Genetic and structural basis for recognition of SARS-CoV-2 spike protein by a two-antibody cocktail

Dong, J.; Zost, S.; Greaney, A.; Starr, T. N.; Dingens, A. S.; Chen, E. C.; Chen, R.; Case, B.; Sutton, R.; Gilchuk, P.; Rodriguez, J.; Armstrong, E.; Gainza, C.; Nargi, R.; Binshtein, E.; Xie, X.; Zhang, X.; Shi, P.-Y.; Logue, J.; Weston, S.; McGrath, M.; Frieman, M.; Brady, T.; Tuffy, K.; Bright, H.; Loo, Y.-M.; McvTamney, P.; Esser, M.; Carnahan, R.; Diamond, M.; Bloom, J.; Crowe, J. E.

doi:10.1101/2021.01.27.428529

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bioRxiv · 10.1101/2021.01.27.428529

Genetic and structural basis for recognition of SARS-CoV-2 spike protein by a two-antibody cocktail

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Abstract

The SARS-CoV-2 pandemic has led to an urgent need to understand the molecular basis for immune recognition of SARS-CoV-2 spike (S) glycoprotein antigenic sites. To define the genetic and structural basis for SARS-CoV-2 neutralization, we determined the structures of two human monoclonal antibodies COV2-2196 and COV2-21301, which form the basis of the investigational antibody cocktail AZD7442, in complex with the receptor binding domain (RBD) of SARS-CoV-2. COV2-2196 forms an "aromatic cage" at the heavy/light chain interface using germline-encoded residues in complementarity determining regions (CDRs) 2 and 3 of the heavy chain and CDRs 1 and 3 of the light chain. These structural features explain why highly similar antibodies (public clonotypes) have been isolated from multiple individuals1-4. The structure of COV2-2130 reveals that an unusually long LCDR1 and HCDR3 make interactions with the opposite face of the RBD from that of COV2-2196. Using deep mutational scanning and neutralization escape selection experiments, we comprehensively mapped the critical residues of both antibodies and identified positions of concern for possible viral escape. Nonetheless, both COV2-2196 and COV2-2130 showed strong neutralizing activity against SARS-CoV-2 strain with recent variations of concern including E484K, N501Y, and D614G substitutions. These studies reveal germline-encoded antibody features enabling recognition of the RBD and demonstrate the activity of a cocktail like AZD7442 in preventing escape from emerging variant viruses.

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Dong, J., Zost, S., Greaney, A., Starr, T. N., Dingens, A. S., Chen, E. C., Chen, R., Case, B., Sutton, R., Gilchuk, P., Rodriguez, J., Armstrong, E., Gainza, C., Nargi, R., Binshtein, E., Xie, X., Zhang, X., Shi, P.-Y., Logue, J., Weston, S., McGrath, M., Frieman, M., Brady, T., Tuffy, K., Bright, H., Loo, Y.-M., McvTamney, P., Esser, M., Carnahan, R., Diamond, M., Bloom, J., Crowe, J. E.. 2021-01-28. Genetic and structural basis for recognition of SARS-CoV-2 spike protein by a two-antibody cocktail. https://doi.org/10.1101/2021.01.27.428529

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