title: ASP0028 in combination with suboptimal-dose of tacrolimus in Cynomolgus monkey renal transplantation model.
abstract: FTY720, a S1P-receptor modulator, has shown to be effective in several transplant and autoimmune disease models, via modulating lymphocyte homing into secondary lymphoid organs (SLOs), and thereby reducing these cells in peripheral blood. ASP0028, a newly developed S1P1/S1P5-selective agonist, presented comparable efficacy to FTY720 and wider safety margins than FTY720. In this study, we assessed the efficacy and safety of ASP0028 co-administered with suboptimal-dose of tacrolimus in the Cynomolgus monkey renal transplantation model. Seven animals in group-1 or group-2 received mono-tacrolimus 1.0mg/kg once a day (QD), or ASP0028 0.6mg/kg plus tacrolimus 1.0mg/kg QD, respectively. Eight animals in group-3 received ASP0028 1.2mg/kg plus tacrolimus 1.0mg/kg QD. The allograft median survival time (MST) in group-2 and group-3 were significantly extended to 41 and 61.5days, versus that of 28days in group-1 (p=0.036 and 0.001, respectively). ASP0028 administration remarkably reduced absolute numbers of peripheral lymphocytes, particularly subsets of CD4+/ or CD8+/naive and central memory cells, CD4+/Treg cells, and to a lesser extent on B cells, but not CD4+/ or CD8+/effector memory cells and NK cells. These data show ASP0028 combined with suboptimal-dose of tacrolimus effectively prolongs renal allograft survival in nonhuman primates (NHPs) with well tolerated safety, supporting its further investigation to optimize CNI-sparing regimens.
authors.affiliation: Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Canada.
authors.forename: Hao
authors.initials: H
authors.lastname: Dun
authors.affiliation: Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Canada.
authors.forename: Lijun
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Canada.
authors.forename: Anlun
authors.initials: A
authors.lastname: Ma
authors.affiliation: Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Canada.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Laboratory Animals Center, the Academy of Military Medical Sciences, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Laboratory Animals Center, the Academy of Military Medical Sciences, Beijing, China.
authors.forename: Jieying
authors.initials: J
authors.lastname: Bai
authors.affiliation: Laboratory Animals Center, the Academy of Military Medical Sciences, Beijing, China.
authors.forename: Guangzhou
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Laboratory Animals Center, the Academy of Military Medical Sciences, Beijing, China.
authors.forename: Liangyan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Koide
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Hanaoka
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Yamamoto
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hirose
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Japan.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Morokata
authors.affiliation: Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Daloze
authors.affiliation: Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Canada. Electronic address: hui.fang.chen@umontreal.ca.
authors.forename: Huifang
authors.initials: H
authors.lastname: Chen
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use; D006084:Graft Rejection / Q000188:drug therapy*; D006801:Humans; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation; D008252:Macaca fascicularis; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000037:antagonists & inhibitors; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016559:Tacrolimus / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D016559:Tacrolimus
keywords: FTY720; Immunosuppressive drugs; Kidney transplantation; Lymphocyte subsets; Nonhuman primates