target through residues 6-9 of the restricting peptide NTDNNLAVY and residues 157-160 of HLA subtype allele A*0101. In some embodiments, the ABP binds to an HLA-peptide target via residues 3-8 of the restricting peptide NTDNNLAVY.

[0016] In another aspect, the ABP comprises a T cell receptor (TCR) or an antigen binding portion thereof. In some embodiments, the TCR or antigen binding portion thereof comprises a TCR variable region. In some embodiments, the TCR or antigen binding portion thereof comprises one or more TCR complementarity determining regions (CDRs). In some embodiments, the TCR comprises an alpha chain and a beta chain. In some embodiments, the TCR comprises a gamma chain and a delta chain. In some embodiments, the antigen binding protein is part of a chimeric antigen receptor (CAR) comprising: an extracellular portion comprising an antigen binding protein; and an intracellular signaling domain. In some embodiments, the antigen binding protein comprises an scFv and the intracellular signaling domain comprises an ITAM. In some embodiments, the intracellular signaling domain comprises a signaling domain of a zeta chain of a CD3-zeta (CD3) chain. In some embodiments, the ABP further comprises a transmembrane domain linking the extracellular domain and the intracellular signaling domain. In some embodiments, the transmembrane domain comprises a transmembrane portion of CD28. In some embodiments, the ABP further comprises an intracellular signaling domain of a T cell costimulatory molecule. In some embodiments, the T cell costimulatory molecule is CD28, 4-1BB, OX-40, ICOS, or any combination thereof.

[0017] In some embodiments, the HLA Class I molecule is HLA subtype A*02:01, and the HLA- restricted peptide comprises the sequence LLASSILCA. In some embodiments, the ABP comprises a TCR a CDR3 sequence that is SEQ ID NO: 4277, 4278, 4279, 4280, or 4281. In some embodiments, the ABP comprises a TCR b CDR3 sequence that is any one of SEQ ID NOS: 4291-4295. In some embodiments, the ABP comprises a CDR3 a and CDR3 b sequence from any one of TCR clonotype ID#: TCR19, TCR21, TCR22, TCR18, or TCR23. In some embodiments, the ABP comprises a TCR a variable (TRAV) amino acid sequence, a TCR a joining (TRAJ) amino acid sequence, a TCR b variable (TRBV) amino acid sequence, a TCR b diversity (TRBD) amino acid sequence, and a TCR b joining (TRBJ) amino acid sequence, wherein each of the TRAV, TRAJ, TRBV, TRBD, and TRBJ amino acid sequences is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the corresponding TRAV, TRAJ, TRBV, TRBD, and TRBJ amino acid sequence of any one of TCR clonotype ID#: TCR19, TCR21, TCR22, TCR18, and TCR23. In some embodiments, the ABP comprises a TCR a constant (TRAC) amino acid sequence. In some embodiments, the ABP comprises a TCR b constant (TRBC) amino acid sequence. In some embodiments, the ABP comprises a TCR a VJ sequence that is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 4306-4310. In some embodiments, the ABP comprises a TCR b V(D)J sequence that is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 4321-4325. In some embodiments, the ABP comprises a TCR a VJ amino acid sequence and a TCR b V(D)J amino acid sequence, wherein each of the TCR a VJ and TCR b V(D)J amino acid sequences is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the corresponding TCR a VJ and TCR b V(D)J amino acid sequence of any one of TCR clonotype ID#: TCR19, TCR21, TCR22, TCR18, and TCR23.

[0018] In some embodiments, the HLA Class I molecule is HLA subtype A*01:01, and the HLA- restricted peptide comprises the sequence EVDPIGHLY. In some embodiments, the ABP comprises a TCR a CDR3 sequence that is any one of SEQ ID NOS: 4273-4276 or 3052-3350. In some embodiments, the ABP comprises a TCR b CDR3 sequence that is any one of SEQ ID NOS: 4287-4290 or 3351-3655. In some embodiments, the ABP comprises a CDR3 a and b sequence from any one of TCR ID#: TCR101-TCR469, TCR2, TCR4, TCR53, TCR54, or TCR101-TCR469. In some embodiments, the ABP comprises a TCR a variable (TRAV) amino acid sequence, a TCR a joining (TRAJ) amino acid sequence, a TCR b variable (TRBV) amino acid sequence, a TCR b diversity (TRBD) amino acid sequence, and a TCR b joining (TRBJ) amino acid sequence, wherein each of the TRAV, TRAJ, TRBV, TRBD, and TRBJ amino acid sequences are at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the corresponding TRAV, TRAJ, TRBV, TRBD, and TRBJ amino acid sequences of any one TCR clonotype selected from TCR ID#: TCR101-TCR469, TCR2, TCR4, TCR53, TCR54, or TCR101-TCR469. In some embodiments, the ABP comprises a TCR a constant (TRAC) amino acid sequence. In some embodiments, the ABP comprises a TCR b constant (TRBC) amino acid sequence. In some embodiments, the ABP comprises a TCR a VJ sequence that is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 3656-3961 or 4302-4305. In some embodiments, the ABP comprises a TCR b V(D)J sequence that is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 3962-4269 or 4317-4320. In some embodiments, the ABP comprises a TCR a VJ amino acid sequence and a TCR b V(D)J amino acid sequence, wherein each of the TCR a VJ and TCR b V(D)J amino acid sequences are at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the corresponding TCR a VJ and TCR b V(D)J amino acid sequences of any one TCR clonotype selected from TCR ID#: TCR101-TCR469, TCR2, TCR4, TCR53, and TCR54.

[0019] In some embodiments, the HLA class I molecule is HLA subtype B*44:02, and the HLA- restricted peptide comprises the sequence GEMSSNSTAL. In some embodiments, the ABP comprises a TCR a CDR3 sequence that is any one of SEQ ID NOS: 4284-4286 or 3138. In some embodiments, the ABP comprises a TCR b CDR3 sequence that is any one of SEQ ID NOS: 4298-4301. In some embodiments, the ABP comprises a CDR3 a and b sequence from any one of TCR ID#: TCR29, TCR30, TCR32, or TCR33. In some embodiments, the ABP comprises a TCR a variable (TRAV) amino acid sequence, a TCR a joining (TRAJ) amino acid sequence, a TCR b variable (TRBV) amino acid sequence, a TCR b diversity (TRBD) amino acid sequence, and a TCR b joining (TRBJ) amino acid sequence, wherein each of the TRAV, TRAJ, TRBV, TRBD, and TRBJ amino acid sequences is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the corresponding TRAV, TRAJ, TRBV, TRBD, and TRBJ amino acid sequences of any one TCR clonotype selected from TCR ID#: TCR29, TCR30, TCR32, or TCR33. In some embodiments, the ABP comprises a TCR a constant (TRAC) amino acid sequence. In some embodiments, the ABP comprises a TCR b constant (TRBC) amino acid sequence. In some embodiments, the ABP comprises a TCR a VJ sequence that is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 4313-4316. In some embodiments, the ABP comprises a TCR b V(D)J sequence that is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 4328-4331. In some embodiments, the ABP comprises a TCR a VJ amino acid sequence and a TCR b V(D)J amino acid sequence, wherein each of the TCR a VJ and TCR b V(D)J amino acid sequences is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the corresponding TCR a VJ and TCR b V(D)J amino acid sequences of any one TCR clonotype selected from TCR ID#: TCR29, TCR30, TCR32, or TCR33.

[0020] In some embodiments, the HLA Class I molecule is HLA subtype A*02:01, and the HLA- restricted peptide comprises the sequence GVYDGEEHSV. In some embodiments, the ABP comprises a TCR a CDR3 sequence that is SEQ ID NO: 4282 or 4283. In some embodiments, the ABP comprises a TCR b CDR3 sequence that is SEQ ID NO: 4296 or 4297. In some embodiments, the ABP comprises a CDR3 a and b sequence from TCR clonotype ID#: TCR26 or TCR28. In some embodiments, the ABP comprises a TCR a variable (TRAV) amino acid sequence, a TCR a joining (TRAJ) amino acid sequence, a TCR b variable (TRBV) amino acid sequence, a TCR b diversity (TRBD) amino acid sequence, and a TCR b joining (TRBJ) amino acid sequence, wherein each of the TRAV, TRAJ, TRBV, TRBD, and TRBJ amino acid sequences are at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the corresponding TRAV, TRAJ, TRBV, TRBD, and TRBJ amino acid sequences of TCR ID#: TCR26 or TCR28. In some embodiments, the ABP comprises a TCR a constant (TRAC) amino acid sequence. In some embodiments, the ABP comprises a TCR b constant (TRBC) amino acid sequence. In some embodiments, the ABP comprises a TCR a VJ sequence that is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 4311 or 4312. In some embodiments, the ABP comprises a TCR b V(D)J sequence that is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 4326 or 4327. In some embodiments, the ABP comprises a TCR a VJ amino acid sequence and a TCR b V(D)J amino acid sequence, wherein each of the TCR a VJ and TCR b (D)J amino acid sequences are at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the corresponding TCR a VJ and TCR b (D)J amino acid sequences of TCR ID#: TCR26 or TCR28.

[0021] In some embodiments, the HLA class I molecule is HLA subtype HLA-A*01:01 and the HLA- restricted peptide comprises the sequence NTDNNLAVY. In some embodiments, the HLA class I molecule is HLA subtype HLA-A*03:01 and the HLA-restricted peptide comprises the sequence GVHGGILNK. In some embodiments, the HLA class I molecule is HLA subtype HLA-A*01:01 and the HLA-restricted peptide comprises the sequence EVDPIGHVY.

[0022] In another aspect, provided herein is an isolated antigen binding protein (ABP) that specifically binds to a human leukocyte antigen (HLA)-peptide target, wherein the HLA-peptide target comprises an HLA-restricted peptide complexed with an HLA class I molecule, wherein the HLA-restricted peptide is located in a peptide binding groove of an alpha 1 / alpha 2 heterodimer portion of the HLA class I molecule, and wherein the HLA-peptide target is selected from Table A. In some embodiments, the HLA-restricted peptide is not from a gene selected from WT1 or MART1. In some embodiments, the HLA-restricted peptide is between about 5 to 15 amino acids in length. In some embodiments, the HLA-restricted peptide is between about 8 to 12 amino acids in length. In some embodiments, the ABP comprises an antibody or antigen binding fragment thereof.

[0023] In some embodiments of any of the antibodies or antigen binding fragments disclosed herein, the antigen binding protein is linked to a scaffold, optionally wherein the scaffold comprises serum albumin or Fc, optionally wherein Fc is human Fc and is of the IgG (IgGl, IgG2, IgG3, IgG4), IgA (IgAl, IgA2), IgD, IgE, or IgM class. In some embodiments of any of the antibodies or antigen binding fragments disclosed herein, the antigen binding protein is linked to a scaffold via a linker, optionally wherein the linker is a peptide linker, optionally wherein the peptide linker is a hinge region of a human antibody. In some embodiments of any of the antibodies or antigen binding fragments disclosed herein, the antigen binding protein comprises a Fv fragment, a Fab fragment, a F(ab')2 fragment, a Fab' fragment, a scFv fragment, a scFv-Fc fragment, and / or a single domain antibody or antigen binding fragment thereof. In some embodiments of any of the antibodies or antigen binding fragments disclosed herein, the antigen binding protein comprises a scFv fragment. In some embodiments of any of the antibodies or antigen binding fragments disclosed herein, the antigen binding protein comprises one or more antibody complementarity determining regions (CDRs), optionally six antibody CDRs. In some embodiments of any of the antibodies or antigen binding fragments disclosed herein, the antigen binding protein comprises an antibody. In some embodiments of any of the antibodies or antigen binding fragments disclosed herein, the antigen binding protein is a monoclonal antibody. In some embodiments of any of the antibodies or antigen binding fragments disclosed herein, the antigen binding protein is a humanized, human, or chimeric antibody. In some embodiments of any of the antibodies or antigen binding fragments disclosed herein, the antigen binding protein is multispecific, optionally bispecific. In some embodiments of any of the antibodies or antigen binding fragments disclosed herein, the antigen binding protein binds to more than one antigen or more than one epitope on a single antigen. In some embodiments of any of the antibodies or antigen binding fragments disclosed herein, the antigen binding protein comprises a heavy chain constant region selected from the IgG, IgA, IgD, IgE, and IgM class. In some embodiments of any of the antibodies or antigen binding fragments disclosed herein, the antigen binding protein comprises a heavy chain constant region of the human IgG class and a subclass selected from IgGl, IgG4, IgG2, and IgG3. In some embodiments of any of the antibodies or antigen binding fragments disclosed herein, the antigen binding protein comprises a modified Fc, optionally wherein the modified Fc comprises one or more mutations that prolong half-life, optionally wherein the one or more mutations that prolong half-life are YTE.

[0024] On the other hand, this article provides an isolated HLA-peptide target comprising an HLA-restricted peptide complexed with an HLAI class molecule, wherein the HLA-restricted peptide is located in the peptide binding groove of the α1 / α2 heterodimer portion of the HLAI class molecule, and wherein the HLA-peptide target is selected from Table A, provided that the isolated HLA-peptide target is not any of target numbers 6364-6369, 6386-6389, 6500, 6521-6524 or 6578 and is not an HLA-peptide target in Table B or Table C.

[0025] In some embodiments, the HLA class I molecule is HLA subtype A*02:01, and the HLA-restricted peptide includes the sequence LLASSILCA; the HLA class I molecule is HLA subtype A*01:01, and the HLA-restricted peptide includes the sequence EVDPIGHLY; the HLA class I molecule is HLA subtype B*44:02, and the HLA-restricted peptide includes the sequence GEMSSNSTAL; the HLA class I molecule is HLA subtype A*02:01 and the HLA-restricted HLA class I molecule is HLA subtype *01:01, and the HLA-restricted peptide includes the sequence EVDPIGHVY, and the restriction peptide includes the sequence GVYDGEEHSV; the HLA class I molecule is HLA subtype HLA-A*01:01, and the HLA-restricted peptide includes the sequence NTDNNLAVY. In some embodiments, the HLA class I molecule is HLA subtype A*02:01, and the HLA-restricted peptide consists of or is substantially composed of the sequence LLASSILCA. In some embodiments, the length of the HLA-restricted peptide is between about 5 and 15 amino acids. In some embodiments, the length of the HLA-restricted peptide is between about 8 and 12 amino acids. In some embodiments, association between the HLA subtype and the restriction peptide stabilizes the non-covalent association between the β2-microglobulin subunit of the HLA subtype and the α-subunit of the HLA subtype. In some embodiments, conditional peptide exchange demonstrates the stable association between the β2-microglobulin subunit of the HLA subtype and the α-subunit of the HLA subtype. In some embodiments, the isolated HLA-peptide target further includes an affinity tag. In some embodiments, the affinity tag is a biotin tag. In some embodiments, the isolated HLA-peptide target is complexed with a detectable marker. In some embodiments, the detectable marker includes a β2-microglobulin binding molecule. In some embodiments, the β2-microglobulin binding molecule is a labeled antibody. In some embodiments, the labeled antibody is an antibody labeled with a fluorescent dye.

[0026] Also provided herein is a composition comprising an HLA-peptide target disclosed herein bound to a solid support. In some embodiments, the solid support comprises a bead, a well, a membrane, a tube, a column, a plate, agarose, a magnetic bead, or a chip. In some embodiments, the HLA-peptide target comprises a first member of an affinity binding pair, and the solid support comprises a second member of the affinity binding pair. In some embodiments, the first member is streptavidin and the second member is biotin.

[0027] Also provided herein is a reaction mixture comprising an isolated and purified a-subunit of an HLA subtype as described in Table A; an isolated and purified b2-microglobulin subunit of the HLA subtype; an isolated and purified restriction peptide as described in Table A; and a reaction buffer.

[0028] Also provided herein is an isolated HLA-peptide target disclosed herein, and a plurality of T cells isolated from a human subject. In some embodiments, the T cells are CD8+ T cells.

[0029] Also provided herein is an isolated polynucleotide comprising a first nucleic acid sequence encoding an HLA-restricted peptide disclosed herein and a second nucleic acid sequence encoding an HLA subtype disclosed herein operably linked to a promoter, wherein the second nucleic acid is operably linked to the same or a different promoter as the first nucleic acid sequence, and wherein the encoded peptide and encoded HLA subtype form an HLA / peptide complex disclosed herein.

[0030] Also provided herein is a kit for expressing a stable HLA-peptide target disclosed herein comprising a first construct comprising a first nucleic acid sequence encoding an HLA-restricted peptide disclosed herein operably linked to a promoter; and instructions for expressing a stable HLA-peptide complex. In some embodiments, the first construct further comprises a second nucleic acid sequence encoding an HLA subtype described herein. In some embodiments, the second nucleic acid sequence is operably linked to the same or a different promoter. In some embodiments, the kit further comprises a second construct comprising a second nucleic acid sequence encoding an HLA subtype disclosed herein. In some embodiments, one or both of the first and second constructs is a lentiviral vector construct.

[0031] Also provided herein is a host cell comprising a heterologous HLA-peptide target disclosed herein. Also provided herein is a polynucleotide encoding an HLA-restricted peptide as described in Table A, e.g., a polynucleotide encoding an HLA-restricted peptide disclosed herein. In some embodiments, an endogenous MHC is not included. In some embodiments, an exogenous HLA is included. In some embodiments, the host cell is a K562 cell.

[0032] Also provided herein is a host cell as described above and a cell culture medium comprising a restricted peptide described in Table A. In some embodiments, the host cell is a cultured cell from a tumor cell line. In some embodiments, the tumor cell line is selected from the group consisting of HCC-1599, NCI-H510A, A375, LN229, NCI-H358, ZR-75-1, MS751, OE19, MOR, BV173, MCF-7, NCI-H82, and NCI-H146.

[0033] In some embodiments, the antigen binding protein binds to the HLA-peptide target through a contact point with the HLA class I molecule and a contact point with the HLA-restricted peptide of the HLA-peptide target.

[0034] In some embodiments, the ABP is used as a medicament. In some embodiments, the ABP is used to treat a cancer, optionally, wherein the cancer expresses or is predicted to express an HLA-peptide target. In some embodiments, the ABP is used to treat a cancer, wherein the cancer is selected from a solid tumor and a hematological tumor.

[0035] Also provided herein is an ABP that is a conservatively modified variant of an ABP disclosed herein. Also provided herein is an antigen binding protein (ABP) that competes for binding with an antigen binding protein disclosed herein. Also provided herein is an antigen binding protein (ABP) that binds to the same HLA-peptide epitope as an antigen binding protein disclosed herein.

[0036] Also provided herein is an engineered cell expressing a receptor comprising an antigen binding protein disclosed herein. In some embodiments, the engineered cell is a T cell, optionally, a cytotoxic T cell (CTL). In some embodiments, the antigen binding protein is expressed from a heterologous promoter.

[0037] Also provided herein is an isolated polynucleotide or a set of polynucleotides encoding an antigen binding protein or antigen binding portion thereof described herein. Also provided herein is an isolated polynucleotide or a set of polynucleotides encoding an HLA / peptide target described herein. Also provided herein is a vector or a set of vectors comprising a polynucleotide or a set of polynucleotides disclosed herein. Also provided herein is a host cell comprising a polynucleotide or a set of polynucleotides described herein, optionally wherein the host cell is a CHO or HEK293, or optionally wherein the host cell is a T cell.

[0038] Also provided herein is a method of producing an antigen binding protein, comprising: expressing an antigen binding protein with a host cell as described above and isolating the expressed antigen binding protein.

[0039] Also provided herein is a pharmaceutical composition comprising an antigen binding protein disclosed herein and a pharmaceutically acceptable excipient. Also provided herein is a method of treating a cancer in a subject, comprising: administering to the subject an effective amount of an antigen binding protein disclosed herein or a pharmaceutical composition disclosed herein, optionally wherein the cancer is selected from a solid tumor and a hematological tumor. In some embodiments, the cancer expresses or is predicted to express an HLA-peptide target.

[0040] Also provided herein is an article of manufacture, comprising an antigen binding protein disclosed herein or a pharmaceutical composition disclosed herein and instructions for use. Also provided herein is a composition comprising at least one HLA-peptide target disclosed herein and an adjuvant. Also provided herein is at least one HLA-peptide target disclosed herein and a pharmaceutically acceptable excipient. Also provided herein is a composition comprising an amino acid sequence comprising, optionally consisting essentially of, or consisting of a polypeptide of at least one HLA-peptide target disclosed in Table A. Also provided herein is a virus comprising an isolated polynucleotide or a set of polynucleotides disclosed herein. In some embodiments, the virus is a filamentous bacteriophage. Also provided herein is a yeast cell comprising an isolated polynucleotide or a set of polynucleotides disclosed herein.

[0041] Also provided herein is a method of identifying an antigen binding protein disclosed herein, comprising: providing at least one HLA-peptide target listed in Table A; and allowing the at least one target to bind to the antigen binding protein, thereby identifying the antigen binding protein. In some embodiments, the antigen binding protein is present in a phage display library comprising a plurality of different antigen binding proteins. In some embodiments, the phage display library is substantially free of antigen binding proteins that non-specifically bind to HLA of the HLA-peptide target. In some embodiments, the antigen binding protein is present in a TCR library comprising a plurality of different TCRs or antigen binding fragments thereof. In some embodiments, the binding step is performed more than one time, optionally, at least three times. In some embodiments, the method further comprises: allowing the antigen binding protein to contact one or more peptide-HLA complexes that are different from the HLA-peptide target, thereby determining whether the antigen binding protein selectively binds to the HLA-peptide target, optionally, wherein the selectivity is determined by measuring the binding affinity of the antigen binding protein to soluble target HLA-peptide complex relative to soluble HLA-peptide complex that is different from the target complex; optionally, wherein the selectivity is determined by measuring the binding affinity of the antigen binding protein to target HLA-peptide complex expressed on the surface of one or more cells relative to the target complex expressed on the surface of one or more cells.

[0042] Also provided herein is a method of identifying an antigen binding protein disclosed herein, comprising: obtaining at least one HLA-peptide target listed in Table A; administering the HLA-peptide target to a subject, optionally in combination with an adjuvant; and isolating an antigen binding protein from the subject. In some embodiments, the isolating an antigen binding protein comprises screening the subject’s serum to identify an antigen binding protein. In some embodiments, the method further comprises: contacting the antigen binding protein with one or more peptide-HLA complexes different from the HLA-peptide target to determine whether the antigen binding protein selectively binds to the HLA-peptide target, optionally wherein the selectivity is determined by measuring the antigen binding protein’s binding affinity to a soluble target HLA-peptide complex relative to the antigen binding protein’s binding affinity to a soluble HLA-peptide complex different from the target complex, optionally wherein the selectivity is determined by measuring the antigen binding protein’s binding affinity to a target HLA-peptide complex expressed on the surface of one or more cells relative to the antigen binding protein’s binding affinity to a HLA-peptide complex different from the HLA-peptide complex expressed on the surface of one or more cells. In some embodiments, the subject is a mouse, a rabbit, or a llama. In some embodiments, the isolating an antigen binding protein comprises: isolating B cells from the subject that express the antigen binding protein, and optionally cloning a sequence encoding the antigen binding protein directly from the isolated B cells. In some embodiments, the method further comprises generating a hybridoma using the B cells. In some embodiments, the method further comprises cloning CDRs from the B cells. In some embodiments, the method further comprises immortalizing the B cells, optionally by EBV transformation. In some embodiments, the method further comprises generating a library of antigen binding proteins comprising the B cells, optionally wherein the library is a phage display library or a yeast display library. In some embodiments, the method further comprises humanizing the antigen binding protein. Also provided herein is a method of identifying an antigen binding protein disclosed herein, comprising: obtaining a cell comprising the antigen binding protein; contacting the cell with an HLA-multimer comprising at least one HLA-peptide target listed in Table A; and identifying the antigen binding protein by binding of the HLA-multimer to the antigen binding protein. Also provided herein is a method of identifying an antigen binding protein disclosed herein, comprising: obtaining one or more cells comprising the antigen binding protein; activating the one or more cells with at least one HLA-peptide target listed in Table A presented on a native or artificial antigen presenting cell (APC); and identifying the antigen binding protein by selecting the one or more cells that are activated by interacting with at least one HLA-peptide target listed in Table A. In some embodiments, the cell is a T cell, optionally a CTL.In some embodiments, the method further comprises isolating the cells, optionally using flow cytometry, magnetic separation, or single cell isolation to isolate the cells. In some embodiments, the method further comprises sequencing the antigen binding protein.

[0043] Also provided herein is a method of identifying an antigen binding protein disclosed herein, comprising: providing at least one HLA-peptide target listed in Table A; and using the target to identify an antigen binding protein. BRIEF DESCRIPTION OF DRAWINGS

[0044] The following description and drawings are helpful in better understanding these and other features, aspects, and advantages of the present application:

[0045] Figure 1 The general structure of a human leukocyte antigen (HLA) class I molecule is shown. User atropos235 by personal work published on en.wikipedia, CC BY 2.5, URL: https: / / commons.wikimedia.org / w / index.php?curid=1805424

[0046] Figure 2 Exemplary construct element sequences for cloning a TCR specific for A*0201_LLASSILCA- (SEQ ID NO: 2737) into an expression system for therapeutic development are depicted.

[0047] Figure 3 Exemplary construct backbone sequences for cloning a TCR specific for A*0201_LLASSILCA- (SEQ ID NO: 2737) into an expression system for therapeutic development are depicted. Figure 3 SEQ ID NO: 4332 is disclosed.

[0048] Figure 4 Exemplary construct sequences for cloning a TCR specific for A*0201_LLASSILCA- (SEQ ID NO: 2737) into an expression system for therapeutic development are depicted. Figure 4 SEQ ID NO: 4333 is disclosed.

[0049] Figure 5 Exemplary construct sequences for cloning a TCR specific for A*0101_EVDPIGHLY (SEQ ID NO: 1) into an expression system for therapeutic development are depicted. Figure 5 SEQ ID NO: 4334 is disclosed.

[0050] Figure 6 Spectral data for the peptide EVDPIGHLY (SEQ ID NO: 1) is shown. This figure contains peptide fragmentation information as well as information related to patient samples, including HLA type.

[0051] Figure 7 Spectroscopy data is shown for the peptide GVHGGILNK (SEQ ID NO: 1424). This figure contains peptide fragmentation information as well as information related to patient samples, including HLA types.

[0052] Figure 7A Spectroscopy data is shown for the peptide GVYDGEEHSV.

[0053] Figure 7B Spectroscopy data is shown for the peptide NTDNNLAVY.

[0054] Figures 7C-7K Spectroscopy data is shown for additional peptides disclosed in Table A.

[0055] Figure 8 Design of Target Screen 1 for G2 target HLA-A*01:01_NTDNNLAVY (SEQ ID NO: 23) is shown.

[0056] Figure 9 A shows the design of the target and micro-pool negative control for the G2 target. Figure 9 A discloses SEQ ID NOs: 23 and 4335-4337, respectively, in order of appearance.

[0057] Figure 9 B shows stability ELISA results for G2 reverse screen “micro-pool” and G2 target. Figure 9 B discloses SEQ ID NOs: 23, 4335-4337, and 4363, respectively, in order of appearance.

[0058] Figure 10 Stability ELISA results are shown for additional G2 “full” pool reverse screen peptides. Figure 10 SEQ ID NOs: 4338-4352 are disclosed, respectively, in order of appearance.

[0059] Figure 11 Design of Target Screen 2 for G7 target HLA-A*02:01_LLASSILCA (SEQ ID NO: 2737) is shown.

[0060] Figure 12 Stability ELISA results are shown for additional G7 “full pool” reverse screen peptides. Figure 12 SEQ ID NOs: 4341-4343, 4350-4358, and 4335-4337 are disclosed, respectively, in order of appearance.

[0061] Figure 13 A shows the design of the target and micro-pool negative control for the G7 target. Figure 13A discloses SEQ ID NOs:2737 and 4338-4340, respectively, in order of appearance.

[0062] Figure 13 B shows stability ELISA results for G7 reverse screen "minipool" and G7 target. Figure 13 B discloses SEQ ID NOs:2737, 4338-4340, and 4344, respectively, in order of appearance.

[0063] Figure 14 A and 14B show phage panning results for G2 and G7 targets, respectively.

[0064] Figure 15 A and 15B show bio-layer interferometry (BLI) results for G2 target Fab clone G-2P1H11 and G7 target G7R4-B5-P2E9, respectively.

[0065] Figure 16 Amino acid substitution map for position scanning experiments described herein is shown. Figure 16 SEQ ID NOs:23 and 2737 are disclosed, respectively, in order of appearance.

[0066] Figure 17A Stability heat map for G2 position variants-HLA is shown. Figure 17A SEQ ID NO:23 is disclosed.

[0067] Figure 17B Affinity heat map for Fab clone G2-P1H11 is shown. Figure 17B SEQ ID NO:23 is disclosed.

[0068] Figure 18A Stability heat map for G7 position variants is shown. Figure 18A SEQ ID NO:2737 is disclosed.

[0069] Figure 18B Affinity heat map for Fab clone G7R4-B5-P2E9 is shown. Figure 18B SEQ ID NO:2737 is disclosed.

[0070] Figure 19 Cell binding results for Fab clones G2-P1H11 and G7R4-B5-P2E9 to K562 cells transduced with HLA pulsed with target or negative control peptide are shown.

[0071] Figure 20A and 20BCell binding results are shown for Fab clones G2-P1H11 and G7R4-B5-P2E9 with HLA-transduced K562 cells pulsed with target or negative control peptides, respectively.

[0072] Figure 21 An example of hydrogen-deuterium exchange (HDX) data plotted on crystal structure PDB 5bs0 is shown.

[0073] Figure 22 An exemplary HDX heat map for scFv clone G2-P1G07 is shown using the unified perturbation view global visualization. Figure 22 SEQ ID NO: 4359 is disclosed.

[0074] Figure 23 HDX heat maps for the HLA alpha 1 and alpha 2 helices are shown for the G2 scFv and Fab clones tested. Figure 23 SEQ ID NOs: 4360-4361 are disclosed, respectively, in order of appearance.

[0075] Figure 24 HDX heat maps for the restricting peptide NTDNNLAVY (SEQ ID NO: 23) are shown for the G2 scFv and Fab clones tested.

[0076] Figure 25 An experimental workflow by which TCRs that specifically bind to HLA-peptide targets were isolated is depicted.

[0077] Figure 26 A flow cytometry sorting procedure for sorting MHC-target-specific CD8+ T cells is shown.

[0078] Figure 27 Flow cytometry results for exemplary HLA-peptide targets B*44:02_GEMSSNSTAL (SEQ ID NO: 2721) and A*01:01_EVDPIGHLY (SEQ ID NO: 1) are shown.

[0079] Figure 28 Flow cytometry results for HLA-PETPIDE target A*03:01_GVHGGILNK (SEQ ID NO: 1424) are shown. Figure 28 “EVDPIGHVY” is also disclosed as SEQ ID NO: 6.

[0080] Figure 29A The total number of isolated CD8+ T cells per HLA-peptide target in all donors tested is shown. Figure 29ASEQ ID NOs:23, 302, 2737, 96, 1424, 2721, 6, and 1, respectively, in order of appearance.

[0081] Figure 29B The frequency of isolated CD8+ T cells per HLA-peptide target in all tested donors is shown. Figure 29B SEQ ID NOs:1, 2737, 302, 1424, 6, 2721, 96, and 23, respectively, in order of appearance.

[0082] Figure 30A The number of unique TCR clonotypes per HLA-peptide target for each tested donor is depicted. Figure 30A SEQ ID NOs:23, 2737, 96, 1424, 2721, 6, and 1, respectively, in order of appearance.

[0083] Figure 30B The total number of unique clonotypes per HLA-peptide target in all tested donors is depicted. Figure 30B SEQ ID NOs:23, 2737, 96, 1424, 2721, 6, and 1, respectively, in order of appearance.

[0084] Figure 31 Examples of Jurkat cells expressing TCRs specific for A*0201_LLASSILCA- (SEQ ID NO: 2737), A*0201_GVYDGEEHSV- (SEQ ID NO: 96), B*4402_GEMSSNSTAL- (SEQ ID NO: 2721), and A*0101_EVDPIGHLY (SEQ ID NO: 1) binding to their respective HLA-peptide targets, but not to control peptide tetramers, are shown.

[0085] Figure 32 Gating strategies and flow data demonstrating that TCR-transduced human CD8+ cells identified herein bind to their specific HLA-peptide targets are shown. Figure 32 SEQ ID NOs:2737 and 2737, respectively, in order of appearance.

[0086] Figure 33 Exemplary lentiviral vectors that can be used to transduce recipient cells with the TCRs disclosed herein are shown. DETAILED DESCRIPTION

[0087] Unless otherwise defined, all technical terms, symbols and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art. In some instances, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein does not necessarily represent a departure from the definition of the term in the art. Methods and procedures described or referenced herein are methods and procedures generally readily understood and applied by those of skill in the art using routine methodology, as for example, the widely used molecular cloning methods described by Sambrook et al., (see Molecular Cloning: A Laboratory Manual, 4th Ed. (2012), Cold Spring Harbor Laboratory Press, New York, Cold Spring Harbor). Appropriate, procedures for using commercially available kits and reagents are generally performed according to manufacturer-defined protocols and conditions, unless otherwise indicated.

[0088] The singular forms "a," "an," and "the" as used herein and in the appended claims are intended to include plural referents unless the context clearly dictates otherwise. The terms "comprising," "having," and the like as used herein are meant to be interpreted apjrely inclusive, meaning that the item or items named following the term are present, but not excluding the presence of one or more additional items in the composition, process, method, etc.

[0089] The term "comprising" as used herein is to be specifically interpreted in the context of the specific recited implementation to specifically include the implementation "consisting of and the implementation "consisting essentially of, unless specifically indicated otherwise. For example, a multispecific ABP "comprising a bifunctional antibody" includes a multispecific ABP "consisting of a bifunctional antibody" and a multispecific ABP "consisting essentially of a bifunctional antibody."

[0090] The term "about" refers to and encompasses a range of values including the value specified after the term and values that are greater than and less than the value specified after the term. In certain embodiments, the term "about" means ± 10%, ± 5%, or ± 1% of the specified value. In certain embodiments, the term "about" means ± one standard deviation of the specified value, as applicable.

[0091] The term "immunoglobulin" refers to a class of structurally related proteins, generally including two pairs of polypeptide chains: one pair of light (L) and one pair of heavy (H) chains. In "intact immunoglobulins," all four chains are inter-connected by disulfide bonds. The structure of immunoglobulins is well characterized. See, e.g., Paul Fundamental Immunology 7th Ed., Chapter 5 (2013), Lippincott Williams & Wilkins Publishers (LWW), Philadelphia, PA. Briefly, each heavy chain typically includes a heavy chain variable region (V H ) and a heavy chain constant region (C H ). The heavy chain constant region typically includes three domains, abbreviated C H1 , CH2 and C H3 Each light chain generally includes a light chain variable region (V L ) and a light chain constant region. The light chain constant region generally includes one domain, abbreviated as C L .

[0092] The term "antigen binding protein" or "ABP" as used herein is used in its broadest sense and includes certain types of molecules that include one or more antigen binding domains that specifically bind to an antigen or epitope.

[0093] In some embodiments, the ABP includes an antibody. In some embodiments, the ABP consists of an antibody. In some embodiments, the ABP consists essentially of an antibody. ABPs specifically include intact antibodies (e.g., intact immunoglobulins), antibody fragments, ABP fragments, and multispecific antibodies. In some embodiments, the ABP includes an alternative scaffold. In some embodiments, the ABP consists of an alternative scaffold. In some embodiments, the ABP consists essentially of an alternative scaffold. In some embodiments, the ABP includes an antibody fragment. In some embodiments, the ABP consists of an antibody fragment. In some embodiments, the ABP consists essentially of an antibody fragment. In some embodiments, the ABP includes a TCR or antigen binding portion thereof. In some embodiments, the ABP consists of a TCR or antigen binding portion thereof. In some embodiments, the ABP consists essentially of a TCR or antigen binding portion thereof. In some embodiments, the CAR includes an ABP. As provided herein, an "HLA-peptide ABP," "anti-HLA-peptide ABP," or "HLA-peptide specific ABP" is an ABP that specifically binds to the antigen HLA-peptide. ABPs include proteins that include one or more antigen binding domains that specifically bind to an antigen or epitope through a variable region, such as a variable region derived from a B cell (e.g., an antibody) or a T cell (e.g., a TCR).

[0094] The term "antibody" as used herein is used in its broadest sense and includes polyclonal and monoclonal antibodies, including intact antibodies and functional (antigen binding) antibody fragments, including fragment antigen binding (Fab) fragments, F(ab')2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rlgG) fragments, variable heavy chain (V H) regions, single-chain antibody fragments (including single-chain variable fragments (scFv)), and single-domain antibody (e.g., sdAb, sdFv, nanobody) fragments. The term encompasses genetically engineered and / or otherwise modified immunoglobulin forms, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and conjugated antibodies, multispecific antibodies (e.g., bispecific antibodies), diabodies, triabodies, and tetrabodies, tandem di-valent scFv, tandem tri-valent scFv. Unless otherwise noted, the term “antibody” is understood to encompass functional antibody fragments thereof. The term also encompasses intact or full-length antibodies, including antibodies of any class or subclass, including IgG and subtypes thereof, IgM, IgE, IgA, and IgD.

[0095] “Variable region” as used herein refers to a variable nucleotide sequence resulting from a recombination event, e.g., which can include V, J, and / or D regions from an immunoglobulin or T cell receptor (TCR) sequence of a B cell or T cell, such as an activated T cell or an activated B cell.

[0096] The term “antigen binding domain” refers to a portion of an ABP that is capable of specifically binding an antigen or epitope. One example of an antigen binding domain is an antigen binding domain formed by an antibody V H -V L dimerization. Another example of an antigen binding domain is an antigen binding domain formed by diversification of certain loops from the tenth fibronectin type III domain from Adnectin. An antigen binding domain can comprise, in order, antibody CDRs 1, 2, and 3 from a heavy chain; and, in order, antibody CDRs 1, 2, and 3 from a light chain. An antigen binding domain can comprise TCR CDRs, e.g., aCDR1, aCDR2, aCDR3, bCDR1, bCDR2, and bCDR3. TCR CDRs are described herein.

[0097] The V H region of an antibody and the V L region can be further subdivided into regions of hypervariability, termed “hypervariable regions” (HVRs), interspersed with regions that are more conserved. These conserved regions are termed framework regions (FRs). Each V H and V L region generally includes three antibody CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. Antibody CDRs are involved in antigen binding and influence antigen specificity and the binding affinity of the ABP. See Kabat et al. Sequences of Proteins of Immunological Interest (Fifth Edition) U.S. Department of Health and Human Services, 1991; and Chothia and Lesk J. Mol. Biol. 196:901-917, 1987. Fundamental Immunology (1991) Paul W. Stites, Ed. Raven Press, New York, NY (1991), the entire contents of which are incorporated herein by reference.

[0098] Based on the sequence of the constant domains of the vertebrate species, the light chains of any vertebrate species are classified as one of two types, called kappa (K) and lambda (l).

