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

Authors
  • Kiesgen, Stefan
  • Arndt, Michaela A E
  • Körber, Christoph
  • Arnold, Ulrich
  • Weber, Tobias
  • Halama, Niels
  • Keller, Armin
  • Bötticher, Benedikt
  • Schlegelmilch, Anne
  • Liebers, Nora
  • Cremer, Martin
  • Herold-Mende, Christel
  • Dyckhoff, Gerhard
  • Federspil, Philippe A
  • Jensen, Alexandra D
  • Jäger, Dirk
  • Kontermann, Roland E
  • Mier, Walter
  • Krauss, Jürgen
Type
Published Article
Journal
Cancer Letters
Publisher
Elsevier
Publication Date
Feb 01, 2015
Volume
357
Issue
1
Pages
364–373
Identifiers
DOI: 10.1016/j.canlet.2014.11.054
PMID: 25434798
Source
Medline
Keywords
License
Unknown

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.

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