Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

Development of an Interleukin-22 based immunocytokine as a novel therapeutic approach in type 2 diabetes (#84)

Sahar Keshvari 1 , Christian Fercher 2 , Ross T Barnard 2 , John B Prins 1 , Sumaira Z Hasnain 1 , Michael A McGuckin 1
  1. Mater Research Institute - University of Queensland, Woolloongabba, QLD, Australia
  2. School of Chemistry & Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia

In Type 2 diabetes β-cell dysfunction is accompanied by adverse cellular responses to high concentration of lipids and glucose, oxidative stress, endoplasmic reticulum (ER) stress and local inflammation. Cellular stress activates an inflammatory response in the cell, stimulating local innate islet inflammation, which in turn exacerbates β-cell further decreasing the ability to synthesise efficacious insulin.

Previously we demonstrated a novel role for Interleukin-22 (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 and 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 ~5% of weight loss in the HFDIO mice over the 2 weeks of treatment, (iii) protected pancreatic islets from oxidative and ER stress 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.

  1. Hasnain, S. Z. et al. Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nat Med, 2014. 20(12): p. 1417-26.
  2. Gulhane, M., et al. High Fat Diets Induce Colonic Epithelial Cell Stress and Inflammation that is Reversed by IL-22, Sci Rep, 2016. 6: p. 28990.