Binding agents

Abstract

The invention relates to antibody molecules and antigen-binding portions thereof which bind specifically to CD47 (Cluster of Differentiation 47, also known as integrin associated protein [IAP]). In aspects of the invention, the anti-CD47 antibody molecules and antigen-binding portions thereof specifically bind to human CD47 and cynomolgus monkey CD47. Medical uses of the anti-CD47 antibody molecules and antigen-binding portions of the invention are disclosed. The anti-CD47 antibody molecules and antigen-binding portions of the invention represent modified and optimised binding molecules compared with a VxP037 murine/humanized anti-CD47 antibody described in WO2014/093678A2.

1 - 34 . (canceled) 
     
     
         35 . A method for treating cancer in a subject, comprising administering to the subject an effective amount of an antibody molecule that specifically binds to human Integrin Associated Protein (CD47) and cynomolgus monkey CD47, or an antigen-binding portion thereof, wherein the antibody molecule or antigen-binding portion comprises:
 (a) a heavy chain variable region comprising a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 49, a HCDR2 of SEQ ID NO: 50, and a HDCR3 of SEQ ID NO: 51; and a light chain variable region comprising a light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 52, a LCDR2 of SEQ ID NO: 53, and a LDCR3 of SEQ ID NO: 54; or   (b) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 49, a HCDR2 of SEQ ID NO: 50, and a HDCR3 of SEQ ID NO: 51; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 52, a LCDR2 of SEQ ID NO: 85, and a LDCR3 of SEQ ID NO: 54.   
     
     
         36 . The method of  claim 35 , wherein the cancer is pancreatic cancer, melanoma, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, stomach cancer, ovarian cancer, urinary bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine or endometrial cancer, cancer of the oral cavity or pharynx, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small bowel or appendix cancer, salivary gland cancer, thyroid gland cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, or cancer of hematological tissues. 
     
     
         37 . The method of  claim 35 , wherein the antibody molecule or antigen-binding portion is humanized or chimeric. 
     
     
         38 . The method of  claim 35 , wherein the heavy chain variable region, the light chain variable region, or both the heavy chain variable region and the light chain variable region of the antibody molecule or antigen-binding portion comprise a human variable domain framework scaffold into which the CDRs have been inserted. 
     
     
         39 . The method of  claim 35 , wherein the heavy chain variable region of the antibody molecule or antigen-binding portion comprises an IGHV5-51 human germline scaffold into which the HCDR1, HCDR2 and HCDR3 sequences have been inserted. 
     
     
         40 . The method of  claim 35 , wherein the light chain variable region of the antibody molecule or antigen-binding portion comprises an IGKV2-28 human germline scaffold into which the LCDR1, LCDR2 and LCDR3 sequences have been inserted. 
     
     
         41 . The method of  claim 35 , wherein the antibody molecule or antigen-binding portion comprises an immunologically inert constant region. 
     
     
         42 . The method of  claim 35 , wherein the antibody molecule or antigen-binding portion is a Fab fragment, a F(ab) 2  fragment, an Fv fragment, a tetrameric antibody, a tetravalent antibody, a multispecific antibody or an scFv. 
     
     
         43 . The method of  claim 42 , wherein the multispecific antibody is a bivalent antibody. 
     
     
         44 . The method of  claim 35 , wherein the antibody molecule or antigen-binding portion specifically binds to mouse CD47. 
     
     
         45 . A method for treating cancer in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising an antibody molecule that specifically binds to human Integrin Associated Protein (CD47) and cynomolgus monkey CD47, or an antigen-binding portion thereof, wherein the antibody molecule or antigen-binding portion comprises:
 (a) a heavy chain variable region comprising a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 49, a HCDR2 of SEQ ID NO: 50, and a HDCR3 of SEQ ID NO: 51; and a light chain variable region comprising a light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 52, a LCDR2 of SEQ ID NO: 53, and a LDCR3 of SEQ ID NO: 54; or   (b) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 49, a HCDR2 of SEQ ID NO: 50, and a HDCR3 of SEQ ID NO: 51; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 52, a LCDR2 of SEQ ID NO: 85, and a LDCR3 of SEQ ID NO: 54.   
     
     
         46 . The method of  claim 45 , wherein the cancer is pancreatic cancer, melanoma, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, stomach cancer, ovarian cancer, urinary bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine or endometrial cancer, cancer of the oral cavity or pharynx, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small bowel or appendix cancer, salivary gland cancer, thyroid gland cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, or cancer of hematological tissues. 
     
