PEDS Advance Access originally published online on August 22, 2006
Protein Engineering Design and Selection 2006 19(10):471-478; doi:10.1093/protein/gzl033
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Human monoclonal antibodies to domain C of tenascin-C selectively target solid tumors in vivo
1 Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zürich Wolfgang-Paulistrasse 10, CH-8093 Zürich 2 PET Center, Division of Nuclear Medicine, University Hospital Zurich CH-8091 Zurich 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
5To whom correspondence should be addressed. E-mail: neri{at}pharma.ethz.ch
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
Received June 30, 2006; accepted July 12, 2006.
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