T cell receptors

Abstract

The present invention provides a T-cell receptor (TCR) that binds to an immunogenic peptide when the peptide is presented by the major histocompatibility complex (MHC).

Description

Technical Field

[0001] This invention relates to T-cell receptors (TCRs), which bind to immunogenic peptides when presented by the major histocompatibility complex (MHC). The invention further relates to immunogenic peptides. Background Technology

[0002] The fifth pillar of cancer care is immunotherapy, which utilizes the immune system's innate ability to recognize cancer cells. In fact, the presence of tumor-infiltrating lymphocytes is associated with better prognosis (see, for example, Zhang, L. et al., New England Journal of Medicine, 348(3), pp. 203-213).

[0003] The ability of T lymphocytes to recognize antigens is determined by the expression of T cell receptors (TCRs). TCR gene therapy is based on the transfer of high-affinity tumor-specific TCR genes into T lymphocytes, thereby enabling specific targeting of desired tumor-associated antigens and producing less toxic, more specific, and more effective therapies. This approach has shown promise in clinical trials.

[0004] One of the major obstacles limiting the use of TCR gene therapy in cancer clinical treatment is the lack of tumor-specific T cells and corresponding TCRs. Tumor-specific T cells targeting tumor-associated antigens (TAAs), i.e., autoproteins overexpressed on cancer cells, are interesting targets in the context of adoptive T-cell therapy. However, the number of isolated TAA-specific T cells remains limited, especially in the case of hematologic malignancies.

[0005] Therefore, the low availability of tumor-specific TCRs remains an open problem limiting the widespread use of TCR-based immunotherapies. Summary of the Invention

[0006] The inventors have identified a novel TCR that binds to immunogenic peptides when presented by the major histocompatibility complex (MHC). The inventors have determined the amino acid sequence of the TCR, including the amino acid sequence of the CDR region of the TCR, which is responsible for the specificity of binding to the immunogenic peptide. The TCR can confer tumor-specific cytolytic function to engineered T cells.

[0007] In one aspect, the present invention provides a T-cell receptor (TCR) that binds to an immunogenic peptide when the peptide is presented by the major histocompatibility complex (MHC), wherein:

[0008] (1) The immunogenic peptide is a human epidermal growth factor receptor 2 (HER2) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CAEGSRYGGATNKLIF (SEQ ID NO: 8) or a variant thereof having up to three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CASSTFPVETQYF (SEQ ID NO: 13) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0009] (2) The immunogenic peptide is a proteinase 3 (PR3) peptide or a neutrophil elastase (NE) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CATYYGQNFVF (SEQ ID NO: 22) or a variant thereof having at most three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CASSFQGYTEAFF (SEQ ID NO: 27) or a variant thereof having at most three amino acid substitutions, additions or deletions;

[0010] (3) The immunogenic peptide is a histone-lysine N-methyltransferase EZH2 (EZH2) peptide or a melanoma preferred expression antigen (PRAME) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes (i) the amino acid sequence of CAVSESPTGFQKLVF (SEQ ID NO: 37) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CAVPHSYNTDKLIF (SEQ ID NO: 42) or a variant thereof having up to three amino acid substitutions, additions or deletions, and CDR3β includes (i) the amino acid sequence of CASSPRGSNTGELFF (SEQ ID NO: 47) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CSARPSEAPQYF (SEQ ID NO: 53) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0011] (4) The immunogenic peptide is a cathepsin G (CTSG) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes (i) the amino acid sequence of CALPSARQLTF (SEQ ID NO: 61) or a variant thereof having up to three amino acid substitutions, additions or deletions, or (ii) the amino acid sequence of CAFMSPEGGSEKLVF (SEQ ID NO: 66) or a variant thereof having up to three amino acid substitutions, additions or deletions, and CDR3β includes (i) the amino acid sequence of CSVPPAGLGAPEAFF (SEQ ID NO: 71) or a variant thereof having up to three amino acid substitutions, additions or deletions, or (ii) the amino acid sequence of CASSPGTGAYNSPLHF (SEQ ID NO: 77) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0012] (5) The immunogenic peptide is a cathepsin G (CTSG) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CAVQASNDYKLSF (SEQ ID NO: 86) or a variant thereof having at most three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CASSVGRATEAFF (SEQ ID NO: 91) or a variant thereof having at most three amino acid substitutions, additions or deletions;

[0013] (6) The immunogenic peptide is a cathepsin G (CTSG) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes (i) the amino acid sequence of CVVNWDNARLMF (SEQ ID NO: 98) or a variant thereof having at most three amino acid substitutions, additions or deletions, or (ii) the amino acid sequence of CATRRAKDRDDKIIF (SEQ ID NO: 459) or a variant thereof having at most three amino acid substitutions, additions or deletions, and CDR3β includes (i) the amino acid sequence of CASSEEGGSTDTQYF (SEQ ID NO: 103) or a variant thereof having at most three amino acid substitutions, additions or deletions, or (ii) the amino acid sequence of CASSLGLAGDYEQYF (SEQ ID NO: 109) or a variant thereof having at most three amino acid substitutions, additions or deletions;

[0014] (7) The immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CAFMKRLTQGGSEKLVF (SEQ ID NO: 119) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes the amino acid sequence of CASSEVYRGHEKLFF (SEQ ID NO: 124) or a variant thereof having at most three amino acid substitutions, additions or deletions;

[0015] (8) The immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CAASIRSSGDKLTF (SEQ ID NO: 133) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes the amino acid sequence of CASSKRTGELFF (SEQ ID NO: 138) or a variant thereof having at most three amino acid substitutions, additions or deletions;

[0016] (9) The immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CALSETLYNQGGKLIF (SEQ ID NO: 144) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes the amino acid sequence of CASSLGTSRSYTDTQYF (SEQ ID NO: 149) or a variant thereof having at most three amino acid substitutions, additions or deletions;

[0017] (10) The immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CALTSDYKLSF (SEQ ID NO: 157) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes (i) the amino acid sequence of CATSDLFGELFF (SEQ ID NO: 162) or a variant thereof having at most three amino acid substitutions, additions or deletions, or (i) the amino acid sequence of CASTTGIYEQYF (SEQ ID NO: 168) or a variant thereof having at most three amino acid substitutions, additions or deletions;

[0018] (11) The immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CAVNSWGKLQF (SEQ ID NO: 176) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes the amino acid sequence of CASHSGLVGTGELFF (SEQ ID NO: 181) or a variant thereof having at most three amino acid substitutions, additions or deletions;

[0019] (12) The immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CASTNFGNEKLTF (SEQ ID NO: 192) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes the amino acid sequence of CASSLSYEQYF (SEQ ID NO: 197) or a variant thereof having at most three amino acid substitutions, additions or deletions;

[0020] (13) The immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises (i) the amino acid sequence of CAVRSHSGNTPLVF (SEQ ID NO: 206) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CAENAGGTSYGKLTF (SEQ ID NO: 211) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (iii) the amino acid sequence of CAMRLPIPNNAGNMLTF (SEQ ID NO: 216) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and CDR3β comprises (i) the amino acid sequence of CASSSPRVGPLYEQYF (SEQ ID NO: 221) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CASSDHDIYNEQFF (SEQ ID NO: 227) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (iii) The amino acid sequence of CASWAEEAEETQYF (SEQ ID NO: 233) or a variant thereof having at most three amino acid substitutions, additions or deletions;

[0021] (14) The immunogenic peptide is a Dickkopf-associated protein 1 (DKK1) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CAVGAWYNQGGKLIF (SEQ ID NO: 241) or a variant thereof having at most three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CASSFGVTGELFF (SEQ ID NO: 246) or a variant thereof having at most three amino acid substitutions, additions or deletions;

[0022] (15) The immunogenic peptide is a mucin-5AC (MUC5AC) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CAGGGSGAGSYQLTF (SEQ ID NO: 254) or a variant thereof having up to three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CAISDPTGDNQPQHF (SEQ ID NO: 259) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0023] (16) The immunogenic peptide is a pregradient protein-2 (AGR2) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CAVQDYGQNFVF (SEQ ID NO: 267) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes the amino acid sequence of CASSPTGSEQYF (SEQ ID NO: 272) or a variant thereof having at most three amino acid substitutions, additions or deletions;

[0024] (17) The immunogenic peptide is a c-MET peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CAAAPNNNDMRF (SEQ ID NO: 280) or a variant thereof having at most three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CASSLLAGGSSYEQYF (SEQ ID NO: 285) or a variant thereof having at most three amino acid substitutions, additions or deletions;

[0025] (18) The immunogenic peptide is a mesothelin (MSLN) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CAAYNDYKLSF (SEQ ID NO: 293) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes the amino acid sequence of CASSLQGVNTEAFF (SEQ ID NO: 298) or a variant thereof having at most three amino acid substitutions, additions or deletions;

[0026] (19) The immunogenic peptide is a CTD phosphatase subunit 1 (CTDP1) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CAMREGTSGTYKYIF (SEQ ID NO: 306) or a variant thereof having up to three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CASSNSASRPEQYV (SEQ ID NO: 311) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0027] (20) The immunogenic peptide is a transformed acidic TACC2-containing peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence CAVSGLGGSNYKLTF (SEQ ID NO: 319) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and CDR3β comprises the amino acid sequence CASRSGTGTMDEQFF (SEQ ID NO: 324) or a variant thereof having at most three amino acid substitutions, additions, or deletions; or

[0028] (21) The immunogenic peptide is a prostaglandin F2 receptor negative regulator (PTGFRN) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CAVNRDDKIIF (SEQ ID NO: 332) or a variant thereof having up to three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CSARDYKQVLRGSYNSPLHF (SEQ ID NO: 337) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0029] In one aspect, the present invention provides a TCR that binds to the human epidermal growth factor receptor 2 (HER2) peptide when presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence of CAEGSRYGGATNKLIF (SEQ ID NO: 8) or a variant thereof having up to three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence of CASSTFPVETQYF (SEQ ID NO: 13) or a variant thereof having up to three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-NSASDY (SEQ ID NO: 6), CDR2α-IRSNMDK (SEQ ID NO: 7), CDR3α-CAEGSRYGGATNKLIF (SEQ ID NO: 8), CDR1β-MNHEY (SEQ ID NO: 11), CDR2β-SVGAGI (SEQ ID NO: 12), and CDR3β-CASSTFPVETQYF (SEQ ID NO: 13), or variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 9 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 14 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 10 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising the amino acid sequence of SEQ ID NO: 15 or a variant thereof having at least 70% sequence identity with it. Suitably, the HER2 peptide comprises or consists of the amino acid sequence of KIFGSLAFL (SEQ ID NO: 5) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0030] In one aspect, the present invention provides a TCR that binds to the PR3 peptide or the NE peptide when presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence of CATYYGQNFVF (SEQ ID NO: 22) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence of CASSFQGYTEAFF (SEQ ID NO: 27) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-VSGNPY (SEQ ID NO: 20), CDR2α-YITGDNLV (SEQ ID NO: 21), CDR3α-CADYYGQNFVF (SEQ ID NO: 22), CDR1β-MDHEN (SEQ ID NO: 25), CDR2β-SYDVKM (SEQ ID NO: 26), and CDR3β-CASSFQGYTEAFF (SEQ ID NO: 27), or variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 23 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 28 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 24 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising the amino acid sequence of SEQ ID NO: 29 or 30 or a variant thereof having at least 70% sequence identity with it. Suitably, the PR3 peptide or NE peptide comprises or consists of the amino acid sequence of VLQELNVTV (SEQ ID NO: 19) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0031] In one aspect, the present invention provides a TCR that binds to the EZH2 peptide or PRAME peptide when presented by the MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising (i) the amino acid sequence of CAVSESPTGFQKLVF (SEQ ID NO: 37) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CAVPHSYNTDKLIF (SEQ ID NO: 42) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising (i) the amino acid sequence of CASSPRGSNTGELFF (SEQ ID NO: 47) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CSARPSEAPQYF (SEQ ID NO: 53) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitablely, the TCR comprises the following CDR sequences: (i) CDR1α-SSVPPY (SEQ ID NO: 35), CDR2α-YTSAATLV (SEQ ID NO: 36), and CDR3α-CAVSESPTGFQKLVF (SEQ ID NO: 37) or (ii) CDR1α-VGISA (SEQ ID NO: 40), CDR2α-LSSGK (SEQ ID NO: 41), and CDR3α-CAVPHSYNTDKLIF (SEQ ID NO: 42); and (i) CDR1β-SNHLY (SEQ ID NO: 45), CDR2β-FYNNEI (SEQ ID NO: 46), and CDR3β-CASSPRGSNTGELFF (SEQ ID NO: 47) or (ii) CDR1β-DFQATT (SEQ ID NO: 51), CDR2β-SNEGSKA (SEQ ID NO: 42), and CDR3α-CAVPHSYNTDKLIF (SEQ ID NO: 42); and (ii) CDR1β-DFQATT (SEQ ID NO: 51), CDR2β-SNEGSKA (SEQ ID NO: 42), and CDR3α-CAVPHSYNTDKLIF (SEQ ID NO: 42). 52) and CDR3β-CSARPSEAPQYF (SEQ ID NO: 53), or variants thereof having up to three amino acid substitutions, additions or deletions.Suitablely, the TCR includes an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 38 or a variant thereof having at least 70% sequence identity with it or (ii) the amino acid sequence of SEQ ID NO: 43 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 48 or a variant thereof having at least 70% sequence identity with it or (ii) the amino acid sequence of SEQ ID NO: 54 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising (i) the amino acid sequence of SEQ ID NO: 39 or a variant thereof having at least 70% sequence identity with it, or (ii) the amino acid sequence of SEQ ID NO: 44 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising (i) the amino acid sequence of SEQ ID NO: 49 or a variant thereof having at least 70% sequence identity with it, or (ii) the amino acid sequence of SEQ ID NO: 55 or 56 or a variant thereof having at least 70% sequence identity with it. Suitably, the EZH2 peptide comprises or consists of the amino acid sequence of KESRPPRKF (SEQ ID NO: 32) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the PRAME peptide comprises or consists of the amino acid sequence of ALYVDSLFFL (SEQ ID NO: 34) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0032] In one aspect, the present invention provides a TCR that binds to a cathepsin G (CTSG) peptide when presented by an MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising (i) an amino acid sequence of CALPSARQLTF (SEQ ID NO: 61) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) an amino acid sequence of CAFMSPEGGSEKLVF (SEQ ID NO: 66) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising (i) an amino acid sequence of CSVPPAGLGAPEAFF (SEQ ID NO: 71) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) an amino acid sequence of CASSPGTGAYNSPLHF (SEQ ID NO: 77) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitablely, the TCR comprises the following CDR sequences: (i) CDR1α-ATGYPS (SEQ ID NO: 59), CDR2α-ATKADDK (SEQ ID NO: 60), and CDR3α-CALPSARQLTF (SEQ ID NO: 61) or (ii) CDR1α-TSENNYY (SEQ ID NO: 64), CDR2α-QEAYKQQN (SEQ ID NO: 65), and CDR3α-CAFMSPEGGSEKLVF (SEQ ID NO: 66); and (i) CDR1β-SQVTM (SEQ ID NO: 69), CDR2β-ANQGSEA (SEQ ID NO: 70), and CDR3β-CSVPPAGLGAPEAFF (SEQ ID NO: 71) or (ii) CDR1β-SEHNR (SEQ ID NO: 75), CDR2β-FQNEAQ (SEQ ID NO: 76), and CDR3β-FQNEAQ (SEQ ID NO: 70). 76) and CDR3β-CASSPGTGAYNSPLHF (SEQ ID NO: 77), or variants thereof having up to three amino acid substitutions, additions or deletions.Suitablely, the TCR includes an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 62 or a variant thereof having at least 70% sequence identity with it or (ii) the amino acid sequence of SEQ ID NO: 67 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 72 or a variant thereof having at least 70% sequence identity with it or (ii) the amino acid sequence of SEQ ID NO: 78 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising (i) the amino acid sequence of SEQ ID NO: 63 or a variant thereof having at least 70% sequence identity with it, or (ii) the amino acid sequence of SEQ ID NO: 68 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising (i) the amino acid sequence of SEQ ID NO: 73 or 74 or a variant thereof having at least 70% sequence identity with it, or (ii) the amino acid sequence of SEQ ID NO: 79 or 80 or a variant thereof having at least 70% sequence identity with it. Suitably, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of GIVSYGKSSGVPPEV (SEQ ID NO: 58) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0033] In one aspect, the present invention provides a TCR that binds to a cathepsin G (CTSG) peptide when presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence of CAVQASNDYKLSF (SEQ ID NO: 86) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence of CASSVGRATEAFF (SEQ ID NO: 91) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-VSGLRG (SEQ ID NO: 84), CDR2α-LYSAGEE (SEQ ID NO: 85), CDR3α-CAVQASNDYKLSF (SEQ ID NO: 86), CDR1β-MNHEY (SEQ ID NO: 89), CDR2β-SMNVEV (SEQ ID NO: 90), and CDR3β-CASSVGRATEAFF (SEQ ID NO: 91), or variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 87 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 92 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 88 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising the amino acid sequence of SEQ ID NO: 93 or 94 or a variant thereof having at least 70% sequence identity with it. Suitably, the CTSG peptide comprises or consists of the amino acid sequence of SXXXPXVFTRVSSFL (SEQ ID NO: 535) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or a fragment thereof. Suitably, the CTSG peptide comprises or consists of the amino acid sequence of SGVPPEVFTRVSSFL (SEQ ID NO: 81) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or a fragment thereof. In some embodiments, the CTSG peptide comprises or consists of SGVPPEVFTRVSSFL (SEQ ID NO: 81) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0034] In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of VFTRVSSFL (SEQ ID NO: 82) or a variant thereof having up to three amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of VPPEVFTRVSSFL (SEQ ID NO: 83) or a variant thereof having up to three amino acid substitutions, additions, or deletions.

[0035] In one aspect, the present invention provides a TCR that binds to the cathepsin G (CTSG) peptide when presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising (i) an amino acid sequence of CVVNWDNARLMF (SEQ ID NO: 98) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) an amino acid sequence of CATRRAKDRDDKIIF (SEQ ID NO: 459) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising (i) an amino acid sequence of CASSEEGGSTDTQYF (SEQ ID NO: 103) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) an amino acid sequence of CASSLGLAGDYEQYF (SEQ ID NO: 109) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitablely, the TCR comprises the following CDR sequences: (i) CDR1α-NSASQS (SEQ ID NO: 96), CDR2α-VYSSGN (SEQ ID NO: 97), CDR3α-CVVNWDNARLMF (SEQ ID NO: 98) or (ii) CDR1α-NSAFQY (SEQ ID NO: 457), CDR2α-TYSSGN (SEQ ID NO: 458), CDR3α-CATRRAKDRDDKIIF (SEQ ID NO: 459); and (i) CDR1β-SNHLY (SEQ ID NO: 101), CDR2β-FYNNEI (SEQ ID NO: 102) and CDR3β-CASSEEGGSTDTQYF (SEQ ID NO: 103) or (ii) CDR1β-SGHNS (SEQ ID NO: 107), CDR2β-FNNNVP (SEQ ID NO: 98). 108) and CDR3β-CASSLGLAGDYEQYF (SEQ ID NO: 109), or variants thereof having up to three amino acid substitutions, additions or deletions.Suitablely, the TCR includes an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 99 or a variant thereof having at least 70% sequence identity with it or (ii) the amino acid sequence of SEQ ID NO: 460 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 104 or a variant thereof having at least 70% sequence identity with it or (ii) the amino acid sequence of SEQ ID NO: 110 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising (i) the amino acid sequence of SEQ ID NO: 100 or a variant thereof having at least 70% sequence identity with it, or (ii) the amino acid sequence of SEQ ID NO: 461 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising (i) the amino acid sequence of SEQ ID NO: 105 or 106 or a variant thereof having at least 70% sequence identity with it, or (ii) the amino acid sequence of SEQ ID NO: 111 or 112 or a variant thereof having at least 70% sequence identity with it. Suitably, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of TMRSFKLLDQMETPL (SEQ ID NO: 95) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0036] In one aspect, the present invention provides a TCR that binds to the CCNA1 peptide when the cyclin A1 (CCNA1) peptide is presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence of CAFMKRLTQGGSEKLVF (SEQ ID NO: 119) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence of CASSEVYRGHEKLFF (SEQ ID NO: 124) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-TSENNYY (SEQ ID NO: 117), CDR2α-QEAYKQQN (SEQ ID NO: 118), CDR3α-CAFMKRLTQGGSEKLVF (SEQ ID NO: 119), CDR1β-SNHLY (SEQ ID NO: 122), CDR2β-FYNNEI (SEQ ID NO: 123), and CDR3β-CASSEVYRGHEKLFF (SEQ ID NO: 124), or variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 120 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 125 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 121 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising the amino acid sequence of SEQ ID NO: 126 or 127 or a variant thereof having at least 70% sequence identity with it. Suitably, the CCNA1 peptide comprises or consists of the following: a nonameric fragment of the amino acid sequence of TEYAEEIYQYL (SEQ ID NO: 114) or a variant thereof having at most three amino acid substitutions, additions, or deletions, preferably wherein the CTSG peptide comprises or consists of the following: the amino acid sequence of YAEEIYQYL (SEQ ID NO: 115) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0037] In one aspect, the present invention provides a TCR that binds to the CCNA1 peptide when the cyclin A1 (CCNA1) peptide is presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence of CAASIRSSGDKLTF (SEQ ID NO: 133) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence of CASSKRTGELFF (SEQ ID NO: 138) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitablely, the TCR comprises the following CDR sequences: CDR1α-DSASNY (SEQ ID NO: 131), CDR2α-IRSNVGE (SEQ ID NO: 132), CDR3α-CAASIRSSGDKLTF (SEQ ID NO: 133), CDR1β-MDHEN (SEQ ID NO: 136), CDR2β-SYDVKM (SEQ ID NO: 137), and CDR3β-CASSKRTGELFF (SEQ ID NO: 138), or variants thereof having up to three amino acid substitutions, additions, or deletions.

[0038] Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 134 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 139 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α-chain and a β-chain, the α-chain comprising the amino acid sequence of SEQ ID NO: 135 or a variant thereof having at least 70% sequence identity with it, and the β-chain comprising the amino acid sequence of SEQ ID NO: 140 or 141 or a variant thereof having at least 70% sequence identity with it. Suitably, the CCNA1 peptide comprises or consists of the following: a nonameric fragment of the amino acid sequence of PETLAAFTGYSLSEI (SEQ ID NO: 128) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0039] In one aspect, the present invention provides a TCR that binds to the CCNA1 peptide when the cyclin A1 (CCNA1) peptide is presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence of CALSETLYNQGGKLIF (SEQ ID NO: 144) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence of CASSLGTSRSYTDTQYF (SEQ ID NO: 149) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-TRDTTYY (SEQ ID NO: 142), CDR2α-RNSFDEQN (SEQ ID NO: 143), CDR3α-CALSETLYNQGGKLIF (SEQ ID NO: 144), CDR1β-SGHTA (SEQ ID NO: 147), CDR2β-FQGNSA (SEQ ID NO: 148), and CDR3β-CASSLGTSRSYTDTQYF (SEQ ID NO: 149), or variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 145 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 150 or a variant thereof having at least 70% sequence identity with it. Suitablely, the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 146 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising the amino acid sequence of SEQ ID NO: 151 or 152 or a variant thereof having at least 70% sequence identity with it.

[0040] In one aspect, the present invention provides a TCR that binds to the CCNA1 peptide when the cyclin A1 (CCNA1) peptide is presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising an amino acid sequence of CALTSDYKLSF (SEQ ID NO: 157) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising (i) an amino acid sequence of CATSDLFGELFF (SEQ ID NO: 162) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (i) an amino acid sequence of CASTTGIYEQYF (SEQ ID NO: 168) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitablely, the TCR comprises the following CDR sequences: CDR1α-SSNFYA (SEQ ID NO: 155), CDR2α-MTLNGDE (SEQ ID NO: 156), CDR3α-CALTSDYKLSF (SEQ ID NO: 157); and (i) CDR1β-KGHDR (SEQ ID NO: 160), CDR2β-SFDVKD (SEQ ID NO: 161) and CDR3β-CATSDLFGELFF (SEQ ID NO: 162) or (ii) CDR1β-SNHLY (SEQ ID NO: 166), CDR2β-FYNNEI (SEQ ID NO: 167) and CDR3β-CASTTGIYEQYF (SEQ ID NO: 168), or variants thereof having at most three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 158 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 163 or a variant thereof having at least 70% sequence identity with it, or (ii) the amino acid sequence of SEQ ID NO: 169 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α-chain and a β-chain, the α-chain comprising the amino acid sequence of SEQ ID NO: 159 or a variant thereof having at least 70% sequence identity with it, and the β-chain comprising (i) the amino acid sequence of SEQ ID NO: 164 or 165 or a variant thereof having at least 70% sequence identity with it, or (ii) the amino acid sequence of SEQ ID NO: 170 or 171 or a variant thereof having at least 70% sequence identity with it.Suitablely, the CCNA1 peptide comprises or consists of the following: a nonameric fragment of the amino acid sequence of AEL SLLEADPFLKYL (SEQ ID NO: 153) or a variant thereof having at most three amino acid substitutions, additions or deletions and / or a nonameric fragment of the amino acid sequence of LLEADPFLKYLPSLI (SEQ ID NO: 527) or a variant thereof having at most three amino acid substitutions, additions or deletions.

[0041] In one aspect, the present invention provides a TCR that binds to the CCNA1 peptide when the cyclin A1 (CCNA1) peptide is presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence of CAVNSWGKLQF (SEQ ID NO: 176) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence of CASHSGLVGTGELFF (SEQ ID NO: 181) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-TSGFNG (SEQ ID NO: 174), CDR2α-NVLDGL (SEQ ID NO: 175), CDR3α-CAVNSWGKLQF (SEQ ID NO: 176), CDR1β-MNHEY (SEQ ID NO: 179), CDR2β-SMNVEV (SEQ ID NO: 180), and CDR3β-CASHSGLVGTGELFF (SEQ ID NO: 181), or variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 177 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 182 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 178 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising the amino acid sequence of SEQ ID NO: 183 or 184 or a variant thereof having at least 70% sequence identity with it. Suitably, the CCNA1 peptide comprises or consists of the following: a nonameric fragment of the amino acid sequence of WEGPGLPDFVF (SEQ ID NO: 172) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0042] In one aspect, the present invention provides a TCR that binds to the CCNA1 peptide when the cyclin A1 (CCNA1) peptide is presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence of CASTNFGNEKLTF (SEQ ID NO: 192) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence of CASSLSYEQYF (SEQ ID NO: 197) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-TSESDYY (SEQ ID NO: 190), CDR2α-QEAYKQQN (SEQ ID NO: 191), CDR3α-CASTNFGNEKLTF (SEQ ID NO: 192), CDR1β-PRHDT (SEQ ID NO: 195), CDR2β-FYEKMQ (SEQ ID NO: 196), and CDR3β-CASSLSYEQYF (SEQ ID NO: 197), or variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 193 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 198 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 194 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising the amino acid sequence of SEQ ID NO: 199 or 200 or a variant thereof having at least 70% sequence identity with it. Suitably, the CCNA1 peptide comprises or consists of the following: a nonameric fragment of the amino acid sequence KRQLLKMEHLLLKVL (SEQ ID NO: 185) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0043] In one aspect, the present invention provides a TCR that binds to the CCNA1 peptide when the cyclin A1 (CCNA1) peptide is presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising (i) the amino acid sequence of CAVRSHSGNTPLVF (SEQ ID NO: 206) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CAENAGGTSYGKLTF (SEQ ID NO: 211) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (iii) the amino acid sequence of CAMRLPIPNNAGNMLTF (SEQ ID NO: 216) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising (i) the amino acid sequence of CASSSPRVGPLYEQYF (SEQ ID NO: 221) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) CASSDHDIYNEQFF (SEQ ID NO: 221) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) CASSDHDIYNEQFF (SEQ ID NO: 221) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (iii) a variant thereof having at most three amino acid substitutions, additions, or deletions, or (iv) a variant thereof having at most three amino acid substitutions, additions, or deletions, or (v ... (ii) The amino acid sequence of (ii) 227 or a variant thereof having at most three amino acid substitutions, additions or deletions, or (iii) The amino acid sequence of CASWAEEAEETQYF (SEQ ID NO: 233) or a variant thereof having at most three amino acid substitutions, additions or deletions.Suitablely, the TCR comprises the following CDR sequences: (i) CDR1α-TSGFYG (SEQ ID NO: 204), CDR2α-NALDGL (SEQ ID NO: 205), and CDR3α-CAVRSHSGNTPLVF (SEQ ID NO: 206) or (ii) CDR1α-NSASDY (SEQ ID NO: 209), CDR2α-IRSNMDK (SEQ ID NO: 210), and CDR3α-CAENAGGTSYGKLTF (SEQ ID NO: 211) or (iii) CDR1α-TSDQSYG (SEQ ID NO: 214), CDR2α-QGSYDEQN (SEQ ID NO: 215), and CDR3α-CAMRLPIPNNAGNMLTF (SEQ ID NO: 216); and (i) CDR1β-SEHNR (SEQ ID NO: 209). 219), CDR2β-FQNEAQ (SEQ ID NO: 220) and CDR3β-CASSSPRVGPLYEQYF (SEQ ID NO: 221) or (ii) CDR1β-SEHNR (SEQ ID NO: 225), CDR2β-FQNEAQ (SEQ ID NO: 226) and CDR3β-CASSDHDIYNEQFF (SEQ ID NO: 227) or (iii) CDR1β-SNHLY (SEQ ID NO: 231), CDR2β-FYNNEI (SEQ ID NO: 232) and CDR3β-CASWAEEAEETQYF (SEQ ID NO: 233), or variants thereof having at most three amino acid substitutions, additions or deletions. Suitablely, the TCR includes an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 207 or a variant thereof having at least 70% sequence identity with it, or (ii) the amino acid sequence of SEQ ID NO: 212 or a variant thereof having at least 70% sequence identity with it, or (iii) the amino acid sequence of SEQ ID NO: 217 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 222 or a variant thereof having at least 70% sequence identity with it, or (ii) the amino acid sequence of SEQ ID NO: 228 or a variant thereof having at least 70% sequence identity with it, or (iii) the amino acid sequence of SEQ ID NO: 234 or a variant thereof having at least 70% sequence identity with it.Suitablely, the TCR comprises an α chain and a β chain, the α chain comprising (i) the amino acid sequence of SEQ ID NO: 208 or a variant thereof having at least 70% sequence identity with it, or (ii) the amino acid sequence of SEQ ID NO: 213 or a variant thereof having at least 70% sequence identity with it, or (iii) the amino acid sequence of SEQ ID NO: 218 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising (i) the amino acid sequence of SEQ ID NO: 223 or 224 or a variant thereof having at least 70% sequence identity with it, or (ii) the amino acid sequence of SEQ ID NO: 229 or 230 or a variant thereof having at least 70% sequence identity with it, or (iii) the amino acid sequence of SEQ ID NO: 235 or 236 or a variant thereof having at least 70% sequence identity with it. Suitablely, the CCNA1 peptide comprises or consists of the following: a nonameric fragment of the amino acid sequence of PETLAAFTGYSLSEI (SEQ ID NO: 201) or a variant thereof having at most three amino acid substitutions, additions or deletions.

