Anti-SIRPa antibodies and their therapeutic applications
The present invention provides new anti-SIRPa antibodies able to specifically antagonize the interaction between SIRPa and CD47, without affecting the interaction between SIRPg and CD47, and their uses.
1. An anti-human Signal regulatory protein alpha (SIRPa) antibody or antigen-binding fragment thereof, which comprises:
a) a heavy chain variable domain comprising HCDR1, HCDR2 and HCDR3, and
b) a light chain variable domain comprising LCDR1, LCDR2 and LCDR3, wherein:
HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 14,
HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 16, and
HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 17 SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20, and wherein:
LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 21,
LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 22, and
LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 23.
2. The anti-human SIRPa antibody or antigen-binding fragment thereof according to claim 1 which does not specifically bind to human SIRPg.
3. The anti-human SIRPa antibody or antigen-binding fragment thereof according to claim 1 , which comprises:
a heavy chain variable domain comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30, and
a light chain variable domain comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 31, SEQ ID NO: 32 and SEQ ID NO: 33.
4. The anti-human SIRPa antibody or antigen-binding fragment thereof according to claim 1 , which comprises:
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, and
a heavy chain variable domain comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30.
5. The anti-human SIRPa antibody or antigen-binding fragment thereof according to claim 1 , which comprises:
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, and
a heavy chain variable domain comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 29 and SEQ ID NO: 30.
6. The anti-human SIRPa antibody or antigen-binding fragment thereof according to claim 1 , which comprises:
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, and
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 30.
7. The anti-human SIRPa antibody according to claim 6 , wherein the antibody is a full-length antibody.
8. The anti-human SIRPa antibody or antigen-binding fragment thereof according to claim 1 , which comprises:
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 24, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 31, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 25, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 25, and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 26, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 26, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 27, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 27, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 28, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 28, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 29, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 29, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 30, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 30, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33.
9. The anti-human SIRPa antibody or antigen-binding fragment thereof according to claim 1 , which is a humanized monoclonal antibody or antigen-binding fragment thereof.
10. The anti-human SIRPa antibody or antigen-binding fragment thereof according to claim 9 , wherein the antibody light chain constant domain is derived from human kappa light chain constant domain or comprises the sequence of SEQ ID NO: 35.
11. The anti-human SIRPa antibody or antigen-binding fragment thereof according to claim 9 , wherein the antibody heavy chain constant domain is derived from a human IgG1, IgG2, IgG3, or IgG4 heavy chain constant domain or comprises the sequence of SEQ ID NO: 34.
12. The anti-human SIRPa antibody or antigen-binding fragment thereof according to claim 1 , wherein said antibody or fragment does not inhibit the binding of human CD47 to human SIRPg.
13. The anti-human SIRPa antibody or antigen-binding fragment thereof according to claim 1 , wherein said antibody or fragment does not specifically bind to human T-cells or to CD3+ T-cells.
14. The anti-human SIRPa antibody or antigen-binding fragment thereof according to claim 1 , wherein said antibody or fragment does not inhibit the proliferation of human T-cells.
15. The anti-human SIRPa antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody or antigen-binding fragment thereof is an antagonist of SIRPa and inhibits the binding of human SIRPa to human CD47.
16. A pharmaceutical composition comprising at least one anti-human SIRPa antibody or antigen-binding fragment thereof of claim 1 , and a pharmaceutically acceptable carrier.
17. The pharmaceutical composition of claim 16 , wherein said composition further comprises at least one second therapeutic agent selected from the group consisting of chemotherapeutic agents, radiotherapy agents, immunotherapeutic agents, cell therapy agents, antibiotics and probiotics.
18. The pharmaceutical composition of claim 17 , wherein the immunotherapeutic agent is a checkpoint blocker or activator of adaptive immune cells selected from the group consisting of an anti-PDL1, anti-PD1, anti-CTLA4, anti-CD137, anti-CD2, anti-CD28, anti-CD40, anti-HVEM, anti-BTLA, anti-CD160, anti-TIGIT, anti-TIM-1/3, anti-LAG-3, anti-2B4, anti-OX40, anti-CD40 agonist, CD40-L, TLR agonists, anti-ICOS, ICOS-L, and a B-cell receptor agonist.
19. The anti-human SIRPa antibody according to claim 1 , wherein the antibody is a recombinant antibody.
20. An anti-human Signal regulatory protein alpha (SIRPa) antibody, which comprises:
a) a heavy chain variable domain comprising HCDR1, HCDR2 and HCDR3, and b) a light chain variable domain comprising LCDR1, LCDR2 and LCDR3, wherein:
HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 14,
HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 16, and
HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 17 SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20, and wherein:
LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 21,
LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 22, and
LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 23.
