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Human monoclonal antibodies to domain C of tenascin-C selectively target solid tumors in vivo

Silacci, Michela ; Brack, Simon S. ; Späth, Nicolas ; Buck, Alfred ; Hillinger, Sven ; Arni, Stephan ; Weder, Walter ; Zardi, Luciano ; Neri, Dario

In: Protein Engineering, Design and Selection, 2006, vol. 19, no. 10, p. 471-478

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    Titre
    • Human monoclonal antibodies to domain C of tenascin-C selectively target solid tumors in vivo
    Auteur
    • Silacci, Michela. Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zürich Wolfgang-Paulistrasse 10, CH-8093 Zürich
    • Brack, Simon S.. Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zürich Wolfgang-Paulistrasse 10, CH-8093 Zürich
    • Späth, Nicolas. PET Center, Division of Nuclear Medicine, University Hospital Zurich CH-8091 Zurich
    • Buck, Alfred. PET Center, Division of Nuclear Medicine, University Hospital Zurich CH-8091 Zurich
    • Hillinger, Sven. Thoracic Surgery, Department of Surgery, University Hospital Zurich Rämistrasse 100, CH-8091 Zurich, Switzerland
    • Arni, Stephan. Thoracic Surgery, Department of Surgery, University Hospital Zurich Rämistrasse 100, CH-8091 Zurich, Switzerland
    • Weder, Walter. Thoracic Surgery, Department of Surgery, University Hospital Zurich Rämistrasse 100, CH-8091 Zurich, Switzerland
    • Zardi, Luciano. Laboratory of Innovative Therapies, Department of Experimental and Clinical Immunology, Advanced Biotechnology Center, Istituto Giannina Gaslini Genoa, Italy
    • Neri, Dario. Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zürich Wolfgang-Paulistrasse 10, CH-8093 Zürich
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Protein Engineering, Design and Selection, 2006, vol. 19, no. 10, p. 471-478. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:303186
    Summary
    We had previously reported that splice isoforms of tenascin-C containing the extra-domain C are virtually absent in normal adult tissues but are highly abundant in high-grade astrocytomas, with a prominent peri-vascular pattern of expression. We now report that the extra-domain C of tenascin-C is strongly expressed in the majority of lung cancers, with a vascular and stromal pattern of expression. Using antibody phage technology, we have generated a human monoclonal antibody (G11), with a dissociation constant KD = 4.2 nM for the human domain C. The G11 antibody, expressed in scFv and in mini-antibody (SIP) format, as well as a scFv-interleukin-2 fusion protein, was then characterized in quantitative biodistribution studies using mice grafted subcutaneously with U87 gliomas, revealing a selective tumor uptake, with tumor/blood ratios up to 11.8:1 at 24 h. A radioiodinated preparation of SIP(G11) was also investigated in a double tracer study using an orthotopic rat glioma model, confirming the antibody's ability to preferentially localize at the tumor site, with tumor/brain ratios superior to the ones observed with 18F-fluorodeoxyglucose. These tumor-targeting properties, together with the strong immunohistochemical staining of human tumor sections, indicate that the G11 antibody may be used as a portable targeting moiety for the selective delivery of imaging and therapeutic agents to gliomas and lung tumors