T-cell receptors

Abstract

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

Description

[0001] T-CELL RECEPTORS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to T-cell receptors (TCRs) which bind to immunogenic peptides when presented by a major histocompatibility complex (MHC). The present invention further relates to immunogenic peptides.

[0004] BACKGROUND TO THE INVENTION

[0005] The fifth pillar of cancer care is represented by immunotherapy, which exploits the innate ability of the immune system to recognize cancer cells. Indeed, the presence of tumourinfiltrating lymphocytes is correlated with a better prognosis (see e.g. Zhang, L., et al. New England journal of medicine, 348(3), pp.203-213).

[0006] The ability of T lymphocytes to recognise an antigen is determined by the expression of a T cell receptor (TCR). TCR gene therapy is based on the genetic transfer of high-avidity tumourspecific TCR genes into T lymphocytes, thus enabling the specific targeting of the desired tumour-associated antigens and leading to a less toxic and more specific and effective therapy. This approach has shown promise in clinical trials.

[0007] One of the main barriers limiting the exploitation of TCR gene therapy for clinical treatment of cancers is the lack of tumour-specific T-cells and corresponding TCRs. Tumour-specific T cells against tumour-associated antigens (TAAs), self-proteins overexpressed on cancer cells, are interesting targets in the context of adoptive T cell therapy. However, the number of isolated TAA-specific T cells is still limited, particularly in the context of blood malignancies.

[0008] Thus, the low availability of tumour-specific TCRs still remains an open issue limiting the broad exploitation of TCR-based immunotherapeutic approaches.

[0009] SUMMARY OF THE INVENTION

[0010] The present inventors have identified novel TCRs which bind to immunogenic peptides when presented by a major histocompatibility complex (MHC). The present inventors have determined the amino acid sequences of the TCRs, including the amino acid sequences of their CDR regions, which are responsible for binding specificity for the immunogenic peptides. The TCRs may endow engineered T cells with tumour-specific cytolytic functions.

[0011] In one aspect, the present invention provides a T-cell receptor (TCR) which binds to an immunogenic peptide when presented by a major histocompatibility complex (MHC), wherein: (1) the immunogenic peptide is a Human epidermal growth factor receptor 2 (HER2) peptide and the TCR comprises a CDR3a 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 a CDR3P 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;

[0012] (2) the immunogenic peptide is a Proteinase 3 (PR3) peptide or a Neutrophil elastase (NE) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CADYYGQNFVF (SEQ ID NO: 22) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSFQGYTEAFF (SEQ ID NO: 27) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0013] (3) the immunogenic peptide is a Histone-lysine N-methyltransferase EZH2 (EZH2) peptide or a Preferentially expressed antigen of melanoma (PRAME) peptide and the TCR comprises a CDR3a comprising (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 a CDR3P comprising (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;

[0014] (4) the immunogenic peptide is a Cathepsin G (CTSG) peptide and the TCR comprises a CDR3a comprising (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 a CDR3P comprising (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;

[0015] (5) the immunogenic peptide is a Cathepsin G (CTSG) peptide and the TCR comprises a CDR3a comprising 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 a CDR3P comprising the amino acid sequence of CASSVGRATEAFF (SEQ ID NO: 91) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0016] (6) the immunogenic peptide is a Cathepsin G (CTSG) peptide and the TCR comprises a CDR3a comprising (i) the amino acid sequence of CVVNWDNARLMF (SEQ ID NO: 98) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CATRRAKDRDDKIIF (SEQ ID NO: 459) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising (i) the amino acid sequence of CASSEEGGSTDTQYF (SEQ ID NO: 103) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CASSLGLAGDYEQYF (SEQ ID NO: 109) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0017] (7) the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAFMKRLTQGGSEKLVF (SEQ ID NO: 119) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSEVYRGHEKLFF (SEQ ID NO: 124) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0018] (8) the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAASIRSSGDKLTF (SEQ ID NO: 133) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSKRTGELFF (SEQ ID NO: 138) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0019] (9) the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CALSETLYNQGGKLIF (SEQ ID NO: 144) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSLGTSRSYTDTQYF (SEQ ID NO: 149) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0020] (10) the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CALTSDYKLSF (SEQ ID NO: 157) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising (i) the amino acid sequence of CATSDLFGELFF (SEQ ID NO: 162) or a variant thereof having up to three amino acid substitutions, additions or deletions or (i) the amino acid sequence of CASTTGIYEQYF (SEQ ID NO: 168) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0021] (11) the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TOR comprises a CDR3a comprising the amino acid sequence of CAVNSWGKLQF (SEQ ID NO: 176) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASHSGLVGTGELFF (SEQ ID NO: 181) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0022] (12) the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CASTNFGNEKLTF (SEQ ID NO: 192) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSLSYEQYF (SEQ ID NO: 197) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0023] (13) the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising (i) the amino acid sequence of CAVRSHSGNTPLVF (SEQ ID NO: 206) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CAENAGGTSYGKLTF (SEQ ID NO: 211) or a variant thereof having up to three amino acid substitutions, additions or deletions or (iii) the amino acid sequence of CAMRLPIPNNAGNMLTF (SEQ ID NO: 216) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising (i) the amino acid sequence of CASSSPRVGPLYEQYF (SEQ ID NO: 221) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CASSDHDIYNEQFF (SEQ ID NO: 227) or a variant thereof having up to three amino acid substitutions, additions or deletions or (iii) the amino acid sequence of CASWAEEAEETQYF (SEQ ID NO: 233) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0024] (14) the immunogenic peptide is a Dickkopf- related protein 1 (DKK1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAVGAWYNQGGKLIF (SEQ ID NO: 241) ora variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSFGVTGELFF (SEQ ID NO: 246) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0025] (15) the immunogenic peptide is a Mucin-5AC (MLIC5AC) peptide and the TOR comprises a CDR3a 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 a CDR3P 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;

[0026] (16) the immunogenic peptide is an Anterior gradient-2 (AGR2) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAVQDYGQNFVF (SEQ ID NO: 267) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSPTGSEQYF (SEQ ID NO: 272) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0027] (17) the immunogenic peptide is a c-MET peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAAAPNNNDMRF (SEQ ID NO: 280) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSLLAGGSSYEQYF (SEQ ID NO: 285) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0028] (18) the immunogenic peptide is a Mesothelin (MSLN) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAAYNDYKLSF (SEQ ID NO: 293) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSLQGVNTEAFF (SEQ ID NO: 298) or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0029] (19) the immunogenic peptide is a CTD phosphatase subunit 1 (CTDP1) peptide and the TCR comprises a CDR3a 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 a CDR3P 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; (20) the immunogenic peptide is a Transforming acidic coiled-coil-containing protein 2 (TACC2) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAVSGLGGSNYKLTF (SEQ ID NO: 319) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASRSGTGTMDEQFF (SEQ ID NO: 324) or a variant thereof having up to three amino acid substitutions, additions or deletions; or

[0030] (21) the immunogenic peptide is a Prostaglandin F2 receptor negative regulator (PTGFRN) peptide and the TCR comprises a CDR3a comprising 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 a CDR3P comprising the amino acid sequence of CSARDYKQVLRGSYNSPLHF (SEQ ID NO: 337) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0031] In one aspect, the present invention provides a TCR which binds to a Human epidermal growth factor receptor 2 (HER2) peptide when presented by an MHC, wherein the TCR comprises a CDR3a 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 a CDR3P 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: CDR1a - NSASDY (SEQ ID NO: 6), CDR2a - IRSNMDK (SEQ ID NO: 7), CDR3a - CAEGSRYGGATNKLIF (SEQ ID NO: 8), CDRi p - MNHEY (SEQ ID NO: 11), CDR2P - SVGAGI (SEQ ID NO: 12), and CDR3P - CASSTFPVETQYF (SEQ ID NO: 13), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 9 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising the amino acid sequence of SEQ ID NO: 14 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 10 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 15 or 16 or variants thereof having at least 70% sequence identity thereto. Suitably, the HER2 peptide comprises or consists of the amino acid sequence of KIFGSLAFL (SEQ ID NO: 5) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0032] In one aspect, the present invention provides a TCR which binds to a Proteinase 3 (PR3) peptide or a Neutrophil elastase (NE) peptide when presented by an MHC, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CADYYGQNFVF (SEQ ID NO: 22) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSFQGYTEAFF (SEQ ID NO: 27) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TOR comprises the following CDR sequences: CDR1a - VSGNPY (SEQ ID NO: 20), CDR2a - YITGDNLV (SEQ ID NO: 21), CDR3a - CADYYGQNFVF (SEQ ID NO: 22), CDR1 - MDHEN (SEQ ID NO: 25), CDR2 - SYDVKM (SEQ ID NO: 26), and CDR3 - CASSFQGYTEAFF (SEQ ID NO: 27), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 23 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising the amino acid sequence of SEQ ID NO: 28 ora variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 24 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 29 or 30 or variants thereof having at least 70% sequence identity thereto. 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 up to three amino acid substitutions, additions or deletions.

[0033] In one aspect, the present invention provides a TCR which binds to a Histone-lysine N- methyltransferase EZH2 (EZH2) peptide or a Preferentially expressed antigen of melanoma (PRAME) peptide when presented by an MHC, wherein the TCR comprises a CDR3a comprising (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 a CDR3P comprising (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. Suitably, the TCR comprises the following CDR sequences: (i) CDR1a - SSVPPY (SEQ ID NO: 35), CDR2a - YTSAATLV (SEQ ID NO: 36), and CDR3a - CAVSESPTGFQKLVF (SEQ ID NO: 37) or (ii) CDR1a - VGISA (SEQ ID NO: 40), CDR2a - LSSGK (SEQ ID NO: 41), and CDR3a - CAVPHSYNTDKLIF (SEQ ID NO: 42), and (i) CDR1 - SNHLY (SEQ ID NO: 45), CDR2 - FYNNEI (SEQ ID NO: 46), and CDR3 - CASSPRGSNTGELFF (SEQ ID NO: 47) or (ii) CDR1 - DFQATT (SEQ ID NO: 51), CDR2 - SNEGSKA (SEQ ID NO: 52), and CDR3 - CSARPSEAPQYF (SEQ ID NO: 53), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 38 or a variant thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 43 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 48 or a variant thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 54 ora variant thereof having at least 70% sequence identity thereto. Suitably, the TOR comprises an a chain comprising (i) the amino acid sequence of SEQ ID NO: 39 or a variant thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 44 ora variant thereof having at least 70% sequence identity thereto; and a chain comprising (i) the amino acid sequence of SEQ ID NO: 49 or 50 or variants thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 55 or 56 or variants thereof having at least 70% sequence identity thereto. Suitably, the EZH2 peptide comprises or consists of the amino acid sequence of KESRPPRKF (SEQ ID NO: 32) or a variant thereof having up to 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 up to three amino acid substitutions, additions or deletions.

[0034] In one aspect, the present invention provides a TOR which binds to a Cathepsin G (CTSG) peptide when presented by an MHC, wherein the TOR comprises a CDR3a comprising (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 a CDR3P comprising (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. Suitably, the TOR comprises the following CDR sequences: (i) CDR1a - ATGYPS (SEQ ID NO: 59), CDR2a - ATKADDK (SEQ ID NO: 60), and CDR3a - CALPSARQLTF (SEQ ID NO: 61) or (ii) CDR1a - TSENNYY (SEQ ID NO: 64), CDR2a - QEAYKQQN (SEQ ID NO: 65), and CDR3a - CAFMSPEGGSEKLVF (SEQ ID NO: 66), and (i) CDR1 - SQVTM (SEQ ID NO: 69), CDR2 - ANQGSEA (SEQ ID NO: 70), and CDR3 - CSVPPAGLGAPEAFF (SEQ ID NO: 71) or (ii) CDR1 - SEHNR (SEQ ID NO: 75), CDR2 - FQNEAQ (SEQ ID NO: 76), and CDR3P - CASSPGTGAYNSPLHF (SEQ ID NO: 77), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably the TCR comprises an a chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 62 or a variant thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 67 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 72 or a variant thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 78 or a variant thereof having at least 70% sequence identity thereto. Suitably the TOR comprises an a chain comprising (i) the amino acid sequence of SEQ ID NO: 63 or a variant thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 68 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising (i) the amino acid sequence of SEQ ID NO: 73 or 74 or variants thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 79 or 80 or variants thereof having at least 70% sequence identity thereto. 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 up to three amino acid substitutions, additions or deletions.

[0035] In one aspect, the present invention provides a TCR which binds to a Cathepsin G (CTSG) peptide when presented by an MHC, wherein the TCR comprises a CDR3a comprising 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 a CDR3P comprising the amino acid sequence of CASSVGRATEAFF (SEQ ID NO: 91) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably the TCR comprises the following CDR sequences: CDR1a - VSGLRG (SEQ ID NO: 84), CDR2a - LYSAGEE (SEQ ID NO: 85), CDR3a - CAVQASNDYKLSF (SEQ ID NO: 86), CDRi - MNHEY (SEQ ID NO: 89), CDR2P - SMNVEV (SEQ ID NO: 90), and CDR3P - CASSVGRATEAFF (SEQ ID NO: 91), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 87 or a variant thereof having at least 70% sequence identity thereto; and a chain variable domain comprising the amino acid sequence of SEQ ID NO: 92 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 88 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 93 or 94 or variants thereof having at least 70% sequence identity thereto. Suitably, the CTSG peptide comprises or consists of the amino acid sequence of SXXXPXVFTRVSSFL (SEQ ID NO: 535) or a variant thereof having up to 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 up to 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 up to three amino acid substitutions, additions or deletions. 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.

[0036] In one aspect, the present invention provides a TCR which binds to a Cathepsin G (CTSG) peptide when presented by an MHC, wherein the TCR comprises a CDR3a comprising (i) the amino acid sequence of CVVNWDNARLMF (SEQ ID NO: 98) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CATRRAKDRDDKIIF (SEQ ID NO: 459) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising (i) the amino acid sequence of CASSEEGGSTDTQYF (SEQ ID NO: 103) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CASSLGLAGDYEQYF (SEQ ID NO: 109) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises the following CDR sequences: (i) CDR1a - NSASQS (SEQ ID NO: 96), CDR2a - VYSSGN (SEQ ID NO: 97), CDR3a - CVVNWDNARLMF (SEQ ID NO: 98) or (ii) CDR1a - NSAFQY (SEQ ID NO: 457), CDR2a - TYSSGN (SEQ ID NO: 458), CDR3a - CATRRAKDRDDKIIF (SEQ ID NO: 459), and (i) CDR1 - SNHLY (SEQ ID NO: 101), CDR2P - FYNNEI (SEQ ID NO: 102), and CDR3P - CASSEEGGSTDTQYF (SEQ ID NO: 103) or (ii) CDR1P - SGHNS (SEQ ID NO: 107), CDR2P - FNNNVP (SEQ ID NO: 108), and CDR3P - CASSLGLAGDYEQYF (SEQ ID NO: 109), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably the TCR comprises an a chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 99 or a variant thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 460 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 104 or a variant thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 110 or a variant thereof having at least 70% sequence identity thereto. Suitably the TCR comprises an a chain comprising (i) the amino acid sequence of SEQ ID NO: 100 or a variant thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 461 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising (i) the amino acid sequence of SEQ ID NO: 105 or 106 or variants thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 111 or 112 or variants thereof having at least 70% sequence identity thereto. 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 up to three amino acid substitutions, additions or deletions.

[0037] In one aspect, the present invention provides a TOR which binds to a Cyclin A1 (CCNA1) peptide when presented by an MHC, wherein the TOR comprises a CDR3a comprising the amino acid sequence of CAFMKRLTQGGSEKLVF (SEQ ID NO: 119) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSEVYRGHEKLFF (SEQ ID NO: 124) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TOR comprises the following CDR sequences: CDR1a - TSENNYY (SEQ ID NO: 117), CDR2a - QEAYKQQN (SEQ ID NO: 118), CDR3a - CAFMKRLTQGGSEKLVF (SEQ ID NO: 119), CDR1 P - SNHLY (SEQ ID NO: 122), CDR2P - FYNNEI (SEQ ID NO: 123), and CDR3P - CASSEVYRGHEKLFF (SEQ ID NO: 124), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 120 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising the amino acid sequence of SEQ ID NO: 125 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 121 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 126 or 127 or variants thereof having at least 70% sequence identity thereto. Suitably, the CCNA1 peptide comprises or consists of a nonameric fragment of the amino acid sequence of TEYAEEIYQYL (SEQ ID NO: 114) or a variant thereof having up to three amino acid substitutions, additions or deletions, preferably wherein the CTSG peptide comprises or consists of the amino acid sequence of YAEEIYQYL (SEQ ID NO: 115) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0038] In one aspect, the present invention provides a TCR which binds to a Cyclin A1 (CCNA1) peptide when presented by an MHC, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAASIRSSGDKLTF (SEQ ID NO: 133) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSKRTGELFF (SEQ ID NO: 138) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1a - DSASNY (SEQ ID NO: 131), CDR2a - IRSNVGE (SEQ ID NO: 132), CDR3a - CAASIRSSGDKLTF (SEQ ID NO: 133), CDRi p - MDHEN (SEQ ID NO: 136), CDR2P - SYDVKM (SEQ ID NO: 137), and CDR3P - CASSKRTGELFF (SEQ ID NO: 138), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 134 or a variant thereof having at least 70% sequence identity thereto; and a P chain variable domain comprising the amino acid sequence of SEQ ID NO: 139 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 135 or a variant thereof having at least 70% sequence identity thereto; and a chain comprising the amino acid sequence of SEQ ID NO: 140 or 141 or variants thereof having at least 70% sequence identity thereto. Suitably, the CCNA1 peptide comprises or consists of a nonameric fragment of the amino acid sequence of PETLAAFTGYSLSEI (SEQ ID NO: 128) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0039] In one aspect, the present invention provides a TCR which binds to a Cyclin A1 (CCNA1) peptide when presented by an MHC, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CALSETLYNQGGKLIF (SEQ ID NO: 144) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSLGTSRSYTDTQYF (SEQ ID NO: 149) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1a - TRDTTYY (SEQ ID NO: 142), CDR2a - RNSFDEQN (SEQ ID NO: 143), CDR3a - CALSETLYNQGGKLIF (SEQ ID NO: 144), CDRi p - SGHTA (SEQ ID NO: 147), CDR2P - FQGNSA (SEQ ID NO: 148), and CDR3P - CASSLGTSRSYTDTQYF (SEQ ID NO: 149), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 145 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising the amino acid sequence of SEQ ID NO: 150 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 146 or a variant thereof having at least 70% sequence identity thereto; and a P chain comprising the amino acid sequence of SEQ ID NO: 151 or 152 or variants thereof having at least 70% sequence identity thereto.

[0040] In one aspect, the present invention provides a TCR which binds to a Cyclin A1 (CCNA1) peptide when presented by an MHC, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CALTSDYKLSF (SEQ ID NO: 157) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising (i) the amino acid sequence of CATSDLFGELFF (SEQ ID NO: 162) or a variant thereof having up to three amino acid substitutions, additions or deletions or (i) the amino acid sequence of CASTTGIYEQYF (SEQ ID NO: 168) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1a - SSNFYA (SEQ ID NO: 155), CDR2a - MTLNGDE (SEQ ID NO: 156), CDR3a - CALTSDYKLSF (SEQ ID NO: 157), and (i) CDR1 - KGHDR (SEQ ID NO: 160), CDR2P - SFDVKD (SEQ ID NO: 161), and CDR3 - CATSDLFGELFF (SEQ ID NO: 162) or (ii) CDR1 P - SNHLY (SEQ ID NO: 166), CDR2P - FYNNEI (SEQ ID NO: 167), and CDR3P - CASTTGIYEQYF (SEQ ID NO: 168), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 158 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 163 or a variant thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 169 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 159 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising (i) the amino acid sequence of SEQ ID NO: 164 or 165 or variants thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 170 or 171 or variants thereof having at least 70% sequence identity thereto. Suitably, the CCNA1 peptide comprises or consists of a nonameric fragment of the amino acid sequence of AELSLLEADPFLKYL (SEQ ID NO: 153) or a variant thereof having up to 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 up to three amino acid substitutions, additions or deletions.

[0041] In one aspect, the present invention provides a TCR which binds to a Cyclin A1 (CCNA1) peptide when presented by an MHC, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAVNSWGKLQF (SEQ ID NO: 176) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASHSGLVGTGELFF (SEQ ID NO: 181) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1a - TSGFNG (SEQ ID NO: 174), CDR2a - NVLDGL (SEQ ID NO: 175), CDR3a - CAVNSWGKLQF (SEQ ID NO: 176), CDRi p - MNHEY (SEQ ID NO: 179), CDR2P - SMNVEV (SEQ ID NO: 180), and CDR3P - CASHSGLVGTGELFF (SEQ ID NO: 181) or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 177 or a variant thereof having at least 70% sequence identity thereto; and a P chain variable domain comprising the amino acid sequence of SEQ ID NO: 182 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 178 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 183 or 184 or variants thereof having at least 70% sequence identity thereto. Suitably, the CCNA1 peptide comprises or consists of a nonameric fragment of the amino acid sequence of WEGPGLPDFVF (SEQ ID NO: 172) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0042] In one aspect, the present invention provides a TOR which binds to a Cyclin A1 (CCNA1) peptide when presented by an MHC, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CASTNFGNEKLTF (SEQ ID NO: 192) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3 comprising the amino acid sequence of CASSLSYEQYF (SEQ ID NO: 197) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1a - TSESDYY (SEQ ID NO: 190), CDR2a - QEAYKQQN (SEQ ID NO: 191), CDR3a - CASTNFGNEKLTF (SEQ ID NO: 192), CDRi p - PRHDT (SEQ ID NO: 195), CDR2P - FYEKMQ (SEQ ID NO: 196), and CDR3P - CASSLSYEQYF (SEQ ID NO: 197), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 193 or a variant thereof having at least 70% sequence identity thereto; and a chain variable domain comprising the amino acid sequence of SEQ ID NO: 198 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 194 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 199 or 200 or variants thereof having at least 70% sequence identity thereto. Suitably, the CCNA1 peptide comprises or consists of a nonameric fragment of the amino acid sequence of KRQLLKMEHLLLKVL (SEQ ID NO: 185) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0043] In one aspect, the present invention provides a TCR which binds to a Cyclin A1 (CCNA1) peptide when presented by an MHC, wherein the TCR comprises a CDR3a comprising (i) the amino acid sequence of CAVRSHSGNTPLVF (SEQ ID NO: 206) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CAENAGGTSYGKLTF (SEQ ID NO: 211) or a variant thereof having up to three amino acid substitutions, additions or deletions or (iii) the amino acid sequence of CAMRLPIPNNAGNMLTF (SEQ ID NO: 216) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising (i) the amino acid sequence of CASSSPRVGPLYEQYF (SEQ ID NO: 221) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CASSDHDIYNEQFF (SEQ ID NO: 227) or a variant thereof having up to three amino acid substitutions, additions or deletions or (iii) the amino acid sequence of CASWAEEAEETQYF (SEQ ID NO: 233) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TOR comprises the following CDR sequences: (i) CDR1a - TSGFYG (SEQ ID NO: 204), CDR2a - NALDGL (SEQ ID NO: 205), and CDR3a - CAVRSHSGNTPLVF (SEQ ID NO: 206) or (ii) CDR1a - NSASDY (SEQ ID NO: 209), CDR2a - IRSNMDK (SEQ ID NO: 210), and CDR3a - CAENAGGTSYGKLTF (SEQ ID NO: 211) or (iii) CDR1a - TSDQSYG (SEQ ID NO: 214), CDR2a - QGSYDEQN (SEQ ID NO: 215), and CDR3a - CAMRLPIPNNAGNMLTF (SEQ ID NO: 216), and (i) CDR1 - SEHNR (SEQ ID NO: 219), CDR2 - FQNEAQ (SEQ ID NO: 220), and CDR3 - CASSSPRVGPLYEQYF (SEQ ID NO: 221) or (ii) CDR1 - SEHNR (SEQ ID NO: 225), CDR2 - FQNEAQ (SEQ ID NO: 226), and CDR3 - CASSDHDIYNEQFF (SEQ ID NO: 227) or (iii) CDR1 - SNHLY (SEQ ID NO: 231), CDR2 - FYNNEI (SEQ ID NO: 232), and CDR3P - CASWAEEAEETQYF (SEQ ID NO: 233), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 207 or a variant thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 212 or a variant thereof having at least 70% sequence identity thereto or (iii) the amino acid sequence of SEQ ID NO: 217 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising (i) the amino acid sequence of SEQ ID NO: 222 or a variant thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 228 or a variant thereof having at least 70% sequence identity thereto or (iii) the amino acid sequence of SEQ ID NO: 234 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising (i) the amino acid sequence of SEQ ID NO: 208 or a variant thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 213 or a variant thereof having at least 70% sequence identity thereto or (iii) the amino acid sequence of SEQ ID NO: 218 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising (i) the amino acid sequence of SEQ ID NO: 223 or 224 or variants thereof having at least 70% sequence identity thereto or (ii) the amino acid sequence of SEQ ID NO: 229 or 230 or variants thereof having at least 70% sequence identity thereto or (iii) the amino acid sequence of SEQ ID NO: 235 or 236 or variants thereof having at least 70% sequence identity thereto. Suitably, the CCNA1 peptide comprises or consists of a nonameric fragment of the amino acid sequence of PETLAAFTGYSLSEI (SEQ ID NO: 201) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0044] In one aspect, the present invention provides a TCR which binds to a Dickkopf-related protein 1 (DKK1) peptide when presented by an MHC, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAVGAWYNQGGKLIF (SEQ ID NO: 241) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSFGVTGELFF (SEQ ID NO: 246) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TOR comprises the following CDR sequences: CDR1a - YGATPY (SEQ ID NO: 239), CDR2a - YFSGDTLV (SEQ ID NO: 240), CDR3a - YFSGDTLV (SEQ ID NO: 241), CDR1 - SGHDY (SEQ ID NO: 244), CDR2 - FNNNVP (SEQ ID NO: 245), and CDR3 - CASSFGVTGELFF (SEQ ID NO: 246), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 242 ora variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising the amino acid sequence of SEQ ID NO: 247 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 243 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 248 or 249 or variants thereof having at least 70% sequence identity thereto. Suitably, the DKK1 peptide comprises or consists of the amino acid sequence of ILYPGGNKV (SEQ ID NO: 238) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0045] In one aspect, the present invention provides a TCR which binds to a Mucin-5AC (MLIC5AC) peptide when presented by an MHC, wherein the TCR comprises a CDR3a 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 a CDR3P 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: CDR1a - DRGSQS (SEQ ID NO: 252), CDR2a - IYSNGD (SEQ ID NO: 253), CDR3a - CAGGGSGAGSYQLTF (SEQ ID NO: 254), CDRi p - ENHRY (SEQ ID NO: 257), CDR2P - SYGVKD (SEQ ID NO: 258), and CDR3P - CAISDPTGDNQPQHF (SEQ ID NO: 259), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 255 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising the amino acid sequence of SEQ ID NO: 260 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 256 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 261 or 262 or variants thereof having at least 70% sequence identity thereto. Suitably, the MUC5AC peptide comprises or consists of the amino acid sequence of FLNDAGACV (SEQ ID NO: 251) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0046] In one aspect, the present invention provides a TOR which binds to an Anterior gradient-2 (AGR2) peptide when presented by an MHC, wherein the TOR comprises a CDR3a comprising the amino acid sequence of CAVQDYGQNFVF (SEQ ID NO: 267) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSPTGSEQYF (SEQ ID NO: 272) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1a - VSGLRG (SEQ ID NO: 265), CDR2a - LYSAGEE (SEQ ID NO: 266), CDR3a - CAVQDYGQNFVF (SEQ ID NO: 267), CDR1 - MNHEY (SEQ ID NO: 270), CDR2 - SMNVEV (SEQ ID NO: 271), and CDR3 - CASSPTGSEQYF (SEQ ID NO: 272), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 268 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising the amino acid sequence of SEQ ID NO: 273 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 269 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 274 or 275 or variants thereof having at least 70% sequence identity thereto. Suitably, the AGR2 peptide comprises or consists of the amino acid sequence of LLVALSYTL (SEQ ID NO: 264) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0047] In one aspect, the present invention provides a TCR which binds to a c-MET peptide when presented by an MHC, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAAAPNNNDMRF (SEQ ID NO: 280) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSLLAGGSSYEQYF (SEQ ID NO: 285) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1a - DSASNY (SEQ ID NO: 278), CDR2a - IRSNVGE (SEQ ID NO: 279), CDR3a - CAAAPNNNDMRF (SEQ ID NO: 280), CDRi p - MNHEY (SEQ ID NO: 283), CDR2P - SVGAGI (SEQ ID NO: 284), and CDR3P - CASSLLAGGSSYEQYF (SEQ ID NO: 285), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 281 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising the amino acid sequence of SEQ ID NO: 286 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 282 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 287 or 288 or variants thereof having at least 70% sequence identity thereto. Suitably, the c-MET peptide comprises or consists of the amino acid sequence of YVDPVITSI (SEQ ID NO: 277) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0048] In one aspect, the present invention provides a TCR which binds to a Mesothelin (MSLN) peptide when presented by an MHC, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAAYNDYKLSF (SEQ ID NO: 293) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSLQGVNTEAFF (SEQ ID NO: 298) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises the following CDR sequences: CDR1a - SSNFYA (SEQ ID NO: 291), CDR2a - MTLNGDE (SEQ ID NO: 292), CDR3a - CAAYNDYKLSF (SEQ ID NO: 293), CDRi p - MNHEY (SEQ ID NO: 296), CDR2 - SMNVEV (SEQ ID NO: 297), and CDR3P - CASSLQGVNTEAFF (SEQ ID NO: 298), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 294 or a variant thereof having at least 70% sequence identity thereto; and a chain variable domain comprising the amino acid sequence of SEQ ID NO: 299 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 295 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 300 or 301 or variants thereof having at least 70% sequence identity thereto. Suitably, the MSLN peptide comprises or consists of the amino acid sequence of KLLGPHVLGV (SEQ ID NO: 290) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0049] In one aspect, the present invention provides a TCR which binds to a CTD phosphatase subunit 1 (CTDP1) peptide when presented by an MHC, wherein the TCR comprises a CDR3a 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 a CDR3P 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: CDR1a - TSDPSYG (SEQ ID NO: 304), CDR2a - QGSYDQQN (SEQ ID NO: 305), CDR3a - CAMREGTSGTYKYIF (SEQ ID NO: 306), CDRi p - SEHNR (SEQ ID NO: 309), CDR2 - FQNEAQ (SEQ ID NO: 310), and CDR3 - CASS N SAS RPEQYV (SEQ ID NO: 311), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TOR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 307 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising the amino acid sequence of SEQ ID NO: 312 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TOR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 308 or a variant thereof having at least 70% sequence identity thereto; and a chain comprising the amino acid sequence of SEQ ID NO: 313 or 314 or variants thereof having at least 70% sequence identity thereto. Suitably, the CTDP1 peptide comprises or consists of the amino acid sequence of YLNKEIEEA (SEQ ID NO: 303) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0050] In one aspect, the present invention provides a TOR which binds to a Transforming acidic coiled-coil-containing protein 2 (TACC2) peptide when presented by an MHO, wherein the TOR comprises a CDR3a comprising the amino acid sequence of CAVSGLGGSNYKLTF (SEQ ID NO: 319) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASRSGTGTMDEQFF (SEQ ID NO: 324) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TOR comprises the following CDR sequences: CDR1a - SSVPPY (SEQ ID NO: 317), CDR2a - YTSAATLV (SEQ ID NO: 318), CDR3a - CAVSGLGGSNYKLTF (SEQ ID NO: 319), CDRip - MNHNY (SEQ ID NO: 322), CDR2P - SVGAGI (SEQ ID NO: 323), and CDR3P - CASRSGTGTMDEQFF (SEQ ID NO: 324), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 320 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising the amino acid sequence of SEQ ID NO: 325 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 321 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 326 or 327 or variants thereof having at least 70% sequence identity thereto. Suitably, the TACC2 peptide comprises or consists of the amino acid sequence of YRNSYEIEY (SEQ ID NO: 316) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0051] In one aspect, the present invention provides a TCR which binds to a Prostaglandin F2 receptor negative regulator (PTGFRN) peptide when presented by an MHC, wherein the TCR comprises a CDR3a comprising 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 a CDR3P comprising the amino acid sequence of CSARDYKQVLRGSYNSPLHF (SEQ ID NO: 337) or a variant thereof having up to three amino acid substitutions, additions or deletions. Suitably, the TOR comprises the following CDR sequences: CDR1 a - DSAIYN (SEQ ID NO: 330), CDR2a - IQSSQRE (SEQ ID NO: 331), CDR3a - CAVNRDDKIIF (SEQ ID NO: 332), CDR1P - DFQATT (SEQ ID NO: 335), CDR2P - SNEGSKA (SEQ ID NO: 336), and CDR3P - CSARDYKQVLRGSYNSPLHF (SEQ ID NO: 337), or variants thereof each having up to three amino acid substitutions, additions or deletions. Suitably, the TCR comprises an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 333 or a variant thereof having at least 70% sequence identity thereto; and a p chain variable domain comprising the amino acid sequence of SEQ ID NO: 338 or a variant thereof having at least 70% sequence identity thereto. Suitably, the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 334 or a variant thereof having at least 70% sequence identity thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 339 or 340 or variants thereof having at least 70% sequence identity thereto. Suitably, the PTGFRN peptide comprises or consists of the amino acid sequence of RLASRPLLL (SEQ ID NO: 329) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0052] In some embodiments, the TCR comprises one or more mutations at the a chain / p chain interface, such that when the a chain and the p chain are expressed in a T-cell, the frequency of mispairing between said chains and endogenous TCR a and p chains is reduced. In some embodiments, the TCR comprises one or more mutations at the a chain / p chain interface, such that when the a chain and the p chain are expressed in a T-cell, the level of expression of the TCR a and p chains is increased. In some embodiments, the one or more mutations introduce a cysteine residue into the constant region domain of each of the a chain and the p chain, wherein the cysteine residues are capable of forming a disulphide bond between the a chain and the p chain. In some embodiments, the one or more mutations are at amino acid positions selected from those disclosed in Table 1 of Boulter, J.M et al. (2003) Protein Engineering 16: 707-711.

