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

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 antibodie...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9762590/
https://www.ncbi.nlm.nih.gov/pubmed/36441829
http://dx.doi.org/10.1371/journal.ppat.1010999
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author 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
author_facet 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
author_sort Kucharska, Iga
collection PubMed
description 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.
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spelling pubmed-97625902022-12-20 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 PLoS Pathog Research Article 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. Public Library of Science 2022-11-28 /pmc/articles/PMC9762590/ /pubmed/36441829 http://dx.doi.org/10.1371/journal.ppat.1010999 Text en © 2022 Kucharska et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
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
High-density binding to Plasmodium falciparum circumsporozoite protein repeats by inhibitory antibody elicited in mouse with human immunoglobulin repertoire
title High-density binding to Plasmodium falciparum circumsporozoite protein repeats by inhibitory antibody elicited in mouse with human immunoglobulin repertoire
title_full High-density binding to Plasmodium falciparum circumsporozoite protein repeats by inhibitory antibody elicited in mouse with human immunoglobulin repertoire
title_fullStr High-density binding to Plasmodium falciparum circumsporozoite protein repeats by inhibitory antibody elicited in mouse with human immunoglobulin repertoire
title_full_unstemmed High-density binding to Plasmodium falciparum circumsporozoite protein repeats by inhibitory antibody elicited in mouse with human immunoglobulin repertoire
title_short High-density binding to Plasmodium falciparum circumsporozoite protein repeats by inhibitory antibody elicited in mouse with human immunoglobulin repertoire
title_sort high-density binding to plasmodium falciparum circumsporozoite protein repeats by inhibitory antibody elicited in mouse with human immunoglobulin repertoire
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9762590/
https://www.ncbi.nlm.nih.gov/pubmed/36441829
http://dx.doi.org/10.1371/journal.ppat.1010999
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