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

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.

Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

“…41 Moreover, targeting the CD47-SIRP a axis has now been shown to increase efficacy of several therapeutic antibodies. 42,43 CD47 is described to be highly expressed on CD38 C MM cells, 44 suggesting that inhibition of the CD47-SIRP a axis might be an interesting therapeutic approach in combination with DARA.…”

How One Thing Led to Another

“…are sensitive to blocking anti-CD47 antibodies (233,234,(241)(242)(243)(244)(245)(246)(247)(248)(249)(250). This makes CD47 the first protooncogene that is universally expressed in all cancers; its function is known, and blockade of its function is therapeutic.…”

Macrophages eat cancer cells using their own calreticulin as a guide: Roles of TLR and Btk

“…Recently a role for PrCR in eliminating living tumor cells has been revealed (1). Several studies have indicated a crucial function of CD47 as an antiphagocytic don't-eat-me signal dominating over PrCR (3)(4)(5)(6)(7)(8)(9)(10). During cancer development, tumor cells up-regulate CD47, which protects them from PrCR (1,3,4,6).…”