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

Citation
H. Wajant 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 solubleTRAIL derivative, ONCOGENE, 20(30), 2001, pp. 4101-4106
Citations number
15
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
ONCOGENE
ISSN journal
09509232 → ACNP
Volume
20
Issue
30
Year of publication
2001
Pages
4101 - 4106
Database
ISI
SICI code
0950-9232(20010705)20:30<4101:DAOTAB>2.0.ZU;2-Q
Abstract
TNF-related apoptosis-inducing ligand (TRAIL) is a typical member of the tu mor necrosis factor (TNF) ligand family that is expressed as a type Il memb rane protein (memTRAIL) and signals apoptosis via the death domain-containi ng receptors TRAIL-R1 and -2, Soluble recombinant derivatives of TRAIL (sTR AIL) 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 T RAIL-R1- and TRAIL-R2-specific antibodies, we demonstrate in this study tha t TRAIL-R1 becomes activated by both the soluble and the membrane-bound for m of the ligand, whereas TRAIL-R2 becomes only activated by memTRAIL or sol uble TRAIL secondarily cross-linked by antibodies. Furthermore, we show tha t 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-dep endent 'immobilization' of the fusion protein to cell surfaces. We conclude that antibody targeting-dependent activation can be used to design selecti ve therapeutics derived of those ligands of the TNF family that are biologi cally inactive in their soluble form.