[0044] In one aspect, the present invention provides a TCR that binds to the DKK1 peptide when the Dickkopf-associated protein A1 (DKK1) peptide is presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence of CAVGAWYNQGGKLIF (SEQ ID NO: 241) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence of CASSFGVTGELFF (SEQ ID NO: 246) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-YGATPY (SEQ ID NO: 239), CDR2α-YFSGDTLV (SEQ ID NO: 240), CDR3α-YFSGDTLV (SEQ ID NO: 241), CDR1β-SGHDY (SEQ ID NO: 244), CDR2β-FNNNVP (SEQ ID NO: 245), and CDR3β-CASSFGVTGELFF (SEQ ID NO: 246), or variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 242 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 247 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 243 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising the amino acid sequence of SEQ ID NO: 248 or 249 or a variant thereof having at least 70% sequence identity with it. Suitably, the DKK1 peptide comprises or consists of the amino acid sequence of ILYPGGNKV (SEQ ID NO: 238) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0045] In one aspect, the present invention provides a TCR that binds to the mucin-5AC (MUC5AC) peptide when presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence of CAGGGSGAGSYQLTF (SEQ ID NO: 254) or a variant thereof having up to three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence of CAISDPTGDNQPQHF (SEQ ID NO: 259) or a variant thereof having up to three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-DRGSQS (SEQ ID NO: 252), CDR2α-IYSNGD (SEQ ID NO: 253), CDR3α-CAGGGSGAGSYQLTF (SEQ ID NO: 254), CDR1β-ENHRY (SEQ ID NO: 257), CDR2β-SYGVKD (SEQ ID NO: 258), and CDR3β-CAISDPTGDNQPQHF (SEQ ID NO: 259), or variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 255 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 260 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 256 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising the amino acid sequence of SEQ ID NO: 261 or 262 or a variant thereof having at least 70% sequence identity with it. Suitably, the MUC5AC peptide comprises or consists of the amino acid sequence of FLNDAGACV (SEQ ID NO: 251) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0046] In one aspect, the present invention provides a TCR that binds to the AGR2 peptide when the current gradient protein-2 (AGR2) peptide is presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence of CAVQDYGQNFVF (SEQ ID NO: 267) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence of CASSPTGSEQYF (SEQ ID NO: 272) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-VSGLRG (SEQ ID NO: 265), CDR2α-LYSAGEE (SEQ ID NO: 266), CDR3α-CAVQDYGQNFVF (SEQ ID NO: 267), CDR1β-MNHEY (SEQ ID NO: 270), CDR2β-SMNVEV (SEQ ID NO: 271), and CDR3β-CASSPTGSEQYF (SEQ ID NO: 272), or variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 268 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 273 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 269 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising the amino acid sequence of SEQ ID NO: 274 or 275 or a variant thereof having at least 70% sequence identity with it. Suitably, the AGR2 peptide comprises or consists of the amino acid sequence of LLVALSYTL (SEQ ID NO: 264) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0047] In one aspect, the present invention provides a TCR that binds to a c-MET peptide when the c-MET peptide is presented by an MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence of CAAAPNNNDMRF (SEQ ID NO: 280) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence of CASSLLAGGSSYEQYF (SEQ ID NO: 285) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-DSASNY (SEQ ID NO: 278), CDR2α-IRSNVGE (SEQ ID NO: 279), CDR3α-CAAAPNNNDMRF (SEQ ID NO: 280), CDR1β-MNHEY (SEQ ID NO: 283), CDR2β-SVGAGI (SEQ ID NO: 284), and CDR3β-CASSLLAGGSSYEQYF (SEQ ID NO: 285), or variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 281 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 286 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 282 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising the amino acid sequence of SEQ ID NO: 287 or 288 or a variant thereof having at least 70% sequence identity with it. Suitably, the c-MET peptide comprises or consists of the amino acid sequence of YVDPVITSI (SEQ ID NO: 277) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0048] In one aspect, the present invention provides a TCR that binds to the mesothelin (MSLN) peptide when presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence of CAAYNDYKLSF (SEQ ID NO: 293) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence of CASSLQGVNTEAFF (SEQ ID NO: 298) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-SSNFYA (SEQ ID NO: 291), CDR2α-MTLNGDE (SEQ ID NO: 292), CDR3α-CAAYNDYKLSF (SEQ ID NO: 293), CDR1β-MNHEY (SEQ ID NO: 296), CDR2β-SMNVEV (SEQ ID NO: 297), and CDR3β-CASSLQGVNTEAFF (SEQ ID NO: 298), or variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 294 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 299 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 295 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising the amino acid sequence of SEQ ID NO: 300 or 301 or a variant thereof having at least 70% sequence identity with it. Suitably, the MSLN peptide comprises or consists of the amino acid sequence of KLLGPHVLGV (SEQ ID NO: 290) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0049] In one aspect, the present invention provides a TCR that binds to the CTDP1 peptide when the CTD phosphatase subunit 1 (CTDP1) peptide is presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence of CAMREGTSGTYKYIF (SEQ ID NO: 306) or a variant thereof having up to three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence of CASSNSASRPEQYV (SEQ ID NO: 311) or a variant thereof having up to three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-TSDPSYG (SEQ ID NO: 304), CDR2α-QGSYDQQN (SEQ ID NO: 305), CDR3α-CAMREGTSGTYKYIF (SEQ ID NO: 306), CDR1β-SEHNR (SEQ ID NO: 309), CDR2β-FQNEAQ (SEQ ID NO: 310), and CDR3β-CASSNSASRPEQYV (SEQ ID NO: 311), or variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 307 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 312 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 308 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising the amino acid sequence of SEQ ID NO: 313 or 314 or a variant thereof having at least 70% sequence identity with it. Suitably, the CTDP1 peptide comprises or consists of the amino acid sequence of YLNKEIEEA (SEQ ID NO: 303) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0050] In one aspect, the present invention provides a TCR that binds to the TACC2 peptide when the acidic coil-and-coil-containing peptide is presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising the amino acid sequence CAVSGLGGSNYKLTF (SEQ ID NO: 319) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprising the amino acid sequence CASRSGTGTMDEQFF (SEQ ID NO: 324) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-SSVPPY (SEQ ID NO: 317), CDR2α-YTSAATLV (SEQ ID NO: 318), CDR3α-CAVSGLGGSNYKLTF (SEQ ID NO: 319), CDR1β-MNHNY (SEQ ID NO: 322), CDR2β-SVGAGI (SEQ ID NO: 323), and CDR3β-CASRSGTGTMDEQFF (SEQ ID NO: 324), or variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 320 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 325 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 321 or a variant thereof having at least 70% sequence identity with it, and the β chain comprising the amino acid sequence of SEQ ID NO: 326 or 327 or a variant thereof having at least 70% sequence identity with it. Suitably, the TACC2 peptide comprises or consists of the amino acid sequence of YRNSYEIEY (SEQ ID NO: 316) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0051] In one aspect, the present invention provides a TCR that binds to a prostaglandin F2 receptor negative regulator (PTGFRN) peptide when presented by MHC, wherein the TCR comprises CDR3α and CDR3β, the CDR3α comprising CAVNRDDKIIF (SEQ ID NO:

[0052] The CDR3β comprises the amino acid sequence of CSARDYKQVLRGSYNSPLHF (SEQ ID NO: 332) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1α-DSAIYN (SEQ ID NO: 330), CDR2α-IQSSQRE (SEQ ID NO: 331), CDR3α-CAVNRDDKIIF (SEQ ID NO: 332), CDR1β-DFQATT (SEQ ID NO: 335), CDR2β-SNEGSKA (SEQ ID NO: 336), and CDR3β-CSARDYKQVLRGSYNSPLHF (SEQ ID NO: 337), or a variant thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 333 or a variant thereof having at least 70% sequence identity with it, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 338 or a variant thereof having at least 70% sequence identity with it. Suitably, the TCR comprises an α-chain and a β-chain, the α-chain comprising the amino acid sequence of SEQ ID NO: 334 or a variant thereof having at least 70% sequence identity with it, and the β-chain comprising the amino acid sequence of SEQ ID NO: 339 or 340 or a variant thereof having at least 70% sequence identity with it. Suitably, the PTGFRN peptide comprises or consists of the amino acid sequence of RLASRPLLL (SEQ ID NO: 329) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0053] In some embodiments, the TCR includes one or more mutations at the α-chain / β-chain interface such that the mismatch frequency between the chain and the endogenous TCR α-chain and β-chain is reduced when the α-chain and β-chain are expressed in T cells. In some embodiments, the TCR includes one or more mutations at the α-chain / β-chain interface such that the expression levels of the TCR α-chain and β-chain are increased when the α-chain and β-chain are expressed in T cells. In some embodiments, the one or more mutations introduce cysteine ​​residues into the constant region domains of each of the α-chain and β-chain, wherein the cysteine ​​residues are capable of forming disulfide bonds between the α-chain and the β-chain. In some embodiments, the one or more mutations are located at amino acid positions selected from those disclosed in Table 1 of Boulter, JM et al. (2003) Protein Engineering 16: 707-711.

[0054] In some embodiments, the TCR includes one or more mutations to remove one or more N-glycosylation sites (see, for example, Kuball, J et al. (2009) J Exp Med 206: 463-75). Suitably, the N-glycosylation site is located within a constant domain of the TCR. In some embodiments, the mutation is a substitution of amino acid N in the NXS / T motif with amino acid Q. For example, the substitution may occur at one or more of the following positions: constant TCR α gene positions 36, 90, or 109; and / or constant TCR β gene position 85.6. In some embodiments, the substitution is located at constant TCR α gene position 36.

[0055] In some implementations, the TCR includes a mouse-derived constant region.

[0056] In some implementations, the TCR is a soluble TCR.

[0057] In another aspect, the present invention provides a polynucleotide encoding an α chain of a T-cell receptor (TCR) according to the invention and / or a β chain of a TCR according to the invention. In some embodiments, the polynucleotide encodes the α chain linked to the β chain. In some embodiments, the polynucleotide further encodes one or more short interfering RNAs (siRNAs) or other agents capable of reducing or preventing the expression of one or more endogenous TCR genes.

[0058] In another aspect, the present invention provides a vector comprising a polynucleotide according to the invention. In some embodiments, the vector is a plasmid or a viral vector. In some embodiments, the vector comprises a polynucleotide encoding one or more CD3 strands, CD8, a suicide gene, and / or selectable markers.

[0059] In another aspect, the present invention provides a cell comprising the TCR of the present invention, the polynucleotide of the present invention, or the vector of the present invention. In some embodiments, the cell further comprises a vector encoding one or more CD3 chains, CD8, a suicide gene, and / or selectable markers.

[0060] In one aspect, the present invention provides a cell comprising the TCR of the present invention, the polynucleotide of the present invention, or the vector of the present invention, and further comprising a vector encoding CD8. For example, when the TCR of the present invention is a cathepsin G-specific TCR, a vector encoding CD8 may be used. In some embodiments, the vector encodes a CD8 α chain. In some embodiments, the vector encodes a CD8 β chain. In some embodiments, the vector encodes both a CD8 α chain and a CD8 β chain. For example, a vector encoding both the CD8 α chain and the CD8 β chain may allow expression of a CD8 αβ heterodimer.

[0061] The cells of this invention can be any suitable cells. Suitably, the cells are T cells, lymphocytes, or stem cells. In some embodiments, the cells are selected from the group consisting of: CD4+ cells, CD8+ cells, naive T cells, memory stem T cells, central memory T cells, double-negative T cells, effector memory T cells, effector T cells, Th0 cells, Tc0 cells, Th1 cells, Tc1 cells, Th2 cells, Tc2 cells, Th17 cells, Th22 cells, γ / δ T cells, natural killer (NK) cells, natural killer T (NKT) cells, cytokine-induced killer (CIK) cells, hematopoietic stem cells, and pluripotent stem cells. In some embodiments, the cells are T cells. In some embodiments, the cells are T cells that have been isolated from a subject.

[0062] In some embodiments, the endogenous genes encoding the TCR α chain and / or the endogenous genes encoding the TCR β chain in the cells are disrupted, suitably so that the endogenous genes encoding the TCR α chain and / or the endogenous genes encoding the TCR β chain are not expressed. In some embodiments, the endogenous genes encoding the TCR α chain and / or the endogenous genes encoding the TCR β chain are disrupted by inserting an expression cassette comprising a polynucleotide sequence encoding the TCR of the present invention. In some embodiments, one or more endogenous genes encoding MHC are disrupted, suitably wherein the cells are allogeneic reactive universal T cells. In some embodiments, endogenous genes involved in persistence, amplification, activity, resistance to exhaustion / senescence / inhibition signals, homing ability, or other T cell functions are disrupted. Suitablely, said endogenous genes involved in persistence, amplification, activity, resistance to exhaustion / senescence / inhibition signals, homing ability, or other T cell functions are selected from the group consisting of: PD1, TIM3, LAG3, 2B4, KLRG1, TGFbR, CD160, TIGIT, CTLA4, and CD39. In some embodiments, said endogenous genes involved in persistence, amplification, activity, resistance to exhaustion / senescence / inhibition signals, homing ability, or other T cell functions are disrupted by integration of an expression cassette, said expression cassette comprising a polynucleotide sequence encoding the TCR of the present invention.

[0063] In some embodiments, the endogenous genes encoding the TCR α chain and the endogenous genes encoding the TCR β chain in the cell are disrupted, appropriately preventing the expression of the endogenous genes encoding the TCR α chain and the endogenous genes encoding the TCR β chain. In some embodiments, the endogenous gene encoding TIGIT is disrupted, appropriately preventing the expression of the endogenous gene encoding TIGIT. In some embodiments, the endogenous gene encoding CD39 is disrupted, appropriately preventing the expression of the endogenous gene encoding CD39.

[0064] In some embodiments, the endogenous genes encoding the TCR α chain, the TCR β chain, and the TIGIT in the cell are disrupted, appropriately causing the endogenous genes encoding the TCR α chain, the TCR β chain, and the TIGIT to be unexpressed.

[0065] In some embodiments, the endogenous genes encoding the TCR α chain, the TCR β chain, and the CD39 in the cell are disrupted, appropriately causing the endogenous genes encoding the TCR α chain, the TCR β chain, and the CD39 to be unexpressed.

[0066] In some embodiments, the endogenous genes encoding the TCR α chain, the TCR β chain, TIGIT, and CD39 in the cell are disrupted, appropriately causing the endogenous genes encoding the TCR α chain, the TCR β chain, TIGIT, and CD39 to be unexpressed.

[0067] In another aspect, the present invention provides a T cell that is genetically engineered (e.g., through gene editing) to modulate persistence, expansion, activity, resistance to exhaustion / senescence / inhibition signals, homing ability, or other T cell functions, wherein the T cell expresses the TCR α chain and / or the TCR β chain of the present invention.

[0068] In another aspect, the present invention provides a T cell that has been genetically engineered (e.g., through gene editing) by means of: targeting an expression cassette into an endogenous gene involved in persistence, amplification, activity, resistance to exhaustion / senescence / inhibition signals, homing ability, or other T cell functions, which has been disrupted by an artificial nuclease, wherein the expression cassette comprises a polynucleotide sequence encoding the TCR α chain and / or the TCR β chain of the present invention.

[0069] In another aspect, the present invention provides a method for preparing cells, the method comprising, for example, introducing the polynucleotide or vector of the present invention into cells in vitro, ex vivo, or in vivo by transfection or transduction.

[0070] In another aspect, the present invention provides a method for preparing cells, the method comprising the step of transducing cells in vitro, in vitro, or in vivo using one or more carriers of the present invention.

[0071] In some implementations, the cells to be transduced or transfected are selected from the group consisting of: T cells, lymphocytes, or stem cells, such as hematopoietic stem cells or induced pluripotent stem cells (iPS). In some implementations, the cells to be transduced or transfected are selected from the group consisting of: CD4+ cells, CD8+ cells, Th0 cells, Tc0 cells, Th1 cells, Tc1 cells, Th2 cells, Tc2 cells, Th17 cells, Th22 cells, γ / δ T cells, natural killer (NK) cells, natural killer T (NKT) cells, double-negative T cells, naive T cells, memory stem T cells, central memory T cells, effector memory T cells, effector T cells, cytokine-induced killer (CIK) cells, hematopoietic stem cells, and pluripotent stem cells.

[0072] In some embodiments, the method of preparing cells includes a step of T cell editing, the step of which includes destroying an endogenous gene encoding the TCR α chain and / or an endogenous gene encoding the TCR β chain with an artificial nuclease, optionally wherein the artificial nuclease is selected from the group consisting of zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR / Cas system.

[0073] In some embodiments, the method of preparing cells includes the step of targeting and integrating an expression cassette into an endogenous gene encoding the TCR α chain and / or an endogenous gene encoding the TCR β chain that has been disrupted by the artificial nuclease, wherein the expression cassette comprises a polynucleotide sequence encoding the TCR of the present invention or a polynucleotide sequence of the present invention.

[0074] In some embodiments, the method of preparing cells includes the step of destroying one or more endogenous genes encoding MHC, wherein suitably the cells prepared by the method are allogeneic reactive universal T cells.

[0075] In some embodiments, the method of preparing cells includes the step of disrupting one or more endogenous genes to modulate persistence, amplification, activity, resistance to exhaustion / senescence / inhibition signals, homing ability, or other T cell functions. Optionally, the method includes the step of targeting an expression cassette into an endogenous gene involved in persistence, amplification, activity, resistance to exhaustion / senescence / inhibition signals, homing ability, or other T cell functions that has been disrupted by an artificial nuclease. The expression cassette includes a polynucleotide sequence encoding the TCR of the present invention. Suitably, the endogenous gene is selected from the group consisting of PD1, TIM3, LAG3, 2B4, KLRG1, TGFbR, CD160, TIGIT, CTLA4, and CD39.

[0076] In some embodiments, the method of preparing cells includes the step of disrupting endogenous genes encoding the TCR α chain and endogenous genes encoding the TCR β chain. In some embodiments, the method of preparing cells includes the step of disrupting the endogenous TIGIT gene. In some embodiments, the method of preparing cells includes the step of disrupting the endogenous genes encoding the TCR α chain, the endogenous genes encoding the TCR β chain, and the endogenous TIGIT gene. In some embodiments, the method of preparing cells includes the step of disrupting the endogenous CD39 gene. In some embodiments, the method of preparing cells includes the step of disrupting the endogenous genes encoding the TCR α chain, the endogenous genes encoding the TCR β chain, the endogenous TIGIT gene, and the endogenous CD39 gene. In some embodiments, the method of preparing cells includes the step of disrupting the endogenous genes encoding the TCR α chain, the endogenous genes encoding the TCR β chain, the endogenous TIGIT gene, and the endogenous CD39 gene.

[0077] In some implementations, two endogenous genes encoding the TCR β chain (e.g., TRBC1 and TRBC2) are disrupted.

[0078] In another aspect, the present invention provides a chimeric molecule comprising the TCR or a portion thereof of the present invention, conjugated to a noncellular substrate, a toxin, and / or an antibody. In some embodiments, the noncellular substrate is selected from the group consisting of nanoparticles, exosomes, and other noncellular substrates.

[0079] In another aspect, the present invention provides a pharmaceutical composition comprising the TCR of the present invention, the polynucleotide of the present invention, the carrier of the present invention, the cell of the present invention, the cell prepared by the method of the present invention, or the chimeric molecule of the present invention.

[0080] In another aspect, the present invention provides cells of the present invention or cells prepared by the methods of the present invention, said cells for use in adoptive cell transfer, suitably for use in adoptive T cell transfer, optionally wherein said adoptive T cell transfer is allogeneic adoptive T cell transfer, autologous adoptive T cell transfer or universal non-allogeneic reactive adoptive T cell transfer.

[0081] In another aspect, the present invention provides the TCR of the present invention, the polynucleotide of the present invention, the carrier of the present invention, the cell of the present invention, the cell prepared by the method of the present invention, the chimeric molecule of the present invention, or the pharmaceutical composition of the present invention, wherein the TCR, the polynucleotide, the carrier, the cell, the chimeric molecule, or the pharmaceutical composition is used in a therapy.

[0082] In another aspect, the present invention provides a TCR of the present invention, a polynucleotide of the present invention, a carrier of the present invention, a cell of the present invention, a cell prepared by the method of the present invention, a chimeric molecule of the present invention, or a pharmaceutical composition of the present invention, wherein the TCR, the polynucleotide, the carrier, the cell, the chimeric molecule, or the pharmaceutical composition is used for the treatment and / or prevention of proliferative disorders.

[0083] In another aspect, the present invention provides a method for treating and / or preventing proliferative disorders, the method comprising the steps of administering to a subject in need the TCR of the present invention, the polynucleotide of the present invention, the carrier of the present invention, the cell of the present invention, the cell prepared by the method of the present invention, the chimeric molecule of the present invention, or the pharmaceutical composition of the present invention.

[0084] The proliferative condition may be a hematologic malignancy or a solid tumor. Suitably, the hematologic malignancy is selected from the group consisting of: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphoblastic leukemia, acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, lymphoma, multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma. Suitably, the solid tumor is selected from the group consisting of: lung cancer, breast cancer, esophageal cancer, gastric cancer, colon cancer, bile duct cancer, pancreatic cancer, ovarian cancer, head and neck cancer, synovial sarcoma, angiosarcoma, osteosarcoma, thyroid cancer, oral cancer, hepatocellular carcinoma, bladder cancer, endometrial cancer, neuroblastoma, rhabdomyosarcoma, liver cancer, melanoma, prostate cancer, kidney cancer, soft tissue sarcoma, urothelial carcinoma, bile duct cancer, glioblastoma, cervical cancer, mesothelioma, and colorectal cancer. In some embodiments, the proliferative condition is acute myeloid leukemia (AML). In some implementations, the proliferative condition is colorectal cancer and / or pancreatic cancer.

[0085] In another aspect, the present invention provides an immunogenic cathepsin G (CTSG) peptide comprising or composed of an amino acid sequence selected from or composed of an amino acid sequence selected from: GIVSYGKSSGVPPEV (SEQ ID NO: 58), SXXXPXVFTRVSSFL (SEQ ID NO: 535), SGVPPEVFTRVSSFL (SEQ ID NO: 81), TMRSFKLLDQMETPL (SEQ ID NO: 95), and variants thereof, each having at most three amino acid substitutions, additions, or deletions. Suitably, the fragment has a length of nine or more amino acids. In some embodiments, the fragment is a nonameric fragment.

[0086] In some embodiments, the CTSG peptide comprises or consists of the following: GIVSYGKSSGVPPEV (SEQ ID NO: 58) or a variant thereof having up to three amino acid substitutions, additions or deletions, or a fragment thereof.

[0087] In some embodiments, the CTSG peptide comprises or consists of the following: SXXXPXVFTRVSSFL (SEQ ID NO: 535) or a variant thereof having up to three amino acid substitutions, additions, or deletions, or an immunogenic fragment thereof. In some embodiments, the CTSG peptide comprises or consists of the following: the amino acid sequence of SGVPPEVFTRVSSFL (SEQ ID NO: 81) or a variant thereof having up to three amino acid substitutions, additions, or deletions, or a fragment thereof. In some embodiments, the CTSG peptide comprises or consists of the following: the amino acid sequence of VFTRVSSFL (SEQ ID NO: 82) or a variant thereof having up to three amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the following: the amino acid sequence of VPPEVFTRVSSFL (SEQ ID NO: 83) or a variant thereof having up to three amino acid substitutions, additions, or deletions.

[0088] In some embodiments, the CTSG peptide comprises or is composed of the following: TMRSFKLLDQMETPL (SEQ ID NO: 95) or a variant thereof having at most three amino acid substitutions, additions or deletions, or a fragment thereof.

[0089] In another aspect, the present invention provides an immunogenic cyclin A1 (CCNA1) peptide comprising or composed of an amino acid sequence selected from or composed of an amino acid sequence selected from: TEYAEEIYQYL (SEQ ID NO: 114), PETLAAFTGYSLSEI (SEQ ID NO: 128), AELSLLLEADPFLKYL (SEQ ID NO: 153), LLEAPFLKYLPSLI (SEQ ID NO: 527), WEGPGLPDFVF (SEQ ID NO: 172), KRQLLKMEHLLLKVL (SEQ ID NO: 185), PETLAAFTGYSLSEI (SEQ ID NO: 201), and variants thereof, each having at most three amino acid substitutions, additions, or deletions. Suitably, the fragment has a length of nine or more amino acids. In some embodiments, the fragment is a nonameric fragment.

[0090] In some embodiments, the CCNA1 peptide comprises or consists of the following: TEYAEEIYQYL (SEQ ID NO: 114) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or a fragment thereof. In some embodiments, the CCNA1 peptide comprises or consists of the following: amino acid sequences of YAEEIYQYL (SEQ ID NO: 115), EYAEEIYQY (SEQ ID NO: 116) or variants thereof having at most three amino acid substitutions, additions, or deletions.

[0091] In some embodiments, the CCNA1 peptide comprises or consists of the following: PETLAAFTGYSLSEI (SEQ ID NO: 128) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or a fragment thereof. In some embodiments, the CCNA1 peptide comprises or consists of the following: amino acid sequences of ETLAAFTGY (SEQ ID NO: 129), LAAFTGYSL (SEQ ID NO: 130) or variants thereof having at most three amino acid substitutions, additions, or deletions.

[0092] In some embodiments, the CCNA1 peptide comprises or consists of: AELSLLLEADPFLKYL (SEQ ID NO: 153) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or a fragment thereof. In some embodiments, the CCNA1 peptide comprises or consists of: LLEADFLKYLPSLI (SEQ ID NO: 527) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or a fragment thereof. In some embodiments, the CCNA1 peptide comprises or consists of: the amino acid sequence of EADPFLKYL (SEQ ID NO: 154) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0093] In some embodiments, the CCNA1 peptide comprises or consists of the following: WEGPGLPDFVF (SEQ ID NO: 172) or a variant thereof having up to three amino acid substitutions, additions, or deletions, or a fragment thereof. In some embodiments, the CCNA1 peptide comprises or consists of the following: the amino acid sequence of GPGLPDFVF (SEQ ID NO: 173) or a variant thereof having up to three amino acid substitutions, additions, or deletions.

[0094] In some embodiments, the CCNA1 peptide comprises or is composed of the following: KRQLLKMEHLLLKVL (SEQ ID NO: 185) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or a fragment thereof. In some embodiments, the CCNA1 peptide comprises or is composed of the following: amino acid sequences of RQLLKMEHL (SEQ ID NO: 186), MEHLLLKVL (SEQ ID NO: 187), MEHLLLKV (SEQ ID NO: 188), KMEHLLLKV (SEQ ID NO: 189) or variants thereof having at most three amino acid substitutions, additions, or deletions.

[0095] In some embodiments, the CCNA1 peptide comprises or consists of the following: PETLAAFTGYSLSEI (SEQ ID NO: 201) or a variant thereof having up to three amino acid substitutions, additions, or deletions, or a fragment thereof. In some embodiments, the CCNA1 peptide comprises or consists of the following: amino acid sequences of ETLAAFTGY (SEQ ID NO: 202), LAAFTGYSL (SEQ ID NO: 203) or variants thereof having up to three amino acid substitutions, additions, or deletions.

[0096] In another aspect, the present invention provides a TCR that binds to an immunogenic CTSG peptide when the CTSG peptide is presented by the major histocompatibility complex (MHC), wherein the immunogenic CTSG peptide comprises or is composed of: SXXXPXVFTRVSSFL (SEQ ID NO: 535) or a variant thereof having at most three amino acid substitutions, additions or deletions, or an immunogenic fragment thereof.

[0097] In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SGVPPEVFTRVSSFL (SEQ ID NO: 81) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or a fragment thereof. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of VFTRVSSFL (SEQ ID NO: 82) or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of VPPEVFTRVSSFL (SEQ ID NO: 83) or a variant thereof having at most three amino acid substitutions, additions, or deletions. Attached Figure Description

[0098] Figure 1 - Using 17 types of HLA-A 02:01 Evaluation of the immune response in T lymphocytes derived from healthy donors after stimulation with immunogenic peptides.

[0099] T lymphocytes from two healthy donors (LAA-HD3 and LAA-HD5) were combined with HLA-A antigen-derived antigens. 02:01 Immunogenic peptides (including EZH2, PRAME, PR3, and NE) or autologous APCs pulsed with an irrelevant peptide pool were co-cultured for 6 hours. Antigen-specific amplification of T lymphocytes was evaluated by flow cytometry, measuring CD107a production and IFN-γ secretion. (A) Results for LAA-HD3 (A, left) and LAA-HD5 (A, right) show greater CD107a and IFN-γ production in response to the LAA pool compared to the irrelevant pool. (B) Clonal amplification of T lymphocytes was evaluated by flow cytometry using a kit covering 70% of the human TCR Vβ repertoire. Results for LAA-HD3, and amplification of TRBV2, TRBV4-1, TRBV4-2, TRBV4-3, and TRBV28 are shown. (C) and (D) LAA-T cells amplified from two healthy donors were characterized by TCR αβ sequencing after several stimulations with the peptide pool. Sequencing results indicated the presence of major clonoids in LAA-HD3 (C) and LAA-HD5 (D). A pie chart depicts the contribution of the most predominant CDR3 amino acid sequence identified at the last time point (e.g., S4 corresponds to sequencing obtained after the fourth round of stimulation) to the TCR repertoire evaluated at each stimulation. Remaining sequences are grouped together in white. HD, healthy donor; S, stimulation; SP, sub-pool; APC, antigen-presenting cell; TRBV, T cell receptor β-chain variable gene; HD, healthy donor; LAA, leukemia-associated antigen; irrelevant, irrelevant peptide pool; CDR3, complementarity-determining region 3; S, stimulation; TRAV, T cell receptor α-chain variable gene; TRAJ, T cell receptor α-chain linker gene; TRBJ, T cell receptor β-chain linker gene; TRBD, T cell receptor β-chain diversity gene.

[0100] Figure 2 - Deconvolution of the mapped grid enables the identification of immunogenic epitopes.

[0101] We identified sub-pools capable of inducing T cell-mediated immune responses by co-culturing T lymphocytes with autologous irradiated APCs previously pulsed with nine SPs containing 17 immunogenic peptides for 6 hours. The results are shown for LAA-HD3 (left) with two immunogenic SPs (SP3 and SP6) and LAA-HD5 (right) with three immunogenic SPs (SP1, SP2, and SP9). HD: healthy donor; S: stimulation; SP: sub-pool; APC: antigen-presenting cell.

[0102] Figure 3 - Evaluation of CTSG-specific T cell enrichment from HD.

[0103] (A) T cells isolated from two HDs (CTSG-HD1, CTSG-HD2) were co-cultured with autologous APCs pulsed with either a CTSG peptide pool or an unrelated peptide pool for 6 hours. The occurrence of CTSG-specific responses was determined by measuring CD107a expression and IFNγ secretion in T cells. The results show the following: enrichment of CTSG-specific lymphocytes over time in cultures stimulated three times with the peptide pool; and the presence of 10%–15% CTSG-specific T cells in HD1 (left) and HD2 (right). (B) Characterization of the Vβ repertoire. Clonal expansion of CTSG-specific T cells isolated from HD1 was evaluated by flow cytometry. Results showed major expression of three Vβs in HD1 (TRBV4-3, TRBV9, and TRBV27). (C) Identification of immunogenic SPs for each HD. SPs inducing immune responses in each analyzed HD were identified by co-culturing T cells with autologous APCs pulsed with each of the 16 CTSG SPs. The results identified SP5, SP6, SP8, SP12, and SP15 of HD1 (C, left) and SP5 and SP16 of HD2 (C, right). Peptides 29, 30, 32, 53, 54, and 56 were identified as potential targets of HD1 (left) by deconvolution of the mapped grid (C, bottom table), while peptide 61 was identified as a potential target of HD2 (right). (D) To confirm the immunogenicity of the identified peptides, T cells were co-cultured with APCs pulsed with individual peptides for 6 hours. The results showed an increased response of CTSG-HD1 T cells to peptides P54 and P56. HD, healthy donor; HLA, human leukocyte antigen; EBV-BLCL, EBV-transformed B lymphoblast cell line; CG, cathepsin G; P, peptide; unr, irrelevant peptide.

[0104] Figure 4 HLA restriction of -CTSG-HD1 T lymphocytes.

[0105] (A) The table shows the EBV cell lines used to identify HLA-restricted CTSG-HD1 T cells. HLA elements carried by EBV cells and shared with HD1 are shown in bold. (B) T lymphocytes from CTSG-HD1 were co-cultured with EBV-BLCL cells that have a restriction element identical to HD1 and pulsed with P54, P56, or an unrelated peptide. When T cells were co-cultured with APCs pulsed with P54, IFNγ production was observed for EBV-BLCL 1 (left side), and for EBV-BLCL 2, 4, and 5, indicating that when P54 is pulsed in HLA-A... When presented on the 02:01 allele, T cells recognize P54, and when P56 is presented on HLA-A... 24:02 and HLA-C At 07:02, upon presentation on the limiting element, T cells recognize P56 (right side). HLA, Human Leukocyte Antigen; EBV-BLCL, EBV-transformed B lymphoblast cell line; CG, cathepsin G; P56, Peptide 56; unrel, irrelevant peptide; CTSG-HD1, cathepsin G-healthy donor 1.

[0106] Figure 5 - Longitudinal TCR sequencing of enriched CTSG-specific T cells.

[0107] After several stimulations with the CTSG pool, T cells generated from two healthy donors included in the experimental setting were characterized by TCR αβ sequencing. Sequencing results showed that CTSG-HD1 (A, B) and CTSG-HD2 (C) had major clonoids. For HD1, we identified two expanded T cell populations that specifically recognized p54 (A) or p56 (B) of the peptide pool. A pie chart depicts the contribution of the most predominant CDR3 amino acid sequence identified at the last time point (e.g., S8 corresponds to the sequencing result obtained after the 8th round of stimulation) to the TCR repertoire evaluated at each stimulation. The remaining sequences are grouped together in white. CDR3, complementarity-determining region 3; S, stimulation; TRAV, T cell receptor α chain variable gene; TRBV, T cell receptor β chain variable gene; TRAJ, T cell receptor α chain linker gene; TRBJ, T cell receptor β chain linker gene; TRBD, T cell receptor β chain diversity gene.

[0108] Figure 6 - T cells specific to P56 were generated and functionally validated through TCR gene transfer and TCR gene editing methods.

[0109] (A) Evaluation of disruption of the endogenous TCR repertoire and CTSG-P56 TCR expression in edited T cells by measuring CD3 surface expression in untransduced or LV-transduced T cells, respectively. (B) Evaluation of disruption of the endogenous TCR repertoire and CTSG-P56 TCR expression in edited T cells by measuring HLA-A expression. 24:02 (EBV-BLCL No. 6) or HLA-C 07:02 (EBV-BLCL 5) T cell function was evaluated by CD107a expression and IFNγ secretion in T cells after 6 hours of co-culturing with EBV cell lines pulsed with P56. Cells that had undergone transfer or TCR editing were used as effector cells in the assay. (C) Phenotypic characterization of edited T cells in terms of TCR disruption efficiency (C, left), expression of the P56-TCR-specific Vβ region (C, middle), and memory phenotype (C, right). HLA, Human Leukocyte Antigen; EBV-BLCL, EBV-transformed B lymphoblast cell line; CTSG, Cathepsin G; P56, Peptide 56; unrel, Irrelevant peptide; TRBV, T cell receptor β chain variable gene; TSCM, Memory Stem T cell; TCM, Central Memory T cell; TEMRA, Terminally Differentiated Effector Memory T cell; TEM, Effector Memory T cell; KO, Knockout.

[0110] Figure 7 -P56αβ-edited T cells recognize HLA-A VFT nonamer on the 24:02 allele, while in HLA-C 07:02 The nonamer identification is not displayed on the limiting element.

