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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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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. |
format | Online Article Text |
id | pubmed-9762590 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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