IP Library › Granted Patent US 12,258,410

Granted Patent B2

US 12,258,410 · App. 18/627,754 · Granted Mar 25, 2025

Anti-SIRPα antibodies and methods of use thereof

Inventors: Andrew Pincetic (San Francisco, CA); Wei-Hsien Ho (Belmont, CA); Patricia Culp (Oakland, CA); Arnon Rosenthal (Woodside, CA)

C07K16/283 C07K16/246 C07K16/2818 C07K16/2827 C07K16/40 C07K16/4283 C12N15/85 C07K2317/21 C07K2317/24 C07K2317/32 C07K2317/55 C07K2317/567 C07K2317/622 C07K2317/732 C07K2317/75 C07K2317/76 C07K2317/92

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Quick Facts

Patent No.: US 12,258,410
App. No.: 18/627,754
Granted: Mar 25, 2025
Kind: B2

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Abstract

The present disclosure is generally directed to compositions that include antibodies, e.g., monoclonal, antibodies, antibody fragments, etc., that specifically bind a SIRPA polypeptide, e.g., a mammalian SIRPA or human SIRPA, and use of such compositions in preventing, reducing risk, or treating an individual in need thereof.

Claims (86)

1. An isolated nucleic acid comprising a nucleic acid sequence encoding an antibody that binds to human SIRPA, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO:20; an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 21; an HVR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 22, 23, and 24; and the light chain variable region comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9; an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10; and an HVR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 11, 12, 13, 14, 15, 16, 17, 18, and 19.

2. The nucleic acid of claim 1 , wherein the heavy chain variable region comprises one, two, three or four frame work regions selected from VH FRI comprising the amino acid sequence of SEQ ID NO:25, VH FR2 comprising the amino acid sequence of SEQ ID NO:26, VH FR3 comprising the amino acid sequence of SEQ ID NO:27, and VH FR4 comprising the amino acid sequence of SEQ ID NO:28; and wherein the light chain variable region comprises one, two, three or four frame work regions selected from VL FRI comprising the amino acid sequence of SEQ ID NO:29, VL FR2 comprising the amino acid sequence of SEQ ID NO:30, VL FR3 comprising the amino acid sequence of SEQ ID NO:31, and VL FR4 comprising the amino acid sequence of SEQ ID NO:32.

3. The nucleic acid of claim 1 , wherein the heavy chain variable region comprises an amino acid sequence at least 90% or at least 95% or at least 99% identical to an amino acid sequence selected from SEQ ID NOs: 33, 34, and 35.

4. The nucleic acid of claim 1 , wherein the light chain variable region comprises an amino acid sequence at least 90% or at least 95% or at least 99% identical to an amino acid sequence selected from SEQ ID NOs: 36, 37, 38, 39, 40, 41, 42, 43, and 44.

5. An isolated nucleic acid comprising a nucleic acid sequence encoding an antibody that binds to human SIRPA, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 33, 34, and 35, and wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 36, 37, 38, 39, 40, 41, 42, 43, and 44.

6. The nucleic acid of claim 1 , wherein the antibody is a monoclonal antibody.

7. The nucleic acid of claim 1 , wherein the antibody is a humanized antibody.

8. The nucleic acid of claim 1 , wherein the antibody is a Fab, Fab′, Fab′-SH, F (ab′) 2, Fv, or scFv fragment.

9. The nucleic acid of claim 1 , wherein the antibody is a multivalent antibody.

10. The nucleic acid of claim 1 , wherein the antibody is of the IgG class, the IgM class, or the IgA class.

11. The nucleic acid of claim 10 , wherein the antibody is of the IgG class and as an IgG1, IgG2, IgG3, or IgG4 isotype.

12. The nucleic acid of claim 1 , wherein the antibody binds to an inhibitory Fc receptor.

13. The nucleic acid of claim 12 , wherein the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcgRIIB).

14. The nucleic acid of claim 13 , wherein the antibody decreases cellular levels of FcgRIIB.

15. The nucleic acid of claim 1 , wherein the anti-SIRPA antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at an amino acid residue selected from the group consisting of: N297A, D265A, D270A, L234A, L235A, G237A, P238D, L328E, E233D, G237D, H268D, P271G, A330R, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, N297Q, P238S, P238A, A327Q, A327G, P329A, K322A, T394D, and any combination thereof, wherein the numbering of the residues is according to EU numbering, or comprises an amino acid deletion in the Fc region at a position corresponding to glycine 236.

