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Potent and specific fusion toxins consisting of a HER2-binding, ABD-derived affinity protein, fused to truncated versions of Pseudomonas exotoxin A
KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
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2019 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 55, no 1, p. 309-319Article in journal (Refereed) Published
Abstract [en]

Fusion toxins consisting of an affinity protein fused to toxic polypeptides derived from Pseudomonas exotoxin A (ETA) are promising agents for targeted cancer therapy. In this study, we examined whether fusion toxins consisting of an albumin binding domain-derived affinity protein (ADAPT) interacting with human epidermal growth factor receptor 2 (HER2), coupled to the ETA-derived polypeptides PE38X8 or PE25, with or without an albumin binding domain (ABD) for half-life extension, can be used for specific killing of HER2-expressing cells. The fusion toxins could easily be expressed in a soluble form in Escherichia coli and purified to homogeneity. All constructs had strong affinity for HER2 (K-D 10 to 26 nM) and no tendency for aggregation could be detected. The fusion toxins including the ABD showed strong interaction with human and mouse serum albumin [equilibrium dissociation constant (K-D) 1 to 3 nM and 2 to 10 nM, respectively]. The in vitro investigation of the cytotoxic potential revealed IC50-values in the picomolar range for cells expressing high levels of HER2. The specificity was also demonstrated, by showing that free HER2 receptors on the target cells are required for fusion toxin activity. In mice, the fusion toxins containing the ABD exhibited an appreciably longer time in circulation. The uptake was highest in liver and kidney. Fusion with PE25 was associated with the highest hepatic uptake. Collectively, the results suggest that fusion toxins consisting of ADAPTs and ETA-derivatives are promising agents for targeted cancer therapy.

Place, publisher, year, edition, pages
2019. Vol. 55, no 1, p. 309-319
Keywords [en]
exotoxin A, Pseudomonas, ABD-derived affinity protein, half-life extension, cancer, human epidermal growth factor receptor 2
National Category
Biochemistry and Molecular Biology Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-392048DOI: 10.3892/ijo.2019.4814ISI: 000476557600026PubMedID: 31180549OAI: oai:DiVA.org:uu-392048DiVA, id: diva2:1349963
Funder
Vinnova, 2016-04060Swedish Cancer Society, CAN 2015/746Available from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-09-10Bibliographically approved

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Altai, MohamedGarousi, JavadOrlova, AnnaTolmachev, Vladimir

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