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Protective non-neutralizing mAbs targets conserved opsonic epitopes on SARS-CoV-2 variants


Antibodies play a central role in the immune defense against SARS-CoV-2. Strong evidence has shown that non-neutralizing antibodies (nnAbs) are important for anti-SARS-Cov-2 immunity through Fc-mediated effector functions. These nnAbs bind to epitopes that could be less subjected to mutations in the emerging variants. When protective, such nnAbs would constitute a more promising alternative to neutralizing mAbs (nAbs). Here, we show that six nnAbs retain binding to Omicron, while two nAbs do not. Furthermore, two of our nnAbs, which are protective in vivo, retained binding to XBB, XBB.1.5, and BQ.1.1. They appear to bind to conserved epitopes on the N-terminal and receptor binding domain (RBD), respectively. As a proof of concept, we show that these protective non-neutralizing antibodies retain potent Fc-mediated opsonic function against BQ.1.1 and XBB. We also show that the Fc-mediated function is further enhanced by expressing the antibodies in the IgG3 subclass and combining them into a dual antibody cocktail. Our work suggests that opsonizing nnAbs could be a viable strategy for anti-SARS-CoV-2 mAb therapies against current and future SARS-CoV-2 variants.