
<ArticleTitle>Differential activation of <prot>TRAIL-R1</prot> and -2 by soluble and membrane TRAIL allows selective surface antigen-directed activation of <prot>TRAIL-R2</prot> by a soluble TRAIL derivative.</ArticleTitle>
<AbstractText>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 (<prot>memTRAIL</prot>) and signals apoptosis via the death domain-containing receptors <prot>TRAIL-R1</prot> and -2. Soluble recombinant derivatives of TRAIL (<prot>sTRAIL</prot>) 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 <prot>TRAIL-R1</prot>- and <prot>TRAIL-R2</prot>-specific antibodies, we demonstrate in this study that <prot>TRAIL-R1</prot> becomes activated by both the soluble and the membrane-bound form of the ligand, whereas <prot>TRAIL-R2</prot> becomes only activated by <prot>memTRAIL</prot> or soluble TRAIL secondarily cross-linked by antibodies. Furthermore, we show that the restricted signal capacity of <prot>sTRAIL</prot> can be readily converted into a fully signal competent <prot>memTRAIL</prot>-like molecule, i.e. a <prot>TRAIL-R2</prot> 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.</AbstractText>
