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• W2113873088 abstract "Designed ankyrin repeat proteins (DARPins) hold great promise as a new class of binding molecules to overcome the limitations of antibodies for biomedical applications. Here, we assessed the potential of an epithelial cell adhesion molecule (EpCAM)-specific DARPin (Ec4) for tumor targeting as a fusion toxin with Pseudomonas aeruginosa exotoxin A.DARPin Ec4 was genetically fused to a truncated form of Pseudomonas aeruginosa exotoxin A (ETA″) and expressed in Escherichia coli. The cytotoxicity of Ec4-ETA″ was measured against tumor cell lines of various histotypes in vitro. Tumor localization and antitumor activity were determined in mice bearing 2 different EpCAM-positive tumor xenografts.Ec4-ETA″ expressed very well in soluble form in the cytoplasm of E. coli and yielded up to 40 mg after purification per liter of culture. The protein was monomeric and the disulfides of ETA″ formed spontaneously. Ec4-ETA″ bound to EpCAM with low nanomolar affinity, similar to free Ec4. Furthermore, it was highly cytotoxic against various EpCAM-positive tumor cell lines in vitro with IC(50) values less than 0.005 pmol/L. This effect was competed by free Ec4, but not by unspecific DARPins. Upon systemic administration in athymic mice, Ec4-ETA″ efficiently localized to EpCAM-positive tumors to achieve maximum accumulation 48 to 72 hours after injection, whereas an irrelevant control fusion toxin did not accumulate. Tumor targeting with Ec4-ETA″ resulted in a strong antitumor response including complete regressions in some animals.Our data show for the first time the potential of DARPins for the generation of protein therapeutics for tumor targeting, and that Ec4-ETA″ deserves attention for clinical development." @default.
• W2113873088 created "2016-06-24" @default.
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• W2113873088 date "2011-01-01" @default.
• W2113873088 modified "2023-10-14" @default.
• W2113873088 title "A Novel Fusion Toxin Derived from an EpCAM-Specific Designed Ankyrin Repeat Protein Has Potent Antitumor Activity" @default.
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• W2113873088 doi "https://doi.org/10.1158/1078-0432.ccr-10-1303" @default.
• W2113873088 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/21075824" @default.
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