[0099] The heavy chains of any vertebrate species are classified as one of five types (or isotypes) called IgA, IgD, IgE, IgG, and IgM. These classes are also referred to as a, d, e, g, and m, respectively. The IgG and IgA classes are further divided into subclasses, based on sequence and functional differences. Humans express the following subclasses: IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[0100] The skilled artisan can determine the boundaries of the antibody CDRs using any of a number of known numbering schemes, including those described in: (Kabat et al., supra) (“Kabat” numbering scheme); (Al-Lazikani et al. (1997) J. Mol. Biol. 273:927-948) (“Chothia” numbering scheme); (MacCallum et al. (1996) J. Mol. Biol. 262:732-745) (“Contact” numbering scheme); (Lefranc et al. Dev. Comp. Immunol. 2003, 27:55-77) (“IMGT” numbering scheme); and (Honegge and Pluckthun J. Mol. Biol. 2001, 309:657-70) (“AHo” numbering scheme); all incorporated by reference in their entireties.

[0101] Table 14 provides the positions of the antibody CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes.

[0102] For example, antibody CDRs can be assigned using ABP numbering software such as Abnum, available at www.bioinf.org.uk / abs / abnum / and described in (Abhinandan and Martin, Immunology, 2008, 45:3832-3839), which is incorporated by reference in its entirety.

[0103] Table 14. Residues in CDRs according to the Kabat and Chothia numbering schemes.

[0104] CDR Kabat Chothia L1 L24-L34 L24-L34 L2 L50-L56 L50-L56 L3 L89-L97 L89-L97 H1 (Kabat numbering) H31-H35B H26-H32 or H34* H1 (Chothia numbering) H31-H35 H26-H32 H2 H50-H65 H52-H56 H3 H95-H102 H95-H102

[0105] * The C-terminal end of CDR-H1 varies between H32 and H34 depending on the length of the CDR when numbered using the Kabat numbering scheme.

[0106] When referring to residues in the ABP heavy chain constant region (e.g., as reported by Kabat et al., supra), the“EU numbering scheme” is generally used. Unless otherwise specified, the EU numbering scheme is used to refer to residues in the ABP heavy chain constant regions described herein.

[0107] The terms“full-length antibody,”“intact antibody,” and“whole antibody,” as used herein, are interchangeable and refer to an antibody having a structure substantially similar to a naturally occurring antibody structure and having heavy chains that include an Fc region. For example, a“full-length antibody” when used in reference to an IgG molecule is an antibody that includes two heavy chains and two light chains.

[0108] The skilled artisan can determine the boundaries of the amino acid sequences of TCR CDRs using any of a number of known numbering schemes, including but not limited to the IMGT unique numbering described in (LeFranc, M.-P Immunol Today 1997 Nov; 18(11): 509); (Lefranc, M.-P "IMGT Locus on Focus: A new section of Experimental and Clinical Immunogenetics," Exp. Clin. Immunogenet. 15, 1-7 (1998)); (Lefranc and Lefranc The T Cell Receptor FactsBook) and (M.-P. Lefranc Developmental and Comparative Immunology 27 (2003) 55-77); all of which are incorporated by reference.

[0109] An "ABP fragment" includes a portion of a complete ABP, such as an antigen binding or variable region of a complete ABP. ABP fragments include, for example, Fv fragments, Fab fragments, F(ab')2 fragments, Fab' fragments, scFv (sFv) fragments, and scFv-Fc fragments. ABP fragments include antibody fragments. Antibody fragments can include Fv fragments, Fab fragments, F(ab')2 fragments, Fab' fragments, scFv (sFv) fragments, scFv-Fc fragments, and TCR fragments.

[0110] An "Fv" fragment includes a non-covalent heterodimer of one heavy chain variable domain and one light chain variable domain.

[0111] In addition to the heavy and light chain variable domains, a "Fab" fragment also includes the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab fragments, for example, can be produced by recombinant means or by papain digestion of full-length ABP.

[0112] An "F(ab')2" fragment contains two Fab fragments that are linked by disulfide bonds at their hinge regions. F(ab')2 fragments can be produced, for example, by recombinant means or by pepsin digestion of intact ABP. F(ab') fragments can be dissociated, for example, by treatment with β-mercaptoethanol.

[0113] A “single-chain Fv” or “sFv” or “scFv” fragment includes a VH domain and a VL domain in a single polypeptide chain. The VH and VL are generally connected by a peptide linker. See Pluckthun A. (1994). Any suitable linker can be used. In some embodiments, the linker is (GGGGS)n. In some embodiments, n = 1, 2, 3, 4, 5, or 6. See ABPs derived from E. coli. Rosenberg M. & Moore G. P. (eds.), The Pharmacology of Monoclonal ABPs, Vol. 113 (pp. 269-315), Springer-Verlag, which is incorporated by reference in its entirety.

[0114] An “scFv-Fc” fragment includes an scFv bound to an Fc domain. For example, the Fc domain can be bound to the C-terminus of the scFv. Depending on the orientation of the variable domains in the scFv (i.e., VH-VL or VL-VH), the Fc domain can follow the VH or the VL. Any suitable Fc domain known in the art or described herein can be used. In some cases, the Fc domain includes an IgG4 Fc domain.

[0115] The term “single domain antibody” refers to a molecule in which one variable domain of an ABP specifically binds an antigen in the absence of another variable domain. Single domain ABPs and fragments thereof are described in: Arabi Ghahroudi et al. FEBS Letters 1998, 414:521-526 and Muyldermans et al. Trends in Biochem. Sci. 2001, 26:230-245, which are incorporated by reference in their entireties. Single domain ABPs are also known as sdAbs or nanobodies.

[0116] The term “Fc region” or “Fc” refers to the C-terminal region of an immunoglobulin heavy chain that interacts with the Fc receptor and certain proteins of the complement system in naturally occurring antibodies. The structure of the Fc region of various immunoglobulins and glycosylation sites contained therein are known in the art. See Schroeder and Cavacini J. Allergy Clin. Immunol. 2010, 125:S41-52, which is incorporated by reference in its entirety. The Fc region can be a naturally occurring Fc region, or a modified Fc region as described in the art or elsewhere in this disclosure.

[0117] The term "alternative scaffold" refers to a molecule in which one or more regions can be diversified to generate one or more antigen binding domains that specifically bind to an antigen or epitope. In some embodiments, the antigen binding domain binds to an antigen or epitope with a specificity and affinity similar to that of an ABP. Exemplary alternative scaffolds include fibronectin (e.g., Adnectins TM ), beta-sandwiches (e.g., iMab), lipocalins (e.g., ), EETI-II / AGRP, BPTI / LACI-D1 / ITI-D2 (e.g., Kunitz domains), thioredoxin peptide aptamer, protein A (e.g., ), ankyrin repeat sequences (e.g., DARPins), gamma-B-crystallin / ubiquitin protein (e.g., Affilins), CTLD3 (e.g., Tetranectins), Fynomers, and (LDLR-A modules) (e.g., Avimers). For additional information on alternative scaffolds, see Binz et al. Nat. Biotechnol. 2005, 23: 1257-1268); Skerra Current Opin. in Biotech. 2007, 18: 295-304); and Silacci et al. J. Biol. Chem. 2014, 289: 14392-14398; all of which are incorporated by reference in their entireties. An alternative scaffold is an ABP.

[0118] A "multispecific ABP" is an ABP that includes two or more different antigen binding domains that collectively specifically bind to two or more different epitopes. The two or more different epitopes can be epitopes on the same antigen (e.g., a single HLA-peptide molecule expressed by a cell) or epitopes on different antigens (e.g., different HLA-peptide molecules expressed by the same cell, or an HLA-peptide molecule and a non-HLA-peptide molecule). In some aspects, the multispecific ABP binds to two different epitopes (i.e., a "bispecific ABP"). In some aspects, the multispecific ABP binds to three different epitopes (i.e., a "trispecific ABP").

[0119] A "monospecific ABP" is an ABP that includes one or more binding sites that specifically bind to a single epitope. For example, an example of a monospecific ABP is a naturally occurring IgG molecule, which, although it is bivalent (i.e., has two antigen binding domains), recognizes the same epitope on both antigen binding domains. Binding specificity can be present in any suitable valency.

[0120] The term “monoclonal antibody” refers to an antibody from a population of antibody molecules that are substantially homogeneous. A substantially homogeneous population of antibody molecules includes antibody molecules having essentially identical and binding the same epitope, except for possible variants that can arise during production of the monoclonal antibody. Typically, only a few of such variants are present. Monoclonal antibodies are typically obtained by a process that involves selecting one antibody from a plurality of antibodies. For example, the selection process can be selecting a unique clone from a collection of clones, such as a collection of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve its affinity for the target (“affinity maturation”), to humanize it, to improve its production in cell culture, and / or to reduce its immunogenicity in a subject.

[0121] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0122] “Humanized” forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from non-human antibodies. For the most part, humanized antibodies are human antibodies (recipient antibody) in which one or more CDR residues are replaced by residues from one or more CDR of a non-human species (donor antibody) such as mouse, rat, rabbit, chicken, or non-human primate having the desired specificity, affinity, or biological effect. In some instances, selected framework region residues of the recipient antibody are replaced by corresponding framework region residues of the donor antibody. Humanized antibodies can also comprise residues that are not found in either the recipient antibody or the donor antibody. Such modifications can be made to further refine antibody function. See Jones et al. Nature 1986, 321 :522-525); (Riechmann et al. Nature 1988, 332:323-329); and (Presta Curr. Op. Struct. Biol. 1992, 2:593-596), each of which is incorporated by reference in its entirety.

[0123] A “human antibody” is an antibody having an amino acid sequence corresponding to an amino acid sequence of an antibody produced by a human or a human cell or an amino acid sequence that is a variant of an amino acid sequence of an antibody produced by a human or a human cell (e.g., obtained from a human source or designed de novo) using a non-human source of antibody library or antibody coding sequence. Human antibodies specifically exclude humanized antibodies.

[0124] “Affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an ABP) and its binding partner (e.g., an antigen or epitope). Unless otherwise indicated, “affinity” as used herein refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an ABP and an antigen or epitope). The affinity of a molecule X for its partner Y can be expressed in terms of the dissociation equilibrium constant (KD). The kinetic elements relating to the dissociation equilibrium constant will be described in more detail below. Affinity can be measured by routine methods known in the art, including the methods described herein, such as surface plasmon resonance (SPR) techniques (e.g., ) or bio-layer interferometry (e.g., ).

[0125] With respect to binding of an ABP to a target molecule, the terms “bind,” “specifically bind,” “bind specifically to,” “specific for,” “selectively bind,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen refer to binding that is distinct from non-specific or non-selective interactions (e.g., with non-target molecules). Specific binding can be measured, for example, by measuring binding to a target molecule and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the control molecule competitively inhibits binding of the ABP to the target molecule. In some aspects, the affinity of an HLA-peptide ABP for a non-target molecule is about 50% less than its affinity for an HLA-peptide. In some aspects, the affinity of an HLA-peptide ABP for a non-target molecule is about 40% less than its affinity for an HLA-peptide. In some aspects, the affinity of an HLA-peptide ABP for a non-target molecule is about 30% less than its affinity for an HLA-peptide. In some aspects, the affinity of an HLA-peptide ABP for a non-target molecule is about 20% less than its affinity for an HLA-peptide. In some aspects, the affinity of an HLA-peptide ABP for a non-target molecule is about 10% less than its affinity for an HLA-peptide. In some aspects, the affinity of an HLA-peptide ABP for a non-target molecule is about 1% less than its affinity for an HLA-peptide. In some aspects, the affinity of an HLA-peptide ABP for a non-target molecule is about 0.1% less than its affinity for an HLA-peptide.

[0126] The term “k d ” (sec -1 ) as used herein refers to the dissociation rate constant of a particular ABP-antigen interaction. The value is also referred to as the koff value.

[0127] The term “k a ” (M -1 ×sec-1 ) refers to the association rate constant for a particular ABP-antigen interaction. This value is also referred to as the konvalue.

[0128] The term "K D " (M) as used herein refers to the dissociation equilibrium constant for a particular ABP-antigen interaction. K D = k d / k a In some embodiments, the affinity of an ABP is according to the K D described. For the sake of clarity, as is known in the art, a smaller K D value indicates a higher affinity interaction, while a larger K D value indicates a lower affinity interaction.

[0129] The term "K A " (M -1 ) as used herein refers to the association equilibrium constant for a particular ABP-antigen interaction. K A = k a / k d .

[0130] An "immunoconjugate" is an ABP conjugated to one or more heterologous molecule, such as a therapeutic agent (e.g., a cytokine) or a diagnostic agent.

[0131] "Fc effector functions" refer to biological activities mediated by the Fc region of an ABP with an Fc region, which can vary with the isotype. Examples of ABP effector functions include Clq binding for complement-dependent cytotoxicity (CDC), Fc receptor binding for ABP-dependent cellular cytotoxicity (ADCC) and ABP-dependent cellular phagocytosis (ADCP).

[0132] The terms "compete with" or "cross-compete with," when used in the context of two or more ABPs, means that the two or more ABPs compete for binding to an antigen (e.g., HLA- peptide). In one exemplary assay, an HLA-peptide is coated on a surface and contacted with a first HLA-peptide ABP, and then a second HLA-peptide ABP is added. In another exemplary assay, a first HLA-peptide ABP is coated on a surface and contacted with an HLA-peptide, and then a second HLA-peptide ABP is added. If the presence of the first HLA-peptide ABP reduces the binding of the second HLA-peptide ABP in either assay, then the ABPs compete with each other. The term "compete with" also encompasses combinations of ABPs in which one ABP reduces the binding of the other ABP, but competition is not observed when the ABPs are added in the reverse order. In some embodiments, however, a first and second ABP inhibit the binding of each other regardless of their order of addition. In some embodiments, one ABP reduces the binding of the other ABP to its antigen by at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95%. A skilled artisan can select the concentrations of ABPs for competition assays based on the affinities of the ABPs for the HLA-peptide and the valency of the ABPs. The assays described in this definition are illustrative, and a skilled artisan can use any suitable assay to determine whether ABPs compete with each other. Suitable assays are described in, e.g., "Immunoassay Methods" in Cox et al. Assay Guidance Manual, updated December 24, 2014 [Internet] (www.ncbi.nlm.nih.gov / books / NBK92434 / ; accessed September 29, 2015); (Silman et al. Cytometry 2001, 44:30-37); and (Finco et al. J. Pharm. Biomed. Anal. 2011, 54:351-358); each of which is incorporated by reference in its entirety.

[0133] The term "epitope" refers to a portion of an antigen to which an ABP specifically binds. Epitopes are typically composed of amino acid residues and / or sugar side chains that are surface accessible and can have specific three-dimensional structural characteristics as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the former, but not the latter, can be lost on denaturing of the antigen. An epitope can include amino acid residues that directly participate in binding and other amino acid residues that do not directly participate in binding. Epitopes to which an ABP binds can be determined using known techniques for determining epitopes, such as, e.g., testing the ABP for binding to HLA-peptide variants with different point mutations or to chimeric HLA-peptide variants.

[0134] The percent "identity" between two polypeptide sequences or between a polypeptide sequence and a reference sequence is determined by comparing the sequences of the two polypeptides after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0135] A "conservative substitution" or "conservative amino acid substitution" is one in which the amino acid is replaced with an amino acid that has similar chemical or functional properties. Conservative substitution tables are well known in the art. For example, in some embodiments, the amino acid groups provided in Tables 15-17 are considered to be conservative substitutions of one another.

[0136] Table 15. Selected amino acid groups that are considered to be conservative substitutions of one another in certain embodiments.

[0137] Acidic residues D and E Basic residues K, R, and H Hydrophilic uncharged residues S, T, N, and Q Aliphatic uncharged residues G, A, V, L, and I Nonpolar uncharged residues C, M, and P Aromatic residues F, Y, and W

[0138] Table 16. Additional selected amino acid groups that are considered to be conservative substitutions of one another in certain embodiments.

[0139] Group 1 A, S, and T Group 2 D and E Group 3 N and Q Group 4 R and K Group 5 I, L, and M Group 6 F, Y, and W

[0140] Table 17. Further selected amino acid groups that are considered to be conservative substitutions of one another in certain embodiments.

[0141]

[0142]

[0143] Additional conservative substitutions can be found, for example, in Creighton, Proteins: Structures and Molecular Properties (2nd ed. 1993) W. H. Freeman & Co., New York, N.Y. An ABP produced by one or more conservative substitutions of an amino acid residue of a parent ABP is referred to as a "conservatively modified variant."

[0144] The term "amino acid" refers to the twenty naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gin; Q), glycine (Gly; G); histidine (His; H), isoleucine (lie; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).

[0145] The term "vector," as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self-replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors."

[0146] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells and their progeny which have a foreign nucleic acid incorporated into their genome. Host cells include "transformants" (or "transformed cells") and "transfectants" (or "transfected cells"), each of which has been transformed or transfected with primary transformants or transfectants and their progeny derived therefrom. Such progeny can not be identical to the parent cell from which they originated as mutations can occur during replication. Host cells can be prokaryotic or eukaryotic.

[0147] The terms "treating" (and variations thereof such as "treat" or "treatment") refer to clinical intervention with the intent to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be prophylactic and / or therapeutic. Desirable effects of treatment include preventing occurrence or reoccurrence of the disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.

[0148] The terms "therapeutically effective amount" or "effective amount," as used herein, refer to the amount of an ABP or pharmaceutical composition provided herein that, when administered to a subject, is effective to treat a disease or condition.

[0149] As used herein, the term "subject" refers to a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cattle, horses, camels, goats, rabbits, and sheep. In some embodiments, the subject is a human. In some embodiments, the subject suffers from a disease or condition that can be treated with the ABP provided herein. In some aspects, the disease or condition is cancer. In some aspects, the disease or condition is a viral infection.

[0150] The term "instructions for use" is used to refer to instructions that are typically included in the commercial packaging of a therapeutic or diagnostic product (e.g., a test kit), which contain information about the indications, usage, dosage, administration, combination therapy, contraindications, and / or warnings for using such a therapeutic or diagnostic product.

[0151] The term "tumor" refers to the growth and proliferation of all proliferative cells (whether malignant or benign), as well as all precancerous and cancerous cells and tissues. The terms "cancer," "carcinoma," "cellular proliferative disorder," "proliferative lesion," and "tumor" are not mutually exclusive herein. The terms "cellular proliferative disorder" and "proliferative lesion" refer to a condition associated with some degree of abnormal cell proliferation. In some embodiments, a cellular proliferative disorder is cancer. In some aspects, a tumor is a solid tumor. In some aspects, a tumor is a hematologic malignancy.

[0152] The term "pharmaceutical composition" refers to a formulation which exists in a form that allows the biological activity of the active ingredient contained therein to effectively treat a subject, and which does not contain any additional components that, in amounts provided in the pharmaceutical composition, would have unacceptable toxicity to the subject.

[0153] The terms “modulate” and “modulation” refer to reducing or suppressing, or alternatively, activating or increasing, the listed variables.

[0154] The terms “increase” and “activation” refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2 times, 3 times, 4 times, 5 times, 10 times, 20 times, 50 times, 100 times or more in the listed variables.

[0155] The terms “reduction” and “suppression” refer to a reduction of the listed variables by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2 times, 3 times, 4 times, 5 times, 10 times, 20 times, 50 times, 100 times or more.

[0156] The term "agonist" refers to the activation of receptor signaling to induce a biological response associated with receptor activation. An "agonist" is an entity that binds to and activates receptors.

[0157] The term "antagonist" refers to an entity that binds to and antagonizes a receptor.

[0158] The terms "nucleic acid" and "polynucleotide" are used interchangeably herein and refer to polymeric forms of nucleotides of any length, either deoxyribonucleotides or ribonucleotides or their analogs. Polynucleotides can comprise or consist of, without limitation, coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA, isolated RNA, nucleic acid probes, and primers. A polynucleotide can include modified nucleotides, such as methylated nucleotides and nucleotide analogs. Exemplary modified nucleotides include, for example, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4- acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2- thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, queosine, 2,6-diaminopurine, 5-methylcytosine, N6-substituted

[0159] Isolated HLA-peptide targets

[0160] The major histocompatibility complex (MHC) is a complex of antigens encoded by a linked set of loci, collectively known as H-2 in mice and HLA in humans. There are two major classes of MHC antigens, class I and class II, each of which includes a group of cell surface glycoproteins that play a role in determining histocompatibility and graft compatibility. In the graft reaction, cytotoxic T cells (CTLs) react primarily to class I glycoproteins, while helper T cells react primarily to class II glycoproteins.

[0161] Human major histocompatibility complex (MHC) class I molecules (interchangeably referred to herein as HLA class I molecules) are expressed on the surface of almost all cells. The function of these molecules is to present peptides, primarily from endogenously synthesized proteins, to CD8+ T cells through interaction with a- b T cell receptors. MHC class I molecules comprise a heterodimer composed of an a chain of 46 kDa size, which is non-covalently associated with a light chain, b-2 microglobulin, of 12 kDa size. The a chain typically includes a1 and a2 domains, which form a groove that presents HLA-restricted peptides, and a3 transmembrane domain that interacts with the CD8 co-receptor of T cells. Figure 1 The general structure of HLA class I molecules is depicted.

[0162] Class I MHC-restricted peptides (also interchangeably referred to herein as HLA-restricted antigens, HLA-restricted peptides, MHC-restricted antigens, restricted peptides, or peptides) generally bind to the heavy chain a1-a2 groove through about two or three anchor residues that interact with corresponding binding pockets in the MHC molecule. The b-2 microglobulin chain plays an important role in MHC class I intracellular trafficking, peptide binding, and conformational stability. For most class I molecules, the formation of a heterotrimeric complex of MHC class I heavy chain, peptide (self, non-self, and / or antigenic), and b-2 microglobulin results in protein maturation and export to the cell surface.

[0163] The binding of a given HLA subtype to an HLA-restricted peptide forms a complex with a unique and novel surface that can be specifically recognized by an ABP, such as, for example, a TCR on a T cell or an antibody or antigen-binding fragment thereof. An HLA complexed with an HLA-restricted peptide is referred to herein as an HLA-peptide or HLA-peptide target. In some cases, the restricted peptide is located in the a1 / a2 groove of the HLA molecule. In some cases, the restricted peptide binds to the a1 / a2 groove of the HLA molecule through about two or three anchor residues that interact with corresponding binding pockets in the HLA molecule.

[0164] Accordingly, provided herein are antigens comprising HLA-peptide targets. An HLA- peptide target can comprise a particular HLA-restricted peptide having a defined amino acid sequence complexed with a particular HLA subtype.

[0165] The HLA-peptide targets identified herein can be useful for tumor immunotherapy. In some embodiments, the HLA-peptide targets identified herein are present on the surface of tumor cells. The HLA-peptide targets identified herein can be expressed by tumor cells in a human subject. The HLA-peptide targets identified herein can be expressed by tumor cells in a population of human subjects. For example, the HLA-peptide targets identified herein can be a shared antigen that is commonly expressed in a population of human subjects having a cancer.

[0166] The HLA-peptide targets discovered herein can have a prevalence in individual tumor types. The prevalence in individual tumor types can be about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. The prevalence in individual tumor types can be about 0.1% to 100%, 0.2 to 50%, 0.5 to 25%, or 1 to 10%.

[0167] Preferably, the HLA-peptide targets are not typically expressed in most normal tissues. For example, in some cases, the HLA-peptide targets can not be expressed in tissues in the Genotype Tissue Expression (GTEx) project, or in some cases, can only be expressed in immune-privileged or non-essential tissues. Exemplary immune-privileged or non-essential tissues include testes, minor salivary glands, endometrium of the uterine cervix, and thyroid. In some cases, the HLA-peptide targets can be considered not to be expressed on essential or non-immune privileged tissues if the gene from which the restricting peptide is derived has a median expression in GTEx samples of less than 0.5 RPKM (reads per million from a gene per kilobase length), if the gene has an expression in GTEX samples of no more than 10 RPKM, or if there are no more than two samples out of all essential tissue samples with a gene expression of greater than or equal to 5 RPKM, or any combination thereof.

[0168] Exemplary HLA class I subtypes of HLA-peptide targets

[0169] There are many MHC haplotypes (interchangeably referred to herein as MHC subtypes, HLA subtypes, MHC types, and HLA types) in humans. Exemplary HLA subtypes include, by way of illustration only: HLA-A2, HLA-A1, HLA-A3, HLA-A11, HLA-A23, HLA-A24, HLA-A25, HLA-A26, HLA-A28, HLA-A29, HLA-A30, HLA-A31, HLA-A32, HLA-A33, HLA-A34, HLA-68, HLA-B7, HLA-B8, HLA-B40, HLA-B44, HLA-B13, HLA-B15, HLA-B-18, HLA-B27, HLA-B35, HLA-B37, HLA-B38, HLA-B39, HLA-B45, HLA-B46, HLA-B49, HLA-B51, HLA-B54, HLA-B55, HLA-B56, HLA-B57, HLA-B58, HLA-C*01, HLA-C*02, HLA-C*03, HLA-C*04, HLA-C*05, HLA-C*06, HLA-C*07, HLA-C*12, HLA-C*14, HLA-C*16, HLA-Cw8, and all 4 and 6 position subtypes thereof. It is known to those skilled in the art that there are allelic variants of the above HLA types, and all such allelic variants are encompassed by the present application. For a complete list of HLA class alleles, please visit http: / / hla.alleles.org / alleles / . For example, a complete list of HLA class I alleles can be found at http: / / hla.alleles.org / alleles / class1.html.

[0170] HLA-restricted peptides

[0171] HLA-restricted peptides (interchangeably referred to herein as“restricted peptides”) can be peptide fragments of tumor-specific genes (e.g., cancer-specific genes). Preferably, the cancer-specific genes are expressed in cancer samples. Genes that are aberrantly expressed in cancer samples can be identified through databases. Exemplary databases include, by way of illustration only, The Cancer Genome Atlas (TCGA) Research Network: http: / / cancergenome.nih.gov / ; the International Cancer Genome Consortium: https: / / dcc.icgc.org / . In some embodiments, a cancer-specific gene has an observed expression of at least 10 RPKM in at least 5 samples from the TCGA database. A cancer-specific gene can have an observable bimodal distribution of expression.

[0172] The cancer-specific gene can have an observed expression of greater than 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 TPM in at least one TCGA tumor tissue. In preferred embodiments, the cancer-specific gene has an observed expression of greater than 100 TPM in at least one TCGA tumor tissue. In some cases, the cancer-specific gene has an observed bimodal distribution of expression in TCGA samples. Without wishing to be bound by theory, this bimodal expression pattern is consistent with a biological model in which expression at baseline is minimal across all tumor samples, while expression is higher in a subset of tumors that have experienced epigenetic dysregulation.

[0173] Preferably, the cancer-specific gene is not typically expressed in most normal tissues. For example, in some cases, the cancer-specific gene can not be expressed in tissues in the Genotype Tissue Expression (GTEx) project, or in some cases, can be expressed in immune-privileged or non-essential tissues. Exemplary immune-privileged or non-essential tissues include testes, minor salivary glands, endometrium of the uterine cervix, and thyroid. In some cases, a cancer-specific gene can be considered not to be expressed on essential or non-immune privileged tissues if the median expression in GTEx samples is less than 0.5 RPKM (reads per million reads from each kilobase length of a gene), if the expression of the gene in GTEX samples does not exceed 10 RPKM, or if there are no more than two samples in all essential tissue samples with gene expression greater than or equal to 5 RPKM, or any combination thereof.

[0174] In some embodiments, by assessing GTEx, a cancer-specific gene meets the following criteria: (1) GTEx median expression in brain, heart, or lung is less than 0.1 transcripts per million (TPM) with no sample exceeding 5 TPM; (2) GTEx median expression in other essential organs (not including testis, thyroid, minor salivary glands) is less than 2 TPM with no sample exceeding 10 TPM.

[0175] In some embodiments, a cancer-specific gene is generally unlikely to be expressed in immune cells, e.g., is not a interferon family gene, is not an eye-related gene, is not an olfactory or taste receptor gene, and is not a gene related to the circadian cycle (e.g., is not a CLOCK, PERIOD, CRY gene).

[0176] The restriction peptide preferably can be present on the surface of a tumor.

[0177] The restriction peptide can be about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, or about 15 amino molecular residues in size, and any ranges derivable therein. In particular embodiments, the restriction peptide is about 8, about 9, about 10, about 11, or about 12 amino molecular residues in size. The restriction peptide can be about 5 to 15 amino acids in length, preferably about 7 to 12 amino acids, or more preferably about 8 to 11 amino acids.

[0178] Exemplary HLA-peptide targets

[0179] Exemplary HLA-peptide targets are shown in Table A. Each row in Table A shows an HLA allele and a corresponding HLA-restricted peptide sequence for each complex. The peptide sequence can consist of the corresponding sequence shown in each row of Table A. Alternatively, the peptide sequence can include the corresponding sequence shown in each row of Table A. Alternatively, the peptide sequence can consist essentially of the corresponding sequence shown in each row of Table A.

[0180] In some embodiments, the HLA-peptide target is a target shown in Table A.

[0181] In some embodiments, the HLA-peptide target is a target shown in Table A, provided that the isolated HLA-peptide target is not any of targets numbers: 6364-6369, 6386-6389, 6500, 6521-6524, or 6578, and is not an HLA-peptide target in Table B or Table C.

[0182] In some embodiments, the HLA-restricted peptide is not selected from a gene that is WT1 or MART1.

[0183] HLA-like molecules that do not associate with restriction peptide ligands are generally unstable. Therefore, association of the restriction peptide with the α1 / α2 groove of the HLA molecule can stabilize the non-covalent association between the β2-microglobulin subunit of the HLA subtype and the α-subunit of the HLA subtype.

[0184] The stability of the nonvalent association between the β2-microglobulin subunit of the HLA isotype and the α-subunit of the HLA isotype can be determined using any suitable method. For example, this stability can be assessed by dissolving insoluble aggregates of the HLA molecule in a high concentration of urea (e.g., about 8 M urea) and determining the ability of the HLA molecule to refold in the presence of a restriction peptide during urea removal (e.g., by dialysis). This refolding method is described, for example, in the Proceedings of the National Academy of Sciences (Proc. Natl. Acad. Sci. USA), Vol. 89, pp. 3429-3433, April 1992, which is incorporated by reference.

[0185] For other examples, this stability can be assessed using conditional HLA class I ligands. Conditional HLA class I ligands are typically designed as short, restricting peptides that can stabilize the association between the β2 and a subunits of the HLA class I molecule by binding to the a1 / a2 groove of the HLA molecule and contain one or more amino acid modifications such that the restricting peptide will cleave upon exposure to a conditional stimulus. Upon cleavage of the conditional ligand, the β2 and a subunits of the HLA molecule dissociate, unless this conditional ligand is exchanged for a restricting peptide that binds to the a1 / a2 groove and stabilizes the HLA molecule. Conditional ligands can be designed by introducing amino acid modifications in known HLA peptide ligands or predicted high affinity HLA peptide ligands. For HLA alleles for which structural information is available, the water accessibility of side chains can also be utilized to select the position at which to introduce the amino acid modification. The use of conditional HLA ligands can be advantageous by allowing the batch production of stable HLA-peptide complexes that can be used to interrogate restricting peptides in a high-throughput manner. Conditional HLA class I ligands and methods of their production are described, for example, in Proc Natl Acad Sci U S A. 2008 Mar 11; 105(10): 3831-3836; Proc Natl Acad Sci U S A. 2008 Mar 11; 105(10): 3825-3830; J Exp Med. 2018 May 7; 215(5): 1493-1504; Choo, J. A. L., et al. Bioorthogonal cleavage and exchange of major histocompatibility complex ligands by employing azobenzene-containing peptides. Angew Chem Int Ed Engl 53, 13390-13394 (2014); Amore, A., et al. Development of a hypersensitive periodate-cleavable amino acid that is methionine- and disulfide-compatible and its application in MHC exchange reagents for T cell characterisation. ChemBioChem 14, 123-131 (2012); Rodenko, B.Chang, C. X. L. et al. Conditional ligands for Asian HLA variants facilitate the definition of CD8+ T-cell responses in acute and chronic viral diseases. Eur J Immunol 43, 1109-1120 (2013). These references are incorporated by reference in their entirety.

[0186] Accordingly, in some embodiments, the ability of an HLA-restricted peptide described herein (e.g., as described in Table A) to stabilize the association of the β2- and a- subunits of an HLA molecule is assessed by performing a conditional ligand-mediated exchange reaction and an HLA stability assay. HLA stability can be assayed using any suitable method, including, for example, mass spectrometry, immunoassays (e.g., ELISA), size exclusion chromatography, and HLA multimer staining followed by flow cytometric evaluation of T cells.

[0187] Other exemplary methods of assessing the stability of the non-covalent association between the β2-microglobulin subunit of an HLA allele and the a-subunit of an HLA allele include performing a peptide exchange using a dipeptide. Peptide exchange using a dipeptide is described in, for example, Proc Natl Acad Sci U S A. 2013 Sep 17; 110(38): 15383-8; Proc Natl Acad Sci U S A. 2015 Jan 6; 112(1): 202-7), which are incorporated by reference.

[0188] Provided herein are useful antigens comprising HLA-peptide targets. HLA-peptide targets can comprise specific HLA-restricted peptides having a defined amino acid sequence complexed with a specific HLA allele.

[0189] HLA-peptide targets can be isolated and / or in substantially pure form. For example, HLA-peptide targets can be isolated from their natural environment, or can be produced by technical means. In some cases, HLA-peptide targets are provided in a form that is substantially free of other peptides or proteins.

[0190] The HLA-peptide targets can exist in soluble form, and optionally, can be recombinant HLA-peptide target complexes. The skilled artisan can use any suitable method to produce and purify recombinant HLA-peptide targets. Suitable methods include, for example, using an E. coli expression system, insect cells, and the like. Other methods include synthetic production, for example, using a cell-free system. WO2017089756 describes an exemplary suitable cell-free system, which is incorporated by reference in its entirety.

[0191] Also provided herein are compositions comprising HLA-peptide targets.

[0192] In some cases, the compositions comprise HLA-peptide targets bound to a solid support. Exemplary solid supports include, but are not limited to, beads, wells, membranes, tubes, columns, plates, agarose gels, magnetic beads, and chips. Exemplary solid supports are described in, for example, Catalysts 2018, 8, 92; doi:10.3390 / catal8020092), which is incorporated by reference in its entirety.

[0193] The HLA-peptide targets can be bound to a solid support by any suitable method known in the art. In some cases, the HLA-peptide targets are covalently bound to the solid support.

[0194] In some cases, the HLA-peptide targets are bound to the solid support through an affinity binding pair. Affinity binding pairs generally involve specific interactions between two molecules. Ligands with affinity for their binding partner molecules can be covalently bound to a solid support, thus serving as baits to immobilize common affinity binding pairs, including, for example, streptavidin and biotin, avidin and biotin; polyhistidine tags with metal ions (such as copper, nickel, zinc, and cobalt); and the like.

[0195] The HLA-peptide targets can comprise a detectable label.

[0196] Pharmaceutical compositions comprising HLA-peptide targets.

[0197] A composition comprising an HLA-peptide target can be a pharmaceutical composition. Such a composition can comprise a plurality of HLA-peptide targets. Exemplary pharmaceutical compositions are described herein. The composition can be capable of eliciting an immune response. The composition can comprise an adjuvant. Suitable adjuvants include, but are not limited to: 1018 ISS, Alum, Aluminum salts, Amplivax, AS15, BCG, CP-870893, CpG7909, CyaA, dSLIM, GM-CSF, IC30, IC31, Imiquimod, ImuFact IMP321, IS Patch, ISS, ISCOMATRIX, JuvImmune, LipoVac, MF59, Monophosphoryl lipid A, Montanide IMS1312, Montanide ISA206, Montanide ISA50V, Montanide ISA-51, OK-432, OM-174, OM-197-MP-EC, ONTAK, PepTel vector system, PLG microparticles, Resiquimod, SRL172, viral particles and other virus-like particles, YF-17D, Aflibercept, R848, beta-glucan, Pam3Cys, Aquila QS21 Stimulon® stimulon derived from saponins (Aquila Biotech, Inc., Worcester, MA, USA), Mycobacterial extract and synthetic bacterial cell wall mimics and other proprietary adjuvants such as Detox. uil or Superfos. Adjuvants such as incomplete Freund’s or GM-CSF are useful. Several immunological adjuvants specific for dendritic cells (e.g., MF59) and their preparation have been described previously (Dupuis M et al. Cell Immunol. 1998, 186(1): 18-27; Allison AC Dev Biol Stand. 1998, 92:3-11). Cytokines can also be used. Several cytokines have been shown to directly affect the migration of dendritic cells to lymphoid tissues (e.g., TNF-a), to accelerate the maturation of dendritic cells into efficient antigen-presenting cells for T lymphocytes (e.g., GM-CSF, IL-1 and IL-4) (U.S. Patent No. 5,849,589, incorporated by reference in its entirety) and to act as immune adjuvants (e.g., IL-12) (Gabrilovich DI et al. J Immunother Emphasis Tumor Immunol. 1996(6):414-418).

[0198] HLA-peptide ABPs

[0199] Also provided herein are ABPs that specifically bind to an HLA-peptide target described herein.

[0200] The HLA-peptide target can be expressed on the surface of any suitable target cell, including tumor cells.

[0201] The ABP can specifically bind to a human leukocyte antigen (HLA)-peptide target, wherein the HLA-peptide target comprises an HLA-restricted peptide complexed with an HLA class I molecule, wherein the HLA-restricted peptide is located in the peptide binding groove of the a1 / a2 heterodimer portion of the HLA class I molecule.

[0202] In some aspects, the ABP does not bind to the HLA class I in the absence of the HLA-restricted peptide. In some aspects, the ABP does not bind to the HLA-restricted peptide in the absence of the human MHC class I. In some aspects, the ABP binds to a tumor cell that presents a human MHC class I complexed with an HLA-restricted peptide, optionally wherein the HLA-restricted peptide is a tumor antigen characteristic of a cancer.

[0203] The ABP can bind to each portion of the HLA-peptide complex (i.e., the HLA and the peptide representing each portion of the complex) when bound together, which forms a new target and protein surface for interaction with and binding by the ABP that is different from the surface presented by the peptide alone or the HLA subtype alone. Generally, in the absence of each portion of the HLA-peptide complex, the new target and protein surface formed by the binding of the HLA to the peptide is not present.

[0204] The ABP is capable of specifically binding to a complex comprising an HLA and an HLA-restricted peptide (HLA-peptide), such as derived from a tumor. In some aspects, the ABP does not bind to the HLA in the absence of the HLA-restricted peptide derived from a tumor. In some aspects, the ABP does not bind to the HLA-restricted peptide derived from a tumor in the absence of the HLA. In some aspects, the ABP binds to the complex comprising the HLA and the HLA-restricted peptide when the HLA-restricted peptide is naturally present on a cell, such as a tumor cell.

[0205] In some embodiments, the ABP provided herein modulates the binding of the HLA- peptide to one or more ligands of the HLA-peptide.

[0206] The ABP can specifically bind to any one of the HLA-peptide targets set forth in Table A. In some embodiments, the ABP specifically binds to an HLA-peptide target that is a target set forth in Table A, provided that the isolated HLA-peptide target is not any one of target numbers: 6364-6369, 6386-6389, 6500, 6521-6524, or 6578, and is not an HLA-peptide target in Table B or Table C. In some embodiments, the HLA-restricted peptide is not a gene selected from WT1 or MART1.

