An anti-SARS-CoV-2 non-neutralizing antibody with Fc-effector function defines a new NTD epitope and delays neuroinvasion and death in K18-hACE2 mice

Beaudoin-Bussières, Guillaume; Chen, Yaozong; Ullah, Irfan; Prévost, Jérémie; Tolbert, William D.; Symmes, Kelly; Ding, Shilei; Benlarbi, Mehdi; Gong, Shang Yu; Tauzin, Alexandra; Gasser, Romain; Chatterjee, Debashree; Vézina, Dani; Goyette, Guillaume; Richard, Jonathan; Zhou, Fei; Stamatatos, Leonidas; McGuire, Andrew T.; Charest, Hughes; Roger, Michel; Pozharski, Edwin; Kumar, Priti; Mothes, Walther; Uchil, Pradeep D.; Pazgier, Marzena; Finzi, Andrés

Emerging evidence in animal models indicate that both neutralizing activity and Fc- mediated effector functions of neutralizing antibodies contribute to protection against SARS-CoV-2. It is unclear if antibody effector functions alone could protect against SARS-CoV-2. Here we isolated CV3-13, a non-neutralizing antibody from a convalescent individual with potent Fc-mediated effector functions that targeted the N- terminal domain (NTD) of SARS-CoV-2 Spike. The cryo-EM structure of CV3-13 in complex with SAR-CoV-2 spike revealed that the antibody bound from a distinct angle of approach to a novel NTD epitope that partially overlapped with a frequently mutated NTD supersite in SARS-CoV-2 variants. While CV3-13 did not alter the replication dynamics of SARS-CoV-2 in a K18-hACE2 transgenic mouse model, an Fc-enhanced CV3-13 significantly delayed neuroinvasion and death in prophylactic settings. Thus, we demonstrate that efficient Fc-mediated effector functions can contribute to the in vivo efficacy of anti-SARS-CoV-2 monoclonal antibodies in the absence of neutralization.