Winkler Emma S, Gilchuk Pavlo, Yu Jinsheng, Bailey Adam L, Chen Rita E, Chong Zhenlu, Zost Seth J, Jang Hyesun, Huang Ying, Allen James D, Case James Brett, Sutton Rachel E, Carnahan Robert H, Darling Tamarand L, Boon Adrianus C M, Mack Matthias, Head Richard D, Ross Ted M, Crowe James E, Diamond Michael S
Department of Medicine, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA.
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Cell. 2021 Apr 1;184(7):1804-1820.e16. doi: 10.1016/j.cell.2021.02.026. Epub 2021 Feb 12.
SARS-CoV-2 has caused the global COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 show promise in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected animals. Whereas Fc effector functions are dispensable when representative neutralizing mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters better than loss-of-function Fc variant mAbs. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and preserved tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes and CD8 T cells for optimal clinical and virological benefit. Thus, potently neutralizing mAbs utilize Fc effector functions during therapy to mitigate lung infection and disease.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引发了全球新冠疫情。尽管被动给予的抗SARS-CoV-2中和抗体在临床试验中显示出前景，但其在体内的作用机制尚未完全明确。在此，我们确定了在感染SARS-CoV-2的动物中中和性人单克隆抗体（mAb）的保护相关因素。当作为预防措施给予代表性中和mAb时，Fc效应功能并非必需，但作为治疗手段时，它们是实现最佳保护所必需的。感染后给予时，完整的mAb比功能缺失的Fc变体mAb能更好地降低小鼠和仓鼠体内的SARS-CoV-2负担并减轻肺部疾病。中和抗体的Fc结合减轻了炎症并改善了呼吸力学，转录谱分析表明这些表型与先天免疫信号减弱和组织修复保留有关。免疫细胞耗竭实验证实，中和mAb需要单核细胞和CD8 T细胞才能实现最佳的临床和病毒学效益。因此，强效中和mAb在治疗过程中利用Fc效应功能来减轻肺部感染和疾病。
