Integrated pipeline for the accelerated discovery of antiviral antibody therapeutics

Gilchuk, Pavlo; Bombardi, Robin G.; Erasmus, Jesse H.; Tan, Qing; Nargi, Rachel; Soto, Cinque; Abbink, Peter; Suscovich, Todd J; Durnell, Lorellin A.; Khandhar, Amit; Archer, Jacob; Liang, Jenny; Fouch, Mallorie E.; Davidson, Edgar; Doranz, Benjamin J.; Jones, Taylor; Larson, Elise; Ertel, Stacey; Granger, Brian; Fuerte-Stone, Jasmine; Roy, Vicky; Broge, Thomas; Linnekin, Thomas C.; Linde, Caitlyn H.; Gorman, Matthew J.; Nkolola, Joseph; Alter, Galit; Reed, Steven G.; Barouch, Dan H.; Diamond, Michael S.; Crowe, James E.; Van Hoeven, Neal; Thackray, Larissa; Carnahan, Robert

The emergence and re-emergence of highly virulent viral pathogens with pandemic potential creates an urgent need for the accelerated discovery of antiviral therapeutics. Antiviral human monoclonal antibodies (mAbs) are promising candidates to prevent or treat severe viral diseases, but their long development timeframes limit their rapid deployment and use. Here, we report the development of an integrated sequence of technologies, including single-cell mRNA sequence analysis, bioinformatics, synthetic biology and high-throughput functional analysis, that enabled the rapid discovery of highly potent antiviral human mAbs, whose activity we validated in vivo. In a 78-day study modelling the deployment of a rapid response to an outbreak, we isolated more than 100 human mAbs specific for the Zika virus, assessed their function, identified 29 of those as having broadly neutralizing activity, and verified the therapeutic potency of the lead candidates in mice and non-human primate models of infection via the delivery of an antibody-encoding mRNA formulation and of the respective IgG antibody. The pipeline provides a roadmap for rapid antibody-discovery programs against viral pathogens of global concern.