Decoy-insensitive TRAIL variants kill tumour cells more efficiently without damaging non-transformed cells

摘要: 5170 Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF death family. It best known for its ability to induce apoptosis selectively in cancer cells but not untransformed cells. TRAIL recognized by four distinct membrane-bound receptors: DR4, DR5, DcR1 and DcR2. Of receptors, only DR4 DR5 contain domain, which required induction apoptosis. DcR2 do have functional domain thus they are thought act as decoy receptors. Currently role receptors TRAIL-resistance tumour controversial, their ubiquitous expression on surface almost all somatic may limit vivo efficiency TRAIL. We previously described successful design DR5-selective variants using computational strategy. found that double mutation at positions D269H/E195R resulted enhanced affinity an 8-12 fold reduced DR4. This mutant showed no binding recombinant 2-10 lower DcR2, compared wild-type Analysis biological functionality confirmed DR5-specific, receptor-agonistic action variant. Furthermore, when TRAIL, displayed 3-5 increased cytotoxic potential DR5-responsive soluble could completely block pro-apoptotic activity On contrary, high concentration reduce pf D269H/E195R. Using neutralizing antibodies we inhibition TRAIL-binding either or increases TRAIL-mediated cell up 42%. Inhibition both cumulative effect with XX% increase death. At same time, neutralization failed further induced D269H/E195R, suggesting greater over wild type due decreased Importantly, cells, primary human keratinocytes endothelial two types shown be sensitive certain forms Overall, these results suggest can greatly death-inducing Selective activation receptor elimination provide higher anti-tumour without leading toxicity non-transformed