8 - CANCELLED - CHARACTERIZATION OF THE JAK INHIBITORS TOFACITINIB AND UPADACITINIB IN HUMAN PRIMARY CELL 3D MODELS OF CROHN'S DISEASE AND ULCERATIVE COLITIS

There is an urgent need for improved models of human inflammatory bowel disease (IBD) to drive the identification and development of novel targeted therapies. 3D models established from intestinal tissues obtained from Crohn’s disease (CD) and ulcerative colitis (UC) patients offer such an opportunity. Unlike traditional 2D monocultures, 3D co-cultures of multiple cell types allow dynamic cell-cell and cell-ECM interactions comparable to those observed in native tissues.

We have developed a powerful human 3D co-culture model of multiple cell types derived from CD or UC patients’ intestinal tissues. These models faithfully replicate various aspects of the IBD disease state, including differences in gene expression patterns relative to healthy donors, compromised epithelial barrier integrity, changes in inflammation, and disrupted fibrotic deposition.

Here we used our proprietary 3D co-culture CD and UC models to characterize the function of two marketed JAK inhibitors (JAKinibs) tofacitinib and upadacitinib. Tofacitinib, a first-generation pan-JAK inhibitor, is approved for the treatment of moderate to severe ulcerative colitis. Upadacitinib is a second-generation JAKinib with preferential JAK1 selectivity, approved for both moderate to severe Crohn’s disease and ulcerative colitis.

Tofacitinib and upadacitinib were evaluated in 3D models of human IBD across a panel of eight CD donors and four UC donors. As expected from this class of immune modulators, administration of either tofacitinib or upadacitinib resulted in significant inhibition of inflammation as demonstrated by the reduction of the pro-inflammatory cytokine IL-6, in both CD and UC donors. In CD donors, both JAKinibs were equally effective in improving epithelial barrier function. However, marked differences were observed between the two JAKinibs in the modulation of biomarkers of fibrosis with upadacitinib being superior.  Interestingly, in UC donors, both JAKinibs were comparable in improving epithelial barrier function and fibrotic activity. The effects seen across the different metrics were concentration-dependent. Importantly, individual differences among CD and UC donors were noted in their response to tofacitinib and upadacitinib.

Our primary multicellular 3D human IBD models demonstrated the superiority of upadacitinib over tofacitinib in CD donors, and their comparability in UC donors. Critically, these findings are consistent with the clinical profile of these two drugs. Hence, 3D human IBD models constitute a powerful tool to predict the relevance of specific targets and assess the efficacy of therapeutic candidates more accurately. Efforts to assess the potential of novel JAK inhibitors, including certain ones not evaluated in CD and UC, are ongoing.