Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy
Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy
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DOI：
10.1016/j.cell.2020.09.035
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发表时间：
2020-11-12
期刊：
影响因子：
64.5
通讯作者：
Qin, Chuan
中科院分区：
文献类型：
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作者：
Du, Shuo;Cao, Yunlong;Qin, Chuan
了解有效的中和抗体（NAb）如何消灭SARS-CoV-2对于有效的治疗开发至关重要。我们先前描述了BD-368-2，一种具有高效力的SARS-CoV-2 NAb;然而，其中和机制在很大程度上是未知的。在这里，我们报告了BD-368-2/三聚体-刺突复合物的3.5埃冷冻-EM结构，揭示了BD-368-2通过同时占据所有三个受体结合结构域（RBD）而完全阻断ACE 2识别，而不管它们的“上”或“下”构象。此外，BD-368-2以低剂量和在不同给药窗口治疗感染的成年仓鼠，与表现出严重间质性肺炎的安慰剂仓鼠相反。此外，BD-368-2的表位完全避免了VH 3 -53/VH 3 -66复发NAb的共同结合位点，这由与RBD的三重共晶体结构证明。BD-368-2与有效的复发性NAb配对在pM水平上中和SARS-CoV-2假病毒，并挽救突变诱导的中和逃逸。总之，我们的结果合理化了一种新的RBD表位，该表位导致高中和效力，并证明了BD-368-2在治疗COVID-19方面的治疗潜力。
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.