The ongoing evolution of SARS-CoV-2 has resulted in the emergence of Omicron, which displays striking immune escape potential through mutations at key antigenic sites on the spike protein. Many of these mutations localize to the spike protein ACE2 receptor-binding domain, annulling the neutralizing activity of therapeutic antibodies that were effective against other Variants of Concern (VOCs) earlier in the pandemic. Here, we identified a receptor-blocking human monoclonal antibody, 87G7, that retained potent in vitro neutralizing activity against SARS-CoV-2 variants including the Alpha, Beta, Gamma, Delta and Omicron (BA.1/BA.2) VOCs. Using cryo-electron microscopy and site-directed mutagenesis experiments, we showed that 87G7 targets a patch of hydrophobic residues in the ACE2-binding site that are highly conserved in SARS-CoV-2 variants, explaining its broad neutralization capacity. 87G7 protected mice and/or hamsters prophylactically against challenge with all current SARS-CoV-2 VOCs, and showed therapeutic activity against SARS-CoV-2 challenge in both animal models. Our findings demonstrate that 87G7 holds promise as a prophylactic or therapeutic agent for COVID-19 that is more resilient to SARS-CoV-2 antigenic diversity.

中文翻译：

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ACE2 阻断抗体可广泛中和和保护 Omicron 和其他受关注的 SARS-CoV-2 变体

SARS-CoV-2 的持续进化导致了 Omicron 的出现，它通过刺突蛋白上关键抗原位点的突变显示出惊人的免疫逃逸潜力。其中许多突变定位于刺突蛋白 ACE2 受体结合域，从而取消了治疗性抗体的中和活性，这些抗体在大流行早期对其他关注的变异 (VOC) 有效。在这里，我们鉴定了一种受体阻断性人单克隆抗体 87G7，它保留了对 SARS-CoV-2 变体（包括 Alpha、Beta、Gamma、Delta 和 Omicron (BA.1/BA.2) VOC）的有效体外中和活性。使用冷冻电子显微镜和定点诱变实验，我们发现 87G7 靶向 ACE2 结合位点中的一片疏水残基，这些残基在 SARS-CoV-2 变体中高度保守，解释其广泛的中和能力。87G7 预防性地保护小鼠和/或仓鼠免受所有当前 SARS-CoV-2 VOC 的攻击，并在两种动物模型中显示出针对 SARS-CoV-2 攻击的治疗活性。我们的研究结果表明，87G7 有望成为 COVID-19 的预防或治疗剂，它对 SARS-CoV-2 抗原多样性更具弹性。