T cell receptors
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.
1. A T cell receptor (TCR) having binding specificity to GVYDGEEHSV (SEQ ID NO: 2) in complex with HLA-A*0201 and GVYDGREHTV (SEQ ID NO: 1) in complex with HLA-A*0201, wherein the TCR comprises a TCR alpha chain variable domain (Vα) comprising complementarity determining regions (CDR) Vα CDR1, Vα CDR2 and Vα CDR3 and a TCR beta chain variable domain (Vβ) comprising Vβ CDR1, CDR2 and Vβ CDR3, wherein
the Vα CDR1 comprises amino acid residues 28-33 of SEQ ID NO: 3;
the Vα CDR2 comprises amino acid residues 48-53 of SEQ ID NO: 3, or amino acid residues 48-53 of SEQ ID NO: 3 with an M51T or M51N substitution;
the Vα CDR3 comprises amino acid residues 91-105 of SEQ ID NO: 3, or amino acid residues 91-105 of SEQ ID NO: 3 with an S94T or S94N substitution;
the Vβ CDR1 comprises amino acid residues 46-50 of SEQ ID NO: 4;
the Vβ CDR2 comprises amino acid residues 68-72 of SEQ ID NO: 4, or amino acid residues 68-72 of SEQ ID NO: 4 with an S68A substitution; and
the Vβ CDR3 comprises amino acid residues 110-123 of SEQ ID NO: 4, or amino acid residues 110-123 of SEQ ID NO: 4 with a substitution selected from the group consisting of (a) S113T, (b) S113N, (c) N119V, (d) N119G, and (e) S113T and N119E, and
wherein at least one of the Vα CDR2, Vα CDR3, Vβ CDR2, and Vβ CDR3 includes one of the corresponding substitutions.
2. The TCR of claim 1 , wherein
the Vα CDR1 comprises amino acid residues 28-33 of SEQ ID NO: 3;
the Vα CDR2 comprises amino acid residues 48-53 of SEQ ID NO: 8 or 9;
the Vα CDR3 comprises amino acid residues 91-105 of SEQ ID NO: 3;
the Vβ CDR1 comprises amino acid residues 46-50 of SEQ ID NO: 4;
the Vβ CDR2 comprises amino acid residues 68-72 of SEQ ID NO: 4 or 11; and
the Vβ CDR3 comprises amino acid residues 110-123 of SEQ ID NO: 4, 10, 11 or 12.
3. The TCR of claim 1 , wherein
the Vα CDR1 comprises amino acid residues 28-33 of SEQ ID NO: 3;
the Vα CDR2 comprises amino acid residues 48-53 of SEQ ID NO: 3, 8 or 9;
the Vα CDR3 comprises amino acid residues 91-105 of SEQ ID NO: 3;
the Vβ CDR1 comprises amino acid residues 46-50 of SEQ ID NO: 4;
the Vβ CDR2 comprises amino acid residues 68-72 of SEQ ID NO: 11; and
the Vβ CDR3 comprises amino acid residues 110-123 of SEQ ID NO: 4, 10, 11 or 12.
4. The TCR of claim 1 , wherein
the Vα CDR1 comprises amino acid residues 28-33 of SEQ ID NO: 3;
the Vα CDR2 comprises amino acid residues 48-53 of SEQ ID NO: 3, 8 or 9;
the Vα CDR3 comprises amino acid residues 91-105 of SEQ ID NO: 3;
the Vβ CDR1 comprises amino acid residues 46-50 of SEQ ID NO: 4;
the Vβ CDR2 comprises amino acid residues 68-72 of SEQ ID NO: 4 or 11; and
the Vβ CDR3 comprises amino acid residues 110-123 of SEQ ID NO: 10, 11, or 12.
5. The TCR of claim 1 , wherein the Vα comprises the amino acid sequence of SEQ ID NO: 8 or 9, and the Vβ comprises the amino acid sequence of SEQ ID NO: 4, 10, 11 or 12.
6. The TCR of claim 1 , wherein the Vα comprises the amino acid sequence of SEQ ID NO: 3, 8 or 9, and the Vβ comprises the amino acid sequence of SEQ ID NO: 10, 11 or 12.
7. The TCR of claim 1 , wherein the Vα comprises the amino acid sequence of SEQ ID NO: 3, and the Vβ comprises the amino acid sequence of SEQ ID NO: 10, 11 or 12.
8. The TCR of claim 1 , wherein the Vα comprises the amino acid sequence of SEQ ID NO: 8, and the Vβ comprises the amino acid sequence of SEQ ID NO: 10, 11 or 12.
9. The TCR of claim 1 , wherein the Vα comprises the amino acid sequence of SEQ ID NO: 9, and the Vβ comprises the amino acid sequence of SEQ ID NO: 10, 11 or 12.
10. The TCR of claim 1 , wherein the Vα comprises the amino acid sequence of SEQ ID NO: 8 or 9, and the Vβ comprises the amino acid sequence of SEQ ID NO: 4.
11. The TCR of claim 1 , wherein the Vα comprises the amino acid sequence of SEQ ID NO: 8 or 9, and the Vβ comprises the amino acid sequence of SEQ ID NO: 10.
12. The TCR of claim 1 , wherein the Vα comprises the amino acid sequence of SEQ ID NO: 8 or 9, and the Vβ comprises the amino acid sequence of SEQ ID NO: 11.
13. The TCR of claim 1 , wherein the Vα comprises the amino acid sequence of SEQ ID NO: 8 or 9, and the Vβ comprises the amino acid sequence of SEQ ID NO: 12.
14. The TCR of claim 1 , 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.
15. The TCR of claim 1 , which is in a single chain format of the type Vα-L-Vβ, Vβ-L-Vα, Vα-Cα-L-Vβ, or Vα-L-Vβ-Cβ, wherein Vα and Vβ are TCR α and β variable regions respectively, Cα and Cβ are TCR α and β constant regions respectively, and L is a linker sequence.
16. One or more polynucleotides encoding the TCR of claim 1 .
17. A cell comprising the one or more polynucleotides of claim 16 .
18. A method for treating cancer in a patient, comprising administering to the patient the cell of claim 17 , wherein the patient has a cancer cell that expresses a melanoma-associated antigen (MAGE) B2 or MAGE A4 protein.