Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy.
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 RBDs. 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.
['Du|Shuo|S|', 'Cao|Yunlong|Y|', 'Zhu|Qinyu|Q|', 'Yu|Pin|P|', 'Qi|Feifei|F|', 'Wang|Guopeng|G|', 'Du|Xiaoxia|X|', 'Bao|Linlin|L|', 'Deng|Wei|W|', 'Zhu|Hua|H|', 'Liu|Jiangning|J|', 'Nie|Jianhui|J|', 'Zheng|Yinghui|Y|', 'Liang|Haoyu|H|', 'Liu|Ruixue|R|', 'Gong|Shuran|S|', 'Xu|Hua|H|', 'Yisimayi|Ayijiang|A|', 'Lv|Qi|Q|', 'Wang|Bo|B|', 'He|Runsheng|R|', 'Han|Yunlin|Y|', 'Zhao|Wenjie|W|', 'Bai|Yali|Y|', 'Qu|Yajin|Y|', 'Gao|Xiang|X|', 'Ji|Chenggong|C|', 'Wang|Qisheng|Q|', 'Gao|Ning|N|', 'Huang|Weijin|W|', 'Wang|Youchun|Y|', 'Xie|X Sunney|XS|', 'Su|Xiao-Dong|XD|', 'Xiao|Junyu|J|', 'Qin|Chuan|C|']
D000818:Animals D057134:Antibodies, Neutralizing D000914:Antibodies, Viral D000937:Antigen-Antibody Reactions D000073640:Betacoronavirus D001665:Binding Sites D000086382:COVID-19 D018352:Coronavirus Infections D006224:Cricetinae D020285:Cryoelectron Microscopy D004195:Disease Models, Animal D000939:Epitopes D005260:Female D008168:Lung D008297:Male D056004:Molecular Dynamics Simulation D058873:Pandemics D011024:Pneumonia, Viral D020836:Protein Structure, Quaternary D000086402:SARS-CoV-2 D064370:Spike Glycoprotein, Coronavirus
SARS-CoV-2 hamster neutralizing antibody cryo-EM RBD epitope COVID-19 antibody cocktail mutation spike