[0207] In more particular embodiments, the ABP specifically binds to an HLA-peptide target selected from any one of: HLA subtype A*02:01 complexed with an HLA-restricted peptide comprising the sequence LLASSILCA, HLA subtype A*01:01 complexed with an HLA-restricted peptide comprising the sequence EVDPIGHLY, HLA subtype B*44:02 complexed with an HLA-restricted peptide comprising the sequence GEMSSNSTAL, HLA subtype A*02:01 complexed with an HLA-restricted peptide comprising the sequence GVYDGEEHSV, HLA subtype *01:01 complexed with an HLA-restricted peptide comprising the sequence EVDPIGHVY, and HLA subtype HLA-A*01:01 complexed with an HLA-restricted peptide comprising the sequence NTDNNLAVY.

[0208] In some embodiments, the ABP is one that competes with an illustrative ABP provided herein. In some aspects, the ABP that competes with an illustrative ABP provided herein and the illustrative ABP provided herein bind to the same epitope.

[0209] In some embodiments, the ABP described herein is referred to herein as a “variant.” In some embodiments, such a variant is derived from a sequence provided herein, e.g., by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such a variant is not derived from a sequence provided herein, but can be isolated de novo, e.g., according to a method provided herein for obtaining an ABP. In some embodiments, a variant is derived from any sequence provided herein, wherein one or more conservative amino acid substitutions are made. In some embodiments, a variant is derived from any sequence provided herein, wherein one or more non-conservative amino acid substitutions are made. Conservative amino acid substitutions are described herein. Exemplary non-conservative amino acid substitutions include those described in J. Immunol. 2008 May 1; 180(9):6116-31, which is incorporated by reference in its entirety. In preferred embodiments, a non-conservative amino acid substitution does not interfere with or inhibit the biological activity of a functional variant. In more preferred embodiments, a non-conservative amino acid substitution enhances the biological activity of a functional variant, thereby enhancing the biological activity of a functional variant compared to a parent ABP.

[0210] ABPs include antibodies or antigen-binding fragments thereof

[0211] The ABP can comprise an antibody or an antigen-binding fragment thereof.

[0212] In some embodiments, the ABP provided herein comprises a light chain. In some aspects, the light chain is a kappa light chain. In certain aspects, the light chain is a lambda light chain.

[0213] In some embodiments, the ABP provided herein comprises a heavy chain. In some aspects, the heavy chain is IgA. In some aspects, the heavy chain is IgD. In some aspects, the heavy chain is IgE. In some aspects, the heavy chain is IgG. In some aspects, the heavy chain is IgM. In some aspects, the heavy chain is IgGl. In some aspects, the heavy chain is IgG2. In some aspects, the heavy chain is IgG3. In some aspects, the heavy chain is IgG4. In some aspects, the heavy chain is IgAl. In some aspects, the heavy chain is IgA2.

[0214] In some embodiments, the ABP provided herein comprises an antibody fragment. In some embodiments, the ABP provided herein consists of an antibody fragment. In some embodiments, the ABP provided herein consists essentially of an antibody fragment. In some aspects, the ABP fragment is an Fv fragment. In some aspects, the ABP fragment is a Fab fragment. In some aspects, the ABP fragment is a F(ab')2 fragment. In some aspects, the ABP fragment is a Fab' fragment. In some aspects, the ABP fragment is a scFv (sFv) fragment. In some aspects, the ABP fragment is a scFv-Fc fragment. In some aspects, the ABP fragment is a fragment of a single domain ABP.

[0215] In some embodiments, the ABP fragment provided herein is derived from an illustrative ABP provided herein. In some embodiments, the ABP fragment provided herein is not derived from an illustrative ABP provided herein, but can be isolated de novo, e.g., according to a method provided herein for obtaining an ABP fragment.

[0216] In some embodiments, the ABP fragment provided herein retains the ability to bind to an HLA-peptide target, as measured by one or more assays or biological effects described herein. In some embodiments, the ABP fragment provided herein retains the ability to prevent an HLA-peptide from interacting with one or more of its ligands, as described herein.

[0217] In some embodiments, the ABP provided herein is a monoclonal ABP. In some embodiments, the ABP provided herein is a polyclonal ABP.

[0218] In some embodiments, the ABP provided herein comprises a chimeric ABP. In some embodiments, the ABP provided herein consists of a chimeric ABP. In some embodiments, the ABP provided herein consists essentially of a chimeric ABP. In some embodiments, the ABP provided herein comprises a humanized ABP. In some embodiments, the ABP provided herein consists of a humanized ABP. In some embodiments, the ABP provided herein consists essentially of a humanized ABP. In some embodiments, the ABP provided herein comprises a human ABP. In some embodiments, the ABP provided herein consists of a human ABP. In some embodiments, the ABP provided herein consists essentially of a human ABP.

[0219] In some embodiments, the ABP provided herein comprises a replacement scaffold. In some embodiments, the ABP provided herein consists of a replacement scaffold. In some embodiments, the ABP provided herein consists essentially of a replacement scaffold. Any suitable replacement scaffold can be used. In some aspects, the replacement scaffold is selected from the group consisting of: Adnectin™, iMab, EETI-II / AGRP, Kunitz domain, thioredoxin peptide aptamer, DARPin, Affilin, Tetranectin, Fynomer, and Avimer.

[0220] Also disclosed herein is an isolated humanized, human, or chimeric ABP that competes with an ABP disclosed herein for binding to an HLA-peptide.

[0221] Also disclosed herein is an isolated humanized, human, or chimeric ABP that binds to an HLA-peptide epitope bound by an ABP described herein.

[0222] In certain aspects, the ABP comprises a human Fc region comprising at least one modification that reduces binding to a human Fc receptor.

[0223] It is known that when ABPs are expressed in cells, the ABPs are post-translationally modified. Examples of post-translational modifications include: cleavage of lysine at the C-terminus of the heavy chain under the action of carboxypeptidases; modification of glutamine or glutamic acid at the N-terminus of the heavy and light chains to pyroglutamic acid under the action of pyroglutamyl methylation, glycosylation, oxidation, deamidation; and glycosylation, such post-translational modifications are known to occur in various ABPs (see Journal of Pharmaceutical Sciences 2008, vol. 97, pages 2426-2447, which is incorporated by reference in its entirety). In some embodiments, the ABP is a post-translationally modified ABP or antigen binding fragment thereof. Examples of post-translationally modified ABPs or antigen binding fragments thereof include: ABPs or antigen binding fragments thereof with pyroglutamyl methylation at the N-terminus of the heavy chain variable region and / or deletion of lysine at the C-terminus of the heavy chain. It is known in the art that such post-translational modifications due to pyroglutamyl methylation at the N-terminus and deletion of lysine at the C-terminus have no effect on the activity of the ABP or fragment thereof (Analytical Biochemistry 2006, vol. 348, pages 24-39, which is incorporated by reference in its entirety).

[0224] Monospecific and multispecific HLA-peptide ABPs

[0225] In some embodiments, the ABPs provided herein are monospecific ABPs. In some embodiments, the ABPs provided herein are multispecific ABPs. In some embodiments, the multispecific ABPs provided herein bind to more than one antigen. In some embodiments, the multispecific ABPs bind to 2 antigens. In some embodiments, the multispecific ABPs bind to 3 antigens. In some embodiments, the multispecific ABPs bind to 4 antigens. In some embodiments, the multispecific ABPs bind to 5 antigens.

[0226] In some embodiments, the multispecific ABPs provided herein bind to more than one epitope on an HLA-peptide antigen. In some embodiments, the multispecific ABPs bind to 2 epitopes on an HLA-peptide antigen. In some embodiments, the multispecific ABPs bind to 3 epitopes on an HLA-peptide antigen.

[0227] Many multispecific ABP constructs are known in the art, and the ABPs provided herein can be provided in the form of any suitable multispecific construct.

[0228] In some embodiments, the multispecific ABP comprises an immunoglobulin comprising at least two different heavy chain variable regions, each paired with a common light chain variable region (i.e., a "common light chain ABP"). The common light chain variable region forms a different antigen binding domain with each of the two different heavy chain variable regions. See Merchant et al. Nat. Biotechnol. 1998, 16:677-681, which is incorporated by reference in its entirety.

[0229] In some embodiments, the multispecific ABP comprises an immunoglobulin comprising an ABP or fragment thereof bound to one or more of the N or C termini of the heavy or light chains of the immunoglobulin. See Coloma and Morrison Nat. Biotechnol. 1997, 15: 159-163, which is incorporated by reference in its entirety. In some aspects, such ABPs comprise tetravalent bispecific ABPs.

[0230] In some embodiments, the multispecific ABP comprises a hybrid immunoglobulin comprising at least two different heavy chain variable regions and at least two different light chain variable regions. See Milstein and Cuello Nature 1983, 305:537-540); and Staerz and Bevan Proc. Natl. Acad. Sci. USA 1986, 83: 1453-1457, each incorporated by reference in its entirety.

[0231] In some embodiments, the multispecific ABP comprises an immunoglobulin chain with modifications to vary the immunoglobulin chain to reduce the formation of byproducts that do not have multispecificity. In some aspects, the ABP comprises one or more "knob-into-hole" modifications, as described in U.S. Patent No. 5,731,168, which is incorporated by reference in its entirety.

[0232] In some embodiments, the multispecific ABP comprises an immunoglobulin chain with one or more electrostatic modifications to facilitate Fc heteromultimer assembly. See WO 2009 / 089004, which is incorporated by reference in its entirety.

[0233] In some embodiments, the multispecific ABP comprises a bispecific single chain molecule. See Traunecker et al. EMBO J. 1991, 10:3655-3659); and Gruber et al. J. Immunol. 1994, 152:5368-5374, each incorporated by reference in its entirety.

[0234] In some embodiments, the multispecific ABP comprises a heavy chain variable domain and a light chain variable domain connected via a polypeptide linker, wherein the linker length is selected to promote assembly of the multispecific ABP with the desired multispecificity. For example, when a heavy chain variable domain and a light chain variable domain are connected by a polypeptide linker having a size of more than 12 amino acid residues, a monospecific scFv is typically formed. See U.S. Pat. Nos. 4,946,778 and 5,132,405, both incorporated by reference in their entireties. In some embodiments, reducing the polypeptide linker length to less than 12 amino acid residues prevents pairing of the heavy and light chain variable domains on the same polypeptide chain, allowing the heavy and light chain variable domains from one chain to pair with complementary domains on another chain. Thus, the resulting ABP has multispecificity, with the specificity of each binding site being allocated by more than one polypeptide chain. Polypeptide chains comprising heavy and light chain variable domains connected by linkers of 3 to 12 amino acid residues primarily form dimers (termed diabodies). Linkers having 0 to 2 amino acid residues, i.e., trimers (termed triabodies) and tetramers (termed tetrabodies) are advantageous. However, in addition to the length of the linker, the exact type of oligomerization appears to depend on the composition of the amino acid residues and the order of the variable domains in each polypeptide chain (e.g., VH-linker-VL versus VL-linker-VH). The skilled artisan can select the appropriate linker length based on the desired multispecificity.

[0235] Fc regions and variants

[0236] In certain embodiments, the ABPs provided herein comprise an Fc region. The Fc region can be wild-type or a variant thereof. In certain embodiments, the ABPs provided herein comprise an Fc region having one or more amino acid substitutions, insertions, or deletions compared to a naturally occurring Fc region. In some aspects, such substitutions, insertions, or deletions result in ABPs having altered stability, glycosylation, or other characteristics. In some aspects, such substitutions, insertions, or deletions result in glycosylated ABPs.

[0237] A "variant Fc region" or "engineered Fc region" comprises an amino acid sequence that differs from that of a native sequence Fc region due to at least one amino acid modification, preferably one or more amino acid substitutions. Preferably, a variant Fc region has at least one amino acid substitution, e.g., from about one to about ten amino acid substitutions, and preferably, from about one to about five amino acid substitutions, with a native sequence Fc region or the Fc region of a parent polypeptide. A variant Fc region herein is preferably at least about 80% homologous to a native sequence Fc region and / or to the Fc region of a parent polypeptide, and most preferably, is at least about 90% homologous thereto, more preferably, is at least about 95% homologous thereto.

[0238] The term "ABP comprising an Fc region" refers to an ABP that includes an Fc region. The C-terminal lysine (residue 447, according to the EU numbering system) of the Fc region can be removed, e.g., during purification of the ABP or by recombinantly engineering the nucleic acid encoding the ABP. Thus, an ABP having an Fc region can include an ABP with or without K447.

[0239] In some aspects, the Fc region of an ABP provided herein is modified to generate an ABP with altered affinity for an Fc receptor, or to generate an ABP that is more immunologically inert. In some embodiments, an ABP variant provided herein has some, but not all, effector functions. Such an ABP can be useful, for example, when the half-life of the ABP is important in vivo, but when certain effector functions (e.g., complement activation and ADCC) are unnecessary or deleterious.

[0240] In some embodiments, the Fc region of an ABP provided herein is a human IgG4 Fc region that includes one or more mutations that stabilize the hinge, S228P and L235E. See Aalberse et al. Immunology 2002, 105:9-19, which is incorporated by reference in its entirety. In some embodiments, the IgG4 Fc region includes one or more of the following mutations: E233P, F234V, and L235A. See Armour et al. Mol. Immunol. 2003, 40:585-593, which is incorporated by reference in its entirety. In some embodiments, the IgG4 Fc region includes a deletion of the G236 position.

[0241] In some embodiments, the Fc region of an ABP provided herein is a human IgG1 Fc region that includes one or more mutations that reduce Fc receptor binding. In some aspects, the one or more mutations occur in a residue selected from S228 (e.g., S228A), L234 (e.g., L234A), L235 (e.g., L235A), D265 (e.g., D265A), and N297 (e.g., N297A). In some aspects, the ABP includes a PVA236 mutation. PVA236 refers to the substitution of PVA for the amino acid sequence ELLG from amino acid position 233 to 236 of IgG1 or EFLG of IgG4. See U.S. Patent No. 9,150,641, which is incorporated by reference in its entirety.

[0242] In some embodiments, the Fc region of an ABP provided herein is modified as described in Armour et al. Eur. J. Immunol. 1999, 29:2613-2624; WO 1999 / 058572; and / or UK Patent Application No. 98099518, each of which is incorporated by reference in its entirety.

[0243] In some embodiments, the Fc region of the ABP provided herein is a human IgG2 Fc region, which includes one or more mutations A330S and P331S.

[0244] In some embodiments, the Fc region of the ABP provided herein has an amino acid substitution at one or more of the following positions: 238, 265, 269, 270, 297, 327, and 329. See U.S. Patent No. 6,737,056, which is incorporated by reference in its entirety. Such Fc mutants include Fc mutants substituted at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called “DANA” Fc mutant, which is substituted at residues 265 and 297 with alanine. See U.S. Patent No. 7,332,581, which is incorporated by reference in its entirety. In some embodiments, the ABP includes an alanine at amino acid position 265. In some embodiments, the ABP includes an alanine at amino acid position 297.

[0245] In certain embodiments, the ABP provided herein includes an Fc region with one or more amino acid substitutions that improve ADCC, such as substitutions at one or more of positions 298, 333, and 334 in the Fc region. In some embodiments, the ABP provided herein includes an Fc region with one or more amino acid substitutions at positions 239, 332, and 330, as described in Lazar et al. Proc. Natl. Acad. Sci. USA 2006, 103:4005-4010), which is incorporated by reference in its entirety.

[0246] In some embodiments, the ABP provided herein includes one or more changes that improve or diminish C1q binding and / or CDC. See U.S. Patent No. 6,194,551; WO 99 / 51642; and (Idusogie et al. J. Immunol. 2000, 164:4178-4184); all incorporated by reference in their entirety.

[0247] In some embodiments, the ABP provided herein includes one or more changes to increase half-life. ABPs with increased half-life and improved binding to the neonatal Fc receptor (FcRn) are described, for example, in Hinton et al. J. Immunol. 2006, 176:346-356; and U.S. Patent Publication No. 2005 / 0014934; both incorporated by reference in their entirety. Such Fc variants include Fc variants substituted at one or more of the following Fc region residues of IgG: 238, 250, 256, 265, 272, 286, 303, 305, 307, 311, 312, 314, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424, 428, and 434.

[0248] In some embodiments, the ABPs provided herein include one or more Fc region variants, as described in U.S. Patent Nos. 7,371,826; 5,648,260; and 5,624,821; Duncan and Winter, Nature 1988, 322:738-740); and WO 94 / 29351; all incorporated by reference in their entireties.

[0249] Antibodies specific for A*02:01_LLASSILCA (G7)

[0250] In some aspects, provided herein are ABPs comprising an antibody or antigen binding fragment thereof that specifically binds to an HLA-peptide target, wherein the HLA class I molecule of the HLA-peptide target is HLA subtype A*02:01, and the HLA-restricted peptide of the HLA-peptide target comprises the sequence LLASSILCA (SEQ ID NO: 2737) (“G7”).

[0251] Sequences of G7-specific antibodies

[0252] ABPs specific for A*02:01_LLASSILCA (SEQ ID NO: 2737) can include one or more sequences, which will be described in detail below.

[0253] CDRs

[0254] An ABP specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include one or more antibody complementarity determining region (CDR) sequences, e.g., can include three heavy chain CDRs (CDR-H1, CDR-H2, CDR-H3) and three light chain CDRs (CDR-L1, CDR-L2, CDR-L3). An ABP specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include one particular heavy chain CDR3 (CDR-H3) sequence and one particular light chain CDR3 (CDR-L3) sequence. In some embodiments, CDR-H3 is SEQ ID NO:3030 and CDR-L3 is SEQ ID NO:3048. In some embodiments, CDR-H3 is SEQ ID NO:3025 and CDR-L3 is SEQ ID NO:3043. In some embodiments, CDR-H3 is SEQ ID NO:3026 and CDR-L3 is SEQ ID NO:3044. In some embodiments, CDR-H3 is SEQ ID NO:3027 and CDR-L3 is SEQ ID NO:3045. In some embodiments, CDR-H3 is SEQ ID NO:3028 and CDR-L3 is SEQ ID NO:3046.

[0255] In some embodiments, CDR-H3 is SEQ ID NO:3029 and CDR-L3 is SEQ ID NO:3047.

[0256] In some embodiments, CDR-H3 is SEQ ID NO:3031 and CDR-L3 is SEQ ID NO:3049.

[0257] In some embodiments, CDR-H3 is SEQ ID NO:3032 and CDR-L3 is SEQ ID NO:3050.

[0258] An ABP specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include CDR-H1 (SEQ ID NO:3010), CDR-H2 (SEQ ID NO:3017), CDR-H3 (SEQ ID NO:3025), CDR-L1 (SEQ ID NO:3033), CDR-L2 (SEQ ID NO:2970), and CDR-L3 (SEQ ID NO:3043). An ABP specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include CDR-H1 (SEQ ID NO:3011), CDR-H2 (SEQ ID NO:3018), CDR-H3 (SEQ ID NO:3026), CDR-L1 (SEQ ID NO:3034), CDR-L2 (SEQ ID NO:2958), and CDR-L3 (SEQ ID NO:3044). An ABP specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include CDR-H1 (SEQ ID NO:3012), CDR-H2 (SEQ ID NO:3019), CDR-H3 (SEQ ID NO:3027), CDR-L1 (SEQ ID NO:3035), CDR-L2 (SEQ ID NO:3039), and CDR-L3 (SEQ ID NO:3045). An ABP specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include CDR-H1 (SEQ ID NO:3013), CDR-H2 (SEQ ID NO:3020), CDR-H3 (SEQ ID NO:3028), CDR-L1 (SEQ ID NO:3036), CDR-L2 (SEQ ID NO:2962), and CDR-L3 (SEQ ID NO:3046). An ABP specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include CDR-H1 (SEQ ID NO:2879), CDR-H2 (SEQ ID NO:3021), CDR-H3 (SEQ ID NO:3029), CDR-L1 (SEQ ID NO:2934), CDR-L2 (SEQ ID NO:3040), and CDR-L3 (SEQ ID NO:3047).An ABP specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include CDR-H1 (SEQ ID NO:3014), CDR-H2 (SEQ ID NO:3022), CDR-H3 (SEQ ID NO:3030), CDR-L1 (SEQ ID NO:3037), CDR-L2 (SEQ ID NO:3041), and CDR-L3 (SEQ ID NO:3048). An ABP specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include CDR-H1 (SEQ ID NO:3015), CDR-H2 (SEQ ID NO:3023), CDR-H3 (SEQ ID NO:3031), CDR-L1 (SEQ ID NO:2946), CDR-L2 (SEQ ID NO:3042), and CDR-L3 (SEQ ID NO:3049). An ABP specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include CDR-H1 (SEQ ID NO:3016), CDR-H2 (SEQ ID NO:3024), CDR-H3 (SEQ ID NO:3032), CDR-L1 (SEQ ID NO:3038), CDR-L2 (SEQ ID NO:3041), and CDR-L3 (SEQ ID NO:3050).

[0259] VL

[0260] An ABP specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include a VL sequence. The VL sequence can be SEQ ID NO:3002. The VL sequence can be SEQ ID NO:3003. The VL sequence can be SEQ ID NO:3004. The VL sequence can be SEQ ID NO:3005. The VL sequence can be SEQ ID NO:3006. The VL sequence can be SEQ ID NO:3007. The VL sequence can be SEQ ID NO:3008. The VL sequence can be SEQ ID NO:3009.

[0261] VH

[0262] An ABP specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include a VL sequence. The VL sequence can be SEQ ID NO:3002. The VL sequence can be SEQ ID NO:3003. The VL sequence can be SEQ ID NO:3004. The VL sequence can be SEQ ID NO:3005. The VL sequence can be SEQ ID NO:3006. The VL sequence can be SEQ ID NO:3007. The VL sequence can be SEQ ID NO:3008. The VL sequence can be SEQ ID NO:3009.

[0263] VH-VL combinations

[0264] An ABP specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include a VL sequence. The VL sequence can be SEQ ID NO:3002. The VL sequence can be SEQ ID NO:3003. The VL sequence can be SEQ ID NO:3004. The VL sequence can be SEQ ID NO:3005. The VL sequence can be SEQ ID NO:3006. The VL sequence can be SEQ ID NO:3007. The VL sequence can be SEQ ID NO:3008. The VL sequence can be SEQ ID NO:3009.

[0265] Antibodies specific for A*01:01_NTDNNLAVY (G2)

[0266] In some aspects, provided herein are ABPs comprising an antibody or antigen binding fragment thereof that specifically binds to an HLA-peptide target, wherein the HLA class I molecule of the HLA-peptide target is HLA subtype A*01:01, and the HLA-restricted peptide of the HLA-peptide target comprises the sequence NTDNNLAVY (SEQ ID NO: 23) (“G2”).

[0267] Sequences of G2-specific antibodies

[0268] ABPs specific for A*01:01_NTDNNLAVY (SEQ ID NO: 23) can comprise one or more sequences, which will be described in detail below.

[0269] CDRs

[0270] ABPs specific for A*01:01_NTDNNLAVY (SEQ ID NO: 23) can comprise one or more antibody complementarity determining region (CDR) sequences, e.g., can comprise three heavy chain CDRs (CDR-H1, CDR-H2, CDR-H3) and three light chain CDRs (CDR-L1, CDR-L2, CDR-L3). ABPs specific for A*01:01_NTDNNLAVY (SEQ ID NO: 23) can comprise one particular heavy chain CDR3 (CDR-H3) sequence and one particular light chain CDR3 (CDR-L3) sequence. In some embodiments, CDR-H3 is SEQ ID NO: 2902 and CDR-L3 is SEQ ID NO: 2971. In some embodiments, CDR-H3 is SEQ ID NO: 2903 and CDR-L3 is SEQ ID NO: 2972. In some embodiments, CDR-H3 is SEQ ID NO: 2903 and CDR-L3 is SEQ ID NO: 2973. In some embodiments, CDR-H3 is SEQ ID NO: 2904 and CDR-L3 is SEQ ID NO: 2974. In some embodiments, CDR-H3 is SEQ ID NO: 2905 and CDR-L3 is SEQ ID NO: 2975.

[0271] In some embodiments, CDR-H3 is SEQ ID NO: 2906 and CDR-L3 is SEQ ID NO: 2976.

[0272] In some embodiments, CDR-H3 is SEQ ID NO:2907, and CDR-L3 is SEQ ID NO:2976.

[0273] In some embodiments, CDR-H3 is SEQ ID NO:2908, and CDR-L3 is SEQ ID NO:2977.

[0274] In some embodiments, CDR-H3 is SEQ ID NO:2909, and CDR-L3 is SEQ ID NO:2972.

[0275] In some embodiments, CDR-H3 is SEQ ID NO:2910, and CDR-L3 is SEQ ID NO:2978.

[0276] In some embodiments, CDR-H3 is SEQ ID NO:2911, and CDR-L3 is SEQ ID NO:2976.

[0277] In some embodiments, CDR-H3 is SEQ ID NO:2912, and CDR-L3 is SEQ ID NO:2978.

[0278] In some embodiments, CDR-H3 is SEQ ID NO:2913, and CDR-L3 is SEQ ID NO:2979.

[0279] In some embodiments, CDR-H3 is SEQ ID NO:2914, and CDR-L3 is SEQ ID NO:2980.

[0280] In some embodiments, CDR-H3 is SEQ ID NO:2903, and CDR-L3 is SEQ ID NO:2981.

[0281] In some embodiments, CDR-H3 is SEQ ID NO:2915, and CDR-L3 is SEQ ID NO:2982.

[0282] In some embodiments, CDR-H3 is SEQ ID NO:2916, and CDR-L3 is SEQ ID NO:2973.

[0283] In some embodiments, CDR-H3 is SEQ ID NO:2917, and CDR-L3 is SEQ ID NO:2972.

[0284] In some embodiments, CDR-H3 is SEQ ID NO:2917, and CDR-L3 is SEQ ID NO:2972.

[0285] In some embodiments, CDR-H3 is SEQ ID NO: 2918, and CDR-L3 is SEQ ID NO: 2974.

[0286] In some embodiments, CDR-H3 is SEQ ID NO: 2919, and CDR-L3 is SEQ ID NO: 2983.

[0287] In some embodiments, CDR-H3 is SEQ ID NO: 2920, and CDR-L3 is SEQ ID NO: 2984.

[0288] In some embodiments, CDR-H3 is SEQ ID NO: 2921, and CDR-L3 is SEQ ID NO: 2972.

[0289] In some embodiments, CDR-H3 is SEQ ID NO: 2922, and CDR-L3 is SEQ ID NO: 2985.

[0290] In some embodiments, CDR-H3 is SEQ ID NO: 2923, and CDR-L3 is SEQ ID NO: 2986.

[0291] In some embodiments, CDR-H3 is SEQ ID NO: 2924, and CDR-L3 is SEQ ID NO: 2987.

[0292] In some embodiments, CDR-H3 is SEQ ID NO: 2925, and CDR-L3 is SEQ ID NO: 2973.

[0293] In some embodiments, CDR-H3 is SEQ ID NO: 2926, and CDR-L3 is SEQ ID NO: 2988.

[0294] In some embodiments, CDR-H3 is SEQ ID NO: 2927, and CDR-L3 is SEQ ID NO: 2989.

[0295] In some embodiments, CDR-H3 is SEQ ID NO: 2928, and CDR-L3 is SEQ ID NO: 2981.

[0296] In some embodiments, CDR-H3 is SEQ ID NO: 2929, and CDR-L3 is SEQ ID NO: 2990.

[0297] In some embodiments, CDR-H3 is SEQ ID NO: 2930, and CDR-L3 is SEQ ID NO: 2989.

[0298] In some embodiments, CDR-H3 is SEQ ID NO: 2931, and CDR-L3 is SEQ ID NO: 2991.

[0299] In some embodiments, CDR-H3 is SEQ ID NO: 2932, and CDR-L3 is SEQ ID NO: 2992.

[0300] In some embodiments, CDR-H3 is SEQ ID NO: 2933, and CDR-L3 is SEQ ID NO: 2993.

[0301] An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2851), CDR-H2 (SEQ ID NO:2880), CDR-H3 (SEQ ID NO:2902), CDR-L1 (SEQ ID NO:2934), CDR-L2 (SEQ ID NO:2955), and CDR-L3 (SEQ ID NO:2971). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2852), CDR-H2 (SEQ ID NO:2881), CDR-H3 (SEQ ID NO:2903), CDR-L1 (SEQ ID NO:2935), CDR-L2 (SEQ ID NO:2956), and CDR-L3 (SEQ ID NO:2972). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2853), CDR-H2 (SEQ ID NO:2882), CDR-H3 (SEQ ID NO:2903), CDR-L1 (SEQ ID NO:2936), CDR-L2 (SEQ ID NO:2957), and CDR-L3 (SEQ ID NO:2973). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2854), CDR-H2 (SEQ ID NO:2882), CDR-H3 (SEQ ID NO:2904), CDR-L1 (SEQ ID NO:2937), CDR-L2 (SEQ ID NO:2958), and CDR-L3 (SEQ ID NO:2974). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2855), CDR-H2 (SEQ ID NO:2883), CDR-H3 (SEQ ID NO:2905), CDR-L1 (SEQ ID NO:2937), CDR-L2 (SEQ ID NO:2958), and CDR-L3 (SEQ ID NO:2975).An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2855), CDR-H2 (SEQ ID NO:2882), CDR-H3 (SEQ ID NO:2906), CDR-L1 (SEQ ID NO:2938), CDR-L2 (SEQ ID NO:2958), and CDR-L3 (SEQ ID NO:2976). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2856), CDR-H2 (SEQ ID NO:2882), CDR-H3 (SEQ ID NO:2907), CDR-L1 (SEQ ID NO:2939), CDR-L2 (SEQ ID NO:2959), and CDR-L3 (SEQ ID NO:2976). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2857), CDR-H2 (SEQ ID NO:2882), CDR-H3 (SEQ ID NO:2908), CDR-L1 (SEQ ID NO:2940), CDR-L2 (SEQ ID NO:2960), and CDR-L3 (SEQ ID NO:2977). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2858), CDR-H2 (SEQ ID NO:2884), CDR-H3 (SEQ ID NO:2909), CDR-L1 (SEQ ID NO:2935), CDR-L2 (SEQ ID NO:2958), and CDR-L3 (SEQ ID NO:2972). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2859), CDR-H2 (SEQ ID NO:2882), CDR-H3 (SEQ ID NO:2910), CDR-L1 (SEQ ID NO:2941), CDR-L2 (SEQ ID NO:2961), and CDR-L3 (SEQ ID NO:2978).An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2852), CDR-H2 (SEQ ID NO:2885), CDR-H3 (SEQ ID NO:2911), CDR-L1 (SEQ ID NO:2942), CDR-L2 (SEQ ID NO:2958), and CDR-L3 (SEQ ID NO:2976). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2860), CDR-H2 (SEQ ID NO:2882), CDR-H3 (SEQ ID NO:2912), CDR-L1 (SEQ ID NO:2943), CDR-L2 (SEQ ID NO:2962), and CDR-L3 (SEQ ID NO:2978). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2861), CDR-H2 (SEQ ID NO:2886), CDR-H3 (SEQ ID NO:2913), CDR-L1 (SEQ ID NO:2944), CDR-L2 (SEQ ID NO:2963), and CDR-L3 (SEQ ID NO:2979). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2862), CDR-H2 (SEQ ID NO:2887), CDR-H3 (SEQ ID NO:2914), CDR-L1 (SEQ ID NO:2945), CDR-L2 (SEQ ID NO:2958), and CDR-L3 (SEQ ID NO:2980). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2855), CDR-H2 (SEQ ID NO:2888), CDR-H3 (SEQ ID NO:2903), CDR-L1 (SEQ ID NO:2941), CDR-L2 (SEQ ID NO:2962), and CDR-L3 (SEQ ID NO:2981).An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2855), CDR-H2 (SEQ ID NO:2889), CDR-H3 (SEQ ID NO:2915), CDR-L1 (SEQ ID NO:2946), CDR-L2 (SEQ ID NO:2958), and CDR-L3 (SEQ ID NO:2982). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2863), CDR-H2 (SEQ ID NO:2883), CDR-H3 (SEQ ID NO:2916), CDR-L1 (SEQ ID NO:2947), CDR-L2 (SEQ ID NO:2958), and CDR-L3 (SEQ ID NO:2973). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2856), CDR-H2 (SEQ ID NO:2890), CDR-H3 (SEQ ID NO:2917), CDR-L1 (SEQ ID NO:2934), CDR-L2 (SEQ ID NO:2962), and CDR-L3 (SEQ ID NO:2972). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2864), CDR-H2 (SEQ ID NO:2891), CDR-H3 (SEQ ID NO:2917), CDR-L1 (SEQ ID NO:2946), CDR-L2 (SEQ ID NO:2964), and CDR-L3 (SEQ ID NO:2972). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2865), CDR-H2 (SEQ ID NO:2882), CDR-H3 (SEQ ID NO:2918), CDR-L1 (SEQ ID NO:2941), CDR-L2 (SEQ ID NO:2962), and CDR-L3 (SEQ ID NO:2974).An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2866), CDR-H2 (SEQ ID NO:2882), CDR-H3 (SEQ ID NO:2919), CDR-L1 (SEQ ID NO:2948), CDR-L2 (SEQ ID NO:2958), and CDR-L3 (SEQ ID NO:2983). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2867), CDR-H2 (SEQ ID NO:2892), CDR-H3 (SEQ ID NO:2920), CDR-L1 (SEQ ID NO:2946), CDR-L2 (SEQ ID NO:2962), and CDR-L3 (SEQ ID NO:2984). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2868), CDR-H2 (SEQ ID NO:2893), CDR-H3 (SEQ ID NO:2921), CDR-L1 (SEQ ID NO:2949), CDR-L2 (SEQ ID NO:2965), and CDR-L3 (SEQ ID NO:2972). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2869), CDR-H2 (SEQ ID NO:2894), CDR-H3 (SEQ ID NO:2922), CDR-L1 (SEQ ID NO:2950), CDR-L2 (SEQ ID NO:2966), and CDR-L3 (SEQ ID NO:2985). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2870), CDR-H2 (SEQ ID NO:2882), CDR-H3 (SEQ ID NO:2923), CDR-L1 (SEQ ID NO:2943), CDR-L2 (SEQ ID NO:2967), and CDR-L3 (SEQ ID NO:2986).An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2871), CDR-H2 (SEQ ID NO:2895), CDR-H3 (SEQ ID NO:2924), CDR-L1 (SEQ ID NO:2951), CDR-L2 (SEQ ID NO:2968), and CDR-L3 (SEQ ID NO:2987). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2872), CDR-H2 (SEQ ID NO:2882), CDR-H3 (SEQ ID NO:2925), CDR-L1 (SEQ ID NO:2952), CDR-L2 (SEQ ID NO:2969), and CDR-L3 (SEQ ID NO:2973). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2873), CDR-H2 (SEQ ID NO:2882), CDR-H3 (SEQ ID NO:2926), CDR-L1 (SEQ ID NO:2943), CDR-L2 (SEQ ID NO:2958), and CDR-L3 (SEQ ID NO:2988). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2852), CDR-H2 (SEQ ID NO:2882), CDR-H3 (SEQ ID NO:2927), CDR-L1 (SEQ ID NO:2935), CDR-L2 (SEQ ID NO:2958), and CDR-L3 (SEQ ID NO:2989). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO:2874), CDR-H2 (SEQ ID NO:2896), CDR-H3 (SEQ ID NO:2928), CDR-L1 (SEQ ID NO:2938), CDR-L2 (SEQ ID NO:2958), and CDR-L3 (SEQ ID NO:2981).An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO: 2875), CDR-H2 (SEQ ID NO: 2897), CDR-H3 (SEQ ID NO: 2929), CDR-L1 (SEQ ID NO: 2953), CDR-L2 (SEQ ID NO: 2961), and CDR-L3 (SEQ ID NO: 2990). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO: 2876), CDR-H2 (SEQ ID NO: 2898), CDR-H3 (SEQ ID NO: 2930), CDR-L1 (SEQ ID NO: 2941), CDR-L2 (SEQ ID NO: 2962), and CDR-L3 (SEQ ID NO: 2989). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO: 2877), CDR-H2 (SEQ ID NO: 2899), CDR-H3 (SEQ ID NO: 2931), CDR-L1 (SEQ ID NO: 2946), CDR-L2 (SEQ ID NO: 2964), and CDR-L3 (SEQ ID NO: 2991). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO: 2878), CDR-H2 (SEQ ID NO: 2900), CDR-H3 (SEQ ID NO: 2932), CDR-L1 (SEQ ID NO: 2946), CDR-L2 (SEQ ID NO: 2958), and CDR-L3 (SEQ ID NO: 2992). An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO:23) can include CDR-H1 (SEQ ID NO: 2879), CDR-H2 (SEQ ID NO: 2901), CDR-H3 (SEQ ID NO: 2933), CDR-L1 (SEQ ID NO: 2954), CDR-L2 (SEQ ID NO: 2970), and CDR-L3 (SEQ ID NO: 2993).

[0302] VL

[0303] An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VL sequence. The VL sequence can be SEQ ID NO: 2816. The VL sequence can be SEQ ID NO: 2817. The VL sequence can be SEQ ID NO: 2818. The VL sequence can be SEQ ID NO: 2819. The VL sequence can be SEQ ID NO: 2820. The VL sequence can be SEQ ID NO: 2821. The VL sequence can be SEQ ID NO: 2822. The VL sequence can be SEQ ID NO: 2823. The VL sequence can be SEQ ID NO: 2824. The VL sequence can be SEQ ID NO: 2825. The VL sequence can be SEQ ID NO: 2826. The VL sequence can be SEQ ID NO: 2827. The VL sequence can be SEQ ID NO: 2828. The VL sequence can be SEQ ID NO: 2829. The VL sequence can be SEQ ID NO: 2830. The VL sequence can be SEQ ID NO: 2831. The VL sequence can be SEQ ID NO: 2832. The VL sequence can be SEQ ID NO: 2833. The VL sequence can be SEQ ID NO: 2834. The VL sequence can be SEQ ID NO: 2835. The VL sequence can be SEQ ID NO: 2836. The VL sequence can be SEQ ID NO: 2837. The VL sequence can be SEQ ID NO: 2838. The VL sequence can be SEQ ID NO: 2839. The VL sequence can be SEQ ID NO: 2840. The VL sequence can be SEQ ID NO: 2841. The VL sequence can be SEQ ID NO: 2842. The VL sequence can be SEQ ID NO: 2843. The VL sequence can be SEQ ID NO: 2844. The VL sequence can be SEQ ID NO: 2845. The VL sequence can be SEQ ID NO: 2846. The VL sequence can be SEQ ID NO: 2847. The VL sequence can be SEQ ID NO: 2848. The VL sequence can be SEQ ID NO: 2849. The VL sequence can be SEQ ID NO: 2850.

