TY - JOUR
T1 - Integrated pipeline for the accelerated discovery of antiviral antibody therapeutics
AU - Gilchuk, Pavlo
AU - Bombardi, Robin G.
AU - Erasmus, Jesse H.
AU - Tan, Qing
AU - Nargi, Rachel
AU - Soto, Cinque
AU - Abbink, Peter
AU - Suscovich, Todd J.
AU - Durnell, Lorellin A.
AU - Khandhar, Amit
AU - Archer, Jacob
AU - Liang, Jenny
AU - Fouch, Mallorie E.
AU - Davidson, Edgar
AU - Doranz, Benjamin J.
AU - Jones, Taylor
AU - Larson, Elise
AU - Ertel, Stacey
AU - Granger, Brian
AU - Fuerte-Stone, Jasmine
AU - Roy, Vicky
AU - Broge, Thomas
AU - Linnekin, Thomas C.
AU - Linde, Caitlyn H.
AU - Gorman, Matthew J.
AU - Nkolola, Joseph
AU - Alter, Galit
AU - Reed, Steven G.
AU - Barouch, Dan H.
AU - Diamond, Michael S.
AU - Crowe, James E.
AU - Van Hoeven, Neal
AU - Thackray, Larissa B.
AU - Carnahan, Robert H.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85088873601&partnerID=8YFLogxK
U2 - 10.1038/s41551-020-0594-x
DO - 10.1038/s41551-020-0594-x
M3 - Article
C2 - 32747832
AN - SCOPUS:85088873601
SN - 2157-846X
VL - 4
SP - 1030
EP - 1043
JO - Nature Biomedical Engineering
JF - Nature Biomedical Engineering
IS - 11
ER -