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A growing body of evidence underscores the role of antibody-dependent cellular cytotoxicity (ADCC) in antiviral immunity. Yet, the mechanisms underlying the ability of certain antibodies (Abs) to mediate potent ADCC activity remain poorly characterized. In particular the contribution of features within the antigen-binding Fab region remains largely unexplored. In this study, we leveraged a collection of 142 SARS-CoV-2 monoclonal Abs to systematically dissect the determinants of ADCC activity. We analyzed their epitope domain target, binding characteristics, neutralization potency, somatic hypermutation (SHM) and CDR3 length to determine the contribution of these features to ADCC activity. We found that ADCC activity is primarily shaped by epitope target - particularly targeting of the S2 domain of the Spike glycoprotein. ADCC potency was not associated with the degree of SHM or neutralization. Notably, ADCC activity was not correlated with binding activity and moderate binding to antigen was sufficient for ADCC activity. By integrating these analyses, we provide a comprehensive framework for understanding the molecular and functional determinants of ADCC. Together, these findings offer novel insights into the mechanisms that underpin ADCC functions, with implications for vaccine design and therapeutic Abs development.