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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...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489885/
https://www.ncbi.nlm.nih.gov/pubmed/32970990
http://dx.doi.org/10.1016/j.cell.2020.09.035
Descripción
Sumario: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.