Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy

被引：181

作者：

Du, Shuo ^{[1
]}

Cao, Yunlong ^{[2
,3
]}

Zhu, Qinyu ^{[1
]}

Yu, Pin ^{[4
,5
]}

Qi, Feifei ^{[4
,5
]}

Wang, Guopeng ^{[1
]}

Du, Xiaoxia ^{[1
,2
,3
]}

Bao, Linlin ^{[4
,5
]}

Deng, Wei ^{[4
,5
]}

Zhu, Hua ^{[4
,5
]}

Liu, Jiangning ^{[4
,5
]}

Nie, Jianhui ^{[6
]}

Zheng, Yinghui ^{[2
,3
]}

Liang, Haoyu ^{[6
]}

Liu, Ruixue ^{[4
,5
]}

Gong, Shuran ^{[4
,5
]}

Xu, Hua ^{[1
]}

Yisimayi, Ayijiang ^{[1
,2
,3
]}

Lv, Qi ^{[4
,5
]}

Wang, Bo ^{[1
]}

He, Runsheng ^{[2
,3
]}

Han, Yunlin ^{[4
,5
]}

Zhao, Wenjie ^{[4
,5
]}

Bai, Yali ^{[2
,3
,7
]}

Qu, Yajin ^{[4
,5
]}

Gao, Xiang ^{[4
,5
]}

Ji, Chenggong ^{[1
]}

Wang, Qisheng ^{[8
]}

Gao, Ning ^{[1
,7
,9
]}

Huang, Weijin ^{[6
]}

Wang, Youchun ^{[6
]}

Xie, X. Sunney ^{[1
,2
,3
,7
]}

Su, Xiao-dong ^{[1
,2
,3
,10
]}

Xiao, Junyu ^{[1
,7
,10
]}

Qin, Chuan ^{[4
,5
]}

机构：

[1] Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China

[2] Peking Univ, Beijing Adv Innovat Ctr Genom ICG, Beijing 100871, Peoples R China

[3] Peking Univ, Biomed Pioneering Innovat Ctr BIOPIC, Beijing 100871, Peoples R China

[4] Chinese Acad Med Sci, Key Lab Human Dis Comparat Med, Inst Lab Anim Sci, Chinese Minist Hlth,Beijing Key Lab Anim Models E, Beijing, Peoples R China

[5] Peking Union Med Coll, Comparat Med Ctr, Beijing, Peoples R China

[6] Natl Inst Food & Drug Control NIFDC, Inst Biol Prod Control, Div HIV AIDS & Sex Transmitted Virus Vaccines, Beijing 102629, Peoples R China

[7] Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China

[8] Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai 201204, Peoples R China

[9] Peking Univ, State Key Lab Membrane Biol, Beijing 100871, Peoples R China

[10] Peking Univ, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China

来源：

CELL | 2020年 / 183卷 / 04期

基金：

美国国家科学基金会;

关键词：

NEUTRALIZING ANTIBODIES; SPIKE;

D O I：

10.1016/j.cell.2020.09.035

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Understanding how potent neutralizing antibodies (NAbs) inhibitSARS-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 mechanismis largely unknown. Here, we report the 3.5-angstrom 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.

引用

页码：1013 / +

页数：24

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