Structural basis for the synergetic neutralization of hepatitis E virus by antibody-antibody interaction

• 成果类型: Article
• 署名作者: Zheng, Minghua; Zhou, Lizhi; Huang, Yang; Zhang, Xiao; Yu, Zihao; Yang, Chengyu; Chen, Yuanzhi; Ying, Dong; Wang, Hong; Chen, Zhenqin; Liu, Chang; Tang, Zimin; Wang, Siling; Wang, Kaihang; Yang, Kaixiang; Lin, Yanqing; Li, Tingting; Zheng, Qingbing; Zheng, Zizheng; Zhang, Jun; Yu, Hai; Li, Shaowei; Gu, Ying; Xia, Ningshao
• 署名单位: Xiamen University; Xiamen University; Chongqing Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10629
• DOI: 10.1073/pnas.2408585121
• 发表日期: 2024-12-03
• 关键词: molecular-cloning; hev; infection; cirrhosis

摘要

Neutralizing antibodies (nAbs) play a crucial role in virology, antibody drug development, and vaccine research. In this study, we investigated the synergistic effect of two hepatitis E virus (HEV) nAbs, 8H3, and 8C11, which have exhibited enhanced neutralizing activity in a rhesus monkey model. We presented crystal structures of 8H3 Fab alone and a triple complex of 8C11 Fab and 8H3 Fab simultaneously binding to the HEV E2s protein (8C11:E2s:8H3). Through structural analysis, we identified critical binding sites and fully elucidated the binding footprints of nAb 8H3 in the 8C11:E2s:8H3 complex the synergetic enhancement of 8C11 to 8H3 converted to an antagonistic effect when 8C11 bound to E2s with pretreatment of 8H3, indicating a unidirectional synergistic effect associated with the sequence of antibody involvement. We demonstrated this in the synergistic interplay between these two nAbs. The two- antibody combination showed a more potent antibody- imposed physical disruption mechanism and enhanced coneutralization in an authentic HEV- based cell model. Our study suggests a strategy for synergistic antibody cocktail design with antibody-antibody side- by- side interaction.