SIRP-α immunoglobulin fusion proteins
The invention discloses immunoglobulin fusion proteins designed to bind both CD47 and a tumor cell antigen. The immunoglobulin fusion proteins include a SIRPα moiety that binds CD47 and an antigen binding site for a tumor cell antigen.
1. A SIRPα antibody fusion protein comprising:
an IgV extracellular domain of SIRPα comprising an amino acid sequence at least 95% identical to residues 3-115 of SEQ ID NO:6, to residues 3-114 of SEQ ID NO:8, or to residues 1-115 of SEQ ID NO:190, and comprising a substitution at one or more positions corresponding to positions 37, 54, or 72 of SEQ ID NO:6, SEQ ID NO:8, or SEQ ID NO:190, wherein the substitution at one or more positions is selected from the group consisting of: Q37W, Q37H, E54P, and M72R; and
an antibody or antigen-binding fragment thereof that binds to a surface antigen on a tumor cell.
2. The SIRPα antibody fusion protein of claim 1 , wherein the surface antigen is a tumor antigen.
3. The SIRPα antibody fusion protein of claim 1 , wherein the IgV extracellular domain of SIRPα comprises an amino acid sequence at least 95% identical to residues 1-115 of SEQ ID NO:6 or to residues 1-114 of SEQ ID NO:8.
4. The SIRPα antibody fusion protein of claim 1 , wherein the IgV extracellular domain of SIRPα comprises an amino acid sequence at least 95% identical to a sequence selected from the group consisting of: residues 1-114 of SEQ ID NO:193, residues 1-115 of SEQ ID NO:194, residues 1-115 of SEQ ID NO:195, residues 1-115 of SEQ ID NO:196, residues 1-114 of SEQ ID NO:197, residues 1-114 of SEQ ID NO:198, residues 1-115 of SEQ ID NO:199, and residues 1-114 of SEQ ID NO:200.
5. The SIRPα antibody fusion protein of claim 1 , wherein the IgV extracellular domain of SIRPα comprises an amino acid sequence at least 95% identical to residues 1-343 of SEQ ID NO:6.
6. A pharmaceutical composition comprising a pharmaceutically effective amount of the SIRPα antibody fusion protein of claim 1 and a pharmaceutically acceptable carrier.
7. The SIRPα antibody fusion protein of claim 2 , wherein the tumor antigen is selected from the group consisting of HER2, HER3, EGFR, CD20, GD2, PD-L1, and CD19.
8. The SIRPα antibody fusion protein of claim 1 , wherein the antibody or antigen-binding fragment thereof is an anti-EGFR antibody.
9. The SIRPα antibody fusion protein of claim 1 , wherein the substitution is Q37W.
10. The SIRPα antibody fusion protein of claim 1 , wherein the substitution is E54P.
11. The SIRPα antibody fusion protein of claim 1 , wherein the IgV extracellular domain of SIRPα comprises the amino acid sequence of SEQ ID NO:135 or SEQ ID NO:136.
12. The SIRPα antibody fusion protein of claim 1 , wherein the IgV extracellular domain of SIRPα comprises the amino acid sequence of SEQ ID NO:141 or SEQ ID NO:142.
13. The SIRPα antibody fusion protein of claim 1 , wherein the IgV extracellular domain of SIRPα is connected to a heavy chain of the antibody or portion thereof.
14. The SIRPα antibody fusion protein of claim 1 , wherein the IgV extracellular domain of SIRPα is connected to a light chain of the antibody or portion thereof.
15. The SIRPα antibody fusion protein of claim 1 , wherein the IgV extracellular domain of SIRPα is connected at its N-terminus to the antibody or antigen-binding fragment thereof.
16. The SIRPα antibody fusion protein of claim 1 , wherein the IgV extracellular domain of SIRPα is connected at its C-terminus to the antibody or antigen-binding fragment thereof.
17. The SIRPα antibody fusion protein of claim 1 , wherein the IgV extracellular domain of SIRPα is connected to an N-terminus of the antibody of antigen-binding fragment thereof.
18. The SIRPα antibody fusion protein of claim 1 , wherein the IgV extracellular domain of SIRPα is connected to a C-terminus of the antibody or antigen-binding fragment thereof.
19. The SIRPα antibody fusion protein of claim 1 , wherein the substitution is Q37H.
20. The SIRPα antibody fusion protein of claim 1 , wherein the substitution is M72R.