P. Gilchuk, Robin Bombardi, Jesse H. Erasmus, Qing Tan, Rachel S. Nargi, C. Soto, P. Abbink, T. Suscovich, Lorellin A. Durnell, A. Khandhar, Jacob Archer, J. Liang, Mallorie E. Fouch, E. Davidson, B. Doranz, Taylor Jones, Elise Larson, S. Ertel, B. Granger, Jasmine Fuerte-Stone, Vicky Roy, Thomas A. Broge, Thomas C. Linnekin, Caitlyn H. Linde, M. Gorman, J. Nkolola, G. Alter, S. Reed, D. Barouch, M. Diamond, J. Crowe, N. Van Hoeven, L. Thackray, R. Carnahan
Nature Biomedical Engineering, 2020
The emergence and re-emergence of highly virulent viral pathogens with the potential to cause a pandemic creates an urgent need for the accelerated discovery of antiviral therapeutics. Antiviral human monoclonal antibodies (mAbs) are promising candidates for the prevention and treatment of 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 enables the rapid discovery of highly potent antiviral human mAbs, the activity of which we validated in vivo. In a 78-d study modelling the deployment of a rapid response to an outbreak, we isolated more than 100 human mAbs that are specific to Zika virus, assessed their function, identified that 29 of these mAbs have broadly neutralizing activity, and verified the therapeutic potency of the lead candidates in mice and non-human primate models of infection through the delivery of an antibody-encoding mRNA formulation and of the respective IgG antibody. The pipeline provides a roadmap for rapid antibody-discovery programmes against viral pathogens of global concern. An antibody-discovery pipeline integrating single-cell mRNA-sequence analysis, bioinformatics, synthetic biology and high-throughput functional analyses enables the rapid discovery of potent human monoclonal antibodies against viral pathogens.
Cited by 11 publications.
Field of study: Medicine