[0053] In some embodiments, the TCR comprises 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 sites are in the TCR constant domains. In some embodiments, the mutation is a substitution of the amino acid N in an N-X-S / T motif with the amino acid Q. For example, the substitution may occur at one or more of the positions: TCR alpha constant gene position 36, 90 or 109; and / or TCR beta constant gene position 85.6. In some embodiments, the substitution is at position 36 of the TCR alpha constant gene. In some embodiments, the TCR comprises a murinised constant region.

[0054] In some embodiments, the TCR is a soluble TCR.

[0055] In another aspect, the invention provides a polynucleotide encoding the a chain of a T-cell receptor (TCR) according to the invention, and / or the p chain of a TCR according to the invention. In some embodiments, the polynucleotide encodes the a chain linked to the chain. In some embodiments, the polynucleotide further encodes one or more short interfering RNA (siRNA) or other agents capable of reducing or preventing expression of one or more endogenous TCR genes.

[0056] In another aspect, the 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, which encodes one or more CD3 chains, CD8, a suicide gene and / or a selectable marker.

[0057] In another aspect, the invention provides a cell comprising a TCR of the invention, a polynucleotide of the invention or a vector of the invention. In some embodiments, the cell further comprises a vector which encodes one or more CD3 chains, CD8, a suicide gene and / or a selectable marker.

[0058] In one aspect, the invention provides a cell comprising a TCR of the invention, a polynucleotide of the invention or a vector of the invention, and further comprises a vector which encodes CD8. The vector encoding CD8 may be, for example, used when the TCR of the invention is a Cathepsin G-specific TCR. In some embodiments, the vector encodes a CD8 a chain. In some embodiments, the vector encodes a CD8 p chain. In some embodiments, the vector encodes a CD8 a chain and a CD8 p chain. For example, a vector that encodes a CD8 a chain and a CD8 p chain may allow expression of a CD8 op heterodimer.

[0059] The cell of the invention may be any suitable cell. Suitably, the cell is a T-cell, a lymphocyte, or a stem cell. In some embodiment, the 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, ThO cells, TcO cells, Th1 cells, Tc1 cells, Th2 cells, Tc2 cells, Th17 cells, Th22 cells, gamma / delta 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 cell is a T-cell. In some embodiments, the cell is a T- cell which has been isolated from a subject. In some embodiments, an endogenous gene encoding a TCR a chain and / or an endogenous gene encoding a TCR p chain in the cell is disrupted, suitably such that the endogenous gene encoding a TCR a chain and / or the endogenous gene encoding a TCR chain is not expressed. In some embodiments, the endogenous gene encoding a TCR a chain and / or the endogenous gene encoding a TCR p chain is disrupted by insertion of an expression cassette comprising a polynucleotide sequence encoding the TCR of the invention. In some embodiments, one or more endogenous genes encoding an MHC is disrupted, suitably wherein the cell is a non-alloreactive universal T-cell. In some embodiments, an endogenous gene involved in persistence, expansion, activity, resistance to exhaustion / senescence / inhibitory signals, homing capacity, or other T-cell functions is disrupted, suitably wherein the endogenous gene involved in persistence, expansion, activity, resistance to exhaustion / senescence / inhibitory signals, homing capacity, or other T-cell functions is selected from the group consisting of PD1, TIM3, LAG3, 2B4, KLRG1, TGFbR, CD160, TIGIT, CTLA4 and CD39. In some embodiments, the endogenous gene involved in persistence, expansion, activity, resistance to exhaustion / senescence / inhibitory signals, homing capacity, or other T-cell functions is disrupted by integration of an expression cassette, wherein the expression cassette comprises a polynucleotide sequence encoding a TCR of the invention.

[0060] In some embodiments, an endogenous gene encoding a TCR a chain and an endogenous gene encoding a TCR p chain in the cell are disrupted, suitably such that the endogenous gene encoding a TCR a chain and the endogenous gene encoding a TCR p chain are not expressed. In some embodiments, an endogenous gene encoding TIGIT is disrupted, suitably such that the endogenous gene encoding TIGIT is not expressed. In some embodiments, an endogenous gene encoding CD39 is disrupted, suitably such that the endogenous gene encoding CD39 is not expressed.

[0061] In some embodiments, an endogenous gene encoding a TCR a chain, an endogenous gene encoding a TCR p chain, and an endogenous gene encoding TIGIT in the cell are disrupted, suitably such that the endogenous gene encoding a TCR a chain, the endogenous gene encoding a TCR p chain, and the endogenous gene encoding TIGIT are not expressed.

[0062] In some embodiments, an endogenous gene encoding a TCR a chain, an endogenous gene encoding a TCR p chain, and an endogenous gene encoding CD39 in the cell are disrupted, suitably such that the endogenous gene encoding a TCR a chain, the endogenous gene encoding a TCR p chain, and the endogenous gene encoding CD39 are not expressed. In some embodiments, an endogenous gene encoding a TCR a chain, an endogenous gene encoding a TCR chain, an endogenous gene encoding TIGIT, and an endogenous gene encoding CD39 in the cell are disrupted, suitably such that the endogenous gene encoding a TCR a chain, the endogenous gene encoding a TCR chain, the endogenous gene encoding TIGIT, and the endogenous gene encoding CD39 are not expressed.

[0063] In another aspect, the invention provides a T-cell genetically engineered (e.g. genetically edited) to modify the persistence, expansion, activity, resistance to exhaustion / senescence / inhibitory signals, homing capacity or other T-cell functions, wherein the T-cell expresses a TCR a chain of the invention and / or a TCR p chain of the invention.

[0064] In another aspect, the invention provides a T cell genetically engineered (e.g. genetically edited) by a protocol which comprises the step of targeted integration of an expression cassette into an endogenous gene involved in persistence, expansion, activity, resistance to exhaustion / senescence / inhibitory signals, homing capacity or other T-cell functions disrupted by an artificial nuclease, wherein the expression cassette comprises a polynucleotide sequence encoding TCR a chain of the invention and / or a TCR p chain of the invention.

[0065] In another aspect, the invention provides a method of preparing a cell, which comprises the step of introducing the polynucleotide or vector of the invention into a cell in vitro, ex vivo or in vivo, for example by transfection or transduction.

[0066] In another aspect, the invention provides a method of preparing a cell, which comprises the step of transducing a cell in vitro, ex vivo or in vivo with one or more vectors of the invention.

[0067] In some embodiments, the cell to be transduced or transfected is 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 embodiments, the cell to be transduced or transfected is selected from the group consisting of CD4+ cells, CD8+ cells, ThO cells, TcO cells, Th1 cells, Tc1 cells, Th2 cells, Tc2 cells, Th17 cells, Th22 cells, gamma / delta 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.

[0068] In some embodiments, the method of preparing a cell comprises the step of T-cell editing, which comprises disrupting an endogenous gene encoding a TCR a chain and / or an endogenous gene encoding a TCR p 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 CRISPR / Cas systems. In some embodiments, the method of preparing a cell comprises the step of targeted integration of an expression cassette into the endogenous gene encoding the TCR a chain and / or the endogenous gene encoding the TCR p chain disrupted by the artificial nuclease, wherein the expression cassette comprises a polynucleotide sequence encoding the TCR of the invention or a polynucleotide sequence of the invention.

[0069] In some embodiments, the method of preparing a cell comprises the step of disrupting one or more endogenous genes encoding an MHC, suitably wherein the cell prepared by the method is a non-alloreactive universal T-cell.

[0070] In some embodiments, the method of preparing a cell comprises the step of disrupting one or more endogenous genes to modify the persistence, expansion, activity, resistance to exhaustion / senescence / inhibitory signals, homing capacity, or other T-cell functions, optionally wherein the method comprises the step of targeted integration of an expression cassette into an endogenous gene involved in persistence, expansion, activity, resistance to exhaustion / senescence / inhibitory signals, homing capacity, or other T-cell functions disrupted by an artificial nuclease, wherein the expression cassette comprises a polynucleotide sequence encoding the TCR of the invention, suitably wherein the endogenous gene is selected from the group consisting of PD1, TIM3, LAG3, 2B4, KLRG1, TGFbR, CD160, TIGIT, CTLA4 and CD39.

[0071] In some embodiments, the method of preparing a cell comprises a step of disrupting an endogenous gene encoding the TCR a chain and an endogenous gene encoding the TCR p chain. In some embodiments, the method of preparing a cell comprises a step of disrupting an endogenous TIGIT gene. In some embodiments, the method of preparing a cell comprises a step of disrupting an endogenous gene encoding the TCR a chain, an endogenous gene encoding the TCR chain, and an endogenous TIGIT gene. In some embodiments, the method of preparing a cell comprises a step of disrupting the endogenous CD39 gene. In some embodiments, the method of preparing a cell comprises a step of disrupting an endogenous gene encoding the TCR a chain, an endogenous gene encoding the TCR p chain, and an endogenous CD39 gene. In some embodiments, the method of preparing a cell comprises a step of disrupting an endogenous gene encoding the TCR a chain, an endogenous gene encoding the TCR p chain, an endogenous TIGIT gene, and an endogenous CD39 gene.

[0072] In some embodiments, two endogenous genes encoding the TCR p chain (e.g. TRBC1 and TRBC2) are disrupted. In another aspect, the invention provides a chimeric molecule comprising the TCR of the invention, or a portion thereof, conjugated to a non-cellular substrate, a toxin and / or an antibody. In some embodiments, the non-cellular substrate is selected from the group consisting of nanoparticles, exosomes and other non-cellular substrates.

[0073] In another aspect, the invention provides a pharmaceutical composition comprising the TCR of the invention, the polynucleotide of the invention, the vector of the invention, the cell of the invention, a cell prepared by the method of the invention, or the chimeric molecule of the invention.

[0074] In another aspect, the invention provides the cell of the invention or a cell prepared by the method of the invention for use in adoptive cell transfer, suitably adoptive T-cell transfer, optionally wherein the adoptive T-cell transfer is allogenic adoptive T-cell transfer, autologous adoptive T-cell transfer, or universal non-alloreactive adoptive T-cell transfer.

[0075] In another aspect, the invention provides the TCR of the invention, the polynucleotide of the invention, the vector of the invention, the cell of the invention, a cell prepared by the method of the invention, the chimeric molecule of the invention, or the pharmaceutical composition of the invention for use in therapy.

[0076] In another aspect, the invention provides the TCR of the invention, the polynucleotide of the invention, the vector of the invention, the cell of the invention, a cell prepared by the method of the invention, a chimeric molecule of the invention, or a pharmaceutical composition of the invention for use in treating and / or preventing a proliferative disorder.

[0077] In another aspect, the invention provides a method for treating and / or preventing a proliferative disorder, which comprises the step of administering the TCR of the invention, the polynucleotide of the invention, the vector of the invention, the cell of the invention, a cell prepared by the method of the invention, a chimeric molecule of the invention, or a pharmaceutical composition of the invention to a subject in need thereof.

[0078] The proliferative disorder may be a haematological malignancy or a solid tumour. Suitably, the haematological malignancy is selected from the group consisting of acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), lymphoblastic leukaemia, acute lymphocytic leukaemia (ALL), myelodysplastic syndromes, lymphoma, multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma. Suitably, the solid tumour is selected from the group consisting of lung cancer, breast cancer, oesophageal cancer, gastric cancer, colon cancer, cholangiocarcinoma, pancreatic cancer, ovarian cancer, head and neck cancers, synovial sarcoma, angiosarcoma, osteosarcoma, thyroid cancer, oral cancer, hepatocellular carcinoma, bladder cancer, endometrial cancer, neuroblastoma, rabdomyosarcoma, liver cancer, melanoma, prostate cancer, renal cancer, soft tissue sarcoma, urothelial cancer, biliary cancer, glioblastoma, cervical cancer, mesothelioma and colorectal cancer. In some embodiments, the proliferative disorder is acute myeloid leukaemia (AML). In some embodiments, the proliferative disorder is colorectal cancer and / or pancreatic cancer.

[0079] In another aspect, the invention provides an immunogenic Cathepsin G (CTSG) peptide comprising or consisting 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 up to three amino acid substitutions, additions or deletions, or a fragment thereof. Suitably, the fragment has a length of nine amino acids or more. In some embodiments, the fragment is a nonameric fragment.

[0080] In some embodiments, the CTSG peptide comprises or consists of GIVSYGKSSGVPPEV (SEQ ID NO: 58) or a variant thereof having up to three amino acid substitutions, additions or deletions, or a fragment thereof.

[0081] In some embodiments, the CTSG peptide comprises or consists of 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 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 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.

[0082] In some embodiments, the CTSG peptide comprises or consists of TMRSFKLLDQMETPL (SEQ ID NO: 95) or a variant thereof having up to three amino acid substitutions, additions or deletions, or a fragment thereof.

[0083] In another aspect, the invention provides an immunogenic Cyclin A1 (CCNA1) peptide comprising or consisting of an amino acid sequence selected from: TEYAEEIYQYL (SEQ ID NO: 114), PETLAAFTGYSLSEI (SEQ ID NO: 128), AELSLLEADPFLKYL (SEQ ID NO: 153), LLEADPFLKYLPSLI (SEQ ID NO: 527), WEGPGLPDFVF (SEQ ID NO: 172), KRQLLKMEHLLLKVL (SEQ ID NO: 185), PETLAAFTGYSLSEI (SEQ ID NO: 201), and variants thereof each having up to three amino acid substitutions, additions or deletions, or a fragment thereof. Suitably, the fragment has a length of nine amino acids or more. In some embodiments, the fragment is a nonameric fragment.

[0084] In some embodiments, the CCNA1 peptide comprises or consists of TEYAEEIYQYL (SEQ ID NO: 114) 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 amino acid sequence of YAEEIYQYL (SEQ ID NO: 115), EYAEEIYQY (SEQ ID NO: 116), or variants thereof having up to three amino acid substitutions, additions or deletions.

[0085] In some embodiments, the CCNA1 peptide comprises or consists of PETLAAFTGYSLSEI (SEQ ID NO: 128) 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 amino acid sequence of ETLAAFTGY (SEQ ID NO: 129), LAAFTGYSL (SEQ ID NO: 130), or variants thereof having up to three amino acid substitutions, additions or deletions.

[0086] In some embodiments, the CCNA1 peptide comprises or consists of AELSLLEADPFLKYL (SEQ ID NO: 153) 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 LLEADPFLKYLPSLI (SEQ ID NO: 527) 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 amino acid sequence of EADPFLKYL (SEQ ID NO: 154) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0087] In some embodiments, the CCNA1 peptide comprises or consists of 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 amino acid sequence of GPGLPDFVF (SEQ ID NO: 173) or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0088] In some embodiments, the CCNA1 peptide comprises or consists of KRQLLKMEHLLLKVL (SEQ ID NO: 185) 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 amino acid sequence 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 up to three amino acid substitutions, additions or deletions. In some embodiments, the CCNA1 peptide comprises or consists of 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 amino acid sequence of ETLAAFTGY (SEQ ID NO: 202), LAAFTGYSL (SEQ ID NO: 203), or variants thereof having up to three amino acid substitutions, additions or deletions.

[0089] In another aspect, the invention provides a TCR which binds to an immunogenic CTSG peptide when presented by a major histocompatibility complex (MHC), wherein the immunogenic CTSG peptide comprises or consists of SXXXPXVFTRVSSFL (SEQ ID NO: 535) or a variant thereof having up to three amino acid substitutions, additions or deletions, or an immunogenic fragment thereof.

[0090] 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 up to 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 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.

[0091] DESCRIPTION OF DRAWINGS

[0092] Figure 1 - Evaluation of the immune responses in healthy donors’ derived T lymphocytes upon stimulations with 17 HLA-A*02:01 immunogenic peptides.

[0093] T lymphocytes from 2 healthy donors (LAA-HD3 and LAA-HD5) were co-cultured for 6 hours with autologous APCs pulsed with HLA-A*02:01 immunogenic peptides derived from antigens including EZH2, PRAME, PR3 and NE, or with a pool of unrelated peptides. The antigenspecific expansion of T lymphocytes was evaluated through flow cytometry analyses by measuring CD107a production and IFN-y secretion. (A) Results showed for both LAA-HD3 (A, left) and for LAA-HD5 (A, right) a higher production of CD 107a and IFN-y in response to the LAA pool compared to the unrelated one. (B) The clonal expansion of T lymphocytes was evaluated by flow cytometry using a kit covering 70% of the human TCR Vp repertoire. Results showed for LAA-HD3 an expansion of TRBV2; TRBV4-1 ;4-2;4-3 and TRBV28. (C) and (D) LAA-T cells expanded from the two healthy donors were characterized by TCR op sequencing after several stimulations with the peptide pool. Sequencing results indicated the presence of predominant clonotypes for LAA-HD3 (C) and LAA-HD5 (D). Pie charts depict the contribution of the most predominant CDR3 amino acid sequences identified at the last time point (e.g. S4 corresponds to the sequencing results obtained following the 4th round of stimulation) to the TCR repertoire at each stimulation evaluated. The remaining sequences are grouped together in white. HD, healthy donor; S, stimulation; SP, sub-pool; APC, antigen presenting cell; TRBV, T cell receptor p chain variable gene; HD, healthy donor; LAA, leukaemia-associated antigen; Unrelated, pool of unrelated peptides; CDR3, complementarity determining region 3; S, stimulation; TRAV, T cell receptor a chain variable gene; TRAJ, T cell receptor a chain joining gene; TRBJ, T cell receptor chain joining gene; TRBD, T cell receptor p chain diversity gene.

[0094] Figure 2 - Deconvolution of a mapping grid enables the identification of the immunogenic epitopes.

[0095] The sub-pools that were able to induce a T cell-mediated immune response were identified through a 6-hour co-culture of T lymphocytes with autologous irradiated APCs previously pulsed with the 9 SPs containing the 17 immunogenic peptides. Results showed for LAA-HD3 (left) 2 immunogenic SPs (SP3 and SP6) and for LAA-HD5 (right) 3 immunogenic SPs (SP1 , SP2 and SP9). HD, healthy donor; S, stimulation; SP, sub-pool; APC, antigen presenting cell.

[0096] Figure 3 - Evaluation of the CTSG-specific T cells enrichment from HDs.

[0097] (A) T cells isolated from 2 HDs (CTSG-HD1 , CTSG-HD2) were co-cultured for 6 hours with autologous APCs pulsed with a CTSG peptide pool or with a pool of unrelated peptides. The occurrence of a CTSG-specific response was determined by measuring CD107a expression and IFNy secretion in T cells. Results show for HD1 (left) an enrichment of CTSG-specific lymphocytes overtime and for HD2 (right) the presence of a 10-15% of CTSG-specific T cells in the culture already upon 3 stimulations with the peptide pool. (B) Characterization of the Vp repertoire. The clonal expansion of T cells specific for CTSG isolated from HD1 was evaluated by flow cytometry. Results show the predominant expression of 3 Vp in HD1 (TRBV4-3, TRBV9 e TRBV27). (C) Identification of the immunogenic SPs for each HD. SPs inducing an immune response in each HD analysed were identified by co-culturing T cells with autologous APCs pulsed with each of the 16 CTSG SPs. Results identified SP5, 6 8, 12 and 15 for HD1 (C, left) and SP5 and 16 for HD2 (C, right). By deconvoluting a mapping grid (C, tables at the bottom), peptides 29, 30, 32, 53, 54 and 56 have been identified as potential target of HD1 (left) and peptide 61 for HD2 (right). (D) To confirm the immunogenicity of the identified peptides, a 6-hour co-culture of T cells with APCs pulsed with the individual peptides was performed. Results show an increased response of CTSG-HD1 T cells towards peptides P54 and P56. HD, healthy donor; HLA, human leukocyte antigen; EBV-BLCL, Epstein Barr virus- transformed B-lymphoblastoid cell line; CG, Cathepsin G; P, peptide; unr, unrelated peptide. Figure 4 - HLA restriction of CTSG-HD1 T lymphocytes.

[0098] (A) Table showing the EBV cell lines employed to identify the HLA restriction of the CTSG- HD1 T cells. HLA elements harboured by the EBV cells and shared with HD1 are in bold. (B) T lymphocytes from CTSG-HD1 were co-cultured with EBV-BLCLs having one restriction element in common with HD1 and pulsed with P54, P56 or with an unrelated peptide. IFNy production was observed for the EBV-BLCL#1 when T cells were in culture with APCs pulsed with P54 (left) and for EBV-BLCLs #2, #4 and #5, suggesting T cells recognized P54 when presented on the HLA-A*02:01 allele and P56 (right) when presented on the HLA-A*24:02 and the HLA-C*07:02 restriction elements. HLA, human leukocyte antigen; EBV-BLCL, Epstein Barr virus-transformed B-lymphoblastoid cell line; CG, Cathepsin G; P56, peptide 56; unrel, unrelated peptide; CTSG-HD1 , Cathepsin G-healthy donor 1.

[0099] Figure 5 - Longitudinal TCR sequencing of enriched CTSG-specific T cells.

[0100] T cells generated from the two healthy donors included in the experimental setting were characterized by TCR ap sequencing after several stimulations with the CTSG pool. Sequencing results indicated the presence of predominant clonotypes for CTSG-HD1 (A,B) and CTSG-HD2 (C). For HD1 , we identified 2 expanded T cell populations specifically recognizing P54 (A) or P56 (B) of the peptide pool. Pie charts depict the contribution of the most predominant CDR3 amino acid sequences identified at the last time point (e.g. S8 corresponds to the sequencing results obtained following the 8th round of stimulation) to the TCR repertoire at each stimulation evaluated. The remaining sequences are grouped together in white. CDR3, complementarity determining region 3; S, stimulation; TRAV, T cell receptor a chain variable gene; TRBV, T-cell receptor chain variable gene; TRAJ, T cell receptor a chain joining gene; TRBJ, T cell receptor p chain joining gene; TRBD, T cell receptor p chain diversity gene.

[0101] Figure 6 - Generation and functional validation of T cells specific for P56 through the TCR gene transfer and the TCR gene editing approaches.

