G-protein-coupled receptor class 5 member D (GPRC5D) is detected in malignant plasma cells in approximately 90% of patients diagnosed with multiple myeloma (MM). Here, we constructed BsAb5003, a novel humanized bispecific monoclonal antibody targeting CD3 and GPRC5D, and evaluated its therapeutic impact on MM. BsAb5003 induced specific cytotoxicity of GPRC5D-positive MM cells with concomitant T cell activation and cytokine release. The efficacy of BsAb5003 was associated with GPRC5D expression levels in MM cell lines. Flow cytometry analysis of bone marrow mononuclear cells (BMMNCs) from 49 MM patients revealed that GPRC5D was expressed in a wide population of MM patients, including heavily treated and high-risk patients. In ex vivo assays using BMMNCs, BsAb5003 induced potent efficacy against CD138 + MM cells in both newly diagnosed and relapsed/refractory patient samples in a GPRC5D expression-dependent manner. BsAb5003 significantly enhanced T cell activation and cytokine production in combination with immunomodulatory drugs (IMiDs) against MM cell lines. BsAb5003 also demonstrated significant inhibition of in vivo tumor growth by recruiting T cells. Taken together, these results suggest that T cell-redirecting bispecific antibody targeting GPRC5D as monotherapy and combination therapy with IMiDs could be a highly potent and effective treatment approach for a wide population of MM patients.

在大约 90% 的多发性骨髓瘤 (MM) 患者的恶性浆细胞中检测到 G 蛋白偶联受体 5 类成员 D (GPRC5D)。在这里，我们构建了 BsAb5003，一种靶向 CD3 和 GPRC5D 的新型人源化双特异性单克隆抗体，并评估了其对 MM 的治疗作用。 BsAb5003 诱导 GPRC5D 阳性 MM 细胞的特异性细胞毒性，并伴随 T 细胞激活和细胞因子释放。 BsAb5003 的功效与 MM 细胞系中的 GPRC5D 表达水平相关。对 49 名 MM 患者的骨髓单核细胞 (BMMNC) 的流式细胞术分析显示，GPRC5D 在广泛的 MM 患者群体中表达，包括接受重度治疗的患者和高危患者。在使用 BMMNC 的离体测定中，BsAb5003 以 GPRC5D 表达依赖性方式在新诊断和复发/难治性患者样本中诱导针对 CD138 + MM 细胞的有效功效。 BsAb5003 与针对 MM 细胞系的免疫调节药物 (IMiD) 联合显着增强 T 细胞活化和细胞因子产生。 BsAb5003 还通过招募 T 细胞来显着抑制体内肿瘤生长。总而言之，这些结果表明，针对 GPRC5D 的 T 细胞重定向双特异性抗体作为单一疗法以及与 IMiD 的联合疗法可能是针对广大 MM 患者群体的高效治疗方法。