Journal Article

A fusogenic dengue virus-derived peptide enhances antitumor efficacy of an antibody–ribonuclease fusion protein targeting the EGF receptor

Stefan Kiesgen, Nora Liebers, Martin Cremer, Ulrich Arnold, Tobias Weber, Armin Keller, Christel Herold-Mende, Gerhard Dyckhoff, Dirk Jäger, Roland E. Kontermann, Michaela A. E. Arndt and Jürgen Krauss

in Protein Engineering, Design and Selection

Volume 27, issue 10, pages 331-338
Published in print October 2014 | ISSN: 1741-0126
Published online October 2014 | e-ISSN: 1741-0134 | DOI: https://dx.doi.org/10.1093/protein/gzu040
A fusogenic dengue virus-derived peptide enhances antitumor efficacy of an antibody–ribonuclease fusion protein targeting the EGF receptor

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Due to its frequent overexpression in a variety of solid tumors the epidermal growth factor receptor (EGFR) is a well-established target for therapeutic interventions in epithelial cancers. In order to target EGFR in head and neck cancer, we have generated a ribonuclease (RNase) fusion protein comprising a humanized anti-EGFR antibody single-chain Fv fragment (scFv) and Ranpirnase, an RNase from Rana pipiens. Fusion of Ranpirnase to the N-terminus of the scFv via a flexible glycine-serine linker (G4S)3 resulted in very poor cytotoxicity of the fusion protein. As endosomal accumulation and lysosomal degradation have been reported to diminish the antitumor efficacy of ribonuclease or toxin-based immunoagents, we explored a fusion peptide from dengue virus that has been reported to be involved in the endosomal escape of the virus. This peptide was introduced as a linker between Ranpirnase and the scFv moiety. The modified immunoRNase exhibited exceptionally high cytotoxicity toward EGFR-expressing head and neck cell lines without affecting specificity. These results indicate that endosomal entrapment needs to be considered for Ranpirnase-based immunoagents and might be overcome by the use of tailored transduction domains from viral proteins.

Keywords: dengue virus; EGFR; endosomal escape; immunoRNase; Ranpirnase

Journal Article.  4025 words.  Illustrated.

Subjects: Proteins

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