[0111] (A) We used online tools to predict the relationship between nonamericomers derived from P56 and HLA-A. 24:02 and HLA-C 07:02 Allele binding affinity. This tool predicts the binding affinity of alleles derived from HLA-A. 24:02 The weak binding affinity of the VFTRVSSFL82 nonamer presented by the molecule (left side) and the HLA-C The same peptide presented at 07:02 showed weak binding affinity, yet it was predicted to bind with a higher affinity to the EVFTRVSSF (SEQ ID NO: 42) nonamer (right side). (B) Edited P56αβ T cells were coupled with HLA-A expression cells. 24:02 or HLA-C 07:02 The limiting element was co-cultured with EBV-BLCL pulses derived from the nonamer and decamer of P56 for 6 hours. When the P7 nonamer (VFTRVSSFL-SEQ ID NO: 82) was generated by HLA-A At 24:02, CD107a production was observed only in T lymphocytes responding to P7 nonamer. (C) Edited P56αβ T cells were compared with HLA-C-expressing cells. 07:02 Alleles were co-cultured with EBV-BLCL pulsed with P56, nonameric and decameric P56. After 6 hours, CD107a production was higher when T lymphocytes were co-cultured with P56-pulsed EBV cells. (D) Edited P56αβ T lymphocytes were co-cultured with HLA-C pulsed with P12, P13 and P56. 07:02 EBV-BLCL co-culture. After 6 hours, CD107a expression and cytokine secretion were assessed, and results showed an increase in percentage after co-culture with P13 and P56. (E) To determine the effects of P13 and P56 on HLA-C 07:02 Allele affinity profile, which will express HLA-C 07:02 EBV-BLCL alleles were used with p13 or p56 alone or with high affinity HLA-C. At 07:02, a combined pulse of the binding peptide (RYRPGTVAL-SEQ ID NO: 423) was administered, and the cells were co-cultured with edited P56 TCR T cells for 6 hours. Comparable CD107a expression and cytokine secretion were detected under P13 and P56 conditions alone, as well as in the presence of a competitor. Sort %, sort percentage; 9mer, nonamer; P56, peptide 56; P1, nonamer 1; P2, nonamer 2; P3, nonamer 3; P4, nonamer 4; p5, nonamer 5; p6, nonamer 6; p7, nonamer 7 (VFT nonamer); p10, decamer; P56αβ, edited T lymphocytes transduced with LV encoding P56αβ TCR; EBV-BLCL, EBV-transformed B lymphoblast cell line; 15mer, 15-amino acid-long peptide; APC, antigen-presenting cell; P12, 12-amino acid-long peptide derived from peptide 56; P13, 13-amino acid-long peptide derived from peptide 56; CTR, high-affinity HLA-C 07:02 Binding peptide (RYRPGTVAL).

[0112] Figure 8 - Determination of P56αβ TCR affinity when recognizing homologous peptides on target cells.

[0113] (A) P56 TCRαβ-edited T lymphocytes were pulsed with HLA-A using a low concentration of P7 nonamer. 24:02 EBV-BLCL (A, top) and HLA-C pulsed with low concentrations of P13 (A, middle) and P56 (A, bottom) 07:02 EBV-BLCL co-culture. CD107a expression and cytokine secretion were evaluated as reads by flow cytometry. (B) LogEC50 values ​​show the profile of low affinity of P56 TCRαβ for the P7 nonamer; higher affinity for P13, but highest affinity for P56. Unstimulated, no target cells added to T cells; PMA / lono, PMA and ionomycin positive controls; P7, P7 nonamer; P13, a 13-amino acid long peptide derived from peptide 56; TCR, T cell receptor; EBV-BLCL, EBV-transformed B lymphoblast cell line; EC50, effector concentration 50.

[0114] Figure 9 - Only HLA-A is expressed 24:02 allele or HLA-C 07:02 Evaluation of the natural processing of the immunogenic epitope derived from peptide 56 on the surface of primary leukemia blast cells with alleles.

[0115] (AB) Edited P56 TCRαβ T lymphocytes were co-cultured for 24 hours with the following: (A) pAML1 and pAML2 (expressing only HLA-A) (24:02 alleles); (B) pAML3, pAML4, and pAML5 (expressing only HLA-C) 07:02 alleles); and (A and B) pAML6 and pAML7 (for HLA-A) 24:02 and HLA-C 07:02 Alleles were negative (as a negative control). T lymphocytes and leukemia blasts were spread at different E:T ratios (5:1; 1:1; 1:5). As an additional negative control, in the absence of T lymphocytes, the corresponding number of leukemia cells were also spread at different E:T ratios. The elimination index of AML blasts was calculated using the following formula: 1 - ((count of leukemia cells at different E:T ratios (5:1; 1:1; 1:5)) / (count of the same leukemia cell alone)). A value of 0 indicates that leukemia cells were not eliminated, while a value of 1 indicates that leukemia cells were completely eliminated. Results are presented as mean standard error (SEM) (N=3). pAML, primary acute myeloid leukemia.

[0116] Figure 10 - Evaluation of cyclin A1-specific T cell enrichment from HD.

[0117] (AC) T cells isolated from three cyclin A1-HD1, cyclin A1-HD2, and cyclin A1-HD3 groups were co-cultured with autologous APCs pulsed with either a cyclin A1 peptide pool or an irrelevant peptide pool for 6 hours. The occurrence of cyclin A1-specific responses was determined by measuring CD107a expression and IFNγ secretion in the T cells. Results showed enrichment of tumor-specific CD8+ and CD4+ T lymphocytes for HD1 (A); 50% enrichment of cyclin A1-specific T cells for HD2 (B); and stepwise enrichment of cyclin A1-specific T cells for HD3 (C). HD represents healthy donors.

[0118] Figure 11 - Identification of peptide pools that elicit T-cell responses.

[0119] Immunogenic SPs for each HD were identified. SPs inducing immune responses in each analyzed HD were identified by co-culturing T cells with autologous APCs pulsed with each of the 22 cyclin A1 SPs. (A) For HD1, the results identified SP4, SP5, SP6, SP8, SP9, SP10, SP12, SP16, SP18, and SP20 of HD1 CD8+ T cells (A, top) and SP3 and SP21 of HD1 CD4+ T cells (A, bottom). (B) For cyclin A1 HD2 T cells, we observed immune responses against SP3, SP4, and SP21. (C) For HD3 cyclin A1 T cells, we observed smaller but still perceptible immune responses against SP3 and SP21.

[0120] Figure 12 - Assessment of immunogenic peptides.

[0121] To confirm the immunogenicity of the identified peptides, T cells were co-cultured with APCs pulsed with individual peptides for 6 hours. Results confirmed that CD4+ (A) and CD8+ (B) cyclin A1-HD1 T cells recognized P102 and P52-P53, respectively. T cells from passaged culture SP12 were co-cultured with SP12 and individual peptides belonging to SP (P4, P5, P6, P7, P10). Analysis showed recognition of P6 and P7 (C). T cells from passaged culture SP20 were co-cultured with SP20 and individual peptides belonging to SP (P92, P93, P94, P95, P98). Analysis showed recognition of P93 and P94 (D). (E) Because P52 and P53 are overlapping peptides, to identify the exact nonamer recognized by HD1 T cells, we co-cultured T cells with APCs pulsed with P52, P53, overlapping 11mer sequences, and three separate nonamers (TEY, EYA, YAE) derived from the 11mer portion. Functional assays showed CD107a expression and IFNg secretion when T cells were co-cultured with APCs pulsed with YAE nonamers. (F) For cyclin A1-HD2 T cells, we confirmed SP19 recognition, and in particular, we identified the immunogenic peptide P81. (G) For cyclin A1-HD3 T cells, we identified peptide P102 as a peptide that elicits an immune response. HD, healthy donor; SP, daughter pool; P, peptide.

[0122] Figure 13 - HLA restriction in cyclin A1-specific T lymphocytes.

[0123] The table shows the EBV cell lines used to identify HLA-restricted cyclin A1-HD2 and HD3 T cells (A and B, left panel). HLA elements carried by EBV cells and shared with HD2 and HD3 are highlighted. T lymphocytes from cyclin A1-HD2 T cells were co-cultured with EBV-BLCL cells that have a restriction element identical to that of HD2 cells and pulsed with P81 or an unrelative peptide. For EBV-BLCL cells 3 and 7 pulsed with P81, IFNγ production and CD107a secretion were observed (A, right panel). For cyclin A1-HD3, we observed recognition of the two EBV cell lines used for assays (B, right panel). HLA, Human Leukocyte Antigen; EBV-BLCL, EBV-transformed B lymphoblast cell line; P81, Peptide 81; unrel, unrelative peptide; HD, healthy donor.

[0124] Figure 14 cellular fluorescence immunoassay of T cell population.

[0125] Characterizing the Vβ repertoire. (A) Evaluation of clonal expansion of T cells specific for cyclin A1 isolated from HD1, HD2, and HD3 by flow cytometry. For HD1 T cells, we performed analyses after 5 and 7 stimulations, clearly observing which Vβs were enriched over time and could therefore be considered specific for epitope recognition. For HD2 (B) and HD3 (C) T cells, we observed significant expansion of one Vβ chain from HD2 and two Vβ chains from HD3. TRBV, variable region of the T cell receptor β chain.

[0126] Figure 15 - Longitudinal TCR sequencing of cyclin A1-enriched cyclin A1-specific T cells.

[0127] After several stimulations with the cyclin A1 pool, T cells generated from three healthy donors included in the experimental setting were characterized by TCR αβ sequencing. Sequencing results showed the presence of major clonoids in different passage cultures derived from HD1 (AE), HD2 (F), and HD3 (G). The pie chart depicts the contribution of the most dominant CDR3 amino acid sequence identified at the last time point (e.g., S8 corresponds to the sequencing result obtained after the 8th round of stimulation) to the TCR repertoire evaluated at each stimulation, with gray shading. The remaining sequences are grouped together in white. CDR3, complementarity-determining region 3; S, stimulation; TRAV, T cell receptor α chain variable gene; TRBV, T cell receptor β chain variable gene; TRAJ, T cell receptor α chain linker gene; TRBJ, T cell receptor β chain linker gene; TRBD, T cell receptor β chain diversity gene.

[0128] Figure 16 - T cells specific to cyclin A1 were generated and functionally validated through TCR gene transfer and TCR gene editing methods.

[0129] (A) Disruption of the endogenous TCR repertoire and distinct TCR expression in edited T cells were evaluated by measuring the surface expression of CD3 and specific Vβ in untransduced or LV-transduced T cells, respectively. (D) Transgenic T cell function was evaluated by measuring CD107a expression and IFNγ secretion in CD8+ and CD4+ T cells after 6 hours of co-culturing with autologous target cells pulsed with specific peptides or irrelevant peptides. Transduced or TCR-edited cells were used as effector cells in the assays. P, peptide; SP, subpool; UT, untransduced; ED, edited; TR, transduced.

[0130] Figure 17 - HLA restriction in cyclin A1-specific T lymphocytes.

[0131] (A) Table shows the EBV cell lines used to identify HLA-restricted cyclin A1-HD1 T cell passage cultures specific for P102 and P52 / P53. HLA elements carried by EBV cells and shared with HD1 are highlighted. For EBV-BLCL 9 pulsed with P52 / P53, IFNγ production and CD107a secretion were observed (left), thus indicating that the restricting element for P52 / 53 TCR is HLA-B. 35:02, and for EBV-BLCL 12 (right side) using P102 pulse, this indicates that the limiting element of P102 TCR is HLA-DRB1. 07:01 or HLA-DQB1 02:02. (B) We validated the results by using only the EBV cell lines identified in the first assay as target cells and transgenic T cells generated using TCR transfer or TCR gene editing protocols as effector cells to perform the functional assay. Both TCRs were able to activate CD4 and CD8 T cells. HLA, Human Leukocyte Antigen; EBV-BLCL, EBV-transformed B lymphoblast cell line; P, Peptide; unr, Irrelevant Peptide; HD, Healthy Donor.

[0132] Figure 18 - T cells engineered to express a TCR specific to the nonameric peptide P52 / P53 eliminate primary leukemia blasts.

[0133] For example, the cellular fluorescence evaluation of target cell killing can be determined by measuring caspase 3 activation after co-culturing with edited T cells. AML1-derived blast cells express HLA-DRB1. 07:01 and HLA-DQB1 The 02:02 allele is present, while AML2 blast cells express HLA-B. 35:02 alleles. ED, edited; P, peptide; AML, acute myeloid leukemia.

[0134] Figure 19 Tumor-specific T-cell expansion in peripheral blood mononuclear cells

[0135] The frequency of CD107a, IFN-γ, TNF-α, and IL-2 positive cells in T cells co-cultured for 6 hours with autologous APCs loaded with unrelated peptides or (A) PDAC or (B) CRC-specific peptide pools is shown.

[0136] Figure 20 - Identification of tumor immunogenic peptides

[0137] The frequency of CD107a, IFN-γ, TNF-α, and IL-2 positive cells in T cells co-cultured for 6 hours with autologous APCs loaded with separate peptide pools for PDAC (AC, left panel) and CRC (D, E, left panel) is shown. A mapping grid defines the peptide pools, where each peptide is present in only two intersecting sub-pools. Peptide-specific recognition was confirmed after co-culturing with autologous APCs or T2 cell lines containing peptide pulses (AE, right panel).

[0138] Figure 21 -Clonal tracking of tumor-specific T cells

[0139] After several stimulations with PDAC or CRC pools, the resulting T cells were characterized by TCRαβ sequencing. Sequencing results showed the presence of a major clonality for each T cell culture analyzed. A pie chart depicts the contribution of the most predominant CDR3 amino acid sequence identified at the last time point (e.g., S8 corresponds to the sequencing result obtained after the 8th round of stimulation) to the TCR repertoire evaluated at each stimulation. The remaining sequences are grouped together in white. (A) DKK1 TCR; (B) MUC5AC TCR; (C) AGR2 TCR; (D) c-MET TCR; (E) MSLN TCR; (F) HER2 TCR; (G) CTDP1 TCR; (H) TACC2TCR; (I) PTGFRN TCR. CDR3, complementarity-determining region 3; S, stimulus; TRAV, variable gene for the α-chain of the T-cell receptor; TRBV, variable gene for the β-chain of the T-cell receptor; TRAJ, α-chain linker gene for the T-cell receptor; TRBJ, β-chain linker gene for the T-cell receptor; TRBD, β-chain diversity gene for the T-cell receptor.

[0140] Figure 22 - Expanded HER2-specific T cells recognize and eliminate HER2+HLA-A2+ cancer cell lines and patient-derived organoids in vitro.

[0141] (A) HER2-transgenic T cells (n=3) were co-cultured with HLA-A0201+ PDAC cell lines (PANC1, BxPCR-A2+, T3M4) at an effector-to-target ratio of 5:1 for 24 hours. Killing is expressed as the area (µm) covered by cells undergoing apoptosis (caspase 3 / 7 activation) over time. 2(B) HER2-transgenic T cells (n=5) were co-cultured with luciferase+HLA-A0201+PDAC cell lines (PANC1, T3M4, and BxPC3-A2+) and HLA-A0201-one (BxPC3-A2-) as a control at an effector-to-target ratio of 1:1 for 24 hours. Specific killing was evaluated by measuring luciferase activity 24 hours after co-culture. The elimination index was calculated as: [1 - (luciferase activity of the target cell line with T cells / luciferase activity of the target cell line alone)]. (C) HER2-transgenic T cells (n=3) were co-cultured with colorectal cancer organoids (PDO) derived from one patient at an effector-to-target ratio of 5:1 for 48 hours. Killing was expressed as the area (µm) covered by cells undergoing apoptosis (caspase 3 / 7 activation). 2 (D) Timeline of in vivo experiments. Luciferase-enzymatic PDO was transplanted into the liver. T cells were injected intrahepatically after 3 days, and a second T cell administration was administered intravenously on day 10. Bioluminescent evaluation of tumor growth (E). Data are presented as mean ± SD. Statistical significance was assessed by fitting linear regression curves of observed outcomes (A, C) or by two-way ANOVA (B, E). P < 0.001 and P < 0.0001.

[0142] Figure 23 - Expanded MSLN-specific T cells recognized and killed Ag+HLA-A0201+ cancer cell lines and patient-derived organoids in vitro.

[0143] (A) MSLN-transgenic T cells (n=3) were co-cultured with the HLA-A0201+ PDAC cell line (PANC1) at an effector-to-target ratio of 5:1 for 24 hours. Killing is expressed as the area (µm) covered by target cells that have undergone apoptosis (caspase 3 / 7 activation) over time. 2 (B) MSLN-transgenic T cells (n=3) were co-cultured with the HLA-mismatched PDAC cell line (BxPC3) as a control at an effector-to-target ratio of 5:1 for 24 hours. Killing is expressed as the area (µm) covered by cells undergoing apoptosis (caspase 3 / 7 activation) over time. 2(C) MSLN-transgenic T cells (n=3) were co-cultured for 50 hours with colorectal cancer organoids derived from one primary tumor (effectant to target ratio 5:1) (left) and one liver metastasis (effectant to target ratio 10:1) (right). Data were normalized at the first useful time point and expressed as mean ± SEM. Statistical significance was assessed by fitting a linear regression curve to the observations. P < 0.05 P < 0.01, P < 0.001, and P < 0.0001

[0144] Figure 24 - Expanded DKK1-specific T cells recognized and killed Ag+HLA-A0201+ cancer cell lines and patient-derived organoids in vitro.

[0145] (A) DKK1-transgenic T cells (n=3) were co-cultured with the HLA-A0201+ PDAC cell line (PANC1) at an effector-to-target ratio of 5:1 for 24 hours. Killing is expressed as the area (µm) covered by target cells that have undergone apoptosis (caspase 3 / 7 activation) over time. 2 (B) DKK1-transgenic T cells (n=3) were co-cultured with the HLA-mismatched PDAC cell line (BxPC3) as a control at an effector-to-target ratio of 5:1 for 24 hours. Killing is expressed as the area (µm) covered by cells undergoing apoptosis (caspase 3 / 7 activation) over time. 2 (C) DKK1-transgenic T cells (n=3) were co-cultured for 50 hours with colorectal cancer organoids derived from one primary tumor (effectant to target ratio 5:1) (left) and one liver metastasis (effectant to target ratio 10:1) (right). Data for the first useful time points are presented as mean ± SEM. Statistical significance was assessed by fitting linear regression curves to the observations. P < 0.05 P < 0.01, P < 0.001, and P < 0.0001

[0146] Figure 25 - Expanded AGR2-specific T cells recognized and killed Ag+HLA-A0201+ cancer cell lines and patient-derived organoids in vitro.

[0147] (A) AGR2-transgenic T cells (n=3) were co-cultured with the HLA-A0201+ PDAC cell line (PANC1) at an effector-to-target ratio of 5:1 for 24 hours. Killing is expressed as the area (µm) covered by target cells that have undergone apoptosis (caspase 3 / 7 activation) over time. 2 (B) AGR2-transgenic T cells (n=3) were co-cultured with the HLA-mismatched PDAC cell line (BxPC3) as a control at an effector-to-target ratio of 5:1 for 24 hours. Killing is expressed as the area (µm) covered by cells undergoing apoptosis (caspase 3 / 7 activation) over time. 2 (C) AGR2-transgenic T cells (n=3) were co-cultured for 50 hours with colorectal cancer organoids derived from one primary tumor (effectant to target ratio 5:1) (left) and one liver metastasis (effectant to target ratio 10:1) (right). Data for the first useful time points are presented as mean ± SEM. Statistical significance was assessed by fitting a linear regression curve to the observations. P < 0.05 P < 0.01, P < 0.001, and P < 0.0001.

[0148] Figure 26 -PR3-TCR engineered T cells target HLA-A expression 02:01+ cytotoxic activity of antigen in leukemia cells.

[0149] (A) Transduction efficiency was measured as the percentage of cells expressing CD3 on their surface, CD3 serving as a surrogate marker of TCR expression (left) and a memory phenotype of edited lymphocytes. (B) In comparison with HLA-A 02:01+ peptide pulses in the degranulation capacity and cytokine secretion of engineered T cells after co-culturing with T2 cells. (C) Bar graphs show the killing efficiency of engineered T cells when co-cultured with leukemia cell lines (K562 and THP1), which was measured by determining the elimination index calculated as follows: [1 - (target cells in co-culture / target cells in single culture)]. The plotted data represent the mean ± SEM of 6 biological replicas from the K562 Tg dataset and the mean ± SEM of 5 biological replicas from the THP1 dataset. (D) Comparison with HLA-A 02:01+ blastoblasts (pAML 8 and pAML 9) or pAML10 (HLA-A) as a control (02:01-) Kill assays were performed on TCR-edited T cells cultured for 24 hours. Notably, in pAML 9, an increased elimination index was observed compared to HLA-mismatched pAML 10 at 1:1 and 1:5 ratios. Data are presented as bar graphs depicting the mean ± SEM of the three biological replicas. The memory subset was defined as follows: T SCM (CD45RA+CD62L+CD95+), T CM (CD45RA-CD62L+), T EM (CD45RA-CD62L-), T EMRA (CD45+CD62L-). PR3, protease 3; HLA, human leukocyte antigen; unrel, irrelevant; CM, central memory; SCM, stem cell memory; EM, effector memory; EMRA, terminal differentiation effector memory; E:T, effector and target; pAML, primary acute myeloid leukemia cells; interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ).

[0150] Figure 27 -CTSG TCR transduced T cells recognize target cells in a CD8 co-receptor-dependent manner.

[0151] A) Engineered T cells and peptide pulses with HLA-A 24:02+ or HLA-C Co-culture of 07:02+ cells showed that lymphocytes expressing CD8+ TCRs could effectively recognize target cells (showing promise in both degranulation and T cell activation). B) Experimental setting used to improve cell viability by exogenously adding CD8 co-receptors. Briefly, after disrupting the endogenous TCR repertoire, naked T cells were first transduced with a LV encoding the CTSG-TCR chain, and then co-transduced with a lentiviral vector (LV) encoding the CD8αβ chain. C) After co-transduction with a CD8-encoding LV, T cells expressing dual-transduced CD4+CD8+ CTSG-TCRs could effectively recognize HLA-A peptide pulses compared to T lymphocytes expressing CD4+ TCRs. 24:02+ or HLA-C 07:02+EBV-BLCL. Data are presented as a bar chart depicting the mean ± SEM of the three biological replicas. CTSG or CG, cathepsin G; HLA, human leukocyte antigen; unrel, irrelevant; EBV-BLCL, EBV-transformed B lymphoblast cell line.

[0152] Figure 28 -CTSG-TCR T cell production.

[0153] A) Experimental layout for engineered T cells expressing CTSG-TCR alone (CTSG-TCR T cells) or in combination with a CD8 co-receptor expressing CTSG-TCR (CTSG-TCR+CD8 T cells). T cells were expanded using G-Rex cell culture plates after TCR gene editing. B) Editing efficiency (left), memory phenotype (middle), and CD4 / CD8 subset composition of the engineered T cell products (right). C) HLA-A in relation to peptide pulses. 24:02+ or HLA-C 07:02+ In vitro evaluation of T cell specificity after co-culture with EBV-BLCL. The results of the obtained G-Rex-expanded T cells summarize the ability of lymphocytes to recognize target cells in an HLA-specific manner and the increased degranulation (top) and activation (bottom) abilities of dual-transduced CD4+CD8+ TCR+ T cells (CTSG-TCR CD4+CD8+ T cells) compared to single-transduced CD4+ TCR+ lymphocytes (CTSG-TCR CD4+ T cells). Data are presented as bar graphs depicting the mean ± SEM of the three biological replicas. The memory subset is defined as follows: T SCM (CD45RA+CD62L+CD95+), T CM (CD45RA-CD62L+), T EM (CD45RA-CD62L-), T EMRA(CD45+CD62L-). CTSG or CG, cathepsin G; HLA, human leukocyte antigen; unrel, irrelevant; CM, central memory; SCM, stem cell memory; EM, effector memory; EMRA, terminal differentiation effector memory; EBV-BLSL, EBV-transformed B lymphoblast cell line.

[0154] Figure 29 - Engineered T cells persisted and expanded in mice carrying leukemia.

[0155] A) Study design for in vivo testing. Timeline of the AML in vivo model. On day -3, mice received 1.5-2 × 10⁻⁶ mmol / L. 6 10 × 10 pAML blastocytes were administered intravenously, followed by 10 × 10 on day 0. 6 Infusion of edited T cells expressing CTSG-TCR. Longitudinal monitoring of T cell and leukemia dynamics was performed weekly via retroorbital blood collection. The schematic diagram depicts two different groups of mice receiving leukemia infusions. Group 1 (top) received HLA-A infusion. 24:02+ blast cells, of which n=6 mice were treated with CTSG-TCR+CD8 transduced T cells, while 4 mice were left untreated. HLA-C was infused into the second group (see below). 07:02+ Leukemia blasts. In this group, nine mice were left untreated, while n=11 and n=7 mice were injected with CTSG-TCR-specific T cells co-transduced with or without the CD8 construct. At sacrifice, tongue, ear, spleen, bone marrow, and peripheral blood were collected. B) Persistence of TCR-T cells in the peripheral circulation of treated mice. HLA-A-carrying mice infused with CTSG TCR+CD8 T cells. 24:02+AML mice (left panel; data in the plot are presented as mean ± SEM of six biological replicas) and HLA-C-carrying mice infused with CTSG TCR+CD8 T cells or CTSG TCR alone. 07:02+AML mice (right figure; data for the plot are represented as mean ± SEM of eleven biological replicas from the CTSG+CD8 subgroup and seven biological replicas from the CTSG subgroup). C and D) were used to treat mice infused with HLA-A 24:02+ (left image) and HLA-C The CD4 / CD8 subset composition (C) and memory phenotype (D) of engineered T cell products from mice with 07:02+ (right image: top image represents CTSG-TCR+CD8 T cells, bottom image represents CTSG-TCR T cells). The memory subset is defined as follows: T SCM (CD45RA+CD62L+CD95+), TCM (CD45RA-CD62L+), T EM (CD45RA-CD62L-), T EMRA (CD45+CD62L-). CTSG or CG, cathepsin G; HLA, human leukocyte antigen; pAML, primary acute myeloid leukemia cells.

[0156] Figure 30 In vivo evaluation of the anti-tumor efficacy of T cells.

[0157] A) AML growth halo measured as primary leukemia blast cell count / μl during the experimental period. The left image indicates HLA-A-carrying cells in untreated or infused CTSG TCR+CD8 T cells. Leukemia burden in 24:02+AML mice (data in the plot are represented as mean ± SEM of six biological replicas in the treatment group and four biological replicas in the control group). The right panel indicates HLA-C-carrying mice that have not been treated or have received CTSG TCR+CD8 T cells and CTSG TCR T cells. Leukemia burden in 07:02+AML mice (data presented as mean ± SEM of seven biological replicas in the CTSG subgroup, eleven biological replicas in the CTSG+CD8 subgroup, and nine biological replicas in the control group). B) A plot depicting the percentage of blast cells present in bone marrow and spleen samples at sacrifice. The results demonstrate the effectiveness of CTSG-TCR T cells and CTSG-TCR+CD8 engineered T cells in reducing tumor growth halo. Conversely, tumor expansion was observed in untreated mice with both types of leukemia. Data presented as six biological replicas in the CTSG+CD8 subgroup and HLA-A Four biological replicas from the 24:02+pAML control group (left image), seven biological replicas from the CTSG subgroup, eleven biological replicas from the CTSG+CD8 subgroup, and HLA-C. 07:02+ pAML control group: mean ± SEM of five biological replicas (right figure). C) This figure shows the HLA-C carriers treated with CTSG+CD8 engineered T cells. CD3+ dynamics over time in mice at 07:02+. This result highlights poor T-cell engraftment over time in mice 17 and 18 (dataset CTSG+CD8) compared to the rest of the mice, which may explain the reduced control of leukemia burden in the mouse bone marrow. In fact, mice 17 and 18 represent two mice in which CTSG+CD8-edited T-cell therapy clearly failed to effectively control leukemia growth (as shown by the triangles and squares in the % of blast cells in the bone marrow in the middle plot of B). Data from the CTSG+CD8 subgroup are presented as mean ± SEM of nine biological replicas. D) These plots depict the change in body weight of each mouse at various time points during the in vivo study (each line represents one mouse), which was calculated as: [(body weight at each time point / basal body weight before T-cell infusion) × 100]. The left plot depicts the infusion of untreated HLA-A The results of mice with 24:02+ leukemia blast cells (top image) and n=6 mice treated with CTSG TCR+CD8 T cells (bottom image). The right image represents mice carrying HLA-C. Weight trends of mice at 07:02+: n=9 untreated mice (top); n=11 mice infused with CTSG TCR+CD8 T cells (middle); and n=7 mice infused with CTSG TCR T cells (bottom).

[0158] Statistical significance was assessed using a two-way ANOVA multiple comparison test, and the obtained p-values ​​indicated [significance / statistics]. p < 0.0001. CTSG, cathepsin G; HLA, human leukocyte antigen.

[0159] Figure 31 -TCR T cells recovered from ex vivo retain their specificity and function.

[0160] By measuring HLA-A infused 24:02+ or HLA-C The degranulation capacity (left panel) and activation status (right panel) of lymphocytes harvested from the spleens of selected mice treated with engineered T cell products or CTSG-TCR+CD8 T cells were used to test their function in vitro. The number of biological replicas is reported in this figure. CTSG, cathepsin G; HLA, human leukocyte antigen; EBV-BLCL, EBV-transformed B lymphoblast cell line; pAML, primary acute myeloid leukemia cells.

[0161] Figure 32- Phenotype of engineered cyclin A1-specific TCR T cells.

[0162] A) Bar graph showing the percentage of CD3 surface expression in a live T cell population used as a substitute for TCR complex presentation. Results show near-complete knockout efficiency as measured in edited LV-untransduced (CTR) T cells and high transduction efficiency as measured in LV-transduced T cells. Edited T cells for each cyclin A1 epitope are named TCR. pYAE TCR SP18 TCR p102 Data are presented as mean ± SEM of 6 biological replicas. B) Bar graph showing the memory subset within CD3+ edited T cells: T SCM (CD45RA+CD62L+CD95+), T CM (CD45RA-CD62L+), T EM (CD45RA-CD62L-), T EMRA (CD45+CD62L-). Data are presented as mean ± SEM of 6 biological replicas.

[0163] Figure 33 -When the P75 epitope is in HLA-C 04:01 SP18-specific TCR engineered T cells recognize the P75 epitope during allele presentation.

[0164] A) Bar graphs represent CD107a expression in CD3+ T cells co-cultured with (associated) EBV-BLCLs (represented by different fill patterns) following SP18 pulses. These EBV-BLCLs share at least one HLA restriction with donor T cells isolated from tumor-specific T cell clones. EBV-BLCLs with irrelevant peptide pulses were included as a negative control. Data depict the mean ± SEM of the three biological replicas. p-values ​​were determined using a two-way ANOVA multiple comparison test. p < 0.05. B) The bar graph depicts the intracellular accumulation of the following cytokines associated with CD8+ T cell activation: interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). T cells were exposed to HLA-A... 33:01 and HLA-C with subpool 18 (SP18) or irrelevant peptide pulses 04:01 EBV-BLCL. Data represent the mean ± SEM of 3 biological replicas. The CD) bar chart represents the HLA-C pulses compared to each peptide included in SP18 or an unrelated peptide used as a control. 04:01+ 6 hours after co-culturing with EBV, CD8+ T lymphocytes showed expression of the degranulation marker CD107a (C) and secretion of pro-inflammatory cytokines IL-2, TNF-α, and IFN-γ (D). Data represent the mean ± SEM of the three biological replicas. E) Bar graphs show the killing efficiency of engineered T cells, which was measured by determining the elimination index calculated as follows: [1 - (target cells in co-culture / target cells in single culture)]. Compared with those T cells pulsed with p75, those T cells pulsed with p75 showed the killing efficiency of engineered T cells. 04:01+ T cells co-cultured with EBV cells showed increased cytotoxicity. The plotted data represent the mean ± SEM of three biological replicas. EBV-BLSL, an EBV-transformed B lymphoblast cell line.

[0165] Figure 34 -TCR p53 and TCR p102 Engineered T cells recognize HLA-I and HLA-II restriction epitopes, respectively.

[0166] A) The bar chart represents the results when HLA-B is used respectively. 35:02+ and HLA-DRB1 07:04+ HLA-DQB1 02:02+EBV-BLCL challenge, CD107a expression (degranulation marker) in two different TCR-engineered T cells retargeted with pYAE or p102 epitopes targeting cyclin A1 during pulsed immunogenic peptide (related peptide) administration. EBV-BLCL was also pulsed with an irrelevant peptide as a negative control. The left and right plots represent the percentage of the degranulation marker CD107a evaluated in CD3+CD8+ or CD3+CD4+ viable T cells, respectively. Data are presented as mean ± SEM of 6 biological replicates. (BC) Bar plots represent HLA-B expression in (B) versus pYAE pulsed T cells. 35:02+ EBV-BLCL co-cultured TCR pYAE-edited T cells and (C) with HLA-DRB1 07:04+HLA-DQB1 02:02+ cytokines released intracellularly by TCR p102 T cells co-cultured with EBV-BLCL pulsed with p102. Each EBV cell line was pulsed with an irrelevant peptide as a negative control. Data are presented as mean ± SEM of the six biological replicas. D) Analysis of the antitumor efficacy of TCR-T cells targeting the p102 (right panel) and pYAE (left panel) epitopes derived from the cyclin A1 tumor antigen. T cell killing activity was determined by measuring the elimination index after 24 hours of co-culture with HLA-restricted EBV-BLCL pulsed with either an associated (related) peptide or an irrelevant peptide (negative control). The plot shown presents data as mean ± SEM of the six biological replicas. E) In the context of the killing assay, T cells retargeted for tumor expression expressed the activation marker CD137, thus confirming TCR activation upon recognition of the corresponding peptide. Statistical significance was assessed by a two-way ANOVA multiple comparison test, and the obtained p-values ​​indicate... p < 0.05 p < 0.01 p < 0.0001. EBV-BLCL, an EBV-transformed B lymphoblast cell line; interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ).