[0304] VH

[0305] ABP specific to A*01:01_NTDNNLAVY (SEQ ID NO:23) may include a VH sequence. The VH sequence may be SEQ ID NO:2781. The VH sequence may be SEQ ID NO:2782. The VH sequence may be SEQ ID NO:2783. The VH sequence may be SEQ ID NO:2784. The VH sequence may be SEQ ID NO:2785. The VH sequence may be SEQ ID NO:2786. The VH sequence may be SEQ ID NO:2787. The VH sequence may be SEQ ID NO:2788. The VH sequence may be SEQ ID NO:2789. The VH sequence may be SEQ ID NO:2790. The VH sequence may be SEQ ID NO:2791. The VH sequence may be SEQ ID NO:2792. The VH sequence may be SEQ ID NO:2793. The VH sequence may be SEQ ID NO:2794. The VH sequence may be SEQ ID NO:2795. The VH sequence may be SEQ ID NO:2796. The VH sequence can be SEQ ID NO:2797. The VH sequence can be SEQ ID NO:2798. The VH sequence can be SEQ ID NO:2799. The VH sequence can be SEQ ID NO:2800. The VH sequence can be SEQ ID NO:2801. The VH sequence can be SEQ ID NO:2802. The VH sequence can be SEQ ID NO:2803. The VH sequence can be SEQ ID NO:2804. The VH sequence can be SEQ ID NO:2805. The VH sequence can be SEQ ID NO:2806. The VH sequence can be SEQ ID NO:2807. The VH sequence can be SEQ ID NO:2808. The VH sequence can be SEQ ID NO:2809. The VH sequence can be SEQ ID NO:2810. The VH sequence can be SEQ ID NO:2811. The VH sequence can be SEQ ID NO:2812. The VH sequence can be SEQ ID NO:2813. The VH sequence can be SEQ ID NO:2814. The VH sequence can be SEQ ID NO:2815.

[0306] VH-VL combination

[0307] An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2781 and a VL sequence that is SEQ ID NO: 2816. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2782 and a VL sequence that is SEQ ID NO: 2817. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2783 and a VL sequence that is SEQ ID NO: 2818. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2784 and a VL sequence that is SEQ ID NO: 2819. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2785 and a VL sequence that is SEQ ID NO: 2820. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2786 and a VL sequence that is SEQ ID NO: 2821. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2787 and a VL sequence that is SEQ ID NO: 2822. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2788 and a VL sequence that is SEQ ID NO: 2823. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2789 and a VL sequence that is SEQ ID NO: 2824. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2790 and a VL sequence that is SEQ ID NO: 2825. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2791 and a VL sequence that is SEQ ID NO: 2826.An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2792 and a VL sequence that is SEQ ID NO: 2827. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2793 and a VL sequence that is SEQ ID NO: 2828. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2794 and a VL sequence that is SEQ ID NO: 2829. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2795 and a VL sequence that is SEQ ID NO: 2830. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2796 and a VL sequence that is SEQ ID NO: 2831. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2797 and a VL sequence that is SEQ ID NO: 2832. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2798 and a VL sequence that is SEQ ID NO: 2833. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2799 and a VL sequence that is SEQ ID NO: 2834. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2800 and a VL sequence that is SEQ ID NO: 2835. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2801 and a VL sequence that is SEQ ID NO: 2836. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2802 and a VL sequence that is SEQ ID NO: 2837.An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2803 and a VL sequence that is SEQ ID NO: 2838. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2804 and a VL sequence that is SEQ ID NO: 2839. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2805 and a VL sequence that is SEQ ID NO: 2840. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2806 and a VL sequence that is SEQ ID NO: 2841. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2807 and a VL sequence that is SEQ ID NO: 2842. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2808 and a VL sequence that is SEQ ID NO: 2843. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2809 and a VL sequence that is SEQ ID NO: 2844. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2810 and a VL sequence that is SEQ ID NO: 2845. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2811 and a VL sequence that is SEQ ID NO: 2846. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2812 and a VL sequence that is SEQ ID NO: 2847. An ABP specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2813 and a VL sequence that is SEQ ID NO: 2848.ABPs specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2814 and a VL sequence that is SEQ ID NO: 2849. ABPs specific for A*01 :01_NTDNNLAVY (SEQ ID NO: 23) can include a VH sequence that is SEQ ID NO: 2815 and a VL sequence that is SEQ ID NO: 2850.

[0308] Receptors

[0309] In the provided ABPs, the HLA-peptide ABPs are receptors. The receptors can include antigen receptors and other chimeric receptors that specifically bind to the HLA-peptide targets disclosed herein. The receptors can be T cell receptors (TCRs). The receptors can be chimeric antigen receptors (CARs).

[0310] TCRs can be soluble or membrane bound. There are functional non-TCR antigen receptors in antigen receptors, such as chimeric antigen receptors (CARs). Cells expressing the receptors and their uses in adoptive cell therapy, such as treating diseases and disorders associated with HLA-peptide expression, including cancer, are also provided.

[0311] Exemplary antigen receptors (including CARs) and methods of engineering and introducing these receptors into cells include those described in, e.g., International Patent Application Publication Nos. WO200014257, WO2013126726, WO2012 / 129514, WO2014031687, WO2013 / 166321, WO2013 / 071154, WO2013 / 123061; U.S. Patent Application Publication Nos. US2002131960, US2013287748, US20130149337; U.S. Patent Nos. 6,451,995, 7,446,190, 8,252,592, 8,339,645, 8,398,282, 7,446,179, 6,410,319, 7,070,995, 7,265,209, 7,354,762, 7,446,191, 8,324,353, and 8,479,118; and European Patent Application No. EP2537416, and / or those described in Sadelain et al. Cancer Discov. 2013 Apr; 3(4): 388-398; Davila et al. (2013) PLoS ONE 8(4): e61338; Turtle et al. Curr. Opin. Immunol. 2012 Oct; 24(5): 633-39; Wu et al. Cancer 2012 Mar; 18(2): 160-75. In some aspects, the antigen receptor comprises a CAR described in U.S. Patent No. 7,446,190, and those CARs described in International Patent Application Publication No. WO / 2014055668A1. Exemplary CARs include those described in any of the above publications, such as WO2014031687, U.S. Patent No. 8,339,645, U.S. Patent No. 7,446,179, US2013 / 0149337, U.S. Patent No. 7,446,190, U.S. Patent No. 8,389,282, etc., wherein the antigen binding moiety (e.g., scFv) is replaced with an antibody (e.g., an antibody provided herein).

[0312] Chimeric receptors contain chimeric antigen receptors (CARs). Chimeric receptors, such as CARs, generally comprise an extracellular antigen binding domain comprising, being, or including one of the provided anti-HLA-peptide ABPs, such as an anti-HLA-peptide antibody. Thus, the extracellular portion of a chimeric receptor (e.g., CAR) typically comprises one or more HLA-peptide-ABPs, such as one or more antigen binding fragments, domains, or portions, or one or more antibody variable domains, and / or an antibody molecule (such as those described herein). In some embodiments, a CAR comprises an HLA-peptide-binding portion or portion of an ABP (e.g., antibody) molecule, such as a variable heavy (VH) chain region and / or a variable light (VL) chain region of an antibody, e.g., an scFv antibody fragment.

[0313] TCR

[0314] In one aspect, an ABP provided herein, e.g., an ABP that specifically binds to an HLA- peptide target disclosed herein, comprises a T cell receptor (TCR). The TCR can be isolated and purified.

[0315] In most T cells, the TCR is a heterodimeric polypeptide with an alpha chain and a beta chain encoded by TRA and TRB, respectively. The alpha chain typically includes an alpha variable region encoded by TRAV, an alpha joining region encoded by TRAJ, and an alpha constant region encoded by TRAC. The beta chain typically includes a beta variable region encoded by TRBV, a beta diversity region encoded by TRBD, a beta joining region encoded by TRBJ, and a beta constant region encoded by TRBC. The TCR-alpha chain is generated by VJ recombination, while the beta chain receptor is generated by V(D)J recombination. Additional diversity of the TCR is derived from junctional diversity. Several bases can be deleted and several bases added (referred to as N and P nucleotides) at each junction. In most T cells, the TCR comprises a gamma chain and a delta chain. The TCR gamma chain is generated by VJ recombination, while the TCR delta chain is generated by V(D)J recombination (Kenneth Murphy, Paul Travers, and Mark Walport Janeway's Immunology 7th edition Garland Science, 2007, which is incorporated by reference in its entirety). The antigen binding site of the TCR typically includes six complementarity determining regions (CDRs). The alpha chain contributes three CDRs: alpha CDR1, alpha CDR2, and alpha CDR3. The beta chain also provides three CDRs: beta CDR1, beta CDR2, and beta CDR3. Alpha CDR3 and beta CDR3 are the regions most affected by V(D)J recombination, and are the cause of most variation in the TCR repertoire.

[0316] TCRs can specifically recognize HLA-peptide targets, such as the HLA-peptide targets disclosed in Table A; thus, TCRs can be ABPs that specifically bind HLA-peptides. TCRs can be soluble, e.g., analogous to antibodies secreted by B cells. TCRs can also be membrane-bound, e.g., bound to a cell such as a T cell or NK cell. Thus, TCRs can be used in the context of soluble antibodies and / or membrane-bound CARs.

[0317] Any of the TCRs disclosed herein can include an alpha variable region, an alpha joining region, optionally an alpha constant region, a beta variable region, optionally a beta diversity region, a beta joining region, and optionally a beta constant region.

[0318] In some embodiments, the TCR or CAR is a recombinant TCR or CAR. A recombinant TCR or CAR can comprise any of the TCRs identified herein, but includes one or more modifications. Exemplary modifications, e.g., amino acid substitutions, are described herein. The amino acid substitutions described herein can be made with reference to IMGT nomenclature and amino acid numbering on the website www.imgt.org.

[0319] A recombinant TCR or CAR can be a human TCR or CAR, which includes an intact human sequence, e.g., a native human sequence. A recombinant TCR or CAR can retain its native human variable domain sequence, but contain modifications to the alpha constant region, the beta constant region, or both the alpha and beta constant regions. Such modifications to the constant regions of a TCR can improve TCR assembly and expression for TCR gene therapy, e.g., by driving preferential pairing of exogenous TCR chains.

[0320] In some embodiments, the alpha and beta constant regions are modified by replacing the mouse constant region sequences with an intact human constant region sequence. Such “humanized” TCRs and methods for making them are described in (Cancer Res. 2006 Sep 1; 66(17): 8878-86), which is incorporated by reference in its entirety.

[0321] In some embodiments, the alpha and beta constant regions are modified by one or more amino acid substitutions in the human TCR alpha constant (TRAC) region, TCR beta constant (TRBC) region, or both TRAC and TRAB regions, i.e., swapping human residues for murine residues (human-murine amino acid exchange). The one or more amino acid substitutions in the TRAC region can include a substitution of Ser at residue 90, a substitution of Asp at residue 91, a substitution of Val at residue 92, a substitution of Pro at residue 93, or any combination thereof. The one or more amino acid substitutions in the human TRBC region can include a substitution of Lys at residue 18, a substitution of Ala at residue 22, a substitution of Ile at residue 133, a substitution of His at residue 139, or any combination thereof. Such targeted amino acid substitutions are described in J. Immunol. 2010 Jun 1; 184(11) 6223-6231, which is incorporated by reference in its entirety.

[0322] In some embodiments, the human TRAC contains a substitution of Asp at residue 210, and the human TRBC contains a substitution of Lys at residue 134. Such substitutions can facilitate salt bridge bonding between the alpha and beta chains and formation of a TCR interchain disulfide bond. These targeted substitutions are described in J. Immunol. 2010 Jun 1; 184(11) 6232-6241, which is incorporated by reference in its entirety.

[0323] In some embodiments, the human TRAC region and the human TRBC region are modified to contain an introduced cysteine, which can improve preferential pairing of the exogenous TCR chains by forming an additional disulfide bond. For example, the human TRAC can contain a Cys substitution at residue 48, and the human TRBC can contain a Cys substitution at residue 57, as described in Cancer Res. 2007 Apr 15; 67(8): 3898-903) and Blood. 2007 Mar 15; 109(6): 2331-8; which are incorporated by reference in their entirety.

[0324] The recombinant TCR or CAR can include other modifications to the alpha and beta chains.

[0325] In some embodiments, the alpha and beta chains are modified by linking the extracellular domains of the alpha and beta chains to a complete human CD3-zeta (CD3-zeta) molecule. Such modifications are described in J. Immunol. 2008 Jun 1; 180(11) 7736-7746; Gene Ther. 2000 Aug; 7(16): 1369-77; and The Open Gene Therapy Journal 2011, 4: 11-22; which are incorporated by reference in their entirety.

[0326] In some embodiments, the alpha chain is modified by introducing a hydrophobic amino acid substitution in the transmembrane region of the alpha chain, as described in The Journal of Immunology, June 1, 2012; 188(11) 5538-5546, which is incorporated by reference in its entirety.

[0327] The alpha chain or the beta chain can be modified by altering any one of the N-glycosylation sites in the amino acid sequence, as described in The Journal of Experimental Medicine, February 16, 2009; 206(2):463-475, which is incorporated by reference in its entirety.

[0328] The alpha chain and the beta chain can each comprise a dimerization domain, for example a heterodimerization domain. Such heterodimerization domains can be leucine zippers (5H3 domains) or hydrophobic proline-rich reverse domains or other similar formats, as known in the art. In one example, the alpha chain and the beta chain can be modified by introducing a 30mer segment at the carboxy terminus of the alpha and beta extracellular domains, wherein the segments selectively associate to form a stable leucine zipper. Such modification is described in: Proceedings of the National Academy of Sciences (PNAS) November 22, 1994; 91(24) 11408-11412, https: / / doi.org / 10.1073 / pnas.91.24.11408 A*02:01_LLASSILCA (SEQ ID NO: 2737) [G7] target-specific TCR which is incorporated by reference in its entirety.

[0329] The TCR identified herein can be modified to comprise mutations that result in increased affinity or half-life, such as the mutations described in WO2012 / 013913, which is incorporated by reference in its entirety.

[0330] The recombinant TCR or CAR can be a single chain TCR (scTCR). Such a scTCR can include an alpha chain variable region sequence fused to the N-terminus of a TCR alpha chain constant region extracellular sequence, a TCR beta chain variable region fused to the N-terminus of a TCR beta chain constant region extracellular sequence, and a linker sequence connecting the C-terminus of the alpha segment to the N-terminus of the beta segment, or vice versa. In some embodiments, the constant region extracellular sequences of the alpha segment and the beta segment of the scTCR are linked by a disulfide bond. In some embodiments, the length of the linker sequence and the location of the disulfide bond are such that the variable region sequences of the alpha segment and the beta segment are oriented toward each other substantially as in a native alpha beta T cell receptor. Exemplary scTCRs are described in U.S. Patent No. 7,569,664, which is incorporated by reference in its entirety.

[0331] In some cases, the variable regions of the scTCR can be covalently linked by short peptide linkers, as described in Gene Therapy, Vol. 7, pp. 1369-1377 (2000). The short peptide linker can be a serine- or glycine-rich linker. For example, the linker can be (Gly4Ser)3, as described in Cancer Gene Therapy (2004) 11, 487-496, which is incorporated by reference in its entirety.

[0332] The recombinant TCR or antigen-binding fragment thereof can be expressed as a fusion protein. For example, the TCR or antigen-binding fragment thereof can be fused to a toxin. Such fusion proteins are described in Cancer Res. 2002 Mar 15;62(6):1757-60. The TCR or antigen-binding fragment thereof can be fused to an antibody Fc region. Such fusion proteins are described in J Immunol. 2017 May 1;198(1 Supplement):120.9.

[0333] In some embodiments, the recombinant receptor such as a TCR or CAR (such as the antibody portion thereof) further comprises a spacer, which can be or comprise at least a portion of an immunoglobulin constant region or variant or modified form thereof, such as a hinge region, e.g., an IgG4 hinge region, and / or a CH1 / CL and / or Fc region. In some embodiments, the constant region or portion is human IgG, such as IgG4 or IgGl. In some aspects, a portion of the constant region is used as a spacer between the antigen recognition component (e.g., scFv) and the transmembrane domain. The length of the spacer can provide for increased cellular responsiveness upon antigen binding as compared to the absence of the spacer. In some examples, the spacer is or is about 12 amino acids in length, or is no more than 12 amino acids in length. Exemplary spacers include those having at least about 10 to 229 amino acids, about 10 to 200 amino acids, about 10 to 175 amino acids, about 10 to 150 amino acids, about 10 to 125 amino acids, about 10 to 100 amino acids, about 10 to 75 amino acids, about 10 to 50 amino acids, about 10 to 40 amino acids, about 10 to 30 amino acids, about 10 to 20 amino acids, or about 10 to 15 amino acids, as well as any integer between the endpoints of any of the recited ranges. In some embodiments, the spacer has about 12 or fewer amino acids, about 119 or fewer amino acids, or about 229 or fewer amino acids. Exemplary spacers include an IgG4 hinge alone, an IgG4 hinge linked to a CH2 and CH3 domain, or an IgG4 hinge linked to a CH3 domain. Exemplary spacers include, but are not limited to, those described in Hudecek et al. (2013) Clin. Cancer Res. 19:3153, or International Patent Application Publication No. WO2014031687. In some embodiments, the constant region or portion is IgD.

[0334] The antigen recognition domain of a receptor such as a TCR or CAR can be linked to one or more intracellular signaling components, such as a signaling component that mimics activation by an antigen receptor complex such as a TCR complex, and / or by signaling through another cell surface receptor. Thus, in some embodiments, the HLA-peptide-specific binding component (e.g., ABP such as an antibody or TCR) is linked to one or more transmembrane and intracellular signaling domains. In some embodiments, the transmembrane domain is fused to the extracellular domain. In one embodiment, a transmembrane domain that is naturally associated with one of the domains in the receptor (e.g., CAR) is used. In some cases, the transmembrane domain is selected or modified by amino acid substitution to avoid association of this domain with a transmembrane domain of the same or a different surface membrane protein, thereby minimizing interactions with other members of the receptor complex.

[0335] In some embodiments, the transmembrane domain is native or synthetic. If native, in some aspects, the domain is derived from any membrane-bound or transmembrane protein. The transmembrane region comprises a transmembrane region derived from (i.e., at least including the transmembrane region of) the alpha, beta, or zeta chain of the T cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CDS, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, and / or CD154. Alternatively, in some embodiments, the transmembrane domain is synthetic. In some aspects, the synthetic transmembrane domain includes primarily hydrophobic residues, such as leucine and valine. In some aspects, there is a triplet of phenylalanine, tryptophan, and valine at each end of the synthetic transmembrane domain. In some embodiments, the connection is made through a linker, spacer, and / or transmembrane domain.

[0336] The intracellular signaling domain contains those that mimic or approximate the signal through a native antigen receptor, the signal through such receptor in combination with a costimulatory receptor, and / or the signal through the costimulatory receptor alone. In some embodiments, there is a short oligonucleotide or polypeptide linker, e.g., a linker between 2 and 10 amino acids in length, such as a linker containing glycine and serine, e.g., a glycine-serine doublet, and forms the connection between the transmembrane domain and the cytoplasmic signaling domain of the receptor.

[0337] The receptor, e.g., TCR or CAR, can comprise at least one or more intracellular signaling components. In some embodiments, the receptor comprises intracellular components of the TCR complex, such as the TCR CD3 chains that mediate T cell activation and cytotoxicity, e.g., the CD3 zeta chain. Thus, in some aspects, the HLA-peptide-binding ABP (e.g., antibody) is linked to one or more cell signaling modules. In some embodiments, the cell signaling module comprises a CD3 transmembrane domain, a CD3 intracellular signaling domain, and / or other CD transmembrane domains. In some embodiments, the receptor (e.g., CAR) further comprises a portion of one or more additional molecules, such as Fc receptor-gamma, CD8, CD4, CD25, or CD16. For example, in some aspects, the CAR comprises a chimeric molecule between CD3-zeta or Fc receptor-gamma and CD8, CD4, CD25, or CD16.

[0338] In some embodiments, once the TCR or CAR is engaged, the cytoplasmic domain or intracellular signaling domain of the receptor activates at least one of normal effector function or an immune cell (e.g., an engineered T cell expressing the receptor) response. For example, in some cases, the receptor induces T cell function, such as cytolytic activity or T helper activity, such as secretion of cytokines or other factors. In some embodiments, for example, if the intracellular signaling domain of the antigen receptor component transduces an effector function signal, a truncated portion of the intracellular signaling domain of the antigen receptor component or a costimulatory molecule is substituted for the intact immunostimulatory chain. In some embodiments, the one or more intracellular signaling domains comprise a cytoplasmic sequence of a T cell receptor (TCR), and in some aspects also include those of a co-receptor that in the native context acts in concert with such receptor to initiate signal transduction upon antigen receptor engagement, and / or any derivative or variant of such molecule, and / or any synthetic sequence with the same function.

[0339] In the case of a native TCR, full activation typically requires not only signaling through the TCR, but also a costimulatory signal. Thus, in some embodiments, to promote full activation, components for generating a secondary signal or costimulatory signal are also included in the receptor. In other embodiments, the receptor does not include components for generating a costimulatory signal. In some aspects, an additional receptor is expressed in the same cell and provides components for generating a secondary signal or costimulatory signal.

[0340] In some aspects, T cell activation is described as being mediated by two classes of cytoplasmic signaling sequences: those that initiate antigen-dependent primary activation through the TCR (primary cytoplasmic signaling sequences), and those that act in an antigen-independent manner to provide a secondary signal or costimulatory signal (secondary cytoplasmic signaling sequences). In some aspects, the receptor includes one or both of such signaling components.

[0341] In some aspects, the receptor includes a primary cytoplasmic signaling sequence that modulates primary activation of the TCR complex. Primary cytoplasmic signaling sequences that act in a stimulatory manner can contain signaling motifs known as immunoreceptor tyrosine-based activation motifs or ITAMs. Examples of ITAM-containing primary cytoplasmic signaling sequences include sequences derived from TCR or CD3 zeta, FcR gamma, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon, CDS, CD22, CD79a, CD79b, and CD66d. In some embodiments, the cytoplasmic signaling molecule in a CAR contains a cytoplasmic signaling domain, a portion thereof, or a sequence derived from CD3 zeta.

[0342] In some embodiments, the receptor comprises a signaling domain and / or a transmembrane portion of a costimulatory receptor, such as CD28, 4-1BB, OX40, DAP10, and ICOS. In some aspects, the same receptor comprises both an activating component and a costimulatory component.

[0343] In some embodiments, the activating domain is comprised within one receptor, while the costimulatory component is provided by another receptor recognizing another antigen. In some embodiments, the receptor comprises both an activating or stimulatory receptor and a costimulatory receptor, each expressed on the same cell (see WO2014 / 055668). In some aspects, the HLA- peptide targeted receptor is a stimulatory or activating receptor. In other aspects, it is a costimulatory receptor. In some embodiments, the cell further comprises an inhibitory receptor (e.g., iCAR, see Fedorov et al. Sci. Transl. Medicine 5(215) (Dec. 2013)), such as a receptor recognizing an antigen other than the HLA-peptide, thereby reducing or inhibiting the activating signal delivered by the HLA-peptide targeted receptor through binding of the inhibitory receptor to its ligand, for example, to reduce off-target effects.

[0344] In certain embodiments, the intracellular signaling domain comprises a CD28 transmembrane domain and signaling domain linked to a CD3 (e.g., CD3-zeta) intracellular domain. In some embodiments, the intracellular signaling domain comprises a chimeric CD28 and CD137 (4-1BB, TNFRSF9) costimulatory domain linked to a CD3-zeta intracellular domain.

[0345] In some embodiments, the receptor comprises one or more, e.g., two or more, costimulatory domains and an activating domain, e.g., a primary activating domain, in the cytoplasmic portion. Exemplary receptors comprise the intracellular components of CD3-zeta, CD28, and 4-1BB.

[0346] In some embodiments, the CAR or other antigen receptor, such as a TCR, also comprises a marker, such as a cell surface marker, which can be used to confirm transduction or engineering of the cell to express the receptor, such as a truncated form of a cell surface receptor, such as truncated EGFR (tEGFR). In some aspects, the marker comprises all or a portion (e.g., a truncated form) of CD34, NGFR, or epidermal growth factor receptor (e.g., tEGFR). In some embodiments, the nucleic acid encoding the marker is operably linked to a polynucleotide encoding a linker sequence, such as a cleavable linker sequence or a ribosomal skip sequence, such as T2A. See WO2014031687. In some embodiments, introduction of a construct encoding a CAR and EGFRt separated by a T2A ribosomal switch can express both proteins from the same construct, such that the EGFRt is available as a marker to detect cells expressing such a construct. In some embodiments, the marker and optional linker sequence can be any of the sequences disclosed in patent application publication no. WO2014031687. For example, the marker can be a truncated EGFR (tEGFR) that is optionally linked to a linker sequence, such as a T2A ribosomal skip sequence.

[0347] In some embodiments, the marker is a molecule, e.g., a cell surface protein, that is not naturally present on a T cell or naturally present on a T cell or portion thereof.

[0348] In some embodiments, the molecule is a non-self molecule, e.g., a non-self protein, i.e., a molecule that is not recognized as “self” by the immune system of the host into which the cell is adoptively transferred.

[0349] In some embodiments, the marker does not have a therapeutic function and / or does not produce an effect in addition to being used as a marker for genetic engineering (e.g., for selection of successfully engineered cells). In other embodiments, the marker can be a therapeutic molecule or a molecule that otherwise exerts some desired effect, such as a ligand for a cell encountered in vivo, such as a costimulatory or immune checkpoint molecule, thereby enhancing and / or attenuating the response of the cell upon adoptive transfer and encounter with the ligand.

[0350] The TCR or CAR can comprise one or modified synthetic amino acids in place of one or more naturally occurring amino acids. Exemplary modified amino acids include, but are not limited to, aminocyclohexane carboxylic acid, norleucine, a-amino nordecanoic acid, homoserine, S-acetylaminomethylcysteine, trans 3- and trans 4-hydroxyproline, 4-aminophenylalanine, 4-nitrophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, (3-phenylserine (3-hydroxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, dihydroindole-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid, aminomalonic acid monoamide, N'-benzyl-N'-methyl lysine, N,'N'-dibenzyl lysine, 6-hydroxy lysine, ornithine, a-aminocyclopentane carboxylic acid, a-aminocyclohexane carboxylic acid, a-aminocycloheptane carboxylic acid, a-(2-amino-2- norbornane)-carboxylic acid, a, g-diaminobutyric acid, a, g-diaminopropionic acid, homophenylalanine, and a-tert-butylglycine.

[0351] In some cases, CARs are referred to as first, second, and / or third generation CARs. In some aspects, a first generation CAR is one that provides only a CD3-chain induced signal upon antigen binding; in some aspects, a second generation CAR is one that provides a signal and a costimulatory signal, such as one comprising an intracellular signaling domain from a costimulatory receptor such as CD28 or CD137; in some aspects, a third generation CAR is one that comprises multiple costimulatory domains of different costimulatory receptors.

[0352] In some embodiments, the chimeric antigen receptor comprises an extracellular portion comprising an antibody or fragment described herein. In some aspects, the chimeric antigen receptor comprises an extracellular portion and an intracellular signaling domain, wherein the extracellular portion comprises an antibody or fragment described herein. In some embodiments, the antibody or fragment comprises a scFv or a single domain VH antibody, and the intracellular domain comprises an ITAM. In some aspects, the intracellular signaling domain comprises the signaling domain of the zeta chain of the CD3, i.e., the zeta (CD3) chain. In some embodiments, the chimeric antigen receptor comprises a transmembrane domain linking the extracellular domain and the intracellular signaling domain.

[0353] In some aspects, the transmembrane domain comprises the transmembrane portion of CD28. The extracellular domain and the transmembrane can be linked directly or indirectly. In some embodiments, the extracellular domain and the transmembrane are linked by a spacer, such as any spacer described herein. In some embodiments, the chimeric antigen receptor comprises an intracellular domain of a T cell costimulatory molecule, such as an intracellular domain between the transmembrane domain and the intracellular signaling domain. In some aspects, the T cell costimulatory molecule is CD28 or 41BB.

[0354] In some embodiments, the CAR contains an antibody (e.g., an antibody fragment), a transmembrane domain that is or contains a transmembrane portion of CD28 or a functional variant thereof, and an intracellular signaling domain that contains a signaling portion of CD28 or a functional variant thereof and a signaling portion of CD3 zeta or a functional variant thereof. In some embodiments, the CAR contains an antibody (e.g., an antibody fragment), a transmembrane domain that is or contains a transmembrane portion of CD28 or a functional variant thereof, and an intracellular signaling domain that contains a signaling portion of 4-1BB or a functional variant thereof and a signaling portion of CD3 zeta or a functional variant thereof. In some such embodiments, the receptor further comprises a spacer that contains a portion of an Ig molecule, such as a human Ig molecule, such as an Ig hinge, e.g., an IgG4 hinge, such as a hinge-only spacer.

[0355] In some embodiments, the transmembrane domain of the receptor (e.g., a CAR) is the transmembrane domain of human CD28 or a variant thereof, e.g., the 27 amino acid sized transmembrane domain of human CD28 (Accession No: P10747.1).

[0356] In some embodiments, the chimeric antigen receptor contains an intracellular domain of a T cell costimulatory molecule. In some aspects, the T cell costimulatory molecule is CD28 or 41BB.

[0357] In some embodiments, the intracellular signaling domain includes an intracellular costimulatory signaling domain of human CD28 or a functional variant thereof or a portion thereof, such as a 41 amino acid sized domain thereof and / or a domain having a LL to GG substitution at positions 186-187 of the native CD28 protein. In some embodiments, the intracellular domain includes an intracellular costimulatory signaling domain of 41BB or a functional variant or portion thereof, such as a 42 amino acid sized cytoplasmic domain of human 4-1BB (Accession No: Q07011.1) or a functional variant or portion thereof.

[0358] In some embodiments, the intracellular signaling domain includes a human CD3 zeta stimulatory signaling domain or a functional variant thereof, such as a 112 AA cytoplasmic domain of isoform 3 of human CD3 zeta (Accession No: P20963.2), or a CD3 zeta signaling domain described in U.S. Patent No. 7,446,190 or U.S. Patent No. 8,911,993.

[0359] In some aspects, the spacer contains only a hinge region of an IgG, such as only a hinge of IgG4 or IgGl. In other embodiments, the spacer is an Ig hinge linked to a CH2 and / or CH3 domain, such as an IgG4 hinge. In some embodiments, the spacer is an Ig hinge linked to a CH2 and CH3 domain, such as an IgG4 hinge. In some embodiments, the spacer is an Ig hinge linked only to a CH3 domain, such as an IgG4 hinge. In some embodiments, the spacer is or includes a glycine-serine rich sequence or other flexible linker, such as a known flexible linker.

[0360] For example, in some embodiments, the CAR comprises an antibody or fragment thereof, such as any HLA-peptide antibody, including sdAbs (e.g., comprising only a VH region) and scFv described herein; a spacer, such as any Ig-hinge containing spacer; a CD28 transmembrane domain; a CD28 intracellular signaling domain; and a CD3 zeta signaling domain. In some embodiments, the CAR comprises an antibody or fragment, such as any HLA-peptide antibody, including sdAbs and scFv described herein; a spacer, such as any Ig-hinge containing spacer; a CD28 transmembrane domain; a CD28 intracellular signaling domain; and a CD3 zeta signaling domain.

[0361] A*01:01_EVDPIGHLY (SEQ ID NO: 3051) target-specific TCR

[0362] In some aspects, provided herein are ABPs comprising a TCR or antigen binding fragment thereof that specifically binds to an HLA-peptide target, wherein the HLA class I molecule of the HLA-peptide target is HLA subtype A*02:01, and the HLA-restricted peptide of the HLA-peptide target comprises the sequence LLASSILCA (SEQ ID NO: 2737) (“G7”).

[0363] A TCR specific for A*02:01_LLASSILCA (SEQ ID NO: 2737) can comprise an alpha CDR3 sequence. The alpha CDR3 sequence can be SEQ ID NO: 4277, 4278, 4279, 4280, or 4281.

[0364] A TCR specific for A*02:01_LLASSILCA (SEQ ID NO: 2737) can comprise a beta CDR3 sequence. The beta CDR3 sequence can be any one of SEQ ID NOs: 4291-4295.

[0365] A TCR specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can comprise a specific alpha CDR3 sequence and a specific beta CDR3 sequence. The alpha CDR3 can be SEQ ID NO:4277 and the beta CDR3 can be SEQ ID NO:4291. The alpha CDR3 can be SEQ ID NO:4278 and the beta CDR3 can be SEQ ID NO:4292. The alpha CDR3 can be SEQ ID NO:4279 and the beta CDR3 can be SEQ ID NO:4293. The alpha CDR3 can be SEQ ID NO:4280 and the beta CDR3 can be SEQ ID NO:4294. The alpha CDR3 can be SEQ ID NO:4281 and the beta CDR3 can be SEQ ID NO:4295.

[0366] A TCR specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can comprise an alpha CDR3 that is SEQ ID NO:4277 and a beta CDR3 that is SEQ ID NO:4291. A TCR specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can comprise an alpha CDR3 that is SEQ ID NO:4278 and a beta CDR3 that is SEQ ID NO:4292. A TCR specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can comprise an alpha CDR3 that is SEQ ID NO:4279 and a beta CDR3 that is SEQ ID NO:4293. A TCR specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can comprise an alpha CDR3 that is SEQ ID NO:4280 and a beta CDR3 that is SEQ ID NO:4294. A TCR specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can comprise an alpha CDR3 that is SEQ ID NO:4281 and a beta CDR3 that is SEQ ID NO:4295.

[0367] A TCR specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include TRAV, TRAJ, TRBV, optionally TRBD, and TRBJ amino acid sequences, optionally a TRAC sequence and optionally a TRBC sequence. Such a TCR can include TRAV19, TRAJ4, TRBV6-5, TRBD2, and TRBJ2-7. Such a TCR can include TRAV5, TRAJ13, TRBV7-9, TRBD1, and TRBJ2-7. Such a TCR can include TRAV3, TRAJ39, TRBV7-9, and TRBJ2-2. Such a TCR can include TRAV38-2DV8, TRAJ21, TRBV9, TRBD1, and TRBJ2-1. Such a TCR can include TRAV4, TRAJ9, TRBV27, and TRBJ1-5.

[0368] A TCR specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include an alpha VJ sequence. The alpha VJ sequence can be any one of SEQ ID NOs: 4306-4310.

[0369] A TCR specific for A*02:01_LLASSILCA (SEQ ID NO:2737) can include a beta V(D)J sequence. The beta V(D)J sequence can be any one of SEQ ID NOs: 4321-4325.

[0370] In some embodiments, the alpha VJ sequence is SEQ ID NO: 4306 and the beta V(D)J sequence is SEQ ID NO: 4321. In some embodiments, the alpha VJ sequence is SEQ ID NO: 4307 and the beta V(D)J sequence is SEQ ID NO: 4322. In some embodiments, the alpha VJ sequence is SEQ ID NO: 4308 and the beta V(D)J sequence is SEQ ID NO: 4323. In some embodiments, the alpha VJ sequence is SEQ ID NO: 4309 and the beta V(D)J sequence is SEQ ID NO: 4324. In some embodiments, the alpha VJ sequence is SEQ ID NO: 4310 and the beta V(D)J sequence is SEQ ID NO: 4325.

[0371] B*44:02_GEMSSNSTAL (SEQ ID NO: 4272) target-specific TCR A*02:01_GVYDGEEHSV (SEQ ID NO: 4271) target-specific TCR

[0372] In some aspects, provided herein are ABPs comprising a TCR or antigen binding fragment thereof that specifically binds to an HLA-peptide target, wherein the HLA class I molecule of the HLA- peptide target is HLA subtype A*01:01, and the HLA-restricted peptide of the HLA-peptide target comprises the sequence EVDPIGHLY (SEQ ID NO: 3051).

[0373] TCRs specific for A*01:01_EVDPIGHLY (SEQ ID NO: 3051) can comprise an alpha CDR3 sequence. The alpha CDR3 sequence can be any of SEQ ID NOs: 3052-3350 or 4273-4276.

[0374] TCRs specific for A*01:01_EVDPIGHLY (SEQ ID NO: 3051) can comprise a beta CDR3 sequence. The beta CDR3 sequence can be any of SEQ ID NOs: 3351-3655 or 4287-4290.

