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Limited Cross-Linking of 4-1BB by 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab.
Cell Rep. 2018 10 23; 25(4):909-920.e4.CR

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.

Authors+Show Affiliations

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.CAS Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China.CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.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.ImmuFuCell Biotechnology, Beijing 100102, China.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.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.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.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; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing 102206, China.Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen 518112, China.Institute of Immunology, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.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.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; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: tienpo@im.ac.cn.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30355497

Citation

Li, Yan, et al. "Limited Cross-Linking of 4-1BB By 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab." Cell Reports, vol. 25, no. 4, 2018, pp. 909-920.e4.
Li Y, Tan S, Zhang C, et al. Limited Cross-Linking of 4-1BB by 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab. Cell Rep. 2018;25(4):909-920.e4.
Li, Y., Tan, S., Zhang, C., Chai, Y., He, M., Zhang, C. W., Wang, Q., Tong, Z., Liu, K., Lei, Y., Liu, W. J., Liu, Y., Tian, Z., Cao, X., Yan, J., Qi, J., Tien, P., Gao, S., & Gao, G. F. (2018). Limited Cross-Linking of 4-1BB by 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab. Cell Reports, 25(4), 909-e4. https://doi.org/10.1016/j.celrep.2018.09.073
Li Y, et al. Limited Cross-Linking of 4-1BB By 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab. Cell Rep. 2018 10 23;25(4):909-920.e4. PubMed PMID: 30355497.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Limited Cross-Linking of 4-1BB by 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab. AU - Li,Yan, AU - Tan,Shuguang, AU - Zhang,Chang, AU - Chai,Yan, AU - He,Mengnan, AU - Zhang,Catherine W-H, AU - Wang,Qihui, AU - Tong,Zhou, AU - Liu,Kefang, AU - Lei,Yifan, AU - Liu,William J, AU - Liu,Yingxia, AU - Tian,Zhigang, AU - Cao,Xuetao, AU - Yan,Jinghua, AU - Qi,Jianxun, AU - Tien,Po, AU - Gao,Shan, AU - Gao,George F, PY - 2018/03/14/received PY - 2018/08/13/revised PY - 2018/09/21/accepted PY - 2018/10/26/entrez PY - 2018/10/26/pubmed PY - 2019/11/15/medline KW - 4-1BB KW - 4-1BB ligand KW - 4-1BBL KW - agonist antibody KW - complex structure KW - cross-linking KW - utomilumab SP - 909 EP - 920.e4 JF - Cell reports JO - Cell Rep VL - 25 IS - 4 N2 - 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. SN - 2211-1247 UR - https://www.unboundmedicine.com/medline/citation/30355497/Limited_Cross_Linking_of_4_1BB_by_4_1BB_Ligand_and_the_Agonist_Monoclonal_Antibody_Utomilumab_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2211-1247(18)31533-X DB - PRIME DP - Unbound Medicine ER -