Fc-engineered antibody therapeutics with improved anti-SARS-CoV-2 efficacy

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(1-4). 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-19(5). 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 Fc. 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 Fc. receptor pathways in driving antibody-mediated antiviral immunity and exclude the possibility of pathogenic or disease-enhancing effects of Fc. 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.

Automated summary

Monoclonal antibodies with optimized Fc domains show superior potency in preventing and treating COVID-19 in animal disease models, reducing the dose required for protection against SARS-CoV-2 challenge and for treating pre-infected animals. Selective engagement of activating Fc receptors results in improved efficacy, highlighting the importance of Fc receptor pathways in driving antibody-mediated antiviral immunity. These findings have implications for the development of Fc-engineered monoclonal antibodies with optimal Fc-effector function against COVID-19.