High-density binding to Plasmodium falciparum circumsporozoite protein repeats by inhibitory antibody elicited in mouse with human immunoglobulin repertoire

Kucharska, Iga; Binter, Špela; Murugan, Rajagopal; Scally, Stephen W.; Ludwig, Julia; Prieto, Katherine; Thai, Elaine; Costa, Giulia; Li, Kan; Horn, Gillian Q.; Flores-Garcia, Yevel; Bosch, Alexandre; Sicard, Taylor; Rubinstein, John L.; Zavala, Fidel; Dennison, S. Moses; Tomaras, Georgia D.; Levashina, Elena A.; Kellam, Paul; Wardemann, Hedda; Julien, Jean-Philippe

doi:10.1371/journal.ppat.1010999

High-density binding to Plasmodium falciparum circumsporozoite protein repeats by inhibitory antibody elicited in mouse with human immunoglobulin repertoire

Journal Article · Mon Nov 28 00:00:00 EST 2022 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1010999· OSTI ID:2470050

Kucharska, Iga ^[1]; Binter, Špela ^[2]; Murugan, Rajagopal ^[3]; Scally, Stephen W. ^[1]; Ludwig, Julia ^[4]; Prieto, Katherine ^[1]; Thai, Elaine ^[5]; Costa, Giulia ^[6]; Li, Kan ^[7]; Horn, Gillian Q. ^[7]; Flores-Garcia, Yevel ^[8]; Bosch, Alexandre ^[1]; Sicard, Taylor ^[5]; Rubinstein, John L. ^[5]; Zavala, Fidel ^[8]; Dennison, S. Moses ^[7]; Tomaras, Georgia D. ^[7]; Levashina, Elena A. ^[6]; Kellam, Paul ^[9]; Wardemann, Hedda ^[4] more »

Hospital for Sick Children Research Institute, Toronto, ON (Canada)
Kymab Ltd. (United Kingdom)
German Cancer Research Institute (DKFZ), Heidelberg (Germany); Leiden Univ. (Netherlands). Medical Center
German Cancer Research Institute (DKFZ), Heidelberg (Germany)
Hospital for Sick Children Research Institute, Toronto, ON (Canada); Univ. of Toronto, ON (Canada)
Max Planck Institute for Infection Biology, Berlin (Germany)
Duke Univ., Durham, NC (United States)
Johns Hopkins Univ., Baltimore, MD (United States)
Kymab Ltd. (United Kingdom); Imperial College, London (United Kingdom)

Antibodies targeting the human malaria parasite Plasmodium falciparum circumsporozoite protein (PfCSP) can prevent infection and disease. PfCSP contains multiple central repeating NANP motifs; some of the most potent anti-infective antibodies against malaria bind to these repeats. Multiple antibodies can bind the repeating epitopes concurrently by engaging into homotypic Fab-Fab interactions, which results in the ordering of the otherwise largely disordered central repeat into a spiral. Here, we characterize IGHV3-33/IGKV1-5-encoded monoclonal antibody (mAb) 850 elicited by immunization of transgenic mice with human immunoglobulin loci. mAb 850 binds repeating NANP motifs with picomolar affinity, potently inhibits Plasmodium falciparum (Pf) in vitro and, when passively administered in a mouse challenge model, reduces liver burden to a similar extent as some of the most potent anti-PfCSP mAbs yet described. Like other IGHV3-33/IGKV1-5-encoded anti-NANP antibodies, mAb 850 primarily utilizes its HCDR3 and germline-encoded aromatic residues to recognize its core NANP motif. Biophysical and cryo-electron microscopy analyses reveal that up to 19 copies of Fab 850 can bind the PfCSP repeat simultaneously, and extensive homotypic interactions are observed between densely-packed PfCSP-bound Fabs to indirectly improve affinity to the antigen. Together, our study expands on the molecular understanding of repeat-induced homotypic interactions in the B cell response against PfCSP for potently protective mAbs against Pf infection.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470050

Journal Information:: PLoS Pathogens, Journal Name: PLoS Pathogens Journal Issue: 11 Vol. 18; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
antibodies
antigens
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health care
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parasitic diseases
sporozoites

High-density binding to Plasmodium falciparum circumsporozoite protein repeats by inhibitory antibody elicited in mouse with human immunoglobulin repertoire

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