Replacement of mycophenolate mofetil with a JAK inhibitor, AS2553627, in combination with low-dose tacrolimus, for renal allograft rejection in non-human primates

摘要

In renal transplant patients, using mycophenolate mofetil (MMF) with calcineurin inhibitors (CNIs; cyclosporine and tacrolimus [TAC]) has led to a significant improvement in graft survival. However, reducing or withholding MMF due to its gastrointestinal adverse events increases rejection risk. CNI-sparing strategies are important to avoid CNI-related nephrotoxicity in clinical settings. Here, we investigated AS2553627, a JAK inhibitor replacing MMF in combination with a sub-therapeutic dose of TAC to treat allograft rejection in a monkey model. AS2553627 inhibited proliferation of IL-2 stimulated T cells with little species difference between monkeys and humans. In MMF monotherapy, oral administration of 20 or 40?mg/kg/day prolonged graft survival with median survival times (MSTs) of 16.5?days and 33?days, respectively, whereas untreated animals showed MST of 6?days. In MMF/TAC (1?mg/kg/day, p.o.) combination therapy, pharmacokinetic analysis indicated that MMF 20?mg/kg/day achieved the clinical target AUC0-24hand prolonged renal allograft survival, with MST of 24?days. Oral administration of AS2553627 0.24?mg/kg/day in combination with TAC significantly prolonged renal allograft survival to MST of >90?days with low plasma creatinine levels. Histopathological analysis revealed that acute T cell-mediated rejection events such as vasculitis and interstitial mononuclear cell infiltration were significantly inhibited in AS2553627/TAC-treated allografts compared with MMF/TAC-treated allografts. All AS2553627/TAC-treated monkeys surviving >90?days exhibited less interstitial fibrosis/tubular atrophy than monkeys in the MMF/TAC group. These results suggest that AS2553627 replacing MMF is an attractive CNI-sparing strategy to prevent renal allograft rejection.