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TNF-Selectokine: a novel prodrug generated for tumor targeting and site-specific activation of tumor necrosis factor

Oncogene volume 21, pages 4257–4265 (2002)Cite this article

Abstract

We describe a TNF fusion protein designated TNF-Selectokine, which is a homo-trimeric molecule comprised of a single chain antibody (scFv) targeting module, a trimerization domain and TNF. TNF-Selectokine exerts high bioactivity towards the targeted and adjacent, antigen negative cells. Membrane targeting dependent immobilization of the TNF-Selectokine induced cell death in TNFR1 and TNFR2 dependent manner, thus cell bound TNF-Selectokine mimicks membrane TNF. To restrict TNF activity to the tumor, a prototype of a TNF-Selectokine prodrug was constructed by insertion of a TNFR1 fragment, separated from TNF by a protease-sensitive linker. The prodrug exerts minimal TNF activity, but can be activated in vitro several thousand-fold by proteolytic digest, showing the principal feasibility of this approach. Choice of cleavage site(s) recognized by protease(s) typically associated with a given carcinoma should allow high dose systemic application of the respective TNF prodrug that unveils its specific bioactivity only in targeted tissues.

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Abbreviations

aa:

amino acid

FACS:

fluorescence activated cell sorter

FAP:

fibroblast activation protein

FCS:

fetal calf serum

dhfr:

dihydrofolate reductase

mAb:

monoclonal antibody

MTD:

maximum tolerated dose

scFv:

single-chain fragment of immunoglobulin variable regions

TNF:

tumor necrosis factor

memTNF:

membrane form of TNF

TNFR:

TNF-Receptor

tPA:

tissue-type plasminogen activator

uPA:

urokinase-type plasminogen activator

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Acknowledgements

We thank Bodo Brocks for providing the scFvMO36 cDNA, RA Kammerer for the tenascin cDNA as well as Wolfgang Rettig and John Park for providing the cell lines HT1080, HT1080#33 and CHO DG44 and expression vector pDG105. This work was supported by a grant from Deutsche Krebshilfe/Dr Mildred Scheel Stiftung. Work on the scFv antibodies was supported by Boehringer Ingelheim Pharma KG.

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  1. Dieter Moosmayer

    Present address: Schering AG, Berlin, Germany

Authors and Affiliations

  1. Institute of Cell Biology and Immunology, University of Stuttgart, Germany

    Thomas Wüest, Elke Gerlach, Debola Banerjee, Jeannette Gerspach, Dieter Moosmayer & Klaus Pfizenmaier

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  1. Thomas Wüest
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Correspondence to Klaus Pfizenmaier.

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Wüest, T., Gerlach, E., Banerjee, D. et al. TNF-Selectokine: a novel prodrug generated for tumor targeting and site-specific activation of tumor necrosis factor. Oncogene 21, 4257–4265 (2002). https://doi.org/10.1038/sj.onc.1205193

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