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Toxins 2016, 8(8), 217; doi:10.3390/toxins8080217

Protection of the Furin Cleavage Site in Low-Toxicity Immunotoxins Based on Pseudomonas Exotoxin A

1
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
2
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
3
Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
4
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA
*
Author to whom correspondence should be addressed.
Academic Editors: David J. Fitzgerald and Tomas Girbes
Received: 5 May 2016 / Revised: 13 June 2016 / Accepted: 29 June 2016 / Published: 25 July 2016
(This article belongs to the Collection Immunotoxins 2016)
View Full-Text   |   Download PDF [1912 KB, uploaded 25 July 2016]   |  

Abstract

Recombinant immunotoxins (RITs) are fusions of an Fv-based targeting moiety and a toxin. Pseudomonas exotoxin A (PE) has been used to make several immunotoxins that have been evaluated in clinical trials. Immunogenicity of the bacterial toxin and off-target toxicity have limited the efficacy of these immunotoxins. To address these issues, we have previously made RITs in which the Fv is connected to domain III (PE24) by a furin cleavage site (FCS), thereby removing unneeded sequences of domain II. However, the PE24 containing RITs do not contain the naturally occurring disulfide bond around the furin cleavage sequence, because it was removed when domain II was deleted. This could potentially allow PE24 containing immunotoxins to be cleaved and inactivated before internalization by cell surface furin or other proteases in the blood stream or tumor microenvironment. Here, we describe five new RITs in which a disulfide bond is engineered to protect the FCS. The most active of these, SS1-Fab-DS3-PE24, shows a longer serum half-life than an RIT without the disulfide bond and has the same anti-tumor activity, despite being less cytotoxic in vitro. These results have significance for the production of de-immunized, low toxicity, PE24-based immunotoxins with a longer serum half-life. View Full-Text
Keywords: recombinant immunotoxin; mesothelin; Pseudomonas exotoxin A; disulfide bond recombinant immunotoxin; mesothelin; Pseudomonas exotoxin A; disulfide bond
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Kaplan, G.; Lee, F.; Onda, M.; Kolyvas, E.; Bhardwaj, G.; Baker, D.; Pastan, I. Protection of the Furin Cleavage Site in Low-Toxicity Immunotoxins Based on Pseudomonas Exotoxin A. Toxins 2016, 8, 217.

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