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Prepublished online as a Blood First Edition Paper on August 21, 2003; DOI 10.1182/blood-2003-04-1039. This Article Full Text (PDF) All Versions of this Article: 2003-04-1039v1 102/13/4384    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Borsi, L. Articles by Zardi, L. Search for Related Content PubMed PubMed Citation Articles by Borsi, L. Articles by Zardi, L. Social Bookmarking                   What's this? Submitted April 4, 2003 Accepted August 14, 2003 Selective targeted delivery of TNF to tumor blood vessels Laura Borsi, Enrica Balza, Barbara Carnemolla, Francesca Sassi, Patrizia Castellani, Alexander Berndt, Hartwig Kosmehl, Attila Biro, Annalisa Siri, Paola Orecchia, Jessica Grassi, Dario Neri, and Luciano Zardi* Laboratory of Cell Biology, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy Institute of Pathology, Friedrich Schiller University, Jena, Germany Institute of Pathology, Helios-Klinikum, Erfurt, Germany Philogen srl, Genoa, Italy Department of Applied BioSciences, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland * Corresponding author; email: luciano.zardi{at}tin.it. We sought to enhance the selective toxicity of tumor necrosis factor alpha (TNF) in order to permit its systemic use in cancer therapy. Since ligand-targeted therapeutics has proven successful in improving the selective toxicity of drugs, we prepared a fusion protein (L19mTNF) composed of mouse TNF and a high affinity antibody fragment (L19 scFv) to the ED-B domain of fibronectin, a marker of angiogenesis. L19mTNF was expressed in mammalian cells, purified and characterized. L19mTNF was an immunoreactive and biologically active homotrimer. Radiolabeled L19mTNF selectively targeted tumor neo-vasculature in tumor-bearing mice, where it accumulated selectively and persistently (tumor-blood ratio of the % ID/g of 700, 48h from injection). L19mTNF showed a greater anticancer therapeutic activity than both mTNF and TN11mTNF, a control fusion protein in which an antibody fragment, irrelevant in the tumor model used, substituted L19, and this activity was further dramatically enhanced by its combination with Melphalan or the recently reported fusion protein L19-IL2. 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