Therapeutic CD47 antibodies
Provided are monoclonal antibodies and antigen-binding fragments thereof that bind to, and inhibit the activity of, CD47, as well as monoclonal antibodies and antigen binding fragments thereof that compete with the former for binding to CD47. Also provided are combinations of any of the foregoing. Such antibody compounds are variously effective in 1) treating tissue ischemia and ischemia-reperfusion injury (IRI) in the setting of organ preservation and transplantation, pulmonary hypertension, sickle cell disease, myocardial infarction, stroke, and other instances of surgery and/or trauma in which IRI is a component of pathogenesis; 2) in treating autoimmune and inflammatory diseases; and 3) as anti-cancer agents that are toxic to susceptible cancer cells, promoting their phagocytic uptake and clearance, or directly killing such cells.
1. A humanized monoclonal antibody, or antigen binding fragment thereof, that specifically binds human, rat, mouse, and pig CD47, and wherein said humanized monoclonal antibody, or antigen-binding fragment thereof, comprises three light chain complementarity-determining regions (LCDRs 1-3) and three heavy chain complementarity-determining regions (HCDRs 1-3), wherein:
LCDR1 comprises the amino acid sequence RSSQSLVHSNGNTYLH (SEQ ID NO:1),
LCDR2 comprises the amino acid sequence KVSYRFS (SEQ ID NO:2); and
LCDR3 comprises the amino acid sequence SQNTHVPRT (SEQ ID NO:3);
HCDR1 comprises the amino acid sequence GYTFTNYYVF (SEQ ID NO:4);
HCDR2 comprises the amino acid sequence DINPVNGDTNFNEKFKN (SEQ ID NO:5); and
HCDR 3 comprises the amino acid sequence GGYTMDY (SEQ ID NO:6).
2. The humanized monoclonal antibody, or antigen binding fragment thereof, of claim 1 , which promotes phagocytosis and/or killing of cells of susceptible cancer.
3. The humanized monoclonal antibody, or antigen binding fragment thereof, of claim 2 , wherein said susceptible cancer is selected from the group consisting of a leukemia, a lymphoma, ovarian cancer, breast cancer, endometrial cancer, colon cancer, rectal cancer, bladder cancer, lung cancer, bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, liver and bile duct cancer, esophageal cancer, renal cancer, thyroid cancer, head and neck cancer, testicular cancer, glioblastoma, astrocytoma, melanoma, and leiomyosarcoma.
4. The humanized monoclonal antibody, or antigen binding fragment thereof, of claim 3 , wherein said leukemia is selected from the group consisting of acute lymphocytic (lymphoblastic) leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, and chronic myeloid leukemia.