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
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
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.