[0375] A TCR specific for A*02:01_EVDPIGHLY (SEQ ID NO: 3052) can include a particular a CDR3 sequence and a particular b CDR3 sequence. The a CDR3 can be SEQ ID NO: 4276 and the b CDR3 can be SEQ ID NO: 4290. The a CDR3 can be SEQ ID NO: 3052 and the b CDR3 can be SEQ ID NO: 3351. The a CDR3 can be SEQ ID NO: 3053 and the b CDR3 can be SEQ ID NO: 3352. The a CDR3 can be SEQ ID NO: 3054 and the b CDR3 can be SEQ ID NO: 3353. The a CDR3 can be SEQ ID NO: 3052 and the b CDR3 can be SEQ ID NO: 3352. The a CDR3 can be SEQ ID NO: 3055 and the b CDR3 can be SEQ ID NO: 3354. The a CDR3 can be SEQ ID NO: 3056 and the b CDR3 can be SEQ ID NO: 3355. The a CDR3 can be SEQ ID NO: 3057 and the b CDR3 can be SEQ ID NO: 3356. The a CDR3 can be SEQ ID NO: 3058 and the b CDR3 can be SEQ ID NO: 3357. The a CDR3 can be SEQ ID NO: 3059 and the b CDR3 can be SEQ ID NO: 3358. The a CDR3 can be SEQ ID NO: 3060 and the b CDR3 can be SEQ ID NO: 3359. The a CDR3 can be SEQ ID NO: 3061 and the b CDR3 can be SEQ ID NO: 3360. The a CDR3 can be SEQ ID NO: 3062 and the b CDR3 can be SEQ ID NO: 3361. The a CDR3 can be SEQ ID NO: 3063 and the b CDR3 can be SEQ ID NO: 3362. The a CDR3 can be SEQ ID NO: 3053 and the b CDR3 can be SEQ ID NO: 3351.The aCDR3 can be SEQ ID NO: 3057 and the bCDR3 can be SEQ ID NO: 3352. The aCDR3 can be SEQ ID NO: 3064 and the bCDR3 can be SEQ ID NO: 3363. The aCDR3 can be SEQ ID NO: 3065 and the bCDR3 can be SEQ ID NO: 3364. The aCDR3 can be SEQ ID NO: 3054 and the bCDR3 can be SEQ ID NO: 3352. The aCDR3 can be SEQ ID NO: 3066 and the bCDR3 can be SEQ ID NO: 3365. The aCDR3 can be SEQ ID NO: 3067 and the bCDR3 can be SEQ ID NO: 3366. The aCDR3 can be SEQ ID NO: 3068 and the bCDR3 can be SEQ ID NO: 3367. The aCDR3 can be SEQ ID NO: 3069 and the bCDR3 can be SEQ ID NO: 3368. The aCDR3 can be SEQ ID NO: 3052 and the bCDR3 can be SEQ ID NO: 3356. The aCDR3 can be SEQ ID NO: 3070 and the bCDR3 can be SEQ ID NO: 3369. The aCDR3 can be SEQ ID NO: 3052 and the bCDR3 can be SEQ ID NO: 3355. The aCDR3 can be SEQ ID NO: 3071 and the bCDR3 can be SEQ ID NO: 3370. The aCDR3 can be SEQ ID NO: 3052 and the bCDR3 can be SEQ ID NO: 3353. The aCDR3 can be SEQ ID NO: 3072 and the bCDR3 can be SEQ ID NO: 3371. The aCDR3 can be SEQ ID NO: 3073 and the bCDR3 can be SEQ ID NO: 3372. The aCDR3 can be SEQ ID NO: 3057 and the bCDR3 can be SEQ ID NO: 3351. The aCDR3 can be SEQ ID NO: 3074 and the bCDR3 can be SEQ ID NO: 3373. The aCDR3 can be SEQ ID NO: 3075 and the bCDR3 can be SEQ ID NO: 3374. The aCDR3 can be SEQ ID NO: 3076 and the bCDR3 can be SEQ ID NO: 3375.The aCDR3 can be SEQ ID NO: 3077, and the bCDR3 can be SEQ ID NO: 3376. The aCDR3 can be SEQ ID NO: 3078, and the bCDR3 can be SEQ ID NO: 3377. The aCDR3 can be SEQ ID NO: 3079, and the bCDR3 can be SEQ ID NO: 3378. The aCDR3 can be SEQ ID NO: 3080, and the bCDR3 can be SEQ ID NO: 3379. The aCDR3 can be SEQ ID NO: 3081, and the bCDR3 can be SEQ ID NO: 3380. The aCDR3 can be SEQ ID NO: 3082, and the bCDR3 can be SEQ ID NO: 3381. The aCDR3 can be SEQ ID NO: 3083, and the bCDR3 can be SEQ ID NO: 3382. The aCDR3 can be SEQ ID NO: 3084, and the bCDR3 can be SEQ ID NO: 3383. The aCDR3 can be SEQ ID NO: 3085, and the bCDR3 can be SEQ ID NO: 3384. The aCDR3 can be SEQ ID NO: 3086, and the bCDR3 can be SEQ ID NO: 3385. The aCDR3 can be SEQ ID NO: 3087, and the bCDR3 can be SEQ ID NO: 3386. The aCDR3 can be SEQ ID NO: 3088, and the bCDR3 can be SEQ ID NO: 3387. The aCDR3 can be SEQ ID NO: 3089, and the bCDR3 can be SEQ ID NO: 3388. The aCDR3 can be SEQ ID NO: 3052, and the bCDR3 can be SEQ ID NO: 3389. The aCDR3 can be SEQ ID NO: 3056, and the bCDR3 can be SEQ ID NO: 3351. The aCDR3 can be SEQ ID NO: 3090, and the bCDR3 can be SEQ ID NO: 3390. The aCDR3 can be SEQ ID NO: 3091, and the bCDR3 can be SEQ ID NO: 3391. The aCDR3 can be SEQ ID NO: 3092, and the bCDR3 can be SEQ ID NO: 3392. The aCDR3 can be SEQ ID NO: 3093, and the bCDR3 can be SEQ ID NO: 3393.The aCDR3 can be SEQ ID NO: 3053 and the bCDR3 can be SEQ ID NO: 3356. The aCDR3 can be SEQ ID NO: 3094 and the bCDR3 can be SEQ ID NO: 3394. The aCDR3 can be SEQ ID NO: 3054 and the bCDR3 can be SEQ ID NO: 3363. The aCDR3 can be SEQ ID NO: 3095 and the bCDR3 can be SEQ ID NO: 3395. The aCDR3 can be SEQ ID NO: 3054 and the bCDR3 can be SEQ ID NO: 3351. The aCDR3 can be SEQ ID NO: 3096 and the bCDR3 can be SEQ ID NO: 3396. The aCDR3 can be SEQ ID NO: 3053 and the bCDR3 can be SEQ ID NO: 3355. The aCDR3 can be SEQ ID NO: 3097 and the bCDR3 can be SEQ ID NO: 3397. The aCDR3 can be SEQ ID NO: 3098 and the bCDR3 can be SEQ ID NO: 3398. The aCDR3 can be SEQ ID NO: 3099 and the bCDR3 can be SEQ ID NO: 3352. The aCDR3 can be SEQ ID NO: 3100 and the bCDR3 can be SEQ ID NO: 3399. The aCDR3 can be SEQ ID NO: 3053 and the bCDR3 can be SEQ ID NO: 3353. The aCDR3 can be SEQ ID NO: 3101 and the bCDR3 can be SEQ ID NO: 3400. The aCDR3 can be SEQ ID NO: 3102 and the bCDR3 can be SEQ ID NO: 3401. The aCDR3 can be SEQ ID NO: 3058 and the bCDR3 can be SEQ ID NO: 3352. The aCDR3 can be SEQ ID NO: 3103 and the bCDR3 can be SEQ ID NO: 3402. The aCDR3 can be SEQ ID NO: 3104 and the bCDR3 can be SEQ ID NO: 3403. The aCDR3 can be SEQ ID NO: 3105 and the bCDR3 can be SEQ ID NO: 3404. The aCDR3 can be SEQ ID NO: 3106 and the bCDR3 can be SEQ ID NO: 3405.The aCDR3 can be SEQ ID NO: 3107, and the bCDR3 can be SEQ ID NO: 3406. The aCDR3 can be SEQ ID NO: 3108, and the bCDR3 can be SEQ ID NO: 3407. The aCDR3 can be SEQ ID NO: 3109, and the bCDR3 can be SEQ ID NO: 3408. The aCDR3 can be SEQ ID NO: 3110, and the bCDR3 can be SEQ ID NO: 3409. The aCDR3 can be SEQ ID NO: 3111, and the bCDR3 can be SEQ ID NO: 3410. The aCDR3 can be SEQ ID NO: 3112, and the bCDR3 can be SEQ ID NO: 3411. The aCDR3 can be SEQ ID NO: 3113, and the bCDR3 can be SEQ ID NO: 3412. The aCDR3 can be SEQ ID NO: 3058, and the bCDR3 can be SEQ ID NO: 3351. The aCDR3 can be SEQ ID NO: 3052, and the bCDR3 can be SEQ ID NO: 3354. The aCDR3 can be SEQ ID NO: 3072, and the bCDR3 can be SEQ ID NO: 3353. The aCDR3 can be SEQ ID NO: 3052, and the bCDR3 can be SEQ ID NO: 3413. The aCDR3 can be SEQ ID NO: 3114, and the bCDR3 can be SEQ ID NO: 3414. The aCDR3 can be SEQ ID NO: 3058, and the bCDR3 can be SEQ ID NO: 3355. The aCDR3 can be SEQ ID NO: 3052, and the bCDR3 can be SEQ ID NO: 3415. The aCDR3 can be SEQ ID NO: 3114, and the bCDR3 can be SEQ ID NO: 3353. The aCDR3 can be SEQ ID NO: 3115, and the bCDR3 can be SEQ ID NO: 3416. The aCDR3 can be SEQ ID NO: 3116, and the bCDR3 can be SEQ ID NO: 3417. The aCDR3 can be SEQ ID NO: 3117, and the bCDR3 can be SEQ ID NO: 3418. The aCDR3 can be SEQ ID NO: 3118, and the bCDR3 can be SEQ ID NO: 3419.The aCDR3 can be SEQ ID NO: 3119 and the bCDR3 can be SEQ ID NO: 3420. The aCDR3 can be SEQ ID NO: 3120 and the bCDR3 can be SEQ ID NO: 3352. The aCDR3 can be SEQ ID NO: 3121 and the bCDR3 can be SEQ ID NO: 3421. The aCDR3 can be SEQ ID NO: 3054 and the bCDR3 can be SEQ ID NO: 3367. The aCDR3 can be SEQ ID NO: 3122 and the bCDR3 can be SEQ ID NO: 3422. The aCDR3 can be SEQ ID NO: 3123 and the bCDR3 can be SEQ ID NO: 3423. The aCDR3 can be SEQ ID NO: 3124 and the bCDR3 can be SEQ ID NO: 3424. The aCDR3 can be SEQ ID NO: 3112 and the bCDR3 can be SEQ ID NO: 3351. The aCDR3 can be SEQ ID NO: 3060 and the bCDR3 can be SEQ ID NO: 3352. The aCDR3 can be SEQ ID NO: 3059 and the bCDR3 can be SEQ ID NO: 3351. The aCDR3 can be SEQ ID NO: 3071 and the bCDR3 can be SEQ ID NO: 3355. The aCDR3 can be SEQ ID NO: 3125 and the bCDR3 can be SEQ ID NO: 3425. The aCDR3 can be SEQ ID NO: 3126 and the bCDR3 can be SEQ ID NO: 3426. The aCDR3 can be SEQ ID NO: 3127 and the bCDR3 can be SEQ ID NO: 3427. The aCDR3 can be SEQ ID NO: 3128 and the bCDR3 can be SEQ ID NO: 3428. The aCDR3 can be SEQ ID NO: 3129 and the bCDR3 can be SEQ ID NO: 3429. The aCDR3 can be SEQ ID NO: 3130 and the bCDR3 can be SEQ ID NO: 3352. The aCDR3 can be SEQ ID NO: 3052 and the bCDR3 can be SEQ ID NO: 3362. The aCDR3 can be SEQ ID NO: 3055 and the bCDR3 can be SEQ ID NO: 3352.The aCDR3 can be SEQ ID NO: 3131 and the bCDR3 can be SEQ ID NO: 3430. The aCDR3 can be SEQ ID NO: 3132 and the bCDR3 can be SEQ ID NO: 3431. The aCDR3 can be SEQ ID NO: 3133 and the bCDR3 can be SEQ ID NO: 3432. The aCDR3 can be SEQ ID NO: 3053 and the bCDR3 can be SEQ ID NO: 3381. The aCDR3 can be SEQ ID NO: 3134 and the bCDR3 can be SEQ ID NO: 3433. The aCDR3 can be SEQ ID NO: 3061 and the bCDR3 can be SEQ ID NO: 3351. The aCDR3 can be SEQ ID NO: 3104 and the bCDR3 can be SEQ ID NO: 3352. The aCDR3 can be SEQ ID NO: 3055 and the bCDR3 can be SEQ ID NO: 3351. The aCDR3 can be SEQ ID NO: 3058 and the bCDR3 can be SEQ ID NO: 3353. The aCDR3 can be SEQ ID NO: 3135 and the bCDR3 can be SEQ ID NO: 3434. The aCDR3 can be SEQ ID NO: 3052 and the bCDR3 can be SEQ ID NO: 3435. The aCDR3 can be SEQ ID NO: 3136 and the bCDR3 can be SEQ ID NO: 3436. The aCDR3 can be SEQ ID NO: 3137 and the bCDR3 can be SEQ ID NO: 3437. The aCDR3 can be SEQ ID NO: 3138 and the bCDR3 can be SEQ ID NO: 3438. The aCDR3 can be SEQ ID NO: 3139 and the bCDR3 can be SEQ ID NO: 3439. The aCDR3 can be SEQ ID NO: 3140 and the bCDR3 can be SEQ ID NO: 3440. The aCDR3 can be SEQ ID NO: 3141 and the bCDR3 can be SEQ ID NO: 3441. The aCDR3 can be SEQ ID NO: 3142 and the bCDR3 can be SEQ ID NO: 3442. The aCDR3 can be SEQ ID NO: 3143 and the bCDR3 can be SEQ ID NO: 3443.The aCDR3 can be SEQ ID NO: 3144 and the bCDR3 can be SEQ ID NO: 3444. The aCDR3 can be SEQ ID NO: 3145 and the bCDR3 can be SEQ ID NO: 3445. The aCDR3 can be SEQ ID NO: 3136 and the bCDR3 can be SEQ ID NO: 3444. The aCDR3 can be SEQ ID NO: 3146 and the bCDR3 can be SEQ ID NO: 3446. The aCDR3 can be SEQ ID NO: 3147 and the bCDR3 can be SEQ ID NO: 3447. The aCDR3 can be SEQ ID NO: 3148 and the bCDR3 can be SEQ ID NO: 3448. The aCDR3 can be SEQ ID NO: 3149 and the bCDR3 can be SEQ ID NO: 3449. The aCDR3 can be SEQ ID NO: 3150 and the bCDR3 can be SEQ ID NO: 3450. The aCDR3 can be SEQ ID NO: 3151 and the bCDR3 can be SEQ ID NO: 3436. The aCDR3 can be SEQ ID NO: 3139 and the bCDR3 can be SEQ ID NO: 3436. The aCDR3 can be SEQ ID NO: 3152 and the bCDR3 can be SEQ ID NO: 3451. The aCDR3 can be SEQ ID NO: 3153 and the bCDR3 can be SEQ ID NO: 3452. The aCDR3 can be SEQ ID NO: 3154 and the bCDR3 can be SEQ ID NO: 3453. The aCDR3 can be SEQ ID NO: 3155 and the bCDR3 can be SEQ ID NO: 3454. The aCDR3 can be SEQ ID NO: 3137 and the bCDR3 can be SEQ ID NO: 3440. The aCDR3 can be SEQ ID NO: 3156 and the bCDR3 can be SEQ ID NO: 3455. The aCDR3 can be SEQ ID NO: 3151 and the bCDR3 can be SEQ ID NO: 3456. The aCDR3 can be SEQ ID NO: 3157 and the bCDR3 can be SEQ ID NO: 3457. The aCDR3 can be SEQ ID NO: 3158 and the bCDR3 can be SEQ ID NO: 3458.The aCDR3 can be SEQ ID NO: 3159 and the bCDR3 can be SEQ ID NO: 3459. The aCDR3 can be SEQ ID NO: 3160 and the bCDR3 can be SEQ ID NO: 3460. The aCDR3 can be SEQ ID NO: 3077 and the bCDR3 can be SEQ ID NO: 3461. The aCDR3 can be SEQ ID NO: 3161 and the bCDR3 can be SEQ ID NO: 3462. The aCDR3 can be SEQ ID NO: 3162 and the bCDR3 can be SEQ ID NO: 3463. The aCDR3 can be SEQ ID NO: 3163 and the bCDR3 can be SEQ ID NO: 3464. The aCDR3 can be SEQ ID NO: 3164 and the bCDR3 can be SEQ ID NO: 3465. The aCDR3 can be SEQ ID NO: 3137 and the bCDR3 can be SEQ ID NO: 3442. The aCDR3 can be SEQ ID NO: 3136 and the bCDR3 can be SEQ ID NO: 3438. The aCDR3 can be SEQ ID NO: 3165 and the bCDR3 can be SEQ ID NO: 3466. The aCDR3 can be SEQ ID NO: 3166 and the bCDR3 can be SEQ ID NO: 3467. The aCDR3 can be SEQ ID NO: 3167 and the bCDR3 can be SEQ ID NO: 3468. The aCDR3 can be SEQ ID NO: 3168 and the bCDR3 can be SEQ ID NO: 3469. The aCDR3 can be SEQ ID NO: 3169 and the bCDR3 can be SEQ ID NO: 3470. The aCDR3 can be SEQ ID NO: 3137 and the bCDR3 can be SEQ ID NO: 3436. The aCDR3 can be SEQ ID NO: 3170 and the bCDR3 can be SEQ ID NO: 3471. The aCDR3 can be SEQ ID NO: 3171 and the bCDR3 can be SEQ ID NO: 3472. The aCDR3 can be SEQ ID NO: 3172 and the bCDR3 can be SEQ ID NO: 3473. The aCDR3 can be SEQ ID NO: 3173 and the bCDR3 can be SEQ ID NO: 3474.The aCDR3 can be SEQ ID NO: 3174, and the bCDR3 can be SEQ ID NO: 3475. The aCDR3 can be SEQ ID NO: 3175, and the bCDR3 can be SEQ ID NO: 3476. The aCDR3 can be SEQ ID NO: 3176, and the bCDR3 can be SEQ ID NO: 3477. The aCDR3 can be SEQ ID NO: 3177, and the bCDR3 can be SEQ ID NO: 3478. The aCDR3 can be SEQ ID NO: 3178, and the bCDR3 can be SEQ ID NO: 3479. The aCDR3 can be SEQ ID NO: 3179, and the bCDR3 can be SEQ ID NO: 3480. The aCDR3 can be SEQ ID NO: 3180, and the bCDR3 can be SEQ ID NO: 3481. The aCDR3 can be SEQ ID NO: 3136, and the bCDR3 can be SEQ ID NO: 3482. The aCDR3 can be SEQ ID NO: 3181, and the bCDR3 can be SEQ ID NO: 3483. The aCDR3 can be SEQ ID NO: 3182, and the bCDR3 can be SEQ ID NO: 3484. The aCDR3 can be SEQ ID NO: 3183, and the bCDR3 can be SEQ ID NO: 3485. The aCDR3 can be SEQ ID NO: 3184, and the bCDR3 can be SEQ ID NO: 3486. The aCDR3 can be SEQ ID NO: 3185, and the bCDR3 can be SEQ ID NO: 3487. The aCDR3 can be SEQ ID NO: 3186, and the bCDR3 can be SEQ ID NO: 3488. The aCDR3 can be SEQ ID NO: 3187, and the bCDR3 can be SEQ ID NO: 3489. The aCDR3 can be SEQ ID NO: 3188, and the bCDR3 can be SEQ ID NO: 3482. The aCDR3 can be SEQ ID NO: 3189, and the bCDR3 can be SEQ ID NO: 3490. The aCDR3 can be SEQ ID NO: 3190, and the bCDR3 can be SEQ ID NO: 3491. The aCDR3 can be SEQ ID NO: 3191, and the bCDR3 can be SEQ ID NO: 3492.The aCDR3 can be SEQ ID NO: 3192, and the bCDR3 can be SEQ ID NO: 3493. The aCDR3 can be SEQ ID NO: 3193, and the bCDR3 can be SEQ ID NO: 3494. The aCDR3 can be SEQ ID NO: 3194, and the bCDR3 can be SEQ ID NO: 3495. The aCDR3 can be SEQ ID NO: 3195, and the bCDR3 can be SEQ ID NO: 3496. The aCDR3 can be SEQ ID NO: 3196, and the bCDR3 can be SEQ ID NO: 3497. The aCDR3 can be SEQ ID NO: 3197, and the bCDR3 can be SEQ ID NO: 3498. The aCDR3 can be SEQ ID NO: 3198, and the bCDR3 can be SEQ ID NO: 3499. The aCDR3 can be SEQ ID NO: 3199, and the bCDR3 can be SEQ ID NO: 3500. The aCDR3 can be SEQ ID NO: 3137, and the bCDR3 can be SEQ ID NO: 3449. The aCDR3 can be SEQ ID NO: 3200, and the bCDR3 can be SEQ ID NO: 3436. The aCDR3 can be SEQ ID NO: 3201, and the bCDR3 can be SEQ ID NO: 3501. The aCDR3 can be SEQ ID NO: 3138, and the bCDR3 can be SEQ ID NO: 3436. The aCDR3 can be SEQ ID NO: 3202, and the bCDR3 can be SEQ ID NO: 3502. The aCDR3 can be SEQ ID NO: 3203, and the bCDR3 can be SEQ ID NO: 3503. The aCDR3 can be SEQ ID NO: 3204, and the bCDR3 can be SEQ ID NO: 3504. The aCDR3 can be SEQ ID NO: 3205, and the bCDR3 can be SEQ ID NO: 3505. The aCDR3 can be SEQ ID NO: 3206, and the bCDR3 can be SEQ ID NO: 3506. The aCDR3 can be SEQ ID NO: 3207, and the bCDR3 can be SEQ ID NO: 3507. The aCDR3 can be SEQ ID NO: 3148, and the bCDR3 can be SEQ ID NO: 3440.The aCDR3 can be SEQ ID NO: 3208, and the bCDR3 can be SEQ ID NO: 3508. The aCDR3 can be SEQ ID NO: 3209, and the bCDR3 can be SEQ ID NO: 3509. The aCDR3 can be SEQ ID NO: 3210, and the bCDR3 can be SEQ ID NO: 3510. The aCDR3 can be SEQ ID NO: 3211, and the bCDR3 can be SEQ ID NO: 3511. The aCDR3 can be SEQ ID NO: 3212, and the bCDR3 can be SEQ ID NO: 3512. The aCDR3 can be SEQ ID NO: 3213, and the bCDR3 can be SEQ ID NO: 3513. The aCDR3 can be SEQ ID NO: 3214, and the bCDR3 can be SEQ ID NO: 3514. The aCDR3 can be SEQ ID NO: 3215, and the bCDR3 can be SEQ ID NO: 3515. The aCDR3 can be SEQ ID NO: 3216, and the bCDR3 can be SEQ ID NO: 3516. The aCDR3 can be SEQ ID NO: 3217, and the bCDR3 can be SEQ ID NO: 3517. The aCDR3 can be SEQ ID NO: 3218, and the bCDR3 can be SEQ ID NO: 3518. The aCDR3 can be SEQ ID NO: 3219, and the bCDR3 can be SEQ ID NO: 3519. The aCDR3 can be SEQ ID NO: 3220, and the bCDR3 can be SEQ ID NO: 3520. The aCDR3 can be SEQ ID NO: 3221, and the bCDR3 can be SEQ ID NO: 3521. The aCDR3 can be SEQ ID NO: 3217, and the bCDR3 can be SEQ ID NO: 3518. The aCDR3 can be SEQ ID NO: 3222, and the bCDR3 can be SEQ ID NO: 3522. The aCDR3 can be SEQ ID NO: 3223, and the bCDR3 can be SEQ ID NO: 3523. The aCDR3 can be SEQ ID NO: 3224, and the bCDR3 can be SEQ ID NO: 3524. The aCDR3 can be SEQ ID NO: 3225, and the bCDR3 can be SEQ ID NO: 3525.The aCDR3 can be SEQ ID NO: 3226 and the bCDR3 can be SEQ ID NO: 3526. The aCDR3 can be SEQ ID NO: 3227 and the bCDR3 can be SEQ ID NO: 3527. The aCDR3 can be SEQ ID NO: 3228 and the bCDR3 can be SEQ ID NO: 3528. The aCDR3 can be SEQ ID NO: 3229 and the bCDR3 can be SEQ ID NO: 3529. The aCDR3 can be SEQ ID NO: 3230 and the bCDR3 can be SEQ ID NO: 3530. The aCDR3 can be SEQ ID NO: 3217 and the bCDR3 can be SEQ ID NO: 3525. The aCDR3 can be SEQ ID NO: 3231 and the bCDR3 can be SEQ ID NO: 3531. The aCDR3 can be SEQ ID NO: 3232 and the bCDR3 can be SEQ ID NO: 3532. The aCDR3 can be SEQ ID NO: 3233 and the bCDR3 can be SEQ ID NO: 3520. The aCDR3 can be SEQ ID NO: 3217 and the bCDR3 can be SEQ ID NO: 3530. The aCDR3 can be SEQ ID NO: 3234 and the bCDR3 can be SEQ ID NO: 3533. The aCDR3 can be SEQ ID NO: 3235 and the bCDR3 can be SEQ ID NO: 3534. The aCDR3 can be SEQ ID NO: 3217 and the bCDR3 can be SEQ ID NO: 3532. The aCDR3 can be SEQ ID NO: 3236 and the bCDR3 can be SEQ ID NO: 3535. The aCDR3 can be SEQ ID NO: 3237 and the bCDR3 can be SEQ ID NO: 3536. The aCDR3 can be SEQ ID NO: 3238 and the bCDR3 can be SEQ ID NO: 3537. The aCDR3 can be SEQ ID NO: 3239 and the bCDR3 can be SEQ ID NO: 3538. The aCDR3 can be SEQ ID NO: 3240 and the bCDR3 can be SEQ ID NO: 3539. The aCDR3 can be SEQ ID NO: 3241 and the bCDR3 can be SEQ ID NO: 3540.The aCDR3 can be SEQ ID NO: 3242 and the bCDR3 can be SEQ ID NO: 3541. The aCDR3 can be SEQ ID NO: 3243 and the bCDR3 can be SEQ ID NO: 3542. The aCDR3 can be SEQ ID NO: 3244 and the bCDR3 can be SEQ ID NO: 3543. The aCDR3 can be SEQ ID NO: 3245 and the bCDR3 can be SEQ ID NO: 3544. The aCDR3 can be SEQ ID NO: 3246 and the bCDR3 can be SEQ ID NO: 3545. The aCDR3 can be SEQ ID NO: 3247 and the bCDR3 can be SEQ ID NO: 3546. The aCDR3 can be SEQ ID NO: 3248 and the bCDR3 can be SEQ ID NO: 3547. The aCDR3 can be SEQ ID NO: 3249 and the bCDR3 can be SEQ ID NO: 3548. The aCDR3 can be SEQ ID NO: 3217 and the bCDR3 can be SEQ ID NO: 3524. The aCDR3 can be SEQ ID NO: 3250 and the bCDR3 can be SEQ ID NO: 3549. The aCDR3 can be SEQ ID NO: 3251 and the bCDR3 can be SEQ ID NO: 3550. The aCDR3 can be SEQ ID NO: 3252 and the bCDR3 can be SEQ ID NO: 3551. The aCDR3 can be SEQ ID NO: 3253 and the bCDR3 can be SEQ ID NO: 3552. The aCDR3 can be SEQ ID NO: 3254 and the bCDR3 can be SEQ ID NO: 3553. The aCDR3 can be SEQ ID NO: 3255 and the bCDR3 can be SEQ ID NO: 3554. The aCDR3 can be SEQ ID NO: 3256 and the bCDR3 can be SEQ ID NO: 3555. The aCDR3 can be SEQ ID NO: 3257 and the bCDR3 can be SEQ ID NO: 3556. The aCDR3 can be SEQ ID NO: 3258 and the bCDR3 can be SEQ ID NO: 3557. The aCDR3 can be SEQ ID NO: 3259 and the bCDR3 can be SEQ ID NO: 3558.The aCDR3 can be SEQ ID NO: 3260, and the bCDR3 can be SEQ ID NO: 3559. The aCDR3 can be SEQ ID NO: 3261, and the bCDR3 can be SEQ ID NO: 3560. The aCDR3 can be SEQ ID NO: 3217, and the bCDR3 can be SEQ ID NO: 3519. The aCDR3 can be SEQ ID NO: 3262, and the bCDR3 can be SEQ ID NO: 3561. The aCDR3 can be SEQ ID NO: 3263, and the bCDR3 can be SEQ ID NO: 3562. The aCDR3 can be SEQ ID NO: 3217, and the bCDR3 can be SEQ ID NO: 3563. The aCDR3 can be SEQ ID NO: 3264, and the bCDR3 can be SEQ ID NO: 3564. The aCDR3 can be SEQ ID NO: 3265, and the bCDR3 can be SEQ ID NO: 3565. The aCDR3 can be SEQ ID NO: 3266, and the bCDR3 can be SEQ ID NO: 3566. The aCDR3 can be SEQ ID NO: 3267, and the bCDR3 can be SEQ ID NO: 3567. The aCDR3 can be SEQ ID NO: 3268, and the bCDR3 can be SEQ ID NO: 3568. The aCDR3 can be SEQ ID NO: 3269, and the bCDR3 can be SEQ ID NO: 3569. The aCDR3 can be SEQ ID NO: 3217, and the bCDR3 can be SEQ ID NO: 3528. The aCDR3 can be SEQ ID NO: 3270, and the bCDR3 can be SEQ ID NO: 3570. The aCDR3 can be SEQ ID NO: 3217, and the bCDR3 can be SEQ ID NO: 3571. The aCDR3 can be SEQ ID NO: 3271, and the bCDR3 can be SEQ ID NO: 3572. The aCDR3 can be SEQ ID NO: 3219, and the bCDR3 can be SEQ ID NO: 3522. The aCDR3 can be SEQ ID NO: 3272, and the bCDR3 can be SEQ ID NO: 3573. The aCDR3 can be SEQ ID NO: 3273, and the bCDR3 can be SEQ ID NO: 3574.The aCDR3 can be SEQ ID NO: 3274 and the bCDR3 can be SEQ ID NO: 3575. The aCDR3 can be SEQ ID NO: 3275 and the bCDR3 can be SEQ ID NO: 3576. The aCDR3 can be SEQ ID NO: 3217 and the bCDR3 can be SEQ ID NO: 3577. The aCDR3 can be SEQ ID NO: 3230 and the bCDR3 can be SEQ ID NO: 3517. The aCDR3 can be SEQ ID NO: 3276 and the bCDR3 can be SEQ ID NO: 3578. The aCDR3 can be SEQ ID NO: 3277 and the bCDR3 can be SEQ ID NO: 3579. The aCDR3 can be SEQ ID NO: 3278 and the bCDR3 can be SEQ ID NO: 3580. The aCDR3 can be SEQ ID NO: 3279 and the bCDR3 can be SEQ ID NO: 3581. The aCDR3 can be SEQ ID NO: 3280 and the bCDR3 can be SEQ ID NO: 3582. The aCDR3 can be SEQ ID NO: 3281 and the bCDR3 can be SEQ ID NO: 3583. The aCDR3 can be SEQ ID NO: 3282 and the bCDR3 can be SEQ ID NO: 3584. The aCDR3 can be SEQ ID NO: 3283 and the bCDR3 can be SEQ ID NO: 3585. The aCDR3 can be SEQ ID NO: 3284 and the bCDR3 can be SEQ ID NO: 3586. The aCDR3 can be SEQ ID NO: 3285 and the bCDR3 can be SEQ ID NO: 3587. The aCDR3 can be SEQ ID NO: 3286 and the bCDR3 can be SEQ ID NO: 3588. The aCDR3 can be SEQ ID NO: 3287 and the bCDR3 can be SEQ ID NO: 3589. The aCDR3 can be SEQ ID NO: 3288 and the bCDR3 can be SEQ ID NO: 3590. The aCDR3 can be SEQ ID NO: 3289 and the bCDR3 can be SEQ ID NO: 3591. The aCDR3 can be SEQ ID NO: 3290 and the bCDR3 can be SEQ ID NO: 3592.The aCDR3 can be SEQ ID NO: 3291 and the bCDR3 can be SEQ ID NO: 3593. The aCDR3 can be SEQ ID NO: 3292 and the bCDR3 can be SEQ ID NO: 3594. The aCDR3 can be SEQ ID NO: 3293 and the bCDR3 can be SEQ ID NO: 3595. The aCDR3 can be SEQ ID NO: 3294 and the bCDR3 can be SEQ ID NO: 3596. The aCDR3 can be SEQ ID NO: 3295 and the bCDR3 can be SEQ ID NO: 3597. The aCDR3 can be SEQ ID NO: 3219 and the bCDR3 can be SEQ ID NO: 3598. The aCDR3 can be SEQ ID NO: 3296 and the bCDR3 can be SEQ ID NO: 3599. The aCDR3 can be SEQ ID NO: 3217 and the bCDR3 can be SEQ ID NO: 3600. The aCDR3 can be SEQ ID NO: 3297 and the bCDR3 can be SEQ ID NO: 3601. The aCDR3 can be SEQ ID NO: 3298 and the bCDR3 can be SEQ ID NO: 3602. The aCDR3 can be SEQ ID NO: 3299 and the bCDR3 can be SEQ ID NO: 3603. The aCDR3 can be SEQ ID NO: 3300 and the bCDR3 can be SEQ ID NO: 3604. The aCDR3 can be SEQ ID NO: 3301 and the bCDR3 can be SEQ ID NO: 3605. The aCDR3 can be SEQ ID NO: 3302 and the bCDR3 can be SEQ ID NO: 3606. The aCDR3 can be SEQ ID NO: 3303 and the bCDR3 can be SEQ ID NO: 3607. The aCDR3 can be SEQ ID NO: 3304 and the bCDR3 can be SEQ ID NO: 3608. The aCDR3 can be SEQ ID NO: 3305 and the bCDR3 can be SEQ ID NO: 3609. The aCDR3 can be SEQ ID NO: 3306 and the bCDR3 can be SEQ ID NO: 3610. The aCDR3 can be SEQ ID NO: 3307 and the bCDR3 can be SEQ ID NO: 3611.The aCDR3 can be SEQ ID NO: 3289 and the bCDR3 can be SEQ ID NO: 3595. The aCDR3 can be SEQ ID NO: 3308 and the bCDR3 can be SEQ ID NO: 3612. The aCDR3 can be SEQ ID NO: 3309 and the bCDR3 can be SEQ ID NO: 3613. The aCDR3 can be SEQ ID NO: 3310 and the bCDR3 can be SEQ ID NO: 3614. The aCDR3 can be SEQ ID NO: 3311 and the bCDR3 can be SEQ ID NO: 3615. The aCDR3 can be SEQ ID NO: 3312 and the bCDR3 can be SEQ ID NO: 3616. The aCDR3 can be SEQ ID NO: 3313 and the bCDR3 can be SEQ ID NO: 3617. The aCDR3 can be SEQ ID NO: 3314 and the bCDR3 can be SEQ ID NO: 3618. The aCDR3 can be SEQ ID NO: 3289 and the bCDR3 can be SEQ ID NO: 3619. The aCDR3 can be SEQ ID NO: 3315 and the bCDR3 can be SEQ ID NO: 3620. The aCDR3 can be SEQ ID NO: 3316 and the bCDR3 can be SEQ ID NO: 3621. The aCDR3 can be SEQ ID NO: 3317 and the bCDR3 can be SEQ ID NO: 3622. The aCDR3 can be SEQ ID NO: 3318 and the bCDR3 can be SEQ ID NO: 3623. The aCDR3 can be SEQ ID NO: 3319 and the bCDR3 can be SEQ ID NO: 3624. The aCDR3 can be SEQ ID NO: 3320 and the bCDR3 can be SEQ ID NO: 3625. The aCDR3 can be SEQ ID NO: 3321 and the bCDR3 can be SEQ ID NO: 3626. The aCDR3 can be SEQ ID NO: 3322 and the bCDR3 can be SEQ ID NO: 3627. The aCDR3 can be SEQ ID NO: 3323 and the bCDR3 can be SEQ ID NO: 3628. The aCDR3 can be SEQ ID NO: 3324 and the bCDR3 can be SEQ ID NO: 3629.The aCDR3 can be SEQ ID NO: 3325, and the bCDR3 can be SEQ ID NO: 3602. The aCDR3 can be SEQ ID NO: 3326, and the bCDR3 can be SEQ ID NO: 3630. The aCDR3 can be SEQ ID NO: 3327, and the bCDR3 can be SEQ ID NO: 3631. The aCDR3 can be SEQ ID NO: 3328, and the bCDR3 can be SEQ ID NO: 3632. The aCDR3 can be SEQ ID NO: 3289, and the bCDR3 can be SEQ ID NO: 3598. The aCDR3 can be SEQ ID NO: 3329, and the bCDR3 can be SEQ ID NO: 3633. The aCDR3 can be SEQ ID NO: 3330, and the bCDR3 can be SEQ ID NO: 3634. The aCDR3 can be SEQ ID NO: 3331, and the bCDR3 can be SEQ ID NO: 3635. The aCDR3 can be SEQ ID NO: 3332, and the bCDR3 can be SEQ ID NO: 3636. The aCDR3 can be SEQ ID NO: 3333, and the bCDR3 can be SEQ ID NO: 3637. The aCDR3 can be SEQ ID NO: 3334, and the bCDR3 can be SEQ ID NO: 3638. The aCDR3 can be SEQ ID NO: 3335, and the bCDR3 can be SEQ ID NO: 3639. The aCDR3 can be SEQ ID NO: 3336, and the bCDR3 can be SEQ ID NO: 3640. The aCDR3 can be SEQ ID NO: 3337, and the bCDR3 can be SEQ ID NO: 3641. The aCDR3 can be SEQ ID NO: 3338, and the bCDR3 can be SEQ ID NO: 3642. The aCDR3 can be SEQ ID NO: 3290, and the bCDR3 can be SEQ ID NO: 3596. The aCDR3 can be SEQ ID NO: 3339, and the bCDR3 can be SEQ ID NO: 3643. The aCDR3 can be SEQ ID NO: 3290, and the bCDR3 can be SEQ ID NO: 3601. The aCDR3 can be SEQ ID NO: 3340, and the bCDR3 can be SEQ ID NO: 3644.The aCDR3 can be SEQ ID NO: 3289, and the bCDR3 can be SEQ ID NO: 3611. The aCDR3 can be SEQ ID NO: 3341, and the bCDR3 can be SEQ ID NO: 3645. The aCDR3 can be SEQ ID NO: 3342, and the bCDR3 can be SEQ ID NO: 3646. The aCDR3 can be SEQ ID NO: 3343, and the bCDR3 can be SEQ ID NO: 3647. The aCDR3 can be SEQ ID NO: 3142, and the bCDR3 can be SEQ ID NO: 3648. The aCDR3 can be SEQ ID NO: 3344, and the bCDR3 can be SEQ ID NO: 3649. The aCDR3 can be SEQ ID NO: 3345, and the bCDR3 can be SEQ ID NO: 3650. The aCDR3 can be SEQ ID NO: 3290, and the bCDR3 can be SEQ ID NO: 3614. The aCDR3 can be SEQ ID NO: 3346, and the bCDR3 can be SEQ ID NO: 3651. The aCDR3 can be SEQ ID NO: 3347, and the bCDR3 can be SEQ ID NO: 3652. The aCDR3 can be SEQ ID NO: 3348, and the bCDR3 can be SEQ ID NO: 3653. The aCDR3 can be SEQ ID NO: 3349, and the bCDR3 can be SEQ ID NO: 3654. The aCDR3 can be SEQ ID NO: 3350, and the bCDR3 can be SEQ ID NO: 3655.

