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bioRxiv · 10.64898/2026.01.30.702933

Structural basis for conserved and distinct antigen recognition by a lineage of malaria-protective antibodies

Jain, M.·Cannac, F.·Agrawal, S.·Lee, W.-H.·Loeffler, J. R.·Fernandez-Quintero, M. L.·Gonzalez-Paez, G. E.·Moskovitz, R.·Ward, A. B.·Wilson, I. A.
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Abstract

Monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) have demonstrated substantial promise in preventing malaria infection and disease. PfCSP is characterized by a central region composed of repetitive NANP motifs, which serve as major targets for protective antibodies. Several potent mAbs targeting this region exhibit homotypic Fab-Fab interactions, which enhance antigen binding and contribute to their neutralization potency. Among these, mAb 399, encoded by the IGHV3-49/IGKV2D-29 (VH3-49/VK2D-29) germline lineages, forms head-to-head inter-Fab contacts mediated primarily by germline-encoded residues. In this study, we determined high-resolution X-ray crystal and cryo-EM structures of two additional Fabs, derived from the same germline lineages, 7160 and 7118, in complex with PfCSP-derived peptides. Both Fabs bound the NANP6 repeats with high affinity (KD 5-10 nM). Fab 7160 formed similar inter-Fab homotypic interactions to Fab 399 upon binding to an extended repeat peptide (NANP), indicating a conserved mode of recognition. In contrast, Fab 7118, which features a longer CDRH3, does not form homotypic contacts. Instead, Fab 7118 induced a bend in the peptide and adopted a distinct binding mode, which prevents inter-Fab interactions. A cryo-EM structure of Fab 7118 in complex with a recombinant shortened PfCSP construct (rsCSP) further revealed potential disruptions at inter-Fab contact sites. These findings highlight the structural versatility of VH3-49/VK2D-29-derived antibodies and demonstrate that CDR loop variations within a shared antibody lineage can modulate antibody conformation, homotypic Fab-Fab interactions, and epitope engagement. Our study provides mechanistic insights into the diverse strategies by which CSP-specific antibodies can achieve high-avidity binding and protective immunity.

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Jain, M., Cannac, F., Agrawal, S., Lee, W.-H., Loeffler, J. R., Fernandez-Quintero, M. L., Gonzalez-Paez, G. E., Moskovitz, R., Ward, A. B., Wilson, I. A.. 2026-01-31. Structural basis for conserved and distinct antigen recognition by a lineage of malaria-protective antibodies. https://doi.org/10.64898/2026.01.30.702933

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