Effects of ASKP1240 Combined With Tacrolimus or Mycophenolate Mofetil on Renal Allograft Survival in Cynomolgus Monkeys

Background. Blocking the CD40-CD154 signal pathway has previously shown promise as a strategy to prevent al-lograft rejection. In this study, the efficacy of a novel fully human anti-CD40 monoclonal antibodyVASKP1240, administered as a monotherapy or combination therapy (subtherapeutic dose of tacrolimus or mycophenolate mofetil), on the prevention of renal allograft rejection was evaluated in Cynomolgus monkeys. Methods. Heterotopic kidney transplants were performed in ABO-compatible, stimulation index 2.5 or higher in the two-way mixed lymphocyte reaction monkey pairs. Animals were divided into 12 groups and observed for a maximum of 180 days. Histopathologic, hematology, and biochemistry analyses were conducted in all groups. Cytokine release (interleukin [IL]-2, IL-4, IL-5, IL-6, tumor necrosis factor, and interferon-F) was investigated in several groups. Results. ASKP1240 prolonged renal allograft survival in a dose-dependentmanner inmonotherapy. Low-dose (2mg/kg) or high-dose (5 mg/kg) ASKP1240, in combination with mycophenolate mofetil (15 mg/kg) or tacrolimus (1 mg/kg), showed a significantly longer allograft survival time compared with monotherapy groups. No obvious side effects including drug-related thromboembolic complications were found. Cytokine release was not induced by ASKP1240 administration. Conclusion. The present study indicates that ASKP1240, alone or in combination with other immunosuppressive drugs, could be a promising antirejection agent in organ transplantation