[0376] A TCR specific for A*01 :01_EVDPIGHLY (SEQ ID NO: 3051) can include TRAV, TRAJ, TRBV, optionally TRBD, and TRBJ amino acid sequences, optionally a TRAC sequence, and optionally a TRBC sequence. Such a TCR can include TRAV24, TRAJ31, TRBV3-1, TRBD1, and TRBJ2-1. Such a TCR can include TRAV3, TRAJ6, TRBV19, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ26, TRBV27, TRBD1, and TRBJ1-6. Such a TCR can include TRAV20, TRAJ15, TRBV27, and TRBJ2-3. Such a TCR can include TRAV12-3, TRAJ20, TRBV20-1, TRBD2, and TRBJ1-2. Such a TCR can include TRAV19, TRAJ40, TRBV20-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ4, TRBV10-3, and TRBJ1-1. Such a TCR can include TRAV12-3, TRAJ20, TRBV20-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV1-1, TRAJ4, TRBV9, TRBD1, and TRBJ1-1. Such a TCR can include TRAV12-1, TRAJ17, TRBV6-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV4, TRAJ47, TRBV20-1, TRBD2, and TRBJ2-3. Such a TCR can include TRAV21, TRAJ6, TRBV5-4, and TRBJ2-1. Such a TCR can include TRAV12-1, TRAJ11, TRBV11-3, TRBD1, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ31, TRBV5-1, TRBD1, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ33, TRBV5-1, TRBD1, and TRBJ2-3. Such a TCR can include TRAV34, TRAJ40, TRBV9, TRBD2, and TRBJ2-7. Such a TCR can include TRAV29DV5, TRAJ29, TRBV7-9, TRBD1, and TRBJ2-3. Such a TCR can include TRAV19, TRAJ40, TRBV20-1, TRBD2, and TRBJ1-2. Such a TCR can include TRAV4, TRAJ47, TRBV20-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ54, TRBV5-1, TRBD1, and TRBJ2-1.Such a TCR can include TRAV21, TRAJ42, TRBV7-9, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ4, TRBV20-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ40, TRBV29-1, and TRBJ2-2. Such a TCR can include TRAV29DV5, TRAJ49, TRBV10-2, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ40, TRBV27, TRBD2, and TRBJ2-2. Such a TCR can include TRAV21, TRAJ11, TRBV5-4, and TRBJ2-2. Such a TCR can include TRAV12-3, TRAJ20, TRBV20-1, TRBD2, and TRBJ2-3. Such a TCR can include TRAV26-2, TRAJ49, TRBV19, and TRBJ1-5. Such a TCR can include TRAV12-3, TRAJ20, TRBV6-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV17, TRAJ34, TRBV11-1, TRBD1, and TRBJ1-2. Such a TCR can include TRAV12-3, TRAJ20, TRBV10-3, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ26, TRBV5-6, TRBD1, and TRBJ2-7. Such a TCR can include TRAV29DV5, TRAJ4, TRBV27, TRBD1, and TRBJ1-5. Such a TCR can include TRAV4, TRAJ47, TRBV20-1, TRBD2, and TRBJ1-2. Such a TCR can include TRAV13-1, TRAJ49, TRBV27, TRBD1, and TRBJ2-7. Such a TCR can include TRAV12-1, TRAJ10, TRBV25-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV29DV5, TRAJ39, TRBV7-9, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ47, TRBV9, TRBD1, and TRBJ1-1. Such a TCR can include TRAV39, TRAJ41, TRBV13, and TRBJ1-4. Such a TCR can include TRAV17, TRAJ53, TRBV29-1, TRBD1, and TRBJ2-1. Such a TCR can include TRAV26-1, TRAJ42, TRBV19, TRBD1, and TRBJ2-3. Such a TCR can include TRAV8-6, TRAJ50, TRBV9, TRBD1, and TRBJ2-7.Such a TCR can include TRAV19, TRAJ10, TRBV7-9, and TRBJ2-7. Such a TCR can include TRAV8-4, TRAJ42, TRBV3-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV12-1, TRAJ47, TRBV5-8, TRBD1, and TRBJ1-1. Such a TCR can include TRAV29DV5, TRAJ42, TRBV10-3, and TRBJ2-7. Such a TCR can include TRAV13-2, TRAJ20, TRBV27, TRBD2, and TRBJ1-1. Such a TCR can include TRAV10, TRAJ9, TRBV3-1, TRBD1, and TRBJ1-3. Such a TCR can include TRAV19, TRAJ27, TRBV27, TRBD1, and TRBJ2-7. Such a TCR can include TRAV9-2, TRAJ20, TRBV12-4, TRBD1, and TRBJ2-1. Such a TCR can include TRAV12-2, TRAJ20, TRBV7-6, TRBD2, and TRBJ2-1. Such a TCR can include TRAV12-1, TRAJ17, TRBV20-1, TRBD2, and TRBJ1-2. Such a TCR can include TRAV30, TRAJ58, TRBV19, and TRBJ2-7. Such a TCR can include TRAV8-1, TRAJ43, TRBV7-8, TRBD2, and TRBJ2-1. Such a TCR can include TRAV13-1, TRAJ9, TRBV9, TRBD1, and TRBJ2-5. Such a TCR can include TRAV12-1, TRAJ29, TRBV6-1, TRBD1, and TRBJ1-2. Such a TCR can include TRAV19, TRAJ40, TRBV20-1, TRBD2, and TRBJ2-3. Such a TCR can include TRAV21, TRAJ43, TRBV7-3, and TRBJ2-2. Such a TCR can include TRAV21, TRAJ4, TRBV5-1, TRBD1, and TRBJ2-1. Such a TCR can include TRAV26-2, TRAJ32, TRBV24-1, TRBD1, and TRBJ2-2. Such a TCR can include TRAV21, TRAJ4, TRBV20-1, TRBD2, and TRBJ1-2. Such a TCR can include TRAV19, TRAJ15, TRBV7-8, TRBD1, and TRBJ2-7. Such a TCR can include TRAV19, TRAJ40, TRBV6-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV12-2, TRAJ13, TRBV25-1, and TRBJ2-7.Such a TCR can include TRAV29DV5, TRAJ54, TRBV7-8, and TRBJ2-1. Such a TCR can include TRAV19, TRAJ53, TRBV20-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV23DV6, TRAJ36, TRBV9, TRBD2, and TRBJ1-2. Such a TCR can include TRAV19, TRAJ40, TRBV10-3, and TRBJ1-1. Such a TCR can include TRAV8-6, TRAJ32, TRBV19, TRBD1, and TRBJ1-1. Such a TCR can include TRAV1-1, TRAJ13, TRBV14, TRBD1, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ6, TRBV20-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ44, TRBV9, and TRBJ2-7. Such a TCR can include TRAV29DV5, TRAJ3, TRBV3-1, TRBD2, and TRBJ2-5. Such a TCR can include TRAV17, TRAJ39, TRBV7-2, and TRBJ1-2. Such a TCR can include TRAV26-2, TRAJ12, TRBV7-9, TRBD1, and TRBJ1-2. Such a TCR can include TRAV29DV5, TRAJ22, TRBV11-3, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ20, TRBV12-4, TRBD2, and TRBJ2-3. Such a TCR can include TRAV12-3, TRAJ3, TRBV27, TRBD1, and TRBJ2-7. Such a TCR can include TRAV27, TRAJ33, TRBV6-5, TRBD2, and TRBJ2-2. Such a TCR can include TRAV13-1, TRAJ22, TRBV12-4, TRBD1, and TRBJ2-3. Such a TCR can include TRAV26-1, TRAJ34, TRBV27, and TRBJ1-2. Such a TCR can include TRAV10, TRAJ4, TRBV7-9, TRBD1, and TRBJ2-4. Such a TCR can include TRAV21, TRAJ6, TRBV20-1, TRBD2, and TRBJ1-2. Such a TCR can include TRAV12-3, TRAJ20, TRBV9, TRBD1, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ26, TRBV10-3, and TRBJ1-1. Such a TCR can include TRAV12-2, TRAJ20, TRBV18, TRBD1, and TRBJ2-7.Such a TCR can include TRAV9-2, TRAJ23, TRBV11-3, TRBD1, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ6, TRBV6-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV12-3, TRAJ20, TRBV7-8, TRBD1, and TRBJ2-2. Such a TCR can include TRAV9-2, TRAJ23, TRBV10-3, and TRBJ1-1. Such a TCR can include TRAV24, TRAJ45, TRBV5-4, TRBD1, and TRBJ1-4. Such a TCR can include TRAV13-1, TRAJ3, TRBV27, TRBD2, and TRBJ1-1. Such a TCR can include TRAV20, TRAJ20, TRBV7-2, TRBD1, and TRBJ2-7. Such a TCR can include TRAV8-4, TRAJ42, TRBV9, TRBD1, and TRBJ2-1. Such a TCR can include TRAV1-2, TRAJ31, TRBV7-9, TRBD1, and TRBJ1-5. Such a TCR can include TRAV12-1, TRAJ13, TRBV20-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV12-1, TRAJ4, TRBV28, TRBD2, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ4, TRBV27, TRBD2, and TRBJ2-2. Such a TCR can include TRAV3, TRAJ9, TRBV7-9, TRBD1, and TRBJ2-7. Such a TCR can include TRAV26-1, TRAJ42, TRBV19, and TRBJ2-2. Such a TCR can include TRAV21, TRAJ47, TRBV19, and TRBJ1-1. Such a TCR can include TRAV26-1, TRAJ34, TRBV20-1, TRBD2, and TRBJ1-2. Such a TCR can include TRAV21, TRAJ31, TRBV20-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV12-1, TRAJ11, TRBV20-1, TRBD2, and TRBJ1-2. Such a TCR can include TRAV17, TRAJ34, TRBV6-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV13-2, TRAJ47, TRBV19, TRBD2, and TRBJ2-1. Such a TCR can include TRAV29DV5, TRAJ28, TRBV27, TRBD2, and TRBJ2-4. Such a TCR can include TRAV13-2, TRAJ17, TRBV27, TRBD2, and TRBJ1-5.Such a TCR can include TRAV38-2DV8, TRAJ57, TRBV5-4, TRBD1, and TRBJ1-2. Such a TCR can include TRAV17, TRAJ32, TRBV7-8, TRBD2, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ39, TRBV20-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV12-3, TRAJ20, TRBV7-9, TRBD1, and TRBJ2-3. Such a TCR can include TRAV1-1, TRAJ4, TRBV20-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV12-1, TRAJ9, TRBV2, TRBD1, and TRBJ2-7. Such a TCR can include TRAV19, TRAJ32, TRBV9, TRBD1, and TRBJ1-2. Such a TCR can include TRAV8-3, TRAJ6, TRBV9, TRBD2, and TRBJ2-1. Such a TCR can include TRAV19, TRAJ40, TRBV7-9, and TRBJ2-7. Such a TCR can include TRAV5, TRAJ37, TRBV5-6, TRBD2, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ33, TRBV20-1, TRBD2, and TRBJ1-2. Such a TCR can include TRAV29DV5, TRAJ3, TRBV20-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV1-1, TRAJ4, TRBV20-1, TRBD2, and TRBJ1-2. Such a TCR can include TRAV21, TRAJ6, TRBV10-3, and TRBJ1-1. Such a TCR can include TRAV19, TRAJ23, TRBV9, TRBD1, and TRBJ1-1. Such a TCR can include TRAV12-2, TRAJ20, TRBV11-2, TRBD2, and TRBJ2-2. Such a TCR can include TRAV1-2, TRAJ15, TRBV24-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ9, TRBV5-4, and TRBJ1-6. Such a TCR can include TRAV8-6, TRAJ12, TRBV7-9, TRBD1, and TRBJ2-2. Such a TCR can include TRAV21, TRAJ31, TRBV11-2, TRBD2, and TRBJ1-2. Such a TCR can include TRAV21, TRAJ41, TRBV9, TRBD1, and TRBJ1-1. Such a TCR can include TRAV25, TRAJ28, TRBV7-2, TRBD2, and TRBJ2-6.Such a TCR can include TRAV21, TRAJ33, TRBV10-3, TRBD1, and TRBJ1-3. Such a TCR can include TRAV21, TRAJ49, TRBV5-1, TRBD1, and TRBJ2-5. Such a TCR can include TRAV1-1, TRAJ34, TRBV6-6, and TRBJ1-5. Such a TCR can include TRAV24, TRAJ6, TRBV7-2, TRBD1, and TRBJ2-1. Such a TCR can include TRAV1-1, TRAJ15, TRBV6-6, and TRBJ1-5. Such a TCR can include TRAV21, TRAJ15, TRBV29-1, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ43, TRBV12-4, and TRBJ1-5. Such a TCR can include TRAV21, TRAJ30, TRBV9, TRBD1, and TRBJ1-4. Such a TCR can include TRAV21, TRAJ31, TRBV5-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV26-1, TRAJ45, TRBV19, TRBD2, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ43, TRBV24-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ31, TRBV24-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV29DV5, TRAJ28, TRBV4-1, TRBD1, and TRBJ1-4. Such a TCR can include TRAV26-2, TRAJ44, TRBV27, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ31, TRBV9, TRBD1, and TRBJ1-5. Such a TCR can include TRAV21, TRAJ36, TRBV9, TRBD1, and TRBJ1-2. Such a TCR can include TRAV21, TRAJ9, TRBV9, TRBD1, and TRBJ1-1. Such a TCR can include TRAV8-3, TRAJ15, TRBV4-1, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ43, TRBV24-1, TRBD1, and TRBJ2-3. Such a TCR can include TRAV29DV5, TRAJ40, TRBV7-9, TRBD1, and TRBJ1-6. Such a TCR can include TRAV30, TRAJ32, TRBV28, TRBD1, and TRBJ1-1. Such a TCR can include TRAV38-2DV8, TRAJ26, TRBV7-9, TRBD2, and TRBJ2-5.Such a TCR can include TRAV12-1, TRAJ6, TRBV20-1, TRBD1, and TRBJ1-3. Such a TCR can include TRAV21, TRAJ47, TRBV5-1, and TRBJ1-1. Such a TCR can include TRAV38-2DV8, TRAJ45, TRBV29-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ15, TRBV7-2, and TRBJ1-1. Such a TCR can include TRAV12-2, TRAJ29, TRBV9, TRBD1, and TRBJ1-1. Such a TCR can include TRAV3, TRAJ6, TRBV28, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ9, TRBV10-3, TRBD1, and TRBJ1-3. Such a TCR can include TRAV1-2, TRAJ15, TRBV7-9, TRBD1, and TRBJ2-2. Such a TCR can include TRAV8-6, TRAJ40, TRBV15, and TRBJ2-5. Such a TCR can include TRAV38-2DV8, TRAJ57, TRBV13, TRBD1, and TRBJ1-4. Such a TCR can include TRAV8-6, TRAJ10, TRBV7-9, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ20, TRBV5-4, TRBD1, and TRBJ1-5. Such a TCR can include TRAV13-1, TRAJ28, TRBV7-8, TRBD1, and TRBJ1-5. Such a TCR can include TRAV21, TRAJ9, TRBV24-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV1-2, TRAJ15, TRBV2, TRBD2, and TRBJ2-1. Such a TCR can include TRAV35, TRAJ26, TRBV27, TRBD1, and TRBJ1-1. Such a TCR can include TRAV38-2DV8, TRAJ43, TRBV5-1, TRBD2, and TRBJ2-5. Such a TCR can include TRAV5, TRAJ32, TRBV19, TRBD2, and TRBJ2-7. Such a TCR can include TRAV13-1, TRAJ21, TRBV5-1, TRBD2, and TRBJ2-7. Such a TCR can include TRAV12-2, TRAJ45, TRBV12-4, TRBD1, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ31, TRBV12-5, and TRBJ2-2. Such a TCR can include TRAV24, TRAJ52, TRBV27, and TRBJ2-1.Such a TCR can include TRAV21, TRAJ52, TRBV19, TRBD1, and TRBJ1-1. Such a TCR can include TRAV36DV7, TRAJ44, TRBV7-9, TRBD1, and TRBJ2-2. Such a TCR can include TRAV3, TRAJ29, TRBV11-2, TRBD1, and TRBJ2-5. Such a TCR can include TRAV1-1, TRAJ15, TRBV13, TRBD1, and TRBJ1-2. Such a TCR can include TRAV29DV5, TRAJ52, TRBV11-3, TRBD1, and TRBJ2-3. Such a TCR can include TRAV12-1, TRAJ6, TRBV19, TRBD1, and TRBJ1-1. Such a TCR can include TRAV19, TRAJ13, TRBV27, TRBD2, and TRBJ2-7. Such a TCR can include TRAV17, TRAJ43, TRBV12-3, and TRBJ1-4. Such a TCR can include TRAV12-3, TRAJ20, TRBV12-4, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ52, TRBV4-1, TRBD2, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ23, TRBV19, TRBD1, and TRBJ2-7. Such a TCR can include TRAV1-1, TRAJ30, TRBV13, TRBD1, and TRBJ1-2. Such a TCR can include TRAV12-2, TRAJ43, TRBV12-4, TRBD2, and TRBJ2-7. Such a TCR can include TRAV24, TRAJ10, TRBV5-1, TRBD1, and TRBJ1-2. Such a TCR can include TRAV5, TRAJ9, TRBV4-1, TRBD2, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ40, TRBV7-8, and TRBJ1-1. Such a TCR can include TRAV13-1, TRAJ45, TRBV9, TRBD1, and TRBJ1-6. Such a TCR can include TRAV12-1, TRAJ26, TRBV4-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV26-2, TRAJ45, TRBV19, and TRBJ1-2. Such a TCR can include TRAV22, TRAJ23, TRBV5-4, TRBD1, and TRBJ1-1. Such a TCR can include TRAV19, TRAJ42, TRBV28, and TRBJ2-7. Such a TCR can include TRAV17, TRAJ52, TRBV7-8, TRBD1, and TRBJ1-2.Such a TCR can include TRAV12-1, TRAJ39, TRBV3-1, TRBD1, and TRBJ2-3. Such a TCR can include TRAV21, TRAJ9, TRBV5-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV1-1, TRAJ5, TRBV24-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV23DV6, TRAJ13, TRBV6-5, TRBD1, and TRBJ2-1. Such a TCR can include TRAV8-6, TRAJ12, TRBV24-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV1-2, TRAJ28, TRBV27, and TRBJ2-3. Such a TCR can include TRAV29DV5, TRAJ34, TRBV4-1, TRBD2, and TRBJ2-3. Such a TCR can include TRAV12-1, TRAJ21, TRBV28, TRBD1, and TRBJ1-5. Such a TCR can include TRAV9-2, TRAJ29, TRBV5-8, TRBD2, and TRBJ1-1. Such a TCR can include TRAV27, TRAJ40, TRBV7-6, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ31, TRBV7-8, TRBD1, and TRBJ1-2. Such a TCR can include TRAV21, TRAJ30, TRBV9, TRBD1, and TRBJ1-1. Such a TCR can include TRAV19, TRAJ30, TRBV20-1, and TRBJ2-1. Such a TCR can include TRAV1-1, TRAJ26, TRBV12-5, TRBD2, and TRBJ2-1. Such a TCR can include TRAV1-2, TRAJ33, TRBV9, TRBD2, and TRBJ2-3. Such a TCR can include TRAV26-1, TRAJ50, TRBV27, TRBD1, and TRBJ2-3. Such a TCR can include TRAV40, TRAJ41, TRBV6-5, TRBD2, and TRBJ1-2. Such a TCR can include TRAV12-2, TRAJ31, TRBV7-9, TRBD1, and TRBJ1-5. Such a TCR can include TRAV5, TRAJ43, TRBV5-1, TRBD1, and TRBJ2-3. Such a TCR can include TRAV24, TRAJ52, TRBV5-1, and TRBJ1-1. Such a TCR can include TRAV1-2, TRAJ11, TRBV7-6, TRBD1, and TRBJ1-3. Such a TCR can include TRAV21, TRAJ33, TRBV5-1, TRBD1, and TRBJ2-7.Such a TCR can include TRAV21, TRAJ39, TRBV10-3, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ20, TRBV14, TRBD1, and TRBJ1-2. Such a TCR can include TRAV29DV5, TRAJ48, TRBV7-9, TRBD1, and TRBJ1-2. Such a TCR can include TRAV13-1, TRAJ22, TRBV29-1, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ33, TRBV10-3, and TRBJ2-1. Such a TCR can include TRAV39, TRAJ49, TRBV24-1, TRBD1, and TRBJ1-4. Such a TCR can include TRAV13-1, TRAJ23, TRBV27, TRBD1, and TRBJ1-2. Such a TCR can include TRAV21, TRAJ9, TRBV9, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ33, TRBV9, and TRBJ1-1. Such a TCR can include TRAV19, TRAJ28, TRBV19, TRBD1, and TRBJ1-4. Such a TCR can include TRAV10, TRAJ8, TRBV5-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ48, TRBV27, TRBD2, and TRBJ2-2. Such a TCR can include TRAV12-2, TRAJ4, TRBV7-2, TRBD2, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ31, TRBV5-1, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ33, TRBV9, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ6, TRBV6-6, TRBD1, and TRBJ1-5. Such a TCR can include TRAV21, TRAJ29, TRBV5-1, TRBD2, and TRBJ2-5. Such a TCR can include TRAV41, TRAJ41, TRBV7-9, TRBD1, and TRBJ1-2. Such a TCR can include TRAV21, TRAJ33, TRBV5-1, and TRBJ1-1. Such a TCR can include TRAV17, TRAJ39, TRBV27, TRBD2, and TRBJ2-1. Such a TCR can include TRAV13-2, TRAJ13, TRBV9, and TRBJ1-3. Such a TCR can include TRAV21, TRAJ33, TRBV5-1, TRBD2, and TRBJ2-5. Such a TCR can include TRAV17, TRAJ57, TRBV9, TRBD2, and TRBJ1-1.Such a TCR can include TRAV5, TRAJ44, TRBV7-9, TRBD1, and TRBJ1-1. Such a TCR can include TRAV3, TRAJ39, TRBV27, TRBD1, and TRBJ1-5. Such a TCR can include TRAV1-2, TRAJ4, TRBV11-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV38-2DV8, TRAJ40, TRBV7-8, TRBD1, and TRBJ2-7. Such a TCR can include TRAV8-3, TRAJ41, TRBV7-9, and TRBJ1-1. Such a TCR can include TRAV5, TRAJ4, TRBV11-2, and TRBJ2-1. Such a TCR can include TRAV24, TRAJ49, TRBV6-5, TRBD1, and TRBJ1-1. Such a TCR can include TRAV4, TRAJ45, TRBV24-1, TRBD2, and TRBJ1-1. Such a TCR can include TRAV29DV5, TRAJ48, TRBV20-1, TRBD2, and TRBJ2-7. Such a TCR can include TRAV26-2, TRAJ44, TRBV6-1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ27, TRBV7-9, and TRBJ1-6. Such a TCR can include TRAV26-1, TRAJ49, TRBV7-9, and TRBJ2-7. Such a TCR can include TRAV12-1, TRAJ5, TRBV7-8, TRBD1, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ33, TRBV9, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ20, TRBV27, TRBD1, and TRBJ2-4. Such a TCR can include TRAV39, TRAJ42, TRBV9, TRBD1, and TRBJ2-7. Such a TCR can include TRAV1-2, TRAJ39, TRBV27, TRBD2, and TRBJ1-4. Such a TCR can include TRAV1-1, TRAJ34, TRBV9, TRBD1, and TRBJ2-3. Such a TCR can include TRAV25, TRAJ34, TRBV29-1, TRBD1, and TRBJ1-2. Such a TCR can include TRAV39, TRAJ39, TRBV30, TRBD1, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ6, TRBV20-1, TRBD2, and TRBJ1-1. Such a TCR can include TRAV8-6, TRAJ30, TRBV9, TRBD2, and TRBJ2-2.Such a TCR can include TRAV21, TRAJ18, TRBV27, TRBD1, and TRBJ1-2. Such a TCR can include TRAV12-3, TRAJ23, TRBV11-3, TRBD1, and TRBJ2-2. Such a TCR can include TRAV12-1, TRAJ47, TRBV5-6, and TRBJ1-2. Such a TCR can include TRAV22, TRAJ31, TRBV5-6, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ33, TRBV14, TRBD1, and TRBJ1-2. Such a TCR can include TRAV1-2, TRAJ31, TRBV2, TRBD2, and TRBJ2-7. Such a TCR can include TRAV1-2, TRAJ5, TRBV20-1, TRBD2, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ33, TRBV5-1, TRBD1, and TRBJ1-2. Such a TCR can include TRAV16, TRAJ28, TRBV7-9, TRBD1, and TRBJ2-1. Such a TCR can include TRAV13-1, TRAJ12, TRBV20-1, TRBD2, and TRBJ1-1. Such a TCR can include TRAV17, TRAJ52, TRBV29-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV36DV7, TRAJ49, TRBV15, TRBD2, and TRBJ2-3. Such a TCR can include TRAV12-3, TRAJ58, TRBV12-4, TRBD2, and TRBJ2-1. Such a TCR can include TRAV16, TRAJ18, TRBV27, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ33, TRBV27, TRBD2, and TRBJ2-2. Such a TCR can include TRAV12-2, TRAJ48, TRBV27, and TRBJ2-6. Such a TCR can include TRAV21, TRAJ33, TRBV2, TRBD1, and TRBJ1-2. Such a TCR can include TRAV29DV5, TRAJ37, TRBV5-4, TRBD2, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ20, TRBV24-1, TRBD1, and TRBJ1-4. Such a TCR can include TRAV12-2, TRAJ6, TRBV15, TRBD1, and TRBJ2-2. Such a TCR can include TRAV12-1, TRAJ42, TRBV27, TRBD1, and TRBJ1-5. Such a TCR can include TRAV1-1, TRAJ23, TRBV25-1, TRBD1, and TRBJ2-7.Such a TCR can include TRAV38-1, TRAJ28, TRBV5-1, TRBD1, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ33, TRBV2, TRBD1, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ31, TRBV5-1, TRBD1, and TRBJ2-7. Such a TCR can include TRAV8-6, TRAJ42, TRBV27, and TRBJ1-1. Such a TCR can include TRAV40, TRAJ32, TRBV7-6, and TRBJ2-2. Such a TCR can include TRAV5, TRAJ5, TRBV20-1, TRBD1, and TRBJ2-5. Such a TCR can include TRAV12-1, TRAJ40, TRBV4-1, and TRBJ2-5. Such a TCR can include TRAV13-2, TRAJ53, TRBV5-1, and TRBJ1-1. Such a TCR can include TRAV12-2, TRAJ48, TRBV5-6, TRBD1, and TRBJ2-2. Such a TCR can include TRAV12-3, TRAJ15, TRBV20-1, and TRBJ2-7. Such a TCR can include TRAV12-3, TRAJ23, TRBV13, TRBD1, and TRBJ2-3. Such a TCR can include TRAV13-2, TRAJ9, TRBV7-3, and TRBJ1-6. Such a TCR can include TRAV21, TRAJ45, TRBV5-1, and TRBJ1-1. Such a TCR can include TRAV25, TRAJ31, TRBV29-1, TRBD1, and TRBJ1-2. Such a TCR can include TRAV34, TRAJ37, TRBV28, and TRBJ1-1. Such a TCR can include TRAV1-2, TRAJ9, TRBV9, TRBD1, and TRBJ2-6. Such a TCR can include TRAV21, TRAJ36, TRBV9, TRBD1, and TRBJ2-7. Such a TCR can include TRAV12-1, TRAJ34, TRBV6-1, and TRBJ2-7. Such a TCR can include TRAV12-1, TRAJ26, TRBV11-3, TRBD1, and TRBJ1-1. Such a TCR can include TRAV17, TRAJ36, TRBV5-4, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ49, TRBV4-1, TRBD1, and TRBJ1-1. Such a TCR can include TRAV12-1, TRAJ13, TRBV9, TRBD2, and TRBJ2-7. Such a TCR can include TRAV24, TRAJ7, TRBV7-9, TRBD1, and TRBJ2-1.Such a TCR can include TRAV21, TRAJ20, TRBV9, TRBD2, and TRBJ1-1. Such a TCR can include TRAV13-2, TRAJ49, TRBV6-1, TRBD1, and TRBJ2-5. Such a TCR can include TRAV21, TRAJ33, TRBV5-5, TRBD1, and TRBJ1-2. Such a TCR can include TRAV12-1, TRAJ39, TRBV4-2, TRBD2, and TRBJ2-7. Such a TCR can include TRAV26-2, TRAJ30, TRBV9, TRBD1, and TRBJ2-7. Such a TCR can include TRAV20, TRAJ45, TRBV5-4, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ31, TRBV7-8, TRBD2, and TRBJ1-2. Such a TCR can include TRAV38-2DV8, TRAJ48, TRBV2, TRBD1, and TRBJ1-5. Such a TCR can include TRAV25, TRAJ15, TRBV9, TRBD1, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ49, TRBV5-4, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ12, TRBV27, TRBD1, and TRBJ2-2. Such a TCR can include TRAV38-2DV8, TRAJ54, TRBV24-1, and TRBJ2-2. Such a TCR can include TRAV17, TRAJ52, TRBV27, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ28, TRBV9, TRBD2, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ36, TRBV4-1, TRBD1, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ31, TRBV5-4, and TRBJ1-2. Such a TCR can include TRAV21, TRAJ33, TRBV5-1, TRBD1, and TRBJ2-3. Such a TCR can include TRAV12-1, TRAJ43, TRBV6-5, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ41, TRBV9, and TRBJ2-2. Such a TCR can include TRAV19, TRAJ40, TRBV20-1, and TRBJ2-7. Such a TCR can include TRAV12-2, TRAJ52, TRBV6-1, TRBD2, and TRBJ2-7. Such a TCR can include TRAV26-1, TRAJ57, TRBV2, and TRBJ2-7.Such a TCR can include TRAV21, TRAJ36, TRBV12-4, TRBD1, and TRBJ1-6. Such a TCR can include TRAV8-4, TRAJ34, TRBV7-9, and TRBJ2-7. Such a TCR can include TRAV19, TRAJ32, TRBV7-9, and TRBJ1-2. Such a TCR can include TRAV21, TRAJ6, TRBV3-1, TRBD2, and TRBJ1-4. Such a TCR can include TRAV13-2, TRAJ29, TRBV5-1, and TRBJ2-2. Such a TCR can include TRAV14DV4, TRAJ26, TRBV7-9, TRBD1, and TRBJ2-5. Such a TCR can include TRAV35, TRAJ44, TRBV27, TRBD1, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ24, TRBV27, TRBD1, and TRBJ1-6. Such a TCR can include TRAV25, TRAJ21, TRBV28, TRBD1, and TRBJ2-7. Such a TCR can include TRAV3, TRAJ36, TRBV28, and TRBJ1-5. Such a TCR can include TRAV26-2, TRAJ52, TRBV5-6, TRBD2, and TRBJ2-1. Such a TCR can include TRAV8-6, TRAJ40, TRBV9, TRBD1, and TRBJ2-7. Such a TCR can include TRAV21, TRAJ42, TRBV28, TRBD1, and TRBJ2-7. Such a TCR can include TRAV12-1, TRAJ32, TRBV20-1, TRBD1, and TRBJ1-1. Such a TCR can include TRAV24, TRAJ24, TRBV28, TRBD2, and TRBJ2-5. Such a TCR can include TRAV21, TRAJ36, TRBV9, TRBD2, and TRBJ1-1. Such a TCR can include TRAV12-1, TRAJ26, TRBV2, and TRBJ1-6. Such a TCR can include TRAV21, TRAJ31, TRBV29-1, TRBD1, and TRBJ1-1. Such a TCR can include TRAV39, TRAJ33, TRBV6-1, and TRBJ1-5. Such a TCR can include TRAV3, TRAJ38, TRBV27, TRBD2, and TRBJ2-7. Such a TCR can include TRAV10, TRAJ33, TRBV30, TRBD2, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ20, TRBV2, TRBD1, and TRBJ2-1. Such a TCR can include TRAV13-1, TRAJ20, TRBV5-1, TRBD1, and TRBJ1-1.Such a TCR can include TRAV27, TRAJ45, TRBV27, TRBD1, and TRBJ1-6. Such a TCR can include TRAV21, TRAJ18, TRBV9, TRBD1, and TRBJ2-1. Such a TCR can include TRAV26-2, TRAJ28, TRBV27, and TRBJ1-5. Such a TCR can include TRAV12-1, TRAJ34, TRBV9, TRBD2, and TRBJ2-7. Such a TCR can include TRAV13-2, TRAJ40, TRBV4-1, and TRBJ1-3. Such a TCR can include TRAV12-1, TRAJ34, TRBV4-2, TRBD2, and TRBJ2-7. Such a TCR can include TRAV13-2, TRAJ46, TRBV7-9, TRBD1, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ36, TRBV9, TRBD2, and TRBJ2-7. Such a TCR can include TRAV1-2, TRAJ20, TRBV11-3, TRBD1, and TRBJ2-3. Such a TCR can include TRAV3, TRAJ6, TRBV12-4, TRBD1, and TRBJ2-2. Such a TCR can include TRAV25, TRAJ32, TRBV19, TRBD1, and TRBJ1-1. Such a TCR can include TRAV21, TRAJ33, TRBV9, TRBD1, and TRBJ1-1. Such a TCR can include TRAV19, TRAJ53, TRBV7-7, TRBD1, and TRBJ2-1. Such a TCR can include TRAV12-1, TRAJ20, TRBV10-3, TRBD2, and TRBJ2-3. Such a TCR can include TRAV12-1, TRAJ34, TRBV6-5, TRBD1, and TRBJ2-7. Such a TCR can include TRAV26-2, TRAJ43, TRBV25-1, TRBD1, and TRBJ1-2. Such a TCR can include TRAV8-6, TRAJ20, TRBV7-9, TRBD1, and TRBJ2-2. Such a TCR can include TRAV3, TRAJ18, TRBV20-1, TRBD2, and TRBJ2-1. Such a TCR can include TRAV21, TRAJ40, TRBV11-3, TRBD1, and TRBJ1-2. Such a TCR can include TRAV2, TRAJ10, TRBV6-5, TRBD2, and TRBJ2-7.

[0377] TCRs specific for A*01:01_EVDPIGHLY (SEQ ID NO: 3051) can include an a VJ sequence. The a VJ sequence can be any of SEQ ID NOs: 3656-3961 or 4302-4305.

[0378] TCRs specific for A*01:01_EVDPIGHLY (SEQ ID NO: 3051) can include a β V(D)J sequence. The β V(D)J sequence can be any of SEQ ID NOs: 3962-4269 or 4317-4320.

