2020年10月12日，《自然》杂志在线发表了美国科学家的一项最新研究成果。来自加州理工学院的Pamela J. Bjorkman团队通过SARS-CoV-2中和抗体结构为治疗策略提供依据。

研究人员表示，COVID-19大流行带来了全球的健康危机。靶向SARS-CoV-2突刺蛋白的宿主ACE2受体结合域（RBD）人类中和抗体（hNAb）具有治疗前景，正在被临床评估。

为了确定SARS-CoV-2中和的结构相关性，研究人员解析了与SARS-CoV-2突刺三聚体或RBD结合的8个不同COVID-19 hNAb新结构。结构上的比较允许将其分为以下几类：（1）带有短CDRH3的VH3-53 hNAb，它们阻断ACE2并仅与“向上的” RBD结合；（2）ACE2阻断hNAb结合“向上”和“向下” RBD并可以接触相邻的RBD；（3）在ACE2位点外结合并识别“向上”和“向下” RBD的hNAb；以及（4）先前描述的抗体，不阻断ACE2，仅结合“向上” RBD。第2类包含四个hNAb，其表位桥接RBD，包括VH3-53 hNAb，该VH3-53 hNAb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/互补位作图显示与宿主来源的N-聚糖几乎没有相互作用，并且抗体体细胞超突变对表位接触的贡献很小。亲和力测量以及天然存在的和体外选择的突刺变体3D定位，提供了深入了解SARS-CoV-2可能从感染期间引起的抗体或通过治疗递送的抗体中逃脱的见解。这些分类和结构分析提供当前和未来靶向人类RBD的抗体分类、亲和力效果的评估、临床组合使用的指导提供了规则，并为深入了解了靶向SARS-CoV-2的免疫反应提供了见解。

附：英文原文

Title: SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies

Author: Christopher O. Barnes, Claudia A. Jette, Morgan E. Abernathy, Kim-Marie A. Dam, Shannon R. Esswein, Harry B. Gristick, Andrey G. Malyutin, Naima G. Sharaf, Kathryn E. Huey-Tubman, Yu E. Lee, Davide F. Robbiani, Michel C. Nussenzweig, Anthony P. West, Pamela J. Bjorkman

Issue&Volume: 2020-10-12

Abstract: The COVID-19 pandemic presents an urgent health crisis. Human neutralizing antibodies (hNAbs) that target the host ACE2 receptor-binding domain (RBD) of the SARS-CoV-2 spike1–5 show therapeutic promise and are being evaluated clincally6–8. To determine structural correlates of SARS-CoV-2 neutralization, we solved 8 new structures of distinct COVID-19 hNAbs5 in complex with SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed classification into categories: (1) VH3-53 hNAbs with short CDRH3s that block ACE2 and bind only to “up” RBDs, (2) ACE2-blocking hNAbs that bind both “up” and “down” RBDs and can contact adjacent RBDs, (3) hNAbs that bind outside the ACE2 site and recognize “up” and “down” RBDs, and (4) Previously-described antibodies that do not block ACE2 and bind only “up” RBDs9. Class 2 comprised four hNAbs whose epitopes bridged RBDs, including a VH3-53 hNAb that used a long CDRH3 with a hydrophobic tip to bridge between adjacent “down” RBDs, thereby locking the spike into a closed conformation. Epitope/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 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, suggesting combinations for clinical use, and providing insight into immune responses against SARS-CoV-2.

DOI: 10.1038/s41586-020-2852-1

Source: https://www.nature.com/articles/s41586-020-2852-1