Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells.
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.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. kimdk1@stanford.edu
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Kim
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Wang
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Willingham
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Martin
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Wernig
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IL
Weissman
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D001842:Bone and Bones / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051928:CD47 Antigen / Q000276:immunology* / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D005333:Fetus / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D010587:Phagocytosis / Q000187:drug effects*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D051928:CD47 Antigen; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse