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: 1) in complex with HLA-A*0201, comprising 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, Vβ 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 I3R substitution;
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, or amino acid residues 46-50 of SEQ ID NO:4 with an H3R substitution;
the Vβ CDR2 comprises amino acid residues 68-72 of SEQ ID NO: 4; 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 an N10K substitution,
wherein at least one of the Vβ CDR1 and Vβ CDR3 includes one of the corresponding substitutions.
2. One or more polynucleotide(s) encoding the TCR of claim 1 .
3. A cell comprising the one or more polynucleotide(s) of claim 2 .
4. A method for treating cancer comprising administering to a cancer patient the cell of claim 3 , wherein the patient has a cancer cell that expresses a melanoma-associated antigen (MAGE) B2 protein.
5. A T cell receptor (TCR) having binding specificity to GVYDGEEHSV (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, Vβ CDR2 and Vβ CDR3, wherein:
the Vα CDR1, Vα CDR2 and Vα CDR3 comprise amino acid residues 28-33, 48-53, and 91-105 of SEQ ID NO: 3 or 7, respectively, and
the Vβ CDR1, Vβ CDR2 and Vβ CDR3 comprise amino acid residues 46-50, 68-72, and 110-123 of SEQ ID NO: 8 or 10, respectively.
6. The TCR of claim 5 , wherein the Vα CDR1, Vα CDR2 and Vα CDR3 comprise amino acid residues 28-33, 48-53, and 91-105 of SEQ ID NO: 3, respectively, and the Vβ CDR1, Vβ CDR2 and Vβ CDR3 comprise amino acid residues 46-50, 68-72, and 110-123 of SEQ ID NO: 8, respectively.
7. The TCR of claim 5 , 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: 8.
8. The TCR of claim 5 , wherein the Vα CDR1, Vα CDR2 and Vα CDR3 comprise amino acid residues 28-33, 48-53, and 91-105 of SEQ ID NO: 3, respectively, and the Vβ CDR1, Vβ CDR2 and Vβ CDR3 comprise amino acid residues 46-50, 68-72, and 110-123 of SEQ ID NO: 10, respectively.
9. The TCR of claim 5 , 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.
10. One or more polynucleotide(s) encoding the TCR of claim 5 .
11. A cell comprising the one or more polynucleotide(s) of claim 10 .
12. A method for treating cancer comprising administering to a cancer patient the cell of claim 11 , wherein the patient has a cancer cell that expresses a melanoma-associated antigen (MAGE) B2 protein.