Antibody-mediated SARS-CoV-2 entry and conformational regulation

Abstract

Antibody-mediated entry (AME) of SARS-CoV-2 into monocytes and macrophages has been linked to activation of inflammatory phenotypes that are associated with severe COVID-19, but why only some antibodies mediate this entry while others do not is unknown. However, it has been demonstrated that conformational dynamics of the SARS-CoV-2 receptor binding domain (RBD) are critical to viral entry, and that antibodies targeting the RBD can conformationally regulate these dynamics. Here, we identified 5 groups of mAbs that target unique epitopes on the SARS-CoV-2 RBD and also are associated with different RBD conformational regulation and AME abilities. Structure alignment and antibody docking analysis elucidated a thermodynamic basis for differences in conformational regulation by these antibody groups. We found that some, but not all, antibody groups were able to mediate entry into THP1-derived macrophages, and also found that this entry was inhibitable by mAbs in other groups. Collectively, these results suggest that there is a connection between RBD conformational regulation, epitope, and AME ability of antibodies. This connection improves understanding of the AME mechanism and how to inhibit AME for SARS-CoV-2, which has potential applications in the continued development of safe and effective vaccines and therapeutics for COVID-19 and related diseases.