[0102] (A) Disruption of the endogenous TCR repertoire in edited T cells and CTSG-P56 TCR expression was evaluated by measuring CD3 surface expression in T cells not transduced or transduced with the LV, respectively. (B) T cell functionality was evaluated by measuring CD107a expression and IFNy secretion in T cells upon 6-hour co-culture with EBV cell lines expressing either the HLA-A*24:02 (EBV-BLCL#6) or the HLA-C*07:02 (EBV-BLCL#5) allele and pulsed with the P56. Either transfer or TCR edited cells were used as effector cells in the assay. (C) Phenotypic characterization of the edited T cells in terms of efficiency of TCR disruption (C, left), expression of the P56-TCR specific Vp region (C, middle) and memory phenotype (C, right). HLA, human leukocyte antigen; EBV-BLCL, Epstein Barr virus- transformed B-lymphoblastoid cell line; CTSG, Cathepsin G; P56, peptide 56; unrel, unrelated peptide; TRBV, T cell receptor p chain variable gene; TSCM, memory stem T cells; TCM, central memory T cells; TEMRA, terminally differentiated effector memory T cells; TEM, effector memory T cells; KO, knockout.

[0103] Figure 7 - P56ap edited T cells recognized the VFT nonamer on the HLA-A*24:02 allele, while showing no nonamer recognition on the HLA-C*07:02 restriction element.

[0104] (A) We predicted the binding affinity of P56-derived nonamers to the HLA-A*24:02 and the HLA-C*07:02 alleles using an online tool. The tool predicted a weak binding affinity for the VFTRVSSFL (SEQ ID NO: 82) nonamer presented by the HLA-A*24:02 molecule (left) and a weak binding affinity of the same peptide presented by the HLA-C*07:02 that however was predicted to be bound with a higher affinity by the EVFTRVSSF (SEQ ID NO: 42)) nonamer (right). (B) Edited P56ap T cells were co-cultured for 6 hours with EBV-BLCLs expressing the HLA-A*24:02 or the HLA-C*07:02 restriction elements and pulsed with the P56-derived nonamers and the decamer. CD107a production in T lymphocytes was only observed in response to the P7 nonamer (VFTRVSSFL - SEQ ID NO: 82) when presented by the HLA- A*24:02 molecule. (C) Edited P56a T cells were co-cultured with the EBV-BLCL expressing the HLA-C*07:02 allele and pulsed with P56, P56-derived nonamers and the decamer. After 6 hours, CD107a production was high when T lymphocytes were co-cultured with P56-pulsed EBV cells. (D) Co-culture of edited P56a T lymphocytes with the HLA-C*07:02 EBV-BLCL pulsed with P12, P13 and P56. After 6 hours, CD107a expression and cytokine secretion were assessed, and results showed increased percentages upon co-culture with P13 and P56. (E) In order to determine the affinity profiles of P13 and P56 to the HLA-C*07:02 allele, the EBV- BLCL expressing the HLA-C*07:02 allele was pulsed with either P13 or P56 alone or in combination with a high-affinity HLA-C*07:02 binding peptide (RYRPGTVAL - SEQ ID NO: 423) and co-cultured for 6 hours with edited P56 TCR T cells. Comparable CD107a expression and cytokines secretion were detected in the condition of P13 and P56 alone and in the condition in which the competitor was present. %Rank, percentage of rank; 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; P56ap, edited T lymphocytes transduced with the LV encoding for the P56ap TCR; EBV-BLCL, Epstein Barr virus- transformed B-lymphoblastoid cell line; 15mer, 15-aa long peptide; APC, antigen presenting cell; P12, a 12-aa long peptide derived from peptide 56; P13, a 13-aa long peptide derived from peptide 56; CTR, the high-affinity HLA-C*07:02 binding peptide (RYRPGTVAL). Figure 8 - Determination of P56ap TCR avidity in recognizing the cognate peptides on target cells.

[0105] (A) P56 TCRap edited T lymphocytes were co-cultured with the HLA-A*24:02 EBV-BLCL pulsed with decreasing concentrations of the P7 nonamer (A, top) and with the HLA-C*07:02 EBV-BLCL pulsed with decreasing concentrations of P13 (A, middle) and P56 (A, bottom). CD107a expression and cytokines secretion was evaluated as readout by flow cytometry analysis. (B) The Log EC50 values show a low avidity profile of P56 TCRap for the P7 nonamer; a higher avidity for P13 but the highest is for P56. Unstimulated, T cells kept without the addition of target cells; PMA / lono, PMA and lonomycin positive control; P7, P7 nonamer; P13, a 13-aa long peptide derived from peptide 56; TCR, T cell receptor; EBV-BLCL, Epstein Barr virus-transformed B-lymphoblastoid cell line; EC50, effector concentration 50.

[0106] Figure 9 - Evaluation of the natural processing of the immunogenic epitopes derived from peptide 56 on the surface of primary leukemic blasts expressing only the HLA- A*24:02 allele or the HLA-C*07:02 allele.

[0107] (A-B) Edited P56 TCRap T lymphocytes were co-cultured for 24 hours with: (A) pAML1 and pAML2 (expressing only the HLA-A*24:02 allele); (B) pAML3, pAML4 and pAML5 (expressing only the HLA-C*07:02 allele); and (A and B) pAML6 and pAML7 (negative for both the HLA- A*24:02 and the HLA-C*07:02 alleles) as a negative control. T lymphocytes and leukemic blasts were plated at different E:T ratios (5:1 ; 1 :1 ; 1 :5). As an additional negative control, the corresponding number of leukemic cells used in the different E:T ratios was also plated in the absence of T lymphocytes. The elimination index of AML blasts was calculated by using the following formula: 1 -((Count of leukemic cells at the different E:T ratios (5: 1 ; 1 : 1 ; 1 :5) ) / (Count of the same leukemic cells alone)). A value of 0 indicates no elimination of leukemic cells while a value of 1 indicates a complete elimination of leukemic cells. Results are presented as the standard error of the mean (SEM) (N=3). pAML, primary acute myeloid leukaemia.

[0108] Figure 10 - Evaluation of the Cyclin A1 -specific T cell enrichment from HDs.

[0109] (A-C) T cells isolated from 3 HDs (Cyclin A1-HD1 , Cyclin A1-HD2, Cyclin A1-HD3) were co- cultured for 6 hours with autologous APCs pulsed with a Cyclin A1 peptide pool or with a pool of unrelated peptides. The occurrence of a Cyclin A1 -specific response was determined by measuring CD107a expression and IFNy secretion in T cells. Results show for HD1 (A) an enrichment of tumour-specific CD8+ and CD4+ T lymphocytes, for HD2 (B) the enrichment of 50% of Cyclin A1-specific T cells and for HD3 (C) a progressive enrichment of Cyclin Al- specific T cells. HD, healthy donor. Figure 11 - Identification of the peptide sub-pools eliciting the T cell response.

[0110] Identification of the immunogenic SPs for each HD. SPs inducing an immune response in each HD analysed have been identified by co-culturing T cells with autologous APCs pulsed with each of the 22 Cyclin A1 SPs. (A) For HD1 , results identify SP4, 5, 6, 8, 9, 10, 12, 16, 18, 20, for the CD8+ T cells of HD1 (A, top) and SP3 and 21 for the CD4+ T cells of HD1 (A, bottom). (B) For Cyclin A1 HD2 T cells, we observed an immune response towards SP3, 4, and 21. (C) For HD3 Cyclin A1 T cells we observed a minor, but still appreciable, immune response towards SP3 and 21.

[0111] Figure 12 - Assessment of the immunogenic peptides.

[0112] To confirm the immunogenicity of the identified peptides, a 6-hour co-culture of T cells with APCs pulsed with the individual peptides was performed. Results have confirmed the recognition of P102 and P52-P53 by CD4+ (A) and CD8+ (B) Cyclin A1-HD1 T cells, respectively. T cells from sub-culture SP12 were co-cultured with the SP12 and with the individual peptides belonging to the SP (P4, P5, P6, P7, P10). The analysis showed the recognition of P6 and P7 (C). T cells from the sub-culture SP20, were co-cultured with the SP20 and with the individual peptides belonging to the SP (P92, P93, P94, P95, P98). The analysis showed the recognition of P93 and P94 (D). (E) As P52 and P53 are overlapping peptides, to identify the exact nonamer recognized by HD1 T cells, we performed a co-culture of T cells with APCs pulsed with P52, P53, the overlapping 11mer sequence and the 3 individual nonamers derived from the 11mer portion (TEY, EYA, YAE). Results of the functional assay showed CD107a expression and IFNg secretion when T cells were co- cultured with APCs pulsed with the YAE nonamer. (F) For Cyclin A1-HD2 T cells, we confirmed recognition of SP19 and in particular we identified the immunogenic peptide P81. (G) For Cyclin A1-HD3 T cells, we identified peptide P102 as the one eliciting the immune response. HD, healthy donor; SP, sub-pool; P, peptide.

[0113] Figure 13 - HLA restriction of Cyclin A1 -specific T lymphocytes.

[0114] Tables showing the EBV cell lines employed to identify the HLA restriction of the Cyclin A1- HD2 and HD3 T cells (A and B, left panels). HLA elements harboured by the EBV cells and shared with HD2 and HD3 are highlighted. T lymphocytes from Cyclin A1-HD2 T cells were co-cultured with EBV-BLCLs having one restriction element in common with HD2 and pulsed with P81 or with an unrelated peptide. IFNy production and CD107a secretion was observed for the EBV-BLCL#3 and #7 pulsed with P81 (A, right). For Cyclin A1-HD3, we observed recognition of both EBV cell lines used for the assay (B, right). HLA, human leukocyte antigen; EBV-BLCL, Epstein Barr virus-transformed B-lymphoblastoid cell line; P81 , peptide 81 ; unrel, unrelated peptide; HD, healthy donor.

[0115] Figure 14 - Cytof I uori metric immunoprofiling of the T cell populations.

[0116] Characterization of the Vp repertoire. (A) The clonal expansion of T cells specific for Cyclin A1 isolated from HD1 , 2 and 3 was evaluated by flow cytometry. For HD1 T cells, we performed the analysis after 5 and 7 stimulations, clearly observing which Vp got enriched overtime and can thus be considered specific for the epitope recognition. For HD2 (B) and HD3 (C) T cells, we observed the clear expansion of 1 V beta chain for HD2 and 2 V beta chains for HD3. TRBV, T cell receptor variable region of the beta chain.

[0117] Figure 15 - Longitudinal TCR sequencing of enriched Cyclin A1 -specific T cells.

[0118] T cells generated from the three healthy donors included in the experimental setting were characterized by TCR op sequencing after several stimulations with the Cyclin A1 pool. Sequencing results indicated the presence of predominant clonotypes for the different subcultures derived from HD1 (A-E), HD2 (F) and HD3 (G). Pie charts depict in shades of grey the contribution of the most predominant CDR3 amino acid sequences identified at the last time point (e.g. S8 corresponds to the sequencing results obtained following the 8th round of stimulation) to the TCR repertoire at each stimulation evaluated. The remaining sequences are grouped together in white. CDR3, complementarity determining region 3; S, stimulation; TRAV, T cell receptor a chain variable gene; TRBV, T-cell receptor p chain variable gene; TRAJ, T cell receptor a chain joining gene; TRBJ, T cell receptor p chain joining gene; TRBD, T cell receptor p chain diversity gene.

[0119] Figure 16 - Generation and functional validation of T cells specific for Cyclin A1 through the TCR gene transfer and the TCR gene editing approaches.

[0120] (A) Disruption of the endogenous TCR repertoire in edited T cells and expression of the different isolated TCRs was evaluated by measuring surface expression of CD3 and of the specific p in T cells not transduced or transduced with the LV, respectively (B, C). (D) Transgenic T cell functionality was evaluated by measuring CD107a expression and IFNy secretion in CD8+ and CD4+ T cells upon 6-hour co-culture with autologous target cells pulsed with the specific peptides or with an unrelated one. Either transfer or TCR edited cells were used as effector cells in the assay. P, peptide; SP, sub-pool; UT, untransduced; ED, edited; TR, transfer.

[0121] Figure 17 - HLA restriction of Cyclin A1 -specific T lymphocytes. (A) Table showing the EBV cell lines employed to identify the HLA restriction of the Cyclin A1- HD1 T cell subcultures specific for P102 and P52 / P53. HLA elements harboured by the EBV cells and shared with HD1 are highlighted. IFNy production and CD107a secretion was observed for the EBV-BLCL#9 pulsed with P52 / P53 (left), thus indicating that the restriction element of P52 / 53 TCR is HLA-B*35:02, and for EBV-BLCL#12 pulsed with P102 (right), thus indicating that the restriction element of P102 TCR is either the HLA-DRB1*07:01 or the HLA- DQB1*02:02. (B) We confirmed the results by performing the functional assay only employing as target cells the EBV cell lines that were recognized in the first assay and as effector cells transgenic T cells generated either with the TCR transfer or the TCR gene editing protocol. Both TCRs were able to activate CD4 as well as CD8 T cells. HLA, human leukocyte antigen; EBV-BLCL, Epstein Barr virus-transformed B-lymphoblastoid cell line; P, peptide; unr, unrelated peptide; HD, healthy donor.

[0122] Figure 18 - T cells engineered to express the TCR specific for a nonamer of P52 / P53 peptides eliminate primary leukemic blasts.

[0123] Cytofluorimetric evaluation of target cell killing as measured by determining the activation of Caspase 3 upon co-culture with edited T cells. Blasts derived from AML1 express the HLA- DRB1*07:01 and the HLA-DQB1*02:02 allele, while blasts of AML2 express the HLA-B*35:02 allele. ED, edited; P, peptide, AML, acute myeloid leukaemia.

[0124] Figure 19 - Tumour-specific T cell expansion from peripheral blood mononuclear cells

[0125] The frequency of CD107a, IFN-y, TNF-a and IL-2 - positive cells is shown in T cells cocultured for 6 hours with autologous APCs loaded with unrelated peptides or with (A) PDAC- or (B) CRC-specific peptide pools after subsequent rounds of stimulation.

[0126] Figure 20 - Identification of the tumour immunogenic peptides

[0127] The frequency of CD107a, IFN-y, TNF-a and IL-2 - positive cells is shown in T cells cocultured for 6 hours with autologous APCs loaded with the individual peptide sub-pools for PDAC (A-C, left panels) and CRC (D,E, left panels). The mapping grid defines sub-pools of peptides, with each peptide being present only in two intersecting sub-pools. Peptide-specific recognition was con-firmed upon co-culture with peptide-pulsed autologous APCs or T2 cell line (A-E, right panels).

[0128] Figure 21 - Clonal tracking of tumour-specific T cells

[0129] T cells generated were characterized by TCR a sequencing after several stimulations with the PDAC or CRC pool. Sequencing results indicated the presence of predominant clonotypes for every T cell culture analysed. Pie charts depict the contribution of the most predominant CDR3 amino acid sequences identified at the last time point (e.g. S8 corresponds to the sequencing results obtained following the 8th round of stimulation) to the TCR repertoire at each stimulation evaluated. 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) TACC2 TCR; (I) PTGFRN TCR. CDR3, complementarity determining region 3; S, stimulation; TRAV, T cell receptor a chain variable gene; TRBV, T- cell receptor p chain variable gene; TRAJ, T cell receptor a chain joining gene; TRBJ, T cell receptor chain joining gene; TRBD, T cell receptor p chain diversity gene.

[0130] Figure 22 - Expanded HER2-specific T cells recognize and eliminate HER2+HLA- A2+cancer cell lines and patient-derived organoids in vitro

[0131] (A) HER2-transgenic T cells (n=3) were co-cultured with HLA-A0201+ PDAC cell lines (PANC1 , BxPCR-A2+, T3M4) for 24 hours in a 5:1 effector to target ratio. Killing is represented as area (pm2) covered by cells undergoing apoptosis (caspase 3 / 7 activation) overtime. (B) HER2-trangenic T cells (n=5) were co-cultured with luciferase+ HLA-A0201+ PDAC cell lines (PANC1 , T3M4 and BxPC3-A2+) and a HLA-A0201- one (BxPC3-A2-) as control for 24 hours in a 1 :1 effector to target ratio. Specific killing was evaluated by measuring luciferase activity 24 hours after the co-culture. Elimination index is calculated as [1- (luciferase activity of target cell lines with T cells / luciferase activity of target cell lines alone)]. (C) HER2-transgenic T cells (n=3) were co-cultured with colorectal cancer organoids derived from 1 patient (PDO) for 48 hours in a 5:1 effector to target ratio. Killing is represented as area (pm2) covered by cells undergoing apoptosis (caspase 3 / 7 activation). (D) Timeline of the in vivo experiment. Luciferated PDOs were transplanted intrahepatically. After 3 days T cells were injected intrahepatically and at day 10 a second administration of T cells was delivered intravenously. Bioluminescence evaluation of tumour growth (E). Data are represented as mean ± SD. Statistical significance was assessed by linear regression curves fitting the observed results (A,C) or two-way ANOVA (B,E).***, P<0.001 and ****, P0.0001.

[0132] Figure 23 - Expanded MSLN-specific T cells recognize and kill Ag+HLA-A0201+ cancer cell lines and patient-derived organoids in vitro

[0133] (A) MSLN-transgenic T cells (n=3) were co-cultured with a HLA-A0201+ PDAC cell lines (PANC1) for 24 hours in a 5:1 effector to target ratio. Killing is represented as area (pm2) covered by target cells undergoing apoptosis (Caspase 3 / 7 activation) overtime. (B) MSLN- transgenic T cells (n=3) were co-cultured with a HLA unmatched PDAC cell line (BxPC3) as control for 24 hours in a 5:1 effector to target ratio. Killing is represented as area (pm2) covered by cells undergoing apoptosis (Caspase 3 / 7 activation) overtime. (C) MSLN-transgenic T cells (n=3) were co-cultured for 50h with patient-derived colorectal cancer organoids derived from 1 primary tumour (left) at 5:1 effector-to-target ratio and 1 liver metastases at 10:1 effector-to- target ratio (right). Data are normalized on the first useful time point and represented as mean ± SEM. Statistical significance was assessed by linear regression curves fitting the observed results. *P<0.05 ** P<0.01 *** P<0.001 and **** P<0.0001

[0134] Figure 24 - Expanded DKK1 -specific T cells recognize and kill Ag+HLA-A0201+ cancer cell lines and patient-derived organoids in vitro

[0135] (A) DKK1 -transgenic T cells (n=3) were co-cultured with a HLA-A0201+ PDAC cell lines (PANC1) for 24 hours in a 5:1 effector to target ratio. Killing is represented as area (pm2) covered by target cells undergoing apoptosis (Caspase 3 / 7 activation) overtime. (B) DKK1- trangenic T cells (n=3) were co-cultured with a HLA unmatched PDAC cell line (BxPC3) as control for 24 hours in a 5:1 effector to target ratio. Killing is represented as area (pm2) covered by cells undergoing apoptosis (Caspase 3 / 7 activation) overtime. (C) DKK1 -transgenic T cells (n=3) were co-cultured for 50h with patient-derived colorectal cancer organoids derived from 1 primary tumour (left) at 5:1 effector-to-target ratio and 1 liver metastases at 10:1 effector-to- target ratio (right). Data on the first useful time point and are represented as mean ± SEM. Statistical significance was assessed by linear regression curves fitting the observed results. *P<0.05 ** P<0.01 *** P<0.001 and **** P<0.0001

[0136] Figure 25 - Expanded AGR2-specific T cells recognize and kill Ag+HLA-A0201+ cancer cell lines and patient-derived organoids in vitro

[0137] (A) AGR2-transgenic T cells (n=3) were co-cultured with a HLA-A0201+ PDAC cell lines (PANC1) for 24 hours in a 5:1 effector to target ratio. Killing is represented as area (pm2) covered by target cells undergoing apoptosis (Caspase 3 / 7 activation) overtime. (B) AGR2- trangenic T cells (n=3) were co-cultured with a HLA unmatched PDAC cell line (BxPC3) as control for 24 hours in a 5:1 effector to target ratio. Killing is represented as area (pm2) covered by cells undergoing apoptosis (Caspase 3 / 7 activation) overtime. (C) AGR2-transgenic T cells (n=3) were co-cultured for 50h with patient-derived colorectal cancer organoids derived from 1 primary tumour (left) at 5:1 effector-to-target ratio and 1 liver metastases at 10:1 effector-to- target ratio (right). Data on the first useful time point and are represented as mean ± SEM. Statistical significance was assessed by linear regression curves fitting the observed results. *P<0.05 ** P<0.01 *** P<0.001 and **** P<0.0001.

[0138] Figure 26 - PR3-TCR engineered T cell cytotoxic activity against HLA-A*02:01 + antigen-expressing leukemic cells. (A) Transduction efficiency measured as percentage of cells expressing on the surface the CD3 as a surrogate marker for TCR expression (left) and memory phenotype of the edited lymphocytes. (B) Degranulation ability and cytokine secretion in engineered T cells upon coculture with HLA-A*02:01+ peptide-pulsed T2 cells. (C) The bar plots illustrate the killing efficiency of engineered T cells when co-cultured with leukemia cell lines (K562 and THP1), measured by determining the elimination index calculated as follows: [1- (target cells in co- culture / target cells in monoculture)]. The graphed data represents the mean ± SEM of 6 biological replicates for K562 Tg dataset and mean ± SEM of 5 biological replicates for THP1 dataset. (D) Killing assay performed on TCR-edited T cells cultured for 24 hours with HLA- A*02:01+ blasts (pAML 8 and 9) or pAMLIO as control (HLA-A*02:01-). Notably, in pAML 9, at both 1 :1 and 1 :5 ratios, an increase in the elimination index was observed compared to H LA-unmatched pAML 10. Data are presented as bar plots, depicting the mean ± SEM of three biological replicates. Memory subsets are defined as follows: TSCM (CD45RA+CD62L+CD95+), TCM (CD45RA-CD62L+), TEM (CD45RA-CD62L-), TEMRA (CD45+CD62L-). PR3, Proteinase 3; HLA, human leukocyte antigen; unrel, unrelated; CM, central memory; SCM, stem cell memory; EM, effector memory; EMRA, terminally differentiated effector memory; E:T, effector to target; pAML, primary acute myeloid leukemia cells; interleukin-2 (IL-2), tumor necrosis factor a (TNF-a), and interferon y (IFN-y).

[0139] Figure 27 - CTSG TCR-transduced T cells recognize target cells in a CD8 co-receptor dependent manner.

[0140] A) Co-culture of engineered T cells with peptide-pulsed HLA-A*24:02+ or HLA-C*07:02+ cells indicate that CD8+ TCR-expressing lymphocytes are capable to efficiently recognize target cells (shown both in terms of degranulation and of T cell activation status). B) Experimental setting employed to improve cell activity by exogenously adding the CD8 co-receptor. Briefly, upon disruption of the endogenous TCR repertoire, naked T cells are at first transduced with the LV encoding for the CTSG-TCR chains and afterwards co-transduced with a lentiviral vector (LV) encoding for the CD8ap chains. C) Upon co-transduction with the CD8-encoding LV, double transduced CD4+CD8+ CTSG-TCR expressing T cells could efficiently recognize peptide-pulsed HLA- A*24:02+ or HLA-C*07:02+ EBV-BLCLs, as compared to the CD4+ TCR- expressing T lymphocytes. Data are presented as bar plots, depicting the mean ± SEM of three biological replicates. CTSG or CG, Cathepsin G; HLA, human leukocyte antigen; unrel, unrelated; EBV-BLCLs, Epstein Barr Virus-transformed B Lymphoblastoid Cell lines.

[0141] Figure 28 - Manufacturing of CTSG-TCR T cells. A) Experimental layout employed to engineer T cells either expressing the CTSG-TCR alone (CTSG-TCR T cells) or in combination with the CD8 co-receptor (CTSG-TCR+CD8 T cells). Upon TCR gene editing, T cells were expanded employing the G-Rex cell culture plates. B) Editing efficiency (left panel), memory phenotype (middle panel) and CD4 / CD8 subset composition (right panel) of the engineered T cell products. C) In vitro evaluation of T cell specificity upon co-culture with peptide-pulsed HLA-A*24:02+ or HLA-C*07:02+ EBV-BLCLs. Results obtained with the G-Rex expanded T cells recapitulated the ability of the lymphocytes to recognize target cells in a H LA-specific manner and the increased capability of double transduced CD4+CD8+ TCR+ T cells (CTSG-TCR CD4+CD8+ T cells) to degranulate (upper panels) and get activated (lower panels) when compared to the single transduced CD4+ TCR+ lymphocytes (CTSG-TCR CD4+ T cells). Data are presented as bar plots, depicting the mean ± SEM of three biological replicates. Memory subsets are defined as follows: TSCM (CD45RA+CD62L+CD95+), TCM (CD45RA-CD62L+), TEM (CD45RA-CD62L-), TEMRA (CD45+CD62L-). CTSG or CG, Cathepsin G; HLA, human leukocyte antigen; unrel, unrelated; CM, central memory; SCM, stem cell memory; EM, effector memory; EMRA, terminally differentiated effector memory; EBV-BLCLs, Epstein Barr Virus-transformed B Lymphoblastoid Cell lines.

[0142] Figure 29 - Engineered T cells persist and expand in leukemia-bearing mice.

[0143] A) Study design of the in vivo testing. Timeline of the AML in vivo model. On day -3, mice received intravenous infusion of 1.5-2x106pAML blasts, followed by the infusion of 10x106CTSG-TCR expressing edited T cells at day 0. Longitudinal monitoring of T cell and leukemia kinetics was weekly evaluated by retro-orbital blood collection. The schematic representation depicts two mice groups differing for the infused leukemia. The first group (upper graphs) was infused with HLA-A*24:02+ blasts, where n=6 mice were treated with CTSG-TCR + CD8 transduced T cells and 4 mice were left untreated. The second group (lower graphs) was infused with HLA-C*07:02+ leukemic blasts. In this group, nine mice were left untreated, while n=11 and n=7 were injected with CTSG-TCR specific T cells co-transduced or not with the CD8 construct, respectively. At sacrifice, tongue, ears, spleen and bone marrow, as well as peripheral blood, were collected. B) Persistence of TCR-T cells in the peripheral circulation of treated mice. HLA-A*24:02+ AML-bearing mice infused with CTSG TCR+CD8 T cells (left panel; graphed data are represented as mean ± SEM of six biological replicates) and HLA- C*07:02 + AML-bearing mice infused with CTSG TCR+CD8 T cells or CTSG TCR alone (right panel; graphed data are represented as mean ± SEM of eleven biological replicates for the CTSG+CD8 subgroup and seven biological replicates for CTSG subgroup). C and D) CD4 / CD8 subset composition (C) and memory phenotype (D) of the engineered T cell products employed for treating mice infused with HLA-A*24:02+ (left panel) and HLA- C*07:02+ (right panels: upper graph represents CTSG-TCR+CD8 T cells while the graph on the bottom represents CTSG-TCR T cells). Memory subsets are defined as follows: TSCM (CD45RA+CD62L+CD95+), TCM (CD45RA-CD62L+), TEM (CD45RA-CD62L-), TEMRA (CD45+CD62L-). CTSG or CG, Cathepsin G; HLA, human leukocyte antigen; pAML, primary acute myeloid leukemia cells.

[0144] Figure 30 - In vivo evaluation of T cell anti-tumor efficacy.