     
         47 . The method of  claim 45 , wherein the antibody molecule or antigen-binding portion is humanized or chimeric. 
     
     
         48 . The method of  claim 45 , wherein the heavy chain variable region, the light chain variable region, or both the heavy chain variable region and the light chain variable region of the antibody molecule or antigen-binding portion comprise a human variable domain framework scaffold into which the CDRs have been inserted. 
     
     
         49 . The method of  claim 45 , wherein the heavy chain variable region of the antibody molecule or antigen-binding portion comprises an IGHV5-51 human germline scaffold into which the HCDR1, HCDR2 and HCDR3 sequences have been inserted. 
     
     
         50 . The method of  claim 45 , wherein the light chain variable region of the antibody molecule or antigen-binding portion comprises an IGKV2-28 human germline scaffold into which the LCDR1, LCDR2 and LCDR3 sequences have been inserted. 
     
     
         51 . The method of  claim 45 , wherein the antibody molecule or antigen-binding portion comprises an immunologically inert constant region. 
     
     
         52 . The method of  claim 45 , wherein the antibody molecule or antigen-binding portion is a Fab fragment, a F(ab) 2  fragment, an Fv fragment, a tetrameric antibody, a tetravalent antibody, a multispecific antibody or an scFv. 
     
     
         53 . The method of  claim 52 , wherein the multispecific antibody is a bivalent antibody. 
     
     
         54 . The method of  claim 45 , wherein the antibody molecule or antigen-binding portion specifically binds to mouse CD47. 
     
     
         55 . The method of  claim 45 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient, carrier, buffer or stabilizer. 
     
     
         56 . A method for treating cancer in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a nucleic acid that encodes an antibody molecule that specifically binds to human Integrin Associated Protein (CD47) and cynomolgus monkey CD47, or an antigen-binding portion thereof, wherein the antibody molecule or antigen-binding portion comprises:
 (a) a heavy chain variable region comprising a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 49, a HCDR2 of SEQ ID NO: 50, and a HDCR3 of SEQ ID NO: 51; and a light chain variable region comprising a light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 52, a LCDR2 of SEQ ID NO: 53, and a LDCR3 of SEQ ID NO: 54; or   (b) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 49, a HCDR2 of SEQ ID NO: 50, and a HDCR3 of SEQ ID NO: 51; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 52, a LCDR2 of SEQ ID NO: 85, and a LDCR3 of SEQ ID NO: 54.   
     
     
         57 . The method of  claim 56 , wherein the cancer is pancreatic cancer, melanoma, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, stomach cancer, ovarian cancer, urinary bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine or endometrial cancer, cancer of the oral cavity or pharynx, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small bowel or appendix cancer, salivary gland cancer, thyroid gland cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, or cancer of hematological tissues. 
     
     
         58 . The method of  claim 56 , wherein the antibody molecule or antigen-binding portion is humanized or chimeric. 
     
     
         59 . The method of  claim 56 , wherein the heavy chain variable region, the light chain variable region, or both the heavy chain variable region and the light chain variable region of the antibody molecule or antigen-binding portion comprise a human variable domain framework scaffold into which the CDRs have been inserted. 
     
     
         60 . The method of  claim 56 , wherein the heavy chain variable region of the antibody molecule or antigen-binding portion comprises an IGHV5-51 human germline scaffold into which the HCDR1, HCDR2 and HCDR3 sequences have been inserted. 
     
     
         61 . The method of  claim 56 , wherein the light chain variable region of the antibody molecule or antigen-binding portion comprises an IGKV2-28 human germline scaffold into which the LCDR1, LCDR2 and LCDR3 sequences have been inserted. 
     
     
         62 . The method of  claim 56 , wherein the antibody molecule or antigen-binding portion comprises an immunologically inert constant region. 
     
     
         63 . The method of  claim 56 , wherein the antibody molecule or antigen-binding portion is a Fab fragment, a F(ab) 2  fragment, an Fv fragment, a tetrameric antibody, a tetravalent antibody, a multispecific antibody or an scFv. 
     
     
         64 . The method of  claim 63 , wherein the multispecific antibody is a bivalent antibody. 
     
     
         65 . The method of  claim 56 , wherein the antibody molecule or antigen-binding portion specifically binds to mouse CD47. 
     
     
         66 . The method of  claim 56 , wherein pharmaceutical composition comprises a pharmaceutically acceptable excipient, carrier, buffer or stabilizer.