Anti-cd47 antibodies and methods of use

Abstract

Disclosed herein are anti-CD47 antibody molecules, their manufacture and use in treating disorders associated with CD47 expression, for example, certain hematological cancers and solid tumors.

What is claimed: 
     
         1 . A composition comprising an isolated monoclonal antibody that specifically binds human CD47, or antigen binding fragment thereof, wherein the monoclonal antibody or antigen binding fragment thereof comprises: a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence set forth in SEQ ID NO: 7; a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence set forth in SEQ ID NO: 8; a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence set forth in SEQ ID NO: 9; a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence set forth in SEQ ID NO: 10; a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence set forth in SEQ ID NO: 11; and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence set forth in SEQ ID NO: 12; and a pharmaceutically acceptable carrier or diluent. 
     
     
         2 . The composition of  claim 1 , wherein the antibody or antigen-binding fragment inhibits the interaction between human CD47 and SIRPα. 
     
     
         3 . The composition of  claim 1 , wherein the antibody or antigen-binding fragment does not cause significant, or detectable, hemagglutination of human erythrocytes relative to a reference monoclonal antibody that specifically binds human CD47 and causes significant, or detectable, hemagglutination of human erythrocytes, or antigen binding fragment thereof. 
     
     
         4 . The composition of  claim 1 , wherein the antibody is a human antibody, and wherein the antibody comprises a wild type human IgG1 or wild type human IgG4 heavy chain constant region. 
     
     
         5 . The composition of  claim 1 , wherein the antibody comprises a mutant IgG1 heavy chain constant region. 
     
     
         6 . The composition of  claim 5 , wherein the mutant IgG1 heavy chain constant region comprises a substitution at Glu233, Leu234, Leu235, Asn297, or a combination thereof, numbering according to EU numbering; or wherein the mutant IgG1 heavy chain constant region comprises an E233P substitution, an L234A or L234E substitution, an L235A substitution, an N297A substitution, or a combination thereof, numbering according to EU numbering. 
     
     
         7 . The composition of  claim 1 , wherein the antibody comprises a mutant IgG4 heavy chain constant region. 
     
     
         8 . The composition of  claim 7 , wherein the mutant IgG4 heavy chain constant region comprises a substitution at Ser228, Leu235, Asn297, or a combination thereof, numbering according to EU numbering; wherein the mutant IgG4 heavy chain constant region comprises an S228P substitution, an L235E substitution, an N297A substitution, or a combination thereof, numbering according to EU numbering; or wherein the mutant IgG4 heavy chain constant region comprises an S228P substitution and an L235E substitution, numbering according to EU numbering. 
     
     
         9 . The composition of  claim 4 , wherein the antibody comprises a human kappa constant region. 
     
     
         10 . A composition comprising an isolated monoclonal antibody that specifically binds human CD47 or an antigen-binding fragment thereof, wherein the monoclonal antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 4 and a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 6; and a pharmaceutically acceptable carrier or diluent. 
     
     
         11 . The composition of  claim 10 , wherein the antibody or antigen-binding fragment inhibits the interaction between human CD47 and SIRPα. 
     
     
         12 . The composition of  claim 10 , wherein the antibody or antigen-binding fragment does not cause significant, or detectable, hemagglutination of human erythrocytes relative to a reference monoclonal antibody that specifically binds human CD47 and causes significant, or detectable, hemagglutination of human erythrocytes, or antigen binding fragment thereof. 
     
     
         13 . The composition of  claim 10 , wherein the antibody is a human antibody, and wherein the antibody comprises a wild-type human IgG1 or wild-type human IgG4 heavy chain constant region. 
     
     
         14 . The composition of  claim 13 , wherein the antibody comprises a human kappa constant region, or wherein the antibody comprises a human kappa constant region comprising the amino acid sequence set forth in SEQ ID NO: 22. 
     
     
         15 . The composition of  claim 13 , wherein the wild-type human IgG4 heavy chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 20. 
     
     
         16 . A composition comprising an isolated monoclonal antibody that specifically binds human CD47, wherein the monoclonal antibody comprises: a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 15, SEQ ID NO: 23, SEQ ID NO: 24, or SEQ ID NO: 25; and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 16 or SEQ ID NO: 26; and a pharmaceutically acceptable carrier or diluent. 
     
     
         17 . The composition of  claim 16 , wherein the antibody inhibits the interaction between human CD47 and SIRPα. 
     
     
         18 . The composition of  claim 16 , wherein the antibody does not cause significant, or detectable, hemagglutination of human erythrocytes relative to a reference monoclonal antibody that specifically binds human CD47 and causes significant, or detectable, hemagglutination of human erythrocytes, or antigen binding fragment thereof. 
     
     
         19 . The composition of  claim 16 , wherein the antibody is a human antibody. 
     
     
         20 . The composition of  claim 16 , wherein the monoclonal antibody comprises: a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 24; and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 26; and a pharmaceutically acceptable carrier or diluent. 
     
     
         21 . A method of treating cancer in a subject in need thereof, wherein the cancer comprises cells that express CD47, the method comprising administering to the subject an effective amount of the composition of  claim 1 .