16. The nucleic acid of claim 1 , wherein the antibody comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: C127S, L234A, L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S, E345R, E430G, S440Y, and any combination thereof, wherein the numbering of the amino acid residues is according to EU or Kabat numbering.

17. An isolated nucleic acid comprising a nucleic acid sequence encoding an antibody that binds human SIRPA, wherein the antibody comprises a heavy chain and a light chain, wherein:

a. the heavy chain comprises the amino acid sequence of SEQ ID NO:47 and the light chain comprises the amino acid sequence of SEQ ID NO:50;

b. the heavy chain comprises the amino acid sequence of SEQ ID NO:48 and the light chain comprises the amino acid sequence of SEQ ID NO:50;

c. the heavy chain comprises the amino acid sequence of SEQ ID NO:49 and the light chain comprises the amino acid sequence of SEQ ID NO:50;

d. the heavy chain comprises the amino acid sequence of SEQ ID NO:53 and the light chain comprises the amino acid sequence of SEQ ID NO:50;

e. the heavy chain comprises the amino acid sequence of SEQ ID NO:54 and the light chain comprises the amino acid sequence of SEQ ID NO:50;

f. the heavy chain comprises the amino acid sequence of SEQ ID NO:51 and the light chain comprises the amino acid sequence of SEQ ID NO:50;

g. the heavy chain comprises the amino acid sequence of SEQ ID NO:52 and the light chain comprises the amino acid sequence of SEQ ID NO:50;

h. the heavy chain comprises the amino acid sequence of SEQ ID NO:55 and the light chain comprises the amino acid sequence of SEQ ID NO:50;

i. the heavy chain comprises the amino acid sequence of SEQ ID NO:56 and the light chain comprises the amino acid sequence of SEQ ID NO:50; or

j. the heavy chain comprises the amino acid sequence of SEQ ID NO:57 and the light chain comprises the amino acid sequence of SEQ ID NO:50.

18. The nucleic acid of claim 1 , wherein the anti-SIRPA antibody decreases cell surface levels of SIRPA, decreases intracellular levels of SIRPA, decreases total cellular levels of SIRPA, or any combination thereof.

19. The nucleic acid of claim 1 , wherein the anti-SIRPA antibody induces SIRPA degradation, induces SIRPA cleavage, induces SIRPA internalization, induces SIRPA shedding, downregulates SIRPA expression, or any combination thereof.

20. The nucleic acid of claim 1 , wherein the antibody reduces cell surface levels of SIRPA in vitro.

21. The nucleic acid of claim 1 , wherein the antibody down-regulates expression of SIRPA in human monocytes.

22. The nucleic acid of claim 1 , wherein the antibody down-regulates expression of SIRPA in human macrophages by about 70-95%.

23. The nucleic acid of claim 1 , wherein the antibody has an affinity (KD) to human SIRPA v1 of less than 6 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

24. The nucleic acid of claim 1 , wherein the antibody has an affinity (KD) to human SIRPA v1 of about 0.1 nM to 2 nM.

25. The nucleic acid of claim 1 , wherein the antibody reduces cell surface levels of SIRPA in vitro with a half maximal effective concentration (EC50) of about 0.05 to 0.20 nM for human SIRPA v1, of about 0.05 to 0.10 nM for human SIRPA v2, and/or of about 0.05 to 1 nM for cyno SIRPA as measured by flow cytometry.

26. The nucleic acid of claim 1 , wherein the antibody binds human SIRPA, human SIRPA v1, human SIRPA v2, cyno SIRPA, marmoset SIRPA, and human SIRPβ3.

27. The nucleic acid of claim 1 , wherein the antibody binds to the D3 domain of human SIRPA v1 of SEQ ID NO:1.

28. The nucleic acid of claim 1 , wherein the antibody binds to amino acid residues R282, Q284, and G337 of human SIRPA v1 of SEQ ID NO:1.

29. The nucleic acid of claim 1 , wherein the anti-SIRPA antibody increases tumor cell phagocytosis in macrophages, increases tumor cell phagocytosis in M1 macrophages, increases tumor cell phagocytosis in M2 macrophages, down-regulates CD14 expression in macrophages, and/or any combination thereof.

