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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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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DOI: https://doi.org/10.1038/sj.onc.1204558
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