P0065Bridging the translational gap: Preclinical efficacy assessment of biologics in humanised mouse models for inflammatory bowel disease

Background Inflammatory bowel disease (IBD) refers to chronic disease that leads to inflammation and fibrosis in the gastrointestinal tract. Recent advances in the development of different biologics shed light on novel therapeutic strategies against IBD¹. However, differences in target structure and immune system between humans and mice hamper pre-clinical evaluation of drug efficacy using in vivo mouse experiments, thereby hindering the progress of developing new candidates. Methods To tackle the challenge above, we established IBD models using humanised mice that can effectively evaluate the efficacy of biologics, regardless of the huge gap between humans and mice. Here, we targeted TNF-like ligand 1A (TL1A), which plays critical roles in regulating the progression of inflammation and fibrosis in IBD². Humanised TL1A mice were subjected to Dextran Sulphate Sodium (DSS), Trinitrobenzene sulphonic acid (TNBS), or CD45RBhigh T cell administration to induce colitis. Tulisokibart, a monoclonal antibody that targets human TL1A, was given to mice for efficacy assessment. Colon length and weight were recorded after sacrifice, and colon tissues were stained for further histopathological evaluation. Results Severe body weight loss and increased disease active index (DAI) scores in the Vehicle group confirmed the successful establishment of colitis in different humanised mice strains. Anti-TL1A treatment successfully reduced body weight loss, DAI scores (Figure 1A) and inflammatory cytokines release in diseased mice. Histological analysis showed reverse inflammatory cell infiltration, crypt structure change and fibrosis in the treatment groups (Figure 1B). Conclusion In this study, we successfully established acute and chronic colitis models in TL1A humanised mouse strains. Treatment with human TL1A antibody effectively alleviated the symptoms of colitis in the colitis-bearing mice. These results show our capability of evaluating drug efficacy against IBD, enabling precious opportunities and reducing R&D cycle for drug screening of novel therapeutic candidates, providing translational insights from bench work to clinical trial. References: 1.Juillerat P, et al. Positioning biologics in the treatment of IBD: A practical guide – Which mechanism of action for whom? Curr Res Pharmacol Drug Discov. 2022;3:100104. doi:10.1016/j.crphar.2022.100104. 2.Solitano V, et al. TL1A inhibition for inflammatory bowel disease treatment: From inflammation to fibrosis. Med. 2024;5(5):386-400. doi:10.1016/j.medj.2024.03.010. Conflict of interest: Yi, Hao: No conflict of interest Ruiqing, Yan: Wang, Guanxiong: No conflict of interest Sheng, Xiao: No conflict of interest