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

Anja Krippner-Heidenreich, Ingo Grunwald, Gudrun Zimmermann, Marie Kühnle, Jeannette Gerspach, Theobald Sterns, Steve D. Shnyder, Jason H. Gill, Daniela N. Männel, Klaus Pfizenmaier, Peter Scheurich

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

54 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)8176-8183
Aantal pagina's8
TijdschriftJournal of Immunology
Volume180
Nummer van het tijdschrift12
DOI's
StatusGepubliceerd - 2008
Extern gepubliceerdJa

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