Cross-neutralizing antibodies bind a SARS-CoV-2 cryptic site and resist circulating variants
Tingting Li, Wenhui Xue, Qingbing Zheng, Shuo Song, Chuanlai Yang, Hualong Xiong, Sibo Zhang, Minqing Hong, Yali Zhang, Hai Yu, Yuyun Zhang, Hui Sun, Yang Huang, Tingting Deng, Xin Chi, Jinjin Li, Shaojuan Wang, Lizhi Zhou, Tingting Chen, Yingbin Wang, Tong Cheng, Tianying Zhang, Quan Yuan, Qinjian Zhao, Jun Zhang, Jason S. McLellan, Z. Hong Zhou, Zheng Zhang, Shaowei Li, Ying Gu, Ningshao Xia
Abstract
The emergence of numerous variants of SARS-CoV-2, the causative agent of COVID-19, has presented new challenges to the global efforts to control the COVID-19 pandemic. Here, we obtain two cross-neutralizing antibodies (7D6 and 6D6) that target Sarbecoviruses' receptor-binding domain (RBD) with sub-picomolar affinities and potently neutralize authentic SARS-CoV-2. Crystal structures show that both antibodies bind a cryptic site different from that recognized by existing antibodies and highly conserved across Sarbecovirus isolates. Binding of these two antibodies to the RBD clashes with the adjacent N-terminal domain and disrupts the viral spike. Both antibodies confer good resistance to mutations in the currently circulating SARS-CoV-2 variants. Thus, our results have direct relevance to public health as options for passive antibody therapeutics and even active prophylactics. They can also inform the design of pan-sarbecovirus vaccines.