[0145] A) AML outgrowth during the experimental time measured as primary leukemic blast count / pl. Left panel indicates the leukemic burden in HLA-A*24:02+ AML-bearing mice untreated or infused with CTSG TCR+CD8 T cells (graphed data are represented as mean ± SEM of six biological replicates in treated group and four for the control group). Right panel indicates the leukemic burden in HLA-C*07:02+ AML-bearing mice untreated or infused with CTSG TCR+CD8 T cells and CTSG TCR T cells (data are represented as mean ± SEM of seven biological replicates for the CTSG subgroup eleven for the CTSG+CD8 subgroup, and nine for the control group. B) Graphs depicting the percentage of blasts present in bone marrow and spleen samples at the time of sacrifice. Results demonstrated the effectiveness of CTSG- TCR T cells, as well as CTSG-TCR+CD8 engineered T cells, in reducing tumor outgrowth. Conversely, tumor expansion was observed in untreated mice for both leukemias. Data are presented as mean ± SEM of six biological replicates for CTSG+CD8 subgroup and of four biological replicates for the HLA-A*24:02+ pAML control group (left graph) and of seven biological replicates for the CTSG subgroup, eleven for the CTSG+CD8 subgroup, and five for the HLA-C*07:02+ pAML control group (right graph). C) The graph displays CD3+ kinetics over time in HLA-C*07:02+ bearing mice treated with CTSG+CD8 engineered T cells. This result highlights a poor T cell engraftment over time in mouse 17 and mouse 18 compared to the rest of the mice (dataset CTSG+CD8), thus likely explaining the reduced control of leukemic burden in mice bone marrow. In fact, mouse 17 and mouse 18 represent two mice in which the CTSG+CD8 edited T cell treatment apparently did not efficiently control leukemia growth (as shown by the triangle and the square in the %blasts in the bone marrow in B middle graph). Data for the CTSG+CD8 subgroup are represented as mean ± SEM of nine biological replicates. D) The graphs depict the body weight variation for each mouse (each line represents a mouse), calculated as [(body weight at each time point I basal body weight before T cell infusion) x 100] at various time points during the in vivo investigation. Left panels depict the results of mice infused with HLA-A*24:02+ leukemic blasts that were not treated (upper graph) and n=6 mice treated with CTSG TCR+CD8 T cells (lower graph). Right panels represent the body weight trends of HLA-C*07:02+ bearing mice: n=9 untreated mice (upper graph); n=11 mice infused with CTSG TCR+CD8 T cells (middle graph); and n=7 mice infused with CTSG TCR T cells (lower graph).

[0146] Statistical significance was evaluated through a two-way ANOVA multiple comparison test, and the obtained p-values are noted as ****p<0,0001. CTSG, Cathepsin G; HLA, human leukocyte antigen.

[0147] Figure 31 - Ex vivo retrieved TCR T cells retain their specificity and functionality.

[0148] Lymphocytes harvested from the spleen of selected mice infused with HLA-A*24:02+ or HLA- C*07:02+ pAMLs and treated with the engineered T cell products or CTSG-TCR+CD8 T cells) were tested for their functionality in vitro by measuring their degranulation capability (left panels) and their activation status (right panels). Number of biological replicates is reported in the figure. CTSG, Cathepsin G; HLA, human leukocyte antigen; EBV-BLCLs, Epstein Barr Virus-transformed B Lymphoblastoid Cell lines; pAML, primary acute myeloid leukemia cells.

[0149] Figure 32 - Phenotype of engineered Cyclin A1 -specific TCR T cells.

[0150] A) Bar plots showing within the alive T cell populations the CD3 surface expression (%), used as a surrogate of TCR complex presentation. Results showed a nearly complete knockout efficiency, as measured in edited LV not transduced (CTR) T cells and a high transduction efficiency, as measured in LV transduced T cells. T edited cells for each Cyclin A1 epitope are named TCRPYAE, TCRSPIS, TCRP2. Data are represented as mean ± SEM of 6 biological replicates. B) Bar plots showing the memory subsets within the CD3+ edited T cells: TSCM (CD45RA+CD62L+CD95+), TCM (CD45RA-CD62L+), TEM (CD45RA-CD62L-), TEMRA (CD45+CD62L-). Data are represented as mean ± SEM of 6 biological replicates.

[0151] Figure 33 - SP18-specific TCR engineered T cells recognize P75 epitope when presented on the HLA-C*04:01 allele.

[0152] A) Bar plots representing CD107a expression in CD3+ T cells after co-culture with SP18- pulsed (related) EBV-BLCLs (represented by distinct filling patterns) that share at least one HLA-restriction with the donor’s T cells from which the tumor-specific T cell clone was isolated. EBV-BLCLs pulsed with an unrelated peptide were included as negative controls. Data depict the mean ± SEM of three biological replicates, p values were determined with two-away ANOVA multiple comparison test: *p<0,05. B) Bar plots depict the intracellular accumulation of cytokines associated with CD8+ T cell activation: interleukin-2 (IL-2), tumor necrosis factor a (TNF-a), and interferon y (IFN-y). T cells were exposed to HLA-A*33:01 , and HLA-C*04:01 EBV-BLCLs pulsed with either the subpool 18 (SP18) or an unrelated peptide. Data represent the mean ± SEM of 3 biological replicates. C-D) Bar plots represent the expression of the degranulation marker CD107a (C) and the secretion of IL-2, TNF-a, and IFN-y proinflammatory cytokines (D) by CD8+ T lymphocytes after 6-hours co-culture with HLA- C*04:01+ EBV pulsed with each peptide included in SP18 or with an unrelated peptide as control. Data represent the mean ± SEM of 3 biological replicates. E) The bar plots illustrate the killing efficiency of engineered T cells, measured by determining the elimination index calculated as it follows: [1- (target cells in co-culture / target cells in monoculture)]. T cells cocultured with HLA-C*04:01+ EBV cells pulsed with p75 exhibited an increase in killing efficacy compared to those encountering EBV cells pulsed with an unrelated peptide. The graphed data represents the mean ± SEM of 3 biological replicates. EBV-BLCLs, Epstein Barr Virus- transformed B Lymphoblastoid Cell lines.

[0153] Figure 34 - TCRP53 and TCRPIO2 engineered T cells recognize HLA-class I and HLA- class Il-restricted epitopes, respectively.

[0154] A) Bar graphs representing CD107a expression (degranulation marker) in T cells engineered with two different TCRs redirected against pYAE or p102 epitopes of Cyclin A1 when challenged with HLA-B*35:02+ and HLA-DRB1*07:04+ HLA-DQB1*02:02+ EBV-BLCLs respectively, pulsed with the immunogenic peptides (related peptide). As negative control, EBV-BLCLs were pulsed also with an unrelated peptide. Left and right panels represent the percentage of the degranulation marker CD107a evaluated in CD3+CD8+ or in CD3+CD4+ living T cells, respectively. Data are represented as mean ± SEM of 6 biological replicates. B- C) Bar graphs representing the cytokine released intracellularly within (B) TCR pYAE edited T cells that were co-cultured with pYAE-pulsed HLA-B*35:02+ EBV-BLCLs and (C) TCR p102 T cells co-cultured with HLA-DRB1*07:04+ HLA-DQB1*02:02+ p102-pulsed EBV-BLCLs. As negative control, each EBV cell line was pulsed with an unrelated peptide. Data are represented as mean ± SEM of 6 biological replicates. D) TCR-T cells targeting the p102 (right graph) and pYAE (left graph) epitopes derived from the Cyclin A1 tumor antigen were analyzed for their anti-tumor efficacy. T cell killing activity was determined by measuring the elimination index following a 24-hour co-culture with H LA-restricted EBV-BLCLs that were either pulsed with the relevant (related) peptide or an unrelated peptide (negative control). The presented graph displays data as the mean ± SEM of six biological replicates. E) In the context of the killing assay, T cells redirected towards the tumor expressed the activation marker CD137, thereby confirming TCR activation upon recognition of the corresponding peptide. Statistical significance was evaluated through a two-way ANOVA multiple comparison test, and the obtained p-values are noted as *p<0,05, **p<0,01 , ****p<0,0001. EBV-BLCLs, Epstein Barr Virus-transformed B Lymphoblastoid Cell lines; interleukin-2 (IL-2), tumor necrosis factor a (TNF-a), and interferon y (IFN-y). Figure 35 - sgRNA scheme.

[0155] Scheme of the sgRNAs designed to target the exon 3 of TRAC, the exon 1 of TRBC1 and TRBC2 and the exon 3 of TIGIT. White boxes represent untranslated regions, yellow boxes represent the coding regions, and black boxes represent stop codons.

[0156] Figure 36 - Assessment of the editing efficiency produced by sgRNAs used with CRISPR / Cas9 or Base Editing systems.

[0157] Indel frequency (A, left) and cytosine base conversion (A, right) produced by sgRNAs targeting TRAC, TRBC1 / 2 and TIGIT. Frequency of modification of bystander cytokines in the target loci (B-C). CD3 and TIGIT protein expression after the simultaneous disruption of the TCR and TIGIT by sgRNAs coupled with BE4max (D). Data are represented by mean ± SEM. n=3.

[0158] Figure 37 - Assessment of off-target events at the genomic level.

[0159] (A) Scheme of the two possible off-target events and strategies to investigate them. (B) Experimental workflow.

[0160] Figure 38 - Assessment of sgRNA-independent off-target editing.

[0161] (A) Percentage of nucleotide conversion at predicted target genes and off-target sites. Data are represented by mean ± SEM. n=3. (B-C) Frequency of variant types (B) and specific nucleotide conversions (C) as measured by ultra-deep whole exome sequencing. n=4.

[0162] Figure 39 - Disruption efficiency of ENTPD1.

[0163] (A) Scheme of the guide-RNAs designed to target ENTPD1. White boxes represent untranslated regions, yellow boxes represent the coding regions, and black boxes represent stop codons. (B) Target cytosine base conversion produced by C1 , 02 and 03 coupled with BE4max. n=3.

[0164] Figure 40 - Elimination of tumor cell lines.

[0165] Elimination of tumor cell lines by TCR-edited T cells redirected against specific tumor antigens (Ag). Data are represented by mean ± SEM. n=3.

[0166] Figure 41 - Elimination of primary CRC patient-derived organoids (PDOs). Elimination of primary CRC patient-derived organoids (PDOs) by TCR-edited T cells redirected against specific tumor antigens. Significance is calculated by the linear regression curve fitting the observed results. Data are represented by mean ± SEM. n=3.

[0167] Figure 42 - Elimination of CRC liver metastases patient-derived organoids (PDOs).

[0168] Elimination of CRC liver metastases patient-derived organoids (PDOs) by TCR-edited T cells redirected against specific tumor antigens. Significance is calculated by the linear regression curve fitting the observed results. Data are represented by mean ± SEM. n=3.

[0169] Figure 43 - Elimination of primary PDAC patient-derived organoids (PDOs).

[0170] Elimination of primary PDAC patient-derived organoids (PDOs) by TCR-edited T cells redirected against specific tumor antigens. Significance is calculated by the linear regression curve fitting the observed results. Data are represented by mean ± SEM. n=3.

[0171] Figure 44 - TIGIT disruption improves the ability of MET-specific T cells to eliminate primary CRC patient-derived organoids (PDOs).

[0172] TIGIT disruption improves the ability of MET-specific T cells to eliminate primary CRC patient- derived organoids (PDOs). Significance is calculated by the linear regression curve fitting the observed results. Data are represented by mean ± SEM. n=3.

[0173] Figure 45 - TIGIT disruption improves the ability of DKK1 -specific T cells to eliminate CRC patient-derived organoids (PDOs).

[0174] TIGIT disruption improves the ability of DKK1 -specific T cells to eliminate primary (A) and metastatic (B) CRC patient-derived organoids (PDOs). Significance is calculated by the linear regression curve fitting the observed results. Data are represented by mean ± SEM. n=3.

[0175] Figure 46 - TIGIT disruption improves the ability of DKK1 -specific T cells to eliminate CRC liver metastases and primary PDAC patient-derived organoids (PDOs).

[0176] TIGIT disruption improves the ability of DKK1-specific T cells to eliminate CRC liver metastases (A) and primary PDAC (B) patient-derived organoids (PDOs). Significance is calculated by the linear regression curve fitting the observed results. Data are represented by mean ± SEM. n=3.

[0177] Figure 47 - TIGIT disruption enables MSLN-specific T cells to control tumor growth in vivo. (A-C) Experimental workflow for the CRC (A) and the PDAC (C) orthothopic mouse model. (B-D) Kinetics of tumour growth measured by in vivo bioluminescence in the CRC (B) and by ultrasound imaging in PDAC (D) models. PDO fold increase is calculated as follows: BLI at day X / BLI at day 0. Significance is calculated by the linear regression curve fitting the observed results.

[0178] Figure 48 - The CTSG TCR does not cross-react with other peptides from the human proteome

[0179] (A and C) List of the sequence of the wild type (wt) and of the synthetic peptides employed for the alanine scanning assay. (B and D) CTSG TCR-transduced T cells were co-cultured with HLA-A*24:02+ (B) or HLA-C*07:02+ (D) EBV-BLCLs pulsed with the cognate wild type epitope (P7 or P56) or with altered-ligand peptides showing an alanine substitution of each residue (at a concentration of 100 .M, graph on the left, or 1 .M, graph on the right). Degranulation activity in CD8+ T cells was employed as readout. Co-culture assays were set up at 1 to 1 effector to target ratio. Data are representative of experiments performed with engineered T cells from 2 different healthy donors. CTSG, Cathepsin G; EBV-BLCLs, Epstein Barr Virus-transformed B Lymphoblastoid Cell lines.

[0180] DETAILED DESCRIPTION

[0181] Various preferred features and embodiments of the present invention will now be described by way of non-limiting examples. This disclosure is not limited by the exemplary methods and materials disclosed herein, and any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of this disclosure. The skilled person will understand that they can combine all features of the invention disclosed herein without departing from the scope of the invention as disclosed.

[0182] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0183] The terms "comprising", "comprises" and "comprised of" as used herein are synonymous with "including", "includes", "containing", or "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or steps. The terms "comprising", "comprises" and "comprised of" also include the term "consisting of".

[0184] Numeric ranges are inclusive of the numbers defining the range. As used herein the term “about” means approximately, in the region of, roughly, or around. Unless otherwise indicated, any nucleic acid sequences are written left to right in 5' to 3' orientation; amino acid sequences are written left to right in amino to carboxy orientation, respectively.

[0185] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that such publications constitute prior art to the claims appended hereto. All publications mentioned in the specification are herein incorporated by reference.

[0186] T-cell receptors (TCRs)

[0187] In one aspect, the present invention provides a T-cell receptor (TCR) which binds to an immunogenic peptide when presented by a major histocompatibility complex (MHC). The present invention also provides an a chain or a chain from such a T cell receptor.

[0188] As used herein the term "T-cell receptor” (TCR) may refer to molecule capable of recognising a peptide when presented by an MHC molecule. TCRs may be found on the surface of T-cells and are responsible for recognising an antigen peptide bound to an MHC molecule. During antigen processing, antigens are degraded inside cells and then antigen peptides carried to the cell surface by MHC molecules. Binding of the TCR to the peptide:MHC complex results in activation of the T lymphocyte on which the TCR is expressed through a series of biochemical events mediated by associated enzymes, co-receptors, and specialized accessory molecules.

[0189] TCR affinity for the peptide may be determined by the association (kon) and dissociation rates (kOff) and represented as the equilibrium dissociation constant (KD). The TCR affinity may be determined by any suitable method, for example by titration calorimetry, surface plasmon resonance (SPR) or fluorescence microscopy-based methods (see e.g. Piepenbrink, K.H., et al., 2009. Methods Enzymol, 466, pp:359-381). The TCR may bind to a peptide when presented by an MHC with an affinity of about 100 pM or less, about 50 pM or less, about 40 pM or less, about 30 pM or less, about 20 pM or less, or about 10 pM or less. The TCR may bind to a peptide when presented by an MHC with an affinity of about 0.1 pM to about 100 pM, about 1 pM to about 100 pM, or about 5 pM to about 100 pM. The TCR may bind to a peptide when presented by an MHC with an affinity of about 0.1 pM to about 10 pM, about 1 pM to about 10 pM, or about 5 pM to about 10 pM.

[0190] The naturally-occurring TCR heterodimer consists of an alpha (a) and beta (P) chain in around 95% of T-cells, whereas around 5% of T-cells have TCRs consisting of gamma (y) and delta (5) chains. Each chain of a natural TCR is a member of the immunoglobulin superfamily and possesses an N-terminal immunoglobulin (Ig)-variable (V) region, a Ig-constant (C) region, a transmembrane / cell membrane-spanning region, and a short cytoplasmic tail at the C-terminal end.

[0191] The TCR of the present invention may be a heterodimer of two chains a and p (or optionally y and 5) or it may be a single chain TCR construct. Suitably, when the TCR of the present invention is a heterodimer of an a chain and a chain, the a chain and p chain bind to the same immunogenic peptide. The a and p chains (or variable domains or CDRs thereof) provided herein may be combined in any suitable combination. For example, when three a chains and three p chains (or variable domains or CDRs thereof) are provided which bind to the same immunogenic peptide, the TCR of the present invention may comprise a combination of a1 / pi , a1 / p2, a1 / p3, a2 / pi , a2 / p2, a2 / p3, a3 / pi , a3 / p2, or a3 / p3. In some embodiments, the TCR of the present invention comprises a combination of an a1 chain (or variable domains or CDRs thereof) and a pi chain (or variable domains or CDRs thereof). In some embodiments, the TCR of the present invention comprises a combination of an a1 chain (or variable domains or CDRs thereof) and a p2 chain (or variable domains or CDRs thereof). In some embodiments, the TCR of the present invention comprises a combination of an a1 chain (or variable domains or CDRs thereof) and a p3 chain (or variable domains or CDRs thereof). In some embodiments, the TCR of the present invention comprises a combination of an a2 chain (or variable domains or CDRs thereof) and a pi chain (or variable domains or CDRs thereof). In some embodiments, the TCR of the present invention comprises a combination of an a2 chain (or variable domains or CDRs thereof) and a p2 chain (or variable domains or CDRs thereof). In some embodiments, the TCR of the present invention comprises a combination of an a2 chain (or variable domains or CDRs thereof) and a p3 chain (or variable domains or CDRs thereof). In some embodiments, the TCR of the present invention comprises a combination of an a3 chain (or variable domains or CDRs thereof) and a pi chain (or variable domains or CDRs thereof). In some embodiments, the TCR of the present invention comprises a combination of an a3 chain (or variable domains or CDRs thereof) and a p2 chain (or variable domains or CDRs thereof). In some embodiments, the TCR of the present invention comprises a combination of an a3 chain (or variable domains or CDRs thereof) and a p3 chain (or variable domains or CDRs thereof).

[0192] A variable domain may determine the specificity of the TCR. The variable domain of both the TCR a chain and p chain have three hypervariable or complementarity determining regions (CDRs). A TCR a chain or p chain, for example, comprises a CDR1 , a CDR2, and a CDR3 in amino to carboxy terminal order. In general, CDR3 is the main CDR responsible for recognizing processed antigens, although CDR1 of the alpha chain has also been shown to interact with the N-terminal part of the antigenic peptide, whereas CDR1 of the beta chain interacts with the C-terminal part of the peptide. CDR2 is thought to recognize the MHC molecule. Suitable variable domains are described herein.

[0193] A TCR of the invention may comprise a constant domain. A constant domain may allow the TCR to associate with other molecules like CD3 which possess three distinct chains (y, 5, and E) in mammals and the ^-chain. These accessory molecules have negatively charged transmembrane regions and are vital to propagating the signal from the TCR into the cell. The CD3- and ^-chains, together with the TCR, form what is known as the T cell receptor complex.

[0194] The constant domain may consist of short connecting sequences in which a cysteine residue forms a disulfide bond, making a link between the two chains. The constant domain may comprise an Ig-constant (C) region, a transmembrane / cell membrane-spanning region and a cytoplasmic tail.

[0195] An a chain of a TCR of the present invention may comprise a constant domain encoded by a TRAC gene. An a chain constant domain may have the amino acid sequence set out in UniProt entry P01848. An example a chain constant domain has the amino acid sequence set out below in SEQ ID NO: 1.

[0196] A TCR of the invention may comprise an a chain constant domain comprising or consisting of the 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 thereto.

[0197] IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFK SNSAVAWSNKSDFACANAFNNS I IPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNL SVIGFRILLLKVAGFNLLMTLRLWSS

[0198] Example a chain constant domain ( SEQ ID NO : 1 )

[0199] A p chain of a TCR of the present invention may comprise a constant domain encoded by a TRBC1 or a TRBC2 gene. A chain constant domain may have the amino acid sequence set out in UniProt entry P01850 or A0A5B9. An example p chain constant domain encoded by a TRBC1 gene has the amino acid sequence set out below in SEQ ID NO: 2. An example p chain constant domain encoded by a TRBC2 gene has the amino acid sequence set out below in SEQ ID NO: 3.

[0200] A TCR of the invention may comprise a p chain constant domain comprising the 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 thereto. DLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVST DPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAK PVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMV KRKDF

[0201] Example p chain constant domain ( SEQ ID NO : 2 )

[0202] DLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVST DPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAK PVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMV KRKDSRG

[0203] Example p chain constant domain ( SEQ ID NO : 3 )

[0204] The TCR of the invention may have one or more additional cysteine residues in each of the a and p chains such that the TCR may comprise two or more disulphide bonds in the constant domains.

[0205] The signal from the T cell complex may be enhanced by simultaneous binding of the MHC molecules by a specific co-receptor. For helper T-cells, this co-receptor may be CD4 (specific for class II MHC); whereas for cytotoxic T-cells, this co-receptor may be CD8 (specific for class I MHC). The co-receptor can allow prolonged engagement between the antigen presenting cell and the T cell and can recruit essential molecules (e.g., LCK) inside the cell involved in the signalling of the activated T lymphocyte.

[0206] The TCR of the invention may be a hybrid TCR comprising sequences derived from more than one species. For example, it has been found that murine TCRs are more efficiently expressed in human T-cells than human TCRs. The TCR may therefore comprise a human variable domain and murine sequences within a constant domain. A disadvantage of this approach is that the murine constant sequences may trigger an immune response, leading to rejection of the transferred T-cells. However, the conditioning regimens used to prepare patients for adoptive T-cell therapy may result in sufficient immunosuppression to allow the engraftment of T-cells expressing murine sequences.

[0207] A TCR of the invention may be a soluble TCR, e.g. omitting or altering one or more constant domains. Other suitable methods for engineering soluble TCRs are known in the art (see e.g. Robinson, R.A., et al., 2021. The FEBS Journal, 288(21), pp.6159-6173).

[0208] The term “soluble TCR” refers to a TCR that is not anchored on the cell surface. Soluble TCR may typically comprise the variable domain and at least part of the constant domain but lack the transmembrane domain and intracellular, cytoplasmic domain. Soluble TCR may comprise stabilising mutations and / or modifications (e.g. such as point mutations, interchain disulphide bonds and / or peptide linkers). Such modifications are known in the art (e.g. Robinson, R.A., et al., 2021. The FEBS Journal, 288(21), pp.6159-6173).

[0209] In some embodiments, the TCR comprises one or more mutations to remove one or more N- glycosylation sites. Suitably, the N-glycosylation sites are in the TCR constant domains. Deletion of N-glycosylation sites in TCR constant domains is described in Kuball, J et al. (2009) J Exp Med 206: 463-75. In some embodiments, the one or more mutations are substitutions of the amino acid N in an N-X-S / T motif with the amino acid Q. For example, the substitution may at one or more of the positions: TCR alpha constant gene position 36, 90 or 109; and / or TCR beta constant gene position 85.6. Suitably, the substitution is at position 36 of the TCR alpha constant gene. Mutations of TCR constant domains disclosed herein may be described based on a numbering convention in which the first amino acid of each of SEQ ID NOs: 1-3 is assigned to be position 2.

[0210] Complementarity determining regions (CDRs)

[0211] T-cell receptor diversity is focused on CDR3 and this region is primarily responsible for antigen recognition. The sequences of the CDR3 regions of the TCR of the invention may be selected from those described herein. A TCR of the present invention may comprise CDRs that comprise or consist of a CDR3a and a CDR3P pair described herein.

[0212] The portion of the TCR that establishes the majority of the contacts with the antigenic peptide bound to the major histocompatibility complex (MHC) is the complementarity determining region 3 (CDR3), which is unique for each T cell clone. The CDR3 region is generated upon somatic rearrangement events occurring in the thymus and involving non-contiguous genes belonging to the variable (V), diversity (D, for p and 5 chains) and joining (J) genes. Furthermore, random nucleotides inserted / deleted at the rearranging loci of each TCR chain gene greatly increase diversity of the highly variable CDR3 sequence. Thus, the frequency of a specific CDR3 sequence in a biological sample indicates the abundance of a specific T cell population. The great diversity of the TCR repertoire in healthy human beings provides a wide range protection towards a variety of foreign antigens presented by MHC molecules on the surface of antigen presenting cells. In this regard, it is of note that theoretically up to 1015different TCRs can be generated in the thymus.

[0213] The sequences of the CDR1 and CDR2 regions of the TCR of the invention may also be selected from those described herein. A TCR of the present invention may comprise CDRs that comprise of consist of CDR1a, CDR2a, CDR3a, CDRip, CDR2P, and CDR3P sets described herein. The CDRs may, for example, comprise one, two, or three substitutions, additions or deletions from the given sequence, provided that the TCR retains the capacity to bind the corresponding immunogenic peptide when presented by an MHC molecule. In some embodiments, each CDR3 comprises 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 comprises up to three substitutions, up to two substitutions, up to one substitution, or any combination thereof. In some embodiments, each CDR comprises 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 comprises up to three substitutions, up to two substitutions, up to one substitution, or any combination thereof.

[0214] Major histocompatibility complex (MHC) molecules

[0215] Typically, TCRs bind to peptides as part of peptide: MHC complex. The TCR of the present invention may bind to an MHC I and / or MHC II peptide complex. The MHC peptide complex may be on the surface of an antigen presenting cell, such as a dendritic cell or a B cell, or any other cell, including cancer cells, or it may be immobilised by, for example, coating on to a bead or plate.

[0216] The human leukocyte antigen system (HLA) is the name of the gene complex which encodes MHC in humans and includes HLA class I antigens (A, B & C) and HLA class II antigens (DP, DQ, & DR). HLA alleles A, B and C present peptides derived mainly from intracellular proteins, e.g. proteins expressed within the cell. The TCR is restricted to a human leukocyte antigen (HLA) allele.

[0217] During T-cell development in vivo, T-cells undergo a positive selection step to ensure recognition of self MHCs followed by a negative step to remove T-cells that bind too strongly to MHC which present self-antigens. As a consequence, certain T-cells and the TCRs they express will only recognise peptides presented by certain types of MHC molecules, i.e. those encoded by particular HLA alleles. This is known as HLA restriction. The preferred MHC binding motifs of different HLA alleles are disclosed in The Immune Epitope Database (IEDB) (Vita, R., et al., 2019. Nucleic acids research, 47(D1), pp.D339-D343).

[0218] Immunogenic peptides

[0219] The TCRs of the present invention bind to an immunogenic peptide when presented by an MHC. As used herein, the term “protein” may include single-chain polypeptide molecules as well as multiple-polypeptide complexes where individual constituent polypeptides are linked by covalent or non-covalent means.

[0220] As used herein, the term “polypeptide” may refer to a polymer in which the monomers are amino acids and are joined together through peptide or disulphide bonds.

[0221] As used herein, the term “peptide” may refer to a plurality of amino acid residues linked by peptide bonds. A peptide may consist of less than about 30, less than about 25, less than about 20, less than 19, less than 18, less than 17, less than 16, less than 15, less than 14, less than 13, less than 12, less than 11 , or less 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, a peptide 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, a peptide of the invention is 9 amino acid residues in length.

[0222] As used herein, the term “immunogenic peptide” or “immunogenic fragment” may refer to a peptide which is capable of being presented by an MHC molecule and subsequently recognised by a TCR. The immunogenic peptide or fragment may be derived from e.g. an AML-associated antigen, a CRC-associated antigen, or a PDAC-associated antigen. An immunogenic peptide or fragment may consist of less than about 30, less than about 25, less than about 20, less than 19, less than 18, less than 17, less than 16, less than 15, less than 14, less than 13, less than 12, less than 11 , or less than 10 amino acid residues. An immunogenic peptide or fragment may consist of 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more amino acid residues. Suitably, an 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, an immunogenic peptide or immunogenic fragment of the invention is 9 amino acid residues in length.

[0223] The immunogenic peptides of the present invention may be derived from any suitable human proteins, for example tumour-associated antigens. As used herein, a “tumour-associated antigen” may refer to an antigenic protein produced in tumour 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. In some embodiments, the immunogenic peptides of the present invention are derived from AML-associated antigens. As used herein, an “AML-associated antigen” may refer to an antigenic protein produced in acute myeloid leukaemia cells. AML-associated antigens may act as useful tumour markers and as potential candidates for use in immunotherapy. AML- associated antigens may include PR3 / NE, EZH2, PRAME, CTSG, and CCNA1.