[0379] In some embodiments, the a VJ sequence is SEQ ID NO: 3656 and the β V(D)J sequence is SEQ ID NO: 3962. In some embodiments, the a VJ sequence is SEQ ID NO: 3657 and the β V(D)J sequence is SEQ ID NO: 3963. In some embodiments, the a VJ sequence is SEQ ID NO: 3658 and the β V(D)J sequence is SEQ ID NO: 3964. In some embodiments, the a VJ sequence is SEQ ID NO: 3659 and the β V(D)J sequence is SEQ ID NO: 3963. In some embodiments, the a VJ sequence is SEQ ID NO: 3660 and the β V(D)J sequence is SEQ ID NO: 3965. In some embodiments, the a VJ sequence is SEQ ID NO: 3661 and the β V(D)J sequence is SEQ ID NO: 3966. In some embodiments, the a VJ sequence is SEQ ID NO: 3662 and the β V(D)J sequence is SEQ ID NO: 3967. In some embodiments, the a VJ sequence is SEQ ID NO: 3663 and the β V(D)J sequence is SEQ ID NO: 3968. In some embodiments, the a VJ sequence is SEQ ID NO: 3664 and the β V(D)J sequence is SEQ ID NO: 3969. In some embodiments, the a VJ sequence is SEQ ID NO: 3665 and the β V(D)J sequence is SEQ ID NO: 3970. In some embodiments, the a VJ sequence is SEQ ID NO: 3666 and the β V(D)J sequence is SEQ ID NO: 3971. In some embodiments, the a VJ sequence is SEQ ID NO: 3667 and the β V(D)J sequence is SEQ ID NO: 3972. In some embodiments, the a VJ sequence is SEQ ID NO: 3668 and the β V(D)J sequence is SEQ ID NO: 3973. In some embodiments, the a VJ sequence is SEQ ID NO: 3657 and the β V(D)J sequence is SEQ ID NO: 3962. In some embodiments, the a VJ sequence is SEQ ID NO: 3662 and the β V(D)J sequence is SEQ ID NO: 3963. In some embodiments, the a VJ sequence is SEQ ID NO: 3669 and the β V(D)J sequence is SEQ ID NO: 3974. In some embodiments, the a VJ sequence is SEQ ID NO: 3670 and the β V(D)J sequence is SEQ ID NO: 3975.In some embodiments, the a VJ sequence is SEQ ID NO: 3658 and the b V(D)J sequence is SEQ ID NO: 3963. In some embodiments, the a VJ sequence is SEQ ID NO: 3671 and the b V(D)J sequence is SEQ ID NO: 3976. In some embodiments, the a VJ sequence is SEQ ID NO: 3672 and the b V(D)J sequence is SEQ ID NO: 3977. In some embodiments, the a VJ sequence is SEQ ID NO: 3673 and the b V(D)J sequence is SEQ ID NO: 3978. In some embodiments, the a VJ sequence is SEQ ID NO: 3674 and the b V(D)J sequence is SEQ ID NO: 3979. In some embodiments, the a VJ sequence is SEQ ID NO: 3659 and the b V(D)J sequence is SEQ ID NO: 3967. In some embodiments, the a VJ sequence is SEQ ID NO: 3675 and the b V(D)J sequence is SEQ ID NO: 3980. In some embodiments, the a VJ sequence is SEQ ID NO: 3659 and the b V(D)J sequence is SEQ ID NO: 3966. In some embodiments, the a VJ sequence is SEQ ID NO: 3676 and the b V(D)J sequence is SEQ ID NO: 3981. In some embodiments, the a VJ sequence is SEQ ID NO: 3659 and the b V(D)J sequence is SEQ ID NO: 3964. In some embodiments, the a VJ sequence is SEQ ID NO: 3677 and the b V(D)J sequence is SEQ ID NO: 3982. In some embodiments, the a VJ sequence is SEQ ID NO: 3678 and the b V(D)J sequence is SEQ ID NO: 3983. In some embodiments, the a VJ sequence is SEQ ID NO: 3662 and the b V(D)J sequence is SEQ ID NO: 3962. In some embodiments, the a VJ sequence is SEQ ID NO: 3679 and the b V(D)J sequence is SEQ ID NO: 3984. In some embodiments, the a VJ sequence is SEQ ID NO: 3680 and the b V(D)J sequence is SEQ ID NO: 3985. In some embodiments, the a VJ sequence is SEQ ID NO: 3681 and the b V(D)J sequence is SEQ ID NO: 3986. In some embodiments, the a VJ sequence is SEQ ID NO: 3682 and the b V(D)J sequence is SEQ ID NO: 3987.In some embodiments, the a VJ sequence is SEQ ID NO: 3683 and the β V(D)J sequence is SEQ ID NO: 3988. In some embodiments, the a VJ sequence is SEQ ID NO: 3684 and the β V(D)J sequence is SEQ ID NO: 3989. In some embodiments, the a VJ sequence is SEQ ID NO: 3685 and the β V(D)J sequence is SEQ ID NO: 3990. In some embodiments, the a VJ sequence is SEQ ID NO: 3686 and the β V(D)J sequence is SEQ ID NO: 3991. In some embodiments, the a VJ sequence is SEQ ID NO: 3687 and the β V(D)J sequence is SEQ ID NO: 3992. In some embodiments, the a VJ sequence is SEQ ID NO: 3688 and the β V(D)J sequence is SEQ ID NO: 3993. In some embodiments, the a VJ sequence is SEQ ID NO: 3689 and the β V(D)J sequence is SEQ ID NO: 3994. In some embodiments, the a VJ sequence is SEQ ID NO: 3690 and the β V(D)J sequence is SEQ ID NO: 3995. In some embodiments, the a VJ sequence is SEQ ID NO: 3691 and the β V(D)J sequence is SEQ ID NO: 3996. In some embodiments, the a VJ sequence is SEQ ID NO: 3692 and the β V(D)J sequence is SEQ ID NO: 3997. In some embodiments, the a VJ sequence is SEQ ID NO: 3693 and the β V(D)J sequence is SEQ ID NO: 3998. In some embodiments, the a VJ sequence is SEQ ID NO: 3694 and the β V(D)J sequence is SEQ ID NO: 3999. In some embodiments, the a VJ sequence is SEQ ID NO: 3695 and the β V(D)J sequence is SEQ ID NO: 4000. In some embodiments, the a VJ sequence is SEQ ID NO: 3661 and the β V(D)J sequence is SEQ ID NO: 3962. In some embodiments, the a VJ sequence is SEQ ID NO: 3696 and the β V(D)J sequence is SEQ ID NO: 4001. In some embodiments, the a VJ sequence is SEQ ID NO: 3697 and the β V(D)J sequence is SEQ ID NO: 4002. In some embodiments, the a VJ sequence is SEQ ID NO: 3698 and the β V(D)J sequence is SEQ ID NO: 4003.In some embodiments, the a VJ sequence is SEQ ID NO: 3699 and the β V(D)J sequence is SEQ ID NO: 4004. In some embodiments, the a VJ sequence is SEQ ID NO: 3700 and the β V(D)J sequence is SEQ ID NO: 3967. In some embodiments, the a VJ sequence is SEQ ID NO: 3701 and the β V(D)J sequence is SEQ ID NO: 4005. In some embodiments, the a VJ sequence is SEQ ID NO: 3658 and the β V(D)J sequence is SEQ ID NO: 3974. In some embodiments, the a VJ sequence is SEQ ID NO: 3702 and the β V(D)J sequence is SEQ ID NO: 4006. In some embodiments, the a VJ sequence is SEQ ID NO: 3658 and the β V(D)J sequence is SEQ ID NO: 3962. In some embodiments, the a VJ sequence is SEQ ID NO: 3703 and the β V(D)J sequence is SEQ ID NO: 4007. In some embodiments, the a VJ sequence is SEQ ID NO: 3657 and the β V(D)J sequence is SEQ ID NO: 3966. In some embodiments, the a VJ sequence is SEQ ID NO: 3704 and the β V(D)J sequence is SEQ ID NO: 4008. In some embodiments, the a VJ sequence is SEQ ID NO: 3705 and the β V(D)J sequence is SEQ ID NO: 4009. In some embodiments, the a VJ sequence is SEQ ID NO: 3706 and the β V(D)J sequence is SEQ ID NO: 3963. In some embodiments, the a VJ sequence is SEQ ID NO: 3707 and the β V(D)J sequence is SEQ ID NO: 4010. In some embodiments, the a VJ sequence is SEQ ID NO: 3657 and the β V(D)J sequence is SEQ ID NO: 3964. In some embodiments, the a VJ sequence is SEQ ID NO: 3708 and the β V(D)J sequence is SEQ ID NO: 4011. In some embodiments, the a VJ sequence is SEQ ID NO: 3709 and the β V(D)J sequence is SEQ ID NO: 4012. In some embodiments, the a VJ sequence is SEQ ID NO: 3663 and the β V(D)J sequence is SEQ ID NO: 3963. In some embodiments, the a VJ sequence is SEQ ID NO: 3710 and the β V(D)J sequence is SEQ ID NO: 4013.In some embodiments, the a VJ sequence is SEQ ID NO: 3711 and the β V(D)J sequence is SEQ ID NO: 4014. In some embodiments, the a VJ sequence is SEQ ID NO: 3712 and the β V(D)J sequence is SEQ ID NO: 4015. In some embodiments, the a VJ sequence is SEQ ID NO: 3713 and the β V(D)J sequence is SEQ ID NO: 4016. In some embodiments, the a VJ sequence is SEQ ID NO: 3714 and the β V(D)J sequence is SEQ ID NO: 4017. In some embodiments, the a VJ sequence is SEQ ID NO: 3715 and the β V(D)J sequence is SEQ ID NO: 4018. In some embodiments, the a VJ sequence is SEQ ID NO: 3716 and the β V(D)J sequence is SEQ ID NO: 4019. In some embodiments, the a VJ sequence is SEQ ID NO: 3717 and the β V(D)J sequence is SEQ ID NO: 4020. In some embodiments, the a VJ sequence is SEQ ID NO: 3718 and the β V(D)J sequence is SEQ ID NO: 4021. In some embodiments, the a VJ sequence is SEQ ID NO: 3719 and the β V(D)J sequence is SEQ ID NO: 4022. In some embodiments, the a VJ sequence is SEQ ID NO: 3720 and the β V(D)J sequence is SEQ ID NO: 4023. In some embodiments, the a VJ sequence is SEQ ID NO: 3663 and the β V(D)J sequence is SEQ ID NO: 3962. In some embodiments, the a VJ sequence is SEQ ID NO: 3659 and the β V(D)J sequence is SEQ ID NO: 3965. In some embodiments, the a VJ sequence is SEQ ID NO: 3677 and the β V(D)J sequence is SEQ ID NO: 4024. In some embodiments, the a VJ sequence is SEQ ID NO: 3721 and the β V(D)J sequence is SEQ ID NO: 4025. In some embodiments, the a VJ sequence is SEQ ID NO: 3722 and the β V(D)J sequence is SEQ ID NO: 4026. In some embodiments, the a VJ sequence is SEQ ID NO: 3663 and the β V(D)J sequence is SEQ ID NO: 3966. In some embodiments, the a VJ sequence is SEQ ID NO: 3659 and the β V(D)J sequence is SEQ ID NO: 4027.In some embodiments, the a VJ sequence is SEQ ID NO: 3722 and the b V(D)J sequence is SEQ ID NO: 3964. In some embodiments, the a VJ sequence is SEQ ID NO: 3723 and the b V(D)J sequence is SEQ ID NO: 4028. In some embodiments, the a VJ sequence is SEQ ID NO: 3724 and the b V(D)J sequence is SEQ ID NO: 4029. In some embodiments, the a VJ sequence is SEQ ID NO: 3725 and the b V(D)J sequence is SEQ ID NO: 4030. In some embodiments, the a VJ sequence is SEQ ID NO: 3726 and the b V(D)J sequence is SEQ ID NO: 4031. In some embodiments, the a VJ sequence is SEQ ID NO: 3727 and the b V(D)J sequence is SEQ ID NO: 4032. In some embodiments, the a VJ sequence is SEQ ID NO: 3728 and the b V(D)J sequence is SEQ ID NO: 4033. In some embodiments, the a VJ sequence is SEQ ID NO: 3729 and the b V(D)J sequence is SEQ ID NO: 4034. In some embodiments, the a VJ sequence is SEQ ID NO: 3658 and the b V(D)J sequence is SEQ ID NO: 3978. In some embodiments, the a VJ sequence is SEQ ID NO: 3730 and the b V(D)J sequence is SEQ ID NO: 4035. In some embodiments, the a VJ sequence is SEQ ID NO: 3731 and the b V(D)J sequence is SEQ ID NO: 4036. In some embodiments, the a VJ sequence is SEQ ID NO: 3732 and the b V(D)J sequence is SEQ ID NO: 4037. In some embodiments, the a VJ sequence is SEQ ID NO: 3719 and the b V(D)J sequence is SEQ ID NO: 3962. In some embodiments, the a VJ sequence is SEQ ID NO: 3665 and the b V(D)J sequence is SEQ ID NO: 3963. In some embodiments, the a VJ sequence is SEQ ID NO: 3664 and the b V(D)J sequence is SEQ ID NO: 3962. In some embodiments, the a VJ sequence is SEQ ID NO: 3676 and the b V(D)J sequence is SEQ ID NO: 3966. In some embodiments, the a VJ sequence is SEQ ID NO: 3733 and the b V(D)J sequence is SEQ ID NO: 4038.In some embodiments, the a VJ sequence is SEQ ID NO: 3734 and the β V(D)J sequence is SEQ ID NO: 4039. In some embodiments, the a VJ sequence is SEQ ID NO: 3735 and the β V(D)J sequence is SEQ ID NO: 4040. In some embodiments, the a VJ sequence is SEQ ID NO: 3736 and the β V(D)J sequence is SEQ ID NO: 4041. In some embodiments, the a VJ sequence is SEQ ID NO: 3737 and the β V(D)J sequence is SEQ ID NO: 4042. In some embodiments, the a VJ sequence is SEQ ID NO: 3738 and the β V(D)J sequence is SEQ ID NO: 3963. In some embodiments, the a VJ sequence is SEQ ID NO: 3659 and the β V(D)J sequence is SEQ ID NO: 3973. In some embodiments, the a VJ sequence is SEQ ID NO: 3660 and the β V(D)J sequence is SEQ ID NO: 3963. In some embodiments, the a VJ sequence is SEQ ID NO: 3739 and the β V(D)J sequence is SEQ ID NO: 4043. In some embodiments, the a VJ sequence is SEQ ID NO: 3740 and the β V(D)J sequence is SEQ ID NO: 4044. In some embodiments, the a VJ sequence is SEQ ID NO: 3741 and the β V(D)J sequence is SEQ ID NO: 4045. In some embodiments, the a VJ sequence is SEQ ID NO: 3657 and the β V(D)J sequence is SEQ ID NO: 3992. In some embodiments, the a VJ sequence is SEQ ID NO: 3742 and the β V(D)J sequence is SEQ ID NO: 4046. In some embodiments, the a VJ sequence is SEQ ID NO: 3666 and the β V(D)J sequence is SEQ ID NO: 3962. In some embodiments, the a VJ sequence is SEQ ID NO: 3711 and the β V(D)J sequence is SEQ ID NO: 3963. In some embodiments, the a VJ sequence is SEQ ID NO: 3660 and the β V(D)J sequence is SEQ ID NO: 3962. In some embodiments, the a VJ sequence is SEQ ID NO: 3663 and the β V(D)J sequence is SEQ ID NO: 3964. In some embodiments, the a VJ sequence is SEQ ID NO: 3743 and the β V(D)J sequence is SEQ ID NO: 4047.In some embodiments, the a VJ sequence is SEQ ID NO: 3744 and the β V(D)J sequence is SEQ ID NO: 4048. In some embodiments, the a VJ sequence is SEQ ID NO: 3745 and the β V(D)J sequence is SEQ ID NO: 4049. In some embodiments, the a VJ sequence is SEQ ID NO: 3746 and the β V(D)J sequence is SEQ ID NO: 4050. In some embodiments, the a VJ sequence is SEQ ID NO: 3747 and the β V(D)J sequence is SEQ ID NO: 4051. In some embodiments, the a VJ sequence is SEQ ID NO: 3748 and the β V(D)J sequence is SEQ ID NO: 4052. In some embodiments, the a VJ sequence is SEQ ID NO: 3749 and the β V(D)J sequence is SEQ ID NO: 4053. In some embodiments, the a VJ sequence is SEQ ID NO: 3750 and the β V(D)J sequence is SEQ ID NO: 4054. In some embodiments, the a VJ sequence is SEQ ID NO: 3751 and the β V(D)J sequence is SEQ ID NO: 4055. In some embodiments, the a VJ sequence is SEQ ID NO: 3752 and the β V(D)J sequence is SEQ ID NO: 4056. In some embodiments, the a VJ sequence is SEQ ID NO: 3753 and the β V(D)J sequence is SEQ ID NO: 4057. In some embodiments, the a VJ sequence is SEQ ID NO: 3754 and the β V(D)J sequence is SEQ ID NO: 4058. In some embodiments, the a VJ sequence is SEQ ID NO: 3755 and the β V(D)J sequence is SEQ ID NO: 4057. In some embodiments, the a VJ sequence is SEQ ID NO: 3756 and the β V(D)J sequence is SEQ ID NO: 4059. In some embodiments, the a VJ sequence is SEQ ID NO: 3757 and the β V(D)J sequence is SEQ ID NO: 4060. In some embodiments, the a VJ sequence is SEQ ID NO: 3758 and the β V(D)J sequence is SEQ ID NO: 4061. In some embodiments, the a VJ sequence is SEQ ID NO: 3759 and the β V(D)J sequence is SEQ ID NO: 4062. In some embodiments, the a VJ sequence is SEQ ID NO: 3760 and the β V(D)J sequence is SEQ ID NO: 4063.In some embodiments, the a VJ sequence is SEQ ID NO: 3761 and the b V(D)J sequence is SEQ ID NO: 4049. In some embodiments, the a VJ sequence is SEQ ID NO: 3748 and the b V(D)J sequence is SEQ ID NO: 4049. In some embodiments, the a VJ sequence is SEQ ID NO: 3762 and the b V(D)J sequence is SEQ ID NO: 4064. In some embodiments, the a VJ sequence is SEQ ID NO: 3763 and the b V(D)J sequence is SEQ ID NO: 4065. In some embodiments, the a VJ sequence is SEQ ID NO: 3764 and the b V(D)J sequence is SEQ ID NO: 4066. In some embodiments, the a VJ sequence is SEQ ID NO: 3765 and the b V(D)J sequence is SEQ ID NO: 4067. In some embodiments, the a VJ sequence is SEQ ID NO: 3746 and the b V(D)J sequence is SEQ ID NO: 4053. In some embodiments, the a VJ sequence is SEQ ID NO: 3766 and the b V(D)J sequence is SEQ ID NO: 4068. In some embodiments, the a VJ sequence is SEQ ID NO: 3761 and the b V(D)J sequence is SEQ ID NO: 4069. In some embodiments, the a VJ sequence is SEQ ID NO: 3767 and the b V(D)J sequence is SEQ ID NO: 4070. In some embodiments, the a VJ sequence is SEQ ID NO: 3768 and the b V(D)J sequence is SEQ ID NO: 4071. In some embodiments, the a VJ sequence is SEQ ID NO: 3769 and the b V(D)J sequence is SEQ ID NO: 4072. In some embodiments, the a VJ sequence is SEQ ID NO: 3770 and the b V(D)J sequence is SEQ ID NO: 4073. In some embodiments, the a VJ sequence is SEQ ID NO: 3771 and the b V(D)J sequence is SEQ ID NO: 4074. In some embodiments, the a VJ sequence is SEQ ID NO: 3772 and the b V(D)J sequence is SEQ ID NO: 4075. In some embodiments, the a VJ sequence is SEQ ID NO: 3773 and the b V(D)J sequence is SEQ ID NO: 4076. In some embodiments, the a VJ sequence is SEQ ID NO: 3774 and the b V(D)J sequence is SEQ ID NO: 4077.In some embodiments, the a VJ sequence is SEQ ID NO: 3775 and the b V(D)J sequence is SEQ ID NO: 4078. In some embodiments, the a VJ sequence is SEQ ID NO: 3746 and the b V(D)J sequence is SEQ ID NO: 4055. In some embodiments, the a VJ sequence is SEQ ID NO: 3745 and the b V(D)J sequence is SEQ ID NO: 4051. In some embodiments, the a VJ sequence is SEQ ID NO: 3776 and the b V(D)J sequence is SEQ ID NO: 4079. In some embodiments, the a VJ sequence is SEQ ID NO: 3777 and the b V(D)J sequence is SEQ ID NO: 4080. In some embodiments, the a VJ sequence is SEQ ID NO: 3778 and the b V(D)J sequence is SEQ ID NO: 4081. In some embodiments, the a VJ sequence is SEQ ID NO: 3779 and the b V(D)J sequence is SEQ ID NO: 4082. In some embodiments, the a VJ sequence is SEQ ID NO: 3780 and the b V(D)J sequence is SEQ ID NO: 4083. In some embodiments, the a VJ sequence is SEQ ID NO: 3746 and the b V(D)J sequence is SEQ ID NO: 4049. In some embodiments, the a VJ sequence is SEQ ID NO: 3781 and the b V(D)J sequence is SEQ ID NO: 4084. In some embodiments, the a VJ sequence is SEQ ID NO: 3782 and the b V(D)J sequence is SEQ ID NO: 4085. In some embodiments, the a VJ sequence is SEQ ID NO: 3783 and the b V(D)J sequence is SEQ ID NO: 4086. In some embodiments, the a VJ sequence is SEQ ID NO: 3784 and the b V(D)J sequence is SEQ ID NO: 4087. In some embodiments, the a VJ sequence is SEQ ID NO: 3785 and the b V(D)J sequence is SEQ ID NO: 4088. In some embodiments, the a VJ sequence is SEQ ID NO: 3786 and the b V(D)J sequence is SEQ ID NO: 4089. In some embodiments, the a VJ sequence is SEQ ID NO: 3787 and the b V(D)J sequence is SEQ ID NO: 4090. In some embodiments, the a VJ sequence is SEQ ID NO: 3788 and the b V(D)J sequence is SEQ ID NO: 4091.In some embodiments, the a VJ sequence is SEQ ID NO: 3789 and the β V(D)J sequence is SEQ ID NO: 4092. In some embodiments, the a VJ sequence is SEQ ID NO: 3790 and the β V(D)J sequence is SEQ ID NO: 4093. In some embodiments, the a VJ sequence is SEQ ID NO: 3791 and the β V(D)J sequence is SEQ ID NO: 4094. In some embodiments, the a VJ sequence is SEQ ID NO: 3755 and the β V(D)J sequence is SEQ ID NO: 4095. In some embodiments, the a VJ sequence is SEQ ID NO: 3792 and the β V(D)J sequence is SEQ ID NO: 4096. In some embodiments, the a VJ sequence is SEQ ID NO: 3793 and the β V(D)J sequence is SEQ ID NO: 4097. In some embodiments, the a VJ sequence is SEQ ID NO: 3794 and the β V(D)J sequence is SEQ ID NO: 4098. In some embodiments, the a VJ sequence is SEQ ID NO: 3795 and the β V(D)J sequence is SEQ ID NO: 4099. In some embodiments, the a VJ sequence is SEQ ID NO: 3796 and the β V(D)J sequence is SEQ ID NO: 4100. In some embodiments, the a VJ sequence is SEQ ID NO: 3797 and the β V(D)J sequence is SEQ ID NO: 4101. In some embodiments, the a VJ sequence is SEQ ID NO: 3798 and the β V(D)J sequence is SEQ ID NO: 4102. In some embodiments, the a VJ sequence is SEQ ID NO: 3799 and the β V(D)J sequence is SEQ ID NO: 4095. In some embodiments, the a VJ sequence is SEQ ID NO: 3800 and the β V(D)J sequence is SEQ ID NO: 4103. In some embodiments, the a VJ sequence is SEQ ID NO: 3801 and the β V(D)J sequence is SEQ ID NO: 4104. In some embodiments, the a VJ sequence is SEQ ID NO: 3802 and the β V(D)J sequence is SEQ ID NO: 4105. In some embodiments, the a VJ sequence is SEQ ID NO: 3803 and the β V(D)J sequence is SEQ ID NO: 4106. In some embodiments, the a VJ sequence is SEQ ID NO: 3804 and the β V(D)J sequence is SEQ ID NO: 4107.In some embodiments, the a VJ sequence is SEQ ID NO: 3805 and the β V(D)J sequence is SEQ ID NO: 4108. In some embodiments, the a VJ sequence is SEQ ID NO: 3806 and the β V(D)J sequence is SEQ ID NO: 4109. In some embodiments, the a VJ sequence is SEQ ID NO: 3807 and the β V(D)J sequence is SEQ ID NO: 4110. In some embodiments, the a VJ sequence is SEQ ID NO: 3808 and the β V(D)J sequence is SEQ ID NO: 4111. In some embodiments, the a VJ sequence is SEQ ID NO: 3809 and the β V(D)J sequence is SEQ ID NO: 4112. In some embodiments, the a VJ sequence is SEQ ID NO: 3810 and the β V(D)J sequence is SEQ ID NO: 4113. In some embodiments, the a VJ sequence is SEQ ID NO: 3746 and the β V(D)J sequence is SEQ ID NO: 4062. In some embodiments, the a VJ sequence is SEQ ID NO: 3811 and the β V(D)J sequence is SEQ ID NO: 4049. In some embodiments, the a VJ sequence is SEQ ID NO: 3812 and the β V(D)J sequence is SEQ ID NO: 4114. In some embodiments, the a VJ sequence is SEQ ID NO: 3747 and the β V(D)J sequence is SEQ ID NO: 4049. In some embodiments, the a VJ sequence is SEQ ID NO: 3813 and the β V(D)J sequence is SEQ ID NO: 4115. In some embodiments, the a VJ sequence is SEQ ID NO: 3814 and the β V(D)J sequence is SEQ ID NO: 4116. In some embodiments, the a VJ sequence is SEQ ID NO: 3815 and the β V(D)J sequence is SEQ ID NO: 4117. In some embodiments, the a VJ sequence is SEQ ID NO: 3816 and the β V(D)J sequence is SEQ ID NO: 4118. In some embodiments, the a VJ sequence is SEQ ID NO: 3817 and the β V(D)J sequence is SEQ ID NO: 4119. In some embodiments, the a VJ sequence is SEQ ID NO: 3818 and the β V(D)J sequence is SEQ ID NO: 4120. In some embodiments, the a VJ sequence is SEQ ID NO: 3758 and the β V(D)J sequence is SEQ ID NO: 4053.In some embodiments, the a VJ sequence is SEQ ID NO: 3819 and the β V(D)J sequence is SEQ ID NO: 4121. In some embodiments, the a VJ sequence is SEQ ID NO: 3820 and the β V(D)J sequence is SEQ ID NO: 4122. In some embodiments, the a VJ sequence is SEQ ID NO: 3821 and the β V(D)J sequence is SEQ ID NO: 4123. In some embodiments, the a VJ sequence is SEQ ID NO: 3822 and the β V(D)J sequence is SEQ ID NO: 4124. In some embodiments, the a VJ sequence is SEQ ID NO: 3823 and the β V(D)J sequence is SEQ ID NO: 4125. In some embodiments, the a VJ sequence is SEQ ID NO: 3824 and the β V(D)J sequence is SEQ ID NO: 4126. In some embodiments, the a VJ sequence is SEQ ID NO: 3825 and the β V(D)J sequence is SEQ ID NO: 4127. In some embodiments, the a VJ sequence is SEQ ID NO: 3826 and the β V(D)J sequence is SEQ ID NO: 4128. In some embodiments, the a VJ sequence is SEQ ID NO: 3827 and the β V(D)J sequence is SEQ ID NO: 4129. In some embodiments, the a VJ sequence is SEQ ID NO: 3828 and the β V(D)J sequence is SEQ ID NO: 4130. In some embodiments, the a VJ sequence is SEQ ID NO: 3829 and the β V(D)J sequence is SEQ ID NO: 4131. In some embodiments, the a VJ sequence is SEQ ID NO: 3830 and the β V(D)J sequence is SEQ ID NO: 4132. In some embodiments, the a VJ sequence is SEQ ID NO: 3831 and the β V(D)J sequence is SEQ ID NO: 4133. In some embodiments, the a VJ sequence is SEQ ID NO: 3832 and the β V(D)J sequence is SEQ ID NO: 4134. In some embodiments, the a VJ sequence is SEQ ID NO: 3828 and the β V(D)J sequence is SEQ ID NO: 4131. In some embodiments, the a VJ sequence is SEQ ID NO: 3833 and the β V(D)J sequence is SEQ ID NO: 4135. In some embodiments, the a VJ sequence is SEQ ID NO: 3834 and the β V(D)J sequence is SEQ ID NO: 4136.In some embodiments, the a VJ sequence is SEQ ID NO: 3835 and the β V(D)J sequence is SEQ ID NO: 4137. In some embodiments, the a VJ sequence is SEQ ID NO: 3836 and the β V(D)J sequence is SEQ ID NO: 4138. In some embodiments, the a VJ sequence is SEQ ID NO: 3837 and the β V(D)J sequence is SEQ ID NO: 4139. In some embodiments, the a VJ sequence is SEQ ID NO: 3838 and the β V(D)J sequence is SEQ ID NO: 4140. In some embodiments, the a VJ sequence is SEQ ID NO: 3839 and the β V(D)J sequence is SEQ ID NO: 4141. In some embodiments, the a VJ sequence is SEQ ID NO: 3840 and the β V(D)J sequence is SEQ ID NO: 4142. In some embodiments, the a VJ sequence is SEQ ID NO: 3841 and the β V(D)J sequence is SEQ ID NO: 4143. In some embodiments, the a VJ sequence is SEQ ID NO: 3828 and the β V(D)J sequence is SEQ ID NO: 4138. In some embodiments, the a VJ sequence is SEQ ID NO: 3842 and the β V(D)J sequence is SEQ ID NO: 4144. In some embodiments, the a VJ sequence is SEQ ID NO: 3843 and the β V(D)J sequence is SEQ ID NO: 4145. In some embodiments, the a VJ sequence is SEQ ID NO: 3844 and the β V(D)J sequence is SEQ ID NO: 4133. In some embodiments, the a VJ sequence is SEQ ID NO: 3828 and the β V(D)J sequence is SEQ ID NO: 4143. In some embodiments, the a VJ sequence is SEQ ID NO: 3845 and the β V(D)J sequence is SEQ ID NO: 4146. In some embodiments, the a VJ sequence is SEQ ID NO: 3846 and the β V(D)J sequence is SEQ ID NO: 4147. In some embodiments, the a VJ sequence is SEQ ID NO: 3828 and the β V(D)J sequence is SEQ ID NO: 4145. In some embodiments, the a VJ sequence is SEQ ID NO: 3847 and the β V(D)J sequence is SEQ ID NO: 4148. In some embodiments, the a VJ sequence is SEQ ID NO: 3848 and the β V(D)J sequence is SEQ ID NO: 4149.In some embodiments, the a VJ sequence is SEQ ID NO: 3849 and the b V(D)J sequence is SEQ ID NO: 4150. In some embodiments, the a VJ sequence is SEQ ID NO: 3850 and the b V(D)J sequence is SEQ ID NO: 4151. In some embodiments, the a VJ sequence is SEQ ID NO: 3851 and the b V(D)J sequence is SEQ ID NO: 4152. In some embodiments, the a VJ sequence is SEQ ID NO: 3852 and the b V(D)J sequence is SEQ ID NO: 4153. In some embodiments, the a VJ sequence is SEQ ID NO: 3853 and the b V(D)J sequence is SEQ ID NO: 4154. In some embodiments, the a VJ sequence is SEQ ID NO: 3854 and the b V(D)J sequence is SEQ ID NO: 4155. In some embodiments, the a VJ sequence is SEQ ID NO: 3855 and the b V(D)J sequence is SEQ ID NO: 4156. In some embodiments, the a VJ sequence is SEQ ID NO: 3831 and the b V(D)J sequence is SEQ ID NO: 4157. In some embodiments, the a VJ sequence is SEQ ID NO: 3856 and the b V(D)J sequence is SEQ ID NO: 4158. In some embodiments, the a VJ sequence is SEQ ID NO: 3857 and the b V(D)J sequence is SEQ ID NO: 4159. In some embodiments, the a VJ sequence is SEQ ID NO: 3858 and the b V(D)J sequence is SEQ ID NO: 4160. In some embodiments, the a VJ sequence is SEQ ID NO: 3859 and the b V(D)J sequence is SEQ ID NO: 4161. In some embodiments, the a VJ sequence is SEQ ID NO: 3828 and the b V(D)J sequence is SEQ ID NO: 4137. In some embodiments, the a VJ sequence is SEQ ID NO: 3860 and the b V(D)J sequence is SEQ ID NO: 4162. In some embodiments, the a VJ sequence is SEQ ID NO: 3861 and the b V(D)J sequence is SEQ ID NO: 4163. In some embodiments, the a VJ sequence is SEQ ID NO: 3862 and the b V(D)J sequence is SEQ ID NO: 4164. In some embodiments, the a VJ sequence is SEQ ID NO: 3863 and the b V(D)J sequence is SEQ ID NO: 4165.In some embodiments, the a VJ sequence is SEQ ID NO: 3864 and the β V(D)J sequence is SEQ ID NO: 4166. In some embodiments, the a VJ sequence is SEQ ID NO: 3865 and the β V(D)J sequence is SEQ ID NO: 4167. In some embodiments, the a VJ sequence is SEQ ID NO: 3866 and the β V(D)J sequence is SEQ ID NO: 4168. In some embodiments, the a VJ sequence is SEQ ID NO: 3867 and the β V(D)J sequence is SEQ ID NO: 4169. In some embodiments, the a VJ sequence is SEQ ID NO: 3868 and the β V(D)J sequence is SEQ ID NO: 4170. In some embodiments, the a VJ sequence is SEQ ID NO: 3869 and the β V(D)J sequence is SEQ ID NO: 4171. In some embodiments, the a VJ sequence is SEQ ID NO: 3870 and the β V(D)J sequence is SEQ ID NO: 4172. In some embodiments, the a VJ sequence is SEQ ID NO: 3871 and the β V(D)J sequence is SEQ ID NO: 4173. In some embodiments, the a VJ sequence is SEQ ID NO: 3828 and the β V(D)J sequence is SEQ ID NO: 4132. In some embodiments, the a VJ sequence is SEQ ID NO: 3872 and the β V(D)J sequence is SEQ ID NO: 4174. In some embodiments, the a VJ sequence is SEQ ID NO: 3873 and the β V(D)J sequence is SEQ ID NO: 4175. In some embodiments, the a VJ sequence is SEQ ID NO: 3828 and the β V(D)J sequence is SEQ ID NO: 4176. In some embodiments, the a VJ sequence is SEQ ID NO: 3874 and the β V(D)J sequence is SEQ ID NO: 4177. In some embodiments, the a VJ sequence is SEQ ID NO: 3875 and the β V(D)J sequence is SEQ ID NO: 4178. In some embodiments, the a VJ sequence is SEQ ID NO: 3876 and the β V(D)J sequence is SEQ ID NO: 4179. In some embodiments, the a VJ sequence is SEQ ID NO: 3877 and the β V(D)J sequence is SEQ ID NO: 4180. In some embodiments, the a VJ sequence is SEQ ID NO: 3878 and the β V(D)J sequence is SEQ ID NO: 4181.In some embodiments, the a VJ sequence is SEQ ID NO: 3879 and the β V(D)J sequence is SEQ ID NO: 4182. In some embodiments, the a VJ sequence is SEQ ID NO: 3828 and the β V(D)J sequence is SEQ ID NO: 4141. In some embodiments, the a VJ sequence is SEQ ID NO: 3880 and the β V(D)J sequence is SEQ ID NO: 4183. In some embodiments, the a VJ sequence is SEQ ID NO: 3828 and the β V(D)J sequence is SEQ ID NO: 4184. In some embodiments, the a VJ sequence is SEQ ID NO: 3881 and the β V(D)J sequence is SEQ ID NO: 4185. In some embodiments, the a VJ sequence is SEQ ID NO: 3830 and the β V(D)J sequence is SEQ ID NO: 4135. In some embodiments, the a VJ sequence is SEQ ID NO: 3882 and the β V(D)J sequence is SEQ ID NO: 4186. In some embodiments, the a VJ sequence is SEQ ID NO: 3883 and the β V(D)J sequence is SEQ ID NO: 4187. In some embodiments, the a VJ sequence is SEQ ID NO: 3884 and the β V(D)J sequence is SEQ ID NO: 4188. In some embodiments, the a VJ sequence is SEQ ID NO: 3885 and the β V(D)J sequence is SEQ ID NO: 4189. In some embodiments, the a VJ sequence is SEQ ID NO: 3828 and the β V(D)J sequence is SEQ ID NO: 4190. In some embodiments, the a VJ sequence is SEQ ID NO: 3841 and the β V(D)J sequence is SEQ ID NO: 4130. In some embodiments, the a VJ sequence is SEQ ID NO: 3886 and the β V(D)J sequence is SEQ ID NO: 4191. In some embodiments, the a VJ sequence is SEQ ID NO: 3887 and the β V(D)J sequence is SEQ ID NO: 4192. In some embodiments, the a VJ sequence is SEQ ID NO: 3888 and the β V(D)J sequence is SEQ ID NO: 4193. In some embodiments, the a VJ sequence is SEQ ID NO: 3889 and the β V(D)J sequence is SEQ ID NO: 4194. In some embodiments, the a VJ sequence is SEQ ID NO: 3890 and the β V(D)J sequence is SEQ ID NO: 4195.In some embodiments, the a VJ sequence is SEQ ID NO: 3891 and the β V(D)J sequence is SEQ ID NO: 4196. In some embodiments, the a VJ sequence is SEQ ID NO: 3892 and the β V(D)J sequence is SEQ ID NO: 4197. In some embodiments, the a VJ sequence is SEQ ID NO: 3893 and the β V(D)J sequence is SEQ ID NO: 4198. In some embodiments, the a VJ sequence is SEQ ID NO: 3894 and the β V(D)J sequence is SEQ ID NO: 4199. In some embodiments, the a VJ sequence is SEQ ID NO: 3895 and the β V(D)J sequence is SEQ ID NO: 4200. In some embodiments, the a VJ sequence is SEQ ID NO: 3896 and the β V(D)J sequence is SEQ ID NO: 4201. In some embodiments, the a VJ sequence is SEQ ID NO: 3897 and the β V(D)J sequence is SEQ ID NO: 4202. In some embodiments, the a VJ sequence is SEQ ID NO: 3898 and the β V(D)J sequence is SEQ ID NO: 4203. In some embodiments, the a VJ sequence is SEQ ID NO: 3899 and the β V(D)J sequence is SEQ ID NO: 4204. In some embodiments, the a VJ sequence is SEQ ID NO: 3900 and the β V(D)J sequence is SEQ ID NO: 4205. In some embodiments, the a VJ sequence is SEQ ID NO: 3901 and the β V(D)J sequence is SEQ ID NO: 4206. In some embodiments, the a VJ sequence is SEQ ID NO: 3902 and the β V(D)J sequence is SEQ ID NO: 4207. In some embodiments, the a VJ sequence is SEQ ID NO: 3903 and the β V(D)J sequence is SEQ ID NO: 4208. In some embodiments, the a VJ sequence is SEQ ID NO: 3904 and the β V(D)J sequence is SEQ ID NO: 4209. In some embodiments, the a VJ sequence is SEQ ID NO: 3905 and the β V(D)J sequence is SEQ ID NO: 4210. In some embodiments, the a VJ sequence is SEQ ID NO: 3830 and the β V(D)J sequence is SEQ ID NO: 4211. In some embodiments, the a VJ sequence is SEQ ID NO: 3906 and the β V(D)J sequence is SEQ ID NO: 4212.In some embodiments, the a VJ sequence is SEQ ID NO: 3828 and the β V(D)J sequence is SEQ ID NO: 4213. In some embodiments, the a VJ sequence is SEQ ID NO: 3907 and the β V(D)J sequence is SEQ ID NO: 4214. In some embodiments, the a VJ sequence is SEQ ID NO: 3908 and the β V(D)J sequence is SEQ ID NO: 4215. In some embodiments, the a VJ sequence is SEQ ID NO: 3909 and the β V(D)J sequence is SEQ ID NO: 4216. In some embodiments, the a VJ sequence is SEQ ID NO: 3910 and the β V(D)J sequence is SEQ ID NO: 4217. In some embodiments, the a VJ sequence is SEQ ID NO: 3911 and the β V(D)J sequence is SEQ ID NO: 4218. In some embodiments, the a VJ sequence is SEQ ID NO: 3912 and the β V(D)J sequence is SEQ ID NO: 4219. In some embodiments, the a VJ sequence is SEQ ID NO: 3913 and the β V(D)J sequence is SEQ ID NO: 4220. In some embodiments, the a VJ sequence is SEQ ID NO: 3914 and the β V(D)J sequence is SEQ ID NO: 4221. In some embodiments, the a VJ sequence is SEQ ID NO: 3915 and the β V(D)J sequence is SEQ ID NO: 4222. In some embodiments, the a VJ sequence is SEQ ID NO: 3916 and the β V(D)J sequence is SEQ ID NO: 4223. In some embodiments, the a VJ sequence is SEQ ID NO: 3917 and the β V(D)J sequence is SEQ ID NO: 4224. In some embodiments, the a VJ sequence is SEQ ID NO: 3899 and the β V(D)J sequence is SEQ ID NO: 4208. In some embodiments, the a VJ sequence is SEQ ID NO: 3918 and the β V(D)J sequence is SEQ ID NO: 4225. In some embodiments, the a VJ sequence is SEQ ID NO: 3919 and the β V(D)J sequence is SEQ ID NO: 4226. In some embodiments, the a VJ sequence is SEQ ID NO: 3920 and the β V(D)J sequence is SEQ ID NO: 4227. In some embodiments, the a VJ sequence is SEQ ID NO: 3921 and the β V(D)J sequence is SEQ ID NO: 4228.In some embodiments, the a VJ sequence is SEQ ID NO: 3922 and the β V(D)J sequence is SEQ ID NO: 4229. In some embodiments, the a VJ sequence is SEQ ID NO: 3923 and the β V(D)J sequence is SEQ ID NO: 4230. In some embodiments, the a VJ sequence is SEQ ID NO: 3924 and the β V(D)J sequence is SEQ ID NO: 4231. In some embodiments, the a VJ sequence is SEQ ID NO: 3899 and the β V(D)J sequence is SEQ ID NO: 4232. In some embodiments, the a VJ sequence is SEQ ID NO: 3925 and the β V(D)J sequence is SEQ ID NO: 4233. In some embodiments, the a VJ sequence is SEQ ID NO: 3926 and the β V(D)J sequence is SEQ ID NO: 4234. In some embodiments, the a VJ sequence is SEQ ID NO: 3927 and the β V(D)J sequence is SEQ ID NO: 4235. In some embodiments, the a VJ sequence is SEQ ID NO: 3928 and the β V(D)J sequence is SEQ ID NO: 4236. In some embodiments, the a VJ sequence is SEQ ID NO: 3929 and the β V(D)J sequence is SEQ ID NO: 4237. In some embodiments, the a VJ sequence is SEQ ID NO: 3930 and the β V(D)J sequence is SEQ ID NO: 4238. In some embodiments, the a VJ sequence is SEQ ID NO: 3931 and the β V(D)J sequence is SEQ ID NO: 4239. In some embodiments, the a VJ sequence is SEQ ID NO: 3932 and the β V(D)J sequence is SEQ ID NO: 4240. In some embodiments, the a VJ sequence is SEQ ID NO: 3933 and the β V(D)J sequence is SEQ ID NO: 4241. In some embodiments, the a VJ sequence is SEQ ID NO: 3934 and the β V(D)J sequence is SEQ ID NO: 4242. In some embodiments, the a VJ sequence is SEQ ID NO: 3935 and the β V(D)J sequence is SEQ ID NO: 4215. In some embodiments, the a VJ sequence is SEQ ID NO: 3936 and the β V(D)J sequence is SEQ ID NO: 4243. In some embodiments, the a VJ sequence is SEQ ID NO: 3937 and the β V(D)J sequence is SEQ ID NO: 4244.In some embodiments, the a VJ sequence is SEQ ID NO: 3938 and the b V(D)J sequence is SEQ ID NO: 4245. In some embodiments, the a VJ sequence is SEQ ID NO: 3899 and the b V(D)J sequence is SEQ ID NO: 4211. In some embodiments, the a VJ sequence is SEQ ID NO: 3939 and the b V(D)J sequence is SEQ ID NO: 4246. In some embodiments, the a VJ sequence is SEQ ID NO: 3940 and the b V(D)J sequence is SEQ ID NO: 4247. In some embodiments, the a VJ sequence is SEQ ID NO: 3941 and the b V(D)J sequence is SEQ ID NO: 4248. In some embodiments, the a VJ sequence is SEQ ID NO: 3942 and the b V(D)J sequence is SEQ ID NO: 4249. In some embodiments, the a VJ sequence is SEQ ID NO: 3943 and the b V(D)J sequence is SEQ ID NO: 4250. In some embodiments, the a VJ sequence is SEQ ID NO: 3944 and the b V(D)J sequence is SEQ ID NO: 4251. In some embodiments, the a VJ sequence is SEQ ID NO: 3945 and the b V(D)J sequence is SEQ ID NO: 4252. In some embodiments, the a VJ sequence is SEQ ID NO: 3946 and the b V(D)J sequence is SEQ ID NO: 4253. In some embodiments, the a VJ sequence is SEQ ID NO: 3947 and the b V(D)J sequence is SEQ ID NO: 4254. In some embodiments, the a VJ sequence is SEQ ID NO: 3948 and the b V(D)J sequence is SEQ ID NO: 4255. In some embodiments, the a VJ sequence is SEQ ID NO: 3900 and the b V(D)J sequence is SEQ ID NO: 4209. In some embodiments, the a VJ sequence is SEQ ID NO: 3949 and the b V(D)J sequence is SEQ ID NO: 4256. In some embodiments, the a VJ sequence is SEQ ID NO: 3900 and the b V(D)J sequence is SEQ ID NO: 4214. In some embodiments, the a VJ sequence is SEQ ID NO: 3950 and the b V(D)J sequence is SEQ ID NO: 4257. In some embodiments, the a VJ sequence is SEQ ID NO: 3899 and the b V(D)J sequence is SEQ ID NO: 4224.In some embodiments, the a VJ sequence is SEQ ID NO: 3951 and the β V(D)J sequence is SEQ ID NO: 4258. In some embodiments, the a VJ sequence is SEQ ID NO: 3952 and the β V(D)J sequence is SEQ ID NO: 4259. In some embodiments, the a VJ sequence is SEQ ID NO: 3953 and the β V(D)J sequence is SEQ ID NO: 4260. In some embodiments, the a VJ sequence is SEQ ID NO: 3751 and the β V(D)J sequence is SEQ ID NO: 4261. In some embodiments, the a VJ sequence is SEQ ID NO: 3954 and the β V(D)J sequence is SEQ ID NO: 4262. In some embodiments, the a VJ sequence is SEQ ID NO: 3955 and the β V(D)J sequence is SEQ ID NO: 4263. In some embodiments, the a VJ sequence is SEQ ID NO: 3956 and the β V(D)J sequence is SEQ ID NO: 4264. In some embodiments, the a VJ sequence is SEQ ID NO: 3957 and the β V(D)J sequence is SEQ ID NO: 4265. In some embodiments, the a VJ sequence is SEQ ID NO: 3958 and the β V(D)J sequence is SEQ ID NO: 4266. In some embodiments, the a VJ sequence is SEQ ID NO: 3959 and the β V(D)J sequence is SEQ ID NO: 4267. In some embodiments, the a VJ sequence is SEQ ID NO: 3960 and the β V(D)J sequence is SEQ ID NO: 4268. In some embodiments, the a VJ sequence is SEQ ID NO: 3961 and the β V(D)J sequence is SEQ ID NO: 4269. In some embodiments, the a VJ sequence is SEQ ID NO: 4302 and the β V(D)J sequence is SEQ ID NO: 4317. In some embodiments, the a VJ sequence is SEQ ID NO: 4303 and the β V(D)J sequence is SEQ ID NO: 4318. In some embodiments, the a VJ sequence is SEQ ID NO: 4304 and the β V(D)J sequence is SEQ ID NO: 4319. In some embodiments, the a VJ sequence is SEQ ID NO: 4305 and the β V(D)J sequence is SEQ ID NO: 4320.

