Neutralization mechanism of human monoclonal antibodies against type B botulinum neurotoxin.
Clostridium botulinum
botulism
human monoclonal antibody
neurotoxin
therapeutics
Journal
Microbiology and immunology
ISSN: 1348-0421
Titre abrégé: Microbiol Immunol
Pays: Australia
ID NLM: 7703966
Informations de publication
Date de publication:
06 Sep 2024
06 Sep 2024
Historique:
revised:
08
07
2024
received:
28
03
2024
accepted:
13
08
2024
medline:
6
9
2024
pubmed:
6
9
2024
entrez:
6
9
2024
Statut:
aheadofprint
Résumé
Botulism is a deadly neuroparalytic condition caused by the botulinum neurotoxin (BoNT) produced by Clostridium botulinum and related species. Toxin-neutralizing antibodies are the most effective treatments for BoNT intoxication. We generated human monoclonal antibodies neutralizing type B botulinum neurotoxin (BoNT/B), designated M2 and M4. The combination of these antibodies exhibited a strong neutralizing effect against BoNT/B toxicity. In this study, we analyzed the mechanisms of action of these antibodies in vitro. M4 binds to the C-terminus of the heavy chain (the receptor-binding domain) and inhibits BoNT/B binding to neuronal PC12 cells. Although M2 recognized the light (L) chain (the metalloprotease domain), it did not inhibit substrate (VAMP2) cleavage in the cleavage assay. M2 increased the surface localization of BoNT/B in PC12 cells at a later time point, suggesting that M2 inhibits the translocation of the L chain from synaptic vesicles to the cytosol. These results indicate that M2 and M4 inhibit the different processes of BoNT/B individually and that multistep inhibition is important for the synergistic effect of the combination of monoclonal antibodies. Our findings may facilitate the development of effective therapeutic antibodies against BoNTs.
Identifiants
pubmed: 39239735
doi: 10.1111/1348-0421.13171
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Japan Society for the Promotion of Science
Organisme : Japan Agency for Medical Research and Development
Informations de copyright
© 2024 The Societies and John Wiley & Sons Australia, Ltd.
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