Antibodies against signal-regulatory protein alpha and methods of use
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.
1. An isolated antibody that binds an extracellular domain of a human SIRP-α v1 or v2 polypeptide, wherein the antibody comprises:
(a) a heavy chain that comprises a heavy chain variable (VH) domain comprising:
(i) an HVR-H1 sequence comprising the amino acid sequence of SNAMS (SEQ ID NO:194),
(ii) an HVR-H2 sequence comprising the amino acid sequence of GISAGGSDTYYPASVKG (SEQ ID NO:195), and
(iii) an HVR-H3 sequence comprising the amino acid sequence of ETWNHLFDY (SEQ ID NO:193); and
(b) a light chain that comprises a light chain variable (VL) domain comprising:
(i) an HVR-L1 sequence comprising the amino acid sequence of SGGSYSSYYYA (SEQ ID NO:170),
(ii) an HVR-L2 sequence comprising the amino acid sequence of SDDKRPS (SEQ ID NO:336), and
(iii) an HVR-L3 sequence comprising the amino acid sequence of GGYDQSSYTNP (SEQ ID NO:172).
2. The antibody of claim 1 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO:263.
3. The antibody of claim 1 , wherein the VL domain comprises the amino acid sequence of SEQ ID NO:252.
4. The antibody of claim 1 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO:263, and wherein the VL domain comprises the amino acid sequence of SEQ ID NO:252.
5. The antibody of claim 1 , wherein the heavy chain further comprises an Fc region.
6. The antibody of claim 5 , wherein the Fc region is a human IgG1 Fc region, a human IgG2 Fc region, or a human IgG4 Fc region.
7. The antibody of claim 6 , wherein the Fc region is 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.
8. The antibody of claim 1 , wherein the light chain further comprises the amino acid sequence of SEQ ID NO:325.
9. The antibody of claim 3 , wherein the light chain further comprises the amino acid sequence of SEQ ID NO:325.
10. The antibody of claim 1 , wherein the light chain further comprises the amino acid sequence of SEQ ID NO:326 or 426.
11. The antibody of claim 3 , wherein the light chain further comprises the amino acid sequence of SEQ ID NO:326 or 426.
12. The antibody of claim 1 , wherein the heavy chain comprises a VH domain comprising the amino acid sequence of SEQ ID NO:263; wherein the heavy chain further 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; wherein the light chain comprises a VL domain comprising the amino acid sequence of SEQ ID NO:252; and wherein the light chain further comprises the amino acid sequence of SEQ ID NO:326.
13. The antibody of claim 1 , wherein the heavy chain comprises a VH domain comprising the amino acid sequence of SEQ ID NO:263; wherein the heavy chain further 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; wherein the light chain comprises a VL domain comprising the amino acid sequence of SEQ ID NO:252; and wherein the light chain further comprises the amino acid sequence of SEQ ID NO:326.
14. The antibody of claim 1 , wherein the heavy chain comprises a VH domain comprising the amino acid sequence of SEQ ID NO:263; wherein the heavy chain further 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; wherein the light chain comprises a VL domain comprising the amino acid sequence of SEQ ID NO:252; and wherein the light chain further comprises the amino acid sequence of SEQ ID NO:326.
15. The antibody of claim 1 , wherein the antibody is a monoclonal antibody.
16. The antibody of claim 1 , wherein the antibody is conjugated to a cytotoxic agent or label.
17. The antibody of claim 4 , wherein the antibody is conjugated to a cytotoxic agent or label.
18. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising the antibody of claim 4 and a pharmaceutically acceptable carrier.
20. A pharmaceutical composition comprising the antibody of claim 12 and a pharmaceutically acceptable carrier.
21. A pharmaceutical composition comprising the antibody of claim 14 and a pharmaceutically acceptable carrier.
22. A pharmaceutical composition comprising the antibody of claim 17 and a pharmaceutically acceptable carrier.
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 is produced.
27. The method of claim 26 , further comprising recovering the antibody from the host cell.
28. A host cell comprising the vector of claim 24 .
29. A method of producing an antibody, the method comprising culturing the host cell of claim 28 such that the antibody is produced.
30. The method of claim 29 , further comprising recovering the antibody from the host cell.