Yuda Junichiro
Department of Hematology and Experimental Therapeutics/ Hematological Treatment Development Promotion Office, Department for the Promotion of Drug and Diagnostic Development, National Cancer Center Hospital East.
Rinsho Ketsueki. 2024;65(9):1049-1057. doi: 10.11406/rinketsu.65.1049.
Patients with triple-class refractory multiple myeloma once had a poor prognosis, but recently developed bispecific antibodies (bsAbs) targeting B-cell maturation antigen (BCMA), G protein-coupled receptor 5D (GPRC5D), and Fc receptor-homolog 5 (FcRH5) have shown significant clinical activity in these patients. However, responses to bsAbs are not universal, and resistance often develops during therapy. Mechanisms that mediate resistance may be tumor-intrinsic or immune-dependent. Tumor-intrinsic factors include antigen loss (biallelic or functional) due to deletion or mutation of target genes, increased soluble BCMA (for BCMA targeting bsAbs), high tumor burden, and extramedullary disease. Immune-mediated resistance highly depends on T cell fitness and the resistant immune environment. This article describes bispecific antibodies against multiple myeloma that are currently being developed.
三重难治性多发性骨髓瘤患者曾经预后较差,但最近开发的靶向B细胞成熟抗原(BCMA)、G蛋白偶联受体5D(GPRC5D)和Fc受体同源物5(FcRH5)的双特异性抗体(bsAbs)在这些患者中显示出显著的临床活性。然而,对bsAbs的反应并不普遍,并且在治疗过程中常常会产生耐药性。介导耐药性的机制可能是肿瘤内在性的或免疫依赖性的。肿瘤内在因素包括由于靶基因缺失或突变导致的抗原丢失(双等位基因或功能性)、可溶性BCMA增加(针对靶向BCMA的bsAbs)、高肿瘤负荷和髓外疾病。免疫介导的耐药性高度依赖于T细胞适应性和耐药性免疫环境。本文描述了目前正在研发的针对多发性骨髓瘤的双特异性抗体。