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Prepublished online as a Blood First Edition Paper on February 27, 2003; DOI 10.1182/blood-2002-10-3089. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-10-3089v1 101/12/4853    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 Hu, P. Articles by Epstein, A. L. Search for Related Content PubMed PubMed Citation Articles by Hu, P. Articles by Epstein, A. L. Related Collections Immunobiology Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 June 2003, Vol. 101, No. 12, pp. 4853-4861 IMMUNOBIOLOGY Generation of low-toxicity interleukin-2 fusion proteins devoid of vasopermeability activity Peisheng Hu, Myra Mizokami, Gina Ruoff, Leslie A. Khawli, and Alan L. Epstein From the Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles. Because of its key role in immunity, interleukin-2 (IL-2) has been studied extensively for the adoptive immunotherapy of cancer. Although systemic administration of IL-2 has been shown to stimulate antitumor responses in vivo, its efficacy in the clinic has been limited by the development of serious side effects, including the induction of vascular leak syndrome. Previously, we have identified a small peptide fragment of IL-2 that was found to contain the entire vasopermeability activity of the cytokine. The identification of the location of this potentially undesirable property of IL-2 enabled us to focus on the generation of mutant derivatives that might be lacking vasopermeability activity but that retain cytokine functionality. In addition to this discovery, our laboratory has constructed monoclonal antibody/IL-2 fusion proteins that can target this potent cytokine directly to tumor for the immunotherapy of both solid and lymphoid malignancies. Using this fusion protein technology, we have constructed a series of point mutations in the newly identified vasopermeability region of IL-2 for the purpose of deleting this activity. Fusion proteins showing reduced or deleted vasopermeability activity were then tested for their cytokine potency by several methods, including their binding to IL-2 receptors, T-cell proliferation assays, the induction of secondary cytokines, dose-escalating toxicity, and finally their ability to treat established solid tumors in syngeneic immunocompetent mice. The results of these studies clearly show that the vasopermeability activity of IL-2 can be substantially deleted by single point mutations such as Arg38Trp without grossly affecting the immune function of the cytokine. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. Acres, M. Gantzer, C. Remy, N. Futin, N. Accart, O. Chaloin, J. Hoebeke, J.-M. Balloul, and S. Paul Fusokine Interleukin-2/Interleukin-18, a Novel Potent Innate and Adaptive Immune Stimulator with Decreased Toxicity Cancer Res., October 15, 2005; 65(20): 9536 - 9546. [Abstract] [Full Text] [PDF] D. Rubin Integrative Tumor Board: Metastatic Renal Cell Carcinoma Integr Cancer Ther, March 1, 2004; 3(1): 34 - 41. [PDF]

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