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* University Stuttgart, Institute of Cell Biology and Immunology, Stuttgart;
University of Regensburg, Institute of Immunology, Regensburg, Germany; and
Institute of Cancer Therapeutics, University of Bradford, Bradford, United Kingdom
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Deutsche Forschungsgemeinschaft Sche 349/7-1 and in part by Sonderforschungsbereich 495 project A4.
2 Current address: Newcastle University, School of Clinical Medical Sciences, 4th Floor Catherine Cookson Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, U.K.
3 A.K.-H. and I.G. contributed equally to this work.
4 Current address: Fraunhofer-Institute for Manufacturing and Advanced Materials, Bonding Technology and Surfaces Department, Wiener Strasse 12, D-28359 Bremen, Germany.
5 Current address: Division of Molecular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany.
6 Address correspondence and reprint requests to Dr. Peter Scheurich, University Stuttgart, Allmandring 31, Stuttgart 70569, Germany. E-mail address: peter.scheurich{at}izi.uni-stuttgart.de
7 Abbreviations used in this paper: scTNF, single-chain TNF; MD, molecular dynamics.
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