biostudies-literatureUnknownChun JNIAID NIH HHSNIH HHSThe monoclonal antibody L9 mediates high-level protection against malaria in children for up to 6 months in Africa. L9 preferentially binds with high affinity to the NVDP minor repeat on the P. falciparum circumsporozoite protein (PfCSP). Here, we sought to improve the affinity of L9 to enhance protection against rare strains with two spatially separated minor repeats or a single minor repeat. Site saturation mutagenesis and yeast display-screening identified a panel of affinity-improved variants. In vivo challenge showed one variant, L9_yd19, to be modestly more potent against a chimeric transgenic Plasmodium encoding PfCSP with two widely spaced minor repeats from a Kenyan parasite strain, with no loss in potency against the benchmark 3D7 strain with its standard combioRxiv : the preprint server for biology2025.09.30.679367https://www.ebi.ac.uk/biostudies/studies/S-EPMC12621802biostudies-literatureAnti-Malaria Antibody Engineering Broadens Recognition Motifs and Reveals New Homotypic Interactions that Enhance Protective Breadth.PMC12621802R01 AI192975DP5 OD023118R01 AI181684Hurlburt NKMiura KLee GATeng ITLei HZavala FTripathi PFahad ASZhou TFlores-Garcia YDeKosky BJMadan BChun JPancera MIdris AHSeder RAFlynn BJKwong PDfalseAnti-Malaria Antibody Engineering Broadens Recognition Motifs and Reveals New Homotypic Interactions that Enhance Protective Breadth.The monoclonal antibody L9 mediates high-level protection against malaria in children for up to 6 months in Africa. L9 preferentially binds with high affinity to the NVDP minor repeat on the P. falciparum circumsporozoite protein (PfCSP). Here, we sought to improve the affinity of L9 to enhance protection against rare strains with two spatially separated minor repeats or a single minor repeat. Site saturation mutagenesis and yeast display-screening identified a panel of affinity-improved variants. In vivo challenge showed one variant, L9_yd19, to be modestly more potent against a chimeric transgenic Plasmodium encoding PfCSP with two widely spaced minor repeats from a Kenyan parasite strain, with no loss in potency against the benchmark 3D7 strain with its standard com2025-01-01T00:00:00Z2025 Oct2026-06-11T03:10:43.32Z2026-06-11T03:07:52.21ZS-EPMC126218024125652810.1101/2025.09.30.679367