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Limited Cross-Linking of 4-1BB by 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab

Limited Cross-Linking of 4-1BB by 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab

Yan Li, Shuguang Tan, Chang Zhang, Yan Chai, Mengnan He, Catherine W-H Zhang, Qihui Wang, Zhou Tong, Kefang Liu, Yifan Lei, William J Liu, Yingxia Liu, Zhigang Tian, Xuetao Cao, Jinghua Yan, Jianxun Qi, etc.

Cell Rep. 2018 Oct 23;25(4):909-920.e4.

PMID: 30355497

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP101702	4,4'-Dimethoxydiphenylamine		101-70-2	Price

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