CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen 518112, China.
Cell Rep. 2018 Oct 23;25(4):909-920.e4. doi: 10.1016/j.celrep.2018.09.073.
Monoclonal antibodies (mAbs) targeting the co-stimulatory molecule 4-1BB are of interest for tumor immunotherapy. We determined the complex structures of human 4-1BB with 4-1BB ligand (4-1BBL) or utomilumab to elucidate the structural basis of 4-1BB activation. The 4-1BB/4-1BBL complex displays a typical TNF/TNFR family binding mode. The structure of utomilumab/4-1BB complex shows that utomilumab binds to dimeric 4-1BB with a distinct but partially overlapping binding area with 4-1BBL. Competitive binding analysis demonstrates that utomilumab blocks the 4-1BB/4-1BBL interaction, indicating the interruption of ligand-mediated signaling. The binding profiles of 4-1BBL and utomilumab to monomeric or dimeric 4-1BB indicate limited cross-linking of 4-1BB molecules. These findings provide mechanistic insight into the binding of 4-1BB with its ligand and its agonist mAb, which may facilitate the future development of anti-4-1BB biologics for tumor immunotherapy.
靶向共刺激分子 4-1BB 的单克隆抗体 (mAb) 是肿瘤免疫治疗的研究热点。我们解析了人 4-1BB 与 4-1BBL 或utomilumab 的复合物结构，以阐明 4-1BB 激活的结构基础。4-1BB/4-1BBL 复合物呈现出典型的 TNF/TNFR 家族结合模式。utomilumab/4-1BB 复合物的结构表明 utomilumab 以独特但部分重叠的结合区域与 4-1BBL 结合形成二聚体 4-1BB。竞争性结合分析表明 utomilumab 阻断了 4-1BB/4-1BBL 相互作用，提示阻断了配体介导的信号转导。4-1BBL 和 utomilumab 对单体或二聚体 4-1BB 的结合谱表明 4-1BB 分子的交联有限。这些发现为 4-1BB 与其配体和激动型 mAb 的结合提供了机制见解，这可能有助于未来开发用于肿瘤免疫治疗的抗 4-1BB 生物制剂。
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