Genentech Research and Early Development, San Francisco, CA, USA.
Affimed GmbH, Heidelberg, Germany.
Leukemia. 2022 Apr;36(4):1006-1014. doi: 10.1038/s41375-021-01478-w. Epub 2022 Jan 10.
Despite the recent progress, multiple myeloma (MM) is still essentially incurable and there is a need for additional effective treatments with good tolerability. RO7297089 is a novel bispecific BCMA/CD16A-directed innate cell engager (ICE) designed to induce BCMA+ MM cell lysis through high affinity binding of CD16A and retargeting of NK cell cytotoxicity and macrophage phagocytosis. Unlike conventional antibodies approved in MM, RO7297089 selectively targets CD16A with no binding of other Fcγ receptors, including CD16B on neutrophils, and irrespective of 158V/F polymorphism, and its activity is less affected by competing IgG suggesting activity in the presence of M-protein. Structural analysis revealed this is due to selective interaction with a single residue (Y140) uniquely present in CD16A opposite the Fc binding site. RO7297089 induced tumor cell killing more potently than conventional antibodies (wild-type and Fc-enhanced) and induced lysis of BCMA+ cells at very low effector-to-target ratios. Preclinical toxicology data suggested a favorable safety profile as in vitro cytokine release was minimal and no RO7297089-related mortalities or adverse events were observed in cynomolgus monkeys. These data suggest good tolerability and the potential of RO7297089 to be a novel effective treatment of MM patients.
尽管最近取得了进展，但多发性骨髓瘤（MM）仍然基本上无法治愈，需要额外的具有良好耐受性的有效治疗方法。RO7297089 是一种新型的双特异性 BCMA/CD16A 导向的固有细胞衔接器（ICE），旨在通过高亲和力结合 CD16A 并重新靶向 NK 细胞毒性和巨噬细胞吞噬作用来诱导 BCMA+ MM 细胞裂解。与 MM 中批准的常规抗体不同，RO7297089 选择性地靶向 CD16A，不与其他 Fcγ 受体结合，包括中性粒细胞上的 CD16B，并且与 158V/F 多态性无关，其活性受竞争 IgG 的影响较小，表明在存在 M 蛋白的情况下具有活性。结构分析表明，这是由于与 Fc 结合位点对面独特存在于 CD16A 中的单个残基（Y140）的选择性相互作用。RO7297089 诱导肿瘤细胞杀伤的效力强于常规抗体（野生型和 Fc 增强型），并在非常低的效应物与靶标比下诱导 BCMA+细胞裂解。临床前毒理学数据表明具有良好的安全性特征，因为体外细胞因子释放最小，并且在食蟹猴中未观察到与 RO7297089 相关的死亡率或不良事件。这些数据表明 RO7297089 具有良好的耐受性和成为 MM 患者新型有效治疗方法的潜力。
