Targeted IL-22 Improves Glucose Tolerance and Reduces Hepatic Steatosis and Hepatic Fibrosis in Murine Models of Diabetes and Liver Disease

The cytokine interleukin-22 (IL-22) is an inhibitor of cellular stress. In HFD murine models, systemic IL-22 is efficacious to restore glucose tolerance, reduce circulating triglycerides and hepatic steatosis, and improve AST:ALT ratio, but is also associated with gut and skin toxicity. As an approach to maintain efficacy without skin/gut adverse effects we have developed a prototype IL-22-based bispecific biologic drug candidate (IL-22-ScFv) which is targeted towards the pancreas and liver. In mouse models of T2D and NAFLD/NASH twice-weekly subcutaneous administration of IL-22-ScFv provides numerous therapeutic and metabolic benefits. After IL-22-ScFv administration for four weeks in HFD mice random glucose, glucose tolerance and insulin tolerance were normalised (c.f. chow fed controls) . Significant reduction in hepatic steatosis was also seen, evidenced by liver weight, histology, oil-red-O, and (normalisation of) key lipogenic gene expression patterns. In both Thioacetamide/HFD and Choline Deficient L-Amino acid defined/HFD mice IL-22-ScFv administration significantly reduced hepatic fibrosis (Masson’s trichrome, picrosirius red, and normalisation of hepatic expression of Col1a1&2, Col3a1, Timp2, Mmp2 and Cd68) . Effective targeting of IL-22 to liver and pancreas was observed with minimal IL-22 exposure to gut and skin. Following four weeks administration of a range of doses of IL-22-ScFv no adverse effects were observed. Histological analysis of gut and skin showed no features of hyperproliferation, consistent with effective targeting of IL-22 to liver and pancreas. Mechanism of action of IL-22-ScFv was again shown to be reduction in cellular stress via IL-22 receptor mediated STAT3 phosphorylation. In conclusion, liver/pancreas targeted IL-22 shows promise as a therapeutic approach to metabolic liver disease, with concomitant improvement in disorders of glucose homeostasis. Disclosure J. B. Prins: None. H. Sajiir: None. S. Keshvari: None. K. Wong: None. J. Lockett: Advisory Panel; Lilly Diabetes. M. Mcguckin: None. S. Z. Hasnain: None.