NZ747962B2

NZ747962B2 - T cell receptors

Info

Publication number: NZ747962B2
Application number: NZ747962A
Authority: NZ
Inventors: Eleanor Bagg; William Lawrance; Nicholas Tribble
Original assignee: Adaptimmune Limited
Filing date: 2017-04-10
Publication date: 2025-03-21

Abstract

The present invention relates to T cell receptors (TCRs) which bind the HLA-A*0201 restricted peptide GVYDGEEHSV (SEQ ID NO: 1) derived from the MAGE-B2 protein. The TCRs of the invention demonstrate excellent specificity profiles for this MAGE epitope. Also provided are nucleic acids encoding the TCRs, cells engineered to present the TCRs, cells harbouring expression vectors encoding the TCRs and pharmaceutical compositions comprising the TCRs, nucleic acids or cells of the invention.

Claims

The Claims Defining the Invention are as Follows:

1. A T cell receptor (TCR) that comprises a TCR alpha chain variable domain and a TCR beta chain variable domain, wherein: Alpha CDR1 is VSPFSN; Alpha CDR2 is LTIMTF or LTIVTF; Alpha CDR3 is CVVSGGTDSWGKLQF; Beta CDR1 is KGHDR; Beta CDR2 is SFDVK or AFDVK; and Beta CDR3 is (a) CATTGQGAYNEQFF or CATTGQGAYEEQFF or CATSGQGAYVEQFF, or (b) CATSGQGAYNEQFF provided that Alpha CDR2 is LTIVTF.

2. A TCR according to claim 1, wherein the TCR has the property of binding to GVYDGEEHSV (SEQ ID No: 2) in complex with HLA-A*0201 and GVYDGREHTV (SEQ ID No: 1) in complex with HLA-A*0201 with a dissociation constant of from 0.05 µM to 20.0 µM when measured with surface plasmon resonance at 25ºC and at a pH between 7.1 and 7.5 using a soluble form of the TCR, and wherein the TCR variable domains form contacts with at least residues V2, Y3 and D4 of GVYDGEEHSV (SEQ ID No: 2).

3. A TCR according to claim 1 or 2, which is an alpha-beta heterodimer, having an alpha chain TRAV10 + TRAC constant domain sequence and a beta chain TRBV24-1 + TRBC-2 constant domain sequence.

4. A TCR as claimed in claim 1 or 2, which is in single chain format of the type Va-L-Vß, Vß-L- Va, Va-Ca-L-Vß, or Va-L-Vß-Cß, wherein Va and Vß are TCR a and ß variable regions respectively, Ca and Cß are TCR a and ß constant regions respectively, and L is a linker sequence.

5. A TCR as claimed in any one of the preceding claims, which is covalently associated with a detectable label, a therapeutic agent or a PK modifying moiety.

6. A TCR as claimed in any one of the preceding claims, wherein the TCR alpha chain variable domain comprises an amino acid sequence that has at least 80% identity to the amino acid sequence of the alpha chain variable domain of SEQ ID NO: 3 and wherein Alpha CDR2 is LTIVTF, and/or the TCR beta chain variable domain comprises an amino acid sequence that has at least 80% identity to the amino acid sequence of SEQ ID NO: 4, and wherein Beta CDR2 is AFDVK and/or wherein Beta CDR3 is CATTGQGAYNEQFF, CATTGQGAYEEQFF or CATSGQGAYVEQFF.

7. A TCR as claimed in any one of the preceding claims, wherein the TCR alpha chain variable domain is comprised in a sequence in which: (i) amino acid residues 1-27 thereof has (a) at least 90% identity to the sequence of amino acid residues 1-27 of SEQ ID No: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); (ii) amino acid residues 28-33 is VSPFSN; (iii) amino acid residues 34-47 thereof has (a) at least 90% identity to the sequence of amino acid residues 34-47 of SEQ ID NO: 3 or (b) has one, two or three amino acid residues insertions, deletions or substitutions relative to the sequence of (a); (iv) amino acid residues 48-53 is LTIMTF or LTIVTF; (v) amino acid residues 54-90 thereof has (a) at least 90% identity to the sequence of amino acid residues 54-90 of SEQ ID No: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); and (vi) amino acid residues 91-105 is CVVSGGTDSWGKLQF.

8. A TCR as claimed in any one of the preceding claims, wherein the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 3 or 7.

