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Single chain TNF, a TNF derivative with enhanced stability and antitumoral activity

Krippner-Heidenreich, A; Grunwald, I; Zimmermann, G; Kühnle, M; Gerspach, J; Sterns, T; Shnyder, S; Gill, J.H; Männel, D; Pfizenmaier, K; Scheurich, P

Authors

A Krippner-Heidenreich

I Grunwald

G Zimmermann

M Kühnle

J Gerspach

T Sterns

S Shnyder

J.H Gill

D Männel

K Pfizenmaier

P Scheurich



Abstract

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.

Citation

Krippner-Heidenreich, A., Grunwald, I., Zimmermann, G., Kühnle, M., Gerspach, J., Sterns, T., …Scheurich, P. (2008). Single chain TNF, a TNF derivative with enhanced stability and antitumoral activity. The Journal of Immunology, 180(12), 8176-8183

Journal Article Type Article
Publication Date Jun 1, 2008
Deposit Date Dec 21, 2012
Journal Journal of Immunology
Print ISSN 0022-1767
Electronic ISSN 1550-6606
Publisher American Association of Immunologists
Peer Reviewed Peer Reviewed
Volume 180
Issue 12
Pages 8176-8183
Publisher URL http://www.jimmunol.org/content/180/12/8176

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