Introduction & Objective: Developing novel therapeutics is critical to provide additional treatment options and improve long‑term outcomes for patients with obesity and diabetes. The atypical cytokine interleukin-22 (IL-22) which acts on epithelial cells has shown a range of metabolic benefits. Here we demonstrate efficacy of a novel long-acting lipidated IL-22 agonist on reducing body weight and improving key metabolic parameters in mice.
Methods: The effect of lipidated IL-22 on obesity at 2 dose levels was investigated in two diet-induced obese (DIO) models - one at standard conditions and one at thermoneutrality including energy expenditure measurements while diabetic db/db mice were used to determine the effect of 3 dose levels on glucose homeostasis.
Results: Lipidated IL-22 dosed for 5 weeks resulted in a dose-dependent reduction in body weight (-7.7%, and -20.2%) compared to vehicle (-1.1%) in DIO mice accompanied by a dose-dependent reduction in food intake. However, the effect of IL-22 was partly food intake independent as weight-matched control animals consumed 16% less food than the lipidated IL-22 comparator group. EchoMRI showed more fat mass loss and less lean mass loss in the lipidated IL-22 group compared to its weight-matched control. Lipidated IL-22 did not increase energy expenditure compared to vehicle at week 1 and 4 in the DIO study at thermoneutrality. In db/db mice, IL-22 dose dependently reduced plasma glucose and %HbA1c at termination (-1.0, -1.3 and -1.7 compared to vehicle). This was accompanied by a dose-dependent improvement in HOMA-IR, in line with the significant reduction in fasting insulin observed in the DIO mice.
Conclusion: A novel long-acting lipidated IL-22 significantly reduced body weight and improved glucose homeostasis through a novel mode-of-action in a variety of mouse models. Safety and tolerability of lipidated IL-22 in humans is currently being investigated in a Phase 1 trial.
M. van de Bunt: Employee; Cytoki Pharma. A. Kjølbye: Employee; Cytoki Pharma. R. Jorgensen: Employee; Cytoki Pharma. Stock/Shareholder; Cytoki Pharma.
