Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells

Leukemia. 2012 Dec;26(12):2538-45. doi: 10.1038/leu.2012.141. Epub 2012 May 30.

Abstract

Multiple myeloma is a plasma cell neoplasm residing in bone marrow. Despite advances in myeloma therapies, novel therapies are required to improve patient outcomes. CD47 is highly expressed on myeloma cells and a potential therapeutic candidate for myeloma therapies. Flow cytometric analysis of patient bone marrow cells revealed that myeloma cells overexpress CD47 when compared with non-myeloma cells in 73% of patients (27/37). CD47 expression protects cells from phagocytosis by transmitting an inhibitory signal to macrophages. Here we show that blocking CD47 with an anti-CD47 monoclonal antibody increased phagocytosis of myeloma cells in vitro. In xenotransplantation models, anti-CD47 antibodies inhibited the growth of RPMI 8226 myeloma cells and led to tumor regression (42/57 mice), implicating the eradication of myeloma-initiating cells. Moreover, anti-CD47 antibodies retarded the growth of patient myeloma cells and alleviated bone resorption in human bone-bearing mice. Irradiation of mice before myeloma cell xenotransplantation abolished the therapeutic efficacy of anti-CD47 antibodies delivered 2 weeks after radiation, and coincided with a reduction of myelomonocytic cells in spleen, bone marrow and liver. These results are consistent with the hypothesis that anti-CD47 blocking antibodies inhibit myeloma growth, in part, by increasing phagocytosis of myeloma cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Anti-Idiotypic / therapeutic use*
  • Antibodies, Monoclonal / therapeutic use*
  • Antibody-Dependent Cell Cytotoxicity
  • Bone and Bones / drug effects
  • Bone and Bones / immunology*
  • Bone and Bones / pathology
  • CD47 Antigen / immunology*
  • CD47 Antigen / pharmacology*
  • DNA-Binding Proteins / physiology
  • Female
  • Fetus / pathology
  • Flow Cytometry
  • Humans
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / pathology
  • Mice
  • Multiple Myeloma / immunology
  • Multiple Myeloma / pathology
  • Multiple Myeloma / prevention & control*
  • Phagocytosis / drug effects*
  • Transplantation, Heterologous
  • Tumor Cells, Cultured

Substances

  • Antibodies, Anti-Idiotypic
  • Antibodies, Monoclonal
  • CD47 Antigen
  • DNA-Binding Proteins
  • Rag2 protein, mouse