T cell receptors and fusion proteins thereof
The present disclosure provides T cell receptor (TCR) fusion proteins comprising a TCR that binds to a GVYDGREHTV (SEQ ID NO:34) HLA-A*02 complex that is covalently linked to a T cell engaging domain that binds a protein expressed on a cell surface of a T cell and an antibody Fc domain, as well as polynucleotides, vectors, kits, host cells, pharmaceutical compositions, methods, and uses related thereto.
1. A T cell receptor (TCR) fusion protein comprising a TCR that binds to GVYDGREHTV (SEQ ID NO: 34) HLA-A*02 complex, wherein the TCR fusion protein comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:29, a second polypeptide comprising the amino acid sequence of SEQ ID NO:30, and a third polypeptide comprising the amino acid sequence of SEQ ID NO:28.
2. A polynucleotide encoding the TCR fusion protein according to claim 1 .
3. A kit of polynucleotides encoding the TCR fusion protein according to claim 1 , wherein the kit comprises a first polynucleotide encoding the first polypeptide, a second polynucleotide encoding the second polypeptide, and a third polynucleotide encoding the third polypeptide.
4. A vector comprising the polynucleotide of claim 2 .
5. A kit of vectors encoding the TCR fusion protein according to claim 1 , wherein the kit comprises a first vector encoding the first polypeptide, a second vector encoding the second polypeptide, and a third vector encoding the third polypeptide.
6. A host cell comprising the polynucleotide of claim 2 .
7. The host cell of claim 6 , wherein the host cell is a mammalian cell.
8. The host cell of claim 7 , wherein the mammalian cell is a Chinese hamster ovary (CHO) cell.
9. A method of producing a TCR fusion protein, comprising culturing the host cell of claim 6 under conditions suitable for production of the TCR fusion protein.
10. The method of claim 9 , further comprising recovering the TCR fusion protein from the host cell.
11. A TCR fusion protein produced by the method of claim 9 .
12. A pharmaceutical composition comprising the TCR fusion protein according to claim 1 and a pharmaceutically acceptable carrier.
13. A method of treating cancer, comprising administering an effective amount of the pharmaceutical composition of claim 12 to an individual.
14. The method of claim 13 , wherein the individual is a human.
15. The method of claim 14 , wherein the individual has a cancer that expresses MAGE-A4.
16. The method of claim 14 , wherein the individual is of HLA-A*02 subtype.
17. The method of claim 13 , wherein the composition is administered intravenously or by intratumoral injection.
18. The method of claim 13 , further comprising administering to the individual a second anti-cancer agent.
19. The fusion protein of claim 1 , wherein the TCR fusion protein is glycosylated at a single N-linked glycosylation site at residue N18 of the first polypeptide, numbering according to SEQ ID NO:29.
20. The fusion protein of claim 1 , wherein the first and third polypeptides are linked via one or more disulfide bonds.
21. The fusion protein of claim 1 , wherein the first and second polypeptides are linked via one or more disulfide bonds.