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^1,2,3,4. 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-19⁵. 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-19^6,7, 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 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，从而大大降低了住院和重症风险^1,2,3,4。治疗通常需要施用高剂量的这些单克隆抗体，并且在预防 COVID-19 住院患者的疾病并发症或死亡率方面效果有限⁵。在这里，我们报告了具有优化 Fc 结构域的抗 SARS-CoV-2 单克隆抗体的开发和评估，这些抗体在预防或治疗 COVID-19 方面显示出卓越的效力。使用几种 COVID-19 的动物疾病模型^6,7，我们证明激活 Fcγ 受体的选择性参与可提高预防和治疗疾病引起的体重减轻和死亡率的功效，显着降低全面保护抵御 SARS-CoV-2 攻击和治疗预感染所需的剂量动物。我们的研究结果强调了 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 Fcγ 受体参与抗 SARS-CoV-2 抗体在感染时产生致病或疾病增强作用的可能性。这些发现对于开发具有最佳 Fc 效应器功能和改善 COVID-19 疾病临床疗效的 Fc 工程单克隆抗体具有重要意义。