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PEDS Advance Access published online on August 22, 2006
Protein Engineering Design and Selection, doi:10.1093/protein/gzl033
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received June 30, 2006
Accepted July 12, 2006

Article

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

Michela Silacci 1, Simon S. Brack 1, Nicolas Späth 2, Alfred Buck 2, Sven Hillinger 3, Stephan Arni 3, Walter Weder 3, Luciano Zardi 4, and Dario Neri 1 *

1 Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zürich, Wolfgang-Paulistrasse 10, CH-8093 Zürich, Switzerland
2 PET Center, Division of Nuclear Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland
3 Thoracic Surgery, Department of Surgery, University Hospital Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland
4 Laboratory of Innovative Therapies, Department of Experimental and Clinical Immunology, Advanced Biotechnology Center, Istituto Giannina Gaslini, Genoa, Italy

* To whom correspondence should be addressed.
Dario Neri, E-mail: neri{at}pharma.ethz.ch


  Abstract

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.

Keywords: angiogenesis; antibody phage display; human monoclonal antibodies; tenascin-c; tumor targeting.
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