Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.
Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.
Biochem Biophys Res Commun. 2021 Jan 15;536:26-31. doi: 10.1016/j.bbrc.2020.12.048. Epub 2020 Dec 22.
Multiple myeloma is a blood cancer characterized by the plasma cell malignancy in the bone marrow, resulting in the destruction of bone tissue. Recently, the US FDA approved two antibody drugs for the treatment of multiple myeloma, daratumumab and isatuximab, targeting CD38, a type II transmembrane glycoprotein highly expressed in plasma cells and multiple myeloma cells. Here, we report the crystal structure of CD38 in complex with the Fab fragment of daratumumab, providing its exact epitope on CD38 and the structural insights into the mechanism of action of the antibody drug. Daratumumab binds to a specific discontinuous region on CD38 that includes residues located opposite to the active site of CD38. All the six complementarity determining regions of daratumumab are involved in the CD38 interaction. The epitopes of daratumumab and isatuximab do not overlap at all and their bindings to CD38 induce different structural changes within the CD38 protein. This structural study can facilitate the design of improved biologics or effective combination therapies for the treatment of multiple myeloma.
多发性骨髓瘤是一种血液癌症，其特征是骨髓中浆细胞恶性肿瘤，导致骨组织破坏。最近，美国食品和药物管理局批准了两种针对 CD38 的抗体药物用于多发性骨髓瘤的治疗，分别是达雷妥尤单抗和伊沙妥昔单抗，CD38 是一种 II 型跨膜糖蛋白，在浆细胞和多发性骨髓瘤细胞中高度表达。在这里，我们报告了 CD38 与达雷妥尤单抗 Fab 片段复合物的晶体结构，提供了 CD38 上确切的抗原表位和抗体药物作用机制的结构见解。达雷妥尤单抗结合 CD38 上一个特定的不连续区域，该区域包括位于 CD38 活性位点对面的残基。达雷妥尤单抗的六个互补决定区都参与了 CD38 的相互作用。达雷妥尤单抗和伊沙妥昔单抗的抗原表位完全不重叠，它们与 CD38 的结合在 CD38 蛋白内诱导不同的结构变化。这项结构研究可以促进设计改进的生物制剂或有效的联合治疗多发性骨髓瘤。
