Antibody potency, effector function, and combinations in protection and therapy for SARS-CoV-2 infection in vivo

Schäfer, Alexandra; Muecksch, Frauke; Lorenzi, Julio C.C.; Leist, Sarah R.; Cipolla, Melissa; Bournazos, Stylianos; Schmidt, Fabian; Maison, Rachel M.; Gazumyan, Anna; Martinez, David R.; Baric, Ralph S.; Robbiani, Davide F.; Hatziioannou, Theodora; Ravetch, Jeffrey V.; Bieniasz, Paul D.; Bowen, Richard A.; Nussenzweig, Michel C.; Sheahan, Timothy P.

SARS-CoV-2, the causative agent of COVID-19, has been responsible for over 42 million infections and 1 million deaths since its emergence in December 2019. There are few therapeutic options and no approved vaccines. Here, we examine the properties of highly potent human monoclonal antibodies (hu-mAbs) in a Syrian hamster model of SARS-CoV-2 and in a mouse-adapted model of SARS-CoV-2 infection (SARS-CoV-2 MA). Antibody combinations were effective for prevention and in therapy when administered early. However, in vitro antibody neutralization potency did not uniformly correlate with in vivo protection, and some hu-mAbs were more protective in combination in vivo. Analysis of antibody Fc regions revealed that binding to activating Fc receptors contributes to optimal protection against SARS-CoV-2 MA. The data indicate that intact effector function can affect hu-mAb protective activity and that in vivo testing is required to establish optimal hu-mAb combinations for COVID-19 prevention.