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Cancer Lett. 2015 Feb 1;357(1):364-373. doi: 10.1016/j.canlet.2014.11.054. Epub 2014 Nov 27.

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

Author information

1
Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, Heidelberg 69120, Germany.
2
Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, Heidelberg 69120, Germany; Immunotherapy Program, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
3
Institute of Anatomy and Cell Biology, Heidelberg University, Im Neuenheimer Feld 307, Heidelberg 69120, Germany.
4
Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, Halle 06120, Germany.
5
Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany; Molecular Cell Biology Group, ENT Department, University of Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany.
6
Molecular Cell Biology Group, ENT Department, University of Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany.
7
Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany.
8
Department of Radiation Oncology, University of Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany; Heidelberg Ion Therapy Center (HIT), Im Neuenheimer Feld 450, Heidelberg 69120, Germany.
9
Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, Stuttgart 70569, Germany.
10
Department of Nuclear Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany.
11
Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, Heidelberg 69120, Germany. Electronic address: juergen.krauss@nct-heidelberg.de.

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.

KEYWORDS:

Diabody; EGFR; Onconase; Ranpirnase; immunoRNase

PMID:
25434798
DOI:
10.1016/j.canlet.2014.11.054
[Indexed for MEDLINE]

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