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Transplantation:
doi: 10.1097/TP.0000000000000236
Basic and Experimental Research

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

Song, Lijun1; Ma, Anlun1; Dun, Hao1; Hu, Yanxin1; Zeng, Lin2; Bai, Jieying2; Zhang, Guangzhou2; Kinugasa, Fumitaka3; Sudo, Yuji4; Miyao, Yasuhiro5; Okimura, Kazumichi6; Miura, Toru6; Daloze, Pierre1; Chen, Huifang1,7

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Abstract

Background: Blocking the CD40-CD154 signal pathway has previously shown promise as a strategy to prevent allograft rejection. In this study, the efficacy of a novel fully human anti-CD40 monoclonal antibody—ASKP1240, 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-γ) was investigated in several groups.

Results: ASKP1240 prolonged renal allograft survival in a dose-dependent manner in monotherapy. Low-dose (2 mg/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.

© 2014 by Lippincott Williams & Wilkins

 

 

 

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