The light chain of the L9 antibody is critical for binding circumsporozoite protein minor repeats and preventing malaria
| Autor: | Lawrence T. Wang, Nicholas K. Hurlburt, Arne Schön, Barbara J. Flynn, Yevel Flores-Garcia, Lais S. Pereira, Patience K. Kiyuka, Marlon Dillon, Brian Bonilla, Fidel Zavala, Azza H. Idris, Joseph R. Francica, Marie Pancera, Robert A. Seder |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Models Molecular Repetitive Sequences Amino Acid Adolescent Amino Acid Motifs Plasmodium falciparum Protozoan Proteins Antibodies Monoclonal Middle Aged General Biochemistry Genetics and Molecular Biology Article Mice Inbred C57BL Immunoglobulin Fab Fragments Young Adult Culicidae Neutralization Tests Animals Humans Cell Lineage Female Immunoglobulin Light Chains Amino Acid Sequence Malaria Falciparum Peptides Protein Binding |
| Zdroj: | Cell Rep |
| ISSN: | 2211-1247 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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