title: 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.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, Heidelberg 69120, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kiesgen
authors.affiliation: 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.
authors.forename: Michaela A E
authors.initials: MAE
authors.lastname: Arndt
authors.affiliation: Institute of Anatomy and Cell Biology, Heidelberg University, Im Neuenheimer Feld 307, Heidelberg 69120, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Körber
authors.affiliation: Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, Halle 06120, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Arnold
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, Heidelberg 69120, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Weber
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, Heidelberg 69120, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Halama
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, Heidelberg 69120, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Keller
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, Heidelberg 69120, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Bötticher
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, Heidelberg 69120, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schlegelmilch
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, Heidelberg 69120, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Liebers
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, Heidelberg 69120, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Cremer
authors.affiliation: 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.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.affiliation: Molecular Cell Biology Group, ENT Department, University of Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dyckhoff
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Federspil
authors.affiliation: 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.
authors.forename: Alexandra D
authors.initials: AD
authors.lastname: Jensen
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, Heidelberg 69120, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, Stuttgart 70569, Germany.
authors.forename: Roland E
authors.initials: RE
authors.lastname: Kontermann
authors.affiliation: Department of Nuclear Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Mier
authors.affiliation: 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.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauss
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D012260:Ribonucleases / Q000235:genetics / Q000494:pharmacology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D066246:ErbB Receptors; D012260:Ribonucleases; C058703:ranpirnase
keywords: Diabody; EGFR; Onconase; Ranpirnase; immunoRNase