Defining the features and structure of neutralizing antibody targeting the silent face of the SARS‐CoV‐2 spike N‐terminal domain

• Published in: MedComm (2020) 2024-12, Vol.5 (12), p.e70008-n/a
• Main Authors: Zhang, Zhaoyong, Zhang, Yuanyuan, Zhang, Yuting, Cheng, Linling, Zhang, Lu, Yan, Qihong, Liu, Xuesong, Chen, Jiantao, Dai, Jun, Guo, Yingying, Wei, Peilan, Xiong, Xinyi, Xiao, Juxue, Zhu, Airu, Zhuo, Jianfen, Cai, Ruoxi, Zhang, Jingjun, Rao, Haiyue, Qu, Bin, Zhang, Shengnan, Feng, Jiaxin, Cheng, Jinling, Su, Jingyi, Chen, Canjie, Li, Shu, Chen, Lei, Jin, Yingkang, Xu, Yonghao, Liu, Xiaoqing, Li, Yimin, Zhao, Jingxian, Wang, Yanqun, Zhou, Qiang, Zhao, Jincun
• Format: Article
• Language: English
• Subjects: Antibodies; glycan shield; neutralizing antibody; N‐terminal domain; SARS‐CoV‐2; Severe acute respiratory syndrome; silent face
• ISSN: 2688-2663; 2688-2663
• DOI: 10.1002/mco2.70008

Research on virus/receptor interactions has uncovered various mechanisms of antibody‐mediated neutralization against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). However, understanding of neutralization by antibodies targeting the silent face, which recognize epitopes on glycan shields, remains limited, and their potential protective efficacy in vivo is not well understood. This study describes a silent face neutralizing antibody, 3711, which targets a non‐supersite on the N‐terminal domain (NTD) of the spike protein. Cryo‐EM structure determination of the 3711 Fab in the spike complex reveals a novel neutralizing epitope shielded by glycans on the spike's silent face. Antibody 3711 inhibits the interaction between the receptor‐binding domain (RBD) and human angiotensin‐converting enzyme 2 (hACE2) through steric hindrance and exhibits superior in vivo protective effects compared to other reported NTD‐targeted monoclonal antibodies (mAbs). Competition assays and antibody repertoire analysis indicate the rarity of antibodies targeting the 3711‐related epitope in SARS‐CoV‐2 convalescents, suggesting the infrequency of NTD silent face‐targeted neutralizing antibodies during SARS‐CoV‐2 infection. As the first NTD silent face‐targeted neutralizing antibody against SARS‐CoV‐2, the identification of mAb 3711, with its novel neutralizing mechanism, enhances our understanding of neutralizing epitopes on glycan shields and elucidates epitope‐guided viral mutations that evade specific antibodies. Silent face targeted neutralizing antibodies of SARS‐CoV‐2 have been rarely reported. We described a neutralizing antibody 3711 targeting a novel epitope shielded by glycans on the spike's silent face, which inhibits the interaction between RBD and hACE2 via steric hindrance. Identification of antibody 3711 with a novel neutralizing mechanism enhances our understanding of neutralizing epitopes on glycan shields of spike.