title: The Effect of ASP2409, a Novel CD86-Selective Variant of CTLA4-Ig, on Renal Allograft Rejection in Nonhuman Primates.
abstract: BACKGROUND
  Blockade of CD28-mediated T cell costimulation by a modified cytotoxic T lymphocyte-associated antigen 4 (CTLA4-Ig), belatacept, is a clinically effective immunosuppressive therapy for the prevention of renal allograft rejection. Use of belatacept-based calcineurin inhibitor-free immunosuppression, however, has demonstrated an increased frequency of cellular rejection episodes and immunosuppression-related safety issues relative to conventional regimens. Furthermore, belatacept typically requires infusion for its administration chronically, which may present an inconvenience to patients. To address these issues, a novel CTLA4-Ig variant, ASP2409, with improved CD86 binding selectivity and affinity relative to belatacept was created using DNA shuffling directed evolution methods.
  
  
  METHODS
  We evaluated the immunosuppressive effect of ASP2409 on in vitro alloimmune T cell responses, in vivo tetanus toxoid (TTx)-induced immunological responses and renal transplantation in cynomolgus monkeys.
  
  
  RESULTS
  ASP2409 had 6.1-fold higher and 2.1-fold lower binding affinity to monkey CD86 and CD80 relative to belatacept, respectively. ASP2409 was 18-fold more potent in suppressing in vitro alloimmune T cell responses relative to belatacept. In a cynomolgus monkey TTx immunization model, ASP2409 inhibited anti-TTx immune responses at a 10-fold lower dose level than belatacept. In a cynomolgus monkey renal transplantation model, subcutaneous injection of 1 mg/kg ASP2409 prevented allograft rejection through complete CD86 and partial CD80 receptor occupancies and dramatically prolonged renal allograft survival in combination with tacrolimus or mycophenolate mofetil/methylprednisolone.
  
  
  CONCLUSIONS
  These results support the potential of ASP2409 as an improved CTLA4-Ig for maintenance immunosuppression in organ transplantation.
authors.affiliation: 1 Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. 2 Department of Molecular Biology, Perseid Therapeutics, Redwood City, CA. 3 Pharmacokinetics-Pharmacodynamics Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. 4 Drug Safety Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Osaka, Japan. 5 Department of Biology and Pharmacology, Perseid Therapeutics, Redwood City, CA. 6 Applied Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. 7 Department of Process Development and Manufacturing, Perseid Therapeutics, Redwood City.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Oshima
authors.forename: Erik E
authors.initials: EE
authors.lastname: Karrer
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kawato
authors.forename: Masashi
authors.initials: M
authors.lastname: Maeda
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Fukahori
authors.forename: Susumu
authors.initials: S
authors.lastname: Tsujimoto
authors.forename: Jun
authors.initials: J
authors.lastname: Hirose
authors.forename: Koji
authors.initials: K
authors.lastname: Nakamura
authors.forename: Takanori
authors.initials: T
authors.lastname: Marui
authors.forename: Fujiko
authors.initials: F
authors.lastname: Takamura
authors.forename: Takahisa
authors.initials: T
authors.lastname: Noto
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Chapin
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Fujii
authors.forename: Margaret
authors.initials: M
authors.lastname: Neighbors
authors.forename: Sridhar
authors.initials: S
authors.lastname: Viswanathan
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Devens
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Higashi
mesh_terms: D000069594:Abatacept / Q000494:pharmacology*; D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000276:immunology; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation; D007700:Kinetics; D008252:Macaca fascicularis; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology; D013745:Tetanus Toxoid / Q000494:pharmacology
chemical_list: C000619913:ASP2409; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D013745:Tetanus Toxoid; D000069594:Abatacept