SARS-CoV-2中和抗體結構為治療策略提供依據
作者：
小柯機器人發布時間：2020/10/13 16:49:16
2020年10月12日，《自然》雜誌在線發表了美國科學家的一項最新研究成果。來自加州理工學院的Pamela J. Bjorkman團隊通過SARS-CoV-2中和抗體結構為治療策略提供依據。
研究人員表示，COVID-19大流行帶來了全球的健康危機。靶向SARS-CoV-2突刺蛋白的宿主ACE2受體結合域（RBD）人類中和抗體（hNAb）具有治療前景，正在被臨床評估。
為了確定SARS-CoV-2中和的結構相關性，研究人員解析了與SARS-CoV-2突刺三聚體或RBD結合的8個不同COVID-19 hNAb新結構。結構上的比較允許將其分為以下幾類：（1）帶有短CDRH3的VH3-53 hNAb，它們阻斷ACE2並僅與「向上的」 RBD結合；（2）ACE2阻斷hNAb結合「向上」和「向下」 RBD並可以接觸相鄰的RBD；（3）在ACE2位點外結合併識別「向上」和「向下」 RBD的hNAb；以及（4）先前描述的抗體，不阻斷ACE2，僅結合「向上」 RBD。第2類包含四個hNAb，其表位橋接RBD，包括VH3-53 hNAb，該VH3-53 hNAb使用帶有疏水尖端的長CDRH3在相鄰的「向下」 RBD之間橋接，從而將刺突鎖定為閉合構象。
表位/互補位作圖顯示與宿主來源的N-聚糖幾乎沒有相互作用，並且抗體體細胞超突變對表位接觸的貢獻很小。親和力測量以及天然存在的和體外選擇的突刺變體3D定位，提供了深入了解SARS-CoV-2可能從感染期間引起的抗體或通過治療遞送的抗體中逃脫的見解。這些分類和結構分析提供當前和未來靶向人類RBD的抗體分類、親和力效果的評估、臨床組合使用的指導提供了規則，並為深入了解了靶向SARS-CoV-2的免疫反應提供了見解。
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