肿瘤细胞治疗研究
英文原题：A BCMA/CD16A bispecific innate cell engager for the treatment of multiple myeloma.
这些数据表明 RO7297089 具有良好的耐受性，并有望成为 MM 患者的一种新型有效治疗。
尽管近年来治疗有所进展，多发性骨髓瘤（MM）总体上仍无法治愈，因此仍需要疗效可靠且耐受性良好的新治疗方法。RO7297089是一种新型BCMA/CD16A双特异性先天免疫细胞衔接器（ICE），旨在通过高亲和力结合CD16A，重新引导自然杀伤（NK）细胞的细胞毒作用和巨噬细胞吞噬作用，从而裂解BCMA阳性的MM细胞。与已获批用于MM的常规抗体不同，RO7297089选择性靶向CD16A，不结合其他Fc受体（包括中性粒细胞上的CD16B），且作用不受158V/F多态性的影响；其活性也较少受到竞争性IgG的影响，提示在存在M蛋白时仍可能保持活性。结构分析显示，这种选择性源于RO7297089与CD16A上一个独有残基Y140的相互作用，该残基位于Fc结合位点对侧。与常规抗体（野生型及Fc增强型）相比，RO7297089诱导肿瘤细胞杀伤的效力更强，并且在极低效靶比下即可裂解BCMA阳性细胞。临床前毒理学数据显示其安全性特征良好：体外细胞因子释放极少，在食蟹猴中也未观察到与RO7297089相关的死亡或不良事件。这些数据提示RO7297089具有良好的耐受性，并有望成为治疗MM患者的一种新型有效疗法。
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 Fc 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.
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