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Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy #MMPMID32970990
Du S; Cao Y; Zhu Q; Yu P; Qi F; Wang G; Du X; Bao L; Deng W; Zhu H; Liu J; Nie J; Zheng Y; Liang H; Liu R; Gong S; Xu H; Yisimayi A; Lv Q; Wang B; He R; Han Y; Zhao W; Bai Y; Qu Y; Gao X; Ji C; Wang Q; Gao N; Huang W; Wang Y; Xie XS; Su XD; Xiao J; Qin C
Cell 2020[Nov]; 183 (4): 1013-1023.e13 PMID32970990show ga
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-A 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.
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Cell 2020 ; 183 (4): 1013-1023.e13
