Molecular determinants of cross-reactivity and potency by VH3-33 antibodies against the Plasmodium falciparum circumsporozoite protein

Thai, Elaine; Murugan, Rajagopal; Binter, Špela; Burn Aschner, Clare; Prieto, Katherine; Kassardjian, Audrey; Obraztsova, Anna S.; Kang, Ryu Won; Flores-Garcia, Yevel; Mathis-Torres, Shamika; Li, Kan; Horn, Gillian Q.; Huntwork, Richard H. C.; Bolscher, Judith M.; de Bruijni, Marloes H. C.; Sauerwein, Robert; Dennison, S. Moses; Tomaras, Georgia D.; Zavala, Fidel; Kellam, Paul; Wardemann, Hedda; Julien, Jean-Philippe

doi:10.1016/j.celrep.2023.113330

Molecular determinants of cross-reactivity and potency by VH3-33 antibodies against the Plasmodium falciparum circumsporozoite protein

Journal Article · Sat Oct 28 00:00:00 EDT 2023 · Cell Reports

DOI:https://doi.org/10.1016/j.celrep.2023.113330· OSTI ID:2470070

Thai, Elaine ^[1]; Murugan, Rajagopal ^[2]; Binter, Špela ^[3]; Burn Aschner, Clare ^[4]; Prieto, Katherine ^[4]; Kassardjian, Audrey ^[1]; Obraztsova, Anna S. ^[5]; Kang, Ryu Won ^[1]; Flores-Garcia, Yevel ^[6]; Mathis-Torres, Shamika ^[6]; Li, Kan ^[7]; Horn, Gillian Q. ^[7]; Huntwork, Richard H. C. ^[7]; Bolscher, Judith M. ^[8]; de Bruijni, Marloes H. C. ^[8]; Sauerwein, Robert ^[8]; Dennison, S. Moses ^[7]; Tomaras, Georgia D. ^[7]; Zavala, Fidel ^[6]; Kellam, Paul ^[9] more »

The Hospital for Sick Children Research Inst., Toronto, ON (Canada); Univ. of Toronto, ON (Canada)
German Cancer Research Center (DKFZ), Heidelberg (Germany)
Kymab Ltd./Sanofi, Cambridge (United Kingdom); RQ Biotechnology Ltd., London (United Kingdom)
The Hospital for Sick Children Research Inst., Toronto, ON (Canada)
German Cancer Research Center (DKFZ), Heidelberg (Germany); Heidelberg Univ. (Germany)
Johns Hopkins Univ., Baltimore, MD (United States)
Duke Univ., Durham, NC (United States)
TropIQ Health Sciences, Nijmegen (Netherlands)
Kymab Ltd./Sanofi, Cambridge (United Kingdom); RQ Biotechnology Ltd., London (United Kingdom); Imperial College, London (United Kingdom)

IGHV3-33-encoded antibodies are prevalent in the human humoral response against the Plasmodium falciparum circumsporozoite protein (PfCSP). Among VH3-33 antibodies, cross-reactivity between PfCSP major repeat (NANP), minor (NVDP), and junctional (NPDP) motifs is associated with high affinity and potent parasite inhibition. However, the molecular basis of antibody cross-reactivity and the relationship with efficacy remain unresolved. Here, we perform an extensive structure-function characterization of 12 VH3-33 anti-PfCSP monoclonal antibodies (mAbs) with varying degrees of cross-reactivity induced by immunization of mice expressing a human immunoglobulin gene repertoire. We identify residues in the antibody paratope that mediate cross-reactive binding and delineate four distinct epitope conformations induced by antibody binding, with one consistently associated with high protective efficacy and another that confers comparably potent inhibition of parasite liver invasion. Our data show a link between molecular features of cross-reactive VH3-33 mAb binding to PfCSP and mAb potency, relevant for the development of antibody-based interventions against malaria.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357; SC0012704

OSTI ID:: 2470070

Journal Information:: Cell Reports, Journal Name: Cell Reports Journal Issue: 11 Vol. 42; ISSN 2211-1247

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
CSP
Fab structure
Plasmodium falciparum
VH3-33 antibodies
antibody
circumsporozoite protein
cross-reactivity
malaria
repeat motifs

Molecular determinants of cross-reactivity and potency by VH3-33 antibodies against the Plasmodium falciparum circumsporozoite protein

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References (68)

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