[0167] Figure 35 -sgRNA protocol.

[0168] Suggestions for sgRNAs designed to target exon 3 of TRAC, exon 1 of TRBC1 and TRBC2, and exon 3 of TIGIT. White boxes represent untranslated regions, yellow boxes represent coding regions, and black boxes represent stop codons.

[0169] Figure 36 - Evaluation of editing efficiency generated by sgRNA used in conjunction with CRISPR / Cas9 or base editing systems.

[0170] Insertion / deletion frequencies (A, left) and cytosine base transitions (A, right) generated by sgRNAs targeting TRAC, TRBC1 / 2, and TIGIT. Modification frequencies of bystander cytokines at target loci (BC). CD3 and TIGIT protein expression after simultaneous disruption of TCR and TIGIT by sgRNAs coupled with BE4max (D). Data are expressed as mean ± SEM. n=3.

[0171] Figure 37 - Assessment of off-target events at the genomic level.

[0172] (A) Two possible off-target events and their research strategies. (B) Experimental workflow.

[0173] Figure 38 Evaluation of sgRNA-independent off-target editing.

[0174] (A) Percentage of nucleotide transitions at predicted target and off-target sites. Data are expressed as mean ± SEM. n=3. (BC) Frequency of change type (B) and frequency of specific nucleotide transitions (C) as measured by ultra-deep whole-exome sequencing. n=4.

[0175] Figure 39 -ENTPD1's destructive efficiency.

[0176] (A) A protocol designed to target ENTPD1 with a guide RNA. White boxes represent untranslated regions, yellow boxes represent coding regions, and black boxes represent stop codons. (B) Target cytosine base transitions generated by C1, C2, and C3 coupled to BE4max. n=3.

[0177] Figure 40 -Elimination of tumor cell lines.

[0178] T-cell cell lines that eliminate tumors by TCR-editing retargeted to specific tumor antigens (Ag). Data are presented as mean ± SEM. n=3.

[0179] Figure 41 - Elimination of organoids (PDO) derived from patients with primary CRC.

[0180] T-cell elimination induced by TCR editing targeting specific tumor antigen retargeting was derived from organoids (PDOs) from patients with primary CRC. Significance was calculated by fitting linear regression curves to the observed results. Data are expressed as mean ± SEM. n=3.

[0181] Figure 42 - Elimination of organoids (PDO) derived from patients with CRC liver metastases.

[0182] T-cell elimination induced by TCR editing targeting specific tumor antigen retargeting was achieved from organoids (PDOs) derived from patients with CRC liver metastases. Significance was calculated by fitting linear regression curves to the observed results. Data are expressed as mean ± SEM. n=3.

[0183] Figure 43 - Elimination of organoids (PDO) derived from patients with primary PDAC.

[0184] T-cell elimination induced by TCR editing targeting specific tumor antigen retargeting was derived from organoids (PDOs) from patients with primary PDAC. Significance was calculated by fitting linear regression curves to the observed outcomes. Data are expressed as mean ± SEM. n=3.

[0185] Figure 44 -TIGIT disruption improves the ability of MET-specific T cells to eliminate organoids (PDOs) derived from patients with primary CRC.

[0186] TIGIT disruption improved the ability of MET-specific T cells to eliminate organoids (PDOs) derived from patients with primary CRC. Significance was calculated by fitting linear regression curves of the observed results. Data are expressed as mean ± SEM. n=3.

[0187] Figure 45 -TIGIT disruption improves the ability of DKK1-specific T cells to eliminate organoids (PDOs) derived from CRC patients.

[0188] TIGIT disruption improved the ability of DKK1-specific T cells to eliminate organoids (PDOs) derived from patients with primary (A) and metastatic (B) CRC. Significance was calculated by fitting linear regression curves of the observed results. Data are expressed as mean ± SEM. n=3.

[0189] Figure 46 -TIGIT disruption improves the ability of DKK1-specific T cells to eliminate organoids (PDOs) from CRC liver metastases and primary PDAC patients.

[0190] TIGIT disruption improved the ability of DKK1-specific T cells to eliminate organoids (PDOs) derived from patients with CRC liver metastases (A) and primary PDAC (B). Significance was calculated by fitting linear regression curves of the observed outcomes. Data are expressed as mean ± SEM. n=3.

[0191] Figure 47 -TIGIT disruption enables MSLN-specific T cells to control tumor growth in vivo.

[0192] (AC) Experimental workflow of orthotopic mouse models of CRC (A) and PDAC (C). (BD) Tumor growth kinetics measured by in vivo bioluminescence in CRC (B) and by ultrasound imaging in PDAC (D) model. The fold increase in PDO was calculated as: BLI on day X / BLI on day 0. Significance was calculated by fitting a linear regression curve of the observed results.

[0193] Figure 48 -CTSG TCR does not cross-react with other peptides from the human proteome.

[0194] (A and C) Sequence lists of wild-type (wt) peptides and synthetic peptides used for alanine scanning assays. (B and D) HLA-A pulses of CTSGTCR-transduced T cells with ligand peptides pulsed with homologous wild-type epitopes (P7 or P56) or with altered ligand peptides showing alanine substitutions for each residue. 24:02+ (B) or HLA-C 07:02+ (D) Co-culture of EBV-BLCL (100 μM, left panel; or 1 μM, right panel). Degranulation activity in CD8+ T cells was used as a reading. Co-culture assays were performed at a 1:1 effector-to-target ratio. Data represent experiments performed using engineered T cells from two different healthy donors. CTSG, cathepsin G; EBV-BLCL, EBV-transformed B lymphoblast cell line. Detailed Implementation

[0195] Various preferred features and embodiments of the invention will now be described with the aid of non-limiting examples. This disclosure is not limited to the exemplary methods and materials disclosed herein, and any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of embodiments of this disclosure. Those skilled in the art will understand that they can combine all the features of the invention disclosed herein without departing from the scope of the disclosed invention.

[0196] It must be noted that, as used herein and in the appended claims, the singular forms “a / an” and “the” include plural references unless the context clearly indicates otherwise.

[0197] As used herein, the term “comprising / comprises / comprised of” is synonymous with “including / includes” and “containing / contains”, and is inclusive or open-ended, and does not exclude additional, unlisted members, elements, or steps. The term “comprising / comprises / comprised of” also includes the term “composed of”.

[0198] Numerical ranges include values ​​within a defined range. As used herein, the term “about” means approximately, nearby, roughly, or around. Unless otherwise specified, correspondingly, any nucleic acid sequence is written from left to right in a 5' to 3' direction; amino acid sequences are written from left to right in an amino to carboxyl direction.

[0199] The publications discussed herein provide only their public disclosure prior to the filing date of this application. Nothing in this document should be construed as an admission that such publications constitute prior art to the appended claims. All publications mentioned in this specification are incorporated herein by reference.

[0200] T cell receptor (TCR)

[0201] In one aspect, the present invention provides a T-cell receptor (TCR) to which an immunogenic peptide binds when presented by the major histocompatibility complex (MHC). The invention also provides an α-chain or β-chain from such a T-cell receptor.

[0202] As used herein, the term "T-cell receptor" (TCR) can refer to a molecule that recognizes a peptide when it is presented by an MHC molecule. TCRs can be present on the surface of T cells and are responsible for recognizing antigenic peptides that bind to MHC molecules. During antigen processing, the antigen is degraded intracellularly, and the antigenic peptide is then carried to the cell surface by MHC molecules. The binding of the TCR to the peptide:MHC complex triggers the activation of T lymphocytes, and the TCR is expressed on T lymphocytes through a series of biochemical events mediated by related enzymes, co-receptors, and specialized helper molecules.

[0203] TCR affinity for peptides can be measured by the association rate (k) on ) and dissociation rate (k off The TCR affinity is determined by any suitable method, such as titration calorimetry, surface plasmon resonance (SPR), or fluorescence microscopy-based methods (see, for example, Piepenbrink, KH et al., 2009. MethodsEnzymol, 466, pp. 359-381). When a peptide is presented by an MHC, the TCR can bind to the peptide with an affinity of about 100 μM or less, about 50 μM or less, about 40 μM or less, about 30 μM or less, about 20 μM or less, or about 10 μM or less. When a peptide is presented by an MHC, the TCR can bind to the peptide with an affinity of about 0.1 μM to about 100 μM, about 1 μM to about 100 μM, or about 5 μM to about 100 μM. When a peptide is presented by MHC, the TCR can bind to the peptide with an affinity of about 0.1 μM to about 10 μM, about 1 μM to about 10 μM, or about 5 μM to about 10 μM.

[0204] Naturally occurring TCR heterodimers consist of alpha (α) and beta (β) chains in approximately 95% of T cells, while approximately 5% of T cells have TCRs composed of gamma (γ) and delta (δ) chains. Each chain of the natural TCR is a member of the immunoglobulin superfamily and possesses an N-terminal immunoglobulin (Ig)-variable (V) region, an Ig-constant (C) region, a transmembrane / transcellular membrane region, and a C-terminal short cytoplasmic tail.

[0205] The TCR of the present invention can be a heterodimer of two chains, α and β (or optionally γ and δ), or it can be a single-chain TCR construct. Suitably, when the TCR of the present invention is a heterodimer of α and β chains, the α and β chains bind to the same immunogenic peptide. The α and β chains (or their variable domains or CDRs) provided herein can be combined in any suitable combination. For example, when three α chains and three β chains (or their variable domains or CDRs) binding to the same immunogenic peptide are provided, the TCR of the present invention can include combinations of α1 / β1, α1 / β2, α1 / β3, α2 / β1, α2 / β2, α2 / β3, α3 / β1, α3 / β2, or α3 / β3. In some embodiments, the TCR of the present invention includes a combination of an α1 chain (or its variable domains or CDRs) and a β1 chain (or its variable domains or CDRs). In some embodiments, the TCR of the present invention comprises a combination of α1 chains (or their variable structural domains or CDRs) and β2 chains (or their variable structural domains or CDRs). In some embodiments, the TCR of the present invention comprises a combination of α1 chains (or their variable structural domains or CDRs) and β3 chains (or their variable structural domains or CDRs). In some embodiments, the TCR of the present invention comprises a combination of α2 chains (or their variable structural domains or CDRs) and β1 chains (or their variable structural domains or CDRs). In some embodiments, the TCR of the present invention comprises a combination of α2 chains (or their variable structural domains or CDRs) and β2 chains (or their variable structural domains or CDRs). In some embodiments, the TCR of the present invention comprises a combination of α2 chains (or their variable structural domains or CDRs) and β3 chains (or their variable structural domains or CDRs). In some embodiments, the TCR of the present invention comprises a combination of α3 chains (or their variable structural domains or CDRs) and β2 chains (or their variable structural domains or CDRs). In some embodiments, the TCR of the present invention comprises a combination of an α3 chain (or its variable domain or CDR) and a β3 chain (or its variable domain or CDR).

[0206] Variable domains determine the specificity of TCRs. Both the α and β chains of the TCR have three hypervariable regions, or complementarity-determining regions (CDRs). For example, the α or β chain of the TCR includes CDR1, CDR2, and CDR3 in an amino-to-carboxyl-terminal sequence. Generally, CDR3 is the major CDR responsible for recognizing processed antigens, but CDR1 of the α chain also shows interaction with the N-terminal portion of the antigenic peptide, while CDR1 of the β chain interacts with the C-terminal portion of the peptide. CDR2 is thought to recognize MHC molecules. This article describes suitable variable domains.

[0207] The TCR of this invention may include a constant domain. The constant domain allows the TCR to associate with other molecules, such as CD3, which have three distinct chains (γ, δ, and ε) and a ζ chain in mammals. These helper molecules have negatively charged transmembrane regions and are essential for transmitting signals from the TCR into the cell. The CD3 chain and the ζ chain, together with the TCR, form the so-called T cell receptor complex.

[0208] The constant domain can consist of short linker sequences in which cysteine ​​residues form disulfide bonds, thereby creating a link between the two chains. The constant domain may include an Ig-constant (C) region, a transmembrane / transcellular membrane region, and a cytoplasmic tail.

[0209] The α-chain of the TCR of the present invention may include a constant domain encoded by the TRAC gene. The α-chain constant domain may have the amino acid sequence described in UniProt entry P01848. An exemplary α-chain constant domain has the following amino acid sequence described in SEQ ID NO: 1.

[0210] The TCR of the present invention may include an α-chain constant domain comprising or consisting of the following: an amino acid sequence of SEQ ID NO: 1 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it.

[0211]

[0212] Exemplary α-chain constant structural domain (SEQ ID NO: 1)

[0213] The β-chain of the TCR of the present invention may include a constant domain encoded by the TRBC1 or TRBC2 gene. The β-chain constant domain may have the amino acid sequence described in UniProt entry P01850 or A0A5B9. An exemplary β-chain constant domain encoded by the TRBC1 gene has the following amino acid sequence described in SEQ ID NO: 2. An exemplary β-chain constant domain encoded by the TRBC2 gene has the following amino acid sequence described in SEQ ID NO: 3.

[0214] The TCR of the present invention may include a β-chain constant domain comprising an amino acid sequence of SEQ ID NO: 2 or 3 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it.

[0215]

[0216] Exemplary β-chain constant structural domain (SEQ ID NO: 2)

[0217]

[0218] Exemplary β-chain constant structural domain (SEQ ID NO: 3)

[0219] The TCR of the present invention may have one or more additional cysteine ​​residues in each of the α chain and β chain such that the TCR may include two or more disulfide bonds in a constant structural domain.

[0220] Signaling from the T cell complex can be enhanced by the simultaneous binding of MHC molecules to specific co-receptors. For helper T cells, this co-receptor may be CD4 (specific to class II MHC); while for cytotoxic T cells, it may be CD8 (specific to class I MHC). This co-receptor allows for prolonged binding between antigen-presenting cells and T cells and recruits essential intracellular molecules involved in signaling of activated T lymphocytes (e.g., LCK).

[0221] The TCR of this invention can be a heterozygous TCR comprising sequences derived from more than one species. For example, it has been found that mouse TCRs are expressed more efficiently in human T cells than human TCRs. Therefore, the TCR may comprise mouse sequences within both human variable and constant domains. A disadvantage of this approach is that the mouse constant sequence may trigger an immune response, leading to rejection of the transferred T cells. However, the modulation protocol used to prepare a patient for adoptive T-cell therapy can induce sufficient immunosuppression to allow the engraftment of T cells expressing mouse sequences.

[0222] The TCR of the present invention may be a soluble TCR, thereby omitting or altering one or more constant structural domains, for example. Other suitable methods for engineering soluble TCRs are known in the art (see, for example, Robinson, RA et al., 2021. The FEBS Journal, 288(21), pp. 6159-6173).

[0223] The term "soluble TCR" refers to a TCR that is not anchored to the cell surface. Soluble TCRs typically include at least a portion of variable and constant domains, but lack transmembrane and intracellular cytoplasmic domains. Soluble TCRs may include stable mutations and / or modifications (e.g., point mutations, interchain disulfide bonds, and / or peptide linkers). Such modifications are known in the art (e.g., Robinson, RA et al., 2021. The FEBS Journal, 288(21), pp. 6159-6173).

[0224] In some embodiments, the TCR includes one or more mutations to remove one or more N-glycosylation sites. Suitablely, the N-glycosylation sites are located within the TCR constant domain. The deletion of N-glycosylation sites in the TCR constant domain is described in Kuball, J et al. (2009) J Exp Med 206:463-75. In some embodiments, the one or more mutations are amino acid Q substituting amino acid N in the NXS / T motif. For example, this substitution may be at one or more of the following positions: TCR α constant gene position 36, 90, or 109; and / or TCR β constant gene position 85.6. Suitablely, this substitution is located at TCR α constant gene position 36. The mutations in the TCR constant domain disclosed herein can be described based on the following numbering rule: wherein the first amino acid of each of SEQ ID NO: 1-3 is assigned to position 2.

[0225] Complementarity Determinant Region (CDR)

[0226] T cell receptor diversity is concentrated on CDR3, and this region is primarily responsible for antigen recognition. The sequence of the CDR3 region of the TCR of the present invention may be selected from those sequences described herein. The TCR of the present invention may include a CDR comprising or composed of the CDR3α and CDR3β pairs described herein.

[0227] The portion of the TCR that establishes most of the contact with antigenic peptides bound to the major histocompatibility complex (MHC) is the complementarity-determining region 3 (CDR3), unique to each T cell clone. The CDR3 region is generated in the thymus during somatic rearrangement events involving non-adjacent genes belonging to variable (V), diverse (D, for β and δ chains), and linking (J) genes. Furthermore, random nucleotide insertions / deletions at rearrangement loci in each TCR chain gene significantly increase the diversity of highly variable CDR3 sequences. Therefore, the frequency of specific CDR3 sequences in a biological sample indicates the abundance of a specific T cell population. The extremely high diversity of the TCR repertoire in healthy humans provides broad protection against a wide variety of foreign antigens presented by MHC molecules on the surface of antigen-presenting cells. In this regard, it is noteworthy that theoretically up to 10 15 Different types of TCRs.

[0228] The sequences of the CDR1 and CDR2 regions of the TCR of the present invention may also be selected from those sequences described herein. The TCR of the present invention may include a CDR comprising the set of CDR1α, CDR2α, CDR3α, CDR1β, CDR2β and CDR3β described herein, or a CDR composed of the set of CDR1α, CDR2α, CDR3α, CDR1β, CDR2β and CDR3β described herein.

[0229] CDRs may include, for example, one, two, or three substitutions, additions, or deletions from a given sequence, provided that the TCR retains the ability to bind the corresponding immunogenic peptide when presented by an MHC molecule. In some embodiments, each CDR3 includes up to three substitutions, additions, or deletions; up to two substitutions, additions, or deletions; up to one substitution, addition, or deletion; or any combination thereof. In some embodiments, each CDR3 includes up to three substitutions, up to two substitutions, up to one substitution; or any combination thereof. In some embodiments, each CDR includes up to three substitutions, additions, or deletions; up to two substitutions, additions, or deletions; up to one substitution, addition, or deletion; or any combination thereof. In some embodiments, each CDR includes up to three substitutions, up to two substitutions, up to one substitution; or any combination thereof.

[0230] Major Histocompatibility Complex (MHC) Molecules

[0231] Typically, TCRs bind to peptides as part of a peptide:MHC complex. The TCRs of this invention can bind to MHC I and / or MHC II peptide complexes. MHC peptide complexes can be on the surface of antigen-presenting cells (such as dendritic cells or B cells) or any other cells (including cancer cells), or they can be immobilized, for example, by coating onto beads or plates.

[0232] The human leukocyte antigen system (HLA) is the name of the gene complex encoding the human MHC and includes HLA class I antigens (A, B, and C) and HLA class II antigens (DP, DQ, and DR). HLA alleles A, B, and C present peptides primarily derived from intracellular proteins (e.g., proteins expressed within the cell). The TCR is limited to human leukocyte antigen (HLA) alleles.

[0233] During T cell development in vivo, T cells undergo a positive selection step to ensure recognition of their own MHCs, followed by a negative step to remove T cells that bind excessively to MHCs presenting their own antigens. Therefore, certain T cells and their expressed TCRs will recognize only peptides presented by certain types of MHC molecules (i.e., those MHCs encoded by specific HLA alleles). This is known as HLA restriction. Preferred MHC-binding motifs for different HLA alleles are disclosed in the Immunoepitaph Database (IEDB) (Vita, R. et al., 2019. Nucleic acids research, 47(D1), pp. D339-D343).

[0234] Immunogenic peptides

[0235] When an immunogenic peptide is presented by the MHC, the TCR of the present invention binds to the immunogenic peptide.

[0236] As used herein, the term "protein" may include single-chain polypeptide molecules as well as multi-peptide complexes, wherein the individual polypeptides are linked together in a covalent or non-covalent manner.

[0237] As used herein, the term “polypeptide” can refer to a polymer in which the monomers are amino acids and are linked together by peptide bonds or disulfide bonds.

[0238] As used herein, the term "peptide" can refer to a plurality of amino acid residues linked by peptide bonds. A peptide may consist of fewer than about 30, fewer than about 25, fewer than about 20, fewer than 19, fewer than 18, fewer than 17, fewer than 16, fewer than 15, fewer than 14, fewer than 13, fewer than 12, fewer than 11, or fewer than 10 amino acid residues. A peptide may consist of 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more amino acid residues. Suitably, the length of a peptide is 5 to 20 amino acids, 8 to 15 amino acid residues, 9 to 14 amino acid residues, 9 to 13 amino acid residues, 9 to 12 amino acid residues, 9 to 11 amino acid residues, or 9 to 10 amino acid residues. In some embodiments, the peptide of the present invention is 9 amino acid residues in length.

[0239] As used herein, the terms "immunogenic peptide" or "immunogenic fragment" can refer to a peptide that can be presented by an MHC molecule and subsequently recognized by a TCR. Immunogenic peptides or fragments can be derived from, for example, AML-associated antigens, CRC-associated antigens, or PDAC-associated antigens. Immunogenic peptides or fragments can consist of fewer than about 30, fewer than about 25, fewer than about 20, fewer than 19, fewer than 18, fewer than 17, fewer than 16, fewer than 15, fewer than 14, fewer than 13, fewer than 12, fewer than 11, or fewer than 10 amino acid residues. Immunogenic peptides or fragments can also consist of 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more amino acid residues. Suitablely, the immunogenic peptide or fragment is 5 to 20 amino acids in length, 8 to 15 amino acid residues in length, 9 to 14 amino acid residues in length, 9 to 13 amino acid residues in length, 9 to 12 amino acid residues in length, 9 to 11 amino acid residues in length, or 9 to 10 amino acid residues in length. In some embodiments, the immunogenic peptide or immunogenic fragment of the present invention is 9 amino acid residues in length.

[0240] The immunogenic peptides of the present invention can be derived from any suitable human protein, such as tumor-associated antigens. As used herein, "tumor-associated antigen" can refer to an antigenic protein produced in tumor cells. In some embodiments, the immunogenic peptides of the present invention are derived from AML-associated antigens, CRC-associated antigens, and / or PDAC-associated antigens.

[0241] In some embodiments, the immunogenic peptides of the present invention are derived from AML-associated antigens. As used herein, "AML-associated antigen" can refer to an antigenic protein produced in acute myeloid leukemia cells. AML-associated antigens can serve as useful tumor markers and potential candidates for immunotherapy. AML-associated antigens may include PR3 / NE, EZH2, PRAME, CTSG, and CCNA1.

[0242] In some embodiments, the immunogenic peptides of the present invention are derived from CRC-associated antigens and / or PDAC-associated antigens. As used herein, "CRC-associated antigen" can refer to an antigenic protein produced in colorectal cancer cells. CRC-associated antigens can serve as useful tumor markers and potential candidates for immunotherapy. As used herein, "PDAC-associated antigen" can refer to an antigenic protein produced in pancreatic ductal adenocarcinoma cells. PDAC-associated antigens can serve as useful tumor markers and potential candidates for immunotherapy. CRC-associated antigens and / or PDAC-associated antigens may include HER2, DKK1, MUC5AC, AGR2, c-MET, MSLN, CTDP1, TACC2, or PTGFRN.

[0243] This invention contemplates various uses of the peptides described herein. For example, the peptides described herein can be administered to subjects, such as human subjects. Administration of the peptides of this invention can elicit an immune response against cells that express or overexpress the corresponding protein, i.e., these peptides can be immunogenic peptides. The peptides described herein can be used to screen for and / or identify novel TCR sequences. For example, T2 cells can be pulsed with the peptides described herein and incubated together with a population of T cells isolated from a donor. In this method, the expression of cytokines (e.g., CD107a and IFNγ) can indicate T cells that recognize the peptide.

[0244] HER2-specific TCR

[0245] In one aspect, the present invention provides a TCR that binds to the HER2 peptide when it is presented by MHC.

[0246] HER2

[0247] HER2 is a protein encoded by the ERBB2 gene, and is also known as human epidermal growth factor receptor 2, receptor tyrosine protein kinase erbB-2, or CD340.

[0248] HER2 is a member of the epidermal growth factor receptor family with tyrosine kinase activity. Dimerization of the receptor induces autophosphorylation of tyrosine residues within the receptor's cytoplasmic domain, initiating multiple signaling pathways that lead to cell proliferation and tumorigenesis. HER2 amplification or overexpression occurs in approximately 15%–30% of breast cancers and 10%–30% of gastric / gastroesophageal cancers. HER2 overexpression has also been observed in other cancers such as ovarian cancer, endometrial cancer, bladder cancer, lung cancer, colon cancer, and head and neck cancer (see, for example, Iqbal, N. and Iqbal, N., 2014. Molecular Biology International, pp. 852-748).

[0249] The HER2 protein may have the amino acid sequence described in UniProt entry P04626. An exemplary HER2 protein has the following amino acid sequence described in SEQ ID NO: 4.

[0250]

[0251] Exemplary HER2 protein (SEQ ID NO: 4)

[0252] HER2 peptide

[0253] As used herein, the term "HER2 peptide" may refer to a peptide comprising an amino acid sequence derived from the HER2 protein. Suitablely, a HER2 peptide may comprise at least five, at least six, at least seven, at least eight, or at least nine adjacent amino acid residues of the HER2 protein amino acid sequence (or a variant thereof). In some embodiments, the HER2 peptide comprises nine adjacent amino acid residues of the HER2 protein amino acid sequence (or a variant thereof).

[0254] HER2 peptides can be immunogenic peptides. HER2 peptides can bind to any suitable MHC. Appropriately, HER2 peptides bind to MHC encoded by HLA class I or HLA class II alleles. Appropriately, HER2 peptides bind to MHC encoded by the HLA-A allele. Appropriately, HER2 peptides bind to MHC encoded by the HLA-A allele. The HER2 allele encodes the MHC. Appropriately, the HER2 peptide binds to the HLA-A receptor. MHC encoded in 0201.

[0255] An exemplary HER2 peptide has the following amino acid sequence as set forth in SEQ ID NO: 5.

[0256] KIFGSLAFL

[0257] Exemplary HER2 peptide (SEQ ID NO: 5)

[0258] The HER2 peptide may comprise or consist of the amino acid sequence of SEQ ID NO: 5 or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the HER2 peptide comprises or consists of the amino acid sequence of SEQ ID NO: 5 or a variant thereof having at most two amino acid substitutions, additions, or deletions. In some embodiments, the HER2 peptide comprises or consists of the amino acid sequence of SEQ ID NO: 5 or a variant thereof having at most one amino acid substitution, addition, or deletion. In some embodiments, the HER2 peptide comprises or consists of the amino acid sequence of SEQ ID NO: 5 or a variant thereof having at most three amino acid substitutions. In some embodiments, the HER2 peptide comprises or consists of the amino acid sequence of SEQ ID NO: 5 or a variant thereof having at most two amino acid substitutions. In some embodiments, the HER2 peptide comprises or consists of the amino acid sequence of SEQ ID NO: 5 or a variant thereof having at most one amino acid substitution. In some embodiments, the HER2 peptide comprises or consists of the amino acid sequence of SEQ ID NO: 5.

[0259] HER2-specific TCR sequence

[0260] The inventors have determined the amino acid sequence of the HER2-specific TCR (including the CDR region), which is responsible for the binding specificity of the HER2 peptide.

[0261] HER2-specific TCRs can be restricted to any suitable MHC (e.g., one or more HLA alleles). Appropriately, HER2-specific TCRs are restricted to HLA class I or HLA class II alleles. Appropriately, HER2-specific TCRs are restricted to HLA-A alleles. Appropriately, HER2-specific TCRs are restricted to HLA-A alleles. 02 Alleles. Appropriately, HER2-specific TCRs are limited to HLA-A. 0201.

[0262] The table below provides an example HER2-specific TCR amino acid sequence.

[0263]

[0264] In one aspect, the present invention provides a TCR comprising CDR3α and / or CDR3β, wherein the CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 8 or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 13 or a variant thereof having at most three amino acid substitutions, additions or deletions.

[0265] In some embodiments, the CDR3 variant has at most two amino acid substitutions, additions, or deletions. In some embodiments, the CDR3 variant has at most one amino acid substitution, addition, or deletion. In some embodiments, the CDR3 variant has at most three amino acid substitutions. In some embodiments, the CDR3 variant has at most two amino acid substitutions. In some embodiments, the CDR3 variant has at most one amino acid substitution.

[0266] In some embodiments, the TCR includes CDR3α and / or CDR3β, wherein the CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 8, and the CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 13.

[0267] In some embodiments, the TCR further comprises (a) CDR1α and (b) CDR2α and / or (a) CDR1β and (b) CDR2β, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 6 or a variant thereof having at most three amino acid substitutions, additions or deletions; (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 7 or a variant thereof having at most three amino acid substitutions, additions or deletions; (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 11 or a variant thereof having at most three amino acid substitutions, additions or deletions; and (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 12 or a variant thereof having at most three amino acid substitutions, additions or deletions.

[0268] In some embodiments, the TCR includes an α-chain variable domain and / or a β-chain variable domain, the α-chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 9 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 14 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0269] In some embodiments, the TCR comprises an α chain and / or a β chain, the α chain comprising or consisting of the amino acid sequence of SEQ ID NO: 10 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or 16 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0270] In one aspect, the present invention provides a TCR comprising (a) CDR1α, (b) CDR2α, (c) CDR3α and / or (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 6 or a variant thereof having at most three amino acid substitutions, additions, or deletions; (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 7 or a variant thereof having at most three amino acid substitutions, additions, or deletions; (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 8 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 11 or a variant thereof having at most three amino acid substitutions, additions, or deletions. The amino acid sequence of SEQ ID NO: 12 or a variant thereof having at most three amino acid substitutions, additions or deletions, wherein (c) CDR3β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 13 or a variant thereof having at most three amino acid substitutions, additions or deletions.

[0271] In some embodiments, the CDR variant has at most two amino acid substitutions, additions, or deletions. In some embodiments, the CDR variant has at most one amino acid substitution, addition, or deletion. In some embodiments, the CDR variant has at most three amino acid substitutions. In some embodiments, the CDR variant has at most two amino acid substitutions. In some embodiments, the CDR variant has at most one amino acid substitution.

[0272] In some embodiments, the TCR includes (a) CDR1α, (b) CDR2α, (c) CDR3α and / or (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 6, (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 7, (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 8, (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 11, (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 12, and (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 13.

[0273] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, the α-chain variable domain comprising or consisting of an amino acid sequence of SEQ ID NO: 9 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising or consisting of an amino acid sequence of SEQ ID NO: 14 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0274] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, wherein the α-chain variable domain comprises or consists of the amino acid sequence of SEQ ID NO: 9 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α-chain variable domain comprises CDR3α, the CDR3α comprising or consists of the amino acid sequence of SEQ ID NO: 8 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the β-chain variable domain comprises or consists of the amino acid sequence of SEQ ID NO: 14 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β-chain variable domain comprises CDR3β, the CDR3β comprising or consists of the following: SEQ ID NO: The amino acid sequence of 13 or its variants having at most three amino acid substitutions, additions or deletions.

[0275] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, wherein the α-chain variable domain comprises or consists of an amino acid sequence of SEQ ID NO: 9 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it, wherein the α-chain variable domain comprises (a) CDR1α, (b) CDR2α, and (c) CDR3α, wherein (a) CDR1α comprises or consists of an amino acid sequence of SEQ ID NO: 6 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2α comprises or consists of an amino acid sequence of SEQ ID NO: 7 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein (c) CDR3α comprises or consists of SEQ ID NO: The amino acid sequence of SEQ ID NO: 14 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein the β-chain variable domain comprises or consists of the following: the amino acid sequence of SEQ ID NO: 14 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it, wherein the β-chain variable domain comprises (a) CDR1β, (b) CDR2β, and (c) CDR3β, wherein (a) CDR1β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 11 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 12 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (c) CDR3β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 13 or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0276] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, the α chain comprising or consisting of the amino acid sequence of SEQ ID NO: 10 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or 16 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0277] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, wherein the α chain comprises or consists of the amino acid sequence of SEQ ID NO: 10 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α chain comprises CDR3α, wherein the CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 8 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein the β chain comprises or consists of the amino acid sequence of SEQ ID NO: 15 or 16 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β chain comprises CDR3β, wherein the CDR3β comprises or consists of the following: SEQ ID NO: The amino acid sequence of 13 or its variants having at most three amino acid substitutions, additions or deletions.

[0278] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, wherein the α chain comprises or consists of the amino acid sequence of SEQ ID NO: 10 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it, wherein the α chain comprises (a) CDR1α, (b) CDR2α, and (c) CDR3α, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 6 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 7 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 8 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the β chain comprises or consists of the amino acid sequence of SEQ ID NO: 10 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the β chain comprises or consists of the amino acid sequence of SEQ ID NO: 10. The amino acid sequence of NO:15 or 16 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, wherein the β chain comprises (a) CDR1β, (b) CDR2β, and (c) CDR3β, wherein (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 11 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 12 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and wherein (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 13 or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0279] PR3 / NE specific TCR

[0280] In one aspect, the present invention provides a TCR that binds to the PR3 / NE peptide when it is presented by MHC.

[0281] PR3 and NE

[0282] PR3 is a protein encoded by the PRTN3 gene, and is also known as protease 3 or myeloblast protease. NE is a protein encoded by the ELANE gene, and is also known as neutrophil elastase or leukocyte elastase.