[0224] In some embodiments, the immunogenic peptides of the present invention are derived from CRC-associated antigens and / or PDAC-associated antigens. As used herein, a “CRC- associated antigen” may refer to an antigenic protein produced in colorectal cancer cells. CRC-associated antigens may act as useful tumour markers and as potential candidates for use in immunotherapy. As used herein, a “PDAC-associated antigen” may refer to an antigenic protein produced in pancreatic ductal adenocarcinoma cells. PDAC-associated antigens may act as useful tumour markers and as potential candidates for use in immunotherapy. CRC- associated antigens and / or PDAC-associated antigens may include HER2, DKK1 , MUC5AC, AGR2, c-MET, MSLN, CTDP1 , TACC2, or PTGFRN.

[0225] Various uses of the peptides described herein are contemplated by the invention. For example, the peptides described herein may be administered to a subject, e.g. a human subject. Administration of the peptides of the invention may elicit an immune response against cells expressing or overexpressing the corresponding protein, i.e. the peptides may be immunogenic peptides. The peptides described herein may be used to screen for and / or identify new TCR sequences. For example, T2 cells may be pulsed with a peptide described herein and incubated with a T-cell population isolated from a donor. In this approach, expression of cytokines, e.g. CD107a and IFNy, may be indicative of T-cells which recognise the peptide.

[0226] HER2 specific TCRs

[0227] In one aspect, the present invention provides a TCR which binds to a HER2 peptide when presented by an MHC.

[0228] HER2

[0229] HER2 is a protein that is encoded by the ERBB2 gene and is also known as Human epidermal growth factor receptor 2, Receptor tyrosine-protein kinase erbB-2, or CD340.

[0230] HER2 is a member of the epidermal growth factor receptor family having tyrosine kinase activity. Dimerization of the receptor results in the auto phosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signalling pathways leading to cell proliferation and tumorigenesis. Amplification or overexpression of HER2 occurs in approximately 15-30% of breast cancers and 10-30% of gastric / gastroesophageal cancers. HER2 overexpression has also been seen in other cancers like ovary, endometrium, bladder, lung, colon, and head and neck (see e.g. Iqbal, N. and Iqbal, N., 2014. Molecular biology international, p.852748).

[0231] The HER2 protein may have the amino acid sequence set out in UniProt entry P04626. An example HER2 protein has the amino acid sequence set out below in SEQ ID NO: 4.

[0232] MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQWQ GNLELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYAL AVLDNGDPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILWKD I FHKNNQLALTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCARCK GPLPTDCCHEQCAAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNP EGRYTFGASCVTACPYNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVC YGLGMEHLREVRAVTSANIQEFAGCKKI FGSLAFLPESFDGDPASNTAPLQPEQLQV FETLEEITGYLYISAWPDSLPDLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLR SLRELGSGLALIHHNTHLCFVHTVPWDQLFRNPHQALLHTANRPEDECVGEGLACHQ LCARGHCWGPGPTQCVNCSQFLRGQECVEECRVLQGLPREYVNARHCLPCHPECQPQ NGSVTCFGPEADQCVACAHYKDPPFCVARCPSGVKPDLSYMPIWKFPDEEGACQPCP INCTHSCVDLDDKGCPAEQRASPLTS I ISAWGILLVWLGWFGILIKRRQQKIRK YTMRRLLQETELVEPLTPSGAMPNQAQMRILKETELRKVKVLGSGAFGTVYKGIWIP DGENVKI PVAI KVLRENT S PKANKE I LDEAYVMAGVGS P YVSRLLG I CLT S TVQLVT QLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLEDVRLVHRDLAARNVLVKS PNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALES ILRRRFTHQSDVWSYGVTV WELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIMVKCWMIDSECRPRF RELVSEFSRMARDPQRFWIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDAEEYLVP QQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLTLGLEPSEEEAPRSPLAPSEGAGS DVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETDGYVAPLTCSPQPEYV NQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGWKDVFAFGGAVENPEYL TPQGGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEYLGLDVP V

[0233] Example HER2 protein ( SEQ ID NO : 4 )

[0234] HER2 peptides

[0235] As used herein, the term “HER2 peptide” may refer to a peptide comprising an amino acid sequence derived from a HER2 protein. Suitably, a HER2 peptide may comprise at least 5, at least 6, at least 7, at least 8, or at least 9 contiguous amino acid residues of a HER2 protein amino acid sequence (or a variant thereof). In some embodiments, a HER2 peptide comprises 9 contiguous amino acid residues of a HER2 protein amino acid sequence (or a variant thereof). The HER2 peptide may be an immunogenic peptide. The HER2 peptide may bind to any suitable MHC. Suitably, the HER2 peptide binds to an MHC encoded by a HLA class I allele or a HLA class II allele. Suitably, the HER2 peptide binds to an MHC encoded by a HLA-A allele. Suitably, the HER2 peptide binds to an MHC encoded by a HLA-A*02 allele. Suitably, the HER2 peptide binds to an MHC encoded by HLA-A*0201.

[0236] An example HER2 peptide has the amino acid sequence set out below in SEQ ID NO: 5.

[0237] KI FGSLAFL

[0238] Example HER2 peptide ( SEQ ID NO : 5 )

[0239] The HER2 peptide may comprise or consist of the amino acid sequence of SEQ ID NO: 5 or a variant thereof having up to 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 up to 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 up to 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 up to 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 up to 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 up to one amino acid substitution. In some embodiments, the HER2 peptide comprises or consists of the amino acid sequence of SEQ ID NO: 5.

[0240] HER2-specific TCR sequences

[0241] The present inventors have determined the amino acid sequences of a HER2-specific TCR, including the CDR regions, which are responsible for binding specificity for the HER2 peptide.

[0242] The HER2-specific TCR may be restricted to any suitable MHC (e.g. one or more HLA allele). Suitably, the HER2-specific TCR is restricted to a HLA class I allele or a HLA class II allele. Suitably, the HER2-specific TCR is restricted to a HLA-A allele. Suitably, the HER2-specific TCR is restricted to a HLA-A*02 allele. Suitably, the HER2-specific TCR is restricted to HLA- A*0201 .

[0243] Example HER2-specific TCR amino acid sequences are provided in the tables below.

[0244] In one aspect, the present invention provides a TCR comprising a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 8 or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0245] In some embodiments, the CDR3 variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR3 variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR3 variants have up to three amino acid substitutions. In some embodiments, the CDR3 variants have up to two amino acid substitutions. In some embodiments, the CDR3 variants have up to one amino acid substitution. In some embodiments, the TCR comprises: a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 8 and / or a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 13.

[0246] In some embodiments, the TCR further comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 6, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or (a) a CDR1 p comprising or consisting of the amino acid sequence of SEQ ID NO: 11 , or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 12, or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0247] In some embodiments, the TCR comprises an a 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 thereto; and / or a p 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 thereto.

[0248] In some embodiments, the TCR comprises an a 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 thereto; and / or a p chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or 16, or variants 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 thereto.

[0249] In one aspect, the present invention provides a TCR comprising (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 6, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 8, or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 11 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 12, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 13, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0250] In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0251] In some embodiments, the TCR comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 6; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 7; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 8; and / or (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 11 ; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 12; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 13.

[0252] In one aspect, the present invention provides a TCR comprising an a 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 thereto; and / or a p 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 thereto.

[0253] In one aspect, the present invention provides a TCR comprising an a 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 thereto, wherein the a chain variable domain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 8 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p 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 thereto, wherein the p chain variable domain comprises a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0254] In one aspect, the present invention provides a TOR comprising an a 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 thereto, wherein the a chain variable domain comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 6, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 8 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p 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 thereto, wherein the p chain variable domain comprises (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 11 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 12, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 13, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0255] In one aspect, the present invention provides a TCR comprising an a 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 thereto; and / or a p chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or 16, or variants 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 thereto.

[0256] In one aspect, the present invention provides a TCR comprising an a 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 thereto, wherein the a chain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 8 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a P chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or 16, or variants 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 thereto, wherein the chain comprises a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0257] In one aspect, the present invention provides a TCR comprising an a 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 thereto, wherein the a chain comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 6, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 8 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or 16, or variants 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 thereto, wherein the p chain comprises (a) a CDR1 p comprising or consisting of the amino acid sequence of SEQ ID NO: 11 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 12, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 13, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0258] PR3 / NE specific TCRs

[0259] In one aspect, the present invention provides a TCR which binds to a PR3 / NE peptide when presented by an MHC.

[0260] PR3 and NE

[0261] PR3 is a protein that is encoded by the PRTN3 gene and is also known as proteinase 3 or Myeloblastin. NE is a protein that is encoded by the ELANE gene and is also known as Neutrophil elastase or leukocyte elastase. PR3 and NE are both serine proteases localized in the primary azurophilic granules of neutrophils whose first function is to fight against bacterial infections by processing pathogenic proteins into smaller peptides both intracellularly and extracellularly. Their overexpression has been observed in the cytoplasm of primary leukemic blasts and leukemic stem cells making them attractive antigens to be selected for the adoptive cell therapy (ACT) of acute myeloid leukaemia (AML) (Greiner, J., et al., 2008. Clinical Cancer Research, 14(22), pp.7161-7166). Moreover, it has been shown that tumour cell lines negative for the expression of PR3 and NE can internalize these antigens from exogenous sources and cross-present them (Alatrash, G., et al, 2018. Oncotarget, 9(4), p.4280). This mechanism of internalization is interesting in ACT since it would enlarge the spectrum of cancer types susceptible to the immunotherapy directed against PR3 and NE.

[0262] The PR3 protein may have the amino acid sequence set out in UniProt entry P24158. An example PR3 protein has the amino acid sequence set out below in SEQ ID NO: 17.

[0263] MAHRPPSPALASVLLALLLSGAARAAEIVGGHEAQPHSRPYMASLQMRGNPGSHFCG GTLIHPSFVLTAAHCLRDIPQRLVNWLGAHNVRTQEPTQQHFSVAQVFLNNYDAEN KLNDVLLIQLSSPANLSASVATVQLPQQDQPVPHGTQCLAMGWGRVGAHDPPAQVLQ ELNVTWTFFCRPHNICTFVPRRKAGICFGDSGGPLICDGI IQGIDSFVIWGCATRL FPDFFTRVALYVDWIRSTLRRVEAKGRP

[0264] Example PR3 protein ( SEQ ID NO : 17 )

[0265] The NE protein may have the amino acid sequence set out in UniProt entry P08246. An example NE protein has the amino acid sequence set out below in SEQ ID NO: 18.

[0266] MTLGRRLACLFLACVLPALLLGGTALASEIVGGRRARPHAWPFMVSLQLRGGHFCGA T L I APNFVMS AAHCVANVNVRAVRWLGAHNL S RRE P TRQVFAVQR I FENG YDPVNL LNDIVILQLNGSATINANVQVAQLPAQGRRLGNGVQCLAMGWGLLGRNRGIASVLQE LNVTWTSLCRRSNVCTLVRGRQAGVCFGDSGSPLVCNGLIHGIASFVRGGCASGLY PDAFAPVAQFVNWIDS I IQRSEDNPCPHPRDPDPASRTH

[0267] Example NE protein ( SEQ ID NO : 18 )

[0268] PR3 / NE peptides

[0269] As used herein, the term “PR3 / NE peptide” may refer to a peptide comprising an amino acid sequence derived from a PR3 protein and / or a NE protein. Suitably, a PR3 / NE peptide may comprise at least 5, at least 6, at least 7, at least 8, or at least 9 contiguous amino acid residues of a PR3 protein amino acid sequence (or a variant thereof) and / or a NE protein amino acid sequence (or a variant thereof). In some embodiments, a PR3 / NE peptide comprises 9 contiguous amino acid residues of a PR3 protein amino acid sequence (or a variant thereof) and / or a NE protein amino acid sequence (or a variant thereof). In some embodiments, a PR3 / NE peptide comprises at least 5, at least 6, at least 7, at least 8, or at least 9 contiguous amino acid residues of a PR3 protein amino acid sequence (or a variant thereof) and a NE protein amino acid sequence (or a variant thereof). In some embodiments, a PR3 / NE peptide comprises at least 9 contiguous amino acid residues of a PR3 protein amino acid sequence (or a variant thereof) and a NE protein amino acid sequence (or a variant thereof).

[0270] The PR3 / NE peptide may be an immunogenic peptide. The PR3 / NE peptide may bind to any suitable MHC. Suitably, the PR3 / NE peptide binds to an MHC encoded by a H LA class I allele or a HLA class II allele. Suitably, the PR3 / NE peptide binds to an MHC encoded by a HLA-A allele. Suitably, the PR3 / NE peptide binds to an MHC encoded by a HLA-A*02 allele. Suitably, the PR3 / NE peptide binds to an MHC encoded by HLA-A*0201.

[0271] An example PR3 / NE peptide has the amino acid sequence set out below in SEQ ID NO: 19.

[0272] VLQELNVTV

[0273] Example PR3 / NE peptide ( SEQ ID NO : 19 )

[0274] The PR3 / NE peptide may comprise or consist of the amino acid sequence of SEQ ID NO: 19 or a variant thereof having up to 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 up to 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 up to 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 up to 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 up to 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 up to one amino acid substitution. In some embodiments, the PR3 / NE peptide comprises or consists of the amino acid sequence of SEQ ID NO: 19.

[0275] PR3 / NE-specific TCR sequences

[0276] The present inventors have determined the amino acid sequences of a PR3 / NE-specific TCR, including the CDR regions, which are responsible for binding specificity for the PR3 / NE peptide.

[0277] The PR3 / NE-specific TCR may be restricted to any suitable MHC (e.g. one or more HLA allele). Suitably, the PR3 / NE-specific TCR is restricted to a HLA class I allele or a HLA class II allele. Suitably, the PR3 / NE-specific TCR is restricted to a HLA-A allele. Suitably, the PR3 / NE-specific TCR is restricted to a HLA-A*02 allele. Suitably, the PR3 / NE-specific TCR is restricted to HLA-A*0201.

[0278] Example PR3 / NE-specific TCR amino acid sequences are provided in the tables below.

[0279] In one aspect, the present invention provides a TCR comprising a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 22 or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 27 or a variant thereof having up to three amino acid substitutions, additions or deletions. In some embodiments, the CDR3 variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR3 variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR3 variants have up to three amino acid substitutions. In some embodiments, the CDR3 variants have up to two amino acid substitutions. In some embodiments, the CDR3 variants have up to one amino acid substitution.

[0280] In some embodiments, the TCR comprises: a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 22 and / or a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 27.

[0281] In some embodiments, the TCR further comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 20, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 21 , or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or (a) a CDR1 p comprising or consisting 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) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 26, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0282] In some embodiments, the TCR comprises an a 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 thereto; and / or a p 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 thereto.

[0283] In some embodiments, the TCR comprises an a 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 thereto; and / or a p chain comprising or consisting of the amino acid sequence of SEQ ID NO: 29 or 30, or variants 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 thereto.

[0284] In one aspect, the present invention provides a TCR comprising (a) a CDR1a comprising or consisting 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) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 21 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 22, or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or (a) a CDR1 p comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 26, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 27, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0285] In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0286] In some embodiments, the TCR comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 20; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 21 ; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 22; and / or (a) a CDRi comprising or consisting of the amino acid sequence of SEQ ID NO: 25; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 26; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 27.

[0287] In one aspect, the present invention provides a TCR comprising an a 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 thereto; and / or a 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 thereto.

[0288] In one aspect, the present invention provides a TCR comprising an a 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 thereto, wherein the a chain variable domain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 22 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p 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 thereto, wherein the chain variable domain comprises a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 27 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0289] In one aspect, the present invention provides a TCR comprising an a 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 thereto, wherein the a chain variable domain comprises (a) a CDR1a comprising or consisting 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) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 21 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 22 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p 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 thereto, wherein the p chain variable domain comprises (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 26, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 27, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0290] In one aspect, the present invention provides a TCR comprising an a 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 thereto; and / or a p chain comprising or consisting of the amino acid sequence of SEQ ID NO: 29 or 30, or variants 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 thereto.

[0291] In one aspect, the present invention provides a TCR comprising an a 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 thereto, wherein the a chain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 22 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p chain comprising or consisting of the amino acid sequence of SEQ ID NO: 29 or 30, or variants 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 thereto, wherein the chain comprises a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 27 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0292] In one aspect, the present invention provides a TCR comprising an a 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 thereto, wherein the a chain comprises (a) a CDR1a comprising or consisting 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) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 21 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 22 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p chain comprising or consisting of the amino acid sequence of SEQ ID NO: 29 or 30, or variants 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 thereto, wherein the p chain comprises (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 26, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 27, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0293] EZH2 / PRAME specific TCRs In one aspect, the present invention provides a TOR which binds to a EZH2 peptide or a PRAME peptide when presented by an MHC.

[0294] EZH2

[0295] EZH2 is a protein that is encoded by the EZH2 gene and is also known as Histone-lysine N- methyltransferase EZH2 or Enhancer of zeste homolog 2.

[0296] EZH2 is a lysine methyltransferase of the Polycomb Repressive Complex 2 (PRC2) that catalyses the addition of three methyl groups to the lysine 27 (K27) of the Histone 3 (H3), thus establishing and maintaining the H3K27 tri-methylation repressive marks (Li, B. and Chng, W.J., 2019. Journal of Hematology & Oncology, 12, pp.1-13.). In physiological conditions, it acts as a tumour suppressor gene but upon oncogenic hits, such as gain-of-function mutations in the EZH2 gene or in its genomic regulators (mRNA or IncRNA), the EZH2 protein can be overexpressed, as it has been shown in a variety of haematological malignancies. However, loss-of-function mutations can also occur in the EZH2 gene, that results in the loss of the trimethylation repressive mark and expression of target genes that drive acute myeloid leukaemia (AML) onset and are associated with a poor prognosis.

[0297] The EZH2 protein may have the amino acid sequence set out in UniProt entry Q15910. An example EZH2 protein has the amino acid sequence set out below in SEQ ID NO: 31.

[0298] MGQTGKKSEKGPVCWRKRVKSEYMRLRQLKRFRRADEVKSMFSSNRQKILERTEILN QEWKQRRIQPVHILTSVSSLRGTRECSVTSDLDFPTQVIPLKTLNAVASVPIMYSWS PLQQNFMVEDETVLHNIPYMGDEVLDQDGTFIEELIKNYDGKVHGDRECGFINDEI F VELVNALGQYNDDDDDDDGDDPEEREEKQKDLEDHRDDKESRPPRKFPSDKI FEAIS SMFPDKGTAEELKEKYKELTEQQLPGALPPECTPNIDGPNAKSVQREQSLHSFHTLF CRRCFKYDCFLHPFHATPNTYKRKNTETALDNKPCGPQCYQHLEGAKEFAAALTAER IKTPPKRPGGRRRGRLPNNSSRPSTPTINVLESKDTDSDREAGTETGGENNDKEEEE KKDETSSSSEANSRCQTPIKMKPNIEPPENVEWSGAEASMFRVLIGTYYDNFCAIAR L I GTKTCRQVYE FRVKE SS I I APAPAEDVDT PPRKKKRKHRLWAAHCRKI QLKKDGS SNHVYNYQPCDHPRQPCDSSCPCVIAQNFCEKFCQCSSECQNRFPGCRCKAQCNTKQ CPCYLAVRECDPDLCLTCGAADHWDSKNVSCKNCS IQRGSKKHLLLAPSDVAGWGI F IKDPVQKNE FI SE YCGE 11 SQDEADRRGKVYDKYMCS FLFNLNNDFWDATRKGNKI RFANHSVNPNCYAKVMMVNGDHRIGI FAKRAIQTGEELFFDYRYSQADALKYVGIER EMEIP

[0299] Example EZH2 protein ( SEQ ID NO : 31 )

[0300] EZH2 peptides

[0301] As used herein, the term “EZH2 peptide” may refer to a peptide comprising an amino acid sequence derived from an EZH2 protein. Suitably, an EZH2 peptide may comprise at least 5, at least 6, at least 7, at least 8, or at least 9 contiguous amino acid residues of a EZH2 protein amino acid sequence (or a variant thereof). In some embodiments, an EZH2 peptide comprises 9 contiguous amino acid residues of a EZH2 protein amino acid sequence (or a variant thereof).

[0302] The EZH2 peptide may be an immunogenic peptide. The EZH2 peptide may bind to any suitable MHC. Suitably, the EZH2 peptide binds to an MHC encoded by a HLA class I allele or a HLA class II allele. Suitably, the EZH2 peptide binds to an MHC encoded by a HLA-A allele. Suitably, the EZH2 peptide binds to an MHC encoded by a HLA-A*02 allele. Suitably, the EZH2 peptide binds to an MHC encoded by HLA-A*0201.

[0303] An example EZH2 peptide has the amino acid sequence set out below in SEQ ID NO: 32.

[0304] KESRPPRKF

[0305] Example EZH2 peptide ( SEQ ID NO : 32 )

[0306] The EZH2 peptide may comprise or consist of the amino acid sequence of SEQ ID NO: 32 or a variant thereof having up to 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 up to 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 up to 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 up to 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 up to 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 up to one amino acid substitution. In some embodiments, the EZH2 peptide comprises or consists of the amino acid sequence of SEQ ID NO: 32.

[0307] PRAME

[0308] PRAME is a protein that is encoded by the PRAME gene and is also known as Melanoma antigen preferentially expressed in tumours, Preferentially expressed antigen of melanoma, or Opa-interacting protein 4.

[0309] PRAME belongs to the Cancer Testis Antigen (CTA) family genes, expressed at high levels on the germ cells of the testis but absent on other healthy tissues. High expression levels of PRAME are detected on malignant cells, including most primary and metastatic melanomas. In its nuclear localization, PRAME interacts with EZH2 to repress the Retinoic Acid Receptor (RAR) signalling cascade that is known to mediate tumour suppression functions. Indeed, the binding of Retinoic Acid (RA) to the RAR in the nucleus induces RAR 2 gene expression and transcription of RA target genes that regulate cell-cycle arrest and caspase-dependent apoptosis pathways in responsive cells. Therefore, inhibition of the RAR signalling by PRAME may represent an important contributory factor in acute myeloid leukaemia (AML) disease progression (see e.g. Wadelin, F., et al., 2010. Molecular cancer, 9, pp.1-10).

[0310] The PRAME protein may have the amino acid sequence set out in UniProt entry P78395. An example PRAME protein has the amino acid sequence set out below in SEQ ID NO: 33.

[0311] MERRRLWGS IQSRYISMSVWTSPRRLVELAGQSLLKDEALAIAALELLPRELFPPLF MAAFDGRHSQTLKAMVQAWPFTCLPLGVLMKGQHLHLETFKAVLDGLDVLLAQEVRP RRWKLQVLDLRKNSHQDFWTVWSGNRASLYSFPEPEAAQPMTKKRKVDGLSTEAEQP FIPVEVLVDLFLKEGACDELFSYLIEKVKRKKNVLRLCCKKLKI FAMPMQDIKMILK MVQLDS IEDLEVTCTWKLPTLAKFSPYLGQMINLRRLLLSHIHASSYISPEKEEQYI AQFTSQFLSLQCLQALYVDSLFFLRGRLDQLLRHVMNPLETLS ITNCRLSEGDVMHL SQSPSVSQLSVLSLSGVMLTDVSPEPLQALLERASATLQDLVFDECGITDDQLLALL PSLSHCSQLTTLSFYGNS IS ISALQSLLQHLIGLSNLTHVLYPVPLESYEDIHGTLH LERLAYLHARLRELLCELGRPSMVWLSANPCPHCGDRTFYDPEPILCPCFMPN

[0312] Example PRAME protein ( SEQ ID NO : 33 )

[0313] PRAME peptides

[0314] As used herein, the term “PRAME peptide” may refer to a peptide comprising an amino acid sequence derived from a PRAME protein. Suitably, a PRAME peptide may comprise at least 5, at least 6, at least 7, at least 8, or at least 9 contiguous amino acid residues of a PRAME protein amino acid sequence (or a variant thereof). In some embodiments, a PRAME peptide comprises 9 contiguous amino acid residues of a PRAME protein amino acid sequence (or a variant thereof).

[0315] The PRAME peptide may be an immunogenic peptide. The PRAME peptide may bind to any suitable MHC. Suitably, the PRAME peptide binds to an MHC encoded by a HLA class I allele or a HLA class II allele. Suitably, the PRAME peptide binds to an MHC encoded by a HLA-A allele. Suitably, the PRAME peptide binds to an MHC encoded by a HLA-A*02 allele. Suitably, the PRAME peptide binds to an MHC encoded by HLA-A*0201.

[0316] An example PRAME peptide has the amino acid sequence set out below in SEQ ID NO: 34.

[0317] ALYVDSLFFL

[0318] Example PRAME peptide ( SEQ ID NO : 34 )

[0319] The PRAME peptide may comprise or consist of the amino acid sequence of SEQ ID NO: 34 or a variant thereof having up to 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 up to 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 up to 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 up to 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 up to 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 up to one amino acid substitution. In some embodiments, the PRAME peptide comprises or consists of the amino acid sequence of SEQ ID NO: 34.

[0320] EZH2 / PRAME-specific TCR sequences

[0321] The present inventors have determined the amino acid sequences of a EZH2 / PRAME-specific TCR, including the CDR regions, which are responsible for binding specificity for the EZH2 or PRAME peptide.

[0322] The EZH2 / PRAME-specific TCR may be restricted to any suitable MHC (e.g. one or more HLA allele). Suitably, the EZH2 / PRAME-specific TCR is restricted to a HLA class I allele or a HLA class II allele. Suitably, the EZH2 / PRAME-specific TCR is restricted to a HLA-A allele. Suitably, the EZH2 / PRAME-specific TCR is restricted to a HLA-A*02 allele. Suitably, the EZH2 / PRAME-specific TCR is restricted to HLA-A*0201.

[0323] Example EZH2 / PRAME-specific TCR amino acid sequences are provided in the tables below. In one aspect, the present invention provides a TCR comprising a CDR3a comprising or consisting of (i) the amino acid sequence of 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 SEQ ID NO: 42 or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or a CDR3P comprising or consisting of (i) the amino acid sequence of 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 SEQ ID NO: 53 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0324] In some embodiments, the CDR3 variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR3 variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR3 variants have up to three amino acid substitutions. In some embodiments, the CDR3 variants have up to two amino acid substitutions. In some embodiments, the CDR3 variants have up to one amino acid substitution.

[0325] In some embodiments, the TCR comprises: a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 37 or 42 and / or a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 47 or 53.

[0326] In some embodiments, the TCR comprises: a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 37 and / or a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 47.

[0327] In some embodiments, the TCR comprises: a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 42 and / or a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 53.

[0328] In some embodiments, the TCR further comprises (i) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 35, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 36, or a variant thereof having up to three amino acid substitutions, additions or deletions; or (ii) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 40, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 41 , or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or (i) (a) a CDRi p comprising or consisting of the amino acid sequence of SEQ ID NO: 45, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 46, or a variant thereof having up to three amino acid substitutions, additions or deletions; or (ii) (a) a CDR1 p comprising or consisting of the amino acid sequence of SEQ ID NO: 51 , or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 52, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0329] In some embodiments, the TCR comprises an a chain variable domain comprising or consisting of (i) 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 thereto, 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 thereto; and / or a chain variable domain comprising or consisting 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 thereto, 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 thereto.

[0330] In some embodiments, the TCR comprises an a chain comprising or consisting of (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 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, 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 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and / or a p chain comprising or consisting of (i) the amino acid sequence of SEQ ID NO: 49 or 50, or variants 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 thereto, or (ii) the amino acid sequence of SEQ ID NO: 55 or 56, or variants 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 thereto.

[0331] In one aspect, the present invention provides a TCR comprising (i) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 35, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 36, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 37, or a variant thereof having up to three amino acid substitutions, additions or deletions; or (ii) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 40, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 41 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 42, or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or (i) (a) a CDR1 p comprising or consisting of the amino acid sequence of SEQ ID NO: 45, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 46, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 47, or a variant thereof having up to three amino acid substitutions, additions or deletions; or (ii) (a) a CDRi comprising or consisting of the amino acid sequence of SEQ ID NO: 51 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 52, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 53, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0332] In one aspect, the present invention provides a TCR comprising (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 35, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 36, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 37, or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or (a) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 45, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 46, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 47, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0333] In one aspect, the present invention provides a TCR comprising (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 40, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 41 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 42, or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or (a) a CDRi comprising or consisting of the amino acid sequence of SEQ ID NO: 51 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 52, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 53, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0334] In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0335] In some embodiments, the TCR comprises (i) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 35; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 36; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 37; or (ii) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 40; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 41 ; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 42; and / or (i) (a) a CDRi comprising or consisting of the amino acid sequence of SEQ ID NO: 45; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 46; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 47; or (ii) (a) a CDRi p comprising or consisting of the amino acid sequence of SEQ ID NO: 51 ; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 52; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 53.

