Highly protective antimalarial antibodies via precision library generation and yeast display screening
Name
jem_20220323.pdf
Description
Published version
Size
8.49 MB
Format
Adobe PDF
Checksum (MD5)
6526cc445abc2e4e7ededebab5f7b22c
Author(s)
Banach, Bailey B
Tripathi, Prabhanshu
Da Silva Pereira, Lais
Gorman, Jason
Nguyen, Thuy Duong
Dillon, Marlon
Fahad, Ahmed S
Kiyuka, Patience K
Madan, Bharat
Wolfe, Jacy R
Date Issued
2022
Journal
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Citation
Banach, Bailey B, Tripathi, Prabhanshu, Da Silva Pereira, Lais, Gorman, Jason, Nguyen, Thuy Duong et al. 2022. "Highly protective antimalarial antibodies via precision library generation and yeast display screening." The Journal of Experimental Medicine, 219 (8).
Version
Final published version
Abstract
The monoclonal antibody CIS43 targets the Plasmodium falciparum circumsporozoite protein (PfCSP) and prevents malaria infection in humans for up to 9 mo following a single intravenous administration. To enhance the potency and clinical utility of CIS43, we used iterative site-saturation mutagenesis and DNA shuffling to screen precise gene-variant yeast display libraries for improved PfCSP antigen recognition. We identified several mutations that improved recognition, predominately in framework regions, and combined these to produce a panel of antibody variants. The most improved antibody, CIS43_Var10, had three mutations and showed approximately sixfold enhanced protective potency in vivo compared to CIS43. Co-crystal and cryo-electron microscopy structures of CIS43_Var10 with the peptide epitope or with PfCSP, respectively, revealed functional roles for each of these mutations. The unbiased site-directed mutagenesis and screening pipeline described here represent a powerful approach to enhance protective potency and to enable broader clinical use of antimalarial antibodies.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1084/JEM.20220323