[0283] PR3 and NE are both serine proteases located in primary aniline granules of neutrophils, whose primary function is to combat bacterial infection by processing pathogenic proteins into smaller peptides both intracellularly and extracellularly. Their overexpression has been observed in the cytoplasm of primary leukemia blasts and leukemia stem cells, making them attractive antigens for adoptive cell therapy (ACT) in acute myeloid leukemia (AML) (Greiner, J. et al., 2008. Clinical Cancer Research, 14(22), pp. 7161-7166). Furthermore, tumor cell lines negative for PR3 and NE expression have been shown to internalize these exogenous antigens and enable their cross-presentation (Alatrash, G. et al., 2018. Oncotarget, 9(4), p. 4280). This internalization mechanism is of interest in ACT because it would broaden the range of cancer types sensitive to immunotherapy targeting PR3 and NE.

[0284] PR3 proteins may have the amino acid sequence described in UniProt entry P24158. An exemplary PR3 protein has the following amino acid sequence described in SEQ ID NO: 17.

[0285]

[0286] Exemplary PR3 protein (SEQ ID NO: 17)

[0287] NE proteins may have the amino acid sequence described in UniProt entry P08246. An exemplary NE protein has the following amino acid sequence described in SEQ ID NO: 18.

[0288]

[0289] Exemplary NE protein (SEQ ID NO: 18)

[0290] PR3 / NE peptide

[0291] As used herein, the term "PR3 / NE peptide" may refer to a peptide comprising an amino acid sequence derived from the PR3 protein and / or the NE protein. Suitably, a PR3 / NE peptide may comprise at least five, at least six, at least seven, at least eight, or at least nine adjacent amino acid residues of the PR3 protein amino acid sequence (or a variant thereof) and / or the NE protein amino acid sequence (or a variant thereof). In some embodiments, a PR3 / NE peptide comprises nine adjacent amino acid residues of the PR3 protein amino acid sequence (or a variant thereof) and / or the NE protein amino acid sequence (or a variant thereof).

[0292] In some embodiments, the PR3 / NE peptide comprises at least 5, at least 6, at least 7, at least 8, or at least 9 adjacent amino acid residues of the PR3 protein amino acid sequence (or a variant thereof) and the NE protein amino acid sequence (or a variant thereof). In some embodiments, the PR3 / NE peptide comprises at least 9 adjacent amino acid residues of the PR3 protein amino acid sequence (or a variant thereof) and the NE protein amino acid sequence (or a variant thereof).

[0293] PR3 / NE peptides can be immunogenic peptides. PR3 / NE peptides can bind to any suitable MHC. Appropriately, PR3 / NE peptides bind to MHC encoded by HLA class I or HLA class II alleles. Appropriately, PR3 / NE peptides bind to MHC encoded by HLA-A alleles. Appropriately, PR3 / NE peptides bind to MHC encoded by HLA-A alleles. The PR3 / NE peptide encodes the MHC gene from the 02 allele. Appropriately, the PR3 / NE peptide binds to the HLA-A receptor. MHC encoded in 0201.

[0294] An exemplary PR3 / NE peptide has the following amino acid sequence as illustrated in SEQ ID NO: 19.

[0295] VLQELNVTV

[0296] Exemplary PR3 / NE peptide (SEQ ID NO: 19)

[0297] The PR3 / NE peptide may comprise or consist of the amino acid sequence of SEQ ID NO: 19 or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the PR3 / NE peptide comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant thereof having at most two amino acid substitutions, additions, or deletions. In some embodiments, the PR3 / NE peptide comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant thereof having at most one amino acid substitution, addition, or deletion. In some embodiments, the PR3 / NE peptide comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant thereof having at most three amino acid substitutions. In some embodiments, the PR3 / NE peptide comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant thereof having at most two amino acid substitutions. In some embodiments, the PR3 / NE peptide comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant thereof having at most one amino acid substitution. In some embodiments, the PR3 / NE peptide comprises or consists of the amino acid sequence of SEQ ID NO: 19.

[0298] PR3 / NE specific TCR sequence

[0299] The inventors have determined the amino acid sequences of PR3 / NE-specific TCRs (including CDR regions), which are responsible for the binding specificity of PR3 / NE peptides.

[0300] PR3 / NE-specific TCRs can be restricted to any suitable MHC (e.g., one or more HLA alleles). Appropriately, PR3 / NE-specific TCRs are restricted to HLA class I or HLA class II alleles. Appropriately, PR3 / NE-specific TCRs are restricted to HLA-A alleles. Appropriately, PR3 / NE-specific TCRs are restricted to HLA-A. 02 Alleles. Appropriately, PR3 / NE-specific TCRs are limited to HLA-A. 0201.

[0301] The table below provides exemplary PR3 / NE-specific TCR amino acid sequences.

[0302]

[0303] In one aspect, the present invention provides a TCR comprising CDR3α and / or CDR3β, wherein the CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 22 or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 27 or a variant thereof having at most three amino acid substitutions, additions or deletions.

[0304] In some embodiments, the CDR3 variant has at most two amino acid substitutions, additions, or deletions. In some embodiments, the CDR3 variant has at most one amino acid substitution, addition, or deletion. In some embodiments, the CDR3 variant has at most three amino acid substitutions. In some embodiments, the CDR3 variant has at most two amino acid substitutions. In some embodiments, the CDR3 variant has at most one amino acid substitution.

[0305] In some embodiments, the TCR includes CDR3α and / or CDR3β, wherein the CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 22, and the CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 27.

[0306] In some embodiments, the TCR further comprises (a) CDR1α and (b) CDR2α and / or (a) CDR1β and (b) CDR2β, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 20 or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 21 or a variant thereof having up to three amino acid substitutions, additions or deletions; (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 25 or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 26 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0307] In some embodiments, the TCR includes an α-chain variable domain and / or a β-chain variable domain, the α-chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 23 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 28 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0308] In some embodiments, the TCR comprises an α chain and / or a β chain, the α chain comprising or consisting of the amino acid sequence of SEQ ID NO: 24 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 29 or 30 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0309] In one aspect, the present invention provides a TCR comprising (a) CDR1α, (b) CDR2α, (c) CDR3α and / or (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 20 or a variant thereof having at most three amino acid substitutions, additions, or deletions; (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 21 or a variant thereof having at most three amino acid substitutions, additions, or deletions; (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 22 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 25 or a variant thereof having at most three amino acid substitutions, additions, or deletions. The amino acid sequence of SEQ ID NO: 27 or a variant thereof having at most three amino acid substitutions, additions or deletions, wherein (c) CDR3β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 27 or a variant thereof having at most three amino acid substitutions, additions or deletions.

[0310] In some embodiments, the CDR variant has at most two amino acid substitutions, additions, or deletions. In some embodiments, the CDR variant has at most one amino acid substitution, addition, or deletion. In some embodiments, the CDR variant has at most three amino acid substitutions. In some embodiments, the CDR variant has at most two amino acid substitutions. In some embodiments, the CDR variant has at most one amino acid substitution.

[0311] In some embodiments, the TCR includes (a) CDR1α, (b) CDR2α, (c) CDR3α and / or (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 20, (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 21, (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 22, (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 25, (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 26, and (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 27.

[0312] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, the α-chain variable domain comprising or consisting of an amino acid sequence of SEQ ID NO: 23 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising or consisting of an amino acid sequence of SEQ ID NO: 28 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0313] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, wherein the α-chain variable domain comprises or consists of the amino acid sequence of SEQ ID NO: 23 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α-chain variable domain comprises CDR3α, wherein the CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 22 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein the β-chain variable domain comprises or consists of the amino acid sequence of SEQ ID NO: 28 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β-chain variable domain comprises CDR3β, wherein the CDR3β comprises or consists of the following: SEQ ID NO: The amino acid sequence of 27 or its variants having at most three amino acid substitutions, additions or deletions.

[0314] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, wherein the α-chain variable domain comprises or consists of the amino acid sequence of SEQ ID NO: 23 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it, wherein the α-chain variable domain comprises (a) CDR1α, (b) CDR2α, and (c) CDR3α, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 20 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 21 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 21. The amino acid sequence of SEQ ID NO: 22 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein the β-chain variable domain comprises or consists of the following: the amino acid sequence of SEQ ID NO: 28 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, wherein the β-chain variable domain comprises (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (a) CDR1β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 25 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 26 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (c) CDR3β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 27 or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0315] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, the α chain comprising or consisting of an amino acid sequence of SEQ ID NO: 24 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising or consisting of an amino acid sequence of SEQ ID NO: 29 or 30 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0316] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, wherein the α chain comprises or consists of the amino acid sequence of SEQ ID NO: 24 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α chain comprises CDR3α, wherein the CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 22 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the β chain comprises or consists of the amino acid sequence of SEQ ID NO: 29 or 30 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β chain comprises CDR3β, wherein the CDR3β comprises or consists of the following: SEQ ID NO: The amino acid sequence of 27 or its variants having at most three amino acid substitutions, additions or deletions.

[0317] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, wherein the α chain comprises or consists of the amino acid sequence of SEQ ID NO: 24 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it, wherein the α chain comprises (a) CDR1α, (b) CDR2α, and (c) CDR3α, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 20 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 21 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 22 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the β chain comprises or consists of the amino acid sequence of SEQ ID NO: 24 ... The amino acid sequence of ID NO: 29 or 30 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, wherein the β chain comprises (a) CDR1β, (b) CDR2β, and (c) CDR3β, wherein (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 25 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 26 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 27 or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0318] EZH2 / PRAME specific TCR

[0319] In one aspect, the present invention provides a TCR that binds to an EZH2 peptide or a PRAME peptide when presented by an MHC.

[0320] EZH2

[0321] EZH2 is a protein encoded by the EZH2 gene, and is also known as histone-lysine N-methyltransferase EZH2 or zeste enhancer homolog 2.

[0322] EZH2 is a lysine methyltransferase of the polycomb repressor complex 2 (PRC2) that catalyzes the addition of three methyl groups to lysine 27 (K27) of histone 3 (H3), thereby establishing and maintaining the H3K27 trimethylation repression marker (Li, B. and Chng, WJ, 2019. Journal of Hematology & Oncology, 12, pp. 1-13). Under physiological conditions, it acts as a tumor suppressor gene, but in oncogenic events (such as gain-of-function mutations in the EZH2 gene or its genomic regulators (mRNA or incRNA), the EZH2 protein can be overexpressed, as shown in various hematologic malignancies. However, loss-of-function mutations can also occur in the EZH2 gene, leading to the loss of the trimethylation repression marker and the expression of target genes that drive acute myeloid leukemia (AML) onset and are associated with poor prognosis.

[0323] EZH2 proteins may have the amino acid sequence described in UniProt entry Q15910. An exemplary EZH2 protein has the following amino acid sequence described in SEQ ID NO: 31.

[0324]

[0325] Exemplary EZH2 protein (SEQ ID NO: 31)

[0326] EZH2 peptide

[0327] As used herein, the term "EZH2 peptide" may refer to a peptide comprising an amino acid sequence derived from the EZH2 protein. Suitablely, an EZH2 peptide may comprise at least 5, at least 6, at least 7, at least 8, or at least 9 adjacent amino acid residues of the EZH2 protein amino acid sequence (or a variant thereof). In some embodiments, an EZH2 peptide comprises 9 adjacent amino acid residues of the EZH2 protein amino acid sequence (or a variant thereof).

[0328] EZH2 peptides can be immunogenic peptides. EZH2 peptides can bind to any suitable MHC. Appropriately, EZH2 peptides bind to MHC encoded by HLA class I or HLA class II alleles. Appropriately, EZH2 peptides bind to MHC encoded by the HLA-A allele. Appropriately, EZH2 peptides bind to MHC encoded by the HLA-A allele. The 02 allele encodes MHC. Appropriately, the EZH2 peptide binds to the HLA-A... MHC encoded in 0201.

[0329] An exemplary EZH2 peptide has the following amino acid sequence as set forth in SEQ ID NO: 32.

[0330]

[0331] Example EZH2 peptide (SEQ ID NO: 32)

[0332] The EZH2 peptide may comprise or consist of the amino acid sequence of SEQ ID NO: 32 or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the EZH2 peptide comprises or consists of the amino acid sequence of SEQ ID NO: 32 or a variant thereof having at most two amino acid substitutions, additions, or deletions. In some embodiments, the EZH2 peptide comprises or consists of the amino acid sequence of SEQ ID NO: 32 or a variant thereof having at most one amino acid substitution, addition, or deletion. In some embodiments, the EZH2 peptide comprises or consists of the amino acid sequence of SEQ ID NO: 32 or a variant thereof having at most three amino acid substitutions. In some embodiments, the EZH2 peptide comprises or consists of the amino acid sequence of SEQ ID NO: 32 or a variant thereof having at most two amino acid substitutions. In some embodiments, the EZH2 peptide comprises or consists of the amino acid sequence of SEQ ID NO: 32 or a variant thereof having at most one amino acid substitution. In some embodiments, the EZH2 peptide comprises or consists of the following amino acid sequence: SEQ ID NO: 32.

[0333] PRAME

[0334] PRAME is a protein encoded by the PRAME gene, and is also known as tumor-preferred melanoma antigen, melanoma-preferred antigen, or Opa-interacting protein 4.

[0335] PRAME belongs to the cancer testis antigen (CTA) family of genes that are highly expressed in germ cells of the testis but absent in other healthy tissues. High levels of PRAME expression have been detected in malignant cells, including most primary and metastatic melanomas. In its nuclear localization, PRAME interacts with EZH2 to inhibit the retinoic acid receptor (RAR) signaling cascade, which is known to mediate tumor suppressor functions. In fact, the binding of retinoic acid (RA) to RAR in the cell nucleus induces RARβ2 gene expression and RA target gene transcription, thereby regulating cell cycle arrest and caspase-dependent apoptosis pathways in responding cells. Therefore, the inhibition of RAR signaling by PRAME may represent an important contributing factor in the progression of acute myeloid leukemia (AML) (see, for example, Wadelin, F. et al., 2010. Molecular cancer, 9, pp. 1-10).

[0336] PRAME proteins may have the amino acid sequence described in UniProt entry P78395. An exemplary PRAME protein has the following amino acid sequence described in SEQ ID NO: 33.

[0337]

[0338] Exemplary PRAME protein (SEQ ID NO: 33)

[0339] PRAME peptide

[0340] As used herein, the term "PRAME peptide" may refer to a peptide comprising an amino acid sequence derived from the PRAME protein. Suitablely, a PRAME peptide may comprise at least 5, at least 6, at least 7, at least 8, or at least 9 adjacent amino acid residues of the PRAME protein amino acid sequence (or a variant thereof). In some embodiments, a PRAME peptide comprises 9 adjacent amino acid residues of the PRAME protein amino acid sequence (or a variant thereof).

[0341] PRAME peptides can be immunogenic peptides. PRAME peptides can bind to any suitable MHC. Appropriately, PRAME peptides bind to MHC encoded by HLA class I or HLA class II alleles. Appropriately, PRAME peptides bind to MHC encoded by HLA-A alleles. Appropriately, PRAME peptides bind to MHC encoded by HLA-A alleles. The 02 allele encodes the MHC. Appropriately, the PRAME peptide binds to the HLA-A... MHC encoded in 0201.

[0342] An exemplary PRAME peptide has the following amino acid sequence as illustrated in SEQ ID NO: 34.

[0343]

[0344] Example PRAME peptide (SEQ ID NO: 34)

[0345] The PRAME peptide may comprise or consist of the amino acid sequence of SEQ ID NO: 34 or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the PRAME peptide comprises or consists of the amino acid sequence of SEQ ID NO: 34 or a variant thereof having at most two amino acid substitutions, additions, or deletions. In some embodiments, the PRAME peptide comprises or consists of the amino acid sequence of SEQ ID NO: 34 or a variant thereof having at most one amino acid substitution, addition, or deletion. In some embodiments, the PRAME peptide comprises or consists of the amino acid sequence of SEQ ID NO: 34 or a variant thereof having at most three amino acid substitutions. In some embodiments, the PRAME peptide comprises or consists of the amino acid sequence of SEQ ID NO: 34 or a variant thereof having at most two amino acid substitutions. In some embodiments, the PRAME peptide comprises or consists of the amino acid sequence of SEQ ID NO: 34 or a variant thereof having at most one amino acid substitution. In some embodiments, the PRAME peptide comprises or consists of the amino acid sequence of SEQ ID NO: 34.

[0346] EZH2 / PRAME specific TCR sequence

[0347] The inventors have determined the amino acid sequences of EZH2 / PRAME-specific TCRs (including CDR regions), which are responsible for binding specificity to EZH2 or PRAME peptides.

[0348] EZH2 / PRAME-specific TCRs can be restricted to any suitable MHC (e.g., one or more HLA alleles). Appropriately, EZH2 / PRAME-specific TCRs are restricted to HLA class I or HLA class II alleles. Appropriately, EZH2 / PRAME-specific TCRs are restricted to HLA-A alleles. Appropriately, EZH2 / PRAME-specific TCRs are restricted to HLA-A. 02 Alleles. Appropriately, the EZH2 / PRAME-specific TCR is limited to HLA-A. 0201.

[0349] The table below provides exemplary EZH2 / PRAME-specific TCR amino acid sequences.

[0350]

[0351]

[0352] In one aspect, the present invention provides a TCR comprising CDR3α and / or CDR3β, wherein CDR3α comprises or consists of: (i) the amino acid sequence of SEQ ID NO: 37 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of SEQ ID NO: 42 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises or consists of: (i) the amino acid sequence of SEQ ID NO: 47 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of SEQ ID NO: 53 or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0353] In some embodiments, the CDR3 variant has at most two amino acid substitutions, additions, or deletions. In some embodiments, the CDR3 variant has at most one amino acid substitution, addition, or deletion. In some embodiments, the CDR3 variant has at most three amino acid substitutions. In some embodiments, the CDR3 variant has at most two amino acid substitutions. In some embodiments, the CDR3 variant has at most one amino acid substitution.

[0354] In some embodiments, the TCR includes CDR3α and / or CDR3β, wherein CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 37 or 42, and CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 47 or 53.

[0355] In some embodiments, the TCR includes CDR3α and / or CDR3β, wherein the CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 37, and the CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 47.

[0356] In some embodiments, the TCR includes CDR3α and / or CDR3β, wherein the CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 42, and the CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 53.

[0357] In some embodiments, the TCR further comprises (i) (a) CDR1α and (b) CDR2α or (ii) (a) CDR1α and (b) CDR2α, and / or (i) (a) CDR1β and (b) CDR2β or (ii) (a) CDR1β and (b) CDR2β, wherein (i) (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 35 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (i) (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 36 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (ii) (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 40 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (ii) (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 35 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (ii) (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 36 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (ii) (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 35 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (ii) (b) CDR2 ... The amino acid sequence of SEQ ID NO: 41 or a variant thereof having at most three amino acid substitutions, additions or deletions, wherein (i) (a) CDR1β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 45 or a variant thereof having at most three amino acid substitutions, additions or deletions, wherein (i) (b) CDR2β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 46 or a variant thereof having at most three amino acid substitutions, additions or deletions, wherein (ii) (a) CDR1β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 51 or a variant thereof having at most three amino acid substitutions, additions or deletions, wherein (ii) (b) CDR2β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 52 or a variant thereof having at most three amino acid substitutions, additions or deletions.

[0358] In some embodiments, the TCR includes an α-chain variable domain and / or a β-chain variable domain, the α-chain variable domain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 38 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) an amino acid sequence of SEQ ID NO: 43 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; the β-chain variable domain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 48 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) SEQ ID NO: 38. The amino acid sequence of NO: 54 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it.

[0359] In some embodiments, the TCR comprises an α chain and / or a β chain, the α chain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 39 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) an amino acid sequence of SEQ ID NO: 44 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; the β chain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 49 or 50 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) a sequence of SEQ ID NO: The amino acid sequence of 55 or 56 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it.

[0360] In one aspect, the present invention provides a TCR comprising (i) (a) CDR1α, (b) CDR2α, (c) CDR3α or (ii) (a) CDR1α, (b) CDR2α, (c) CDR3α, and / or (i) (a) CDR1β, (b) CDR2β, (c) CDR3β or (ii) (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (i) (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 35 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (i) (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 36 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and wherein (i) (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 36. The amino acid sequence of SEQ ID NO: 47 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (ii) (a) CDR1α comprises or consists of the following: the amino acid sequence of SEQ ID NO: 40 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (ii) (b) CDR2α comprises or consists of the following: the amino acid sequence of SEQ ID NO: 41 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (ii) (c) CDR3α comprises or consists of the following: the amino acid sequence of SEQ ID NO: 42 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (i) (a) CDR1β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 45 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (i) (b) CDR2β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 46 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (i) (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 47 or a variant thereof having at most three amino acid substitutions, additions or deletions; (ii) (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 51 or a variant thereof having at most three amino acid substitutions, additions or deletions; (ii) (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 52 or a variant thereof having at most three amino acid substitutions, additions or deletions; and (ii) (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 53 or a variant thereof having at most three amino acid substitutions, additions or deletions.

[0361] In one aspect, the present invention provides a TCR comprising (a) CDR1α, (b) CDR2α, (c) CDR3α and / or (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 35 or a variant thereof having at most three amino acid substitutions, additions, or deletions; (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 36 or a variant thereof having at most three amino acid substitutions, additions, or deletions; (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 37 or a variant thereof having at most three amino acid substitutions, additions, or deletions; (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 45 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 45. The amino acid sequence of SEQ ID NO: 46 or a variant thereof having at most three amino acid substitutions, additions or deletions, wherein (c) CDR3β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 47 or a variant thereof having at most three amino acid substitutions, additions or deletions.

[0362] In one aspect, the present invention provides a TCR comprising (a) CDR1α, (b) CDR2α, (c) CDR3α and / or (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 40 or a variant thereof having at most three amino acid substitutions, additions, or deletions; (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 41 or a variant thereof having at most three amino acid substitutions, additions, or deletions; (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 42 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 51 or a variant thereof having at most three amino acid substitutions, additions, or deletions. The amino acid sequence of 52 or a variant thereof having at most three amino acid substitutions, additions or deletions, wherein (c) CDR3β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 53 or a variant thereof having at most three amino acid substitutions, additions or deletions.

[0363] In some embodiments, the CDR variant has at most two amino acid substitutions, additions, or deletions. In some embodiments, the CDR variant has at most one amino acid substitution, addition, or deletion. In some embodiments, the CDR variant has at most three amino acid substitutions. In some embodiments, the CDR variant has at most two amino acid substitutions. In some embodiments, the CDR variant has at most one amino acid substitution.

[0364] In some embodiments, the TCR includes (i) (a) CDR1α, (b) CDR2α, (c) CDR3α or (ii) (a) CDR1α, (b) CDR2α, (c) CDR3α, and / or (i) (a) CDR1β, (b) CDR2β, (c) CDR3β or (ii) (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (i) (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 35, (i) (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 36, (i) (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 37, and (ii) (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 40. (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 41, and (ii) (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 42, and (i) (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 45, and (i) (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 46, and (i) (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 47, and (ii) (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 51, and (ii)(b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 52, and (ii) (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 53.

[0365] In some embodiments, the TCR includes (a) CDR1α, (b) CDR2α, (c) CDR3α and / or (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 35, (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 36, (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 37, (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 45, (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 46, and (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 47.

[0366] In some embodiments, the TCR includes (a) CDR1α, (b) CDR2α, (c) CDR3α and / or (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 40, (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 41, (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 42, (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 51, (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 52, and (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 53.

[0367] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, the α-chain variable domain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 38 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) an amino acid sequence of SEQ ID NO: 43 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; the β-chain variable domain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 48 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) The amino acid sequence of SEQ ID NO: 54 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it.

[0368] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, wherein the α-chain variable domain comprises or consists of: (i) an amino acid sequence of SEQ ID NO: 38 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α-chain variable domain comprises CDR3α, the CDR3α comprising or consists of: an amino acid sequence of SEQ ID NO: 37 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) an amino acid sequence of SEQ ID NO: 43 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α-chain variable domain comprises CDR3α, the CDR3α comprising or consists of: SEQ ID NO: The amino acid sequence of SEQ ID NO: 42 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein the β-chain variable domain comprises or consists of: (i) the amino acid sequence of SEQ ID NO: 48 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β-chain variable domain comprises CDR3β, wherein the CDR3β comprises or consists of: the amino acid sequence of SEQ ID NO: 47 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of SEQ ID NO: 54 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β-chain variable domain comprises CDR3β, wherein the CDR3β comprises or consists of: SEQ ID NO: The amino acid sequence of 53 or its variants having at most three amino acid substitutions, additions or deletions.

[0369] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, wherein the α-chain variable domain comprises or consists of: (i) an amino acid sequence of SEQ ID NO: 38 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it, wherein the α-chain variable domain comprises (a) CDR1α, (b) CDR2α, and (c) CDR3α, wherein (a) CDR1α comprises or consists of: an amino acid sequence of SEQ ID NO: 35 or a variant thereof having at most three amino acid substitutions, additions, or deletions; (b) CDR2α comprises or consists of: an amino acid sequence of SEQ ID NO: 36 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and (c) CDR3α comprises or consists of: SEQ ID NO: The amino acid sequence of SEQ ID NO: 47 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of SEQ ID NO: 43 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, wherein the α-chain variable domain comprises (a) CDR1α, (b) CDR2α, (c) CDR3α, wherein (a) CDR1α comprises or consists of the following: the amino acid sequence of SEQ ID NO: 40 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2α comprises or consists of the following: the amino acid sequence of SEQ ID NO: 41 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (c) CDR3α comprises or consists of the following: SEQ ID NO: The amino acid sequence of SEQ ID NO: 42 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein the β-chain variable domain comprises or consists of the following: (i) the amino acid sequence of SEQ ID NO: 48 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it, wherein the β-chain variable domain comprises (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (a) CDR1β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 45 or a variant thereof having at most three amino acid substitutions, additions, or deletions,The (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 46 or a variant thereof having at most three amino acid substitutions, additions, or deletions; the (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 47 or a variant thereof having at most three amino acid substitutions, additions, or deletions; or (ii) the amino acid sequence of SEQ ID NO: 54 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it, wherein the β-chain variable domain comprises (a) CDR1β, (b) CDR2β, and (c) CDR3β, wherein (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 51 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and the (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 51 or a variant thereof having at most three amino acid substitutions, additions, or deletions; the (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 51. The amino acid sequence of SEQ ID NO: 52 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (c) CDR3β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 53 or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0370] In some embodiments, the TCR includes an α-chain variable domain and / or a β-chain variable domain, the α-chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 38 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 48 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0371] In some embodiments, the TCR includes an α-chain variable domain and / or a β-chain variable domain, the α-chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 43 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 54 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0372] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, the α chain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 39 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) an amino acid sequence of SEQ ID NO: 44 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; the β chain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 49 or 50 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) SEQ ID NO: The amino acid sequence of 55 or 56 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it.

[0373] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, the α chain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 39 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α chain comprises CDR3α, the CDR3α comprising or consisting of: an amino acid sequence of SEQ ID NO: 35 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) an amino acid sequence of SEQ ID NO: 44 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α chain comprises CDR3α, the CDR3α comprising or consisting of: SEQ ID NO: The amino acid sequence of SEQ ID NO: 42 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein the β chain comprises or consists of: (i) the amino acid sequence of SEQ ID NO: 49 or 50 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β chain comprises CDR3β, wherein the CDR3β comprises or consists of: the amino acid sequence of SEQ ID NO: 47 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of SEQ ID NO: 55 or 56 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β chain comprises CDR3β, wherein the CDR3β comprises or consists of: SEQ ID NO: The amino acid sequence of 53 or its variants having at most three amino acid substitutions, additions or deletions.

[0374] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, the α chain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 39 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α chain comprises (a) CDR1α, (b) CDR2α, (c) CDR3α, wherein (a) CDR1α comprises or consists of: an amino acid sequence of SEQ ID NO: 35 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2α comprises or consists of: an amino acid sequence of SEQ ID NO: 36 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (c) CDR3α comprises or consists of: an amino acid sequence of SEQ ID NO: 37 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) SEQ ID The amino acid sequence of SEQ ID NO: 44 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, wherein the α chain comprises (a) CDR1α, (b) CDR2α, (c) CDR3α, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 40 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 41 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 42 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and the β chain comprises or consists of: (i) SEQ ID NO: The amino acid sequence of SEQ ID NO: 49 or 50, or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, wherein the β chain comprises (a) CDR1β, (b) CDR2β, and (c) CDR3β, wherein (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 45, or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 46, or a variant thereof having at most three amino acid substitutions, additions, or deletions.The (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 47 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of SEQ ID NO: 55 or 56 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β chain comprises (a) CDR1β, (b) CDR2β, and (c) CDR3β, wherein (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 51 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 52 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 52 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 55 or 56. The amino acid sequence of 53 or its variants having at most three amino acid substitutions, additions, or deletions.

[0375] In some embodiments, the TCR comprises an α chain and / or a β chain, the α chain comprising or consisting of the amino acid sequence of SEQ ID NO: 39 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 49 or 50 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0376] In some embodiments, the TCR comprises an α chain and / or a β chain, the α chain comprising or consisting of the amino acid sequence of SEQ ID NO: 44 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 55 or 56 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0377] cathepsin G (CTSG) specific TCR

[0378] In one aspect, the present invention provides a TCR that binds to a CTSG peptide when the CTSG peptide is presented by an MHC.

[0379] CTSG

[0380] Cathepsin G (CTSG) is a protein encoded by the CTSG gene.

[0381] Cathepsin G is expressed in the early stages of myeloid differentiation and participates in the degradation of extracellular matrix components, the cleavage of inflammatory mediators, immune responses, and antigen presentation. Currently, CTSG is considered a potential leukemia-associated antigen because it is aberrantly overexpressed in leukemia blasts characterized by an immature phenotype. In fact, CTSG peptides have been shown to be naturally processed and presented on the surface of leukemia cells, making this antigen an ideal target for adoptive immunotherapy (see Papadopoulos, KP et al., 1997. The Journal of the American Society of Hematology, 90(12), pp. 4938-4946).

[0382] CTSG proteins may have the amino acid sequence described in UniProt entry P08311. An exemplary CTSG protein has the following amino acid sequence described in SEQ ID NO: 57.

[0383]

[0384] Exemplary CTSG protein (SEQ ID NO: 57)

[0385] CTSG peptide

[0386] As used herein, the term "CTSG peptide" may refer to a peptide comprising an amino acid sequence derived from the CTSG protein. Suitablely, a CTSG peptide may comprise at least five, at least six, at least seven, at least eight, or at least nine adjacent amino acid residues of the CTSG protein amino acid sequence (or a variant thereof). In some embodiments, a CTSG peptide comprises nine adjacent amino acid residues of the CTSG protein amino acid sequence (or a variant thereof).

[0387] In one aspect, the present invention provides a CTSG peptide comprising or consisting of an amino acid sequence selected from or composed of an amino acid sequence selected from SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81, SEQ ID NO: 95, and variants thereof having at most three amino acid substitutions, additions, or deletions. Suitably, the CTSG peptide is an isolated peptide.

[0388] In some embodiments, the CTSG peptide comprises or consists of the amino acid sequences of SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81, and SEQ ID NO: 95, or variants thereof having at most two amino acid substitutions, additions, or deletions (or fragments thereof). In some embodiments, the CTSG peptide comprises or consists of the amino acid sequences of SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81, and SEQ ID NO: 95, or variants thereof having at most one amino acid substitution, addition, or deletion (or fragments thereof). In some embodiments, the CTSG peptide comprises or consists of the amino acid sequences of SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81, and SEQ ID NO: 95, or variants thereof having at most three amino acid substitutions (or fragments thereof). In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81, SEQ ID NO: 95, or a variant thereof having at most two amino acid substitutions (or a fragment thereof). In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81, SEQ ID NO: 95, or a variant thereof having at most one amino acid substitution (or a fragment thereof). In some embodiments, the CTSG peptide comprises or consists of the following: SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81, or SEQ ID NO: 95 (or a fragment thereof).

[0389] In some embodiments, the CTSG peptide has fewer than 14, 13, 12, 11, or 10 amino acid residues. In some embodiments, the CTSG peptide consists of about 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more amino acid residues. In some embodiments, the CTSG peptide is about 9 to 14 amino acid residues long, about 9 to 13 amino acid residues long, about 9 to 12 amino acid residues long, about 9 to 11 amino acid residues long, or about 9 to 10 amino acid residues long. In some embodiments, the CTSG peptide is a nonameric fragment.

[0390] In some embodiments, the CTSG peptide comprises: a nonameric fragment of the amino acid sequence SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81, SEQ ID NO: 95, or a variant thereof having at most two amino acid substitutions, additions, or deletions (or fragments thereof). In some embodiments, the CTSG peptide comprises: a nonameric fragment of the amino acid sequence SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81, SEQ ID NO: 95, or a variant thereof having at most one amino acid substitution, addition, or deletion (or fragments thereof). In some embodiments, the CTSG peptide comprises: a nonameric fragment of the amino acid sequence SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81, SEQ ID NO: 95, or a variant thereof having at most three amino acid substitutions (or fragments thereof). In some embodiments, the CTSG peptide comprises: a nonameric fragment of the amino acid sequence SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81, or SEQ ID NO: 95, or a variant thereof having at most two amino acid substitutions (or a fragment thereof). In some embodiments, the CTSG peptide comprises: a nonameric fragment of the amino acid sequence SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81, or SEQ ID NO: 95, or a variant thereof having at most one amino acid substitution (or a fragment thereof). In some embodiments, the CTSG peptide comprises: a nonameric fragment of SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81, or SEQ ID NO: 95.

[0391] Exemplary CTSG peptide and CTSG-specific TCR sequence 1

[0392] An exemplary CTSG peptide has the following amino acid sequence as set forth in SEQ ID NO: 58.

