W69 - Effect of Chronic Exposure to Abrocitinib on Immune Homeostasis in Mice

Abrocitinib (PF-04965842) is an oral JAK1 selective inhibitor and in development for type 2 inflammation disorders such as atopic dermatitis. Despite the broad impact of JAK inhibition on signaling mechanisms, the effect of abrocitinib on immune homeostasis has not been well studied. Therefore, we administered abrocitinib at 100mg/kg daily for three weeks to 3-month-old C57BL/6 mice and performed a comprehensive immunologic profiling to determine the impact of chronic JAK1 inhibition on immune homeostasis in adult mice. Pharmacokinetic profile at 30mg/kg showed that abrocitinib had a short half-life (45min) and a complete clearance 8 hours post-dose. Target engagement analysis indicated the effect of abrocitinib on JAK1 inhibition lasted less than 6 hours. Immunological analysis revealed an impact in splenic NK cells, macrophages, and monocytes. In thymus, data pointed out modification in double negative thymocytes CD4-CD8- subset. As to the B cells subset, we noticed a decrease in precursors B cells in bone marrow and subsequently a decrease in T1 and T2 transitional B cells in spleen. Altogether, these data show that JAK1 chronic inhibition in adult mice causes some delay in maturation of B cells and thymocytes and confirmed a decrease in splenic NK cells and macrophages populations, similar to results obtained in preclinical chronic studies with baricitinib (JAK1/JAK2) and tofacitinib (JAK1/JAK3 inhibitor). Further studies, such as a genomic profiling to assess abrocitinib effects on the chromatin modification and a transcriptomic analysis, may help to understand the mechanisms underlying the delay in the maturation and terminal differentiation of these cell subsets.