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Blood, 15 December 2003, Vol. 102, No. 13, pp. 4384-4392. Prepublished online as a Blood First Edition Paper on August 21, 2003; DOI 10.1182/blood-2003-04-1039. This Article Full Text 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 Citation Map 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. Related Collections Hemostasis, Thrombosis, and Vascular Biology Neoplasia Signal Transduction Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Selective targeted delivery of TNF to tumor blood vessels Laura Borsi, Enrica Balza, Barbara Carnemolla, Francesca Sassi, Patrizia Castellani, Alexander Berndt, Hartwig Kosmehl, Attila Birò, Annalisa Siri, Paola Orecchia, Jessica Grassi, Dario Neri, and Luciano Zardi From the Laboratory of Cell Biology, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; Institut of Pathology, Friedrich Schiller University, Jena, Germany; Institute of Pathology, HELIOS-Klinikum Erfurt, Germany; Philogen srl, Siena, Italy; and the Department of Applied BioSciences of the Swiss Federal Institute of Technology (ETH), Zürich, Switzerland. We sought to enhance the selective toxicity of tumor necrosis factor (TNF) to permit its systemic use in cancer therapy. Because ligand-targeted therapeutics have 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 extradomain B (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 neovasculature in tumor-bearing mice, where it accumulated selectively and persistently (tumor-to-blood ratio of the percentage of injected dose per gram [%ID/g] of 700, 48 hours 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 for L19. This activity was further dramatically enhanced by its combination with melphalan or the recently reported fusion protein L19-IL2. In conclusion, L19mTNF allows concentrating therapeutically active doses of TNF at the tumor level, thus opening new possibilities for the systemic use of TNF in cancer therapy. (Blood. 2003;102:4384-4392) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Ventura, F. Sassi, S. Fossati, A. Parodi, W. Blalock, E. Balza, P. Castellani, L. Borsi, B. Carnemolla, and L. Zardi Use of Uteroglobin for the Engineering of Polyvalent, Polyspecific Fusion Proteins J. Biol. Chem., September 25, 2009; 284(39): 26646 - 26654. [Abstract] [Full Text] [PDF] C. Schliemann, A. Palumbo, K. Zuberbuhler, A. Villa, M. Kaspar, E. Trachsel, W. Klapper, H. D. Menssen, and D. 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