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Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy.
Cell. 2020 11 12; 183(4):1013-1023.e13.Cell

Abstract

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.

Authors+Show Affiliations

School of Life Sciences, Peking University, Beijing 100871, China.Beijing Advanced Innovation Center for Genomics (ICG) & Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing 100871, China.School of Life Sciences, Peking University, Beijing 100871, China.Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.School of Life Sciences, Peking University, Beijing 100871, China.School of Life Sciences, Peking University, Beijing 100871, China; Beijing Advanced Innovation Center for Genomics (ICG) & Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing 100871, China.Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China.Beijing Advanced Innovation Center for Genomics (ICG) & Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing 100871, China.Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China.Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.School of Life Sciences, Peking University, Beijing 100871, China.School of Life Sciences, Peking University, Beijing 100871, China; Beijing Advanced Innovation Center for Genomics (ICG) & Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing 100871, China.Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.School of Life Sciences, Peking University, Beijing 100871, China.Beijing Advanced Innovation Center for Genomics (ICG) & Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing 100871, China.Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.Beijing Advanced Innovation Center for Genomics (ICG) & Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.School of Life Sciences, Peking University, Beijing 100871, China.Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201204, China.School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; State Key Laboratory of Membrane Biology, Peking University, Beijing 100871, China.Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China.Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China.School of Life Sciences, Peking University, Beijing 100871, China; Beijing Advanced Innovation Center for Genomics (ICG) & Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. Electronic address: sunneyxie@pku.edu.cn.School of Life Sciences, Peking University, Beijing 100871, China; Beijing Advanced Innovation Center for Genomics (ICG) & Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing 100871, China; State Key Laboratory of Protein and Plant Gene Research, Peking University, Beijing 100871, China. Electronic address: xdsu@pku.edu.cn.School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; State Key Laboratory of Protein and Plant Gene Research, Peking University, Beijing 100871, China. Electronic address: junyuxiao@pku.edu.cn.Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China. Electronic address: qinchuan@pumc.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32970990

Citation

Du, Shuo, et al. "Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy." Cell, vol. 183, no. 4, 2020, pp. 1013-1023.e13.
Du S, Cao Y, Zhu Q, et al. Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy. Cell. 2020;183(4):1013-1023.e13.
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., ... Qin, C. (2020). Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy. Cell, 183(4), 1013-e13. https://doi.org/10.1016/j.cell.2020.09.035
Du S, et al. Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy. Cell. 2020 11 12;183(4):1013-1023.e13. PubMed PMID: 32970990.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy. AU - Du,Shuo, AU - Cao,Yunlong, AU - Zhu,Qinyu, AU - Yu,Pin, AU - Qi,Feifei, AU - Wang,Guopeng, AU - Du,Xiaoxia, AU - Bao,Linlin, AU - Deng,Wei, AU - Zhu,Hua, AU - Liu,Jiangning, AU - Nie,Jianhui, AU - Zheng,Yinghui, AU - Liang,Haoyu, AU - Liu,Ruixue, AU - Gong,Shuran, AU - Xu,Hua, AU - Yisimayi,Ayijiang, AU - Lv,Qi, AU - Wang,Bo, AU - He,Runsheng, AU - Han,Yunlin, AU - Zhao,Wenjie, AU - Bai,Yali, AU - Qu,Yajin, AU - Gao,Xiang, AU - Ji,Chenggong, AU - Wang,Qisheng, AU - Gao,Ning, AU - Huang,Weijin, AU - Wang,Youchun, AU - Xie,X Sunney, AU - Su,Xiao-Dong, AU - Xiao,Junyu, AU - Qin,Chuan, Y1 - 2020/09/14/ PY - 2020/07/07/received PY - 2020/08/14/revised PY - 2020/09/10/accepted PY - 2020/9/25/pubmed PY - 2020/11/26/medline PY - 2020/9/24/entrez KW - COVID-19 KW - RBD KW - SARS-CoV-2 KW - antibody cocktail KW - cryo-EM KW - epitope KW - hamster KW - mutation KW - neutralizing antibody KW - spike SP - 1013 EP - 1023.e13 JF - Cell JO - Cell VL - 183 IS - 4 N2 - 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. SN - 1097-4172 UR - https://www.unboundmedicine.com/medline/citation/32970990/Structurally_Resolved_SARS_CoV_2_Antibody_Shows_High_Efficacy_in_Severely_Infected_Hamsters_and_Provides_a_Potent_Cocktail_Pairing_Strategy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(20)31232-0 DB - PRIME DP - Unbound Medicine ER -