National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
United States
Citation
Journal: J Exp Med / Year: 2022 Title: Highly protective antimalarial antibodies via precision library generation and yeast display screening. Authors: Bailey B Banach / Prabhanshu Tripathi / Lais Da Silva Pereira / Jason Gorman / Thuy Duong Nguyen / Marlon Dillon / Ahmed S Fahad / Patience K Kiyuka / Bharat Madan / Jacy R Wolfe / Brian ...Authors: Bailey B Banach / Prabhanshu Tripathi / Lais Da Silva Pereira / Jason Gorman / Thuy Duong Nguyen / Marlon Dillon / Ahmed S Fahad / Patience K Kiyuka / Bharat Madan / Jacy R Wolfe / Brian Bonilla / Barbara Flynn / Joseph R Francica / Nicholas K Hurlburt / Neville K Kisalu / Tracy Liu / Li Ou / Reda Rawi / Arne Schön / Chen-Hsiang Shen / I-Ting Teng / Baoshan Zhang / Marie Pancera / Azza H Idris / Robert A Seder / Peter D Kwong / Brandon J DeKosky / 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. ...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.
Mass: 1562.553 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
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Antibody , 2 types, 2 molecules HL
#1: Antibody
CIS43_Var2FabHeavychain
Mass: 24281.320 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody
CIS43_Var2FabLightchain
Mass: 24172.723 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
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