The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein 1 – 5 show promise therapeutically and are being evaluated clinically 6 – 8 . Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies 5 in complex with the SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed us to classify the antibodies into categories: (1) neutralizing antibodies encoded by the VH3-53 gene segment with short CDRH3 loops that block ACE2 and bind only to ‘up’ RBDs; (2) ACE2-blocking neutralizing antibodies that bind both up and ‘down’ RBDs and can contact adjacent RBDs; (3) neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and (4) previously described antibodies that do not block ACE2 and bind only to up RBDs 9 . Class 2 contained four neutralizing antibodies with epitopes that bridged RBDs, including a VH3-53 antibody that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking the spike into a closed conformation. Epitope and paratope mapping revealed few interactions with host-derived N -glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 to escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects and suggesting combinations for clinical use, and provide insight into immune responses against SARS-CoV-2. Eight structures of human neutralizing antibodies that target the SARS-CoV-2 spike receptor-binding domain are reported and classified into four categories, suggesting combinations for clinical use.

中文翻译：

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SARS-CoV-2 中和抗体结构为治疗策略提供信息


2019 年冠状病毒病 (COVID-19) 大流行带来了紧迫的健康危机。针对严重急性呼吸综合征冠状病毒-2 (SARS-CoV-2) 刺突蛋白 1 – 5 的宿主 ACE2 受体结合域 (RBD) 的人类中和抗体显示出治疗前景，并正在临床评估 6 – 8 。在这里，为了确定 SARS-CoV-2 中和的结构相关性，我们解决了与 SARS-CoV-2 刺突三聚体或 RBD 复合的不同 COVID-19 人类中和抗体 5 的八种新结构。结构比较使我们能够将抗体分为几类：（1）由 VH3-53 基因片段编码的中和抗体，其具有短 CDRH3 环，可阻断 ACE2 并仅与“上”RBD 结合； (2) ACE2 阻断中和抗体，可结合上和“下”RBD，并可接触相邻的 RBD； (3) 中和抗体，结合在 ACE2 位点之外并识别上、下 RBD； (4) 先前描述的不阻断 ACE2 且仅与 RBD 结合的抗体 9 。 2 类包含四种具有桥接 RBD 的表位的中和抗体，其中包括一种 VH3-53 抗体，该抗体使用带有疏水尖端的长 CDRH3 在相邻的向下 RBD 之间桥接，从而将刺突锁定为闭合构象。表位和互补位作图揭示了与宿主衍生的N-聚糖的相互作用很少，并且抗体体细胞超突变对表位接触的贡献较小。对自然发生的和体外选择的刺突突变体进行 3D 亲和力测量和绘图，有助于深入了解 SARS-CoV-2 逃离感染期间引发的抗体或治疗过程中产生的抗体的可能性。 这些分类和结构分析提供了将当前和未来的人类 RBD 靶向抗体分类、评估亲合力效应并建议临床使用组合的规则，并提供了对 SARS-CoV-2 免疫反应的深入了解。报道了针对 SARS-CoV-2 刺突受体结合域的八种人类中和抗体结构，并将其分为四类，建议临床使用的组合。