Yamin Rachel, Jones Andrew T, Hoffmann Hans-Heinrich, Schäfer Alexandra, Kao Kevin S, Francis Rebecca L, Sheahan Timothy P, Baric Ralph S, Rice Charles M, Ravetch Jeffrey V, Bournazos Stylianos
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY, USA.
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
Nature. 2021 Nov;599(7885):465-470. doi: 10.1038/s41586-021-04017-w. Epub 2021 Sep 21.
Monoclonal antibodies with neutralizing activity against SARS-CoV-2 have demonstrated clinical benefits in cases of mild-to-moderate SARS-CoV-2 infection, substantially reducing the risk for hospitalization and severe disease. Treatment generally requires the administration of high doses of these monoclonal antibodies and has limited efficacy in preventing disease complications or mortality among hospitalized patients with COVID-19. Here we report the development and evaluation of anti-SARS-CoV-2 monoclonal antibodies with optimized Fc domains that show superior potency for prevention or treatment of COVID-19. Using several animal disease models of COVID-19, we demonstrate that selective engagement of activating Fcγ receptors results in improved efficacy in both preventing and treating disease-induced weight loss and mortality, significantly reducing the dose required to confer full protection against SARS-CoV-2 challenge and for treatment of pre-infected animals. Our results highlight the importance of Fcγ receptor pathways in driving antibody-mediated antiviral immunity and exclude the possibility of pathogenic or disease-enhancing effects of Fcγ receptor engagement of anti-SARS-CoV-2 antibodies upon infection. These findings have important implications for the development of Fc-engineered monoclonal antibodies with optimal Fc-effector function and improved clinical efficacy against COVID-19 disease.
对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）具有中和活性的单克隆抗体已在轻度至中度SARS-CoV-2感染病例中显示出临床益处，大幅降低了住院风险和重症风险。治疗通常需要给予高剂量的这些单克隆抗体，且在预防COVID-19住院患者的疾病并发症或死亡方面疗效有限。在此，我们报告了具有优化Fc结构域的抗SARS-CoV-2单克隆抗体的研发和评估，这些抗体在预防或治疗COVID-19方面表现出卓越的效力。利用多种COVID-19动物疾病模型，我们证明激活型Fcγ受体的选择性结合可提高预防和治疗疾病诱导的体重减轻及死亡的疗效，显著降低给予完全保护以抵御SARS-CoV-2攻击以及治疗预感染动物所需的剂量。我们的结果突出了Fcγ受体途径在驱动抗体介导的抗病毒免疫中的重要性，并排除了抗SARS-CoV-2抗体的Fcγ受体结合在感染时产生致病或疾病增强效应的可能性。这些发现对开发具有最佳Fc效应功能和更高抗COVID-19疾病临床疗效的Fc工程单克隆抗体具有重要意义。
