Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Leukemia. 2012 Dec;26(12):2538-45. doi: 10.1038/leu.2012.141. Epub 2012 May 30.
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.
多发性骨髓瘤是一种存在于骨髓中的浆细胞瘤。尽管骨髓瘤疗法取得了进展，但仍需要新的疗法来改善患者的预后。CD47 在骨髓瘤细胞中高度表达，是骨髓瘤疗法的潜在治疗候选物。对患者骨髓细胞的流式细胞分析显示，与 73%（27/37）的非骨髓瘤细胞相比，骨髓瘤细胞过度表达 CD47。CD47 的表达通过向巨噬细胞传递抑制信号来保护细胞免受吞噬作用。在这里，我们表明，用抗 CD47 单克隆抗体阻断 CD47 会增加骨髓瘤细胞在体外的吞噬作用。在异种移植模型中，抗 CD47 抗体抑制 RPMI 8226 骨髓瘤细胞的生长并导致肿瘤消退（42/57 只小鼠），这意味着骨髓瘤起始细胞被根除。此外，抗 CD47 抗体延迟了患者骨髓瘤细胞的生长并减轻了人骨载瘤小鼠的骨质吸收。在骨髓瘤细胞异种移植前对小鼠进行辐照，会消除辐照后 2 周给予抗 CD47 抗体的治疗效果，同时脾脏、骨髓和肝脏中的髓系细胞减少。这些结果与抗 CD47 阻断抗体通过增加骨髓瘤细胞的吞噬作用来抑制骨髓瘤生长的假说一致。