9. A TCR according to any one of the preceding claims, wherein the TCR beta chain variable domain is comprised in a sequence in which: (i) amino acid residues 1-45 thereof has (a) at least 90% identity to the sequence of amino acid residues 1-45 of SEQ ID No: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); (ii) amino acid residues 46-50 is KGHDR; (iii) amino acid residues 51-67 thereof has (a) at least 90% identity to the sequence of amino acid residues 51-67 of SEQ ID NO: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); (iv) amino acid residues 68-72 is SFDVK or AFDVK; (v) amino acid residues 73-109 thereof has (a) at least 90% identity to the sequence of amino acid residues 73-109 of SEQ ID NO: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); and (vi) amino acid residues 110-123 is CATTGQGAYNEQFF or CATTGQGAYEEQFF or CATSGQGAYVEQFF or CATSGQGAYNEQFF.

10. A TCR as claimed in any one of the preceding claims, wherein the TCR beta chain variable domain is comprised in the amino acid sequence of any one of SEQ ID NOs: 4, 10, 11 or 12.

11. A TCR as claimed in any one of the preceding claims, wherein: the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 7, and the TCR beta chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 4; or the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 3, and the TCR beta chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 10; or the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 3, and the TCR beta chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 11; or the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 3, and the TCR beta chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 12.

12. Nucleic acid encoding a TCR as claimed in any one of the preceding claims.

13. An isolated cell, presenting a TCR as claimed in any one of claims 1 to 11.

14. The isolated cell according to claim 13, wherein the cell is a T-cell.

15. An isolated cell presenting a TCR encoded by a nucleic acid, wherein the nucleic acid encodes a TCR than comprises: (A) a TCR alpha chain variable domain in which: (i) amino acid residues 1-27 thereof has (a) at least 90% identity to the sequence of amino acid residues 1-27 of SEQ ID No: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); (ii) amino acid residues 28-33 is VSPFSN; (iii) amino acid residues 34-47 thereof has (a) at least 90% identity to the sequence of amino acid residues 34-47 of SEQ ID NO: 3 or (b) has one, two or three amino acid residues insertions, deletions or substitutions relative to the sequence of (a); (iv) amino acid residues 48-53 is LTIMTF or LTIVTF; (v) amino acid residues 54-90 thereof has (a) at least 90% identity to the sequence of amino acid residues 54-90 of SEQ ID No: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); and (vi) amino acid residues 91-105 is CVVSGGTDSWGKLQF; and (B) a TCR beta chain variable domain in which: (i) amino acid residues 1-45 thereof has (a) at least 90% identity to the amino acid sequence of residues 1-45 of SEQ ID No: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); (ii) amino acid residues 46-50 is KGHDR; (iii) amino acid residues 51-67 thereof has (a) at least 90% identity to the sequence of amino acid residues 51-67 of SEQ ID NO: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); (iv) amino acid residues 68-72 is SFDVK or AFDVK; (v) amino acid residues 73-109 thereof has (a) at least 90% identity to the sequence of amino acid residues 73-109 of SEQ ID NO: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); and (vi) amino acid residues 110-123 is (a) CATTGQGAYNEQFF or CATTGQGAYEEQFF or CATSGQGAYVEQFF, or (b) CATSGQGAYNEQFF provided that Alpha CDR2 is LTIVTF.

16. An isolated cell harbouring: (a) a TCR expression vector which comprises nucleic acid as claimed in claim 12 in a single open reading frame, or two distinct open reading frames encoding the alpha chain and the beta chain respectively; or (b) a first expression vector which comprises nucleic acid encoding the alpha chain of a TCR as claimed in any one of claims 1 to 11, and a second expression vector which comprises nucleic acid encoding the beta chain of a TCR as claimed in any one of claims 1 to 11.

17. A pharmaceutical composition comprising a TCR as claimed in any one of claims 1 to 11, nucleic acid of claim 12 or a cell as claimed in any one of claims 13 to 16, together with one or more pharmaceutically acceptable carriers or excipients.

18. The TCR of any one of claims 1 to 11, nucleic acid of claim 12 or cell of any one of claims 13 to 16 for use in medicine.

19. Use of the TCR of any one of claims 1 to 11, the nucleic acid of claim 12, or the cell of any one of claims 13 to 16, in the manufacture of a medicament for the treatment of cancer.