P070 Novel long-acting lipidated interleukin-22 normalises colonic inflammation in an acute DSS colitis model

Abstract

Abstract Background Most current treatments and new agents in clinical development for Inflammatory Bowel Disease (IBD) focus on inhibition of excessive inflammation. However, clinical remission rates for IBD have reached a plateau. New approaches directly improving mucosal healing, a process associated with reduced hospitalizations and long-term remission, therefore have great potential for addressing the unmet need. The cytokine interleukin-22 (IL-22) plays a key role in epithelial healing and has shown early proof-of-concept as a potential drug class in a phase 1 trial in Ulcerative Colitis. Here we present results from a mouse model of colitis on the efficacy of lipidated IL-22 analogues, which maintain more native-like molecular properties than current IL-22 modalities in development. Methods Chow-fed female C57Bl/6JRj mice were randomized to 4 groups (n=8 per group) based on body weight. Three groups received 2.5% (w/v) Dextran Sulfate Sodium (DSS) in the drinking water for 7 days from the start of the study. Animals receiving water without DSS served as healthy controls. Mice in the DSS groups received vehicle or lipidated IL-22 intraperitoneally at two dose levels for the entire duration of the study (10 days). At termination, plasma was sampled for assessment of target engagement biomarkers and intestines were removed and measured for weight and length before stereological analysis. Results Mice subjected to DSS developed colitis characterized by sustained weight loss and bloody diarrhoea. Vehicle dosed DSS mice showed clear histological features of colitis, with significantly (P<0.05) increased weight/length ratio of the colon as well as colonic mucosal, submucosal and inflammation volumes compared to healthy controls. Treatment with lipidated IL-22 significantly (P<0.05) improved all these parameters except mucosal volume compared to vehicle dosed DSS mice; in particular colonic inflammation volume was normalized to healthy control levels. Dose-dependent biomarker responses (e.g. Peptide YY levels) confirmed target engagement of the lipidated IL-22. Conclusion Novel long-acting lipidated IL-22, which acts on epithelial repair mechanisms, demonstrated strong improvements in histological parameters with normalisation of colonic inflammation in a DSS model of colitis. These beneficial effects were accompanied by dose-dependent increases in target engagement biomarkers. The underlying lipidation technology used for engineering these compounds has validated best in class potential in marketed treatments due to its molecular properties (e.g. size and potency). Clinical trials to assess safety and efficacy of lipidated IL-22 are expected to commence early 2023.