多发性骨髓瘤 (MM) 是一种复杂的血液恶性肿瘤，其特征是浆细胞异常产生抗体。尽管治疗取得了进展，但许多患者会出现疾病复发或变得难以治疗。 G 蛋白偶联受体 C 类 5 成员 D (GPRC5D) 是一种主要在 MM 细胞中表达的孤儿 GPCR，正在成为 MM 免疫治疗的一个有希望的靶标。 Talquetamab 是一种经美国食品和药物管理局批准的 T 细胞导向双特异性抗体，用于治疗 MM，靶向 GPRC5D。在这里，我们利用冷冻电子显微镜阐明了与他克他单抗Fab片段复合的GPRC5D的结构，为双特异性抗体识别GPRC5D提供了基础。 GPRC5D 通过一个原聚体的跨膜螺旋 (TM)4 和另一个原聚体的 TM4/5 之间的界面形成对称同二聚体。单个他克他单抗 Fab 与 GPRC5D 二聚体相互作用，其方向朝向二聚体界面。他克他单抗的所有六个互补决定区均与细胞外环和 TM3/5/7 结合。特别是，抗体精氨酸残基的侧链渗透到 GPRC5D 细胞外表面的浅袋中。该结构为优化针对 GPRC5D 的抗体设计以用于复发或难治性 MM 治疗提供了见解。版权所有 © 2024 Elsevier Ltd。保留所有权利。

Multiple myeloma (MM) is a complex hematological malignancy characterized by abnormal antibody production from plasma cells. Despite advances in the treatment, many patients experience disease relapse or become refractory to treatment. G-protein-coupled receptor class C group 5 member D (GPRC5D), an orphan GPCR predominantly expressed in MM cells, is emerging as a promising target for MM immunotherapy. Talquetamab, a Food and Drug Administration-approved T-cell-directing bispecific antibody developed for treatment of MM, targets GPRC5D. Here, we elucidate the structure of GPRC5D complexed with the Fab fragment of talquetamab, using cryo-electron microscopy, providing the basis for recognition of GPRC5D by the bispecific antibody. GPRC5D forms a symmetric homodimer with the interface between transmembrane helix (TM)4 of one protomer and TM4/5 of the other protomer. A single talquetamab Fab interacts with the GPRC5D dimer with its orientation toward the dimer interface. All six complementarity-determining regions of talquetamab engage with extracellular loops and TM3/5/7. In particular, the side-chain of an arginine residue from the antibody penetrates into a shallow pocket on the extracellular surface of GPRC5D. The structure offers insights for optimizing antibody design against GPRC5D for relapsed or refractory MM therapy.Copyright © 2024 Elsevier Ltd. All rights reserved.