30. The nucleic acid of claim 1 , wherein the anti-SIRPA antibody enhances T cell proliferation.

31. The nucleic acid of claim 1 , wherein the anti-SIRPA antibody enhances T cell proliferation without blocking the interaction of SIRP□ and CD47.

32. The nucleic acid of claim 1 , wherein the anti-SIRPA antibody stimulates ROS production in monocytes and/or increases IL-8 expression in monocytes.

33. The nucleic acid of claim 1 , wherein the anti-SIRPA antibody inhibits tumor growth in vivo.

34. The nucleic acid of claim 1 , wherein the anti-SIRPA antibody reduces the number of CD14+ myeloid cells in peripheral blood and/or increases the number of CD14+ myeloid cells in a tumor.

35. The nucleic acid of claim 1 , wherein the antibody binds human SIRPA but does not substantially block binding of CD47 to SIRPA.

36. A vector comprising the nucleic acid of claim 1 .

37. An isolated host cell comprising the nucleic acid of claim 1 .

38. A method of producing an antibody that binds to human SIRPA, comprising culturing the cell of claim 37 so that the antibody is produced.

39. The method of claim 38 , further comprising recovering the antibody produced by the cell.

40. The nucleic acid of claim 1 , wherein the heavy chain variable region comprises an amino acid sequence at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 33, 34, and 35.

41. The nucleic acid of claim 1 , wherein the light chain variable region comprises an amino acid sequence at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 36, 37, 38, 39, 40, 41, 42, 43, and 44.

42. The nucleic acid of claim 1 , wherein the heavy chain variable region comprises an amino acid sequence at least 99% identical to an amino acid sequence selected from SEQ ID NOs: 33, 34, and 35.

43. The nucleic acid of claim 1 , wherein the light chain variable region comprises an amino acid sequence at least 99% identical to an amino acid sequence selected from SEQ ID NOs: 36, 37, 38, 39, 40, 41, 42, 43, and 44.

44. The nucleic acid of claim 1 , wherein the heavy chain variable region comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO:20; an HVR-H2 comprising the amino acid sequence of SEQ ID NO:21; an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24; and the light chain variable region comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9; an HVR-L2 comprising the amino acid sequence of SEQ ID NO:10; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16.

45. The nucleic acid of claim 44 , wherein the heavy chain variable region comprises one, two, three or four frame work regions selected from VH FRI comprising the amino acid sequence of SEQ ID NO:25, VH FR2 comprising the amino acid sequence of SEQ ID NO:26, VH FR3 comprising the amino acid sequence of SEQ ID NO:27, and VH FR4 comprising the amino acid sequence of SEQ ID NO: 28; and/or wherein the light chain variable region comprises one, two, three or four frame work regions selected from VL FRI comprising the amino acid sequence of SEQ ID NO:29, VL FR2 comprising the amino acid sequence of SEQ ID NO:30, VL FR3 comprising the amino acid sequence of SEQ ID NO:31, and VL FR4 comprising the amino acid sequence of SEQ ID NO:32.

46. The nucleic acid of claim 44 , wherein the heavy chain variable region comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 35.

47. The nucleic acid of claim 44 , wherein the light chain variable region comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 41.

48. The nucleic acid of claim 44 , wherein the heavy chain variable region comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 35.

49. The nucleic acid of claim 44 , wherein the light chain variable region comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 41.

50. The nucleic acid of claim 44 , wherein the heavy chain variable region comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 35.

51. The nucleic acid of claim 44 , wherein the light chain variable region comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 41.

52. The nucleic acid of claim 1 , wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO: 35, and wherein the light chain variable region comprises an amino acid sequence of SEQ ID NO: 41.

53. The nucleic acid of claim 44 , wherein the antibody is of the IgG class, the IgM class, or the IgA class.

54. The nucleic acid of claim 53 , wherein the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.

55. The nucleic acid of claim 54 , wherein the anti-SIRPA antibody has a human IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at an amino acid residue selected from the group consisting of: N297A, D265A, D270A, L234A, L235A, G237A, P238D, L328E, E233D, G237D, H268D, P271G, A330R, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, N297Q, P238S, P238A, A327Q, A327G, P329A, K322A, N325S, L328F, T394D, and any combination thereof, wherein the numbering of the residues is according to EU numbering, or comprises an amino acid deletion in the Fc region at a position corresponding to glycine 236.

