P969 Unveiling the molecular mechanisms of the combination of vedolizumab with JAK inhibitors in Crohn’s Disease through a systems biology and artificial intelligence-based approach

Abstract

Abstract Background Clinical evidence supports the combination therapy of vedolizumab (a gut-selective, anti-lymphocyte trafficking drug inhibiting α4β7-integrin) with JAK 1, 2, 3 inhibitors (JAKi) for Inflammatory Bowel Disease. However, the mechanistic explanation for the improved outcomes in Ulcerative Colitis patients treated with vedolizumab plus JAKi remains unknown and even more in Crohn's Disease (CD). In this study we used an unbiased in silico systems biology and artificial intelligence approach to gain a holistic view of the mechanisms that may underpin the potential benefits of the mentioned combination therapy in the treatment of CD. Methods The drugs under study -vedolizumab and JAKi- and CD were characterized at protein level by compiling data from extensive literature search. Through it, human protein interaction networks focused on CD protein effectors were generated and used to construct mathematical models using Therapeutic Performance Mapping System (TPMS) technology (Anaxomics Biotech, Barcelona, Spain). Sampling-based methods were employed to assess the impact on CD of the combined therapy vedolizumab plus JAKi and to describe underlying molecular mechanisms. Results Characterization of CD allowed identifying 4 pathological processes (referred to as motives-M) underlying the manifestation of the disease: intestinal barrier disruption (M1), increased innate immune response (M2), chronic inflammation and Th1/Th17 adaptive immune response (M3) and tissue remodeling (M4) and the molecular effectors or proteins involved in each motive. The combination of vedolizumab and JAKi induced a high degree of reversion of the effectors altered in CD (54.76%), higher than the percentage reverted by the individual drugs. Combined vedolizumab plus JAKi therapy mainly modulated M3, where both drugs mostly converge although by distinct mechanisms, thus providing additional individual benefits. The combination therapy reverted a great percentage of M3 effectors, for example, CCR9 and FASLG which were increased in CD, were reverted (or downregulated). In addition to M3 modulation, the combination therapy also modulated M1 and M4. In M1, vedolizumab is the one that would provide more complementary mechanisms apart from those that already converge in both drugs. Regarding M4, it seems that main contribution comes from complementarity pathways of the different mechanisms of action of each individual drug. Conclusion The constructed in silico models reveal that the combined vedolizumab plus JAKi therapy could modulate a high array of effectors altered in CD, more than any of the therapies alone, by enhancing the effects of the individual drugs, and provide a mechanistic rationale for employing the combination of these drugs as potential therapy for CD.