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EP-4735471-A2 - T-CELL RECEPTORS

EP4735471A2EP 4735471 A2EP4735471 A2EP 4735471A2EP-4735471-A2

Abstract

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

Inventors

  • BONINI, MARIA CHIARA
  • RUGGIERO, Eliana
  • Potenza, Alessia
  • SPIGA, Martina

Assignees

  • Ospedale San Raffaele S.r.l.
  • Università Vita-Salute San Raffaele

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1 . 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 of CASSEVYRGHEKLFF (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 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 (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. 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. 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. 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. 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 amino acid sequence of SEQ ID NO: 92 or a variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.
  6. 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. 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. 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. 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 acid sequence of CSVPPAGLGAPEAFF (SEQ ID NO: 71) or (ii) the amino acid sequence of CASSPGTGAYNSPLHF (SEQ ID NO: 77).
  10. 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. 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. 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. 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. 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. 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. 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. 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 least 95%, 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. 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. 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. 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.

Description

T-CELL RECEPTORS FIELD OF THE INVENTION 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. BACKGROUND TO THE INVENTION 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). 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. 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. Thus, the low availability of tumour-specific TCRs still remains an open issue limiting the broad exploitation of TCR-based immunotherapeutic approaches. SUMMARY OF THE INVENTION 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. 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; (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; (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; (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; (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 o