Role of Nonneutralizing Antibodies and Fc Effector Functions in Inhibiting SARS-CoV-2 Infection

Abstract Neutralizing monoclonal antibodies (mAbs) are a key component of antiviral therapeutics against SARS-CoV-2; however, the contribution of Fc-mediated effector functions remains underexplored. Here, we compare the antiviral activities of the neutralizing and non-neutralizing mAbs CB6 and CR3022, respectively. The Fc regions of both plant-produced mAbs carried nonfucosylated, non-galactosylated complex glycans (pCB6 and pCR3022), and CR3022 was also produced with mammalian-typical galactosylated, fucosylated glycans (mCR3022). pCR3022 exhibited markedly enhanced antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cell-mediated virus inhibition (ADCVI) compared to mCR3022, indicating a significant impact of Fc glycosylation on antiviral activity despite the lack of neutralization. pCB6 exhibited potent neutralization while further enhancing virus clearance through synergistic Fc effector activity. Our findings suggest that Fc-mediated mechanisms, especially ADCC and ADCVI, can contribute substantially to viral control and may be particularly valuable against immune-evasive variants. These results advance our understanding of the functional roles that non-neutralizing antibodies can play in SARS-CoV-2 infection and highlight the potential of Fc glycoengineering to modulate the antiviral efficacy of both neutralizing and non-neutralizing mAbs.