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Differential activation of TRAIL-R1 and -2 by soluble and membrane TRAIL allows selective surface antigen-directed activation of TRAIL-R2 by a soluble TRAIL derivative

Oncogene volume 20, pages 4101–4106 (2001)Cite this article

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) is a typical member of the tumor necrosis factor (TNF) ligand family that is expressed as a type II membrane protein (memTRAIL) and signals apoptosis via the death domain-containing receptors TRAIL-R1 and -2. Soluble recombinant derivatives of TRAIL (sTRAIL) are considered as novel tumors therapeutics because of their selective apoptosis inducing activity in a variety of human tumors but not in normal cells. Using antagonistic antigen-binding fragment (Fab) preparations of TRAIL-R1- and TRAIL-R2-specific antibodies, we demonstrate in this study that TRAIL-R1 becomes activated by both the soluble and the membrane-bound form of the ligand, whereas TRAIL-R2 becomes only activated by memTRAIL or soluble TRAIL secondarily cross-linked by antibodies. Furthermore, we show that the restricted signal capacity of sTRAIL can be readily converted into a fully signal competent memTRAIL-like molecule, i.e. a TRAIL-R2 stimulating ligand, by genetic fusion to an antibody derivative that allows antigen-dependent ‘immobilization’ of the fusion protein to cell surfaces. We conclude that antibody targeting-dependent activation can be used to design selective therapeutics derived of those ligands of the TNF family that are biologically inactive in their soluble form.

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Acknowledgements

We thank P Schneider and J Tschopp (University of Lausanne, Switzerland) for kindly providing Flag-tagged TRAIL and TRAIL-R1/2-Fc. We further thank WJ Rettig and J Park (Boehringer Ingelheim Pharma KG, Germany) for supply with cF19 and HT1080-Fap. We thank H Yagita (Juntendo University School of Medicine, Japan) and A Ashkenazi (Genentech Inc., USA) for anti-TRAIL mAbs RIK-2 and 2G9 and 2E11, respectively.

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  1. Dieter Moosmayer

    Present address: Enabling Technologies, Schering AG, D-13342, Berling, Germany

Authors and Affiliations

  1. Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, Stuttgart, 70569, Germany

    Harald Wajant, Dieter Moosmayer, Thomas Wüest, Till Bartke, Elke Gerlach, Ulrike Schönherr, Nathalie Peters, Peter Scheurich & Klaus Pfizenmaier

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  1. Harald Wajant
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Correspondence to Harald Wajant.

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Wajant, H., Moosmayer, D., Wüest, T. et al. Differential activation of TRAIL-R1 and -2 by soluble and membrane TRAIL allows selective surface antigen-directed activation of TRAIL-R2 by a soluble TRAIL derivative. Oncogene 20, 4101–4106 (2001). https://doi.org/10.1038/sj.onc.1204558

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