Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions for optimal therapeutic protection

Antibodies serve protection against infectious diseases by neutralizing the invading pathogens, as well as they promote immune-mediated cellular clearance, enhancement of antigen presentation, CD8+ T cell responses and reshaping of inflammation by an effector function triggered by interaction of Fc region of antibody with cellular Fc receptor. To study the Fc effector function of therapeutic monoclonal antibody (mAb) against SARS-CoV-2 infection, loss-of-function Fc variant mAb was generated, and the protection activity of intact mAb was compared with those of the mAb variant. It was shown that Fc effector function was essential for the optimal therapy against viral infection in hACE2 Tg mice. Gene transcriptional profiling demonstrated that the effective protection requires genes associated with diminished innate immune signaling and tissue repair induced by the Fc effector function. Monocytes and CD8+ T cells were identified to be the critical factors for the clinical benefit engaged by neutralizing mAb.