IP Library › Granted Patent US 12,404,340
Granted Patent B2
US 12,404,340 · App. 17/337,180 · Granted Sep 2, 2025

Antibodies against signal-regulatory protein alpha and methods of use

Inventors: Jaume Pons (San Francisco, CA); Bang Janet Sim (South San Francisco, CA); Hong Wan (Foster City, CA); Tracy Chia-Chien Kuo (San Carlos, CA); Steven Elliot Kauder (San Mateo, CA); William Don Harriman (Alameda, CA); Shelley Izquierdo (Berkeley, CA)
Assignee: ALX Oncology Inc.
C07K16/2896C07K16/2803C07K16/2818G01N33/6854A61K2039/505A61K2039/507C07K16/2827C07K2317/23C07K2317/24C07K2317/30C07K2317/31C07K2317/34C07K2317/52C07K2317/56C07K2317/565C07K2317/622C07K2317/76C07K2317/92G01N2333/70503G01N2333/70596G01N2500/02
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Quick Facts
Patent No.
US 12,404,340
App. No.
17/337,180
Granted
Sep 2, 2025
Kind
B2
Abstract

Provided herein, inter alia, are isolated antibodies that bind an extracellular domain of a human SIRP-α v1 polypeptide (e.g., the D1 domain), an extracellular domain of a human SIRP-α v2 polypeptide, or both. In some embodiments, the antibodies also bind an extracellular domain of a monkey SIRP-α polypeptide, an extracellular domain of a mouse SIRP-α polypeptide, an extracellular domain of a human SIRP-β polypeptide, and/or an extracellular domain of a human SIRP-γ polypeptide. In some embodiments, the antibodies block or do not binding between an extracellular domain of a human SIRP-α polypeptide and an IgSF domain of a human CD47 polypeptide, while in some embodiments, the antibodies reduce the affinity of a human SIRP-α polypeptide for binding an IgSF domain of a human CD47 polypeptide. Further provided herein are methods, polynucleotides, vectors, and host cells related thereto.

Claims (69)

1. An isolated antibody that binds an extracellular domain of a human SIRP-α polypeptide, wherein the antibody comprises:

(a) a heavy chain variable (VH) domain comprising:

(i) an HVR-H1 sequence comprising the amino acid sequence of SYDMN (SEQ ID NO: 270), SYDVN (SEQ ID NO:221), or SYDLN (SEQ ID NO:313);

(ii) an HVR-H2 sequence comprising the amino acid sequence of LISGSGEIIYYADSVKG (SEQ ID NO: 156); and

(iii) an HVR-H3 sequence comprising the amino acid sequence of ENNRYRFFDD (SEQ ID NO: 157); and

(b) a light chain variable (VL) domain comprising:

(i) an HVR-L1 sequence comprising the amino acid sequence of RASQSVYTYLA (SEQ ID NO:158);

(ii) an HVR-L2 sequence comprising the amino acid sequence of GASSRAT (SEQ ID NO:159); and

(iii) an HVR-L3 sequence comprising the amino acid sequence of QQYYDRPPLT (SEQ ID NO:160).

2. The antibody of claim 1 , wherein the VH domain comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 249, 133, 260, or 329; and the VL domain comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 134, 250, or 251.

3. The antibody of claim 1 , wherein:

(a) the VH domain comprises the amino acid sequence of SEQ ID NO: 133, and the VL domain comprises the amino acid sequence of SEQ ID NO:134;

(b) the VH domain comprises the amino acid sequence of SEQ ID NO:260, and the VL domain comprises the amino acid sequence of SEQ ID NO:134;

(c) the VH domain comprises the amino acid sequence of SEQ ID NO:329, and the VL domain comprises the amino acid sequence of SEQ ID NO:134;

(d) the VH domain comprises the amino acid sequence of SEQ ID NO: 133, and the VL domain comprises the amino acid sequence of SEQ ID NO:250;

(e) the VH domain comprises the amino acid sequence of SEQ ID NO:260, and the VL domain comprises the amino acid sequence of SEQ ID NO:250;

(f) the VH domain comprises the amino acid sequence of SEQ ID NO:329, and the VL domain comprises the amino acid sequence of SEQ ID NO:250;

(g) the VH domain comprises the amino acid sequence of SEQ ID NO: 133, and the VL domain comprises the amino acid sequence of SEQ ID NO:251;

