P023 SZN-1326, a Wnt agonist, improved epithelial healing and ameliorated colitis in a chronic DSS model, in stark contrast to anti-TNF and anti-IL-12/23p40 antibodies

Abstract

Abstract Background All currently approved treatments for Inflammatory bowel disease (IBD) and the majority of drugs in the pipeline are anti-inflammatory agents. Clinical remission rates have reached a plateau, and there is an unmet need for agents that directly repair and regenerate the intestinal epithelial barrier as mucosal healing has been associated with improved clinical outcomes. Wnt/β-catenin signaling promotes intestinal stem cell renewal and epithelial regeneration. We have engineered a Wnt activator, SZN-1326, which increased Wnt target gene expression in the colon of mice treated with Dextran Sulfate Sodium (DSS), an animal model of IBD and demonstrated efficacy in the acute and chronic forms of this model. The goal of this study was to compare the efficacy of SZN-1326 to the anti-inflammatory agents anti-TNFα or anti-IL-12/23p40 antibodies in a chronic DSS model. Methods 7- to 8-week old female C57BL6/J mice were administered 3% DSS for three 7-day cycles separated by 7-days off, followed by a 3-day 1% DSS wash-out period. SZN-1326 was injected intraperitoneally (I.P.) at 1, 3, or 10 mg/kg for 2, 4 or 6 doses. Anti-TNFa (MP6-XT22, Biolegend) was injected I.P. at 5 or 25 mg/kg for 4 or 7 doses, and the mice were euthanized on day 38. A separate study examined the efficacy of SZN-1326 relative to anti-IL-12/23p40 (C17.8, Bioxcell) in the same model. Anti-IL12/23p40 antibody at 3 or 10 mg/kg for 4 or 8 doses was given on days 23 or 7 respectively. Results During each cycle of DSS treatment, animals exhibited a marked increase in disease activity index (DAI), characterized by body weight loss, diarrhea and bleeding. SZN-1326 at various dosing regimen (1 mg/kg for 4 doses to 10 mg/kg for 2, 4 or 6 doses) significantly improved body weights and decreased DAI compared to isotype control, while anti-TNFa or anti-IL12/23p40 had no efficacy on body weight restoration or DAI. The antibodies could be detected in the serum in accordance with their doses. Treatment with SZN-1326, but not with anti-TNFα significantly decreased colon inflammation, mucosal erosion and overall histopathological score. Further, SZN-1326 treatment significantly reduced serum levels of IL-6 and lipocalin-2, while anti-TNFa decreased only lipocalin-2 levels and anti-IL12/23p40 reduced serum IL-6 level. Conclusion In a chronic mouse IBD model, SZN-1326 at various dosing regimens stimulated intestinal epithelial regeneration, induced mucosal healing and restored the epithelial barrier resulting in reduced inflammation, improved body weight and reduced disease activity. In contrast, treatment with anti-TNFα or anti-IL-12/23p40 antibodies led to reduction only in certain serum inflammatory cytokines but had no efficacy on DAI or colon histology in this model.