In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 18, No. 11 ( 2022-11-28), p. e1010999-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1010999
DOI:
10.1371/journal.ppat.1010999.g001
DOI:
10.1371/journal.ppat.1010999.g002
DOI:
10.1371/journal.ppat.1010999.g003
DOI:
10.1371/journal.ppat.1010999.g004
DOI:
10.1371/journal.ppat.1010999.g005
DOI:
10.1371/journal.ppat.1010999.g006
DOI:
10.1371/journal.ppat.1010999.g007
DOI:
10.1371/journal.ppat.1010999.t001
DOI:
10.1371/journal.ppat.1010999.t002
DOI:
10.1371/journal.ppat.1010999.s001
DOI:
10.1371/journal.ppat.1010999.s002
DOI:
10.1371/journal.ppat.1010999.s003
DOI:
10.1371/journal.ppat.1010999.s004
DOI:
10.1371/journal.ppat.1010999.s005
DOI:
10.1371/journal.ppat.1010999.s006
DOI:
10.1371/journal.ppat.1010999.s007
DOI:
10.1371/journal.ppat.1010999.s008
DOI:
10.1371/journal.ppat.1010999.s009
DOI:
10.1371/journal.ppat.1010999.s010
DOI:
10.1371/journal.ppat.1010999.s011
DOI:
10.1371/journal.ppat.1010999.s012
DOI:
10.1371/journal.ppat.1010999.s013
DOI:
10.1371/journal.ppat.1010999.s014
DOI:
10.1371/journal.ppat.1010999.s015
DOI:
10.1371/journal.ppat.1010999.s016
DOI:
10.1371/journal.ppat.1010999.s017
DOI:
10.1371/journal.ppat.1010999.s018
DOI:
10.1371/journal.ppat.1010999.s019
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2205412-1
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