(h) the VH domain comprises the amino acid sequence of SEQ ID NO:260, and the VL domain comprises the amino acid sequence of SEQ ID NO:251;

(i) the VH domain comprises the amino acid sequence of SEQ ID NO:329, and the VL domain comprises the amino acid sequence of SEQ ID NO:251;

(j) the VH domain comprises the amino acid sequence of SEQ ID NO:249, and the VL domain comprises the amino acid sequence of SEQ ID NO:134;

(k) the VH domain comprises the amino acid sequence of SEQ ID NO:249, and the VL domain comprises the amino acid sequence of SEQ ID NO:250; or

(l) the VH domain comprises the amino acid sequence of SEQ ID NO:249, and the VL domain comprises the amino acid sequence of SEQ ID NO:251.

4. The antibody of claim 1 , wherein the antibody enhances phagocytosis by a macrophage expressing a human SIRP-α polypeptide.

5. The antibody of claim 1 , wherein the antibody enhances activation of a dendritic cell expressing a human SIRP-α polypeptide.

6. The antibody of claim 1 , wherein the antibody inhibits in vivo growth of a tumor that expresses CD47.

7. The antibody of claim 1 , wherein the antibody does not prevent interactions between a CD47-expressing cell and a T cell.

8. The antibody of claim 1 , wherein the antibody is a monoclonal antibody.

9. The antibody of claim 1 , wherein the antibody is a scFv-Fc antibody.

10. The antibody of claim 1 , wherein the antibody comprises a light chain constant region comprising the amino acid sequence of SEQ ID NO:325, 326, or 426.

11. The antibody of claim 1 , wherein the antibody comprises an Fc region.

12. The antibody of claim 11 , wherein the antibody comprises an antibody heavy chain polypeptide that comprises the VH domain and a constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 320-324.

13. The antibody of claim 11 , wherein the Fc region is a human Fc region selected from the group consisting of an IgG1 Fc region, an IgG2 Fc region, and an IgG4 Fc region.

14. The antibody of claim 11 , wherein the Fc region comprises a human IgG1 Fc region comprising one or more mutations selected from the group consisting of L234A, L235A, G237A, and N297A, according to EU numbering.

15. The antibody of claim 11 , wherein the Fc region comprises a human IgG2 Fc region comprising one or more mutations selected from the group consisting of A330S, P331S and N297A, according to EU numbering.

16. The antibody of claim 11 , wherein the Fc region comprises a human IgG4 Fc region comprising one or more mutations selected from the group consisting of S228P, E233P, F234V, L235A, L235E, delG236, and N297A, according to EU numbering.

17. The antibody of claim 1 , wherein the antibody is an antibody fragment selected from the group consisting of a Fab, F(ab′)2, Fab′-SH, Fv, and scFv fragment.

18. The antibody of claim 1 , wherein the antibody is conjugated to a cytotoxic agent or label.

19. The antibody of claim 1 , wherein the antibody is a bispecific antibody.

20. The antibody of claim 19 , wherein the antibody comprises a first antigen binding domain comprising the VH and VL domain that bind an extracellular domain of a human SIRP-α polypeptide and a second antigen binding domain comprising a second VH domain and second VL domain that bind an antigen expressed by a cancer cell.

21. The antibody of claim 20 , wherein the antigen expressed by the cancer cell is selected from the group consisting of CD19, CD20, CD22, CD30, CD33, CD38, CD52, CD56, CD70, CD74, CD79b, CD123, CD138, CS1/SLAMF7, Trop-2, 5T4, EphA4, BCMA, Mucin 1, Mucin 16, PD-L1, PTK7, STEAP1, Endothelin B Receptor, mesothelin, EGFRVIII, ENPP3, SLC44A4, GNMB, nectin 4, NaPi2b, LIV-1A, Guanylyl cyclase C, DLL3, EGFR, HER2, VEGF, VEGFR, integrin αVβ3, integrin α5β1, MET, IGF1R, TRAILR1, TRAILR2, RANKL, FAP, Tenascin, Le y , EpCAM, CEA, gpA33, PSMA, TAG72, a mucin, CAIX, EPHA3, folate receptor α, GD2, GD3, and an MHC/peptide complex comprising a peptide from NY-ESO-1/LAGE, SSX-2, MAGE-A3, gp100/pmel17, Melan-A/MART-1, gp75/TRP1, tyrosinase, TRP2, CEA, PSA, TAG-72, immature laminin receptor, MOK/RAGE-1, WT-1, SAP-1, BING-4, EpCAM, MUC1, PRAME, survivin, BRCA1, BRCA2, CDK4, CML66, MART-2, p53, Ras, β-catenin, TGF-βRII, HPV E6, or HPV E7.

