Structurally resolved SARS-CoV-2 antibody shows high efficacy in severely infected hamsters and provides a potent cocktail pairing strategy

Du, Shuo; Cao, Yunlong; Zhu, Qinyu; Yu, Pin; Qi, Feifei; Wang, Guopeng; Du, Xiaoxia; Bao, Linlin; Deng, Wei; Zhu, Hua; Liu, Jiangning; Nie, Jianhui; Zheng, Yinghui; Liang, Haoyu; Liu, Ruixue; Gong, Shuran; Xu, Hua; Yisimayi, Ayijiang; Lv, Qi; Wang, Bo; He, Runsheng; Han, Yunlin; Zhao, Wenjie; Bai, Yali; Qu, Yajin; Gao, Xiang; Ji, Chenggong; Wang, Qisheng; Gao, Ning; Huang, Weijin; Wang, Youchun; Xie, X. Sunney; Su, Xiao-dong; Xiao, Junyu; Qin, Chuan

Understanding how potent neutralizing antibodies (NAbs) inhibit SARS-CoV-2 is critical for effective therapeutic development. We previously described BD-368-2, a SARS-CoV-2 NAb with high potency; however, its neutralization mechanism is largely unknown. Here we report the 3.5-Å cryo-EM structure of BD-368-2/trimeric-spike complex, revealing that BD-368-2 fully blocks ACE2 recognition by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their “up” or “down” conformations. Also, BD-368-2 treats infected adult hamsters at low dosages and at various administering windows, in contrast to placebo hamsters that manifested severe interstitial pneumonia. Moreover, BD-368-2’s epitope completely avoids the common binding site of VH3-53/VH3-66 recurrent NAbs, evidenced by tripartite co-crystal structures with RBD. Pairing BD-368-2 with a potent recurrent NAb neutralizes SARS-CoV-2 pseudovirus at pM level and rescues mutation-induced neutralization escapes. Together, our results rationalized a new RBD epitope that leads to high neutralization potency and demonstrated BD-368-2’s therapeutic potential in treating COVID-19.