preclinical studies of a death receptor 5 fusion protein that ameliorates acute liver failure

Acute liver failure (alf) is a life-threatening disease with a high mortality rate. there is an urgent need to develop new drugs with high efficacy and low toxicity. in this study, we produced a pharmaceutical-grade soluble death receptor 5 (sdr5)-fc fusion protein for treating alf and evaluated the pharmacology, safety, pharmacokinetics, efficacy, and mechanisms of sdr5-fc in mice, rats, and cynomolgus monkeys. sdr5-fc bound with high affinity to both human and monkey tumor necrosis factor-related apoptosis-inducing ligand (trail) effectively blocked trail-induced apoptosis in vitro and significantly ameliorated alf induced by concanavalin a (con a) in mice. mechanistically, sdr5-fc inhibited hepatocyte death and reduced inflammation in vivo. furthermore, sdr5-fc attenuated the production of inflammatory cytokines by splenocytes activated with con a or an anti-cd3 antibody in vitro. consistent with these results, splenocytes from trail−/− mice produced much lower levels of inflammatory cytokines than those from trail+/+ mice. in cynomolgus monkeys, sdr5-fc was safe and well tolerated when intravenously administered as a single dose of up to 1200 mg/kg or multiple doses of 100 mg/kg. after treatment with a single dose, linear pharmacokinetics with a mean half-life of > 1.9 days were observed. after 12 weekly doses, sdr5-fc exposure increased in an approximately dose-proportional manner, and the mean accumulation ratio ranged from 1.82- to 2.11-fold. these results support further clinical development of our sdr5-fc protein as the first trail-targeting drug for alf treatment.