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-Bussieres, G.; Chen, Y.; Ullah, I.; Prevost, J.; Tolbert, W. D.; Symmes, K.; Ding, S.; Benlarbi, M.; Gong, S. Y.; Tauzin, A.; Gasser, R.; Chatterjee, D.; Vezina, D.; Goyette, G.; Richard, J.; Zhou, F.; Stamatatos, L.; McGuire, A. T.; Charest, H.; Roger, M.; Pozharski, E.; Kumar, P.; Mothes, W.; Uchil, P. D.; Pazgier, M.; Finzi, A.

doi:10.1101/2021.09.08.459408

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bioRxiv · 10.1101/2021.09.08.459408

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

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Abstract

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.

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Beaudoin-Bussieres, G., Chen, Y., Ullah, I., Prevost, J., Tolbert, W. D., Symmes, K., Ding, S., Benlarbi, M., Gong, S. Y., Tauzin, A., Gasser, R., Chatterjee, D., Vezina, D., Goyette, G., Richard, J., Zhou, F., Stamatatos, L., McGuire, A. T., Charest, H., Roger, M., Pozharski, E., Kumar, P., Mothes, W., Uchil, P. D., Pazgier, M., Finzi, A.. 2021-09-08. 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. https://doi.org/10.1101/2021.09.08.459408

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