56. The nucleic acid of claim 55 , wherein the antibody comprises N325S and L328F substitutions.

57. The nucleic acid of claim 54 , which is a full length antibody, and wherein the heavy chain comprises a C-terminal lysine residue.

58. The nucleic acid of claim 54 , wherein the heavy chain lacks a C-terminal lysine residue.

59. The nucleic acid of claim 44 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 53.

60. The nucleic acid of claim 44 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 53 except for the C-terminal lysine residue of SEQ ID NO: 53.

61. The nucleic acid of claim 44 , wherein the light chain comprises the amino acid sequence of SEQ ID NO: 50.

62. The nucleic acid of claim 1 , wherein the antibody further comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 53 and a light chain comprising the amino acid sequence of SEQ ID NO: 50.

63. The nucleic acid of claim 1 , wherein the antibody further comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 53 except for the C-terminal lysine residue of SEQ ID NO: 53, and wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 50.

64. The nucleic acid of claim 1 , wherein the antibody further comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO: 53 and a light chain consisting of the amino acid sequence of SEQ ID NO: 50.

65. The nucleic acid of claim 1 , wherein the antibody further comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO: 53 except for the C-terminal lysine residue of SEQ ID NO: 53, and wherein the antibody comprises a light chain consisting of the amino acid sequence of SEQ ID NO: 50.

66. The nucleic acid of claim 44 , wherein the anti-SIRPA antibody decreases cell surface levels of SIRPA, decreases intracellular levels of SIRPA, decreases total cellular levels of SIRPA, or any combination thereof.

67. The nucleic acid of claim 44 , wherein the anti-SIRPA antibody induces SIRPA degradation, induces SIRPA cleavage, induces SIRPA internalization, induces SIRPA shedding, downregulates SIRPA expression, or any combination thereof.

68. The nucleic acid of claim 44 , wherein the antibody reduces cell surface levels of SIRPA in vitro and/or in vivo.

69. The nucleic acid of claim 44 , wherein the antibody down-regulates expression of SIRPA in human monocytes and/or human macrophages.

70. The nucleic acid of claim 69 , wherein the antibody down-regulates expression of SIRPA in human macrophages by about 70-95%.

71. The nucleic acid of claim 44 , wherein the antibody has an affinity (KD) to human SIRPA v1 of less than 6 nM.

72. The nucleic acid of claim 44 , wherein the antibody has an affinity (KD) to human SIRPA v1 of about 0.1 nM to 2 nM.

73. The nucleic acid of claim 44 , wherein the antibody reduces cell surface levels of SIRPA in vitro with a half maximal effective concentration (EC50) of about 0.05 to 0.20 nM for human SIRPA v1, of about 0.05 to 0.10 nM for human SIRPA v2, and/or of about 0.05 to 1 nM for cyno SIRPA as measured by flow cytometry.

74. The nucleic acid of claim 44 , wherein the antibody binds human SIRPA, human SIRPA v1, human SIRPA v2, cyno SIRPA, marmoset SIRPA, and human SIRPß3.

75. The nucleic acid of claim 44 , wherein the antibody binds to the D3 domain of human SIRPA v1 of SEQ ID NO:1.

76. The nucleic acid of claim 75 , wherein the antibody binds to amino acid residues R282, Q284, and G337 of human SIRPA v1 of SEQ ID NO:1.

Assignments (2)

SECURITY INTEREST Recorded Nov 14, 2024

From: ALECTOR, INC.; ALECTOR LLC

To: HERCULES CAPITAL, INC., AS AGENT

Reel/Frame 069386/0141 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 6, 2024

From: PINCETIC, ANDREW; HO, WEI-HSIEN; CULP, PATRICIA; ROSENTHAL, ARNON

To: ALECTOR LLC

Reel/Frame 067325/0446 →

Continuity (4)

Division 17707637 · Mar 29, 2022

Division 16421692 · May 24, 2019

Provisional Application 62676813 · May 25, 2018

Related Publication 20240301071A1 · Sep 12, 2024

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