title: Effects of ASKP1240 combined with tacrolimus or mycophenolate mofetil on renal allograft survival in Cynomolgus monkeys.
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.
  
  
  CONCLUSIONS
  The present study indicates that ASKP1240, alone or in combination with other immunosuppressive drugs, could be a promising antirejection agent in organ transplantation.
authors.affiliation: 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.
authors.forename: Lijun
authors.initials: L
authors.lastname: Song
authors.forename: Anlun
authors.initials: A
authors.lastname: Ma
authors.forename: Hao
authors.initials: H
authors.lastname: Dun
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Hu
authors.forename: Lin
authors.initials: L
authors.lastname: Zeng
authors.forename: Jieying
authors.initials: J
authors.lastname: Bai
authors.forename: Guangzhou
authors.initials: G
authors.lastname: Zhang
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kinugasa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sudo
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miyao
authors.forename: Kazumichi
authors.initials: K
authors.lastname: Okimura
authors.forename: Toru
authors.initials: T
authors.lastname: Miura
authors.forename: Pierre
authors.initials: P
authors.lastname: Daloze
authors.forename: Huifang
authors.initials: H
authors.lastname: Chen
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000097:blood; D061067:Antibodies, Monoclonal, Humanized; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D016207:Cytokines / Q000097:blood; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation; D008252:Macaca fascicularis; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D016559:Tacrolimus / Q000008:administration & dosage* / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019013:CD40 Antigens; D016207:Cytokines; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; C586087:bleselumab; D009173:Mycophenolic Acid; D016559:Tacrolimus