Genmab, 3584 CM Utrecht, The Netherlands.
J Immunol. 2011 Feb 1;186(3):1840-8. doi: 10.4049/jimmunol.1003032. Epub 2010 Dec 27.
CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.
CD38 是一种 II 型跨膜糖蛋白，在包括多发性骨髓瘤（MM）在内的血液恶性肿瘤中高度表达，是一种很有前途的单抗免疫治疗靶点。在这项研究中，我们描述了达妥木单抗的细胞毒性作用机制。达妥木单抗是一种针对独特 CD38 表位的新型、高亲和力、治疗性人源单抗。达妥木单抗在表达 CD38 的淋巴瘤和 MM 衍生细胞系以及患者 MM 细胞中诱导了强大的抗体依赖的细胞毒性作用，无论是使用自体还是同种异体效应细胞。与其他 CD38 单抗相比，达妥木单抗在诱导患者 MM 细胞补体依赖性细胞毒性方面表现出更强的能力。重要的是，达妥木单抗诱导的抗体依赖的细胞毒性和补体依赖性细胞毒性不受骨髓基质细胞的存在影响，表明达妥木单抗可以在保留骨髓微环境的肿瘤中有效杀死 MM 肿瘤细胞。在体内，达妥木单抗具有高度的活性，在低剂量时即可阻断异种移植物肿瘤的生长。总之，我们的研究结果表明，达妥木单抗通过多种细胞毒性机制能够有效地杀死表达 CD38 的肿瘤细胞，包括患者 MM 细胞。这些发现支持达妥木单抗用于治疗 CD38 阳性 MM 肿瘤的临床开发。
