Antibodies capable of binding HLA-A2/TyrD in an HLA restricted manner and uses thereof
Antibodies capable of binding HLA-A2/Tyrosinase (TyrD) in an HLA restricted manner are provided. Specifically, the antibodies are capable of binding HLA-A2/TyrD369-377 in an HLA restricted manner. Further provided are complementary determining region (CDR) sequences of heavy chain and light chain of antibodies, and methods of using the antibodies for the treatment of cancer.
1. An antibody comprising an antigen binding domain comprising CDR sequences which are N—C ordered:
CDR1 Heavy
Chain (HC)
SEQ ID NO: 8
TSGMGVS
CDR2 HC
SEQ ID NO: 9
HIYWDDDKRYNPSLKS
CDR3 HC
SEQ ID NO: 10
KDYGSSFYAMHY
CDR1 Light
Chain (LC)
SEQ ID NO: 5
KASQDIHNYIA
CDR2 LC
SEQ ID NO: 6
YTSTLQP
CDR3 LC
SEQ ID NO: 7
LQYDNLWT
wherein a variable region of said heavy chain of the antibody is as set forth in SEQ ID NO: 4 and said antibody is capable of binding HLA-A2/Tyr D369-377 in an HLA restricted manner.
2. An antibody comprising an antigen binding domain comprising CDR sequences which are N—C ordered:
CDR1 Heavy
Chain (HC)
SEQ ID NO: 8
TSGMGVS
CDR2 HC
SEQ ID NO: 9
HIYWDDDKRYNPSLKS
CDR3 HC
SEQ ID NO: 10
KDYGSSFYAMHY
CDR1 Light
Chain (LC)
SEQ ID NO: 5
KASQDIHNYIA
CDR2 LC
SEQ ID NO: 6
YTSTLQP
CDR3 LC
SEQ ID NO: 7
LQYDNLWT
wherein a variable region of said heavy chain of the antibody is as set forth in SEQ ID NO: 4, a variable region of said light chain of the antibody is as set forth in SEQ ID NO: 2 and said antibody is capable of binding HLA-A2/Tyr D369-377 in an HLA restricted manner.
3. The antibody of claim 1 or 2 , wherein said antibody is an IgG antibody.
4. The antibody of claim 1 , wherein said antibody is a chimeric antibody.
5. The antibody of claim 1 or claim 2 , wherein said antibody is an antibody fragment.
6. The antibody of claim 5 selected from the group consisting of Fab, F(ab′)2, Fv, scFv, dsFv and a single domain molecule.
7. The antibody of claim 1 or claim 2 , wherein said heavy chain of the antibody is as set forth in SEQ ID NO: 21 or 27.
8. The antibody of claim 1 , wherein said light chain of the antibody is as set forth in SEQ ID NO: 2, 19 or 25.
9. The antibody of claim 1 or claim 2 comprising a therapeutic moiety.
10. The antibody of claim 9 , wherein said therapeutic moiety is selected from the group consisting of a cytotoxic moiety, a toxic moiety, a cytokine moiety and a drug.
11. The antibody of claim 9 , wherein said therapeutic moiety comprises a cell.
12. The antibody of claim 11 , wherein said cell is selected from the group consisting of an αβ T-cell, γδ T-cell, NK, CIK, NKT, macrophage and a B cell.
13. The antibody of claim 1 or claim 2 , wherein said antibody is a bispecific antibody.
14. The antibody of claim 13 , wherein said bispecific antibody comprises an anti-CD3 or an anti-CD16.
15. The antibody of claim 14 , wherein said anti-CD3 comprises an scFv.
16. A chimeric antigen receptor comprising the antibody according to claim 1 or claim 2 .
17. An isolated polynucleotide comprising a nucleic acid sequence encoding the antibody of claim 1 or claim 2 .
18. An expression vector comprising the polynucleotide of claim 17 operably linked to a cis-acting regulatory element.
19. The expression vector of claim 18 being a viral vector.
20. A cell comprising the polynucleotide of claim 17 .
21. A pharmaceutical composition comprising the antibody of claim 1 or claim 2 .
22. A method of treating melanoma or glioblastoma, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody of claim 1 or claim 2 , and wherein said melanoma or glioblastoma expresses TyrD 369-377 , thereby treating the melanoma or glioblastoma.
23. A method of treating melanoma or glioblastoma, comprising administering to a subject in need thereof a therapeutically effective amount of the expression vector of claim 18 , and wherein said melanoma or glioblastoma expresses TyrD 369-377 , thereby treating the melanoma or glioblastoma.
24. A cell comprising the expression vector of claim 18 .
25. A method of treating melanoma or glioblastoma, comprising administering to a subject in need thereof a therapeutically effective amount of a cell according to claim 20 , and wherein said melanoma or glioblastoma expresses TyrD 369-377 , thereby treating the melanoma or glioblastoma.
26. A method of treating melanoma or glioblastoma, comprising administering to a subject in need thereof a therapeutically effective amount of a cell according to claim 24 , and wherein said melanoma or glioblastoma expresses TyrD 369-377 , thereby treating the melanoma or glioblastoma.
27. An isolated polynucleotide comprising a nucleic acid sequence encoding the chimeric antigen receptor according to claim 16 .
28. An expression vector comprising the polynucleotide of claim 27 operably linked to a cis-acting regulatory element.
29. The expression vector of claim 28 , being a viral vector.
30. A cell comprising the polynucleotide of claim 27 .
31. A cell comprising the expression vector of claim 28 .
32. A method of treating melanoma or glioblastoma, comprising administering to a subject in need thereof a therapeutically effective amount of the cell according to claim 30 , and wherein said melanoma or glioblastoma expresses TyrD 369-377 , thereby treating the melanoma or glioblastoma.
33. A method of treating melanoma or glioblastoma, comprising administering to a subject in need thereof a therapeutically effective amount of the cell according to claim 31 , and wherein said melanoma or glioblastoma expresses TyrD 369-377 , thereby treating the melanoma or glioblastoma.
34. A pharmaceutical composition comprising the expression vector of claim 18 .
35. A pharmaceutical composition comprising a cell of claim 20 .
36. A pharmaceutical composition comprising a cell of claim 24 .
37. A pharmaceutical composition comprising a cell of claim 30 .
38. A pharmaceutical composition comprising a cell of claim 31 .
39. The antibody of claim 2 , wherein said light chain of the antibody is as set forth in SEQ ID NO: 25.