The light chain of the L9 antibody is critical for binding circumsporozoite protein minor repeats and preventing malaria

Cell Rep. 2022 Feb 15;38(7):110367. doi: 10.1016/j.celrep.2022.110367.

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.

Keywords: Malaria; NVDP minor repeats; Plasmodium falciparum circumsporozoite protein; monoclonal antibodies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / isolation & purification
  • Antibodies, Monoclonal / metabolism*
  • Cell Lineage
  • Culicidae / parasitology
  • Female
  • Humans
  • Immunoglobulin Fab Fragments / metabolism
  • Immunoglobulin Light Chains / metabolism*
  • Malaria, Falciparum / immunology*
  • Malaria, Falciparum / prevention & control*
  • Mice, Inbred C57BL
  • Middle Aged
  • Models, Molecular
  • Neutralization Tests
  • Peptides / chemistry
  • Peptides / metabolism
  • Plasmodium falciparum / immunology
  • Protein Binding
  • Protozoan Proteins / metabolism*
  • Repetitive Sequences, Amino Acid*
  • Young Adult

Substances

  • Antibodies, Monoclonal
  • Immunoglobulin Fab Fragments
  • Immunoglobulin Light Chains
  • Peptides
  • Protozoan Proteins
  • circumsporozoite protein, Protozoan