An enhanced intracellular delivery platform based on a distant diphtheria toxin homolog that evades pre-existing antitoxin antibodies.

Autor:	Gill SK; Department of Biochemistry, University of Toronto, Toronto, ON, M5S1A8, Canada.; Molecular Medicine Program, The Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, ON, M5G 0A4, Canada., Sugiman-Marangos SN; Molecular Medicine Program, The Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, ON, M5G 0A4, Canada., Beilhartz GL; Molecular Medicine Program, The Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, ON, M5G 0A4, Canada., Mei E; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S1A8, Canada.; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada., Taipale M; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S1A8, Canada.; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada., Melnyk RA; Department of Biochemistry, University of Toronto, Toronto, ON, M5S1A8, Canada. roman.melnyk@sickkids.ca.; Molecular Medicine Program, The Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, ON, M5G 0A4, Canada. roman.melnyk@sickkids.ca.
Jazyk:	angličtina
Zdroj:	EMBO molecular medicine [EMBO Mol Med] 2024 Oct; Vol. 16 (10), pp. 2638-2651. Date of Electronic Publication: 2024 Aug 19.
DOI:	10.1038/s44321-024-00116-z
Abstrakt:	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. (© 2024. The Author(s).)
Databáze:	MEDLINE
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