Polyfunctionality of broadly reactive non-neutralizing SARS-CoV-2 RBD antibodies

Persistent SARS-CoV-2 viral escape hindered the search for broad pan-neutralizer monoclonal antibody candidates. To unravel properties of cross-reactive SARS-CoV-2 anti-RBD monoclonal antibodies (mAbs), we identified, cloned, produced, and characterized anti-RBD specific mAbs from convalescent donors infected during the first wave of pandemic. We observed a strong dichotomy between the mAbs based on reactivity profile. The majority (55%) were poorly cross-reactive yet displayed potent neutralization together with strong Fc effector functions, including ADCC, CDC, and ADCP. In contrast, 45% were broadly cross-reactive, maintaining activity against highly mutated Omicron variants (e.g., BA.2.86, EG.5.1), but lacked neutralization and ADCP, while preserving other Fc-mediated functions. Rare intermediates bridged these groups combining cross-reactivity antiviral potency. Those mAbs were also able to induce SARS-CoV-2 homotrimeric spike conformational changes, increasing anti-FP reactivity and potency. These findings suggest a potential protective role for non-neutralizing, cross-reactive anti-RBD mAbs in mitigating SARS-CoV-2 reinfection.