[0336] In some embodiments, the TCR comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 35; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 36; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 37; and / or (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 45; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 46; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 47.

[0337] In some embodiments, the TOR comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 40; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 41 ; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 42; and / or (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 51 ; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 52; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 53.

[0338] In one aspect, the present invention provides a TCR comprising an a chain variable domain comprising or consisting of (i) 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 thereto, 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 thereto; and / or a p chain variable domain comprising or consisting 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 thereto, 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 thereto.

[0339] In one aspect, the present invention provides a TCR comprising an a chain variable domain comprising or consisting of (i) 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 thereto, wherein the a chain variable domain comprises a CDR3a comprising or consisting of the amino acid sequence of 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 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 thereto, wherein the a chain variable domain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 42 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p chain variable domain comprising or consisting 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 thereto, wherein the p chain variable domain comprises a CDR3P comprising or consisting of the amino acid sequence of 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 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 thereto, wherein the chain variable domain comprises a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 53 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0340] In one aspect, the present invention provides a TCR comprising an a chain variable domain comprising or consisting of (i) 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 thereto, wherein the a chain variable domain comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 35, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 36, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of 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 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 thereto, wherein the a chain variable domain comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 40, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 41 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 42 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p chain variable domain comprising or consisting 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 thereto, wherein the p chain variable domain comprises (a) a CDRi p comprising or consisting of the amino acid sequence of SEQ ID NO: 45, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 46, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of 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 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 thereto, wherein the p chain variable domain comprises (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 51 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 52, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 53, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0341] In some embodiments, TCR comprises an a 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 thereto; and / or a 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 thereto.

[0342] In some embodiments, TCR comprises an a 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 thereto; and / or a p 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 thereto.

[0343] In one aspect, the present invention provides a TCR comprising an a chain comprising or consisting of (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 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, 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 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and / or a p chain comprising or consisting of (i) the amino acid sequence of SEQ ID NO: 49 or 50, or variants 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 thereto, or (ii) the amino acid sequence of SEQ ID NO: 55 or 56, or variants 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 thereto.

[0344] In one aspect, the present invention provides a TCR comprising an a chain comprising or consisting of (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 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, wherein the a chain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 35 or a variant thereof having up to three amino acid substitutions, additions or deletions, 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 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, wherein the a chain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 42 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p chain comprising or consisting of (i) the amino acid sequence of SEQ I D NO: 49 or 50, or variants 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 thereto, wherein the chain comprises a CDR3P comprising or consisting of the amino acid sequence of 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 SEQ ID NO: 55 or 56, or variants 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 thereto, wherein the p chain comprises a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 53 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0345] In one aspect, the present invention provides a TCR comprising an a chain comprising or consisting of (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 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, wherein the a chain comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 35, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 36, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of 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 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 thereto, wherein the a chain comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 40, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 41 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 42 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p chain comprising or consisting of (i) the amino acid sequence of SEQ ID NO: 49 or 50, or variants 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 thereto, wherein the chain comprises (a) a CDRi p comprising or consisting of the amino acid sequence of SEQ ID NO: 45, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 46, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of 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 SEQ ID NO: 55 or 56, or variants 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 thereto, wherein the p chain comprises (a) a CDRi p comprising or consisting of the amino acid sequence of SEQ ID NO: 51 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 52, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 53, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0346] In some embodiments, the TCR comprises an a 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 thereto; and / or a p chain comprising or consisting of the amino acid sequence of SEQ ID NO: 49 or 50, or variants 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 thereto.

[0347] In some embodiments, the TCR comprises an a 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 thereto; and / or a p chain comprising or consisting of the amino acid sequence of SEQ ID NO: 55 or 56, or variants 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 thereto.

[0348] Cathepsin G (CTSG) specific TCRs

[0349] In one aspect, the present invention provides a TOR which binds to a CTSG peptide when presented by an MHC.

[0350] CTSG

[0351] Cathepsin G (CTSG) is a protein that is encoded by the CTSG gene.

[0352] Cathepsin G is expressed in the early stages of the myeloid differentiation, is involved in the degradation of the extracellular matrix components, in the cleavage of inflammatory mediators, in the immune response and in the antigenic presentation. Nowadays, CTSG is considered as a possible leukaemia associated antigen as it is aberrantly overexpressed in the leukemic blasts, characterized by an immature phenotype. In fact, it has been demonstrated that CTSG peptides are naturally processed and presented on the surface of the leukemic cells, thus rendering this antigen an ideal target for the adoptive immunotherapy (see Papadopoulos, K.P., et al., 1997. The Journal of the American Society of Hematology, 90(12), pp.4938-4946).

[0353] The CTSG protein may have the amino acid sequence set out in UniProt entry P08311. An example CTSG protein has the amino acid sequence set out below in SEQ ID NO: 57.

[0354] MQPLLLLLAFLLPTGAEAGEI IGGRESRPHSRPYMAYLQIQSPAGQSRCGGFLVRED FVLTAAHCWGSNINVTLGAHNIQRRENTQQHITARRAIRHPQYNQRTIQNDIMLLQL SRRVRRNRNVNPVALPRAQEGLRPGTLCTVAGWGRVSMRRGTDTLREVQLRVQRDRQ CLRI FGSYDPRRQICVGDRRERKAAFKGDSGGPLLCNNVAHGIVSYGKSSGVPPEVF TRVSSFLPWIRTTMRSFKLLDQMETPL

[0355] Example CTSG protein ( SEQ ID NO : 57 )

[0356] CTSG peptides

[0357] As used herein, the term “CTSG peptide” may refer to a peptide comprising an amino acid sequence derived from a CTSG protein. Suitably, a CTSG peptide may comprise at least 5, at least 6, at least 7, at least 8, or at least 9 contiguous amino acid residues of a CTSG protein amino acid sequence (or a variant thereof). In some embodiments, a CTSG peptide comprises 9 contiguous amino acid residues of a CTSG protein amino acid sequence (or a variant thereof).

[0358] In one aspect, the invention provides a CTSG peptide comprising or consisting 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 each having up to three amino acid substitutions, additions or deletions, or a fragment thereof. Suitably, the CTSG peptide is an isolated peptide.

[0359] 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 variants thereof having up to two 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 SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81 , SEQ ID NO: 95, or variants thereof having up to one amino acid substitution, addition or deletion (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 variants thereof having up to three 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 variants thereof having up to 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 variants thereof having up to one amino acid substitution (or a fragment thereof). In some embodiments, the CTSG peptide comprises or consists of SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81 , or SEQ ID NO: 95 (or a fragment thereof).

[0360] In some embodiments, the CTSG peptide is less than 14, less than 13, less than 12, less than 11 , or less than 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 in length, about 9 to 13 amino acid residues in length, about 9 to 12 amino acid residues in length, about 9 to 11 amino acid residues in length, or about 9 to 10 amino acid residues in length. In some embodiments, the CTSG peptide is a nonameric fragment.

[0361] In some embodiments, the CTSG peptide consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81 , SEQ ID NO: 95, or variants thereof having up to two amino acid substitutions, additions or deletions (or a fragment thereof). In some embodiments, the CTSG peptide consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81 , SEQ ID NO: 95, or variants thereof having up to one amino acid substitution, addition or deletion (or a fragment thereof). In some embodiments, the CTSG peptide consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81 , SEQ ID NO: 95, or variants thereof having up to three amino acid substitutions (or a fragment thereof). In some embodiments, the CTSG peptide consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81 , SEQ ID NO: 95, or variants thereof having up to two amino acid substitutions (or a fragment thereof). In some embodiments, the CTSG peptide consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81 , SEQ ID NO: 95, or variants thereof having up to one amino acid substitution (or a fragment thereof). In some embodiments, the CTSG peptide consists of a nonameric fragment of SEQ ID NO: 58, SEQ ID NO: 535, SEQ ID NO: 81 , or SEQ ID NO: 95.

[0362] Example CTSG peptides and CTSG-specific TOR sequences 1

[0363] An example CTSG peptide has the amino acid sequence set out below in SEQ ID NO: 58.

[0364] GIVSYGKSSGVPPEV

[0365] Example CTSG peptide 1 ( SEQ ID NO : 58 )

[0366] In one aspect, the invention provides a CTSG peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 58 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 amino acid sequence of SEQ ID NO: 58 or a variant thereof having up to two 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 SEQ ID NO: 58 or a variant thereof having up to one amino acid substitution, addition or deletion (or a fragment 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 up to three 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 or a variant thereof having up to 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 or a variant thereof having up to one amino acid substitution (or a fragment thereof). In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 58 (or a fragment thereof).

[0367] In one aspect, the 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 up to 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 up to 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 up to 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 up to 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 up to two 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 up to one amino acid substitution. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 58.

[0368] The CTSG peptide may be an immunogenic peptide. The CTSG peptide may bind to any suitable MHC. Suitably, the CTSG peptide binds to an MHC encoded by a HLA class I allele or a HLA class II allele. Suitably, the CTSG peptide binds to an MHC encoded by a HLA-A allele. Suitably, the CTSG peptide binds to an MHC encoded by a HLA-A*02 allele. Suitably, the CTSG peptide binds to an MHC encoded by HLA-A*0201.

[0369] The present inventors have determined the amino acid sequences of a CTSG-specific TCR, including the CDR regions, which are responsible for binding specificity for the CTSG peptide.

[0370] The CTSG-specific TCR may be restricted to any suitable MHC (e.g. one or more HLA allele). Suitably, the CTSG-specific TCR is restricted to a HLA class I allele or a HLA class II allele. Suitably, the CTSG-specific TCR is restricted to a HLA-A allele. Suitably, the CTSG-specific TCR is restricted to a HLA-A*02 allele. Suitably, the CTSG-specific TCR is restricted to HLA- A*0201 .

[0371] Example CTSG-specific TCR amino acid sequences are provided in the tables below.

[0372] In one aspect, the present invention provides a TCR comprising a CDR3a comprising or consisting of (i) the amino acid sequence of 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 SEQ ID NO: 66 or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or a CDR3P comprising or consisting of (i) the amino acid sequence of 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 SEQ ID NO: 77 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0373] In some embodiments, the CDR3 variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR3 variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR3 variants have up to three amino acid substitutions. In some embodiments, the CDR3 variants have up to two amino acid substitutions. In some embodiments, the CDR3 variants have up to one amino acid substitution.

[0374] In some embodiments, the TCR comprises: a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 61 or 66 and / or a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 71 or 77.

[0375] In some embodiments, the TCR further comprises (i) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 59, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 60, or a variant thereof having up to three amino acid substitutions, additions or deletions; or (ii) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 64, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 65, or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or (i) (a) a CDRi p comprising or consisting of the amino acid sequence of SEQ ID NO: 69, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 70, or a variant thereof having up to three amino acid substitutions, additions or deletions; or (ii) (a) a CDRi p comprising or consisting of the amino acid sequence of SEQ ID NO: 75, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 76, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0376] In some embodiments, the TOR comprises an a chain variable domain comprising or consisting of (i) the 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 thereto, 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 thereto; and / or a p chain variable domain comprising or consisting of (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 thereto, 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 thereto.

[0377] In some embodiments, the TCR comprises an a chain comprising or consisting of (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 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, 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 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and / or a p chain comprising or consisting of (i) the amino acid sequence of SEQ ID NO: 73 or 74, or variants 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 thereto, or (ii) the amino acid sequence of SEQ ID NO: 79 or 80, or variants 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 thereto.

[0378] In one aspect, the present invention provides a TCR comprising (i) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 59, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 60, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 61 , or a variant thereof having up to three amino acid substitutions, additions or deletions; or (ii) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 64, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 65, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 66, or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or (i) (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 69, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 70, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ I D NO: 71 , or a variant thereof having up to three amino acid substitutions, additions or deletions; or (ii) (a) a CDRi comprising or consisting of the amino acid sequence of SEQ ID NO: 75, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 76, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 77, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0379] In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0380] In some embodiments, the TCR comprises (i) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 59; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 60; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 61 ; or (ii) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 64; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 65; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 66; and / or (i) (a) a CDRi comprising or consisting of the amino acid sequence of SEQ ID NO: 69; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 70; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 71 ; or (ii) (a) a CDRi p comprising or consisting of the amino acid sequence of SEQ ID NO: 75; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 76; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 77.

[0381] In one aspect, the present invention provides a TOR comprising an a chain variable domain comprising or consisting of (i) the 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 thereto, 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 thereto; and / or a p chain variable domain comprising or consisting of (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 thereto, 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 thereto.

[0382] In one aspect, the present invention provides a TCR comprising an a chain variable domain comprising or consisting of (i) the 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 thereto, wherein the a chain variable domain comprises a CDR3a comprising or consisting of the amino acid sequence of 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 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 thereto, wherein the a chain variable domain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 66 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p chain variable domain comprising or consisting of (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 thereto, wherein the p chain variable domain comprises a CDR3P comprising or consisting of the amino acid sequence of 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 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 thereto, wherein the p chain variable domain comprises a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 77 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0383] In one aspect, the present invention provides a TOR comprising an a chain variable domain comprising or consisting of (i) the 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 thereto, wherein the a chain variable domain comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 59, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 60, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of 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 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 thereto, wherein the a chain variable domain comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 64, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 65, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 66 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p chain variable domain comprising or consisting of (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 thereto, wherein the p chain variable domain comprises (a) a CDRi p comprising or consisting of the amino acid sequence of SEQ ID NO: 69, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 70, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of 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 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 thereto, wherein the p chain variable domain comprises (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 75, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 76, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 77, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0384] In one aspect, the present invention provides a TOR comprising an a chain comprising or consisting of (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 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, 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 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and / or a p chain comprising or consisting of (i) the amino acid sequence of SEQ ID NO: 73 or 74, or variants 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 thereto, or (ii) the amino acid sequence of SEQ ID NO: 79 or 80, or variants 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 thereto.

[0385] In one aspect, the present invention provides a TCR comprising an a chain comprising or consisting of (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 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, wherein the a chain comprises a CDR3a comprising or consisting of the amino acid sequence of 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 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 thereto, wherein the a chain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 66 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p chain comprising or consisting of (i) the amino acid sequence of SEQ I D NO: 73 or 74, or variants 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 thereto, wherein the p chain comprises a CDR3P comprising or consisting of the amino acid sequence of 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 SEQ ID NO: 79 or 80, or variants 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 thereto, wherein the p chain comprises a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 77 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0386] In one aspect, the present invention provides a TOR comprising an a chain comprising or consisting of (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 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, wherein the a chain comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 59, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 60, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of 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 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 thereto, wherein the a chain comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 64, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 65, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 66 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p chain comprising or consisting of (i) the amino acid sequence of SEQ ID NO: 73 or 74, or variants 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 thereto, wherein the p chain comprises (a) a CDRi p comprising or consisting of the amino acid sequence of SEQ ID NO: 69, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 70, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of 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 SEQ ID NO: 79 or 80, or variants 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 thereto, wherein the p chain comprises (a) a CDRi p comprising or consisting of the amino acid sequence of SEQ ID NO: 75, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 76, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 77, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0387] Example CTSG peptides and CTSG-specific TOR sequences 2

[0388] Another example CTSG peptide has the amino acid sequence set out below in SEQ ID NO: 81.

[0389] SGVPPEVFTRVSS FL

[0390] Example CTSG peptide 2 ( SEQ ID NO : 81 )

[0391] 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. Thus, in one embodiment, the invention provides a CTSG peptide comprising a conservative substitution at one or more of positions 2, 3, 4 and / or 6 of SEQ ID NO: 81.

[0392] The CTSG peptide may have the amino acid sequence set out below in SEQ ID NO: 535.

[0393] SXXXPXVFTRVSS FL , wherein X i s any amino acid ( SEQ ID NO : 535 )

[0394] In one aspect, the invention provides a CTSG peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 535 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 SEQ ID NO: 535 or a variant thereof having up to 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 up to 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 up to 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 up to 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 up to 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 an MHC encoded by a HLA-C*07 allele. Suitably, the CTSG peptide binds to an MHC encoded by HLA-C*0702. Suitably, the CTSG peptide binds to an MHC encoded by a HLA- A*24 allele. Suitably, the CTSG peptide binds to an MHC encoded by HLA-A*2402. Suitably, the CTSG peptide binds to an MHC encoded by a HLA-C*07 allele and an MHC encoded by a HLA-A*24 allele. Suitably, the CTSG peptide binds to an MHC encoded by HLA-C*0702 and an MHC encoded by HLA-A*2402.

[0395] In one aspect, the invention provides a CTSG peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 81 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 SEQ ID NO: 81 or a variant thereof having up to 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 up to 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 up to 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 up to 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 up to one amino acid substitution. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 81 .

[0396] In one aspect, the 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 up to 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 up to 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 up to 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 up to 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 up to two 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 up to one amino acid substitution. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 81. Suitably, the CTSG peptide binds to an MHC encoded by a HLA-C*07 allele. Suitably, the CTSG peptide binds to an MHC encoded by HLA-C*0702. Suitably, the CTSG peptide binds to an MHC encoded by a HLA-A*24 allele. Suitably, the CTSG peptide binds to an MHC encoded by HLA-A*2402. Suitably, the CTSG peptide binds to an MHC encoded by a HLA-C*07 allele and an MHC encoded by a HLA-A*24 allele. Suitably, the CTSG peptide binds to an MHC encoded by HLA-C*0702 and an MHC encoded by HLA-A*2402.

[0397] An example fragment has the amino acid sequence set out below in SEQ ID NO: 82.

[0398] VFTRVSSFL

[0399] Example CTSG peptide 2 - fragment 1 ( SEQ ID NO : 82 )

[0400] In one aspect, the invention provides a CTSG peptide comprising or consisting of the amino acid sequence of 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 SEQ ID NO: 82 or a variant thereof having up to 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 up to 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 up to 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 up to 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 up to 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 an MHC encoded by a HLA-A*24 allele. Suitably, the CTSG peptide binds to an MHC encoded by HLA-A*2402.

[0401] Another example fragment has the amino acid sequence set out below in SEQ ID NO: 83.

[0402] VPPEVFTRVSSFL

[0403] Example CTSG peptide 2 - fragment 2 ( SEQ ID NO : 83 )

[0404] In one aspect, the invention provides a CTSG peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 83 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 SEQ ID NO: 83 or a variant thereof having up to 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 up to 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 up to 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 up to 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 up to 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 an MHC encoded by a HLA-C*07 allele. Suitably, the CTSG peptide binds to an MHC encoded by HLA-C*0702.

[0405] Other example fragments have the amino acid sequence set out below in SEQ ID NO: 420, 421 and 422.

[0406] EVFTRVSSF

[0407] Example CTSG peptide 2 - fragment 3 ( SEQ ID NO : 420 )

[0408] EVFTRVSSFL

[0409] Example CTSG peptide 2 - fragment 4 ( SEQ ID NO : 421 )

[0410] VPPEVFTRVSSF

[0411] Example CTSG peptide 2 - fragment 5 ( SEQ ID NO : 422 )

[0412] In one aspect, the invention provides a CTSG peptide comprising or consisting of the amino acid sequence of any of SEQ I D NOs: 420 to 422, or variants 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 any of SEQ ID NOs: 420 to 422, or variants thereof having up to two amino acid substitutions, additions or deletions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of any of SEQ ID NOs: 420 to 422, or variants thereof having up to one amino acid substitution, addition or deletion. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of any of SEQ ID NOs: 420 to 422, or variants thereof having up to three amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of any of SEQ ID NOs: 420 to 422, or variants thereof having up to two amino acid substitutions. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of any of SEQ ID NOs: 420 to 422, or variants thereof having up to one amino acid substitution. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of any of SEQ ID NOs: 420 to 422.

[0413] The CTSG peptide may be an immunogenic peptide. The CTSG peptide may bind to any suitable MHC. Suitably, the CTSG peptide binds to an MHC encoded by a HLA class I allele or a HLA class II allele. Suitably, the CTSG peptide binds to an MHC encoded by a HLA-A allele or a HLA-C allele. Suitably, the CTSG peptide binds to an MHC encoded by a HLA-A*24 allele or a HLA-C*07 allele. Suitably, the CTSG peptide binds to an MHC encoded by HLA- A*2402 or HLA-C*0702. Suitably, the CTSG peptide binds to an MHC encoded by a HLA-A allele and a HLA-C allele. Suitably, the CTSG peptide binds to an MHC encoded by a HLA- A*24 allele and an MHC encoded by a HLA-C*07 allele. Suitably, the CTSG peptide binds to an MHC encoded by HLA-A*2402 and an MHC encoded by HLA-C*0702.

[0414] The present inventors have determined the amino acid sequences of a CTSG-specific TCR, including the CDR regions, which are responsible for binding specificity for the CTSG peptide.

[0415] The CTSG-specific TCR may be restricted to any suitable MHC (e.g. one or more HLA allele). Suitably, the CTSG-specific TCR is restricted to a HLA class I allele or a HLA class II allele. Suitably, the CTSG-specific TCR is restricted to a HLA-A allele or a HLA-C allele. Suitably, the CTSG-specific TCR is restricted to a HLA-A*24 allele or a HLA-C*07 allele. Suitably, the CTSG-specific TCR is restricted to HLA-A*2402 or HLA-C*0702. Suitably, the CTSG-specific TCR is restricted to a HLA-A allele and a HLA-C allele. Suitably, the CTSG-specific TCR is restricted to a HLA-A*24 allele and a HLA-C*07 allele. Suitably, the CTSG-specific TCR is restricted to HLA-A*2402 and HLA-C*0702.

[0416] Example CTSG-specific TOR amino acid sequences are provided in the tables below.

[0417] As used herein, the terms “TCR P56”, “P56 TCR”, “P56ap”, “P56 TCRaP”, and “CTSG TOR” may be used interchangeably, and refer to a TCR comprising an a chain variable domain comprising the amino acid sequence of SEQ ID NO: 87 or a variant thereof; and a p chain variable domain comprising the amino acid sequence of SEQ ID NO: 92 or a variant thereof, unless otherwise specified.

[0418] In one aspect, the present invention provides a TCR comprising a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 86 or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 91 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0419] In some embodiments, the CDR3 variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR3 variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR3 variants have up to three amino acid substitutions. In some embodiments, the CDR3 variants have up to two amino acid substitutions. In some embodiments, the CDR3 variants have up to one amino acid substitution.

[0420] In some embodiments, the TCR comprises: a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 86 and / or a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 91.

[0421] In some embodiments, the TCR further comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 84, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 85, or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or (a) a CDR1 p comprising or consisting 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) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 90, or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0422] In some embodiments, the TOR comprises an a 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 thereto; and / or a p 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 thereto.

[0423] In some embodiments, the TCR comprises an a 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 thereto; and / or a chain comprising or consisting of the amino acid sequence of SEQ ID NO: 93 or 94, or variants 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 thereto.

[0424] In one aspect, the present invention provides a TCR comprising (a) a CDR1a comprising or consisting 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) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 85, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 86, or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or (a) a CDR1 p comprising or consisting of the amino acid sequence of SEQ ID NO: 89, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 90, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 91 , or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0425] In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution. In some embodiments, the TCR comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 84; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 85; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 86; and / or (a) a CDRi p comprising or consisting of the amino acid sequence of SEQ ID NO: 89; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 90; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 91.

[0426] In one aspect, the present invention provides a TCR comprising an a 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 thereto; and / or a p 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 thereto.

[0427] In one aspect, the present invention provides a TCR comprising an a 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 thereto, wherein the a chain variable domain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 86 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p 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 thereto, wherein the p chain variable domain comprises a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 91 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0428] In one aspect, the present invention provides a TCR comprising an a 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 thereto, wherein the a chain variable domain comprises (a) a CDR1a comprising or consisting 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) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 85, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 86 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p 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 thereto, wherein the chain variable domain comprises (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 89, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 90, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 91 , or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0429] In one aspect, the present invention provides a TCR comprising an a 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 thereto; and / or a p chain comprising or consisting of the amino acid sequence of SEQ ID NO: 93 or 94, or variants 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 thereto.

[0430] In one aspect, the present invention provides a TCR comprising an a 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 thereto, wherein the a chain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 86 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p chain comprising or consisting of the amino acid sequence of SEQ ID NO: 93 or 94, or variants 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 thereto, wherein the p chain comprises a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 91 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0431] In one aspect, the present invention provides a TCR comprising an a 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 thereto, wherein the a chain comprises (a) a CDR1a comprising or consisting 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) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 85, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 86 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p chain comprising or consisting of the amino acid sequence of SEQ ID NO: 93 or 94, or variants 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 thereto, wherein the chain comprises (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 89, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 90, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 91 , or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0432] In one aspect, the invention provides a TCR which binds to an immunogenic CTSG peptide when presented by a major histocompatibility complex (MHC), wherein the immunogenic CTSG peptide comprises or consists of SXXXPXVFTRVSSFL (SEQ ID NO: 535) or a variant thereof having up to three amino acid substitutions, additions or deletions, or an immunogenic fragment thereof.

[0433] 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 up to 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 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.

[0434] Suitably, the CTSG peptide binds to an MHC encoded by a HLA class I allele or a HLA class II allele. Suitably, the CTSG peptide binds to an MHC encoded by a HLA-A allele or a HLA-C allele. Suitably, the CTSG peptide binds to an MHC encoded by a HLA-A*24 allele or a HLA- C*07 allele. Suitably, the CTSG peptide binds to an MHC encoded by a HLA-A*2402 allele or HLA-C*0702. Suitably, the CTSG peptide binds to an MHC encoded by a HLA-A allele and an MHC encoded by a HLA-C allele. Suitably, the CTSG peptide binds to an MHC encoded by a HLA-A*24 allele and an MHC encoded by a HLA-C*07 allele. Suitably, the CTSG peptide binds to an MHC encoded by HLA-A*2402 and an MHC encoded by HLA-C*0702.

[0435] Suitably, the CTSG-specific TCR is restricted to a H LA class I allele or a H LA class II allele. Suitably, the CTSG-specific TCR is restricted to a HLA-A allele or a HLA-C allele. Suitably, the CTSG-specific TCR is restricted to a HLA-A*24 allele or a HLA-C*07 allele. Suitably, the CTSG-specific TCR is restricted to HLA-A*2402 or HLA-C*0702. Suitably, the CTSG-specific TCR is restricted to a HLA-A allele and a HLA-C allele. Suitably, the CTSG-specific TCR is restricted to a HLA-A*24 allele and a HLA-C*07 allele. Suitably, the CTSG-specific TCR is restricted to HLA-A*2402 and HLA-C*0702.

[0436] Example CTSG peptides and CTSG-specific TCR sequences 3

[0437] Another example CTSG peptide has the amino acid sequence set out below in SEQ ID NO: 95.

[0438] TMRSFKLLDQMETPL

[0439] Example CTSG peptide 3 ( SEQ ID NO : 95 )

[0440] In one aspect, the invention provides a CTSG peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 95 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 SEQ ID NO: 95 or a variant thereof having up to 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 up to 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 up to 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 up to 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 up to one amino acid substitution. In some embodiments, the CTSG peptide comprises or consists of the amino acid sequence of SEQ ID NO: 95.

[0441] In one aspect, the 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 up to 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 up to 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 up to 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 up to 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 up to two 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 up to one amino acid substitution. In some embodiments, the CTSG peptide comprises or consists of a nonameric fragment of the amino acid sequence of SEQ ID NO: 95.

[0442] The CTSG peptide may be an immunogenic peptide. The CTSG peptide may bind to any suitable MHC. Suitably, the CTSG peptide binds to an MHC encoded by a HLA class I allele or a HLA class II allele. The present inventors have determined the amino acid sequences of a CTSG-specific TOR, including the CDR regions, which are responsible for binding specificity for the CTSG peptide.

[0443] The CTSG-specific TCR may be restricted to any suitable MHC (e.g. one or more HLA allele).

