Therapeutic cd47 antibodies

Abstract

Provided are anti-CD47 monoclonal antibodies (anti-CD47 mAbs) with distinct functional profiles as described herein, methods to generate anti-CD47 mAbs, and to methods of using these anti-CD47 mAbs as therapeutics for the prevention and treatment of solid and hematological cancers, ischemia-reperfusion injury, cardiovascular diseases, autoimmune diseases, inflammatory diseases or as diagnostics for determining the level of CD47 in tissue samples.

What is claimed: 
     
         1 . A method of treating cancer in a subject comprising administering to the subject an effective amount of an anti-CD47 antibody molecule or antigen-binding fragment thereof that specifically binds CD47 and comprises:
 a variable heavy chain CDR1 amino acid sequence (HCDR1) amino acid sequence set forth in SEQ ID NO:3;   a variable heavy chain CDR2 amino acid sequence (HCDR2) amino acid sequence set forth in SEQ ID NO:6;   a variable heavy chain CDR3 amino acid sequence (HCDR3) amino acid sequence set forth in SEQ ID NO:10;   a variable light chain CDR1 amino acid sequence (LCDR1) amino acid sequence set forth in SEQ ID NO:14;   a variable light chain CDR2 amino acid sequence (LCDR2) amino acid sequence set forth in SEQ ID NO:17; and   a variable light chain CDR3 amino acid sequence (LCDR3) amino acid sequence set forth in SEQ ID NO:18.   
     
     
         2 . The method of  claim 1 , wherein the anti-CD47 antibody molecule or antigen-binding fragment thereof, is administered in combination with a chemotherapeutic agent or therapeutic antibody molecule. 
     
     
         3 . The method of  claim 1 , wherein the anti-CD47 antibody molecule or antigen-binding fragment thereof, further comprises a heavy chain variable domain (V H ) and a light chain variable domain (V L ), selected from:
 (i) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:36 and a light chain variable domain comprising the amino acid sequence SEQ ID NO:51;   (ii) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:36 and a light chain variable domain comprising the amino acid sequence SEQ ID NO:52;   (iii) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:37 and a light chain variable domain comprising the amino acid sequence SEQ ID NO:51;   (iv) a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:37 and a light chain variable domain comprising the amino acid sequence SEQ ID NO:52;   (v) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain comprising the amino acid sequence SEQ ID NO:51; and   (vi) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain comprising the amino acid sequence SEQ ID NO:52.   
     
     
         4 . The method of  claim 3 , wherein the anti-CD47 antibody molecule or antigen-binding fragment thereof further comprises an IgG isotype selected from IgG1, IgG-N297Q, IgG2, IgG4, IgG4 S228P, and IgG4 PE. 
     
     
         5 . The method of  claim 3 , wherein the anti-CD47 antibody molecule or antigen fragment thereof further comprises one heavy chain and one light chain selected from:
 (i) a heavy chain comprising the amino acid sequence of SEQ ID NO:81 and a light chain comprising the amino acid sequence SEQ ID NO:73;   (ii) a heavy chain comprising the amino acid sequence of SEQ ID NO:80 and a light chain comprising the amino acid sequence SEQ ID NO:70;   (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:81 and a light chain comprising the amino acid sequence SEQ ID NO:70;   (iv) a heavy chain comprising the amino acid sequence of SEQ ID NO:79 and a light chain comprising the amino acid sequence SEQ ID NO:70;   (v) a heavy chain comprising the amino acid sequence of SEQ ID NO:79 and a light chain comprising the amino acid sequence SEQ ID NO:73;   (vi) a heavy chain comprising the amino acid sequence of SEQ ID NO:80 and a light chain comprising the amino acid sequence SEQ ID NO:73.   
     
     
         6 . The method of  claim 5 , wherein the anti-CD47 antibody molecule or antigen binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:80 and a light chain comprising the amino acid sequence SEQ ID NO:70. 
     
     
         7 . The method of  claim 1 , wherein the cancer is a leukemia, a lymphoma, ovarian cancer, breast cancer, endometrial cancer, colon cancer (colorectal cancer), rectal cancer, bladder cancer, urothelial cancer, lung cancer (non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung), bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, gall bladder cancer, bile duct cancer, esophageal cancer, renal cell carcinoma, thyroid cancer, squamous cell carcinoma of the head and neck (head and neck cancer), testicular cancer, cancer of the endocrine gland, cancer of the adrenal gland, cancer of the pituitary gland, cancer of the skin, cancer of soft tissues, cancer of blood vessels, cancer of brain, cancer of nerves, cancer of eyes, cancer of meninges, cancer of oropharynx, cancer of hypopharynx, cancer of cervix, and cancer of uterus, glioblastoma, meduloblastoma, astrocytoma, glioma, meningioma, gastrinoma, neuroblastoma, melanoma, myelodysplastic syndrome, and a sarcoma. 
     
     
         8 . The method of  claim 7 , wherein said leukemia is systemic mastocytosis, acute lymphocytic (lymphoblastic) leukemia (ALL), T cell—ALL, acute myeloid leukemia (AML), myelogenous leukemia, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), chronic myeloid leukemia (CML), myeloproliferative disorder/neoplasm, myelodysplastic syndrome, monocytic cell leukemia, and plasma cell leukemia; wherein said lymphoma is histiocytic lymphoma and T cell lymphoma, a B cell lymphoma, including Hodgkin's lymphoma and non-Hodgkin's lymphoma, such as low grade/follicular non-Hodgkin's lymphoma (NHL), cell lymphoma (FCC), mantle cell lymphoma (MCL), diffuse large cell lymphoma (DLCL), small lymphocytic (SL) NHL, intermediate grade/follicular NHL, intermediate grade diffuse NHL, high grade immunoblastic NHL, high grade lymphoblastic NHL, high grade small non-cleaved cell NHL, bulky disease NHL, and Waldenstrom's Macroglobulinemia; and wherein said sarcoma is selected from the group consisting of osteosarcoma, Ewing's sarcoma, leiomyosarcoma, synovial sarcoma, alveolar soft part sarcoma, angiosarcoma, liposarcoma, fibrosarcoma, rhabdomyosarcoma, and chrondrosarcoma. 
     
     
         9 . The method of  claim 1 , wherein the anti-CD47 antibody molecule or antigen-fragment thereof is administered in combination with a pharmaceutically or physiologically acceptable carrier, diluent, or excipient. 
     
     
         10 . The method of  claim 1 , wherein the anti-CD47 antibody molecule or antigen-binding fragment thereof is administered intravenously. 
     
     
         11 . The method of  claim 1 , wherein the anti-CD47 antibody molecule or antigen-binding fragment thereof is administered subcutaneously.