An EGF receptor targeting Ranpirnase-diabody fusion protein mediates potent antitumour activity in vitro and in vivo.

Abstract

Cytotoxic ribonucleases such as the leopard frog derivative Ranpirnase (Onconase(®)) have emerged as a valuable new class of cancer therapeutics. Clinical trials employing single agent Ranpirnase in cancer patients have demonstrated significant clinical activity and surprisingly low immunogenicity. However, dose-limiting toxicity due to unspecific uptake of the RNase into non-cancerous cells is reached at relatively low concentrations of > 1 mg/m(2). We have in the present study generated a dimeric anti-EGFR Ranpirnase-diabody fusion protein capable to deliver two Ranpirnase moieties per molecule to EGFR-positive tumour cells. We show that this compound mediated far superior efficacy for killing EGFR-positive tumour cells than a monomeric counterpart. Most importantly, cell killing was restricted to EGFR-positive target cells and no dose-limiting toxicity of Ranpirnase-diabody was observed in mice. These data indicate that by targeted delivery of Ranpirnase non-selective toxicity can be abolished and suggests Ranpirnase-diabody as a promising new drug for therapeutic interventions in EGFR-positive cancers.

• Authors: Stefan Kiesgen, Michaela A E Arndt, Christoph Körber, Ulrich Arnold, Tobias Weber, Niels Halama, Armin Keller, Benedikt Bötticher, Anne Schlegelmilch, Nora Liebers, Martin Cremer, Christel Herold-Mende, Gerhard Dyckhoff, Philippe A Federspil, Alexandra D Jensen, Dirk Jäger, Roland E Kontermann, Walter Mier, Jürgen Krauss
• Journal: Cancer letters (Cancer Lett) Vol. 357 Issue 1 Pg. 364-373 (Feb 01 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25434798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Recombinant Fusion Proteins
• ErbB Receptors
• Ribonucleases
• ranpirnase

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Squamous Cell (drug therapy, enzymology)
• Cell Line, Tumor
• Disease-Free Survival
• ErbB Receptors (metabolism)
• Female
• Head and Neck Neoplasms (drug therapy, enzymology)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Recombinant Fusion Proteins (pharmacology)
• Ribonucleases (genetics, pharmacology)
• Squamous Cell Carcinoma of Head and Neck
• Xenograft Model Antitumor Assays