[0444] Suitably, the CTSG-specific TCR is restricted to a HLA class I allele or a HLA class II allele.

[0445] Example CTSG-specific TCR amino acid sequences are provided in the tables below.

[0446] In one aspect, the present invention provides a TCR comprising a CDR3a comprising or consisting of (i) the amino acid sequence of SEQ ID NO: 98 or a variant thereof having up to three amino acid substitutions, additions or deletions, or (ii) the amino acid sequence of SEQ ID NO: 459 or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or a CDR3P comprising or consisting of (i) the amino acid sequence of SEQ ID NO: 103 or a variant thereof having up to three amino acid substitutions, additions or deletions, or (ii) the amino acid sequence of SEQ ID NO: 109 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0447] In some embodiments, the CDR3 variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR3 variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR3 variants have up to three amino acid substitutions. In some embodiments, the CDR3 variants have up to two amino acid substitutions. In some embodiments, the CDR3 variants have up to one amino acid substitution.

[0448] In some embodiments, the TCR comprises: a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 98 or 459 and / or a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 103 or 109.

[0449] In some embodiments, the TCR further comprises (i) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 96, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 97, or a variant thereof having up to three amino acid substitutions, additions or deletions; or (ii) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 457, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 458, or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or (i) (a) a CDRi p comprising or consisting of the amino acid sequence of SEQ ID NO: 101 , or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 102, or a variant thereof having up to three amino acid substitutions, additions or deletions; or (ii) (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 107, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 108, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0450] In some embodiments, the TCR comprises an a chain variable domain comprising or consisting of (i) the 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 thereto, or (ii) the 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 thereto; and / or a p chain variable domain comprising or consisting of (i) the 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 thereto, or (ii) the amino acid sequence of SEQ 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 thereto.

[0451] In some embodiments, the TCR comprises an a chain comprising or consisting of (i) the 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 thereto, or (ii) the 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 thereto; and / or a chain comprising or consisting of (i) the amino acid sequence of SEQ ID NO: 105 or 106, or variants 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 thereto, or (ii) the amino acid sequence of SEQ ID NO: 111 or 112, or variants 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 thereto.

[0452] In one aspect, the present invention provides a TCR comprising (i) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 96, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 97, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 98, or a variant thereof having up to three amino acid substitutions, additions or deletions; or (ii) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 457, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 458, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 459, or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or (i) (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 101 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 102, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 103, or a variant thereof having up to three amino acid substitutions, additions or deletions; or (ii) (a) a CDRi comprising or consisting of the amino acid sequence of SEQ ID NO: 107, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 108, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 109, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0453] In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0454] In some embodiments, the TCR comprises (i) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 96; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 97; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 98; or (ii) (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 457; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 458; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 459; and / or (i) (a) a CDRi comprising or consisting of the amino acid sequence of SEQ ID NO: 101 ; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 102; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 103; or (ii) (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 107; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 108; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 109.

[0455] In one aspect, the present invention provides a TCR comprising an a chain variable domain comprising or consisting of (i) the 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 thereto, or (ii) the 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 thereto; and / or a p chain variable domain comprising or consisting of (i) the 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 thereto, or (ii) the amino acid sequence of SEQ 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 thereto.

[0456] In one aspect, the present invention provides a TOR comprising an a chain variable domain comprising or consisting of (i) the 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 thereto, wherein the a chain variable domain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 98 or a variant thereof having up to three amino acid substitutions, additions or deletions, or (ii) the 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 thereto, wherein the a chain variable domain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 459 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a chain variable domain comprising or consisting of (i) the 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 thereto, wherein the p chain variable domain comprises a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 103 or a variant thereof having up to three amino acid substitutions, additions or deletions, or (ii) the amino acid sequence of SEQ 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 thereto, wherein the p chain variable domain comprises a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 109 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0457] In one aspect, the present invention provides a TCR comprising an a chain variable domain comprising or consisting of (i) the 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 thereto, wherein the a chain variable domain comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 96, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 97, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 98 or a variant thereof having up to three amino acid substitutions, additions or deletions, or (ii) the 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 thereto, wherein the a chain variable domain comprises (a) a CDR1a comprising or consisting of the amino acid sequence of SEQ ID NO: 457, or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0458] (b) a CDR2a comprising or consisting of the amino acid sequence of SEQ ID NO: 458, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 459 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a p chain variable domain comprising or consisting of (i) the 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 thereto, wherein the chain variable domain comprises (a) a CDRi p comprising or consisting of the amino acid sequence of SEQ ID NO: 101 , or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 102, or a variant thereof having up to three amino acid substitutions, additions or deletions; (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 103, or a variant thereof having up to three amino acid substitutions, additions or deletions, or (ii) the amino acid sequence of SEQ 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 thereto, wherein the p chain variable domain comprises (a) a CDRip comprising or consisting of the amino acid sequence of SEQ ID NO: 107, or a variant thereof having up to three amino acid substitutions, additions or deletions; (b) a CDR2P comprising or consisting of the amino acid sequence of SEQ ID NO: 108, or a variant thereof having up to three amino acid substitutions, additions or deletions;

[0459] (c) a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 109, or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0460] In one aspect, the present invention provides a TCR comprising an a chain comprising or consisting of (i) the 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 thereto, or (ii) the 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 thereto; and / or a p chain comprising or consisting of (i) the amino acid sequence of SEQ ID NO: 105 or 106, or variants 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 thereto, or (ii) the amino acid sequence of SEQ ID NO: 111 or 112, or variants 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 thereto.

[0461] In one aspect, the present invention provides a TCR comprising an a chain comprising or consisting of (i) the 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 thereto, wherein the a chain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 98 or a variant thereof having up to three amino acid substitutions, additions or deletions, or (ii) the 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 thereto, wherein the a chain comprises a CDR3a comprising or consisting of the amino acid sequence of SEQ ID NO: 459 or a variant thereof having up to three amino acid substitutions, additions or deletions; and / or a chain comprising or consisting of (i) the amino acid sequence of SEQ ID NO: 105 or 106, or variants 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 thereto, wherein the P chain comprises a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 103 or a variant thereof having up to three amino acid substitutions, additions or deletions, or (ii) the amino acid sequence of SEQ ID NO: 111 or 112, or variants 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 thereto, wherein the p chain comprises a CDR3P comprising or consisting of the amino acid sequence of SEQ ID NO: 109 or a variant thereof having up to three amino acid substitutions, additions or deletions.

[0462] In one aspect, the present invention provides a TCR comprising an a chain comprising or consisting of (i) the 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 9...

Claims

CLAIMS1 . A T-cell receptor (TCR) which binds to an immunogenic peptide when presented by a major histocompatibility complex (MHC), wherein:(1) the immunogenic peptide is a Cathepsin G (CTSG) peptide and the TCR comprises a CDR3a comprising 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 a CDR3P comprising 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 comprises a CDR3a comprising (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 a CDR3P comprising (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 comprises a CDR3a comprising (i) the amino acid sequence of CVVNWDNARLMF (SEQ ID NO: 98) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CATRRAKDRDDKIIF (SEQ ID NO: 459) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising (i) the amino acid sequence of CASSEEGGSTDTQYF (SEQ ID NO: 103) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CASSLGLAGDYEQYF (SEQ ID NO: 109) or a variant thereof having up to three amino acid substitutions, additions or deletions;(4) the immunogenic peptide is a Mesothelin (MSLN) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAAYNDYKLSF (SEQ ID NO: 293) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSLQGVNTEAFF (SEQ ID NO: 298) or a variant thereof having up to three amino acid substitutions, additions or deletions;(5) the immunogenic peptide is a Dickkopf- related protein 1 (DKK1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAVGAWYNQGGKLIF (SEQ ID NO: 241) ora variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSFGVTGELFF (SEQ ID NO: 246) or a variant thereof having up to three amino acid substitutions, additions or deletions;(6) the immunogenic peptide is a Human epidermal growth factor receptor 2 (HER2) peptide and the TCR comprises a CDR3a 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 a CDR3P 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;(7) the immunogenic peptide is a Proteinase 3 (PR3) peptide or a Neutrophil elastase (NE) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CADYYGQNFVF (SEQ ID NO: 22) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSFQGYTEAFF (SEQ ID NO: 27) or a variant thereof having up to three amino acid substitutions, additions or deletions;(8) the immunogenic peptide is a Histone-lysine N-methyltransferase EZH2 (EZH2) peptide or a Preferentially expressed antigen of melanoma (PRAME) peptide and the TCR comprises a CDR3a comprising (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 a CDR3P comprising (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 comprises a CDR3a comprising the amino acid sequence of CAFMKRLTQGGSEKLVF (SEQ ID NO: 119) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence ofCASSEVYRGHEKLFF (SEQ ID NO: 124) or a variant thereof having up to three amino acid substitutions, additions or deletions;(10) the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TOR comprises a CDR3a comprising the amino acid sequence of CAASIRSSGDKLTF (SEQ ID NO: 133) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSKRTGELFF (SEQ ID NO: 138) or a variant thereof having up to three amino acid substitutions, additions or deletions;(11) the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CALSETLYNQGGKLIF (SEQ ID NO: 144) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSLGTSRSYTDTQYF (SEQ ID NO: 149) or a variant thereof having up to three amino acid substitutions, additions or deletions;(12) the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CALTSDYKLSF (SEQ ID NO: 157) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising (i) the amino acid sequence of CATSDLFGELFF (SEQ ID NO: 162) or a variant thereof having up to three amino acid substitutions, additions or deletions or (i) the amino acid sequence of CASTTGIYEQYF (SEQ ID NO: 168) or a variant thereof having up to three amino acid substitutions, additions or deletions;(13) the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAVNSWGKLQF (SEQ ID NO: 176) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASHSGLVGTGELFF (SEQ ID NO: 181) or a variant thereof having up to three amino acid substitutions, additions or deletions;(14) the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CASTNFGNEKLTF (SEQ ID NO: 192) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSLSYEQYF (SEQ ID NO: 197) or a variant thereof having up to three amino acid substitutions, additions or deletions;(15) the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising (i) the amino acid sequence of CAVRSHSGNTPLVF (SEQ ID NO: 206) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CAENAGGTSYGKLTF (SEQ ID NO: 211) or a variant thereof having up to three amino acid substitutions, additions or deletions or (iii) the amino acid sequence of CAMRLPIPNNAGNMLTF (SEQ ID NO: 216) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising (i) the amino acid sequence of CASSSPRVGPLYEQYF (SEQ ID NO: 221) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CASSDHDIYNEQFF (SEQ ID NO: 227) or a variant thereof having up to three amino acid substitutions, additions or deletions or (iii) the amino acid sequence of CASWAEEAEETQYF (SEQ ID NO: 233) or a variant thereof having up to three amino acid substitutions, additions or deletions;(16) the immunogenic peptide is a Mucin-5AC (MLIC5AC) peptide and the TCR comprises a CDR3a 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 a CDR3P 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;(17) the immunogenic peptide is an Anterior gradient-2 (AGR2) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAVQDYGQNFVF (SEQ ID NO: 267) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSPTGSEQYF (SEQ ID NO: 272) or a variant thereof having up to three amino acid substitutions, additions or deletions;(18) the immunogenic peptide is a c-MET peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAAAPNNNDMRF (SEQ ID NO: 280) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSLLAGGSSYEQYF (SEQ ID NO: 285) or a variant thereof having up to three amino acid substitutions, additions or deletions;(19) the immunogenic peptide is a CTD phosphatase subunit 1 (CTDP1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAMREGTSGTYKYIF (SEQ ID NO: 306) or a variant thereof having up to three aminoacid substitutions, additions or deletions, and a CDR3P 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;(20) the immunogenic peptide is a Transforming acidic coiled-coil-containing protein 2 (TACC2) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAVSGLGGSNYKLTF (SEQ ID NO: 319) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASRSGTGTMDEQFF (SEQ ID NO: 324) or a variant thereof having up to three amino acid substitutions, additions or deletions; or(21) the immunogenic peptide is a Prostaglandin F2 receptor negative regulator (PTGFRN) peptide and the TCR comprises a CDR3a comprising 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 a CDR3P comprising the amino acid sequence of CSARDYKQVLRGSYNSPLHF (SEQ ID NO: 337) or a variant thereof having up to 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 a CDR3a comprising 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 a CDR3P comprising the amino acid sequence of CASSVGRATEAFF (SEQ ID NO: 91) or a variant thereof having up to three amino acid substitutions, additions or deletions.

3. The TCR according to claim 2, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAVQASNDYKLSF (SEQ ID NO: 86), and a CDR3P comprising 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: CDR1a - VSGLRG (SEQ ID NO: 84), CDR2a - LYSAGEE (SEQ ID NO: 85), CDR3a - CAVQASNDYKLSF (SEQ ID NO: 86), CDRip - MNHEY (SEQ ID NO: 89), CDR2P - SMNVEV (SEQ ID NO: 90), and CDR3P - CASSVGRATEAFF (SEQ ID NO: 91), or variants thereof each having up to three amino acid substitutions, additions or deletions.

5. The TCR according to any of claims 2 to 4, wherein the TCR comprises an a 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 thereto; and a p chain variable domain comprising the aminoacid 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 thereto.

6. The TOR according to any of claims 2 to 5, wherein the TOR comprises an a 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 thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 93 or 94 or variants 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 thereto.

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

8. The TCR according to claim 1 , wherein the immunogenic peptide is a Cathepsin G (CTSG) peptide and the TCR comprises a CDR3a comprising (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 a CDR3P comprising (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.

9. The TCR according to claim 8, wherein the TCR comprises a CDR3a comprising (i) the amino acid sequence of CALPSARQLTF (SEQ ID NO: 61) or (ii) the amino acid sequence of CAFMSPEGGSEKLVF (SEQ ID NO: 66), and a CDR3P comprising (i) the amino acidsequence of CSVPPAGLGAPEAFF (SEQ ID NO: 71) or (ii) the amino acid sequence of CASSPGTGAYNSPLHF (SEQ ID NO: 77).

10. The TOR according to claim 8 or 9, wherein the TOR comprises the following CDR sequences: (i) CDR1a - ATGYPS (SEQ ID NO: 59), CDR2a - ATKADDK (SEQ ID NO: 60), and CDR3a - CALPSARQLTF (SEQ ID NO: 61) or (ii) CDR1a - TSENNYY (SEQ ID NO: 64), CDR2a - QEAYKQQN (SEQ ID NO: 65), and CDR3a - CAFMSPEGGSEKLVF (SEQ ID NO: 66), and (i) CDR1 - SQVTM (SEQ ID NO: 69), CDR2 - ANQGSEA (SEQ ID NO: 70), and CDR3P - CSVPPAGLGAPEAFF (SEQ ID NO: 71) or (ii) CDR1 - SEHNR (SEQ ID NO: 75), CDR2P - FQNEAQ (SEQ ID NO: 76), and CDR3P - CASSPGTGAYNSPLHF (SEQ ID NO: 77), or variants thereof each having up to three amino acid substitutions, additions or deletions.

11. The TCR according to any of claims 8 to 10, wherein the TCR comprises an a chain variable domain comprising (i) the 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 thereto 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 98%, or at least 99% sequence identity thereto; and a p chain variable domain comprising (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 98%, or at least 99% sequence identity thereto 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 98%, or at least 99% sequence identity thereto.

12. The TCR according to any of claims 8 to 11 , wherein the TCR comprises an a 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 thereto 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 thereto; and a p chain comprising (i) the amino acid sequence of SEQ ID NO: 73 or 74 or variants 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 thereto or (ii) the amino acid sequence of SEQ ID NO: 79 or 80 or variants 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 thereto.

13. The TCR according to any of claims 8 to 12, wherein 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 up to three amino acid substitutions, additions or deletions.

14. The TCR according to claim 1 , wherein the immunogenic peptide is a Cathepsin G (CTSG) peptide and the TCR comprises a CDR3a comprising (i) the amino acid sequence of CVVNWDNARLMF (SEQ ID NO: 98) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CATRRAKDRDDKIIF (SEQ ID NO: 459) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising (i) the amino acid sequence of CASSEEGGSTDTQYF (SEQ ID NO: 103) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CASSLGLAGDYEQYF (SEQ ID NO: 109) or a variant thereof having up to three amino acid substitutions, additions or deletions.

15. The TCR according to claim 14, wherein the TCR comprises a CDR3a comprising (i) the amino acid sequence of CVVNWDNARLMF (SEQ ID NO: 98) or (ii) the amino acid sequence of CATRRAKDRDDKIIF (SEQ ID NO: 459), and a CDR3P comprising (i) the amino acid sequence of CASSEEGGSTDTQYF (SEQ ID NO: 103) or (ii) the amino acid sequence of CASSLGLAGDYEQYF (SEQ ID NO: 109).

16. The TCR according to claim 14 or 15, wherein the TCR comprises the following CDR sequences: (i) CDR1a - NSASQS (SEQ ID NO: 96), CDR2a - VYSSGN (SEQ ID NO: 97), CDR3a - CVVNWDNARLMF (SEQ ID NO: 98) or (ii) CDR1a - NSAFQY (SEQ ID NO: 457), CDR2a - TYSSGN (SEQ ID NO: 458), CDR3a - CATRRAKDRDDKIIF (SEQ ID NO: 459), and (i) CDR1 P - SNHLY (SEQ ID NO: 101), CDR2P - FYNNEI (SEQ ID NO: 102), and CDR3P - CASSEEGGSTDTQYF (SEQ ID NO: 103) or (ii) CDRip - SGHNS (SEQ ID NO: 107), CDR2P - FNNNVP (SEQ ID NO: 108), and CDR3P - CASSLGLAGDYEQYF (SEQ ID NO: 109), or variants thereof each having up to three amino acid substitutions, additions or deletions.

17. The TCR according to any of claims 14 to 16, wherein the TCR comprises an a chain variable domain comprising (i) the 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 thereto or (ii) the 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 thereto; and a p chain variable domain comprising (i) the 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 least95%, at least 98%, or at least 99% sequence identity thereto or (ii) the amino acid sequence of SEQ 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 98%, or at least 99% sequence identity thereto.

18. The TOR according to any of claims 14 to 17, wherein the TOR comprises an a chain comprising (i) the 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 thereto or (ii) the 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 thereto; and a chain comprising (i) the amino acid sequence of SEQ ID NO: 105 or 106 or variants 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 thereto or (ii) the amino acid sequence of SEQ ID NO: 111 or 112 or variants 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 thereto.

19. The TCR according to any of claims 14 to 18, wherein 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 up to three amino acid substitutions, additions or deletions.

20. The TCR according to claim 1 , wherein the immunogenic peptide is a Human epidermal growth factor receptor 2 (HER2) peptide and the TCR comprises a CDR3a 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 a CDR3P 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.

21. The TCR according to claim 20, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAEGSRYGGATNKLIF (SEQ ID NO: 8), and a CDR3P comprising 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: CDR1a - NSASDY (SEQ ID NO: 6), CDR2a - IRSNMDK (SEQ ID NO: 7), CDR3a - CAEGSRYGGATNKLIF (SEQ ID NO: 8), CDRi p - MNHEY (SEQ ID NO: 11), CDR2P - SVGAGI (SEQ ID NO: 12), and CDR3P - CASSTFPVETQYF (SEQ ID NO: 13), or variants thereof each having up to three amino acid substitutions, additions or deletions.

23. The TCR according to any of claims 20 to 22, wherein the TCR comprises an a chain variable domain comprising 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 98%, or at least 99% sequence identity thereto; and a p chain variable domain comprising 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 98%, or at least 99% sequence identity thereto.

24. The TCR according to any of claims 20 to 23, wherein the TCR comprises an a 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 thereto; and a chain comprising the amino acid sequence of SEQ ID NO: 15 or 16 or variants 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 thereto.

25. The TCR according to any of claims 20 to 24, wherein the HER2 peptide comprises or consists of 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 according to claim 1 , wherein the immunogenic peptide is a Proteinase 3 (PR3) peptide or a Neutrophil elastase (NE) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CADYYGQNFVF (SEQ ID NO: 22) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSFQGYTEAFF (SEQ ID NO: 27) or a variant thereof having up to three amino acid substitutions, additions or deletions.

27. The TCR according to claim 26, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CADYYGQNFVF (SEQ ID NO: 22), and a CDR3P comprising 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: CDR1a - VSGNPY (SEQ ID NO: 20), CDR2a - YITGDNLV (SEQ ID NO: 21), CDR3a - CADYYGQNFVF (SEQ ID NO: 22), CDRip - MDHEN (SEQ ID NO: 25), CDR2P - SYDVKM (SEQ ID NO: 26), and CDR3P - CASSFQGYTEAFF (SEQ ID NO: 27), or variants thereof each having up to three amino acid substitutions, additions or deletions.

29. The TCR according to any of claims 26 to 28, wherein the TCR comprises an a 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%, atleast 98%, or at least 99% sequence identity thereto; and a p 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 thereto.

30. The TOR according to any of claims 26 to 29, wherein the TOR comprises an a 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 thereto; and a chain comprising the amino acid sequence of SEQ ID NO: 29 or 30 or variants 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 thereto.

31. The TCR according to any of claims 26 to 30, wherein the peptide comprises or consists of the amino acid sequence of VLQELNVTV (SEQ ID NO: 19) or a variant thereof having up to 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 Preferentially expressed antigen of melanoma (PRAME) peptide and the TCR comprises a CDR3a comprising (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 a CDR3P comprising (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.

33. The TCR according to claim 32, wherein the TCR comprises a CDR3a comprising (i) the amino acid sequence of CAVSESPTGFQKLVF (SEQ ID NO: 37) or (ii) the amino acid sequence of CAVPHSYNTDKLIF (SEQ ID NO: 42), and a CDR3P comprising (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) CDR1a - SSVPPY (SEQ ID NO: 35), CDR2a - YTSAATLV (SEQ ID NO: 36), and CDR3a - CAVSESPTGFQKLVF (SEQ ID NO: 37) or (ii) CDR1a - VGISA (SEQ ID NO: 40), CDR2a - LSSGK (SEQ ID NO: 41), and CDR3a - CAVPHSYNTDKLIF (SEQ ID NO: 42), and (i) CDR1 - SNHLY (SEQ ID NO: 45), CDR2 - FYNNEI (SEQ ID NO: 46), and CDR3 - CASSPRGSNTGELFF (SEQ ID NO: 47) or (ii) CDR1 - DFQATT (SEQ ID NO: 51), CDR2 -SNEGSKA (SEQ ID NO: 52), and CDR3 - CSARPSEAPQYF (SEQ ID NO: 53), or variants thereof each having up to three amino acid substitutions, additions or deletions.

35. The TOR according to any of claims 32 to 34, wherein the TOR comprises an a chain variable domain comprising (i) 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 98%, or at least 99% sequence identity thereto 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 98%, or at least 99% sequence identity thereto; and a p chain variable domain comprising (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 98%, or at least 99% sequence identity thereto 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 98%, or at least 99% sequence identity thereto.

36. The TOR according to any of claims 32 to 35, wherein the TOR comprises an a 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 thereto 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 thereto; and a chain comprising (i) the amino acid sequence of SEQ ID NO: 49 or 50 or variants 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 thereto or (ii) the amino acid sequence of SEQ ID NO: 55 or 56 or variants 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 thereto.

37. The TOR according to any of claims 32 to 36, wherein the EZH2 peptide comprises or consists of the amino acid sequence of KESRPPRKF (SEQ ID NO: 32) or a variant thereof having up to three amino acid substitutions, additions or deletions; or (ii) a Preferentially expressed antigen of melanoma (PRAME) peptide when presented by an MHO, wherein the PRAME peptide comprises or consists of the amino acid sequence of ALYVDSLFFL (SEQ ID NO: 34) or a variant thereof having up to three amino acid substitutions, additions or deletions.

38. The TOR according to claim 1 , wherein the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TOR comprises a CDR3a comprising the amino acid sequence of CAFMKRLTQGGSEKLVF (SEQ ID NO: 119) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequenceof CASSEVYRGHEKLFF (SEQ ID NO: 124) or a variant thereof having up to three amino acid substitutions, additions or deletions.

39. The TCR according to claim 38, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAFMKRLTQGGSEKLVF (SEQ ID NO: 119), and a CDR3 comprising 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: CDR1a - TSENNYY (SEQ ID NO: 117), CDR2a - QEAYKQQN (SEQ ID NO: 118), CDR3a - CAFMKRLTQGGSEKLVF (SEQ ID NO: 119), CDR1 - SNHLY (SEQ ID NO: 122), CDR2P - FYNNEI (SEQ ID NO: 123), and CDR3 - CASSEVYRGHEKLFF (SEQ ID NO: 124), or variants thereof each having up to three amino acid substitutions, additions or deletions.

41. The TCR according to any of claims 38 to 40, wherein the TCR comprises an a chain variable domain comprising the 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 thereto; and a p chain variable domain comprising the 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 thereto.

42. The TCR according to any of claims 38 to 41 , wherein the TCR comprises an a chain comprising the 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 thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 126 or 127 or variants 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 thereto.

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

44. The TCR according to claim 1 , wherein the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAASIRSSGDKLTF (SEQ ID NO: 133) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence ofCASSKRTGELFF (SEQ ID NO: 138) or a variant thereof having up to three amino acid substitutions, additions or deletions.

45. The TOR according to claim 44, wherein the TOR comprises a CDR3a comprising the amino acid sequence of CAASIRSSGDKLTF (SEQ ID NO: 133), and a CDR3P comprising 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: CDR1a - DSASNY (SEQ ID NO: 131), CDR2a - IRSNVGE (SEQ ID NO: 132), CDR3a - CAASIRSSGDKLTF (SEQ ID NO: 133), CDR1 - MDHEN (SEQ ID NO: 136), CDR2P - SYDVKM (SEQ ID NO: 137), and CDR3P - CASSKRTGELFF (SEQ ID NO: 138), or variants thereof each having up to three amino acid substitutions, additions or deletions.

47. The TCR according to any of claims 44 to 46, wherein the TCR comprises an a chain variable domain comprising the 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 thereto; and a p chain variable domain comprising the 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 thereto.

48. The TCR according to any of claims 44 to 47, wherein the TCR comprises an a chain comprising the 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 thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 140 or 141 or variants 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 thereto.

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

50. The TCR according to claim 1 , wherein the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CALSETLYNQGGKLIF (SEQ ID NO: 144) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSLGTSRSYTDTQYF (SEQ ID NO: 149) or a variant thereof having up to three amino acid substitutions, additions or deletions.

51. The TCR according to claim 50, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CALSETLYNQGGKLIF (SEQ ID NO: 144), and a CDR3P comprising 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: CDR1a - TRDTTYY (SEQ ID NO: 142), CDR2a - RNSFDEQN (SEQ ID NO: 143), CDR3a - CALSETLYNQGGKLIF (SEQ ID NO: 144), CDR1 - SGHTA (SEQ ID NO: 147), CDR2P - FQGNSA (SEQ ID NO: 148), and CDR3P - CASSLGTSRSYTDTQYF (SEQ ID NO: 149), or variants thereof each having up to three amino acid substitutions, additions or deletions.

53. The TCR according to any of claims 50 to 52, wherein the TCR comprises an a chain variable domain comprising the 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 thereto; and a p chain variable domain comprising the 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 thereto.

54. The TCR according to any of claims 50 to 53, wherein the TCR comprises an a chain comprising the 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 thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 151 or 152 or variants 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 thereto.

55. The TCR according to claim 1 , wherein the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CALTSDYKLSF (SEQ ID NO: 157) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising (i) the amino acid sequence of CATSDLFGELFF (SEQ ID NO: 162) or a variant thereof having up to three amino acid substitutions, additions or deletions or (i) the amino acid sequence of CASTTGIYEQYF (SEQ ID NO: 168) or a variant thereof having up to three amino acid substitutions, additions or deletions.

56. The TCR according to claim 55, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CALTSDYKLSF (SEQ ID NO: 157), and a CDR3P comprising (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: CDR1a - SSNFYA (SEQ ID NO: 155), CDR2a - MTLNGDE (SEQ ID NO: 156), CDR3a - CALTSDYKLSF (SEQ ID NO: 157), and (i) CDR1 - KGHDR (SEQ ID NO: 160), CDR2P - SFDVKD (SEQ ID NO: 161), and CDR3 - CATSDLFGELFF (SEQ ID NO: 162) or (ii) CDR1 P - SNHLY (SEQ ID NO: 166), CDR2P - FYNNEI (SEQ ID NO: 167), and CDR3P - CASTTGIYEQYF (SEQ ID NO: 168), or variants thereof each having up to three amino acid substitutions, additions or deletions.

