T cell-mediated approaches have shown promise in myeloma treatment. However, there are currently a limited number of specific myeloma antigens that can be targeted, and MM remains an incurable disease. G-protein coupled receptor class 5 member D (GPRC5D) is expressed in multiple myeloma (MM) and smoldering multiple myeloma patient plasma cells. Here we demonstrate that GPRC5D protein is present on the surface of MM cells and describe JNJ-64407564, a GPRC5DxCD3 bispecific antibody that recruits CD3+ T cells to GPRC5D+ MM cells and induces killing of GPRC5D+ cells. In vitro, JNJ-64407564 induced specific cytotoxicity of GPRC5D+ cells with concomitant T cell activation and also killed plasma cells in MM patient samples ex vivo. JNJ-64407564 can recruit T cells and induce tumor regression in GPRC5D+ MM murine models which coincide with T cell infiltration at the tumor site. This antibody is also able to induce cytotoxicity of patient primary MM cells from bone marrow which is the natural site of this disease. GPRC5D is a promising surface antigen for MM immunotherapy and JNJ-64407564 is currently being evaluated in a Phase I clinical trial in patients with relapsed or refractory MM (NCT03399799).

中文翻译：

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AT细胞重定向双特异性G蛋白偶联受体5类成员DxCD3抗体治疗多发性骨髓瘤

T 细胞介导的方法在骨髓瘤治疗中显示出前景。然而，目前可以靶向的特定骨髓瘤抗原数量有限，MM 仍然是一种无法治愈的疾病。G 蛋白偶联受体第 5 类成员 D (GPRC5D) 在多发性骨髓瘤 (MM) 和阴燃多发性骨髓瘤患者浆细胞中表达。在这里，我们证明 GPRC5D 蛋白存在于 MM 细胞表面，并描述了 JNJ-64407564，这是一种 GPRC5DxCD3 双特异性抗体，可将 CD3+ T 细胞募集到 GPRC5D+ MM 细胞并诱导杀死 GPRC5D+ 细胞。在体外，JNJ-64407564 在伴随 T 细胞活化的同时诱导 GPRC5D+ 细胞的特异性细胞毒性，并且还在体外杀死 MM 患者样本中的浆细胞。JNJ-64407564 可以在 GPRC5D+ MM 鼠模型中募集 T 细胞并诱导肿瘤消退，这与肿瘤部位的 T 细胞浸润一致。该抗体还能够诱导来自骨髓的患者原代 MM 细胞的细胞毒性，骨髓是该疾病的自然部位。GPRC5D 是一种很有前景的 MM 免疫治疗表面抗原，JNJ-64407564 目前正在复发或难治性 MM 患者的 I 期临床试验中进行评估 (NCT03399799)。