Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an immune effector protein that induces apoptosis in virus-infected and cancer cells by activating death receptor-4 (DR4) and/or death receptor-5 (DR5) without deleterious activity toward DR4/DR5-expressing normal cells (Ashkenazi et al., 2008). Consequently, DR4/DR5 agonists are promising anticancer agents. Treatment with “first-generation” DR4/DR5-targeted therapeutics, such as recombinant human soluble tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) and agonistic DR4/DR5 antibodies, was well tolerated but had disappointing clinical activity (Ashkenazi, 2015).
