The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was separately cloned by scientists at Genentech and Immunex (now Amgen) about a decade ago. Around 1996, the first death receptor (DR4) or receptor type 1 for TRAIL was discovered independently at the University of Michigan and at Human Genome Sciences. Now, ten different molecular entities targeting TRAIL-R1 and/or TRAIL-R2 are in early clinical development up to phase II. Targeting the death receptors DR4 and/or DR5 (= TRAIL-R1 and/or TRAIL-R2) appears a cancer target because it induces selective apoptosis of cancer cells while sparing normal cells. While hepatotoxicity has been a concern about the safety of apoptosis inducing treatment strategies, so far no liver-related severe adverse event has occurred. The main barriers in development of death receptor targeting antibodies, proteins and gene therapy approaches are spontaneous and induced resistance to treatment. This requires the combination of death receptor targeting molecules with chemotherapy slowing down the development speed of clinical development.

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