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.
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Acknowledgements
We thank Dr Bruno C Medeiros for providing patient specimens; Libuse Jerabek, Theresa Storm and Adriane Mosley for laboratory and mouse management; Drs Ingrid Ibarra and Yasuo Mori for their help with interpretation of bone marrow cell morphology; Kipp Weiskopf for helpful comments on phagocytosis assay. In addition, we thank patients who consented to donate specimens. A part of this research was presented in the Lymphoma and Myeloma 2011 meeting. Dongkyoon Kim was supported by the Irvington Institute Fellowship Program of the Cancer Research Institute (initially by the Irvington Institute for Immunological Research and The Dana Foundation). This research was supported by co-sponsorship (SPO no.: 43710) of the Multiple Myeloma Research Foundation and the Leukemia Lymphoma Society, and by the Ludwig Institute. Irving L Weissman is a Daniel K and Virginia Ludwig Professor at Stanford.
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ILW et al. filed US. Patent Application Serial No. 12/321,215 entitled ‘Methods for Manipulating Phagocytosis Mediated by CD47.’ The other authors declare no conflict of interest.
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Kim, D., Wang, J., Willingham, S. et al. Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells. Leukemia 26, 2538–2545 (2012). https://doi.org/10.1038/leu.2012.141
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DOI: https://doi.org/10.1038/leu.2012.141
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