2. Academic Validation
  3. 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

  • Cell Rep. 2018 Oct 23;25(4):909-920.e4. doi: 10.1016/j.celrep.2018.09.073.
Yan Li 1,  Shuguang Tan 2,  Chang Zhang 3,  Yan Chai 4,  Mengnan He 1,  Catherine W-H Zhang 5,  Qihui Wang 6,  Zhou Tong 7,  Kefang Liu 8,  Yifan Lei 4,  William J Liu 9,  Yingxia Liu 10,  Zhigang Tian 11,  Xuetao Cao 12,  Jinghua Yan 6,  Jianxun Qi 1,  Po Tien 13,  Shan Gao 14,  George F Gao 15
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 CAS Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China.
  • 4 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 5 ImmuFuCell Biotechnology, Beijing 100102, China.
  • 6 Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen 518112, China; CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 7 Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen 518112, China; CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Shanxi Academy of Advanced Research and Innovation, Taiyuan 030032, China.
  • 8 University of Chinese Academy of Sciences, Beijing 100049, China; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing 102206, China.
  • 9 Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen 518112, China; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing 102206, China.
  • 10 Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen 518112, China.
  • 11 Institute of Immunology, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.
  • 12 Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
  • 13 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. Electronic address: tienpo@im.ac.cn.
  • 14 CAS Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China; Shanxi Academy of Advanced Research and Innovation, Taiyuan 030032, China. Electronic address: gaos@sibet.ac.cn.
  • 15 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; Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen 518112, China; Shanxi Academy of Advanced Research and Innovation, Taiyuan 030032, China; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing 102206, China. Electronic address: gaof@im.ac.cn.
PMID: 30355497 DOI: 10.1016/j.celrep.2018.09.073
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.

Keywords

4-1BB; 4-1BB ligand; 4-1BBL; agonist antibody; complex structure; cross-linking; utomilumab.

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