Integrated technology platform for accelerated discovery of antiviral antibody therapeutics

Gilchuk, P.; Bombardi, R. G.; Erasmus, J. H.; Tan, Q.; Nargi, R. S.; Soto, C.; Abbink, P.; Suscovich, T. J.; Dunellin, L. A.; Khandhar, A.; Archer, J.; Liang, J.; Fouch, M. E.; Davidson, E.; Doranz, B.; Jones, T.; Larson, E.; Ertel, S.; Granger, B.; Fuerte-Stone, J.; Roy, V.; Broge, T.; Linnekin, T. C.; Linde, C. H.; Gorman, M. J.; Nkolola, J.; Alter, G.; Reed, S. G.; Barouch, D. H.; Diamond, M. S.; Crowe, J. E.; Van Hoeven, N.; Thackray, L.; Carnahan, R. H.

doi:10.1101/2020.05.12.090944

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bioRxiv · 10.1101/2020.05.12.090944

Integrated technology platform for accelerated discovery of antiviral antibody therapeutics

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Abstract

The emergence and reemergence of highly virulent viral pathogens with pandemic potential has created an urgent need for accelerated discovery of antiviral therapeutics. Antiviral human monoclonal (mAbs) are promising drug candidates to prevent or treat severe viral diseases, but the long timelines needed for discovery limits their rapid deployment and use. Here, we report the development of an integrated sequence of technologies incorporating advances in single-cell mRNA sequence analysis, bioinformatics, synthetic biology, and high-throughput functional analysis that allowed us to discover highly potent antiviral human mAbs and validate their activity in vivo at an unprecedented scale, speed, and efficiency. In a 78-day study, modeling deployment of a rapid response platform to an outbreak, we isolated >100 individual Zika virus (ZIKV) specific human mAbs, assessed their function, identified 29 broadly-neutralizing mAbs, and verified therapeutic potency of lead candidates with antibody-encoding mRNA formulation and/or IgG protein delivery in mice and nonhuman primates. Our work provides a roadmap for the rapid antibody discovery programs against viral pathogens of global concern.

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Gilchuk, P., Bombardi, R. G., Erasmus, J. H., Tan, Q., Nargi, R. S., Soto, C., Abbink, P., Suscovich, T. J., Dunellin, L. A., Khandhar, A., Archer, J., Liang, J., Fouch, M. E., Davidson, E., Doranz, B., Jones, T., Larson, E., Ertel, S., Granger, B., Fuerte-Stone, J., Roy, V., Broge, T., Linnekin, T. C., Linde, C. H., Gorman, M. J., Nkolola, J., Alter, G., Reed, S. G., Barouch, D. H., Diamond, M. S., Crowe, J. E., Van Hoeven, N., Thackray, L., Carnahan, R. H.. 2020-05-14. Integrated technology platform for accelerated discovery of antiviral antibody therapeutics. https://doi.org/10.1101/2020.05.12.090944

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