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Lookup NU author(s): Dr Anja Krippner-Heidenreich, Dr Jason GillORCiD
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The inflammatory and proapoptotic cytokine TNF possesses a compelling potential as an antitumoral therapeutic agent. Possible target cells include the malignant cells themselves, the tumor vasculature, or the immune system. As the clinical use of TNF is limited by systemic toxicity, targeting strategies using TNF-based fusion proteins are currently used. A major obstacle, however, is that homotrimeric TNF ligands are prone to activity loss due to dissociation into their monomers. In this study, we report the construction of single-chain TNF molecule, a TNF mutant consisting of three TNF monomers fused by short peptide linkers. In comparison to wild-type TNF, single-chain TNF was found to possess increased stability in vitro and in vivo, displayed reduced systemic toxicity yet slightly enhanced antitumoral activity in mouse models. Creation of single-chain variants is a new approach for improvement of functional activity of therapeutics based on TNF family ligands.
Author(s): Krippner-Heidenreich A, Grunwald I, Zimmermann G, Kühnle M, Gerspach J, Sterns T, Shnyder SD, Gill JH, Männel DN, Pfizenmaier K, Scheurich P
Publication type: Article
Publication status: Published
Journal: Journal of Immunology
Year: 2008
Volume: 180
Issue: 12
Pages: 8176-8183
ISSN (print): 0022-1767
ISSN (electronic): 1550-6606
Publisher: American Association of Immunologists
URL: http://www.jimmunol.org/cgi/content/full/180/12/8176
