High affinity Sirp-alpha reagents and methods of using

Patent metadata

Field	Value
Publication number	US-9944911-B2
Application number	US-201314371370-A
Country	US
Kind code	B2
Filing date	Jan 17, 2013
Priority date	Jan 17, 2012
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

High affinity SIRP-α reagent are provided, which (i) comprise at least one amino acid change relative to the wild-type protein; and (ii) have an increased affinity for CD47 relative to the wild-type protein. Compositions and methods are provided for modulating phagocytosis in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a high affinity SIRPα reagent, which blocks the physiological binding interaction between SIRPα and its ligand CD47.

First claim

What is claimed is:

1. A soluble high affinity SIRPα polypeptide comprising an amino acid sequence set forth in SEQ ID NO: 10, wherein the high affinity SIRPα polypeptide lacks a SIRPα transmembrane domain.

2. The soluble high affinity SIRPα polypeptide of claim 1 , wherein the high affinity SIRPα polypeptide has a K D less than 279 nM for human CD47.

3. The soluble high affinity SIRPα polypeptide of claim 1 , wherein the high affinity SIRPα polypeptide comprises amino acid sequences from SIRPα outside of the d1 domain.

4. The soluble high affinity SIRPα polypeptide of claim 1 , wherein the high affinity SIRPα polypeptide is multimeric.

5. The soluble high affinity SIRPα polypeptide of claim 1 , wherein the high affinity SIRPα polypeptide is monomeric.

6. A therapeutic formulation comprising the soluble high affinity SIRPα polypeptide of claim 1 and a pharmaceutically acceptable excipient.

7. The soluble high affinity SIRPα polypeptide of claim 1 , further comprising a detectable label.

8. A method of imaging a tumor, the method comprising contacting cancer cells expressing CD47 with a polypeptide as set forth in claim 7 .

9. The soluble high affinity SIRPα polypeptide of claim 1 , wherein the high affinity SIRPα polypeptide is fused to an immunoglobulin Fc sequence.

10. A therapeutic formulation comprising the soluble high affinity SIRPα polypeptide of claim 9 and a pharmaceutically acceptable excipient.

11. A method of increasing phagocytosis of a cell expressing human CD47, the method comprising contacting the cell with a formulation of claim 10 .

12. The method of claim 11 , further comprising contacting the cell with a tumor specific antibody.

13. The method of claim 11 , wherein the contacting is in vitro.

14. The method of claim 11 , wherein the contacting is in vivo.

15. The method of claim 11 , wherein the cell expressing human CD47 is a cancer cell.

Assignees

• Univ Leland Stanford Junior

Inventors

• Ring Aaron Michael
• Garcia Kenan Christopher
• Weiskopf Kipp Andrew
• Levin Aron M
• Weissman Irving L

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K38/16

  Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)} · CPC title

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title

• C07K14/4703 Primary

  Inhibitors; Suppressors · CPC title