Interleukin-22 (IL-22), a cytokine produced by immune cells, is involved in homeostasis, inflammation and repair in the skin and mucosal tissues. However, IL-22 receptor (IL-22R1) is most highly expressed by secretory cells in the pancreatic islets. Previously we demonstrated a novel role for IL-22 as a natural regulator of β-cell insulin biosynthesis and secretion, which protects the β-cell from stress, prevents hypersecretion of poor quality insulin, and suppresses innate islet inflammation¹. However, due to the pleiotropic nature of cytokines, prolonged administration of high IL-22 doses in human patients might potentially lead to deleterious off-target effects in other tissues such as increased/uncontrolled cell proliferation in the gut and skin². Thus, fusion protein candidates were created using human IL-22 and a single-chain variable fragment composed of a single-chain antibody domain specific to rodent and human pancreatic islets (IL22-ScFv).

In the current study we tested the hypothesis that IL22-ScFv fusion proteins target pancreatic islets and would restore metabolic function in preclinical murine models of diabetes by IL-22 receptor-mediated suppression of oxidative/ER stress in pancreatic islets. In high fat diet induced obese (HFDIO) mice IL22-ScFv (i) increased the activation of downstream signalling effectors in pancreas compared to other responsive tissues, (ii) induced ~2% of weight loss and more specifically reduced body fat composition in the HFDIO mice over the 2 weeks of treatment, (iii) restores the production of high quality insulin and (iii) effectively restored glycaemic control within 10 days of commencement of treatment.

Collectively these results demonstrate that IL-22-based biologics can be effectively targeted to the pancreas and retain its biological activity, providing proof of principle that IL-22 targeting can be used to reduce side effects on other tissues while retaining beneficial metabolic effects.