[0393]

[0394] Exemplary CTSG peptide 1 (SEQ ID NO: 58)

[0395] In one aspect, the present invention provides a CTSG peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 58 or a variant thereof having at most three amino acid substitutions, additions, or deletions (or fragments thereof). In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 58 or a variant thereof having at most two amino acid substitutions, additions, or deletions (or fragments thereof). In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 58 or a variant thereof having at most one amino acid substitution, addition, or deletion (or fragments thereof). In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 58 or a variant thereof having at most three amino acid substitutions (or fragments thereof). In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 58 or a variant thereof having at most two amino acid substitutions (or fragments thereof). In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 58 or a variant thereof having at most one amino acid substitution (or fragments thereof). In some embodiments, the CTSG peptide comprises or consists of the following: the amino acid sequence (or a fragment thereof) of SEQ ID NO: 58.

[0396] In one aspect, the present invention provides a CTSG peptide comprising or consisting of a nonameric fragment of the amino acid sequence of SEQ ID NO: 58 or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 58 or a variant thereof having at most two amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 58 or a variant thereof having at most one amino acid substitution, addition, or deletion. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 58 or a variant thereof having at most three amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 58 or a variant thereof having at most two amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the following: a nonameric fragment of the amino acid sequence of SEQ ID NO: 58 or a variant thereof having at most one amino acid substitution. In some embodiments, the CTSG peptide comprises or consists of the following: a nonameric fragment of the amino acid sequence of SEQ ID NO: 58.

[0397] CTSG peptides can be immunogenic peptides. CTSG peptides can bind to any suitable MHC. Appropriately, CTSG peptides bind to MHC encoded by HLA class I or HLA class II alleles. Appropriately, CTSG peptides bind to MHC encoded by HLA-A alleles. Appropriately, CTSG peptides bind to MHC encoded by HLA-A alleles. The 02 allele encodes the MHC. Appropriately, the CTSG peptide binds to the HLA-A... MHC encoded in 0201.

[0398] The inventors have determined the amino acid sequences of CTSG-specific TCRs (including CDR regions), which are responsible for the binding specificity of CTSG peptides.

[0399] CTSG-specific TCRs can be restricted to any suitable MHC (e.g., one or more HLA alleles). Appropriately, CTSG-specific TCRs are restricted to HLA class I or HLA class II alleles. Appropriately, CTSG-specific TCRs are restricted to HLA-A alleles. Appropriately, CTSG-specific TCRs are restricted to HLA-A. 02 Alleles. Appropriately, CTSG-specific TCRs are limited to HLA-A. 0201.

[0400] The table below provides exemplary CTSG-specific TCR amino acid sequences.

[0401]

[0402]

[0403] In one aspect, the present invention provides a TCR comprising CDR3α and / or CDR3β, wherein CDR3α comprises or consists of: (i) the amino acid sequence of SEQ ID NO: 61 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of SEQ ID NO: 66 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises or consists of: (i) the amino acid sequence of SEQ ID NO: 71 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of SEQ ID NO: 77 or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0404] In some embodiments, the CDR3 variant has at most two amino acid substitutions, additions, or deletions. In some embodiments, the CDR3 variant has at most one amino acid substitution, addition, or deletion. In some embodiments, the CDR3 variant has at most three amino acid substitutions. In some embodiments, the CDR3 variant has at most two amino acid substitutions. In some embodiments, the CDR3 variant has at most one amino acid substitution.

[0405] In some embodiments, the TCR includes CDR3α and / or CDR3β, wherein CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 61 or 66, and CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 71 or 77.

[0406] In some embodiments, the TCR further comprises (i) (a) CDR1α and (b) CDR2α or (ii) (a) CDR1α and (b) CDR2α, and / or (i) (a) CDR1β and (b) CDR2β or (ii) (a) CDR1β and (b) CDR2β, wherein (i) (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 59 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (i) (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 60 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (ii) (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 64 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (ii) (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 64 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (ii) (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 64. The amino acid sequence of SEQ ID NO: 65 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (i) (a) CDR1β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 69 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (i) (b) CDR2β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 70 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (ii) (a) CDR1β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 75 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (ii) (b) CDR2β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 76 or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0407] In some embodiments, the TCR includes an α-chain variable domain and / or a β-chain variable domain, the α-chain variable domain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 62 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) an amino acid sequence of SEQ ID NO: 67 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; the β-chain variable domain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 72 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) SEQ ID NO: 67. The amino acid sequence of NO: 78 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it.

[0408] In some embodiments, the TCR comprises an α chain and / or a β chain, the α chain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 63 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) an amino acid sequence of SEQ ID NO: 68 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; the β chain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 73 or 74 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) a sequence of SEQ ID NO: The amino acid sequence of 79 or 80 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it.

[0409] In one aspect, the present invention provides a TCR comprising (i) (a) CDR1α, (b) CDR2α, (c) CDR3α or (ii) (a) CDR1α, (b) CDR2α, (c) CDR3α, and / or (i) (a) CDR1β, (b) CDR2β, (c) CDR3β or (ii) (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (i) (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 59 or a variant thereof having at most three amino acid substitutions, additions, or deletions; (i) (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 60 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and (i) (c) CDR3α comprises or consists of the following: SEQ ID NO: The amino acid sequence of SEQ ID NO: 61 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (ii) (a) CDR1α comprises or consists of the following: the amino acid sequence of SEQ ID NO: 64 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (ii) (b) CDR2α comprises or consists of the following: the amino acid sequence of SEQ ID NO: 65 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (ii) (c) CDR3α comprises or consists of the following: the amino acid sequence of SEQ ID NO: 66 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (i) (a) CDR1β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 69 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (i) (b) CDR2β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 70 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (i) (c) CDR3β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 71 or a variant thereof having at most three amino acid substitutions, additions or deletions; (ii) (a) CDR1β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 75 or a variant thereof having at most three amino acid substitutions, additions or deletions; (ii) (b) CDR2β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 76 or a variant thereof having at most three amino acid substitutions, additions or deletions; and (ii) (c) CDR3β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 77 or a variant thereof having at most three amino acid substitutions, additions or deletions.

[0410] In some embodiments, the CDR variant has at most two amino acid substitutions, additions, or deletions. In some embodiments, the CDR variant has at most one amino acid substitution, addition, or deletion. In some embodiments, the CDR variant has at most three amino acid substitutions. In some embodiments, the CDR variant has at most two amino acid substitutions. In some embodiments, the CDR variant has at most one amino acid substitution.

[0411] In some embodiments, the TCR includes (i) (a) CDR1α, (b) CDR2α, (c) CDR3α or (ii) (a) CDR1α, (b) CDR2α, (c) CDR3α, and / or (i) (a) CDR1β, (b) CDR2β, (c) CDR3β or (ii) (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (i) (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 59, (i) (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 60, (i) (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 61, and (ii) (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 64. (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 65, and (ii) (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 66, and (i) (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 69, and (i) (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 70, and (i) (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 71, and (ii) (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 75, and (ii)(b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 76, and (ii) (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 77.

[0412] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, the α-chain variable domain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 62 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) an amino acid sequence of SEQ ID NO: 67 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; the β-chain variable domain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 72 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) The amino acid sequence of SEQ ID NO: 78 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it.

[0413] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, wherein the α-chain variable domain comprises or consists of: (i) an amino acid sequence of SEQ ID NO: 62 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α-chain variable domain comprises CDR3α, the CDR3α comprising or consists of: an amino acid sequence of SEQ ID NO: 61 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) an amino acid sequence of SEQ ID NO: 67 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α-chain variable domain comprises CDR3α, the CDR3α comprising or consists of: SEQ ID NO: The amino acid sequence of SEQ ID NO: 76 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein the β-chain variable domain comprises or consists of the following: (i) the amino acid sequence of SEQ ID NO: 72 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β-chain variable domain comprises CDR3β, wherein the CDR3β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 71 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of SEQ ID NO: 78 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β-chain variable domain comprises CDR3β, wherein the CDR3β comprises or consists of the following: SEQ ID NO: The amino acid sequence of 77 or its variants having at most three amino acid substitutions, additions or deletions.

[0414] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, wherein the α-chain variable domain comprises or consists of: (i) an amino acid sequence of SEQ ID NO: 62 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it, wherein the α-chain variable domain comprises (a) CDR1α, (b) CDR2α, and (c) CDR3α, wherein (a) CDR1α comprises or consists of: an amino acid sequence of SEQ ID NO: 59 or a variant thereof having at most three amino acid substitutions, additions, or deletions; (b) CDR2α comprises or consists of: an amino acid sequence of SEQ ID NO: 60 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and (c) CDR3α comprises or consists of: SEQ ID NO: The amino acid sequence of SEQ ID NO: 61 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of SEQ ID NO: 67 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, wherein the α-chain variable domain comprises (a) CDR1α, (b) CDR2α, (c) CDR3α, wherein (a) CDR1α comprises or consists of the following: the amino acid sequence of SEQ ID NO: 64 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2α comprises or consists of the following: the amino acid sequence of SEQ ID NO: 65 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (c) CDR3α comprises or consists of the following: SEQ ID NO: The amino acid sequence of SEQ ID NO: 76 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein the β-chain variable domain comprises or consists of the following: (i) the amino acid sequence of SEQ ID NO: 72 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it, wherein the β-chain variable domain comprises (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (a) CDR1β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 69 or a variant thereof having at most three amino acid substitutions, additions, or deletions,The (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 70 or a variant thereof having at most three amino acid substitutions, additions, or deletions; the (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 71 or a variant thereof having at most three amino acid substitutions, additions, or deletions; or (ii) the amino acid sequence of SEQ ID NO: 78 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it, wherein the β-chain variable domain comprises (a) CDR1β, (b) CDR2β, and (c) CDR3β, wherein (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 75 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and the (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 75 or a variant thereof having at most three amino acid substitutions, additions, or deletions; The amino acid sequence of SEQ ID NO: 76 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (c) CDR3β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 77 or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0415] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, the α chain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 63 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) an amino acid sequence of SEQ ID NO: 68 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; the β chain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 73 or 74 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) SEQ ID NO: The amino acid sequence of 79 or 80 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it.

[0416] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, the α chain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 63 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α chain comprises CDR3α, the CDR3α comprising or consisting of: an amino acid sequence of SEQ ID NO: 61 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) an amino acid sequence of SEQ ID NO: 68 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α chain comprises CDR3α, the CDR3α comprising or consisting of: SEQ ID NO: The amino acid sequence of SEQ ID NO: 76 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein the β chain comprises or consists of: (i) the amino acid sequence of SEQ ID NO: 73 or 74 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β chain comprises CDR3β, wherein the CDR3β comprises or consists of: the amino acid sequence of SEQ ID NO: 71 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of SEQ ID NO: 79 or 80 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β chain comprises CDR3β, wherein the CDR3β comprises or consists of: SEQ ID NO: The amino acid sequence of 77 or its variants having at most three amino acid substitutions, additions or deletions.

[0417] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, the α chain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 63 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α chain comprises (a) CDR1α, (b) CDR2α, (c) CDR3α, wherein (a) CDR1α comprises or consists of: an amino acid sequence of SEQ ID NO: 59 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2α comprises or consists of: an amino acid sequence of SEQ ID NO: 60 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (c) CDR3α comprises or consists of: an amino acid sequence of SEQ ID NO: 61 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) SEQ ID The amino acid sequence of SEQ ID NO: 68 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, wherein the α chain comprises (a) CDR1α, (b) CDR2α, (c) CDR3α, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 64 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 65 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 66 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and the β chain comprises or consists of: (i) SEQ ID NO: The amino acid sequence of 73 or 74, or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, wherein the β chain comprises (a) CDR1β, (b) CDR2β, and (c) CDR3β, wherein (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 69, or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 70, or a variant thereof having at most three amino acid substitutions, additions, or deletions.The (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 71 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of SEQ ID NO: 79 or 80 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β chain comprises (a) CDR1β, (b) CDR2β, and (c) CDR3β, wherein (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 75 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 76 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 76 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein SEQ ID NO: 79 or 80 is a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, wherein the β chain comprises (a) CDR1β, (b) CDR2β, and (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 75, at least 75%, and (d) CDR3β, at least ... The amino acid sequence of 77 or its variants having at most three amino acid substitutions, additions, or deletions.

[0418] Exemplary CTSG peptide and CTSG-specific TCR sequence 2

[0419] Another exemplary CTSG peptide has the following amino acid sequence as set forth in SEQ ID NO: 81.

[0420]

[0421] Example CTSG peptide 2 (SEQ ID NO: 81)

[0422] The inventors have determined that residues 2, 3, 4, and 6 of SEQ ID NO: 81 are not essential for MHC binding and / or TCR recognition. Therefore, in one embodiment, the present invention provides a CTSG peptide comprising conserved substitutions at one or more of positions 2, 3, 4, and / or 6 of SEQ ID NO: 81.

[0423] The CTSG peptide may have the amino acid sequence described in SEQ ID NO: 535.

[0424] Where X is any amino acid (SEQ ID NO: 535)

[0425] In one aspect, the present invention provides a CTSG peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 535 or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 535 or a variant thereof having at most two amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 535 or a variant thereof having at most one amino acid substitution, addition, or deletion. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 535 or a variant thereof having at most three amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 535 or a variant thereof having at most two amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 535 or a variant thereof having at most one amino acid substitution. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 535. Suitably, the CTSG peptide binds to HLA-C. The 07 allele encodes the MHC. Appropriately, the CTSG peptide binds to the HLA-C... 0702 encodes MHC. Appropriately, the CTSG peptide binds to HLA-A. The MHC is encoded by 24 alleles. Appropriately, the CTSG peptide binds to HLA-A... MHC encoded by 2402. Appropriately, the CTSG peptide binds to HLA-C. The 07 allele encodes the MHC and is generated by HLA-A. The MHC is encoded by 24 alleles. Appropriately, the CTSG peptide binds to HLA-C. MHC encoded by 0702 and HLA-A MHC encoded in 2402.

[0426] In one aspect, the present invention provides a CTSG peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 81 or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 81 or a variant thereof having at most two amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 81 or a variant thereof having at most one amino acid substitution, addition, or deletion. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 81 or a variant thereof having at most three amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 81 or a variant thereof having at most two amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 81 or a variant thereof having at most one amino acid substitution. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 81.

[0427] In one aspect, the present invention provides a CTSG peptide comprising or consisting of a nonameric fragment of the amino acid sequence of SEQ ID NO: 81 or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 81 or a variant thereof having at most two amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 81 or a variant thereof having at most one amino acid substitution, addition, or deletion. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 81 or a variant thereof having at most three amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 81 or a variant thereof having at most two amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the following: a nonameric fragment of the amino acid sequence of SEQ ID NO: 81 or a variant thereof having at most one amino acid substitution. Suitably, the CTSG peptide binds to HLA-C. The 07 allele encodes the MHC. Appropriately, the CTSG peptide binds to the HLA-C... 0702 encodes MHC. Appropriately, the CTSG peptide binds to HLA-A. The MHC is encoded by 24 alleles. Appropriately, the CTSG peptide binds to HLA-A... MHC encoded by 2402. Appropriately, the CTSG peptide binds to HLA-C. The 07 allele encodes the MHC and is generated by HLA-A. The MHC is encoded by 24 alleles. Appropriately, the CTSG peptide binds to HLA-C. MHC encoded by 0702 and HLA-A MHC encoded in 2402.

[0428] An exemplary fragment has the following amino acid sequence as set forth in SEQ ID NO: 82.

[0429]

[0430] Exemplary CTSG peptide 2-fragment 1 (SEQ ID NO: 82)

[0431] In one aspect, the present invention provides a CTSG peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 82 or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 82 or a variant thereof having at most two amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 82 or a variant thereof having at most one amino acid substitution, addition, or deletion. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 82 or a variant thereof having at most three amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 82 or a variant thereof having at most two amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 82 or a variant thereof having at most one amino acid substitution. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 82. Suitably, the CTSG peptide binds to HLA-A. The MHC is encoded by 24 alleles. Appropriately, the CTSG peptide binds to HLA-A... MHC encoded in 2402.

[0432] Another exemplary fragment has the following amino acid sequence as illustrated in SEQ ID NO: 83.

[0433]

[0434] Exemplary CTSG peptide 2-fragment 2 (SEQ ID NO: 83)

[0435] In one aspect, the present invention provides a CTSG peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 83 or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 83 or a variant thereof having at most two amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 83 or a variant thereof having at most one amino acid substitution, addition, or deletion. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 83 or a variant thereof having at most three amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 83 or a variant thereof having at most two amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 83 or a variant thereof having at most one amino acid substitution. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 83. Suitably, the CTSG peptide binds to HLA-C. The 07 allele encodes the MHC. Appropriately, the CTSG peptide binds to the HLA-C... MHC encoded in 0702.

[0436] Other exemplary fragments have the following amino acid sequences as illustrated in SEQ ID NO: 420, 421 and 422.

[0437]

[0438] Exemplary CTSG peptide 2-fragment 3 (SEQ ID NO: 420)

[0439]

[0440] Exemplary CTSG peptide 2-fragment 4 (SEQ ID NO: 421)

[0441]

[0442] Exemplary CTSG peptide 2-fragment 5 (SEQ ID NO: 422)

[0443] In one aspect, the present invention provides a CTSG peptide comprising or consisting of the amino acid sequence of any one of SEQ ID NO: 420 to 422 or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 420 to 422 or a variant thereof having at most two amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 420 to 422 or a variant thereof having at most one amino acid substitution, addition, or deletion. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 420 to 422 or a variant thereof having at most three amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 420 to 422 or a variant thereof having at most two amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 420 to 422 or a variant thereof having at most one amino acid substitution.

[0444] CTSG peptides can be immunogenic peptides. CTSG peptides can bind to any suitable MHC. Appropriately, CTSG peptides bind to MHC encoded by HLA class I or HLA class II alleles. Appropriately, CTSG peptides bind to MHC encoded by HLA-A or HLA-C alleles. Appropriately, CTSG peptides bind to MHC encoded by HLA-A... 24 alleles or HLA-C The 07 allele encodes the MHC. Appropriately, the CTSG peptide binds to the HLA-A receptor. 2402 or HLA-C The MHC encoded by 0702. Appropriately, the CTSG peptide binds to the MHC encoded by the HLA-A and HLA-C alleles. Appropriately, the CTSG peptide binds to the MHC encoded by the HLA-A allele. 24 alleles encode MHC and HLA-C The 07 allele encodes the MHC. Appropriately, the CTSG peptide binds to the HLA-A receptor. MHC encoded by 2402 and derived from HLA-C MHC encoded in 0702.

[0445] The inventors have determined the amino acid sequences of CTSG-specific TCRs (including CDR regions), which are responsible for the binding specificity of CTSG peptides.

[0446] CTSG-specific TCRs can be restricted to any suitable MHC (e.g., one or more HLA alleles). Appropriately, CTSG-specific TCRs are restricted to HLA class I or HLA class II alleles. Appropriately, CTSG-specific TCRs are restricted to HLA-A or HLA-C alleles. Appropriately, CTSG-specific TCRs are restricted to HLA-A... 24 alleles or HLA-C 07 allele. Appropriately, CTSG-specific TCRs are limited to HLA-A. 2402 or HLA-C 0702. Appropriately, CTSG-specific TCRs are limited to the HLA-A and HLA-C alleles. Appropriately, CTSG-specific TCRs are limited to HLA-A. 24 alleles and HLA-C 07 allele. Appropriately, CTSG-specific TCRs are limited to HLA-A. 2402 and HLA-C 0702.

[0447] The table below provides exemplary CTSG-specific TCR amino acid sequences.

[0448]

[0449] Unless otherwise specified, as used herein, the terms “TCR P56”, “P56 TCR”, “P56αβ”, “P56 TCRαβ” and “CTSG TCR” are used interchangeably and refer to a TCR that includes an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 87 or a variant thereof, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 92 or a variant thereof.

[0450] In one aspect, the present invention provides a TCR comprising CDR3α and / or CDR3β, wherein the CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 86 or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 91 or a variant thereof having at most three amino acid substitutions, additions or deletions.

[0451] In some embodiments, the CDR3 variant has at most two amino acid substitutions, additions, or deletions. In some embodiments, the CDR3 variant has at most one amino acid substitution, addition, or deletion. In some embodiments, the CDR3 variant has at most three amino acid substitutions. In some embodiments, the CDR3 variant has at most two amino acid substitutions. In some embodiments, the CDR3 variant has at most one amino acid substitution.

[0452] In some embodiments, the TCR includes CDR3α and / or CDR3β, wherein the CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 86, and the CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 91.

[0453] In some embodiments, the TCR further comprises (a) CDR1α and (b) CDR2α and / or (a) CDR1β and (b) CDR2β, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 84 or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 85 or a variant thereof having up to three amino acid substitutions, additions or deletions; (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 89 or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 90 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0454] In some embodiments, the TCR includes an α-chain variable domain and / or a β-chain variable domain, the α-chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 87 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 92 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0455] In some embodiments, the TCR comprises an α chain and / or a β chain, the α chain comprising or consisting of the amino acid sequence of SEQ ID NO: 88 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 93 or 94 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0456] In one aspect, the present invention provides a TCR comprising (a) CDR1α, (b) CDR2α, (c) CDR3α and / or (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 84 or a variant thereof having at most three amino acid substitutions, additions, or deletions; (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 85 or a variant thereof having at most three amino acid substitutions, additions, or deletions; (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 86 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 89 or a variant thereof having at most three amino acid substitutions, additions, or deletions. The amino acid sequence of 90 or a variant thereof having at most three amino acid substitutions, additions or deletions, wherein (c) CDR3β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 91 or a variant thereof having at most three amino acid substitutions, additions or deletions.

[0457] In some embodiments, the CDR variant has at most two amino acid substitutions, additions, or deletions. In some embodiments, the CDR variant has at most one amino acid substitution, addition, or deletion. In some embodiments, the CDR variant has at most three amino acid substitutions. In some embodiments, the CDR variant has at most two amino acid substitutions. In some embodiments, the CDR variant has at most one amino acid substitution.

[0458] In some embodiments, the TCR includes (a) CDR1α, (b) CDR2α, (c) CDR3α and / or (a) CDR1β, (b) CDR2β, (c) CDR3β, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 84, (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 85, (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 86, (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 89, (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 90, and (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 91.

[0459] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, the α-chain variable domain comprising or consisting of an amino acid sequence of SEQ ID NO: 87 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising or consisting of an amino acid sequence of SEQ ID NO: 92 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0460] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, wherein the α-chain variable domain comprises or consists of the amino acid sequence of SEQ ID NO: 87 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α-chain variable domain comprises CDR3α, the CDR3α comprising or consists of the amino acid sequence of SEQ ID NO: 86 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the β-chain variable domain comprises or consists of the amino acid sequence of SEQ ID NO: 92 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β-chain variable domain comprises CDR3β, the CDR3β comprising or consists of the following: SEQ ID NO: The amino acid sequence of 91 or its variants having at most three amino acid substitutions, additions or deletions.

[0461] In one aspect, the present invention provides a TCR comprising an α-chain variable domain and / or a β-chain variable domain, wherein the α-chain variable domain comprises or consists of the amino acid sequence of SEQ ID NO: 87 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it, wherein the α-chain variable domain comprises (a) CDR1α, (b) CDR2α, and (c) CDR3α, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 84 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 85 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 85. The amino acid sequence of SEQ ID NO: 96 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein the β-chain variable domain comprises or consists of the following: the amino acid sequence of SEQ ID NO: 92 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, wherein the β-chain variable domain comprises (a) CDR1β, (b) CDR2β, and (c) CDR3β, wherein (a) CDR1β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 89 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 90 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (c) CDR3β comprises or consists of the following: the amino acid sequence of SEQ ID NO: 91 or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0462] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, the α chain comprising or consisting of an amino acid sequence of SEQ ID NO: 88 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising or consisting of an amino acid sequence of SEQ ID NO: 93 or 94 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith.

[0463] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, wherein the α chain comprises or consists of the amino acid sequence of SEQ ID NO: 88 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the α chain comprises CDR3α, wherein the CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 86 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein the β chain comprises or consists of the amino acid sequence of SEQ ID NO: 93 or 94 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith, wherein the β chain comprises CDR3β, wherein the CDR3β comprises or consists of the following: SEQ ID NO: The amino acid sequence of 91 or its variants having at most three amino acid substitutions, additions or deletions.

[0464] In one aspect, the present invention provides a TCR comprising an α chain and / or a β chain, wherein the α chain comprises or consists of the amino acid sequence of SEQ ID NO: 88 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it, wherein the α chain comprises (a) CDR1α, (b) CDR2α, and (c) CDR3α, wherein (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 84 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 85 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and (c) CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 86 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the β chain comprises or consists of the amino acid sequence of SEQ ID NO: 88 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the β chain comprises or consists of the amino acid sequence of SEQ ID NO: 88. The amino acid sequence of ID NO: 93 or 94 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, wherein the β chain comprises (a) CDR1β, (b) CDR2β, and (c) CDR3β, wherein (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 89 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 90 or a variant thereof having at most three amino acid substitutions, additions, or deletions; and wherein (c) CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 91 or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0465] In one aspect, the present invention provides a TCR that binds to an immunogenic CTSG peptide when the peptide is presented by the major histocompatibility complex (MHC), wherein the immunogenic CTSG peptide comprises or is composed of: SXXXPXVFTRVSSFL (SEQ ID NO: 535) or a variant thereof having at most three amino acid substitutions, additions or deletions, or an immunogenic fragment thereof.

[0466] In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SGVPPEVFTRVSSFL (SEQ ID NO: 81) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or a fragment thereof. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of VFTRVSSFL (SEQ ID NO: 82) or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of VPPEVFTRVSSFL (SEQ ID NO: 83) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0467] Appropriately, the CTSG peptide binds to the MHC encoded by the HLA class I or HLA class II allele. Appropriately, the CTSG peptide binds to the MHC encoded by the HLA-A or HLA-C allele. Appropriately, the CTSG peptide binds to the MHC encoded by the HLA-A allele. 24 alleles or HLA-C The 07 allele encodes the MHC. Appropriately, the CTSG peptide binds to the HLA-A receptor. 2402 allele or HLA-C The CTSG peptide binds to the MHC encoded by the HLA-A allele and the MHC encoded by the HLA-C allele. The CTSG peptide binds to the MHC encoded by the HLA-A allele. 24 alleles encode MHC and HLA-C The 07 allele encodes the MHC. Appropriately, the CTSG peptide binds to the HLA-A receptor. MHC encoded by 2402 and derived from HLA-C MHC encoded in 0702.

[0468] Appropriately, CTSG-specific TCRs are limited to HLA class I or HLA class II alleles. Appropriately, CTSG-specific TCRs are limited to HLA-A or HLA-C alleles. Appropriately, CTSG-specific TCRs are limited to HLA-A. 24 alleles or HLA-C 07 allele. Appropriately, CTSG-specific TCRs are limited to HLA-A. 2402 or HLA-C 0702. Appropriately, CTSG-specific TCRs are limited to the HLA-A and HLA-C alleles. Appropriately, CTSG-specific TCRs are limited to HLA-A. 24 alleles and HLA-C 07 allele. Appropriately, CTSG-specific TCRs are limited to HLA-A. 2402 and HLA-C 0702.

[0469] Exemplary CTSG peptide and CTSG-specific TCR sequence 3

[0470] Another exemplary CTSG peptide has the following amino acid sequence as illustrated in SEQ ID NO: 95.

[0471]

[0472] Exemplary CTSG peptide 3 (SEQ ID NO: 95)

[0473] In one aspect, the present invention provides a CTSG peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 95 or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 95 or a variant thereof having at most two amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 95 or a variant thereof having at most one amino acid substitution, addition, or deletion. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 95 or a variant thereof having at most three amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 95 or a variant thereof having at most two amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 95 or a variant thereof having at most one amino acid substitution. In some embodiments, the CTSG peptide comprises or consists of the following amino acid sequence: SEQ ID NO: 95.

[0474] In one aspect, the present invention provides a CTSG peptide comprising or consisting of a nonameric fragment of the amino acid sequence of SEQ ID NO: 95 or a variant thereof having at most three amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 95 or a variant thereof having at most two amino acid substitutions, additions, or deletions. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 95 or a variant thereof having at most one amino acid substitution, addition, or deletion. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 95 or a variant thereof having at most three amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 95 or a variant thereof having at most two amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the following: a nonameric fragment of the amino acid sequence of SEQ ID NO: 95 or a variant thereof having at most one amino acid substitution. In some embodiments, the CTSG peptide comprises or consists of the following: a nonameric fragment of the amino acid sequence of SEQ ID NO: 95.

[0475] CTSG peptides can be immunogenic peptides. CTSG peptides can bind to any suitable MHC. Appropriately, CTSG peptides bind to MHC encoded by HLA class I or HLA class II alleles.

[0476] The inventors have determined the amino acid sequences of CTSG-specific TCRs (including CDR regions), which are responsible for the binding specificity of CTSG peptides.

[0477] CTSG-specific TCRs can be limited to any suitable MHC (e.g., one or more HLA alleles). Appropriately, CTSG-specific TCRs are limited to HLA class I alleles or HLA class II alleles.

[0478] The table below provides exemplary CTSG-specific TCR amino acid sequences.

[0479]

[0480]

[0481] In one aspect, the present invention provides a TCR comprising CDR3α and / or CDR3β, wherein CDR3α comprises or consists of: (i) the amino acid sequence of SEQ ID NO: 98 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of SEQ ID NO: 459 or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises or consists of: (i) the amino acid sequence of SEQ ID NO: 103 or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of SEQ ID NO: 109 or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0482] In some embodiments, the CDR3 variant has at most two amino acid substitutions, additions, or deletions. In some embodiments, the CDR3 variant has at most one amino acid substitution, addition, or deletion. In some embodiments, the CDR3 variant has at most three amino acid substitutions. In some embodiments, the CDR3 variant has at most two amino acid substitutions. In some embodiments, the CDR3 variant has at most one amino acid substitution.

[0483] In some embodiments, the TCR includes CDR3α and / or CDR3β, wherein the CDR3α comprises or consists of the amino acid sequence of SEQ ID NO: 98 or 459, and the CDR3β comprises or consists of the amino acid sequence of SEQ ID NO: 103 or 109.

[0484] In some embodiments, the TCR further comprises (i) (a) CDR1α and (b) CDR2α or (ii) (a) CDR1α and (b) CDR2α, and / or (i) (a) CDR1β and (b) CDR2β or (ii) (a) CDR1β and (b) CDR2β, wherein (i) (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 96 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (i) (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 97 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (ii) (a) CDR1α comprises or consists of the amino acid sequence of SEQ ID NO: 457 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (ii) (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 457 or a variant thereof having at most three amino acid substitutions, additions, or deletions; wherein (ii) (b) CDR2α comprises or consists of the amino acid sequence of SEQ ID NO: 457. The amino acid sequence of 458 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (i) (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 101 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (i) (b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 102 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (ii) (a) CDR1β comprises or consists of the amino acid sequence of SEQ ID NO: 107 or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein (ii)(b) CDR2β comprises or consists of the amino acid sequence of SEQ ID NO: 108 or a variant thereof having at most three amino acid substitutions, additions, or deletions.

[0485] In some embodiments, the TCR includes an α-chain variable domain and / or a β-chain variable domain, the α-chain variable domain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 99 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) an amino acid sequence of SEQ ID NO: 460 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; the β-chain variable domain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 104 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) SEQ ID NO: 99. The amino acid sequence of ID NO: 110 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it.

[0486] In some embodiments, the TCR comprises an α chain and / or a β chain, the α chain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 100 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) an amino acid sequence of SEQ ID NO: 461 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; the β chain comprising or consisting of: (i) an amino acid sequence of SEQ ID NO: 105 or 106 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity therewith; or (ii) SEQ ID NO: The amino acid sequence of 111 or 112 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with it.

[0487] In one aspect, the present invention provides a TCR comprising (i) (a) CDR1α, (b) CDR2α, (c) ...

