Structural insights for neutralization of BA.1 and BA.2 Omicron variants by a broadly neutralizing SARS-CoV-2 antibody

Kumar, S.; Patel, A.; Lai, L.; Chakravarthy, C.; Valanparambil, R.; Davis-Gardner, M. E.; Edara, V. V.; Linderman, S.; Reddy, E. S.; Gottimukkala, K.; Nayak, K.; Bajpai, P.; Singh, V.; Frank, F.; Cheedarla, N.; Verkerke, H.; Neish, A. S.; Roback, J. D.; Mantus, G.; Goel, P. K.; Rahi, M.; Davis, C. W.; Wrammert, J.; Suthar, M. S.; Ahmed, R.; Ortlund, E.; Sharma, A.; Krishna, K. M.; Chandele, A.

doi:10.1101/2022.05.13.491770

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bioRxiv · 10.1101/2022.05.13.491770

Structural insights for neutralization of BA.1 and BA.2 Omicron variants by a broadly neutralizing SARS-CoV-2 antibody

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Abstract

The SARS-CoV-2 BA.1 and BA.2 (Omicron) variants contain more than 30 mutations within the spike protein and evade therapeutic monoclonal antibodies (mAbs). Here, we report a receptor-binding domain (RBD) targeting human antibody (002-S21F2) that effectively neutralizes live viral isolates of SARS-CoV-2 variants of concern (VOCs) including Alpha, Beta, Gamma, Delta, and Omicron (BA.1 and BA.2) with IC50 ranging from 0.02 - 0.05 g/ml. This near germline antibody 002-S21F2 has unique genetic features that are distinct from any reported SARS-CoV-2 mAbs. Structural studies of the full-length IgG in complex with spike trimers (Omicron and WA.1) reveal that 002-S21F2 recognizes an epitope on the outer face of RBD (class-3 surface), outside the ACE2 binding motif and its unique molecular features enable it to overcome mutations found in the Omicron variants. The discovery and comprehensive structural analysis of 002-S21F2 provide valuable insight for broad and potent neutralization of SARS-CoV-2 Omicron variants BA.1 and BA.2.

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Kumar, S., Patel, A., Lai, L., Chakravarthy, C., Valanparambil, R., Davis-Gardner, M. E., Edara, V. V., Linderman, S., Reddy, E. S., Gottimukkala, K., Nayak, K., Bajpai, P., Singh, V., Frank, F., Cheedarla, N., Verkerke, H., Neish, A. S., Roback, J. D., Mantus, G., Goel, P. K., Rahi, M., Davis, C. W., Wrammert, J., Suthar, M. S., Ahmed, R., Ortlund, E., Sharma, A., Krishna, K. M., Chandele, A.. 2022-05-13. Structural insights for neutralization of BA.1 and BA.2 Omicron variants by a broadly neutralizing SARS-CoV-2 antibody. https://doi.org/10.1101/2022.05.13.491770

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