22. The antibody of claim 1 , wherein the antibody is a human antibody.

23. A polynucleotide encoding the antibody of claim 1 .

24. A vector comprising the polynucleotide of claim 23 .

25. A host cell comprising the polynucleotide of claim 23 .

26. A method of producing an antibody, the method comprising culturing the host cell of claim 25 such that the antibody that binds the extracellular domain of a human SIRP-α polypeptide is produced.

27. The method of claim 26 , further comprising recovering the antibody from the host cell.

28. The antibody of claim 1 , wherein the antibody binds an extracellular domain of a human SIRP-α v1 polypeptide comprising the amino acid sequence of

(SEQ ID NO: 5)

EEELQVIQPDKSVLVAAGETATLRCTATSLIPVGPIQWFRGAGPGRELIY

NQKEGHFPRVTTVSDLTKRNNMDFSIRIGNITPADAGTYYCVKFRKGSPD

DVEFKSGAGTELSVRAKPS.

29. The antibody of claim 1 , wherein the antibody binds an extracellular domain of a human SIRP-α v2 polypeptide comprising the amino acid sequence of

(SEQ ID NO: 6)

EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELI

YNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGS

PDTEFKSGAGTELSVRAKPS.

30. The antibody of claim 1 , wherein the antibody is capable of binding an extracellular domain of a human SIRP-α v1 polypeptide comprising the amino acid sequence of EEELQVIQPDKSVLVAAGETATLRCTATSLIPVGPIQWFRGAGPGRELIYNQKEGHFPRV TTVSDLTKRNNMDFSIRIGNITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS (SEQ ID NO:5) and is capable of binding an extracellular domain of a human SIRP-α v2 polypeptide comprising the amino acid sequence of

(SEQ ID NO: 6)

EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIY

NQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPD

TEFKSGAGTELSVRAKPS.

31. The antibody of claim 1 , wherein the antibody binds an extracellular domain of a cynomolgus SIRP-α polypeptide comprising the amino acid sequence of SEQ ID NO:11.

32. The antibody of claim 1 , wherein the antibody binds an extracellular domain of a murine SIRP-α polypeptide comprising the amino acid sequence of SEQ ID NO:7.

33. The antibody of claim 1 , wherein the antibody binds the extracellular domain of a human SIRP-β polypeptide comprising the amino acid sequence of SEQ ID NO:13.

34. The antibody of claim 1 , wherein the antibody does not block binding between an extracellular domain of a human SIRP-α polypeptide and an IgSF domain of a human CD47 polypeptide.

35. A host cell comprising the vector of claim 24 .

36. A method of producing an antibody, the method comprising culturing the host cell of claim 35 such that the antibody that binds the extracellular domain of a human SIRP-α polypeptide is produced.

37. The method of claim 36 , further comprising recovering the antibody from the host cell.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 4, 2021
From: HARRIMAN, WILLIAM DON; IZQUIERDO, SHELLEY
To: CRYSTAL BIOSCIENCE INC.
Reel/Frame 056446/0234 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 4, 2021
From: PONS, JAUME; SIM, BANG JANET; WAN, HONG; KUO, TRACY CHIA-CHIEN; KAUDER, STEVEN ELLIOT
To: ALEXO THERAPEUTICS INC.
Reel/Frame 056446/0243 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 4, 2021
From: CRYSTAL BIOSCIENCE INC.
To: ALEXO THERAPEUTICS INC.
Reel/Frame 056446/0248 →
CHANGE OF NAME Recorded Jun 4, 2021
From: ALEXO THERAPEUTICS INC.
To: ALX ONCOLOGY INC.
Reel/Frame 056493/0336 →
Continuity (4)
Division 15710798 · Sep 20, 2017
Provisional Application 62515480 · Jun 5, 2017
Provisional Application 62397752 · Sep 21, 2016
Related Publication 20230018821A1 · Jan 19, 2023
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