58. The TCR according to any of claims 55 to 57, wherein the TCR comprises an a chain variable domain comprising the 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 thereto; and a p chain variable domain comprising (i) the 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 thereto or (ii) the 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 thereto.

59. The TCR according to any of claims 55 to 58, wherein the TCR comprises an a chain comprising the 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 thereto; and a p chain comprising (i) the amino acid sequence of SEQ ID NO: 164 or 165 or variants 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 thereto or (ii) the amino acid sequence of SEQ ID NO: 170 or 171 or variants 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 thereto.

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

61. The TCR according to claim 1 , wherein the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAVNSWGKLQF (SEQ ID NO: 176) or a variant thereof having up to three amino acidsubstitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASHSGLVGTGELFF (SEQ ID NO: 181) or a variant thereof having up to three amino acid substitutions, additions or deletions.

62. The TCR according to claim 61 , wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAVNSWGKLQF (SEQ ID NO: 176), and a CDR3P comprising 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: CDR1a - TSGFNG (SEQ ID NO: 174), CDR2a - NVLDGL (SEQ ID NO: 175), CDR3a - CAVNSWGKLQF (SEQ ID NO: 176), CDR1 - MNHEY (SEQ ID NO: 179), CDR2 - SMNVEV (SEQ ID NO: 180), and CDR3 - CASHSGLVGTGELFF (SEQ ID NO: 181) or variants thereof each having up to three amino acid substitutions, additions or deletions.

64. The TCR according to any of claims 61 to 63, wherein the TCR comprises an a chain variable domain comprising the 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 thereto; and a p chain variable domain comprising the 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 thereto.

65. The TCR according to any of claims 61 to 64, wherein the TCR comprises an a chain comprising the 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 thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 183 or 184 or variants 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 thereto.

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

67. The TCR according to claim 1 , wherein the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CASTNFGNEKLTF (SEQ ID NO: 192) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence ofCASSLSYEQYF (SEQ ID NO: 197) or a variant thereof having up to three amino acid substitutions, additions or deletions.

68. The TCR according to claim 67, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CASTNFGNEKLTF (SEQ ID NO: 192), and a CDR3P comprising 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: CDR1a - TSESDYY (SEQ ID NO: 190), CDR2a - QEAYKQQN (SEQ ID NO: 191), CDR3a - CASTNFGNEKLTF (SEQ ID NO: 192), CDR1 - PRHDT (SEQ ID NO: 195), CDR2 - FYEKMQ (SEQ ID NO: 196), and CDR3 - CASSLSYEQYF (SEQ ID NO: 197), or variants thereof each having up to three amino acid substitutions, additions or deletions.

70. The TCR according to any of claims 67 to 69, wherein the TCR comprises an a chain variable domain comprising the 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 thereto; and a p chain variable domain comprising the 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 thereto.

71. The TCR according to any of claims 67 to 70, wherein the TCR comprises an a chain comprising the 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 thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 199 or 200 or variants 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 thereto.

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

73. The TCR according to claim 1 , wherein the immunogenic peptide is a Cyclin A1 (CCNA1) peptide and the TCR comprises a CDR3a comprising (i) the amino acid sequence of CAVRSHSGNTPLVF (SEQ ID NO: 206) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CAENAGGTSYGKLTF (SEQ ID NO: 211) or a variant thereof having up to three amino acid substitutions, additions or deletions or (iii) the amino acid sequence of CAMRLPIPNNAGNMLTF (SEQ ID NO: 216)or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising (i) the amino acid sequence of CASSSPRVGPLYEQYF (SEQ ID NO: 221) or a variant thereof having up to three amino acid substitutions, additions or deletions or (ii) the amino acid sequence of CASSDHDIYNEQFF (SEQ ID NO: 227) ora variant thereof having up to three amino acid substitutions, additions or deletions or (iii) the amino acid sequence of CASWAEEAEETQYF (SEQ ID NO: 233) or a variant thereof having up to three amino acid substitutions, additions or deletions.

74. The TCR according to claim 73, wherein the TCR comprises a CDR3a comprising (i) the amino acid sequence of CAVRSHSGNTPLVF (SEQ ID NO: 206) or (ii) the amino acid sequence of CAENAGGTSYGKLTF (SEQ ID NO: 211) or (iii) the amino acid sequence of CAMRLPIPNNAGNMLTF (SEQ ID NO: 216), and a CDR3P comprising (i) the amino acid sequence of CASSSPRVGPLYEQYF (SEQ ID NO: 221) or (ii) the amino acid sequence of CASSDHDIYNEQFF (SEQ ID NO: 227) or (iii) the amino acid sequence of CASWAEEAEETQYF (SEQ ID NO: 233).

75. The TCR according to claim 73 or 74, wherein the TCR comprises the following CDR sequences: (i) CDR1a - TSGFYG (SEQ ID NO: 204), CDR2a - NALDGL (SEQ ID NO: 205), and CDR3a - CAVRSHSGNTPLVF (SEQ ID NO: 206) or (ii) CDR1a - NSASDY (SEQ ID NO: 209), CDR2a - IRSNMDK (SEQ ID NO: 210), and CDR3a - CAENAGGTSYGKLTF (SEQ ID NO: 211) or (iii) CDR1a - TSDQSYG (SEQ ID NO: 214), CDR2a - QGSYDEQN (SEQ ID NO: 215), and CDR3a - CAMRLPIPNNAGNMLTF (SEQ ID NO: 216), and (i) CDRi p - SEHNR (SEQ ID NO: 219), CDR2P - FQNEAQ (SEQ ID NO: 220), and CDR3P - CASSSPRVGPLYEQYF (SEQ ID NO: 221) or (ii) CDR1 p - SEHNR (SEQ ID NO: 225), CDR2P - FQNEAQ (SEQ ID NO: 226), and CDR3P - CASSDHDIYNEQFF (SEQ ID NO: 227) or (iii) CDRi p - SNHLY (SEQ ID NO: 231), CDR2P - FYNNEI (SEQ ID NO: 232), and CDR3P - CASWAEEAEETQYF (SEQ ID NO: 233), or variants thereof each having up to three amino acid substitutions, additions or deletions.

76. The TCR according to any of claims 73 to 75, wherein the TCR comprises an a chain variable domain comprising (i) the 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 thereto or (ii) the 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 thereto or (iii) the 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 thereto; and a p chain variable domain comprising (i) the amino acidsequence 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 thereto 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 thereto 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 thereto.

77. The TCR according to any of claims 73 to 76, wherein the TCR comprises an a chain comprising (i) the 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 thereto or (ii) the 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 thereto or (iii) the 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 thereto; and a chain comprising (i) the amino acid sequence of SEQ ID NO: 223 or 224 or variants 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 thereto or (ii) the amino acid sequence of SEQ ID NO: 229 or 230 or variants 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 thereto or (iii) the amino acid sequence of SEQ ID NO: 235 or 236 or variants 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 thereto.

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

79. The TCR according to claim 1 , wherein the immunogenic peptide is a Dickkopf-related protein 1 (DKK1) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAVGAWYNQGGKLIF (SEQ ID NO: 241) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSFGVTGELFF (SEQ ID NO: 246) or a variant thereof having up to three amino acid substitutions, additions or deletions.

80. The TCR according to claim 79, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAVGAWYNQGGKLIF (SEQ ID NO: 241), and a CDR3P comprising 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: CDR1a - YGATPY (SEQ ID NO: 239), CDR2a - YFSGDTLV (SEQ ID NO: 240), CDR3a - YFSGDTLV (SEQ ID NO: 241), CDR1 - SGHDY (SEQ ID NO: 244), CDR2 - FNNNVP (SEQ ID NO: 245), and CDR3 - CASSFGVTGELFF (SEQ ID NO: 246), or variants thereof each having up to three amino acid substitutions, additions or deletions.

82. The TCR according to any of claims 79 to 81 , wherein the TCR comprises an a chain variable domain comprising the 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 thereto; and a p chain variable domain comprising the 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 thereto.

83. The TCR according to any of claims 79 to 82, wherein the TCR comprises an a chain comprising the 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 thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 248 or 249 or variants 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 thereto.

84. The TCR according to any of claims 79 to 83, wherein the DKK1 peptide comprises or consists of 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 according to claim 1 , wherein the immunogenic peptide is a Mucin-5AC (MUC5AC) peptide and the TCR comprises a CDR3a 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 a CDR3P 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.

86. The TCR according to claim 85, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAGGGSGAGSYQLTF (SEQ ID NO: 254), and a CDR3P comprising 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: CDR1a - DRGSQS (SEQ ID NO: 252), CDR2a - IYSNGD (SEQ ID NO: 253), CDR3a - CAGGGSGAGSYQLTF (SEQ ID NO: 254), CDR1 - ENHRY (SEQ ID NO: 257), CDR2P - SYGVKD (SEQ ID NO: 258), and CDR3 - CAISDPTGDNQPQHF (SEQ ID NO: 259), or variants thereof each having up to three amino acid substitutions, additions or deletions.

88. The TCR according to any of claims 85 to 87, wherein the TCR comprises an a chain variable domain comprising the 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 thereto; and a p chain variable domain comprising the 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 thereto.

89. The TCR according to any of claims 85 to 88, wherein the TCR comprises an a chain comprising the 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 thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 261 or 262 or variants 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 thereto.

90. The TCR according to any of claims 85 to 89, wherein the MLIC5AC peptide comprises or consists of the amino acid sequence of FLNDAGACV (SEQ ID NO: 251) or a variant thereof having up to three amino acid substitutions, additions or deletions.

91. The TCR according to claim 1 , wherein the immunogenic peptide is an Anterior gradient- 2 (AGR2) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAVQDYGQNFVF (SEQ ID NO: 267) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSPTGSEQYF (SEQ ID NO: 272) or a variant thereof having up to three amino acid substitutions, additions or deletions.

92. The TCR according to claim 91 , wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAVQDYGQNFVF (SEQ ID NO: 267), and a CDR3P comprising 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: CDR1a - VSGLRG (SEQ ID NO: 265), CDR2a - LYSAGEE (SEQ ID NO: 266),CDR3a - CAVQDYGQNFVF (SEQ ID NO: 267), CDRip - MNHEY (SEQ ID NO: 270), CDR2 - SMNVEV (SEQ ID NO: 271), and CDR3 - CASSPTGSEQYF (SEQ ID NO: 272), or variants thereof each having up to three amino acid substitutions, additions or deletions.

94. The TOR according to any of claims 91 to 93, wherein the TOR comprises an a chain variable domain comprising the 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 thereto; and a p chain variable domain comprising the 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 thereto.

95. The TOR according to any of claims 91 to 94, wherein the TOR comprises an a chain comprising the 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 thereto; and a chain comprising the amino acid sequence of SEQ ID NO: 274 or 275 or variants 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 thereto.

96. The TOR according to any of claims 91 to 95, wherein the AGR2 peptide comprises or consists of 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 TOR according to claim 1 , wherein the immunogenic peptide is a c-MET peptide and the TOR comprises a CDR3a comprising the amino acid sequence of CAAAPNNNDMRF (SEQ ID NO: 280) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSLLAGGSSYEQYF (SEQ ID NO: 285) or a variant thereof having up to three amino acid substitutions, additions or deletions.

98. The TOR according to claim 97, wherein the TOR comprises a CDR3a comprising the amino acid sequence of CAAAPNNNDMRF (SEQ ID NO: 280), and a CDR3P comprising 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: CDR1a - DSASNY (SEQ ID NO: 278), CDR2a - IRSNVGE (SEQ ID NO: 279), CDR3a - CAAAPNNNDMRF (SEQ ID NO: 280), CDRip - MNHEY (SEQ ID NO: 283), CDR2P - SVGAGI (SEQ ID NO: 284), and CDR3P - CASSLLAGGSSYEQYF (SEQ ID NO: 285), or variants thereof each having up to three amino acid substitutions, additions or deletions.

100. The TCR according to any of claims 97 to 99, wherein the TCR comprises an a chain variable domain comprising the 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 thereto; and a p chain variable domain comprising the 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 thereto.

101. The TCR according to any of claims 97 to 100, wherein the TCR comprises an a chain comprising the 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 thereto; and a chain comprising the amino acid sequence of SEQ ID NO: 287 or 288 or variants 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 thereto.

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

103. The TCR according to claim 1 , wherein the immunogenic peptide is a Mesothelin (MSLN) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAAYNDYKLSF (SEQ ID NO: 293) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASSLQGVNTEAFF (SEQ ID NO: 298) or a variant thereof having up to three amino acid substitutions, additions or deletions.

104. The TCR according to claim 103, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAAYNDYKLSF (SEQ ID NO: 293), and a CDR3P comprising 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: CDR1a - SSNFYA (SEQ ID NO: 291), CDR2a - MTLNGDE (SEQ ID NO: 292), CDR3a - CAAYNDYKLSF (SEQ ID NO: 293), CDRi p - MNHEY (SEQ ID NO: 296), CDR2P - SMNVEV (SEQ ID NO: 297), and CDR3P - CASSLQGVNTEAFF (SEQ ID NO: 298), or variants thereof each having up to three amino acid substitutions, additions or deletions.

106. The TCR according to any of claims 103 to 105, wherein the TCR comprises an a chain variable domain comprising the 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%, atleast 98%, or at least 99% sequence identity thereto; and a p chain variable domain comprising the 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 thereto.

107. The TOR according to any of claims 103 to 106, wherein the TOR comprises an a chain comprising the 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 thereto; and a chain comprising the amino acid sequence of SEQ ID NO: 300 or 301 or variants 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 thereto.

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

109. The TCR according to claim 1 , wherein the immunogenic peptide is a CTD phosphatase subunit 1 (CTDP1) peptide and the TCR comprises a CDR3a 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 a CDR3P 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.

110. The TCR according to claim 109, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAMREGTSGTYKYIF (SEQ ID NO: 306), and a CDR3P comprising 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: CDR1a - TSDPSYG (SEQ ID NO: 304), CDR2a - QGSYDQQN (SEQ ID NO: 305), CDR3a - CAMREGTSGTYKYIF (SEQ ID NO: 306), CDR1 p - SEHNR (SEQ ID NO: 309), CDR2P - FQNEAQ (SEQ ID NO: 310), and CDR3P - CASSNSASRPEQYV (SEQ ID NO: 311), or variants thereof each having up to three amino acid substitutions, additions or deletions.

112. The TCR according to any of claims 109 to 111 , wherein the TCR comprises an a chain variable domain comprising the 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 thereto; and a p chain variable domain comprising the amino acid sequence of SEQ ID NO: 312 or a variant thereof having at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

113. The TCR according to any of claims 109 to 112, wherein the TCR comprises an a chain comprising the 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 thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 313 or 314 or variants 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 thereto.

114. The TCR according to claim 109 to 113, wherein the CTDP1 peptide comprises or consists of 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 according to claim 1 , wherein the immunogenic peptide is a Transforming acidic coiled-coil-containing protein 2 (TACC2) peptide and the TCR comprises a CDR3a comprising the amino acid sequence of CAVSGLGGSNYKLTF (SEQ ID NO: 319) or a variant thereof having up to three amino acid substitutions, additions or deletions, and a CDR3P comprising the amino acid sequence of CASRSGTGTMDEQFF (SEQ ID NO: 324) or a variant thereof having up to three amino acid substitutions, additions or deletions.

116. The TCR according to claim 115, wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAVSGLGGSNYKLTF (SEQ ID NO: 319), and a CDR3P comprising the amino acid sequence of CASRSGTGTMDEQFF (SEQ ID NO: 324).

117. The TCR according to claim 115 or 116, wherein the TCR comprises the following CDR sequences: CDR1a - SSVPPY (SEQ ID NO: 317), CDR2a - YTSAATLV (SEQ ID NO: 318), CDR3a - CAVSGLGGSNYKLTF (SEQ ID NO: 319), CDRip - MNHNY (SEQ ID NO: 322), CDR2P - SVGAGI (SEQ ID NO: 323), and CDR3P - CASRSGTGTMDEQFF (SEQ ID NO: 324), or variants thereof each having up to three amino acid substitutions, additions or deletions.

118. The TCR according to any of claims 115 to 117, wherein the TCR comprises an a chain variable domain comprising the 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 thereto; and a chain variable domain comprising the 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 thereto.

119. The TCR according to any of claims 115 to 118, wherein the TCR comprises an a chain comprising the 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 thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 326 or 327 or variants 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 thereto.

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

121. The TCR according to claim 1 , wherein the immunogenic peptide is a Prostaglandin F2 receptor negative regulator (PTGFRN) peptide and the TCR comprises a CDR3a comprising 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 a CDR3P comprising the amino acid sequence of CSARDYKQVLRGSYNSPLHF (SEQ ID NO: 337) or a variant thereof having up to three amino acid substitutions, additions or deletions.

122. The TCR according to claim 121 , wherein the TCR comprises a CDR3a comprising the amino acid sequence of CAVNRDDKIIF (SEQ ID NO: 332), and a CDR3P comprising 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: CDR1a - DSAIYN (SEQ ID NO: 330), CDR2a - IQSSQRE (SEQ ID NO: 331), CDR3a - CAVNRDDKIIF (SEQ ID NO: 332), CDRi p - DFQATT (SEQ ID NO: 335), CDR2P - SNEGSKA (SEQ ID NO: 336), and CDR3P - CSARDYKQVLRGSYNSPLHF (SEQ ID NO: 337), or variants thereof each having up to three amino acid substitutions, additions or deletions.

124. The TCR according to any of claims 121 to 123, wherein the TCR comprises an a chain variable domain comprising the 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 thereto; and a chain variable domain comprising the 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 thereto.

125. The TCR according to any of claims 121 to 124, wherein the TCR comprises an a chain comprising the amino acid sequence of SEQ ID NO: 334 or a variant thereof having at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto; and a p chain comprising the amino acid sequence of SEQ ID NO: 339 or 340 or variants 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 thereto.

126. The TOR according to any of claims 121 to 125, wherein the PTGFRN peptide comprises or consists of 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 preceding claim, wherein the TCR comprises one or more mutations at the a chain / p chain interface, such that when the a chain and the p chain are expressed in a T-cell, the frequency of mispairing between said chains and endogenous TCR a and p chains is reduced.

128. The TCR according to claim 127, wherein the one or more mutations introduce a cysteine residue into the constant region domain of each of the a chain and the p chain, wherein the cysteine residues are capable of forming a disulphide bond between the a chain and the p chain.

129. The TCR according to any preceding claim, wherein the TCR comprises a murinised constant region.

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

131. A polynucleotide encoding the a chain and / or the p chain of a TCR according to any of claims 1-130.

132. The polynucleotide according to claim 131 , wherein the polynucleotide encodes the a chain linked to the p chain.

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

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

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 a polynucleotide which encodes one or more CD3 chains, CD8, a suicide gene and / or a selectable marker.

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

138. The cell according to claim 137, wherein the cell further comprises a vector which encodes one or more CD3 chains, CD8, a suicide gene and / or a selectable marker.

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 according to 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, ThO cells, TcO cells, Th1 cells, Tc1 cells, Th2 cells, Tc2 cells, Th17 cells, Th22 cells, gamma / delta 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 of claims 137-140, wherein the cell is a T-cell, optionally wherein the cell is a T-cell which has been isolated from a subject.

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

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

144. The cell according to any of claims 137-143, wherein an endogenous gene involved in persistence, expansion, activity, resistance to exhaustion / senescence / inhibitory signals, homing capacity, or other T-cell functions is disrupted, optionally wherein the endogenous gene involved in persistence, expansion, activity, resistance to exhaustion / senescence / inhibitory signals, homing capacity, or other T-cell functions is selected from the group consisting of PD1, TIM3, LAG3, 2B4, KLRG1, TGFbR, CD160, TIGIT, CTLA4 and CD39.

145. A method of preparing a cell, which comprises the step of introducing a polynucleotide according to any of claims 131-133 or a vector according to any of claims 134-136 into a cell in vitro, ex vivo or in vivo, for example by transfection or transduction.

146. The method according to claim 145, wherein the method comprises the step of T-cell editing, which comprises disrupting an endogenous gene encoding a TCR a chain and / or an endogenous gene encoding a TCR p 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 CRISPR / Cas systems.

147. The method according to claim 146, wherein the method comprises the step of targeted integration of an expression cassette into the endogenous gene encoding the TCR a chain and / or the endogenous gene encoding the TCR chain disrupted by the artificial nuclease, wherein the expression cassette comprises a polynucleotide sequence encoding the TCR of any of claims 1-130.

148. The method according to any of claims 145-147, wherein the method comprises the step of disrupting one or more endogenous genes encoding an MHC, optionally wherein the cell prepared by the method is a non-alloreactive universal T-cell.

149. The method according to any of claims 145-148, wherein the method comprises the step of disrupting one or more endogenous genes to modify the persistence, expansion, activity, resistance to exhaustion / senescence / inhibitory signals, homing capacity, or other T-cell functions, optionally wherein the method comprises the step of targeted integration of an expression cassette into an endogenous gene involved in persistence, expansion, activity, resistance to exhaustion / senescence / inhibitory signals, homing capacity, or other T-cell functions disrupted by an artificial nuclease, wherein the expression cassette comprises a polynucleotide sequence encoding the TCR of any of claims 1-130, 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 the TCR of any of claims 1-130, or a portion thereof, conjugated to a non-cellular substrate, a toxin and / or an antibody, optionally wherein the non- cellular substrate is selected from the group consisting of nanoparticles, exosomes and other non-cellular substrates.

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

152. A cell according to any of claims 137-144 or a cell prepared by the method of any of claims 145-149 for use in adoptive cell transfer, preferably adoptive T-cell transfer, optionally wherein the adoptive T-cell transfer is allogenic adoptive T-cell transfer, autologous adoptive T-cell transfer, or universal non-alloreactive adoptive T-cell transfer.

153. A TCR according to any of claims 1-130, a polynucleotide according to any of claims 131- 133, a vector according to any of claims 134-136, a cell according to any of claims 137-144, a cell prepared by a method according to any of claims 145-149, a chimeric molecule according to claim 150, or a pharmaceutical composition according to claim 151 for use in therapy.

154. A TCR according to any of claims 1-130, a polynucleotide according to any of claims 131- 133, a vector according to any of claims 134-136, a cell according to any of claims 137-144, a cell prepared by a method according to any of claims 145-149, a chimeric molecule according to claim 150, or a pharmaceutical composition according to claim 151 for use in treating and / or preventing a proliferative disorder.

155. The TCR, polynucleotide, vector, cell, chimeric molecule, or pharmaceutical composition for use according to claim 154, wherein the proliferative disorder is a haematological malignancy or a solid tumour, optionally wherein the haematological malignancy is selected from the group consisting of acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), lymphoblastic leukaemia, acute lymphocytic leukaemia (ALL), myelodysplastic syndromes, lymphoma, multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma, optionally wherein the solid tumour is selected from the group consisting of lung cancer, breast cancer, oesophageal cancer, gastric cancer, colon cancer, cholangiocarcinoma, pancreatic cancer, ovarian cancer, head and neck cancers, synovial sarcoma, angiosarcoma, osteosarcoma, thyroid cancer, oral cancer, hepatocellular carcinoma, bladder cancer, endometrial cancer, neuroblastoma, rabdomyosarcoma, liver cancer, melanoma, prostate cancer, renal cancer, soft tissue sarcoma, urothelial cancer, biliary cancer, glioblastoma, mesothelioma, cervical cancer, and colorectal cancer.

156. The TCR, polynucleotide, vector, cell, chimeric molecule, or pharmaceutical composition for use according to claim 154, wherein the proliferative disorder is acute myeloid leukaemia (AML), or wherein the proliferative disorder is colorectal cancer and / or pancreatic cancer.

157. A method for treating and / or preventing a proliferative disorder, which comprises the step of administering a therapeutically effective amount of the TCR of any of claims 1-130, the polynucleotide of any of claims 131-133, the vector of any of claims 134-136, the cell of any of claims 137-144, a cell prepared by the method of any of claims 145-149, the chimeric molecule of claim 150, or the pharmaceutical composition of claim 151 to a subject in need thereof.

158. The method according to claim 157, wherein the proliferative disorder is a haematological malignancy or a solid tumour, optionally wherein the haematological malignancy is selected from the group consisting of acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), lymphoblastic leukaemia, acute lymphocytic leukaemia (ALL), myelodysplastic syndromes, lymphoma, multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma, optionally wherein the solid tumour is selected from the group consisting of lung cancer, breast cancer, oesophageal cancer, gastric cancer, colon cancer, cholangiocarcinoma, pancreatic cancer, ovarian cancer, head and neck cancers, synovial sarcoma, angiosarcoma, osteosarcoma, thyroid cancer, oral cancer, hepatocellular carcinoma, bladder cancer, endometrial cancer, neuroblastoma, rabdomyosarcoma, liver cancer, melanoma, prostate cancer, renal cancer, soft tissue sarcoma, urothelial cancer, biliary cancer, glioblastoma, mesothelioma, cervical cancer, and colorectal cancer.

159. The method according to claim 157, wherein the proliferative disorder is acute myeloid leukaemia (AML) or wherein the proliferative disorder is colorectal cancer and / or pancreatic cancer.

160. Use of the TCR of any of claims 1-130, the polynucleotide of any of claims 131-133, the vector of any of claims 134-136, the cell of any of claims 137-144, a cell prepared by the method of any of claims 145-149, the chimeric molecule of claim 150, or the pharmaceutical composition of claim 151 in the manufacture of a medicament for the treatment and / or prevention of a proliferative disorder.

161. The use according to claim 160, wherein the proliferative disorder is a haematological malignancy or a solid tumour, optionally wherein the haematological malignancy is selected from the group consisting of acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), lymphoblastic leukaemia, acute lymphocytic leukaemia (ALL), myelodysplastic syndromes, lymphoma, multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma, optionally wherein the solid tumour is selected from the group consisting of lung cancer, breast cancer, oesophageal cancer, gastric cancer, colon cancer, cholangiocarcinoma, pancreatic cancer, ovarian cancer, head and neck cancers, synovial sarcoma, angiosarcoma,osteosarcoma, thyroid cancer, oral cancer, hepatocellular carcinoma, bladder cancer, endometrial cancer, neuroblastoma, rabdomyosarcoma, liver cancer, melanoma, prostate cancer, renal cancer, soft tissue sarcoma, urothelial cancer, biliary cancer, glioblastoma, mesothelioma, cervical cancer, and colorectal cancer.

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

163. An isolated immunogenic Cathepsin G (CTSG) peptide comprising or consisting 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 up to three amino acid substitutions, additions or deletions, or an immunogenic fragment thereof.

164. The isolated immunogenic CTSG peptide according to claim 163, wherein the CTSG peptide comprises or consists of 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 consists of SXXXPXVFTRVSSFL (SEQ ID NO: 535) or a variant thereof having up to three amino acid substitutions, additions or deletions, or an immunogenic fragment thereof, preferably wherein the CTSG peptide comprises or consists of 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 an immunogenic fragment thereof, preferably wherein 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, or wherein 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.

166. The isolated immunogenic CTSG peptide according to claim 163, wherein the CTSG peptide comprises or consists of 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 of claims 163-166, wherein the immunogenic fragment has a length of nine amino acids or more, preferably wherein the immunogenic fragment is a nonameric fragment.

168. An isolated immunogenic Cyclin A1 (CCNA1) peptide comprising or consisting of an amino acid sequence selected from: TEYAEEIYQYL (SEQ ID NO: 114), PETLAAFTGYSLSEI (SEQ ID NO: 128), AELSLLEADPFLKYL (SEQ ID NO: 153), LLEADPFLKYLPSLI (SEQ ID NO: 527), WEGPGLPDFVF (SEQ ID NO: 172), KRQLLKMEHLLLKVL (SEQ ID NO: 185), PETLAAFTGYSLSEI (SEQ ID NO: 201), and variants thereof each having up to three amino acid substitutions, additions or deletions, or an immunogenic fragment thereof.

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

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

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

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

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

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

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

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

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