High-resolution map of the Fc functions mediated by COVID-19-neutralizing antibodies

Abstract

A growing body of evidence shows that fragment crystallizable (Fc)-dependent antibody effector functions play an important role in protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To unravel the mechanisms that drive these responses, we analyzed the phagocytosis and complement deposition mediated by a panel of 482 human monoclonal antibodies (nAbs) neutralizing the original Wuhan virus, expressed as recombinant IgG1. Our study confirmed that nAbs no longer neutralizing SARS-CoV-2 Omicron variants can retain their Fc functions. Surprisingly, we found that nAbs with the most potent Fc function recognize the N-terminal domain, followed by those targeting class 3 epitopes in the receptor binding domain. Interestingly, nAbs direct against the class 1/2 epitopes in the receptor binding motif, which are the most potent in neutralizing the virus, were the weakest in Fc functions. The divergent properties of the neutralizing and Fc function–mediating antibodies were confirmed by the use of different B cell germlines and by the observation that Fc functions of polyclonal sera differ from the profile observed with nAbs, suggesting that non-neutralizing antibodies also contribute to Fc functions. These data provide a high-resolution picture of the Fc-antibody response to SARS-CoV-2 and suggest that the Fc contribution should be considered for the design of improved vaccines, the selection of therapeutic antibodies, and the evaluation of correlates of protection.

Sotrovimab: A Review of Its Efficacy against SARS-CoV-2 Variants

“…Sotrovimab serum half-life was improved by inserting the Met428Leu/Asn434Ser (LS) mutation (Xtend TM ) in the Fc region. Unlike with other half-life extended anti-Spike mAbs, this mutation does not impact the ADCC functions of sotrovimab, which are important for its activity against SARS-CoV-2 [ 7 , 8 , 9 ]. This mutation was previously used in the mAb ravulizumab (approved for paroxysmal nocturnal hemoglobinuria).…”