Novel Engineered Targeted Interferon-gamma Blocks Hepatic Fibrogenesis in Mice

Liver fibrogenesis is a process tightly controlled by endogenous anti-and pro-fibrogenic factors. Interferon gamma (IFN gamma) is a potent antifibrogenic cytokine in vitro and might therefore represent a powerful therapeutic entity. However, its poor pharmacokinetics and adverse effects, due to the presence of IFN gamma receptors on nearly all cells, prevented its clinical application so far. We hypothesized that delivery of IFN gamma specifically to the disease-inducing cells and concurrently avoiding its binding to nontarget cells might increase therapeutic efficacy and avoid side effects. We conjugated IFN gamma to a cyclic peptide recognizing the platelet-derived growth factor beta receptor (PDGF beta R) which is strongly up-regulated on activated hepatic stellate cells (HSC), the key effector cells responsible for hepatic fibrogenesis. The IFN gamma conjugates were analyzed in vitro for PDGF beta R-specific binding and biological effects and in vivo in acute (early) and chronic (progressive and established) carbon-tetrachloride-induced liver fibrosis in mice. The targeted-IFN gamma construct showed PDGF beta R-specific binding to fibroblasts and HSC and inhibited their activation in vitro. In vivo, the targeted-IFN gamma construct attenuated local HSC activation in an acute liver injury model. In the established liver fibrosis model, it not only strongly inhibited fibrogenesis but also induced fibrolysis. In contrast, nontargeted IFN gamma was ineffective in both models. Moreover, in contrast to unmodified IFN gamma, our engineered targeted-IFN gamma did not induce IFN gamma-related side effects such as systemic inflammation, hyperthermia, elevated plasma triglyceride levels, and neurotropic effects. Conclusion: This study presents a novel HSC-targeted engineered-IFN gamma, which in contrast to systemic IFN gamma, blocked liver fibrogenesis and is devoid of side effects, by specifically acting on the key pathogenic cells within the liver. (HEPATOLOGY 2011;54:586-596)