Figure 4: TRAIL/TRAIL-receptor signaling and design of TRAILR agonists. (a) Membrane expressed TRAIL triggers apoptotic signaling via TRAIL-R1 and TRAIL-R2, whereas soluble TRAIL only efficiently activates TRAIL-R1. Recombinant nontargeted sTRAIL thus predominantly triggers TRAIL-R1 apoptotic signaling. Recombinant TRAIL-R1 or TRAIL-R2 agonistic antibodies can selectively activate TRAIL-R1 or TRAIL-R2, respectively. (b) Tumor-targeted delivery of sTRAIL, using scFv:sTRAIL, results in conversion of sTRAIL to membrane-like TRAIL that can induce apoptosis via TRAIL-R1 and TRAIL-R2. The antibody fragment may inhibit or activate target antigen signaling and thereby contribute to the antitumor activity of scFv:sTRAIL. (c) Targeting of T-cell markers CD7 or CD3 with K12:TRAIL and antiCD3:TRAIL, respectively, equips T-cells with membrane-like proapoptotic TRAIL that enhances antitumor T-cell activity. The antiCD3 scFv can also trigger stimulatory signaling in resting T-cells and trigger granzyme/perforin-mediated cytotoxicity.