P111 Efficacy of a novel long-acting lipidated interleukin-22, alone and in combination with anti-TNF treatment, in a murine chronic DSS colitis model
Van De Bunt, M.(1)*;D'Alessio, S.(2);Norrild, J.C.(3);Kjølbye, A.L.(1);Jorgensen, R.(1);
(1)Cytoki Pharma, Research & Development, Hellerup, Denmark;(2)PhoenixLAB srls, Research, Lodi, Italy;(3)Cytoki Pharma, CMC & Quality, Hellerup, Denmark;
Most current treatments and new agents in clinical development for Inflammatory Bowel Disease focus on inhibition of excessive inflammation. However, to break the ceiling on current clinical remission rates, new approaches, for example targeting mucosal healing, are needed. The cytokine interleukin-22 (IL-22) plays a key role in epithelial healing and has 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 demonstrating the efficacy of IL-22 agonism and complementarity with existing immunomodulatory treatment options.
Eight-week-old female C57Bl/6N mice (n=56) were subjected to a DSS-induced model of colitis; mice were given 2% (weight/volume) DSS in the drinking water for three 7-day cycles followed by 7 days of regular drinking water. Mice were treated from day 18 until the end of study with either vehicle, lipidated IL-22, an anti-murine TNF antibody at a suboptimal dose, a combination of the lipidated IL-22 and anti-TNF, and, as positive control, anti-murine TNF at an optimal dose. Colitis severity was monitored during the study and at study end endoscopic scoring was performed. Colon length and weight were measured, and histological analysis on formalin-fixed paraffin sections performed by a blinded pathologist.
At termination, all treatment groups showed reduced body weight loss and improved DAI scores compared to vehicle treated animals, which was significant for all but the suboptimal anti-TNF group. Combination treatment resulted in an additive treatment effect compared to single treatment alone, with mean DAI improving by 13% and 48% for the anti-TNF and IL-22 groups alone versus 68% in combination. Similar effects were observed for the endoscopic and histological scores. The compositive endoscopic score improved by 21% (anti-TNF) and 55% (IL-22) versus 66% for the combination, and histological scores 22% and 52% versus 66%. These combination results likely represent the maximum response that can be achieved in the model, since the improvements obtained are the same as those for the treatment positive control for the model (68% and 62% improvements in endoscopic and histological scores, respectively).
A novel long-acting lipidated IL-22, which acts on epithelial repair mechanisms, demonstrated strong and significant improvements on all measured parameters in a chronic DSS model of colitis. Combining the IL-22 mode-of-action with an immunomodulatory agent, exemplified by a murine anti-TNF antibody, demonstrated the complementarity of IL-22 agonism to existing treatment options. Clinical trials to assess safety and tolerability of lipidated IL-22 are expected to commence at the start of 2023.