2. Academic Validation
  3. Effects of ASKP1240 combined with tacrolimus or mycophenolate mofetil on renal allograft survival in Cynomolgus monkeys

Effects of ASKP1240 combined with tacrolimus or mycophenolate mofetil on renal allograft survival in Cynomolgus monkeys

  • Transplantation. 2014 Aug 15;98(3):267-76. doi: 10.1097/TP.0000000000000236.
Lijun Song 1,  Anlun Ma,  Hao Dun,  Yanxin Hu,  Lin Zeng,  Jieying Bai,  Guangzhou Zhang,  Fumitaka Kinugasa,  Yuji Sudo,  Yasuhiro Miyao,  Kazumichi Okimura,  Toru Miura,  Pierre Daloze,  Huifang Chen
Affiliations

Affiliation

  • 1 1 Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada. 2 Laboratory Animals Center, the Academy of Military Medical Sciences, Beijing, China. 3 Translational and Development Pharmacology-US, Drug Discovery Research, Astellas Research Institute of America LLC, Northbrook, IL. 4 Astellas Research Technology Inc., Osaka, Japan. 5 Drug Metabolism Research Labs. Astellas Pharma Inc., Osaka, Japan. 6 Pharmacological Research Labs., Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan. 7 Address correspondence to: Huifang Chen, M.D., Ph.D., Laboratory of Experimental Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montréal, 2099 Alexandre de Sève, Montréal, Room Y1611, Québec, Canada H2L 2W5.
PMID: 24992357 DOI: 10.1097/TP.0000000000000236
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.

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