Discovery of a SARS-CoV-2 Broadly-Acting Neutralizing Antibody with Activity against Omicron and Omicron + R346K Variants

Duty, J. A.; Kraus, T. A.; Zhou, H.; Zhang, Y.; Shaabani, N.; Yildiz, S.; Du, N.; Singh, A.; Miorin, L.; Li, D.; Stegman, K.; Ophir, S. I.; Cao, X.; Atanasoff, K.; Lim, R.; Kowdle, S. S.; Carreno, J. M.; Rivero-Nava, L.; Raskin, A.; Moreno, E.; Johnson, S.; Rathnasinghe, R.; Pai, C. I.; Kehrer, T.; Paz Cabral, E.; Jangra, S.; Healy, L. D.; Singh, G.; Warang, P.; Simon, V.; Sordillo, M. E.; van Bakel, H.; Liu, Y.; Sun, W.; Kerwin, L.; Palese, P.; Teijaro, J.; Schotsaert, M.; Krammer, F.; Bresson, D.; Garcia-Sastre, A.; Fu, Y.; Lee, B.; Powers, C.; Moran, T. M.; Ji, H.; Tortorella, D.; Allen, R.

doi:10.1101/2022.01.19.476998

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bioRxiv · 10.1101/2022.01.19.476998

Discovery of a SARS-CoV-2 Broadly-Acting Neutralizing Antibody with Activity against Omicron and Omicron + R346K Variants

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Abstract

The continual emergence of SARS-CoV-2 variants of concern, in particular the newly emerged Omicron (B.1.1.529) variant, has rendered ineffective a number of previously EUA approved SARS-CoV-2 neutralizing antibody therapies. Furthermore, even those approved antibodies with neutralizing activity against Omicron are reportedly ineffective against the subset of Omicron variants that contain a R346K substitution, demonstrating the continued need for discovery and characterization of candidate therapeutic antibodies with the breadth and potency of neutralizing activity required to treat newly diagnosed COVID-19 linked to recently emerged variants of concern. Following a campaign of antibody discovery based on the vaccination of Harbour H2L2 mice with defined SARS-CoV-2 spike domains, we have characterized the activity of a large collection of Spike-binding antibodies and identified a lead neutralizing human IgG1 LALA antibody, STI-9167. STI-9167 has potent, broad-spectrum neutralizing activity against the current SARS-COV-2 variants of concern and retained activity against the Omicron and Omicron + R346K variants in both pseudotype and live virus neutralization assays. Furthermore, STI-9167 nAb administered intranasally or intravenously provided protection against weight loss and reduced virus lung titers to levels below the limit of quantitation in Omicron-infected K18-hACE2 transgenic mice. With this established activity profile, a cGMP cell line has been developed and used to produce cGMP drug product intended for use in human clinical trials.

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Duty, J. A., Kraus, T. A., Zhou, H., Zhang, Y., Shaabani, N., Yildiz, S., Du, N., Singh, A., Miorin, L., Li, D., Stegman, K., Ophir, S. I., Cao, X., Atanasoff, K., Lim, R., Kowdle, S. S., Carreno, J. M., Rivero-Nava, L., Raskin, A., Moreno, E., Johnson, S., Rathnasinghe, R., Pai, C. I., Kehrer, T., Paz Cabral, E., Jangra, S., Healy, L. D., Singh, G., Warang, P., Simon, V., Sordillo, M. E., van Bakel, H., Liu, Y., Sun, W., Kerwin, L., Palese, P., Teijaro, J., Schotsaert, M., Krammer, F., Bresson, D., Garcia-Sastre, A., Fu, Y., Lee, B., Powers, C., Moran, T. M., Ji, H., Tortorella, D., Allen, R.. 2022-01-20. Discovery of a SARS-CoV-2 Broadly-Acting Neutralizing Antibody with Activity against Omicron and Omicron + R346K Variants. https://doi.org/10.1101/2022.01.19.476998

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