1Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Zürich, Switzerland2Institute of Pathology, Friedrich Schiller University, Jena, Germany3Institute of Pathology, Helios Klinikum Erfurt, Erfurt, Germany4Department of Experimental and Clinical Immunology, Istituto Giannina Gaslini, Advanced Biotechnology Center, Genoa, Italy*Dr. Ronca's current address is: Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy.*Correspondence to: Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology Zürich, Wolfgang-Pauli-Strasse 10, ETH Hönggerberg, HCI G396, CH-8093 Zürich, Switzerland/
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A number of cytokines are either approved drugs or are in advanced clinical trials, yet these biopharmaceuticals do not typically localize efficiently in solid tumors and manifest their therapeutic potential at the expense of severe side effects. The targeted delivery of cytokines to solid tumors is a promising avenue for increasing the therapeutic index of these biopharmaceuticals. We engineered a fusion protein between scFv(L19), a human antibody fragment specific to the EDB domain of fibronectin, and a cysteine-free mutant of murine interferon-γ. The resulting fusion protein was capable of targeting new blood vessels in solid tumors, and the targeting efficiency was strikingly increased in tumor-bearing knockout mice lacking the interferon-γ receptor. ScFv(L19)-interferon-γ displayed a strong antitumor effect in both subcutaneous and metastatic murine F9 teratocarcinomas, but was not efficacious as single agent when used to treat C51 and CT26 tumors. The potency of this fusion protein could be substantially enhanced by combination with doxorubicin and other immunocytokines. These findings are of clinical relevance, as the EDB domain is a marker of angiogenesis, with identical sequence in mouse and man, which is abundantly expressed in a variety of aggressive solid tumors but is undetectable in most normal tissues. Supplementary material for this article can be found on theInternational Journal of Cancerwebsite athttp://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.htm.