Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) continue to wreak havoc across the globe. Higher transmissibility and immunologic resistance of VOCs bring unprecedented challenges to epidemic extinguishment. Here we describe a monoclonal antibody, 2G1, that neutralizes all current VOCs and has surprising tolerance to mutations adjacent to or within the interaction epitope. Cryo-electron microscopy structure reveals a strong hydrophobic effect, which is revealed in nanomolar to sub-nanomolar affinities to spike proteins. The epitope of 2G1 on RBD partially overlaps with angiotensin converting enzyme 2 (ACE2) interface, which enables 2G1 to block interaction between RBD and ACE2. The narrow binding epitope but high affinity bestows outstanding therapeutic efficacy upon 2G1 that neutralized VOCs with sub-nanomolar half maximal inhibitory concentration. In SARS-CoV-2, Beta or Delta variant-challenged transgenic mice and rhesus macaques models, 2G1 protected animals from clinical illness and eliminated viral burden, without serious impact to animal safety. Mutagenesis experiments suggested that 2G1 is potentially capable of dealing with emerging SARS-CoV-2 variants in the future. This report characterized the therapeutic antibodies specific to the tip of spike against SARS-CoV-2 variants and highlights the potential clinical applications as well as for developing vaccine and cocktail therapy.

Hang Ma, Yingying Guo, Haoneng Tang, Chien-Te K. Tseng, Lei Wang, Huifang Zong, Zhenyu Wang, Yang He, Yunsong Chang, Shusheng Wang, Haiqiu Huang, Yong Ke, Yunsheng Yuan, Mingyuan Wu, Yuanyuan Zhang, Alexandra Drelich, Kempahai Rayavara Kempahai, Bi-Hung Peng, Kainyong Yang, Haiyang Yin, Junlun Liu, Yali Yue, Wenbo Xu, Shuangli Zhu, Tianjiao Ji, Xiaoyu Zhang, Ziqi Wang, Gang Li, Guangchun Liu, Jingjing Song, Lingling Mu, ZongShang Xiang, Zhangyi Song, Hua Chen, Yanlin Bian, Baohong Zhang, Hui Chen, Jiawei Zhang, Yunji Liao, Li Zhang, Yi Chen, John Gilly, Xiaodong Xiao, Lei Han, Hua Jiang, Yueqing Xie, Qiang Zhou, Jianwei Zhu