Potent Neutralization of Omicron and other SARS-CoV-2 Variants of Concern by Biparatopic Human VH Domains

Chen, C.; Martinez, D. R.; Marti, M. M.; Schaefer, A.; Cheng, M. H.; Mannar, D.; Zhu, X.; Berezuk, A. M.; Banerjee, A.; Sobolewski, M. D.; Kim, A.; Treat, B. R.; Da Silva Castanha, P. M.; Enick, N.; McCormick, K. D.; Liu, X.; Adams, C.; Hines, M. G.; Sun, Z.; Chen, W.; Jacobs, J. L.; Barratt-Boyes, S. M.; Mellors, J. W.; Baric, R. S.; Bahar, I.; Dimitrov, D. S.; Subramaniam, S.; Saville, J. W.; Li, W.

doi:10.1101/2022.02.18.481058

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bioRxiv · 10.1101/2022.02.18.481058

Potent Neutralization of Omicron and other SARS-CoV-2 Variants of Concern by Biparatopic Human VH Domains

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Abstract

The emergence of SARS-CoV-2 variants of concern (VOCs) requires the development of next-generation biologics that are effective against a variety of strains of the virus. Herein, we characterize a human VH domain, F6, which we generated by sequentially panning large phage displayed VH libraries against receptor binding domains (RBDs) containing VOC mutations. Cryo-EM analyses reveal that F6 has a unique binding mode that spans a broad surface of the RBD and involves the antibody framework region. Attachment of an Fc region to a fusion of F6 and ab8, a previously characterized VH domain, resulted in a construct (F6-ab8-Fc) that neutralized Omicron pseudoviruses with a half-maximal neutralizing concentration (IC50) of 4.8 nM in vitro. Additionally, prophylactic treatment using F6-ab8-Fc reduced live Beta (B.1.351) variant viral titers in the lungs of a mouse model. Our results provide a new potential therapeutic against SARS-CoV-2 VOCs - including the recently emerged Omicron variant - and highlight a vulnerable epitope within the spike protein RBD that may be exploited to achieve broad protection against circulating variants.

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Chen, C., Martinez, D. R., Marti, M. M., Schaefer, A., Cheng, M. H., Mannar, D., Zhu, X., Berezuk, A. M., Banerjee, A., Sobolewski, M. D., Kim, A., Treat, B. R., Da Silva Castanha, P. M., Enick, N., McCormick, K. D., Liu, X., Adams, C., Hines, M. G., Sun, Z., Chen, W., Jacobs, J. L., Barratt-Boyes, S. M., Mellors, J. W., Baric, R. S., Bahar, I., Dimitrov, D. S., Subramaniam, S., Saville, J. W., Li, W.. 2022-02-18. Potent Neutralization of Omicron and other SARS-CoV-2 Variants of Concern by Biparatopic Human VH Domains. https://doi.org/10.1101/2022.02.18.481058

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