An enhanced intracellular delivery platform based on a distant diphtheria toxin homolog that evades pre-existing antitoxin antibodies.
Antidrug Antibodies
Chelona Toxin
Diphtheria Toxin
Immunotoxin
Intracellular Delivery
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: Germany
ID NLM: 101487380
Informations de publication
Date de publication:
19 Aug 2024
19 Aug 2024
Historique:
received:
02
05
2024
accepted:
18
07
2024
revised:
15
07
2024
medline:
20
8
2024
pubmed:
20
8
2024
entrez:
19
8
2024
Statut:
aheadofprint
Résumé
Targeted intracellular delivery of therapeutic proteins remains a significant unmet challenge in biotechnology. A promising approach is to leverage the intrinsic capabilities of bacterial toxins like diphtheria toxin (DT) to deliver a potent cytotoxic enzyme into cells with an associated membrane translocation moiety. Despite showing promising clinical efficacy, widespread deployment of DT-based therapeutics is complicated by the prevalence of pre-existing antibodies in the general population arising from childhood DT toxoid vaccinations, which impact the exposure, efficacy, and safety of these potent molecules. Here, we describe the discovery and characterization of a distant DT homolog from the ancient reptile pathogen Austwickia chelonae that we have dubbed chelona toxin (ACT). We show that ACT is comparable to DT structure and function in all respects except that it is not recognized by pre-existing anti-DT antibodies circulating in human sera. Furthermore, we demonstrate that ACT delivers heterologous therapeutic cargos into target cells more efficiently than DT. Our findings highlight ACT as a promising new chassis for building next-generation immunotoxins and targeted delivery platforms with improved pharmacokinetic and pharmacodynamic properties.
Identifiants
pubmed: 39160301
doi: 10.1038/s44321-024-00116-z
pii: 10.1038/s44321-024-00116-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Canadian Government | Canadian Institutes of Health Research (CIHR)
ID : 452580
Organisme : Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)
ID : RGPIN-2023-05371
Informations de copyright
© 2024. The Author(s).
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