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
  • 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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