| Literature DB >> 35736810 |
Bailey B Banach1, Prabhanshu Tripathi2, Lais Da Silva Pereira2, Jason Gorman2, Thuy Duong Nguyen3, Marlon Dillon2, Ahmed S Fahad3, Patience K Kiyuka2, Bharat Madan3, Jacy R Wolfe3, Brian Bonilla2, Barbara Flynn2, Joseph R Francica2, Nicholas K Hurlburt4, Neville K Kisalu2, Tracy Liu2, Li Ou2, Reda Rawi2, Arne Schön5, Chen-Hsiang Shen2, I-Ting Teng2, Baoshan Zhang2, Marie Pancera2,4, Azza H Idris2, Robert A Seder2, Peter D Kwong2, Brandon J DeKosky1,3,6,7,8.
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.Entities:
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Year: 2022 PMID： 35736810 PMCID： PMC9242090 DOI： 10.1084/jem.20220323
Source DB: PubMed Journal: J Exp Med ISSN： 0022-1007 Impact factor: 17.579