A fusogenic dengue virus-derived peptide enhances antitumor efficacy of an antibody-ribonuclease fusion protein targeting the EGF receptor.
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.
['Kiesgen|Stefan|S|', 'Liebers|Nora|N|', 'Cremer|Martin|M|', 'Arnold|Ulrich|U|', 'Weber|Tobias|T|', 'Keller|Armin|A|', 'Herold-Mende|Christel|C|', 'Dyckhoff|Gerhard|G|', 'Jäger|Dirk|D|', 'Kontermann|Roland E|RE|', 'Arndt|Michaela A E|MA|', 'Krauss|Jürgen|J|']
D000970:Antineoplastic Agents D045744:Cell Line, Tumor D002470:Cell Survival D003716:Dengue Virus D066246:ErbB Receptors D006801:Humans D011993:Recombinant Fusion Proteins D012260:Ribonucleases D057127:Single-Chain Antibodies
EGFR Ranpirnase dengue virus endosomal escape immunoRNase