Claims

1. A T-cell receptor (TCR) that binds to an immunogenic peptide when the peptide is presented by the major histocompatibility complex (MHC), wherein: (1) The immunogenic peptide is a cathepsin G (CTSG) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CAVQASNDYKLSF (SEQ ID NO: 86) or a variant thereof having up to three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CASSVGRATEAFF (SEQ ID NO: 91) or a variant thereof having up to three amino acid substitutions, additions or deletions; (2) The immunogenic peptide is a cathepsin G (CTSG) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes (i) the amino acid sequence of CALPSARQLTF (SEQ ID NO: 61) or a variant thereof having up to three amino acid substitutions, additions or deletions, or (ii) the amino acid sequence of CAFMSPEGGSEKLVF (SEQ ID NO: 66) or a variant thereof having up to three amino acid substitutions, additions or deletions, and CDR3β includes (i) the amino acid sequence of CSVPPAGLGAPEAFF (SEQ ID NO: 71) or a variant thereof having up to three amino acid substitutions, additions or deletions, or (ii) the amino acid sequence of CASSPGTGAYNSPLHF (SEQ ID NO: 77) or a variant thereof having up to three amino acid substitutions, additions or deletions; (3) The immunogenic peptide is a cathepsin G (CTSG) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes (i) the amino acid sequence of CVVNWDNARLMF (SEQ ID NO: 98) or a variant thereof having at most three amino acid substitutions, additions or deletions, or (ii) the amino acid sequence of CATRRAKDRDDKIIF (SEQ ID NO: 459) or a variant thereof having at most three amino acid substitutions, additions or deletions, and CDR3β includes (i) the amino acid sequence of CASSEEGGSTDTQYF (SEQ ID NO: 103) or a variant thereof having at most three amino acid substitutions, additions or deletions, or (ii) the amino acid sequence of CASSLGLAGDYEQYF (SEQ ID NO: 109) or a variant thereof having at most three amino acid substitutions, additions or deletions; (4) The immunogenic peptide is a mesothelin (MSLN) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CAAYNDYKLSF (SEQ ID NO: 293) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes the amino acid sequence of CASSLQGVNTEAFF (SEQ ID NO: 298) or a variant thereof having at most three amino acid substitutions, additions or deletions; (5) The immunogenic peptide is a Dickkopf-associated protein 1 (DKK1) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CAVGAWYNQGGKLIF (SEQ ID NO: 241) or a variant thereof having at most three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CASSFGVTGELFF (SEQ ID NO: 246) or a variant thereof having at most three amino acid substitutions, additions or deletions; (6) The immunogenic peptide is a human epidermal growth factor receptor 2 (HER2) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CAEGSRYGGATNKLIF (SEQ ID NO: 8) or a variant thereof having up to three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CASSTFPVETQYF (SEQ ID NO: 13) or a variant thereof having up to three amino acid substitutions, additions or deletions; (7) The immunogenic peptide is a proteinase 3 (PR3) peptide or a neutrophil elastase (NE) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CATYYGQNFVF (SEQ ID NO: 22) or a variant thereof having at most three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CASSFQGYTEAFF (SEQ ID NO: 27) or a variant thereof having at most three amino acid substitutions, additions or deletions; (8) The immunogenic peptide is a histone-lysine N-methyltransferase EZH2 (EZH2) peptide or a melanoma preferred expression antigen (PRAME) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes (i) the amino acid sequence of CAVSESPTGFQKLVF (SEQ ID NO: 37) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CAVPHSYNTDKLIF (SEQ ID NO: 42) or a variant thereof having up to three amino acid substitutions, additions or deletions, and CDR3β includes (i) the amino acid sequence of CASSPRGSNTGELFF (SEQ ID NO: 47) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CSARPSEAPQYF (SEQ ID NO: 53) or a variant thereof having up to three amino acid substitutions, additions or deletions; (9) The immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CAFMKRLTQGGSEKLVF (SEQ ID NO: 119) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes the amino acid sequence of CASSEVYRGHEKLFF (SEQ ID NO: 124) or a variant thereof having at most three amino acid substitutions, additions or deletions; (10) The immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CAASIRSSGDKLTF (SEQ ID NO: 133) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes the amino acid sequence of CASSKRTGELFF (SEQ ID NO: 138) or a variant thereof having at most three amino acid substitutions, additions or deletions; (11) The immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CALSETLYNQGGKLIF (SEQ ID NO: 144) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes the amino acid sequence of CASSLGTSRSYTDTQYF (SEQ ID NO: 149) or a variant thereof having at most three amino acid substitutions, additions or deletions; (12) The immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CALTSDYKLSF (SEQ ID NO: 157) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes (i) the amino acid sequence of CATSDLFGELFF (SEQ ID NO: 162) or a variant thereof having at most three amino acid substitutions, additions or deletions, or (i) the amino acid sequence of CASTTGIYEQYF (SEQ ID NO: 168) or a variant thereof having at most three amino acid substitutions, additions or deletions; (13) The immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CAVNSWGKLQF (SEQ ID NO: 176) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes the amino acid sequence of CASHSGLVGTGELFF (SEQ ID NO: 181) or a variant thereof having at most three amino acid substitutions, additions or deletions; (14) The immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CASTNFGNEKLTF (SEQ ID NO: 192) or a variant thereof having at most three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CASSLSYEQYF (SEQ ID NO: 197) or a variant thereof having at most three amino acid substitutions, additions or deletions; (15) The immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises (i) the amino acid sequence of CAVRSHSGNTPLVF (SEQ ID NO: 206) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CAENAGGTSYGKLTF (SEQ ID NO: 211) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (iii) the amino acid sequence of CAMRLPIPNNAGNMLTF (SEQ ID NO: 216) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and CDR3β comprises (i) the amino acid sequence of CASSSPRVGPLYEQYF (SEQ ID NO: 221) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CASSDHDIYNEQFF (SEQ ID NO: 227) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (iii) The amino acid sequence of CASWAEEAEETQYF (SEQ ID NO: 233) or a variant thereof having at most three amino acid substitutions, additions or deletions; (16) The immunogenic peptide is a mucin-5AC (MUC5AC) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CAGGGSGAGSYQLTF (SEQ ID NO: 254) or a variant thereof having up to three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CAISDPTGDNQPQHF (SEQ ID NO: 259) or a variant thereof having up to three amino acid substitutions, additions or deletions; (17) The immunogenic peptide is a pregradient protein-2 (AGR2) peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CAVQDYGQNFVF (SEQ ID NO: 267) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes the amino acid sequence of CASSPTGSEQYF (SEQ ID NO: 272) or a variant thereof having at most three amino acid substitutions, additions or deletions; (18) The immunogenic peptide is a c-MET peptide, and the TCR includes CDR3α and CDR3β, wherein the CDR3α includes the amino acid sequence of CAAAPNNNDMRF (SEQ ID NO: 280) or a variant thereof having at most three amino acid substitutions, additions or deletions, and the CDR3β includes the amino acid sequence of CASSLLAGGSSYEQYF (SEQ ID NO: 285) or a variant thereof having at most three amino acid substitutions, additions or deletions; (19) The immunogenic peptide is a CTD phosphatase subunit 1 (CTDP1) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CAMREGTSGTYKYIF (SEQ ID NO: 306) or a variant thereof having up to three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CASSNSASRPEQYV (SEQ ID NO: 311) or a variant thereof having up to three amino acid substitutions, additions or deletions; (20) The immunogenic peptide is a transformed acidic TACC2-containing peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence CAVSGLGGSNYKLTF (SEQ ID NO: 319) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and CDR3β comprises the amino acid sequence CASRSGTGTMDEQFF (SEQ ID NO: 324) or a variant thereof having at most three amino acid substitutions, additions, or deletions; or (21) The immunogenic peptide is a prostaglandin F2 receptor negative regulator (PTGFRN) peptide, and the TCR includes CDR3α and CDR3β, wherein CDR3α includes the amino acid sequence of CAVNRDDKIIF (SEQ ID NO: 332) or a variant thereof having at most three amino acid substitutions, additions or deletions, and CDR3β includes the amino acid sequence of CSARDYKQVLRGSYNSPLHF (SEQ ID NO: 337) or a variant thereof having at most three amino acid substitutions, additions or deletions.

2. The TCR according to claim 1, wherein the immunogenic peptide is a cathepsin G (CTSG) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAVQASNDYKLSF (SEQ ID NO: 86) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence of CASSVGRATEAFF (SEQ ID NO: 91) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

3. The TCR according to claim 2, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAVQASNDYKLSF (SEQ ID NO: 86) and CDR3β comprises the amino acid sequence of CASSVGRATEAFF (SEQ ID NO: 91).

4. The TCR according to claim 2 or 3, wherein the TCR comprises the following CDR sequences: CDR1α-VSGLRG (SEQ ID NO: 84), CDR2α-LYSAGEE (SEQ ID NO: 85), CDR3α-CAVQASNDYKLSF (SEQ ID NO: 86), CDR1β-MNHEY (SEQ ID NO: 89), CDR2β-SMNVEV (SEQ ID NO: 90), and CDR3β-CASSVGRATEAFF (SEQ ID NO: 91), or variants thereof having at most three amino acid substitutions, additions, or deletions.

5. The TCR according to any one of claims 2 to 4, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 87 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 92 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

6. The TCR according to any one of claims 2 to 5, wherein the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 88 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising the amino acid sequence of SEQ ID NO: 93 or 94 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

7. The TCR according to any one of claims 2 to 6, wherein the CTSG peptide comprises or is composed of the following: The amino acid sequence of SXXXPXVFTRVSSFL (SEQ ID NO: 535) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or a fragment thereof, preferably wherein the CTSG peptide comprises or is composed of the following: the amino acid sequence of SGVPPEVFTRVSSFL (SEQ ID NO: 81) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or a fragment thereof, preferably wherein the CTSG peptide comprises or is composed of the following: (a) the amino acid sequence of SGVPPEVFTRVSSFL (SEQ ID NO: 81) or a variant thereof having at most three amino acid substitutions, additions, or deletions; (b) the amino acid sequence of VFTRVSSFL (SEQ ID NO: 82) or a variant thereof having at most three amino acid substitutions, additions, or deletions; or (c) the amino acid sequence of VPPEVFTRVSSFL (SEQ ID NO: 83) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

8. The TCR of claim 1, wherein the immunogenic peptide is a cathepsin G (CTSG) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises (i) the amino acid sequence of CALPSARQLTF (SEQ ID NO: 61) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CAFMSPEGGSEKLVF (SEQ ID NO: 66) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises (i) the amino acid sequence of CSVPPAGLGAPEAFF (SEQ ID NO: 71) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CASSPGTGAYNSPLHF (SEQ ID NO: 77) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

9. The TCR according to claim 8, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises (i) the amino acid sequence of CALPSARQLTF (SEQ ID NO: 61) or (ii) the amino acid sequence of CAFMSPEGGSEKLVF (SEQ ID NO: 66), and wherein CDR3β comprises (i) the amino acid sequence of CSVPPAGLGAPEAFF (SEQ ID NO: 71) or (ii) the amino acid sequence of CASSPGTGAYNSPLHF (SEQ ID NO: 77).

10. The TCR according to claim 8 or 9, wherein the TCR comprises the following CDR sequences: (i) CDR1α-ATGYPS (SEQ ID NO: 59), CDR2α-ATKADDK (SEQ ID NO: 60), and CDR3α-CALPSARQLTF (SEQ ID NO: 61) or (ii) CDR1α-TSENNYY (SEQ ID NO: 64), CDR2α-QEAYKQQN (SEQ ID NO: 65), and CDR3α-CAFMSPEGGSEKLVF (SEQ ID NO: 66); and (i) CDR1β-SQVTM (SEQ ID NO: 69), CDR2β-ANQGSEA (SEQ ID NO: 70), and CDR3β-CSVPPAGLGAPEAFF (SEQ ID NO: 71) or (ii) CDR1β-SEHNR (SEQ ID NO: 75), CDR2β-FQNEAQ (SEQ ID NO: 76), and CDR3β-FQNEAQ (SEQ ID NO: 70). 76) and CDR3β-CASSPGTGAYNSPLHF (SEQ ID NO: 77), or variants thereof having up to three amino acid substitutions, additions or deletions.

11. The TCR according to any one of claims 8 to 10, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising (i) an amino acid sequence of SEQ ID NO: 62 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, or (ii) an amino acid sequence of SEQ ID NO: 67 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising (i) an amino acid sequence of SEQ ID NO: 72 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, or (ii) an amino acid sequence of SEQ ID NO: The amino acid sequence of 78 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with it.

12. The TCR according to any one of claims 8 to 11, wherein the TCR comprises an α chain and a β chain, the α chain comprising (i) the amino acid sequence of SEQ ID NO: 63 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith or (ii) the amino acid sequence of SEQ ID NO: 68 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising (i) the amino acid sequence of SEQ ID NO: 73 or 74 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith or (ii) the amino acid sequence of SEQ ID NO: The amino acid sequence of 79 or 80 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with it.

13. The TCR according to any one of claims 8 to 12, wherein the CTSG peptide comprises or is composed of the following: The nonameric fragment of the amino acid sequence GIVSYGKSSGVPPEV (SEQ ID NO: 58) or a variant thereof having at most three amino acid substitutions, additions or deletions.

14. The TCR of claim 1, wherein the immunogenic peptide is a cathepsin G (CTSG) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises (i) the amino acid sequence of CVVNWDNARLMF (SEQ ID NO: 98) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CATRRAKDRDDKIIF (SEQ ID NO: 459) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises (i) the amino acid sequence of CASSEEGGSTDTQYF (SEQ ID NO: 103) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CASSLGLAGDYEQYF (SEQ ID NO: 109) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

15. The TCR of claim 14, wherein the TCR comprises CDR3α and CDR3β, wherein the CDR3α comprises the amino acid sequence of (i) CVVNWDNARLMF (SEQ ID NO: 98) or (ii) CATRRAKDRDDKIIF (SEQ ID NO: 459), and the CDR3β comprises the amino acid sequence of (i) CASSEEGGSTDTQYF (SEQ ID NO: 103) or (ii) CASSLGLAGDYEQYF (SEQ ID NO: 109).

16. The TCR according to claim 14 or 15, wherein the TCR comprises the following CDR sequences: (i) CDR1α-NSASQS (SEQ ID NO: 96), CDR2α-VYSSGN (SEQ ID NO: 97), CDR3α-CVVNWDNARLMF (SEQ ID NO: 98) or (ii) CDR1α-NSAFQY (SEQ ID NO: 457), CDR2α-TYSSGN (SEQ ID NO: 458), CDR3α-CATRRAKDRDDKIIF (SEQ ID NO: 459); and (i) CDR1β-SNHLY (SEQ ID NO: 101), CDR2β-FYNNEI (SEQ ID NO: 102) and CDR3β-CASSEEGGSTDTQYF (SEQ ID NO: 103) or (ii) CDR1β-SGHNS (SEQ ID NO: 107), CDR2β-FNNNVP (SEQ ID NO: 98). SEQ ID NO: 108) and CDR3β-CASSLGLAGDYEQYF (SEQ ID NO: 109), or variants thereof having up to three amino acid substitutions, additions or deletions.

17. The TCR according to any one of claims 14 to 16, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising (i) an amino acid sequence of SEQ ID NO: 99 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith or (ii) an amino acid sequence of SEQ ID NO: 460 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising (i) an amino acid sequence of SEQ ID NO: 104 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith or (ii) SEQ ID NO: The amino acid sequence of 110 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with it.

18. The TCR according to any one of claims 14 to 17, wherein the TCR comprises an α chain and a β chain, the α chain comprising (i) an amino acid sequence of SEQ ID NO: 100 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith or (ii) an amino acid sequence of SEQ ID NO: 461 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising (i) an amino acid sequence of SEQ ID NO: 105 or 106 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith or (ii) a sequence of SEQ ID NO: The amino acid sequence of 111 or 112 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with it.

19. The TCR according to any one of claims 14 to 18, wherein the CTSG peptide comprises or is composed of the following: The nonameric fragment of the amino acid sequence TMRSFKLLDQMETPL (SEQ ID NO: 95) or a variant thereof having at most three amino acid substitutions, additions or deletions.

20. The TCR of claim 1, wherein the immunogenic peptide is a human epidermal growth factor receptor 2 (HER2) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAEGSRYGGATNKLIF (SEQ ID NO: 8) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence of CASSTFPVETQYF (SEQ ID NO: 13) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

21. The TCR of claim 20, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAEGSRYGGATNKLIF (SEQ ID NO: 8) and CDR3β comprises the amino acid sequence of CASSTFPVETQYF (SEQ ID NO: 13).

22. The TCR according to claim 20 or 21, wherein the TCR comprises the following CDR sequences: CDR1α-NSASDY (SEQ ID NO: 6), CDR2α-IRSNMDK (SEQ ID NO: 7), CDR3α-CAEGSRYGGATNKLIF (SEQ ID NO: 8), CDR1β-MNHEY (SEQ ID NO: 11), CDR2β-SVGAGI (SEQ ID NO: 12), and CDR3β-CASSTFPVETQYF (SEQ ID NO: 13), or variants thereof having at most three amino acid substitutions, additions, or deletions.

23. The TCR according to any one of claims 20 to 22, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 9 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising an amino acid sequence of SEQ ID NO: 14 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

24. The TCR according to any one of claims 20 to 23, wherein the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 10 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising the amino acid sequence of SEQ ID NO: 15 or 16 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

25. The TCR according to any one of claims 20 to 24, wherein the HER2 peptide comprises or is composed of the following: The amino acid sequence of KIFGSLAFL (SEQ ID NO: 5) or a variant thereof having up to three amino acid substitutions, additions or deletions.

26. The TCR of claim 1, wherein the immunogenic peptide is a proteinase 3 (PR3) peptide or a neutrophil elastase (NE) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CATYYGQNFVF (SEQ ID NO: 22) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence of CASSFQGYTEAFF (SEQ ID NO: 27) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

27. The TCR of claim 26, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CATYYGQNFVF (SEQ ID NO: 22) and CDR3β comprises the amino acid sequence of CASSFQGYTEAFF (SEQ ID NO: 27).

28. The TCR according to claim 26 or 27, wherein the TCR comprises the following CDR sequences: CDR1α-VSGNPY (SEQ ID NO: 20), CDR2α-YITGDNLV (SEQ ID NO: 21), CDR3α-CADYYGQNFVF (SEQ ID NO: 22), CDR1β-MDHEN (SEQ ID NO: 25), CDR2β-SYDVKM (SEQ ID NO: 26), and CDR3β-CASSFQGYTEAFF (SEQ ID NO: 27), or variants thereof having at most three amino acid substitutions, additions, or deletions.

29. The TCR according to any one of claims 26 to 28, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising the amino acid sequence of SEQ ID NO: 23 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising the amino acid sequence of SEQ ID NO: 28 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

30. The TCR according to any one of claims 26 to 29, wherein the TCR comprises an α chain and a β chain, the α chain comprising the amino acid sequence of SEQ ID NO: 24 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising the amino acid sequence of SEQ ID NO: 29 or 30 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

31. The TCR according to any one of claims 26 to 30, wherein the peptide comprises or is composed of the following: an amino acid sequence of VLQELNVTV (SEQ ID NO: 19) or a variant thereof having at most three amino acid substitutions, additions or deletions.

32. The TCR according to claim 1, wherein the immunogenic peptide is a histone-lysine N-methyltransferase EZH2 (EZH2) peptide or a melanoma preferred expression antigen (PRAME) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises (i) the amino acid sequence of CAVSESPTGFQKLVF (SEQ ID NO: 37) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CAVPHSYNTDKLIF (SEQ ID NO: 42) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises (i) the amino acid sequence of CASSPRGSNTGELFF (SEQ ID NO: 47) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CSARPSEAPQYF (SEQ ID NO: 53) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

33. The TCR according to claim 32, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises (i) the amino acid sequence of CAVSESPTGFQKLVF (SEQ ID NO: 37) or (ii) the amino acid sequence of CAVPHSYNTDKLIF (SEQ ID NO: 42), and wherein CDR3β comprises (i) the amino acid sequence of CASSPRGSNTGELFF (SEQ ID NO: 47) or (ii) the amino acid sequence of CSARPSEAPQYF (SEQ ID NO: 53).

34. The TCR according to claim 32 or 33, wherein the TCR comprises the following CDR sequences: (i) CDR1α-SSVPPY (SEQ ID NO: 35), CDR2α-YTSAATLV (SEQ ID NO: 36), and CDR3α-CAVSESPTGFQKLVF (SEQ ID NO: 37) or (ii) CDR1α-VGISA (SEQ ID NO: 40), CDR2α-LSSGK (SEQ ID NO: 41), and CDR3α-CAVPHSYNTDKLIF (SEQ ID NO: 42); and (i) CDR1β-SNHLY (SEQ ID NO: 45), CDR2β-FYNNEI (SEQ ID NO: 46), and CDR3β-CASSPRGSNTGELFF (SEQ ID NO: 47) or (ii) CDR1β-DFQATT (SEQ ID NO: 51), CDR2β-SNEGSKA (SEQ ID NO: 52), and CDR3α-CAVPHSYNTDKLIF (SEQ ID NO: 42); and (i) CDR1β-SNHLY (SEQ ID NO: 45), CDR2β-FYNNEI (SEQ ID NO: 46), and CDR3β-CASSPRGSNTGELFF (SEQ ID NO: 47) or (ii) CDR1β-DFQATT (SEQ ID NO: 51), CDR2β-SNEGSKA (SEQ ID NO: 52), and CDR3α-CAVPHSYNTDKLIF (SEQ ID NO: 42). NO: 52) and CDR3β-CSARPSEAPQYF (SEQ ID NO: 53), or variants thereof having up to three amino acid substitutions, additions or deletions.

35. The TCR according to any one of claims 32 to 34, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising (i) an amino acid sequence of SEQ ID NO: 38 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, or (ii) an amino acid sequence of SEQ ID NO: 43 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising (i) an amino acid sequence of SEQ ID NO: 48 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, or (ii) an amino acid sequence of SEQ ID NO: The amino acid sequence of 54 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with it.

36. The TCR according to any one of claims 32 to 35, wherein the TCR comprises an α chain and a β chain, the α chain comprising (i) the amino acid sequence of SEQ ID NO: 39 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith or (ii) the amino acid sequence of SEQ ID NO: 44 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, the β chain comprising (i) the amino acid sequence of SEQ ID NO: 49 or 50 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith or (ii) the amino acid sequence of SEQ ID NO: The amino acid sequence of 55 or 56 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with it.

37. The TCR according to any one of claims 32 to 36, wherein the EZH2 peptide comprises or is composed of the following: The amino acid sequence of KESRPPRKF (SEQ ID NO: 32) or a variant thereof having at most three amino acid substitutions, additions or deletions; or (ii) a melanoma preferentially expressed antigen (PRAME) peptide when presented by MHC, wherein the PRAME peptide comprises or is composed of the following: the amino acid sequence of ALYVDSLFFL (SEQ ID NO: 34) or a variant thereof having at most three amino acid substitutions, additions or deletions.

38. The TCR of claim 1, wherein the immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAFMKRLTQGGSEKLVF (SEQ ID NO: 119) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence of CASSEVYRGHEKLFF (SEQ ID NO: 124) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

39. The TCR of claim 38, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAFMKRLTQGGSEKLVF (SEQ ID NO: 119) and CDR3β comprises the amino acid sequence of CASSEVYRGHEKLFF (SEQ ID NO: 124).

40. The TCR according to claim 38 or 39, wherein the TCR comprises the following CDR sequences: CDR1α-TSENNYY (SEQ ID NO: 117), CDR2α-QEAYKQQN (SEQ ID NO: 118), CDR3α-CAFMKRLTQGGSEKLVF (SEQ ID NO: 119), CDR1β-SNHLY (SEQ ID NO: 122), CDR2β-FYNNEI (SEQ ID NO: 123), and CDR3β-CASSEVYRGHEKLFF (SEQ ID NO: 124), or variants thereof having at most three amino acid substitutions, additions, or deletions.

41. The TCR according to any one of claims 38 to 40, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 120 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising an amino acid sequence of SEQ ID NO: 125 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

42. The TCR according to any one of claims 38 to 41, wherein the TCR comprises an α chain and a β chain, the α chain comprising an amino acid sequence of SEQ ID NO: 121 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising an amino acid sequence of SEQ ID NO: 126 or 127 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

43. The TCR according to any one of claims 38 to 42, wherein the CCNA1 peptide comprises or is composed of the following: The nonameric fragment of the amino acid sequence of TEYAEEIYQYL (SEQ ID NO: 114) or a variant thereof having at most three amino acid substitutions, additions or deletions, preferably wherein the CTSG peptide comprises or is composed of the following: the amino acid sequence of YAEEIYQYL (SEQ ID NO: 115) or a variant thereof having at most three amino acid substitutions, additions or deletions.

44. The TCR of claim 1, wherein the immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAASIRSSGDKLTF (SEQ ID NO: 133) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence of CASSKRTGELFF (SEQ ID NO: 138) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

45. The TCR of claim 44, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAASIRSSGDKLTF (SEQ ID NO: 133) and CDR3β comprises the amino acid sequence of CASSKRTGELFF (SEQ ID NO: 138).

46. ​​The TCR according to claim 44 or 45, wherein the TCR comprises the following CDR sequences: CDR1α-DSASNY (SEQ ID NO: 131), CDR2α-IRSNVGE (SEQ ID NO: 132), CDR3α-CAASIRSSGDKLTF (SEQ ID NO: 133), CDR1β-MDHEN (SEQ ID NO: 136), CDR2β-SYDVKM (SEQ ID NO: 137), and CDR3β-CASSKRTGELFF (SEQ ID NO: 138), or variants thereof having at most three amino acid substitutions, additions, or deletions.

47. The TCR according to any one of claims 44 to 46, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 134 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising an amino acid sequence of SEQ ID NO: 139 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

48. The TCR according to any one of claims 44 to 47, wherein the TCR comprises an α chain and a β chain, the α chain comprising an amino acid sequence of SEQ ID NO: 135 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising an amino acid sequence of SEQ ID NO: 140 or 141 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

49. The TCR according to any one of claims 44 to 48, wherein the CCNA1 peptide comprises or is composed of the following: The nonameric fragment of the amino acid sequence of PETLAAFTGYSLSEI (SEQ ID NO: 128) or a variant thereof having at most three amino acid substitutions, additions or deletions.

50. The TCR of claim 1, wherein the immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CALSETLYNQGGKLIF (SEQ ID NO: 144) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises a nonameric fragment of the amino acid sequence of CASSLGTSRSYTDTQYF (SEQ ID NO: 149) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

51. The TCR of claim 50, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CALSETLYNQGGKLIF (SEQ ID NO: 144) and CDR3β comprises the amino acid sequence of CALSETLYNQGGKLIF (SEQ ID NO: 149).

52. The TCR according to claim 50 or 51, wherein the TCR comprises the following CDR sequences: CDR1α-TRDTTYY (SEQ ID NO: 142), CDR2α-RNSFDEQN (SEQ ID NO: 143), CDR3α-CALSETLYNQGGKLIF (SEQ ID NO: 144), CDR1β-SGHTA (SEQ ID NO: 147), CDR2β-FQGNSA (SEQ ID NO: 148), and CDR3β-CASSLGTSRSYTDTQYF (SEQ ID NO: 149), or variants thereof having at most three amino acid substitutions, additions, or deletions.

53. The TCR according to any one of claims 50 to 52, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 145 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising an amino acid sequence of SEQ ID NO: 150 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

54. The TCR according to any one of claims 50 to 53, wherein the TCR comprises an α chain and a β chain, the α chain comprising an amino acid sequence of SEQ ID NO: 146 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising an amino acid sequence of SEQ ID NO: 151 or 152 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

55. The TCR of claim 1, wherein the immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CALTSDYKLSF (SEQ ID NO: 157) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises (i) the amino acid sequence of CATSDLFGELFF (SEQ ID NO: 162) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (i) the amino acid sequence of CASTTGIYEQYF (SEQ ID NO: 168) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

56. The TCR of claim 55, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CALTSDYKLSF (SEQ ID NO: 157), and wherein CDR3β comprises (i) the amino acid sequence of CATSDLFGELFF (SEQ ID NO: 162) or (ii) the amino acid sequence of CASTTGIYEQYF (SEQ ID NO: 168).

57. The TCR according to claim 55 or 56, wherein the TCR comprises the following CDR sequences: CDR1α-SSNFYA (SEQ ID NO: 155), CDR2α-MTLNGDE (SEQ ID NO: 156), CDR3α-CALTSDYKLSF (SEQ ID NO: 157); and (i) CDR1β-KGHDR (SEQ ID NO: 160), CDR2β-SFDVKD (SEQ ID NO: 161) and CDR3β-CATSDLFGELFF (SEQ ID NO: 162) or (ii) CDR1β-SNHLY (SEQ ID NO: 166), CDR2β-FYNNEI (SEQ ID NO: 167) and CDR3β-CASTTGIYEQYF (SEQ ID NO: 168), or variants thereof having at most three amino acid substitutions, additions or deletions.

58. The TCR according to any one of claims 55 to 57, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 158 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising (i) an amino acid sequence of SEQ ID NO: 163 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, or (ii) an amino acid sequence of SEQ ID NO: 169 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

59. The TCR according to any one of claims 55 to 58, wherein the TCR comprises an α chain and a β chain, the α chain comprising an amino acid sequence of SEQ ID NO: 159 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising (i) an amino acid sequence of SEQ ID NO: 164 or 165 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, or (ii) an amino acid sequence of SEQ ID NO: 170 or 171 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

60. The TCR according to any one of claims 55 to 59, wherein the CCNA1 peptide comprises or is composed of: a nonameric fragment of the amino acid sequence of AELSLLLEADPFLKYL (SEQ ID NO: 153) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and / or wherein the CCNA1 peptide comprises or is composed of: The nonameric fragment of the amino acid sequence of LLEADPFLKYLPSLI (SEQ ID NO: 527) or a variant thereof having at most three amino acid substitutions, additions or deletions.

61. The TCR of claim 1, wherein the immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAVNSWGKLQF (SEQ ID NO: 176) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence of CASHSGLVGTGELFF (SEQ ID NO: 181) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

62. The TCR according to claim 61, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAVNSWGKLQF (SEQ ID NO: 176) and CDR3β comprises the amino acid sequence of CASHSGLVGTGELFF (SEQ ID NO: 181).

63. The TCR according to claim 61 or 62, wherein the TCR comprises the following CDR sequences: CDR1α-TSGFNG (SEQ ID NO: 174), CDR2α-NVLDGL (SEQ ID NO: 175), CDR3α-CAVNSWGKLQF (SEQ ID NO: 176), CDR1β-MNHEY (SEQ ID NO: 179), CDR2β-SMNVEV (SEQ ID NO: 180), and CDR3β-CASHSGLVGTGELFF (SEQ ID NO: 181), or variants thereof having at most three amino acid substitutions, additions, or deletions.

64. The TCR according to any one of claims 61 to 63, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 177 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising an amino acid sequence of SEQ ID NO: 182 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

65. The TCR according to any one of claims 61 to 64, wherein the TCR comprises an α chain and a β chain, the α chain comprising an amino acid sequence of SEQ ID NO: 178 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising an amino acid sequence of SEQ ID NO: 183 or 184 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

66. The TCR according to any one of claims 61 to 65, wherein the CCNA1 peptide comprises or is composed of the following: The nonameric fragment of the amino acid sequence of WEGPGLPDFVF (SEQ ID NO: 172) or a variant thereof having at most three amino acid substitutions, additions or deletions.

67. The TCR of claim 1, wherein the immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CASTNFGNEKLTF (SEQ ID NO: 192) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence of CASSLSYEQYF (SEQ ID NO: 197) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

68. The TCR of claim 67, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CASTNFGNEKLTF (SEQ ID NO: 192) and CDR3β comprises the amino acid sequence of CASSLSYEQYF (SEQ ID NO: 197).

69. The TCR according to claim 67 or 68, wherein the TCR comprises the following CDR sequences: CDR1α-TSESDYY (SEQ ID NO: 190), CDR2α-QEAYKQQN (SEQ ID NO: 191), CDR3α-CASTNFGNEKLTF (SEQ ID NO: 192), CDR1β-PRHDT (SEQ ID NO: 195), CDR2β-FYEKMQ (SEQ ID NO: 196), and CDR3β-CASSLSYEQYF (SEQ ID NO: 197), or variants thereof having at most three amino acid substitutions, additions, or deletions.

70. The TCR according to any one of claims 67 to 69, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 193 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising an amino acid sequence of SEQ ID NO: 198 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

71. The TCR according to any one of claims 67 to 70, wherein the TCR comprises an α chain and a β chain, the α chain comprising an amino acid sequence of SEQ ID NO: 194 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising an amino acid sequence of SEQ ID NO: 199 or 200 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

72. The TCR according to any one of claims 67 to 71, wherein the CCNA1 peptide comprises or is composed of the following: The nonameric fragment of the amino acid sequence KRQLLKMEHLLLKVL (SEQ ID NO: 185) or a variant thereof having at most three amino acid substitutions, additions or deletions.

73. The TCR of claim 1, wherein the immunogenic peptide is a cyclin A1 (CCNA1) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises (i) the amino acid sequence of CAVRSHSGNTPLVF (SEQ ID NO: 206) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CAENAGGTSYGKLTF (SEQ ID NO: 211) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (iii) the amino acid sequence of CAMRLPIPNNAGNMLTF (SEQ ID NO: 216) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and the CDR3β comprises (i) the amino acid sequence of CASSSPRVGPLYEQYF (SEQ ID NO: 221) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) CASSDHDIYNEQFF (SEQ ID NO: 206) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (iii) the amino acid sequence of CAENAGGTSYGKLTF (SEQ ID NO: 211) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CAENAGGTSYGKLTF (SEQ ID NO: 216 ...iii) the amino acid sequence of CAENAGGTSYGKLTF (SEQ ID NO: 216) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or (ii) the amino acid sequence of CAENAGGTSYGKLTF (SEQ ID NO: 216) or (ii) The amino acid sequence of (NO:227) or a variant thereof having at most three amino acid substitutions, additions or deletions, or (iii) The amino acid sequence of CASWAEEAEETQYF (SEQ ID NO: 233) or a variant thereof having at most three amino acid substitutions, additions or deletions.

74. The TCR according to claim 73, wherein the TCR comprises CDR3α and CDR3β, wherein the CDR3α comprises the amino acid sequence of (i) CAVRSHSGNTPLVF (SEQ ID NO: 206) or (ii) CAENAGGTSYGKLTF (SEQ ID NO: 211) or (iii) CAMRLPIPNNAGNMLTF (SEQ ID NO: 216), and the CDR3β comprises the amino acid sequence of (i) CASSSPRVGPLYEQYF (SEQ ID NO: 221) or (ii) CASDHDIYNEQFF (SEQ ID NO: 227) or (iii) CASWAEEAEETQYF (SEQ ID NO: 233).

