Daratumumab(DARA)是一种人类CD38特异性IgG1抗体,正在临床开发中用于治疗多发性骨髓瘤(MM)。IgG1抗体诱导巨噬细胞介导的吞噬作用的潜力,结合已知的巨噬细胞在MM和其他血液肿瘤的肿瘤微环境中的存在,导致我们研究了抗体依赖性的贡献,巨噬细胞介导的吞噬作用对DARA的作用机制。活细胞成像显示DARA有效诱导巨噬细胞介导的吞噬作用,其中单个巨噬细胞快速并依次吞噬多个肿瘤细胞。在体外流式细胞术测定中还观察到小鼠和人巨噬细胞的DARA依赖性吞噬作用,使用一系列MM和Burkitt淋巴瘤细胞系。吞噬作用有助于DARA的体内抗肿瘤活性,在皮下和静脉内白血病异种移植小鼠模型中。最后,显示DARA诱导从12名MM患者中的11名分离的MM细胞的巨噬细胞介导的吞噬作用,所述MM患者显示可变水平的CD38表达。总之,我们证明吞噬作用是一种快速,可能有助于DARA在多发性骨髓瘤和潜在的其他血液肿瘤中的治疗活性的有效和临床相关的作用机制。
Daratumumab (DARA) is a human CD38-specific IgG1 antibody that is in clinical development for the treatment of multiple myeloma (MM). The potential for IgG1 antibodies to induce macrophage-mediated phagocytosis, in combination with the known presence of macrophages in the tumor microenvironment in MM and other hematological tumors, led us to investigate the contribution of antibody-dependent, macrophage-mediated phagocytosis to DARA\'s mechanism of action. Live cell imaging revealed that DARA efficiently induced macrophage-mediated phagocytosis, in which individual macrophages rapidly and sequentially engulfed multiple tumor cells. DARA-dependent phagocytosis by mouse and human macrophages was also observed in an in vitro flow cytometry assay, using a range of MM and Burkitt\'s lymphoma cell lines. Phagocytosis contributed to DARA\'s anti-tumor activity in vivo, in both a subcutaneous and an intravenous leukemic xenograft mouse model. Finally, DARA was shown to induce macrophage-mediated phagocytosis of MM cells isolated from 11 of 12 MM patients that showed variable levels of CD38 expression. In summary, we demonstrate that phagocytosis is a fast, potent and clinically relevant mechanism of action that may contribute to the therapeutic activity of DARA in multiple myeloma and potentially other hematological tumors.