ASP2409, A Next-Generation CTLA4-Ig, Versus Belatacept in Renal Allograft Survival in Cynomolgus Monkeys.
Belatacept is the first costimulatory blockade agent approved for maintenance immunosuppression in kidney transplant recipients. Clinical results have indicated that belatacept is associated with superior renal function and improved metabolic profile; however, higher incidence of acute rejection and posttransplant lymphoproliferative disorder are the shortcomings of this agent. In this study, ASP2409, a new cytotoxic T-lymphocyte associated protein 4-immunoglobulin possessing 14-fold higher in vitro CD86 binding affinity than belatacept, was tested for renal allograft survival in cynomolgus monkeys. ASP2409 monotherapy dose-dependently prolonged renal allograft survival. Low-dose ASP2409 in combination with a subtherapeutic dose of tacrolimus showed much longer median survival time than monotherapy. Similar allograft survival results were observed in regimens based on high-dose ASP2409, belatacept, and therapeutic-dose tacrolimus. The results of renal allograft histopathology with high-dose ASP2409-based regimens were not inferior to the belatacept-based regimen. Moreover, higher frequencies of FoxP3-positive regulatory T cells in renal allografts were observed in ASP2409- and belatacept-based regimens compared with tacrolimus-based regimens. No serious side effects related to ASP2409 administration were found during the study. These data suggest that ASP2409 is a promising candidate for calcineurin inhibitor-sparing or -avoidance regimens.
Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
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Song
Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
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Ma
Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
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Dun
Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
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Hu
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
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Fujii
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
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Kinugasa
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
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Oshima
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
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Higashi
Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
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Daloze
Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
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Chen
D000069594:Abatacept / Q000494:pharmacology*; D000818:Animals; D051940:B7-2 Antigen / Q000276:immunology; D004359:Drug Therapy, Combination; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology; D006085:Graft Survival / Q000187:drug effects*; D018796:Immunoconjugates / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007676:Kidney Failure, Chronic / Q000601:surgery*; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D008252:Macaca fascicularis; D008297:Male; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*; D014184:Transplantation, Homologous
C000619913:ASP2409; D051940:B7-2 Antigen; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D016559:Tacrolimus
animal models: nonhuman primate; basic (laboratory) research/science; fusion proteins and monoclonal antibodies: costimulation molecule specific; immunosuppressant; immunosuppression/immune modulation; kidney transplantation/nephrology; pharmacokinetics/pharmacodynamics; rejection: acute