75. The TCR according to claim 73 or 74, wherein the TCR comprises the following CDR sequences: (i) CDR1α-TSGFYG (SEQ ID NO: 204), CDR2α-NALDGL (SEQ ID NO: 205), and CDR3α-CAVRSHSGNTPLVF (SEQ ID NO: 206) or (ii) CDR1α-NSASDY (SEQ ID NO: 209), CDR2α-IRSNMDK (SEQ ID NO: 210), and CDR3α-CAENAGGTSYGKLTF (SEQ ID NO: 211) or (iii) CDR1α-TSDQSYG (SEQ ID NO: 214), CDR2α-QGSYDEQN (SEQ ID NO: 215), and CDR3α-CAMRLPIPNNAGNMLTF (SEQ ID NO: 216); and (i) CDR1β-SEHNR (SEQ ID NO: 209). 219), CDR2β-FQNEAQ (SEQ ID NO: 220) and CDR3β-CASSSPRVGPLYEQYF (SEQ ID NO: 221) or (ii) CDR1β-SEHNR (SEQ ID NO: 225), CDR2β-FQNEAQ (SEQ ID NO: 226) and CDR3β-CASSDHDIYNEQFF (SEQ ID NO: 227) or (iii) CDR1β-SNHLY (SEQ ID NO: 231), CDR2β-FYNNEI (SEQ ID NO: 232) and CDR3β-CASWAEEAEETQYF (SEQ ID NO: 233), or variants thereof having at most three amino acid substitutions, additions or deletions.

76. The TCR according to any one of claims 73 to 75, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising (i) an amino acid sequence of SEQ ID NO: 207 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith; or (ii) an amino acid sequence of SEQ ID NO: 212 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith; or (iii) an amino acid sequence of SEQ ID NO: 217 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith; and the β-chain variable domain comprising (i) SEQ ID NO: The amino acid sequence of SEQ ID NO: 222 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity; or (ii) the amino acid sequence of SEQ ID NO: 228 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity; or (iii) the amino acid sequence of SEQ ID NO: 234 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

77. The TCR according to any one of claims 73 to 76, wherein the TCR comprises an α chain and a β chain, the α chain comprising (i) an amino acid sequence of SEQ ID NO: 208 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith; or (ii) an amino acid sequence of SEQ ID NO: 213 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith; or (iii) an amino acid sequence of SEQ ID NO: 218 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith; the β chain comprising (i) SEQ ID NO: The amino acid sequence of 223 or 224 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity; or (ii) the amino acid sequence of SEQ ID NO: 229 or 230 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity; or (iii) the amino acid sequence of SEQ ID NO: 235 or 236 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

78. The TCR according to any one of claims 73 to 77, wherein the CCNA1 peptide comprises or is composed of the following: The nonameric fragment of the amino acid sequence of PETLAAFTGYSLSEI (SEQ ID NO: 201) or a variant thereof having at most three amino acid substitutions, additions or deletions.

79. The TCR of claim 1, wherein the immunogenic peptide is a Dickkopf-associated protein 1 (DKK1) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAVGAWYNQGGKLIF (SEQ ID NO: 241) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence of CASSFGVTGELFF (SEQ ID NO: 246) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

80. The TCR of claim 79, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAVGAWYNQGGKLIF (SEQ ID NO: 241) and CDR3β comprises the amino acid sequence of CASSFGVTGELFF (SEQ ID NO: 246).

81. The TCR according to claim 79 or 80, wherein the TCR comprises the following CDR sequences: CDR1α-YGATPY (SEQ ID NO: 239), CDR2α-YFSGDTLV (SEQ ID NO: 240), CDR3α-YFSGDTLV (SEQ ID NO: 241), CDR1β-SGHDY (SEQ ID NO: 244), CDR2β-FNNNVP (SEQ ID NO: 245), and CDR3β-CASSFGVTGELFF (SEQ ID NO: 246), or variants thereof having at most three amino acid substitutions, additions, or deletions.

82. The TCR according to any one of claims 79 to 81, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 242 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising an amino acid sequence of SEQ ID NO: 247 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

83. The TCR according to any one of claims 79 to 82, wherein the TCR comprises an α chain and a β chain, the α chain comprising an amino acid sequence of SEQ ID NO: 243 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising an amino acid sequence of SEQ ID NO: 248 or 249 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

84. The TCR according to any one of claims 79 to 83, wherein the DKK1 peptide comprises or is composed of the following: The amino acid sequence of ILYPGGNKV (SEQ ID NO: 238) or a variant thereof having up to three amino acid substitutions, additions or deletions.

85. The TCR of claim 1, wherein the immunogenic peptide is a mucin-5AC (MUC5AC) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAGGGSGAGSYQLTF (SEQ ID NO: 254) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence of CAISDPTGDNQPQHF (SEQ ID NO: 259) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

86. The TCR according to claim 85, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAGGGSGAGSYQLTF (SEQ ID NO: 254) and CDR3β comprises the amino acid sequence of CAISDPTGDNQPQHF (SEQ ID NO: 259).

87. The TCR according to claim 85 or 86, wherein the TCR comprises the following CDR sequences: CDR1α-DRGSQS (SEQ ID NO: 252), CDR2α-IYSNGD (SEQ ID NO: 253), CDR3α-CAGGGSGAGSYQLTF (SEQ ID NO: 254), CDR1β-ENHRY (SEQ ID NO: 257), CDR2β-SYGVKD (SEQ ID NO: 258), and CDR3β-CAISDPTGDNQPQHF (SEQ ID NO: 259), or variants thereof having at most three amino acid substitutions, additions, or deletions.

88. The TCR according to any one of claims 85 to 87, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 255 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising an amino acid sequence of SEQ ID NO: 260 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

89. The TCR according to any one of claims 85 to 88, wherein the TCR comprises an α chain and a β chain, the α chain comprising an amino acid sequence of SEQ ID NO: 256 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising an amino acid sequence of SEQ ID NO: 261 or 262 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

90. The TCR according to any one of claims 85 to 89, wherein the MUC5AC peptide comprises or is composed of the amino acid sequence of FLNDAGACV (SEQ ID NO: 251) or a variant thereof having at most three amino acid substitutions, additions or deletions.

91. The TCR of claim 1, wherein the immunogenic peptide is a pregradient protein-2 (AGR2) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAVQDYGQNFVF (SEQ ID NO: 267) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence of CASSPTGSEQYF (SEQ ID NO: 272) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

92. The TCR according to claim 91, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAVQDYGQNFVF (SEQ ID NO: 267) and CDR3β comprises the amino acid sequence of CASSPTGSEQYF (SEQ ID NO: 272).

93. The TCR according to claim 91 or 92, wherein the TCR comprises the following CDR sequences: CDR1α-VSGLRG (SEQ ID NO: 265), CDR2α-LYSAGEE (SEQ ID NO: 266), CDR3α-CAVQDYGQNFVF (SEQ ID NO: 267), CDR1β-MNHEY (SEQ ID NO: 270), CDR2β-SMNVEV (SEQ ID NO: 271), and CDR3β-CASSPTGSEQYF (SEQ ID NO: 272), or variants thereof having at most three amino acid substitutions, additions, or deletions.

94. The TCR according to any one of claims 91 to 93, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 268 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising an amino acid sequence of SEQ ID NO: 273 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

95. The TCR according to any one of claims 91 to 94, wherein the TCR comprises an α chain and a β chain, the α chain comprising an amino acid sequence of SEQ ID NO: 269 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising an amino acid sequence of SEQ ID NO: 274 or 275 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

96. The TCR according to any one of claims 91 to 95, wherein the AGR2 peptide comprises or is composed of the following: The amino acid sequence of LLVALSYTL (SEQ ID NO: 264) or a variant thereof having up to three amino acid substitutions, additions or deletions.

97. The TCR of claim 1, wherein the immunogenic peptide is a c-MET peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAAAPNNNDMRF (SEQ ID NO: 280) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence of CASSLLAGGSSYEQYF (SEQ ID NO: 285) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

98. The TCR of claim 97, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAAAPNNNDMRF (SEQ ID NO: 280) and CDR3β comprises the amino acid sequence of CASSLLAGGSSYEQYF (SEQ ID NO: 285).

99. The TCR according to claim 97 or 98, wherein the TCR comprises the following CDR sequences: CDR1α-DSASNY (SEQ ID NO: 278), CDR2α-IRSNVGE (SEQ ID NO: 279), CDR3α-CAAAPNNNDMRF (SEQ ID NO: 280), CDR1β-MNHEY (SEQ ID NO: 283), CDR2β-SVGAGI (SEQ ID NO: 284), and CDR3β-CASSLLAGGSSYEQYF (SEQ ID NO: 285), or variants thereof having at most three amino acid substitutions, additions, or deletions.

100. The TCR according to any one of claims 97 to 99, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 281 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising an amino acid sequence of SEQ ID NO: 286 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

101. The TCR according to any one of claims 97 to 100, wherein the TCR comprises an α chain and a β chain, the α chain comprising an amino acid sequence of SEQ ID NO: 282 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising an amino acid sequence of SEQ ID NO: 287 or 288 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

102. The TCR according to any one of claims 97 to 101, wherein the c-MET peptide comprises or is composed of the following: an amino acid sequence of YVDPVITSI (SEQ ID NO: 277) or a variant thereof having at most three amino acid substitutions, additions or deletions.

103. The TCR of claim 1, wherein the immunogenic peptide is a mesothelin (MSLN) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAAYNDYKLSF (SEQ ID NO: 293) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence of CASSLQGVNTEAFF (SEQ ID NO: 298) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

104. The TCR according to claim 103, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAAYNDYKLSF (SEQ ID NO: 293) and CDR3β comprises the amino acid sequence of CASSLQGVNTEAFF (SEQ ID NO: 298).

105. The TCR according to claim 103 or 104, wherein the TCR comprises the following CDR sequences: CDR1α-SSNFYA (SEQ ID NO: 291), CDR2α-MTLNGDE (SEQ ID NO: 292), CDR3α-CAAYNDYKLSF (SEQ ID NO: 293), CDR1β-MNHEY (SEQ ID NO: 296), CDR2β-SMNVEV (SEQ ID NO: 297), and CDR3β-CASSLQGVNTEAFF (SEQ ID NO: 298), or variants thereof having at most three amino acid substitutions, additions, or deletions.

106. The TCR according to any one of claims 103 to 105, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 294 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising an amino acid sequence of SEQ ID NO: 299 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

107. The TCR according to any one of claims 103 to 106, wherein the TCR comprises an α chain and a β chain, the α chain comprising an amino acid sequence of SEQ ID NO: 295 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising an amino acid sequence of SEQ ID NO: 300 or 301 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

108. The TCR according to any one of claims 103 to 107, wherein the MSLN peptide comprises or is composed of the following: The amino acid sequence of KLLGPHVLGV (SEQ ID NO: 290) or a variant thereof having at most three amino acid substitutions, additions or deletions.

109. The TCR of claim 1, wherein the immunogenic peptide is a CTD phosphatase subunit 1 (CTDP1) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAMREGTSGTYKYIF (SEQ ID NO: 306) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence of CASSNSASRPEQYV (SEQ ID NO: 311) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

110. The TCR of claim 109, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAMREGTSGTYKYIF (SEQ ID NO: 306) and CDR3β comprises the amino acid sequence of CASSNSASRPEQYV (SEQ ID NO: 311).

111. The TCR according to claim 109 or 110, wherein the TCR comprises the following CDR sequences: CDR1α-TSDPSYG (SEQ ID NO: 304), CDR2α-QGSYDQQN (SEQ ID NO: 305), CDR3α-CAMREGTSGTYKYIF (SEQ ID NO: 306), CDR1β-SEHNR (SEQ ID NO: 309), CDR2β-FQNEAQ (SEQ ID NO: 310), and CDR3β-CASSNSASRPEQYV (SEQ ID NO: 311), or variants thereof having at most three amino acid substitutions, additions, or deletions.

112. The TCR according to any one of claims 109 to 111, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 307 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising an amino acid sequence of SEQ ID NO: 312 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

113. The TCR according to any one of claims 109 to 112, wherein the TCR comprises an α chain and a β chain, the α chain comprising an amino acid sequence of SEQ ID NO: 308 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising an amino acid sequence of SEQ ID NO: 313 or 314 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

114. The TCR according to claims 109 to 113, wherein the CTDP1 peptide comprises or is composed of the following: The amino acid sequence of YLNKEIEEA (SEQ ID NO: 303) or a variant thereof having up to three amino acid substitutions, additions or deletions.

115. The TCR of claim 1, wherein the immunogenic peptide is a transformed acidic coil-and-coil protein 2 (TACC2) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence CAVSGLGGSNYKLTF (SEQ ID NO: 319) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence CASRSGTGTMDEQFF (SEQ ID NO: 324) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

116. The TCR of claim 115, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence CAVSGLGGSNYKLTF (SEQ ID NO: 319) and CDR3β comprises the amino acid sequence CASRSGTGTMDEQFF (SEQ ID NO: 324).

117. The TCR according to claim 115 or 116, wherein the TCR comprises the following CDR sequences: CDR1α-SSVPPY (SEQ ID NO: 317), CDR2α-YTSAATLV (SEQ ID NO: 318), CDR3α-CAVSGLGGSNYKLTF (SEQ ID NO: 319), CDR1β-MNHNY (SEQ ID NO: 322), CDR2β-SVGAGI (SEQ ID NO: 323), and CDR3β-CASRSGTGTMDEQFF (SEQ ID NO: 324), or variants thereof having at most three amino acid substitutions, additions, or deletions.

118. The TCR according to any one of claims 115 to 117, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 320 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising an amino acid sequence of SEQ ID NO: 325 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

119. The TCR according to any one of claims 115 to 118, wherein the TCR comprises an α chain and a β chain, the α chain comprising an amino acid sequence of SEQ ID NO: 321 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising an amino acid sequence of SEQ ID NO: 326 or 327 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

120. The TCR according to any one of claims 115 to 119, wherein the TACC2 peptide comprises or is composed of the following: The amino acid sequence of YRNSYEIEY (SEQ ID NO: 316) or a variant thereof having at most three amino acid substitutions, additions or deletions.

121. The TCR of claim 1, wherein the immunogenic peptide is a prostaglandin F2 receptor negative regulator (PTGFRN) peptide, and the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAVNRDDKIIF (SEQ ID NO: 332) or a variant thereof having at most three amino acid substitutions, additions, or deletions, and wherein CDR3β comprises the amino acid sequence of CSARDYKQVLRGSYNSPLHF (SEQ ID NO: 337) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

122. The TCR according to claim 121, wherein the TCR comprises CDR3α and CDR3β, wherein CDR3α comprises the amino acid sequence of CAVNRDDKIIF (SEQ ID NO: 332) and CDR3β comprises the amino acid sequence of CSARDYKQVLRGSYNSPLHF (SEQ ID NO: 337).

123. The TCR according to claim 121 or 122, wherein the TCR comprises the following CDR sequences: CDR1α-DSAIYN (SEQ ID NO: 330), CDR2α-IQSSQRE (SEQ ID NO: 331), CDR3α-CAVNRDDKIIF (SEQ ID NO: 332), CDR1β-DFQATT (SEQ ID NO: 335), CDR2β-SNEGSKA (SEQ ID NO: 336), and CDR3β-CSARDYKQVLRGSYNSPLHF (SEQ ID NO: 337), or variants thereof having at most three amino acid substitutions, additions, or deletions.

124. The TCR according to any one of claims 121 to 123, wherein the TCR comprises an α-chain variable domain and a β-chain variable domain, the α-chain variable domain comprising an amino acid sequence of SEQ ID NO: 333 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β-chain variable domain comprising an amino acid sequence of SEQ ID NO: 338 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

125. The TCR according to any one of claims 121 to 124, wherein the TCR comprises an α chain and a β chain, the α chain comprising an amino acid sequence of SEQ ID NO: 334 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, and the β chain comprising an amino acid sequence of SEQ ID NO: 339 or 340 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith.

126. The TCR according to any one of claims 121 to 125, wherein the PTGFRN peptide comprises or is composed of the following: The amino acid sequence of RLASRPLLL (SEQ ID NO: 329) or a variant thereof having up to three amino acid substitutions, additions or deletions.

127. The TCR according to any of the preceding claims, wherein the TCR includes one or more mutations at the α-chain / β-chain interface such that when the α-chain and the β-chain are expressed in T cells, the mismatch frequency between the chains and the endogenous TCR α-chain and β-chain is reduced.

128. The TCR of claim 127, wherein the one or more mutations introduce cysteine ​​residues into the constant region domains of each of the α chain and the β chain, wherein the cysteine ​​residues are capable of forming disulfide bonds between the α chain and the β chain.

129. The TCR according to any of the preceding claims, wherein the TCR includes a mouse-derived constant region.

130. The TCR according to any of the preceding claims, wherein the TCR is a soluble TCR.

131. A polynucleotide encoding the α chain and / or the β chain of the TCR according to any one of claims 1 to 130.

132. The polynucleotide of claim 131, wherein the polynucleotide encodes the α chain linked to the β chain.

133. The polynucleotide of claim 131 or 132, wherein the polynucleotide further encodes one or more short interfering RNAs (siRNAs) or other agents capable of reducing or preventing the expression of one or more endogenous TCR genes.

134. A vector comprising a polynucleotide according to any one of claims 131 to 133.

135. The vector according to claim 134, wherein the vector is a plasmid or a viral vector.

136. The vector according to claim 134 or 135, wherein the vector comprises polynucleotides encoding one or more CD3 chains, CD8, suicide genes and / or optional markers.

137. A cell comprising a TCR according to any one of claims 1 to 130, a polynucleotide according to any one of claims 131 to 133, or a vector according to any one of claims 134 to 136.

138. The cell of claim 137, wherein the cell further comprises a vector encoding one or more CD3 chains, CD8, a suicide gene, and / or optional markers.

139. The cell according to claim 137 or 138, wherein the cell is a T cell, a lymphocyte, or a stem cell.

140. The cell of claim 139, wherein the T cell, the lymphocyte, or the stem cell is selected from the group consisting of: CD4+ cells, CD8+ cells, naive T cells, memory stem T cells, central memory T cells, double-negative T cells, effector memory T cells, effector T cells, Th0 cells, Tc0 cells, Th1 cells, Tc1 cells, Th2 cells, Tc2 cells, Th17 cells, Th22 cells, γ / δ T cells, natural killer (NK) cells, natural killer T (NKT) cells, cytokine-induced killer (CIK) cells, hematopoietic stem cells, and pluripotent stem cells.

141. The cell according to any one of claims 137 to 140, wherein the cell is a T cell, optionally wherein the cell is a T cell that has been isolated from the subject.

142. The cell according to any one of claims 137 to 141, wherein the endogenous gene encoding the TCR α chain and / or the endogenous gene encoding the TCR β chain is disrupted, preferably such that the endogenous gene encoding the TCR α chain and / or the endogenous gene encoding the TCR β chain is not expressed, optionally wherein the endogenous gene encoding the TCR α chain and / or the endogenous gene encoding the TCR β chain is disrupted by insertion into an expression cassette comprising a polynucleotide sequence encoding the TCR according to any one of claims 1 to 130.

143. The cell according to any one of claims 137 to 142, wherein one or more endogenous genes encoding MHC are disrupted.

144. The cell according to any one of claims 137 to 143, wherein endogenous genes involved in persistence, amplification, activity, resistance to exhaustion / senescence / inhibition signals, homing ability, or other T cell functions are disrupted, optionally wherein the endogenous genes involved in persistence, amplification, activity, resistance to exhaustion / senescence / inhibition signals, homing ability, or other T cell functions are selected from the group consisting of: PD1, TIM3, LAG3, 2B4, KLRG1, TGFbR, CD160, TIGIT, CTLA4, and CD39.

145. A method for preparing cells, the method comprising, for example, introducing a polynucleotide according to any one of claims 131 to 133 or a vector according to any one of claims 134 to 136 into cells in vitro, ex vivo, or in vivo by transfection or transduction.

146. The method of claim 145, wherein the method includes a step of T cell editing, the step comprising disrupting an endogenous gene encoding the TCR α chain and / or an endogenous gene encoding the TCR β chain with an artificial nuclease, preferably wherein the artificial nuclease is selected from the group consisting of zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR / Cas system.

147. The method of claim 146, wherein the method comprises the step of targeting and integrating an expression cassette into an endogenous gene encoding the TCR α chain and / or an endogenous gene encoding the TCR β chain that has been disrupted by the artificial nuclease, wherein the expression cassette comprises a polynucleotide sequence encoding a TCR according to any one of claims 1 to 130.

148. The method according to any one of claims 145 to 147, wherein the method comprises the step of destroying one or more endogenous genes encoding MHC, optionally wherein the cells prepared by the method are allogeneic reactive universal T cells.

149. The method of any one of claims 145 to 148, wherein the method comprises the step of disrupting one or more endogenous genes to modulate persistence, amplification, activity, resistance to exhaustion / senescence / inhibition signals, homing ability, or other T cell functions, optionally wherein the method comprises the step of targeting an expression cassette into an endogenous gene involved in persistence, amplification, activity, resistance to exhaustion / senescence / inhibition signals, homing ability, or other T cell functions that has been disrupted by an artificial nuclease, wherein the expression cassette comprises a polynucleotide sequence encoding a TCR according to any one of claims 1 to 130, optionally wherein the endogenous gene is selected from the group consisting of: PD1, TIM3, LAG3, 2B4, KLRG1, TGFbR, CD160, TIGIT, CTLA4, and CD39.

150. A chimeric molecule comprising a TCR or a portion thereof according to any one of claims 1 to 130, conjugated to a noncellular substrate, a toxin, and / or an antibody, optionally wherein the noncellular substrate is selected from the group consisting of nanoparticles, exosomes, and other noncellular substrates.

151. A pharmaceutical composition comprising a TCR according to any one of claims 1 to 130, a polynucleotide according to any one of claims 131 to 133, a carrier according to any one of claims 134 to 136, a cell according to any one of claims 137 to 144, a cell prepared by the method according to any one of claims 145 to 149, or a chimeric molecule according to claim 150.

152. The cells according to any one of claims 137 to 144 or the cells prepared by the method according to any one of claims 145 to 149, the cells being used in adoptive cell transfer, preferably in adoptive T cell transfer, optionally wherein the adoptive T cell transfer is allogeneic adoptive T cell transfer, autologous adoptive T cell transfer or universal non-allogeneic reactive adoptive T cell transfer.

153. The TCR according to any one of claims 1 to 130, the polynucleotide according to any one of claims 131 to 133, the carrier according to any one of claims 134 to 136, the cell according to any one of claims 137 to 144, the cell prepared by the method according to any one of claims 145 to 149, the chimeric molecule according to claim 150, or the pharmaceutical composition according to claim 151, wherein the TCR, the polynucleotide, the carrier, the cell, the chimeric molecule, or the pharmaceutical composition is used in a therapy.

154. The TCR according to any one of claims 1 to 130, the polynucleotide according to any one of claims 131 to 133, the carrier according to any one of claims 134 to 136, the cell according to any one of claims 137 to 144, the cell prepared by the method according to any one of claims 145 to 149, the chimeric molecule according to claim 150, or the pharmaceutical composition according to claim 151, wherein the TCR, the polynucleotide, the carrier, the cell, the chimeric molecule, or the pharmaceutical composition is used for the treatment and / or prevention of proliferative disorders.

155. The TCR, polynucleotide, carrier, cell, chimeric molecule, or pharmaceutical composition of claim 154, wherein the proliferative condition is a hematologic malignancy or solid tumor, optionally wherein the hematologic malignancy is selected from the group consisting of: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphoblastic leukemia, acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, lymphoma, multiple myeloma, non-Hodgkin's lymphoma. Tumors and Hodgkin's lymphoma, optionally wherein the solid tumors are selected from the group consisting of: lung cancer, breast cancer, esophageal cancer, gastric cancer, colon cancer, bile duct cancer, pancreatic cancer, ovarian cancer, head and neck cancer, synovial sarcoma, angiosarcoma, osteosarcoma, thyroid cancer, oral cancer, hepatocellular carcinoma, bladder cancer, endometrial cancer, neuroblastoma, rhabdomyosarcoma, liver cancer, melanoma, prostate cancer, kidney cancer, soft tissue sarcoma, urothelial carcinoma, bile duct cancer, glioblastoma, mesothelioma, cervical cancer, and colorectal cancer.

156. The TCR, polynucleotide, carrier, cell, chimeric molecule, or pharmaceutical composition of claim 154, wherein the proliferative condition is acute myeloid leukemia (AML), or wherein the proliferative condition is colorectal cancer and / or pancreatic cancer.

157. A method for treating and / or preventing proliferative disorders, the method comprising administering to a subject in need a therapeutically effective amount of any one of claims 1 to 130, any one of claims 131 to 133, any one of claims 134 to 136, any one of claims 137 to 144, cells prepared by the method of any one of claims 145 to 149, a chimeric molecule according to claim 150, or a pharmaceutical composition according to claim 151.

158. The method of claim 157, wherein the proliferative disease is a hematologic malignancy or a solid tumor, optionally wherein the hematologic malignancy is selected from the group consisting of: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphoblastic leukemia, acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, lymphoma, multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma, optionally wherein the solid tumor is selected from the group consisting of: lung cancer, breast cancer, esophageal cancer, gastric cancer, colon cancer, bile duct cancer, pancreatic cancer, ovarian cancer, head and neck cancer, synovial sarcoma, angiosarcoma, osteosarcoma, thyroid cancer, oral cancer, hepatocellular carcinoma, bladder cancer, endometrial cancer, neuroblastoma, rhabdomyosarcoma, liver cancer, melanoma, prostate cancer, kidney cancer, soft tissue sarcoma, urothelial carcinoma, bile duct cancer, glioblastoma, mesothelioma, cervical cancer, and colorectal cancer.

159. The method of claim 157, wherein the proliferative condition is acute myeloid leukemia (AML) or wherein the proliferative condition is colorectal cancer and / or pancreatic cancer.

160. Use of the TCR according to any one of claims 1 to 130, the polynucleotide according to any one of claims 131 to 133, the carrier according to any one of claims 134 to 136, the cell according to any one of claims 137 to 144, the cell prepared by the method according to any one of claims 145 to 149, the chimeric molecule according to claim 150, or the pharmaceutical composition according to claim 151, wherein the TCR, the polynucleotide, the carrier, the cell, the chimeric molecule, or the pharmaceutical composition is used to manufacture an agent for treating and / or preventing proliferative disorders.

161. The use according to claim 160, wherein the proliferative disease is a hematologic malignancy or solid tumor, optionally wherein the hematologic malignancy is selected from the group consisting of: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphoblastic leukemia, acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, lymphoma, multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma, optionally wherein the solid tumor is selected from the group consisting of: lung cancer, breast cancer, esophageal cancer, gastric cancer, colon cancer, bile duct cancer, pancreatic cancer, ovarian cancer, head and neck cancer, synovial sarcoma, angiosarcoma, osteosarcoma, thyroid cancer, oral cancer, hepatocellular carcinoma, bladder cancer, endometrial cancer, neuroblastoma, rhabdomyosarcoma, liver cancer, melanoma, prostate cancer, kidney cancer, soft tissue sarcoma, urothelial carcinoma, bile duct cancer, glioblastoma, mesothelioma, cervical cancer, and colorectal cancer.

162. The use according to claim 160, wherein the proliferative condition is acute myeloid leukemia (AML) or wherein the proliferative condition is colorectal cancer and / or pancreatic cancer.

163. An isolated immunogenic cathepsin G (CTSG) peptide, said isolated immunogenic CTSG peptide comprising or consisting of an amino acid sequence selected from the following: GIVSYGKSSGVPPEV (SEQ ID NO: 58), SXXXPXVFTRVSSFL (SEQ ID NO: 535), SGVPPEVFTRVSSFL (SEQ ID NO: 81), TMRSFKLLDQMETPL (SEQ ID NO: 95), and variants thereof having up to three amino acid substitutions, additions, or deletions, or immunogenic fragments thereof.

164. The isolated immunogenic CTSG peptide according to claim 163, wherein the CTSG peptide comprises or is composed of the following: GIVSYGKSSGVPPEV (SEQ ID NO: 58) or a variant thereof having up to three amino acid substitutions, additions or deletions or an immunogenic fragment thereof.

165. The isolated immunogenic CTSG peptide according to claim 163, wherein the CTSG peptide comprises or is composed of the following: SXXXPXVFTRVSSFL (SEQ ID NO: 535) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or an immunogenic fragment thereof, preferably wherein the CTSG peptide comprises or is composed of the following: the amino acid sequence of SGVPPEVFTRVSSFL (SEQ ID NO: 81) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or an immunogenic fragment thereof, preferably wherein the CTSG peptide comprises or is composed of the following: the amino acid sequence of VFTRVSSFL (SEQ ID NO: 82) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or wherein the CTSG peptide comprises or is composed of the following: the amino acid sequence of VPPEVFTRVSSFL (SEQ ID NO: 83) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

166. The isolated immunogenic CTSG peptide according to claim 163, wherein the CTSG peptide comprises or is composed of the following: TMRSFKLLDQMETPL (SEQ ID NO: 95) or a variant thereof having up to three amino acid substitutions, additions or deletions or an immunogenic fragment thereof.

167. The isolated immunogenic CTSG peptide according to any one of claims 163 to 166, wherein the immunogenic fragment has a length of nine or more amino acids, preferably wherein the immunogenic fragment is a nonamic fragment.

168. An isolated immunogenic cyclin A1 (CCNA1) peptide, said isolated immunogenic CCNA1 peptide comprising or consisting of an amino acid sequence selected from the following: TEYAEEIYQYL (SEQ ID NO: 114), PETLAAFTGYSLSEI (SEQ ID NO: 128), AELSLLLEADPFLKYL (SEQ ID NO: 153), LLEAPFLKYLPSLI (SEQ ID NO: 527), WEGPGLPDFVF (SEQ ID NO: 172), KRQLLKMEHLLLKVL (SEQ ID NO: 185), PETLAAFTGYSLSEI (SEQ ID NO: 201), and variants thereof having at most three amino acid substitutions, additions, or deletions, or immunogenic fragments thereof.

169. The isolated immunogenic CCNA1 peptide according to claim 168, wherein the CCNA1 peptide comprises or is composed of the following: TEYAEEIYQYL (SEQ ID NO: 114) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or an immunogenic fragment thereof, preferably wherein the CCNA1 peptide comprises or is composed of the following: the amino acid sequence of YAEEIYQYL (SEQ ID NO: 115) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or wherein the CCNA1 peptide comprises or is composed of the following: the amino acid sequence of EYAEEIYQY (SEQ ID NO: 116) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

170. The isolated immunogenic CCNA1 peptide according to claim 168, wherein the CCNA1 peptide comprises or is composed of the following: PETLAAFTGYSLSEI (SEQ ID NO: 128) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or an immunogenic fragment thereof, preferably wherein the CCNA1 peptide comprises or is composed of the following: the amino acid sequence of ETLAAFTGY (SEQ ID NO: 129) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or wherein the CCNA1 peptide comprises or is composed of the following: the amino acid sequence of LAAFTGYSL (SEQ ID NO: 130) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

171. The isolated immunogenic CCNA1 peptide according to claim 168, wherein the CCNA1 peptide comprises or is composed of: AELSLLLEADPFLKYL (SEQ ID NO: 153) or a variant thereof having at most three amino acid substitutions, additions or deletions, or an immunogenic fragment thereof, or wherein the CCNA1 peptide comprises or is composed of: LLEADPFLKYLPSLI (SEQ ID NO: 527) or a variant thereof having at most three amino acid substitutions, additions or deletions, or an immunogenic fragment thereof, preferably wherein the CCNA1 peptide comprises or is composed of the following: the amino acid sequence of EADPFLKYL (SEQ ID NO: 154) or a variant thereof having at most three amino acid substitutions, additions or deletions.

172. The isolated immunogenic CCNA1 peptide according to claim 168, wherein the CCNA1 peptide comprises or is composed of the following: WEGPGLPDFVF (SEQ ID NO: 172) or a variant thereof having at most three amino acid substitutions, additions or deletions, or an immunogenic fragment thereof, preferably wherein the CCNA1 peptide comprises or is composed of the following: the amino acid sequence of GPGLPDFVF (SEQ ID NO: 173) or a variant thereof having at most three amino acid substitutions, additions or deletions.

173. The isolated immunogenic CCNA1 peptide according to claim 168, wherein the CCNA1 peptide comprises or is composed of the following: KRQLLKMEHLLLKVL (SEQ ID NO: 185) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or an immunogenic fragment thereof, preferably wherein the CCNA1 peptide comprises or is composed of the following: the amino acid sequence of RQLLKMEHL (SEQ ID NO: 186) or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein the CCNA1 peptide comprises or is composed of the following: the amino acid sequence of MEHLLLKVL (SEQ ID NO: 187) or a variant thereof having at most three amino acid substitutions, additions, or deletions, wherein the CCNA1 peptide comprises or is composed of the following: the amino acid sequence of MEHLLLKV (SEQ ID NO: 188) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or wherein the CCNA1 peptide comprises or is composed of the following: the amino acid sequence of KMEHLLLKV (SEQ ID NO: 189) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

174. The isolated immunogenic CCNA1 peptide according to claim 168, wherein the CCNA1 peptide comprises or is composed of the following: PETLAAFTGYSLSEI (SEQ ID NO: 201) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or an immunogenic fragment thereof, preferably wherein the CCNA1 peptide comprises or is composed of the following: the amino acid sequence of ETLAAFTGY (SEQ ID NO: 202) or a variant thereof having at most three amino acid substitutions, additions, or deletions, or wherein the CCNA1 peptide comprises or is composed of the following: the amino acid sequence of LAAFTGYSL (SEQ ID NO: 203) or a variant thereof having at most three amino acid substitutions, additions, or deletions.

175. The isolated immunogenic CCNA1 peptide according to any one of claims 168 to 174, wherein the immunogenic fragment has a length of nine or more amino acids, preferably wherein the immunogenic fragment is a nonameric fragment.

176. A T-cell receptor (TCR) that binds to an immunogenic CTSG peptide when the CTSG peptide is presented by the major histocompatibility complex (MHC), wherein the immunogenic CTSG peptide is as defined in claim 165.

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