[0380] Engineered cells

[0381] In some aspects, provided herein are ABPs comprising a TCR or antigen binding fragment thereof that specifically binds to an HLA-peptide target, wherein the HLA class I molecule of the HLA-peptide target is HLA subtype B*44:02, and the HLA-restricted peptide of the HLA-peptide target comprises the sequence GEMSSNSTAL (SEQ ID NO: 4272).

[0382] A TCR specific for B*44:02_GEMSSNSTAL (SEQ ID NO: 4272) can comprise an alpha CDR3 sequence. The alpha CDR3 sequence can be any of SEQ ID NOs: 4284-4286 or 3138.

[0383] A TCR specific for B*44:02_GEMSSNSTAL (SEQ ID NO: 4272) can comprise a beta CDR3 sequence. The beta CDR3 sequence can be any of SEQ ID NOs: 4298-4301.

[0384] A TCR specific for B*44:02_GEMSSNSTAL (SEQ ID NO: 4272) can comprise a particular alpha CDR3 sequence and a particular beta CDR3 sequence. The alpha CDR3 can be SEQ ID NO: 4284 and the beta CDR3 can be SEQ ID NO: 4298. The alpha CDR3 can be SEQ ID NO: 4285 and the beta CDR3 can be SEQ ID NO: 4299. The alpha CDR3 can be SEQ ID NO: 4286 and the beta CDR3 can be SEQ ID NO: 4300. The alpha CDR3 can be SEQ ID NO: 3138 and the beta CDR3 can be SEQ ID NO: 4301.

[0385] A TCR specific for B*44:02_GEMSSNSTAL (SEQ ID NO: 4272) can comprise TRAV, TRAJ, TRBV, optionally TRBD, and TRBJ amino acid sequences, optionally a TRAC sequence, and optionally a TRBC sequence. Such a TCR can comprise TRAV19, TRAJ39, TRBV7-6, TRBD1, and TRBJ1-1. Such a TCR can comprise TRAV36DV7, TRAJ34, TRBV7-6, TRBD2, and TRBJ2-2. Such a TCR can comprise TRAV24, TRAJ15, TRBV7-6, TRBD2, and TRBJ2-1. Such a TCR can comprise TRAV8-4, TRAJ12, TRBV12-4, TRBD2, and TRBJ2-3.

[0386] TCRs specific for B*44:02_GEMSSNSTAL (SEQ ID NO: 4272) can include an a VJ sequence. The a VJ sequence can be any of SEQ ID NOS: 4313-4316.

[0387] TCRs specific for B*44:02_GEMSSNSTAL (SEQ ID NO: 4272) can include a b V(D)J sequence. The b V(D)J sequence can be any of SEQ ID NOS: 4328-4331.

[0388] In some embodiments, the a VJ sequence is SEQ ID NO: 4313 and the b V(D)J sequence is SEQ ID NO: 4328. In some embodiments, the a VJ sequence is SEQ ID NO: 4314 and the b V(D)J sequence is SEQ ID NO: 4329. In some embodiments, the a VJ sequence is SEQ ID NO: 4315 and the b V(D)J sequence is SEQ ID NO: 4330. In some embodiments, the a VJ sequence is SEQ ID NO: 4316 and the b V(D)J sequence is SEQ ID NO: 4331.

[0389] Figure 2

[0390] In some aspects, provided herein are ABPs comprising a TCR or antigen binding fragment thereof that specifically binds to an HLA-peptide target, wherein the HLA class I molecule of the HLA-peptide target is HLA subtype A*02:01, and the HLA-restricted peptide of the HLA-peptide target comprises the sequence GVYDGEEHSV (SEQ ID NO: 4271).

[0391] TCRs specific for A*02:01_GVYDGEEHSV (SEQ ID NO: 4271) can include an a CDR3 sequence. The a CDR3 sequence can be any of SEQ ID NOS: 4282-4283.

[0392] TCRs specific for A*02:01_GVYDGEEHSV (SEQ ID NO: 4271) can include a b CDR3 sequence. The b CDR3 sequence can be any of SEQ ID NOS: 4296-4297.

[0393] A TCR specific for A*02:01_GVYDGEEHSV (SEQ ID NO: 4271) can include a particular a CDR3 sequence and a particular b CDR3 sequence. The a CDR3 can be SEQ ID NO: 4282 and the b CDR3 can be SEQ ID NO: 4296. The a CDR3 can be SEQ ID NO: 4283 and the b CDR3 can be SEQ ID NO: 4297.

[0394] A TCR specific for A*02:01_GVYDGEEHSV (SEQ ID NO: 4271) can include TRAV, TRAJ, TRBV, optionally TRBD, and TRBJ amino acid sequences, optionally a TRAC sequence, and optionally a TRBC sequence. Such a TCR can include TRAV13-1, TRAJ11, TRBV6-3, and TRBJ2-1. Such a TCR can include TRAV14DV4, TRAJ54, TRBV4-3, TRBD1, and TRBJ2-4.

[0395] A TCR specific for A*02:01_GVYDGEEHSV (SEQ ID NO: 4271) can include an a VJ sequence. The a VJ sequence can be any of SEQ ID NOs: 4311-4312.

[0396] A TCR specific for A*02:01_GVYDGEEHSV (SEQ ID NO: 4271) can include a b V(D)J sequence. The b V(D)J sequence can be any of SEQ ID NOs: 4326-4327.

[0397] In some embodiments, the a VJ sequence is SEQ ID NO: 4311 and the b V(D)J sequence is SEQ ID NO: 4326. In some embodiments, the a VJ sequence is SEQ ID NO: 4312 and the b V(D)J sequence is SEQ ID NO: 4327.

[0398] Figure 3

[0399] Also provided are cells, such as antigen receptor-containing cells, e.g., containing an antigen receptor (e.g., CAR or TCR) comprising an extracellular domain of an anti-HLA- peptide ABP as described herein. Also provided are populations of such cells and compositions containing such cells. In some embodiments, a composition or population is enriched for such cells, such as at least 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or greater than 99 percent of the cells in the composition express an HLA-peptide ABP, or are of a certain type of cell (such as T cells or CD8+ or CD4+ cells). In some embodiments, a composition includes at least one cell containing an antigen receptor disclosed herein. Included in the compositions are pharmaceutical compositions and formulations for administration, such as for adoptive cell therapy. Also provided are therapeutic methods of administering the cells and compositions to a subject, e.g., a patient.

[0400] Accordingly, also provided are genetically engineered cells expressing an ABP comprising a receptor (e.g., TCR or CAR). The cells are generally eukaryotic cells, such as mammalian cells, and often human cells. In some embodiments, the cells are derived from blood, bone marrow, lymph, or lymphoid organs, the cells are cells of the immune system, such as cells of innate or adaptive immunity, e.g., myeloid or lymphoid cells, including lymphocytes, generally T cells and / or NK cells. Other exemplary cells include stem cells, such as pluripotent and multipotent stem cells, including induced pluripotent stem cells (iPSCs). The cells are generally primary cells, such as cells isolated directly from a subject and / or isolated from a subject and frozen. In some embodiments, the cells include one or more subsets of T cells or other cell types, such as whole T cell populations, CD4+ cells, CD8+ cells, and subsets thereof, such as those defined by function, activation state, maturity, differentiation potential, expansion, recycling, localization and / or persistence capacity, antigen specificity, type of antigen receptor, presence in a particular organ or compartment, secretion profile of markers or cytokines, and / or degree of differentiation. With respect to the subject to be treated, the cells can be allogeneic and / or autologous. The methods include off-the-shelf methods. In some aspects, such as for the prior art, the cells are multipotent and / or pluripotent, such as stem cells, such as induced pluripotent stem cells (iPSCs). In some embodiments, the methods include isolating cells from a subject, preparing, treating, culturing, and / or engineering them as described herein, and reintroducing them into the same patient, either before or after cryopreservation.

[0401] Subtypes and subpopulations of T cells and / or CD4+ and / or CD8+ T cells include naive T (TN) cells, effector T cells (TEFF), memory T cells and subtypes thereof, such as stem cell memory T (TSCM) cells, central memory T (TCM) cells, effector memory T (TEM) cells or terminally differentiated effector memory T cells, tumor-infiltrating lymphocytes (TILs), immature T cells, mature T cells, helper T cells, cytotoxic T cells, mucosa-associated non-variant T (MALT) cells, naturally occurring and adoptively regulatory T (Treg) cells, helper T cells such as TH1 cells, TH2 cells, TH3 cells, TH17 cells, TH9 cells, TH22 cells, follicular helper T cells, alpha / beta T cells, and delta / gamma T cells.

[0402] In some embodiments, the cell is a natural killer (NK) cell. In some embodiments, the cell is a monocyte or granulocyte, e.g., a myelocyte, macrophage, neutrophil, dendritic cell, mast cell, eosinophil, and / or basophil.

[0403] The cell can be genetically modified to reduce expression or knock out an endogenous TCR. Such modifications are described in Mol Ther Nucleic Acids. 2012 Dec; 1(12): e63; Blood. 2011 Aug 11; 118(6): 1495-503; Blood. 2012 Jun 14; 119(24): 5697-5705; Torikai and Hiroki et al. “HLA and TCR Knockout by Zinc Finger Nucleases: Toward ‘off-the-Shelf’ Allogeneic T-Cell Therapy for CD19+ Malignancies”; Blood. 116.21 (2010): 3766; Blood. 2018 Jan 18; 131(3): 311-322, doi: 10.1182 / blood-2017-05-787598; and WO2016069283, which are incorporated by reference in their entirety.

[0404] The cells can be genetically modified to facilitate secretion of cytokines. Such modifications are described in Hsu C. Hughes MS. Zheng Z. Bray RB. Rosenberg SA. Morgan RA "Primary human T lymphocytes engineered with a codon-optimized IL-15 gene resist cytokine withdrawal-induced apoptosis and persist long-term in the absence of exogenous cytokine" J Immunol 2005; 175:7226-34; Quintarelli C. Vera JF. Savoldo B. Giordano Attianese GM. Pule M. Foster AE "Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes" Blood 2007; 110:2793-802; Hsu C. Jones SA. Cohen CJ. Zheng Z. Kerstann K. Zhou J "Cytokine-independent growth and clonal expansion of a primary human CD8+ T-cell clone following retroviral transduction with the IL-15 gene" Blood 2007; 109:5168-77).

[0405] It has been shown that a mismatch between chemokine receptors on T cells and tumor-secreted chemokines is responsible for suboptimal trafficking of T cells into the tumor microenvironment. To improve therapeutic efficacy, cells can be genetically modified to increase recognition of chemokines in the tumor microenvironment. Examples of such modifications are described in Moon E.K., Carpenito C., Sun J., Wang L.C., Kapoor V., Predina J. "Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor" Clin Cancer Res 2011; 17:4719-4730; and Craddock J.A., Lu A., Bear A., Pule M., Brenner M.K., Rooney C.M. et al. "Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b." J Immunother. 2010; 33:780-788).

[0406] Cells can be genetically modified to enhance expression of costimulatory / enhancing receptors such as CD28 and 41BB.

[0407] Adverse reactions to T cell therapies can include cytokine release syndrome and persistent B cell depletion. Introduction of a suicide / safety switch in recipient cells can improve the safety of cell therapies. Thus, cells can be genetically modified to include a suicide / safety switch. A suicide / safety switch can be a gene that confers reagent (e.g., drug) sensitivity on cells expressing the gene and causes cell death when the cells are contacted with or exposed to the reagent. Exemplary suicide / safety switches are described in (Protein Cell 2017 Aug; 8(8): 573-589). A suicide / safety switch can be HSV-TK. A suicide / safety switch can be cytosine deaminase, purine nucleoside phosphorylase, or nitroreductase. A suicide / safety switch can be RapaCIDe™, described in U.S. Patent Application Publication No. US20170166877A1. A suicide / safety switch system can be CD20 / rituximab, described in Haematologica 2009 Sep; 94(9): 1316-1320). These references are incorporated by reference in their entirety.

[0408] The TCR or CAR can be introduced into the recipient cell as a split receptor that assembles only in the presence of a heterodimericizing small molecule. Such a system is described in Science 2015 Oct 16; 350(6258): aab4077, and U.S. Patent No. 9,587,020, which are incorporated by reference in their entirety.

[0409] In some embodiments, the cell comprises one or more nucleic acids, e.g., a polynucleotide encoding a TCR or CAR disclosed herein, wherein the polynucleotide is introduced by genetic engineering such that a recombinant TCR or CAR or genetically engineered TCR or CAR disclosed herein is expressed. In some embodiments, the nucleic acid is heterologous, i.e., not normally present in the cell or sample obtained from the cell, such as a sample obtained from another organism or cell, e.g., the cell is not normally found in the engineered cell and / or organism from which such cell is derived. In some embodiments, the nucleic acid is not naturally occurring, e.g., the nucleic acid is not found in nature, comprising a nucleic acid that comprises a chimeric combination of nucleic acids encoding various domains from a plurality of different cell types.

[0410] The nucleic acid can comprise a codon-optimized nucleotide sequence. Without being bound by a particular theory or mechanism, it is believed that codon optimization of a nucleotide sequence increases the efficiency of translation of the mRNA transcript. Codon optimization of a nucleotide sequence can involve replacing one codon that encodes the same amino acid with a natural codon, but it can be translated by tRNA that is more readily available within the cell, thereby increasing the efficiency of translation. Optimization of a nucleotide sequence can also reduce mRNA secondary structures that would interfere with translation, thereby increasing the efficiency of translation.

[0411] A construct or vector can be used to introduce a TCR or CAR into a recipient cell. Exemplary constructs are described herein. The polynucleotides encoding the alpha and beta chains of a TCR or CAR can be present in a single construct or in separate constructs. The polynucleotides encoding the alpha and beta chains can be operably linked to a promoter, such as a heterologous promoter. The heterologous promoter can be a strong promoter, such as EF1a, CMV, PGK1, Ubc, beta-actin, CAG promoter, and the like. The heterologous promoter can be a weak promoter. The heterologous promoter can be an inducible promoter. Exemplary inducible promoters include, but are not limited to, TRE, NFAT, GAL4, LAC, and the like. Other exemplary inducible expression systems are described in U.S. Pat. Nos. 5,514,578, 6,245,531, 7,091,038, and European Pat. No. 0517805, which are incorporated by reference in their entirety.

[0412] A construct for introducing a TCR or CAR into a recipient cell can also include a polynucleotide encoding a signal peptide (signal peptide element). The signal peptide can facilitate surface transport of the introduced TCR or CAR. Exemplary signal peptides include, but are not limited to, CD8 signal peptide, immunoglobulin signal peptide, with specific examples including GM-CSF and IgG kappa. Such signal peptides are described in Trends Biochem Sci. 2006 Oct; 31(10): 563-71; Epub 2006 Aug 21; and An et al. “Construction of a New Anti-CD19 Chimeric Antigen Receptor and the Anti-Leukemia Function Study of the Transduced T Cells.” Oncotarget 7.9 (2016): 10638-10649; Public Library of Science (PLoS) website, Aug 16, 2018; which are incorporated by reference in their entirety.

[0413] In some cases, such as where the a chain and b chain are expressed from a single construct or open reading frame, or where the construct includes a marker gene, the construct can include a ribosomal skip sequence. The ribosomal skip sequence can be a 2A peptide, such as a P2A or T2A peptide. Exemplary P2A and T2A peptides are described in Science Reports, Vol. 7, Article Number: 2193 (2017), which is incorporated by reference in its entirety. In some cases, a FURIN / PACE cleavage site is introduced upstream of the 2A element. FURIN / PACE cleavage sites are described, for example, at http: / / www.nuolan.net / substrates.html. The cleavage peptide can also be a cleavage site for Factor Xa. In cases where the a chain and b chain are expressed from a single construct or open reading frame, the construct can include an internal ribosome entry site (IRES).

[0414] The construct can further include one or more marker genes. Exemplary marker genes include, but are not limited to, GFP, luciferase, HA, lacZ. The marker can be a selection marker, such as an antibiotic resistance marker, heavy metal resistance marker, or biocide resistance marker, as known to those of skill in the art. The marker can be a complementation marker for an auxotrophic host. Exemplary complementation markers and auxotrophic hosts are described in Gene 2001 Jan 24;263(1-2): 159-69). Such markers can be expressed through an IRES, a frameshift sequence, a 2A peptide linker, a fusion to the TCR or CAR, or a separate promoter.

[0415] Exemplary vectors or systems for introducing a TCR or CAR into a recipient cell include, but are not limited to, adeno-associated virus, adenovirus, adenovirus + modified vaccinia, ankara virus (MVA), adenovirus + retrovirus, adenovirus + sendai virus, adenovirus + vaccinia virus, alphavirus (VEE) replicon vaccine, antisense oligonucleotide, bifidobacterium longum, CRISPR-Cas9, escherichia coli, flavivirus, gene gun, herpes virus, herpes simplex virus, lactococcus lactis, electroporation, lentivirus, lipofection, listeria monocytogenes, measles virus, modified vaccinia ankara virus (MVA), mRNA electroporation, naked / plasmid DNA, naked / plasmid DNA + adenovirus, naked / plasmid DNA + modified vaccinia ankara virus (MVA), naked / plasmid DNA + RNA transfer, naked / plasmid DNA + vaccinia virus, newcastle disease virus, non-viral vector, PiggyBac™ (PB) transposon, nanoparticle-based system, poliovirus, poxvirus, poxvirus + vaccinia virus, retrovirus, RNA transfer, RNA transfer + naked / plasmid DNA, RNA virus, saccharomyces cerevisiae, salmonella typhimurium, semliki forest virus, sendai virus, shigella dysenteriae, simian virus, siRNA, sleeping beauty transposon, streptococcus mutans, vaccinia virus, venezuelan equine encephalitis virus replicon, vesicular stomatitis virus, and vibrio cholerae.

[0416] In preferred embodiments, the TCR or CAR is introduced into the recipient cell by adeno-associated virus (AAV), adenovirus, CRISPR-CAS9, herpes virus, lentivirus, lipofection, mRNA electroporation, PiggyBac™ (PB) transposon, retrovirus, RNA transfer, or sleeping beauty transposon. TM (PB) transposon, retrovirus, RNA transfer, or sleeping beauty transposon.

[0417] In some embodiments, the vector used to introduce a TCR or CAR into a recipient cell is a viral vector. Exemplary viral vectors include adenoviral vectors, adeno-associated virus (AAV) vectors, lentiviral vectors, herpes viral vectors, retroviral vectors, and the like. Such vectors are described herein.

[0418] Exemplary embodiments of TCR constructs for introducing a TCR or CAR into a recipient cell include Figure 4In some embodiments, the TCR construct comprises, in the 5’-3’ direction, the following polynucleotide sequences: a promoter sequence, a signal peptide sequence, a TCR beta variable (TCRpv) sequence, a TCR beta constant (TCRpC) sequence, a cleavage peptide (e.g., P2A), a signal peptide sequence, a TCR alpha variable (TCRaV) sequence, and a TCR alpha constant (TCRaC) sequence. In some embodiments, the TCRpC and TCRaC sequences of the construct comprise one or more murine regions, e.g., a complete murine constant sequence or a human-murine amino acid exchange as described herein. In some embodiments, the construct further comprises 3’ of the TCRaC sequence, a cleavage peptide sequence (e.g., T2A), and a reporter gene. In one embodiment, the construct comprises, in the 5’-3’ direction, the following polynucleotide sequences: a promoter sequence, a signal peptide sequence, a TCR beta variable (TCRpv) sequence, a TCR beta constant (TCRpC) sequence comprising one or more murine regions, a cleavage peptide (e.g., P2A), a signal peptide sequence, a TCR alpha variable (TCRaV) sequence, and a TCR alpha constant (TCRaC) sequence comprising one or more murine regions, a cleavage peptide (e.g., T2A), and a reporter gene.

[0419] Figure 5 Exemplary construct backbone sequences are depicted for cloning of TCRs into expression systems for therapeutic development.

[0420] Nucleotides, vectors, host cells, and related methods thereof Exemplary construct sequences are depicted for cloning of identified A*0201-LLASSILCA specific TCRs into expression systems for therapeutic development.

[0421] Methods of making HLA-peptide ABPs Exemplary construct sequences are depicted for cloning of identified A*0101_EVDPIGHLY specific TCRs into expression systems for therapeutic development.

[0422] Methods of identifying ABPs

[0423] Also provided are isolated nucleic acids encoding the HLA-peptide ABP, vectors comprising the nucleic acids, and host cells comprising the vectors and nucleic acids, and recombinant techniques for producing the ABP.

[0424] The nucleic acid can be a recombinant nucleic acid. A recombinant nucleic acid can be constructed outside of a living cell by joining a natural or synthetic nucleic acid fragment to a nucleic acid molecule or replication product thereof that is replicable in a living cell. For purposes herein, replication can be in vitro replication or in vivo replication.

[0425] For recombinant production of an ABP, a nucleic acid encoding the ABP can be isolated and inserted into a replicable vector for further cloning (i.e., amplification of the DNA) or for expression. In some aspects, the nucleic acid can be produced by homologous recombination, e.g., as described in U.S. Patent No. 5,204,244, which is incorporated by reference in its entirety.

[0426] A number of different vectors are known in the art. Vector components generally include one or more of: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence, e.g., as described in U.S. Patent No. 5,534,615, which is incorporated by reference in its entirety.

[0427] Exemplary vectors or constructs suitable for expression of an ABP (e.g., a TCR, CAR, antibody, or antigen-binding fragment thereof) include, e.g., the pUC series (Fermentas BioTechnologies), the pBluescript series (Stratagene, La Jolla, CA, USA), the pET series (Novagen, Madison, WI, USA), the pGEX series (Pharmacia Biotech, Uppsala, Sweden), and the pEX series (Clontech, Palo Alto, CA, USA). Bacteriophage vectors, such as AGT10, AGT11, AZap II (Stratagene), AEMBL4, and AMMl 149, are also suitable for expression of the ABPs described herein.

[0428] Illustrative examples of suitable host cells are provided below. These host cells are not limiting, and any suitable host cell can be used to produce the ABPs provided herein.

[0429] Suitable host cells include any prokaryotic (e.g., bacterial), lower eukaryotic (e.g., yeast), or higher eukaryotic (e.g., mammalian) cell. Suitable prokaryotes include eubacteria such as gram-positive and gram-negative organisms, e.g., Enterobacteriaceae such as Escherichia (E. coli), Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella (S. typhimurium), Serratia (S. marcescens), Shigella, Bacillus (B. subtilis and B. licheniformis), Pseudomonas (P. aeruginosa), and Streptomyces. A useful E. coli cloning host is E. coli 294, although other strains such as E. coli B, E. coli X1776, and E. coli W3110 can also be used.

[0430] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are also suitable cloning or expression hosts for HLA-peptide ABP-encoding vectors. Saccharomyces cerevisiae or common baker's yeast is a commonly used lower eukaryotic host microorganism. However, many other genera, species, and strains are available and useful, such as Schizosaccharomyces; Kluyveromyces (K. lactis, K. fragil is, K. bulgaricus, K. wickerhamii, K. waltii, K. drosophilarum, K. thermotolerans, and K. marxianus); Yarrowia; Pichia; Candida (C. albicans); Trichoderma; Neurospora; Schwanniomyces (S. occidentalis); and filamentous fungi such as, for example, Penicillium, Talaromyces, and Aspergillus (A. nidulans and A. niger).

[0431] Useful mammalian host cells include COS-7 cells, HEK293 cells; baby hamster kidney (BHK) cells; Chinese hamster ovary (CHO); mouse Sertoli cells; African green monkey kidney cells (VERO-76), and the like.

[0432] Host cells for production of HLA-peptide ABPs can be cultured in a variety of media. Commercially available media such as, for example, Ham F10, Minimal Essential Medium (MEM), RPMI-1640, and Dulbecco's Modified Eagle's Medium (DMEM) are suitable for use in culturing host cells. In addition, any of the media described in Ham et al. Meth. Enz. 1979, 58:44; Barnes et al. Anal. Biochem. 1980, 102:255; and U.S. Pat. Nos. 4,767,704; 4,657,866; 4,927,762; 4,560,655; and 5,122,469; or WO 90 / 03430 and WO 87 / 00195 can be used, each of which is incorporated by reference in its entirety.

[0433] Any of these media can be supplemented as necessary with hormones and / or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics, trace elements, and glucose or an equivalent energy source. Other necessary supplements can also be included at appropriate concentrations that are known to those skilled in the art.

[0434] Culture conditions, such as temperature, pH, and the like, will be apparent to the ordinarily skilled artisan as being those previously used with the host cells for expression.

[0435] When using recombinant techniques, the ABP can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the ABP is produced intracellularly, in a first step, the particles of the host cell or cell lysate fragments are removed, for example, by centrifugation or ultrafiltration. Carter et al. Bio / Technology 1992, 10: 163-167, which is incorporated by reference in its entirety, describes a method for isolating ABP secreted into the periplasmic space of E. coli. Briefly, cell pastes are thawed in the presence of sodium acetate (pH 3.5), EDTA, and phenylmethylsulfonyl fluoride (PMSF) for about 30 minutes. Cell debris can be removed by centrifugation.

[0436] In some embodiments, the ABP is produced in a non-cellular system. In some aspects, the non-cellular system is an in vitro transcription and translation system, as described in Yin et al. mAbs 2012, 4: 217-225, which is incorporated by reference in its entirety. In some aspects, the non-cellular system utilizes a non-cellular extract from a eukaryotic cell or a prokaryotic cell. In some aspects, the prokaryotic cell is E. coli. Cell-free expression of ABP can be useful, for example, when ABP accumulates in cells in insoluble aggregates or when the yield from periplasmic expression is low.

[0437] In the case of ABP secretion into the medium, the supernatant from such expression systems is generally first concentrated with a commercially available protein concentration filter (e.g., an Amicon cell). or ultrafiltration unit). Proteinase inhibitors, such as PMSF, can be included in any of the foregoing steps to inhibit proteolysis, and antibiotics can be included to prevent the growth of adventitious contaminants.

[0438] ABP compositions prepared from cells can be purified using, for example, hydroxylapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being particularly useful purification technique. The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain present in the ABP. Protein A can be used to purify ABPs comprising human γΐ, γ2, or γ4 heavy chains (Lindmark et al. J. Immunol. Meth. 1983, 62: 1-13, which is incorporated by reference in its entirety). Protein G can be used to purify all mouse isotypes and human γ3 (Guss et al. EMBO J. 1986, 5: 1567-1575, which is incorporated by reference in its entirety).

[0439] The matrix to which the affinity ligand is attached is usually agarose, but ot...

Claims

1. An isolated antigen-binding protein (ABP) that specifically binds to a human leukocyte antigen (HLA)-peptide target, wherein the HLA-peptide target comprises an HLA-restricted peptide complexed with an HLAI class molecule, wherein the HLA-restricted peptide is located in a peptide-binding groove of the α1 / α2 heterodimeric portion of the HLAI class molecule, and wherein: the HLA class I molecule is HLA subtype HLA-A*01:01, and the HLA-restricted peptide consists of the sequence NTDNNLAVY and wherein the ABP comprises an antibody or antigen-binding fragment thereof comprising: a. a CDR-H1 consisting of the sequence set forth in SEQ ID NO: 2878, a CDR-H2 consisting of the sequence set forth in SEQ ID NO: 2900, a CDR-H3 consisting of the sequence set forth in SEQ ID NO: 2932, a CDR-L1 consisting of the sequence set forth in SEQ ID NO: 2946, a CDR-L2 consisting of the sequence set forth in SEQ ID NO: 2958, a CDR-L3 consisting of the sequence set forth in SEQ ID NO: 2992; or b. a CDR-H1 consisting of the sequence set forth in SEQ ID NO: 2867, a CDR-H2 consisting of the sequence set forth in SEQ ID NO: 2892, a CDR-H3 consisting of the sequence set forth in SEQ ID NO: 2920, a CDR-L1 consisting of the sequence set forth in SEQ ID NO: 2946, a CDR-L2 consisting of the sequence set forth in SEQ ID NO: 2962, a CDR-L3 consisting of the sequence set forth in SEQ ID NO: 2984.

2. The isolated ABP of claim 1, wherein the ABP comprises: a. a VH sequence selected from SEQ ID NO: 2814.

3. The isolated ABP of claim 1, wherein the ABP comprises: a. a VL sequence selected from SEQ ID NO: 2849.

4. The isolated ABP of claim 1, wherein the ABP comprises: a. a VH sequence of SEQ ID NO: 2814 and a VL sequence of SEQ ID NO: 2849.

5. The isolated ABP of claim 1, wherein the ABP comprises: b. a VH sequence selected from SEQ ID NO: 2802.

6. The isolated ABP of claim 1, wherein the ABP comprises: b. a VL sequence selected from SEQ ID NO: 2837.

7. The isolated ABP of claim 1, wherein the ABP comprises: b. a VH sequence of SEQ ID NO: 2802 and a VL sequence of SEQ ID NO: 2837.

8. The isolated ABP of claim 1, wherein the antigen binding protein is part of a chimeric antigen receptor (CAR) comprising: an extracellular domain comprising an antigen binding protein; and an intracellular signaling domain.

9. The isolated ABP of claim 8, wherein the antigen binding protein comprises a scFv and the intracellular signaling domain comprises an ITAM.

10. The isolated ABP of claim 8, wherein the intracellular signaling domain comprises a signaling domain of a zeta chain of a CD3-zeta (CD3) chain.

11. The isolated ABP of any one of claims 8-10, further comprising a transmembrane domain linking the extracellular domain and the intracellular signaling domain.

12. The isolated ABP of claim 11, wherein the transmembrane domain comprises a transmembrane portion of CD28.

13. The isolated ABP of claim 8, further comprising an intracellular signaling domain of a T cell costimulatory molecule.

14. The isolated ABP of claim 13, wherein the T cell costimulatory molecule is CD28, 4-1BB, OX-40, ICOS, or any combination thereof.

15. The isolated ABP of claim 1, wherein the antigen binding protein is linked to human Fc.

16. The isolated ABP of claim 1, wherein the antigen binding protein is linked to a scaffold by a linker.

17. The isolated ABP of claim 1, wherein the antigen binding protein comprises a Fv fragment, a Fab fragment, a F(ab')2 fragment, a Fab' fragment, a scFv fragment, and / or a scFv-Fc fragment.

18. The isolated ABP of claim 17, wherein the antigen binding protein comprises a scFv fragment.

19. The isolated ABP of claim 1, wherein the antigen binding protein is a monoclonal antibody.

20. The isolated ABP of claim 1, wherein the antigen binding protein is a humanized antibody.

21. The isolated ABP of claim 1, wherein the antigen binding protein is a human or chimeric antibody.

22. The isolated ABP of claim 1, wherein the antigen binding protein is multispecific or bispecific.

23. The isolated ABP of claim 1, wherein the antigen binding protein binds to more than one antigen or more than one epitope on a single antigen.

24. The isolated ABP of claim 1, wherein the antigen binding protein comprises a heavy chain constant region of a class selected from the group consisting of IgG, IgA, IgD, IgE, and IgM.

25. The isolated ABP of claim 1, wherein the antigen binding protein comprises a heavy chain constant region of a human IgG class and a subclass selected from the group consisting of IgG1, IgG4, IgG2, and IgG3.

26. The isolated ABP of claim 1, wherein the antigen binding protein comprises a modified Fc.

27. An engineered cell expressing a chimeric antigen receptor comprising the antigen binding protein of any one of the preceding claims.

28. The engineered cell of claim 27, which is a T cell.

29. The engineered cell of claim 27, which is a cytotoxic T cell (CTL).

30. The engineered cell of any one of claims 27-29, wherein the antigen binding protein is expressed from a heterologous promoter.

31. An isolated polynucleotide or set of polynucleotides encoding the antigen binding protein, or antigen binding portion thereof, of any one of claims 1-26.

32. A vector or set of vectors comprising the polynucleotide or set of polynucleotides of claim 31.

33. A host cell comprising the polynucleotide or set of polynucleotides of claim 31, or the vector or set of vectors of claim 32.

34. A method of producing an antigen binding protein, comprising: expressing the antigen binding protein with the host cell of claim 33, and isolating the expressed antigen binding protein.

35. A pharmaceutical composition comprising the antigen binding protein of any one of claims 1-26, and a pharmaceutically acceptable excipient.

36. A kit comprising the antigen binding protein of any one of claims 1-26, or the pharmaceutical composition of claim 35, and instructions for use.

37. A virus comprising the isolated polynucleotide or set of polynucleotides of claim 31.

38. The virus of claim 37, wherein the virus is a filamentous bacteriophage.

39. A yeast cell comprising the isolated polynucleotide or set of polynucleotides of claim 31.

40. A method of identifying an antigen binding protein according to any one of claims 1- 26, comprising: providing an HLA-peptide target, wherein the HLA-peptide target comprises an HLA- restricted peptide complexed with an HLA class I molecule, wherein the HLA-restricted peptide is located in a peptide binding groove of an alpha 1 / alpha 2 heterodimer portion of the HLA class I molecule, and wherein: the HLA class I molecule is HLA subtype HLA-A*01:01, and the HLA-restricted peptide consists of the sequence NTDNNLAVY; and binding the HLA-peptide target with the antigen binding protein, thereby identifying the antigen binding protein.

41. The method of claim 40, wherein the antigen binding protein is present in a phage display library comprising a plurality of different antigen binding proteins.

42. The method of claim 40, wherein the binding step is performed more than once.

43. The method of any one of claims 40-42, further comprising: contacting the antigen binding protein with one or more peptide-HLA complexes different from the HLA-peptide target to determine whether the antigen binding protein selectively binds the HLA-peptide target.

44. The method of claim 43, wherein selectivity is determined by measuring the binding affinity of the antigen binding protein to a soluble target HLA-peptide complex relative to a soluble HLA-peptide complex different from the target complex.

45. The method of claim 44, wherein selectivity is determined by measuring the binding affinity of the antigen binding protein to a target HLA-peptide complex expressed on the surface of one or more cells relative to an HLA-peptide complex different from the target complex expressed on the surface of one or more cells.

46. A method of identifying an antigen binding protein according to any one of claims 1-26, comprising: obtaining one or more cells comprising the antigen binding protein; 47. A method of identifying an antigen binding protein according to any one of claims 1-26, comprising: activating the one or more cells with at least one HLA-peptide target presented on a natural or artificial antigen presenting cell (APC), wherein the HLA-peptide target comprises an HLA-restricted peptide in complex with an HLA class I molecule, wherein the HLA-restricted peptide is located in the peptide binding groove of the a1 / a2 heterodimeric part of the HLA class I molecule, and wherein: the HLA class I molecule is HLA subtype HLA-A*01 :01, and the HLA-restricted peptide consists of the sequence NTDNNLAVY; and identifying the antigen binding protein via selection of one or more cells that are activated by interaction with the at least one HLA-peptide target.

48. The method of claim 46 or 47, wherein the cells are T cells.

49. The method of claim 46 or 47, wherein the cells are cytotoxic T cells (CTLs). isolating the cells.

50. The method of claim 46 or 47, further comprising:

51. The method of claim 50, wherein the cells are isolated using flow cytometry.

52. The method of claim 50, wherein the cells are isolated using magnetic separation.

53. The method of claim 50, wherein the cells are isolated using single cell isolation. sequencing the antigen binding protein.

54. The method of claim 50, further comprising: obtaining one or more cells comprising the antigen binding protein; activating the one or more cells with at least one HLA-peptide target presented on a natural or artificial antigen presenting cell (APC), wherein the HLA-peptide target comprises an HLA-restricted peptide in complex with an HLA class I molecule, wherein the HLA-restricted peptide is located in the peptide binding groove of the a1 / a2 heterodimeric part of the HLA class I molecule, and wherein: the HLA class I molecule is HLA subtype HLA-A*01 :01, and the HLA-restricted peptide consists of the sequence NTDNNLAVY; and identifying the antigen binding protein via selection of one or more cells that are activated by interaction with the at least one HLA-peptide target.

48. The method of claim 46 or 47, wherein the cells are T cells.

49. The method of claim 46 or 47, wherein the cells are cytotoxic T cells (CTLs). isolating the cells.

51. The method of claim 50, wherein the cells are isolated using flow cytometry.

52. The method of claim 50, wherein the cells are isolated using magnetic separation.

53. The method of claim 50, wherein the cells are isolated using single cell isolation. sequencing the antigen binding protein. obtaining one or more cells comprising the antigen binding protein; activating the one or more cells with at least one HLA-peptide target presented on a natural or artificial antigen presenting cell (APC), wherein the HLA-peptide target comprises an HLA-restricted peptide in complex with an HLA class I molecule, wherein the HLA-restricted peptide is located in the peptide binding groove of the a1 / a2 heterodimeric part of the HLA class I molecule, and wherein: the HLA class I molecule is HLA subtype HLA-A*01 :01, and the HLA-restricted peptide consists of the sequence NTDNNLAVY; and identifying the antigen binding protein via selection of one or more cells that are activated by interaction with the at least one HLA-peptide target.

48. The method of claim 46 or 47, wherein the cells are T cells.

49. The method of claim 46 or 47, wherein the cells are cytotoxic T cells (CTLs). isolating the cells.

51. The method of claim 50, wherein the cells are isolated using flow cytometry.

52. The method of claim 50, wherein the cells are isolated using magnetic separation.

53. The method of claim 50, wherein the cells are isolated using single cell isolation. sequencing the antigen binding protein.

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