21. The anti-human SIRPa antibody according to claim 20 , which comprises:
a heavy chain variable domain comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30, and
a light chain variable domain comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 31, SEQ ID NO: 32 and SEQ ID NO: 33.
22. The anti-human SIRPa antibody according to claim 20 , which comprises:
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 24, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 31, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 25, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 25, and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 26, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 26, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 27, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 27, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 28, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 28, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 29, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 29, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 30, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, or
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 30, and
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33.
23. The anti-human SIRPa antibody according to claim 20 , which is a humanized monoclonal antibody or antigen-binding fragment thereof.
24. The anti-human SIRPa antibody according to claim 23 , wherein the antibody light chain constant domain is derived from human kappa light chain constant domain or comprises the sequence of SEQ ID NO: 35.
25. The anti-human SIRPa antibody according to claim 23 , wherein the antibody heavy chain constant domain is derived from a human IgG1, IgG2, IgG3, or IgG4 heavy chain constant domain or comprises the sequence of SEQ ID NO: 34.
26. A pharmaceutical composition comprising at least one anti-human SIRPa antibody of claim 20 , and a pharmaceutically acceptable carrier.
27. The pharmaceutical composition of claim 26 , wherein said composition further comprises at least one second therapeutic agent comprising an immunotherapeutic agent, wherein the immunotherapeutic agent is a checkpoint blocker or activator of adaptive immune cells selected from the group consisting of an anti-PDL1, anti-PD1, anti-CTLA4, anti-CD137, anti-CD2, anti-CD28, anti-CD40, anti-HVEM, anti-BTLA, anti-CD160, anti-TIGIT, anti-TIM-1/3, anti-LAG-3, anti-2B4, anti-OX40, anti-CD40 agonist, CD40-L, TLR agonists, anti-ICOS, ICOS-L, and a B-cell receptor agonist.
28. The anti-human SIRPa antibody according to claim 20 , which comprises:
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32 and
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 30.
29. The anti-human SIRPa antibody according to claim 20 , which comprises:
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, and
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 27.
30. The anti-human SIRPa antibody according to claim 20 , which comprises:
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, and
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 27.
31. The anti-human SIRPa antibody according to claim 20 , which comprises:
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, and
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 28.
32. The anti-human SIRPa antibody according to claim 20 , which comprises:
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, and
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 28.
33. The anti-human SIRPa antibody according to claim 20 which comprises
a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 42, and
a light chain comprising the amino acid sequence set forth in SEQ ID NO: 44.
34. The anti-human SIRPa antibody according to claim 20 which comprises
a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 39, and
a light chain comprising the amino acid sequence set forth in SEQ ID NO: 44.
35. The anti-human SIRPa antibody according to claim 20 which comprises
a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 39, and
a light chain comprising the amino acid sequence set forth in SEQ ID NO: 45.
36. The anti-human SIRPa antibody according to claim 20 which comprises
a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 40, and
a light chain comprising the amino acid sequence set forth in SEQ ID NO: 44.
37. The anti-human SIRPa antibody according to claim 20 which comprises
a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 40, and
a light chain comprising the amino acid sequence set forth in SEQ ID NO: 45.
38. An anti-human SIRPa antibody, which comprises:
a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, and
a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 30.
39. The anti-human SIRPa antibody according to claim 38 , wherein the antibody is a monoclonal antibody.
40. The anti-human SIRPa antibody according to claim 38 , wherein the antibody is a humanized antibody.
41. The anti-human SIRPa antibody according to claim 38 , wherein the antibody is a recombinant antibody.
42. The anti-human SIRPa antibody according to claim 38 , wherein the antibody is a chimeric antibody.
43. The anti-human SIRPa antibody according to claim 38 , wherein the antibody heavy chain constant domain is derived from a human IgG1, IgG2, IgG3, or IgG4 heavy chain constant domain and the antibody light chain constant domain is derived from a human kappa light chain constant domain.
44. The anti-human SIRPa antibody according to claim 38 , wherein the antibody heavy chain constant domain comprises the sequence of SEQ ID NO: 34.
45. The anti-human SIRPa antibody according to claim 38 , wherein and the antibody light chain constant domain comprises the sequence of SEQ ID NO: 35.
46. An anti-human Signal regulatory protein alpha SIRPa antibody which comprises
a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 42, and
a light chain comprising the amino acid sequence set forth in SEQ ID NO: 45.
47. An anti-human Signal regulatory protein alpha (SIRPa) antibody, which comprises:
a) a heavy chain variable domain comprising HCDR1, HCDR2 and HCDR3, and
b) a light chain variable domain comprising LCDR1, LCDR2 and LCDR3,wherein:
HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 14,
HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 16, and
HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 20, and wherein:
LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 21,
LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 22, and
LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 23.