The Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
Oncology Research & Development, GlaxoSmithKline, Collegeville, PA;
Blood. 2014 May 15;123(20):3128-38. doi: 10.1182/blood-2013-10-535088. Epub 2014 Feb 25.
B-cell maturation antigen (BCMA), highly expressed on malignant plasma cells in human multiple myeloma (MM), has not been effectively targeted with therapeutic monoclonal antibodies. We here show that BCMA is universally expressed on the MM cell surface and determine specific anti-MM activity of J6M0-mcMMAF (GSK2857916), a novel humanized and afucosylated antagonistic anti-BCMA antibody-drug conjugate via a noncleavable linker. J6M0-mcMMAF specifically blocks cell growth via G2/M arrest and induces caspase 3-dependent apoptosis in MM cells, alone and in coculture with bone marrow stromal cells or various effector cells. It strongly inhibits colony formation by MM cells while sparing surrounding BCMA-negative normal cells. J6M0-mcMMAF significantly induces effector cell-mediated lysis against allogeneic or autologous patient MM cells, with increased potency and efficacy compared with the wild-type J6M0 without Fc enhancement. The antibody-dependent cell-mediated cytotoxicity and apoptotic activity of J6M0-mcMMAF is further enhanced by lenalidomide. Importantly, J6M0-mcMMAF rapidly eliminates myeloma cells in subcutaneous and disseminated mouse models, and mice remain tumor-free up to 3.5 months. Furthermore, J6M0-mcMMAF recruits macrophages and mediates antibody-dependent cellular phagocytosis of MM cells. Together, these results demonstrate that GSK2857916 has potent and selective anti-MM activities via multiple cytotoxic mechanisms, providing a promising next-generation immunotherapeutic in this cancer.
B 细胞成熟抗原（BCMA）在人类多发性骨髓瘤（MM）中的恶性浆细胞上高度表达，尚未被有效的治疗性单克隆抗体靶向。我们在此表明，BCMA 在 MM 细胞表面普遍表达，并通过非裂解连接子确定了新型人源化去岩藻糖基化拮抗型抗 BCMA 抗体药物偶联物 J6M0-mcMMAF（GSK2857916）对 MM 的特异性抗 MM 活性。J6M0-mcMMAF 通过 G2/M 期阻滞特异性阻断细胞生长，并在 MM 细胞中诱导 caspase3 依赖性细胞凋亡，无论是单独作用还是与骨髓基质细胞或各种效应细胞共培养时都是如此。它强烈抑制 MM 细胞的集落形成，同时保留周围的 BCMA 阴性正常细胞。J6M0-mcMMAF 可显著诱导效应细胞介导的同种异体或自体患者 MM 细胞溶解，与无 Fc 增强的野生型 J6M0 相比，其效力和功效均有所提高。与 lenalidomide 联合使用时，J6M0-mcMMAF 的抗体依赖性细胞介导的细胞毒性和凋亡活性进一步增强。重要的是，J6M0-mcMMAF 可快速消除皮下和播散性小鼠模型中的骨髓瘤细胞，且小鼠在长达 3.5 个月的时间内保持无肿瘤状态。此外，J6M0-mcMMAF 可募集巨噬细胞并介导 MM 细胞的抗体依赖性细胞吞噬作用。综上所述，这些结果表明，GSK2857916 通过多种细胞毒性机制具有强大而选择性的抗 MM 活性，为这种癌症提供了一种有前途的下一代免疫疗法。
