101. The light chain of the L9 antibody is critical for binding circumsporozoite protein minor repeats and preventing malaria.
- Author
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Wang LT, Hurlburt NK, Schön A, Flynn BJ, Flores-Garcia Y, Pereira LS, Kiyuka PK, Dillon M, Bonilla B, Zavala F, Idris AH, Francica JR, Pancera M, and Seder RA
- Subjects
- Adolescent, Adult, Amino Acid Motifs, Amino Acid Sequence, Animals, Antibodies, Monoclonal isolation & purification, Cell Lineage, Culicidae parasitology, Female, Humans, Immunoglobulin Fab Fragments metabolism, Mice, Inbred C57BL, Middle Aged, Models, Molecular, Neutralization Tests, Peptides chemistry, Peptides metabolism, Plasmodium falciparum immunology, Protein Binding, Young Adult, Mice, Antibodies, Monoclonal metabolism, Immunoglobulin Light Chains metabolism, Malaria, Falciparum immunology, Malaria, Falciparum prevention & control, Protozoan Proteins metabolism, Repetitive Sequences, Amino Acid
- Abstract
L9 is a potent human monoclonal antibody (mAb) that preferentially binds two adjacent NVDP minor repeats and cross-reacts with NANP major repeats of the Plasmodium falciparum circumsporozoite protein (PfCSP) on malaria-infective sporozoites. Understanding this mAb's ontogeny and mechanisms of binding PfCSP will facilitate vaccine development. Here, we isolate mAbs clonally related to L9 and show that this B cell lineage has baseline NVDP affinity and evolves to acquire NANP reactivity. Pairing the L9 kappa light chain (L9κ) with clonally related heavy chains results in chimeric mAbs that cross-link two NVDPs, cross-react with NANP, and more potently neutralize sporozoites in vivo compared with their original light chain. Structural analyses reveal that the chimeric mAbs bound minor repeats in a type-1 β-turn seen in other repeat-specific antibodies. These data highlight the importance of L9κ in binding NVDP on PfCSP to neutralize sporozoites and suggest that PfCSP-based immunogens might be improved by presenting ≥2 NVDPs., Competing Interests: Declaration of interests R.A.S., J.R.F., and L.T.W. have submitted US Provisional Patent Application No. 62/842590, filed May 3, 2019, describing mAb L9. All other authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)
- Published
- 2022
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