Highly protective antimalarial antibodies via precision library generation and yeast display screening.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
01 08 2022
01 08 2022
Historique:
received:
21
02
2022
revised:
19
05
2022
accepted:
23
05
2022
entrez:
23
6
2022
pubmed:
24
6
2022
medline:
28
6
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35736810
pii: 213306
doi: 10.1084/jem.20220323
pmc: PMC9242090
pii:
doi:
Substances chimiques
Antibodies, Protozoan
0
Antimalarials
0
Malaria Vaccines
0
Protozoan Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : R01 AI141452
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI143407
Pays : United States
Organisme : Simons Foundation
ID : SF349247
Organisme : National Resource for Automated Molecular Microscopy
Organisme : New York Structural Biology Center
Organisme : NIH HHS
ID : DP5OD023118
Pays : United States
Organisme : Departments of Chemical Engineering and Pharmaceutical Chemistry
Organisme : National Institute of Allergy and Infectious Diseases
Organisme : New York State Foundation for Science, Technology and Innovation
Organisme : Simons Electron Microscopy Center
Organisme : University of Kansas
Informations de copyright
© 2022 Banach et al.
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