ASP0028 in combination with suboptimal-dose of tacrolimus in Cynomolgus monkey renal transplantation model

• Published in: Transplant immunology 2017-02, Vol.40, p.57-65
• Main Authors: Dun, Hao, Song, Lijun, Ma, Anlun, Hu, Yanxin, Zeng, Lin, Bai, Jieying, Zhang, Guangzhou, Zhang, Liangyan, Koide, Kumi, Okada, Yohei, Hanaoka, Kaori, Yamamoto, Rie, Hirose, Jun, Morokata, Tatsuaki, Daloze, Pierre, Chen, Huifang
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Animals; B-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Disease Models, Animal; Drug Therapy, Combination; Fingolimod Hydrochloride - therapeutic use; FTY720; Graft Rejection - drug therapy; Humans; Immunologic Memory; Immunosuppressive Agents - therapeutic use; Immunosuppressive drugs; Kidney Transplantation; Lymphocyte subsets; Macaca fascicularis; Nonhuman primates; Receptors, Lysosphingolipid - agonists; Receptors, Lysosphingolipid - antagonists & inhibitors; T-Lymphocytes, Regulatory - immunology; Tacrolimus - therapeutic use; Treatment Outcome
• ISSN: 0966-3274; 1878-5492
• DOI: 10.1016/j.trim.2017.01.002

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 1.0 mg/kg once a day (QD), or ASP0028 0.6 mg/kg plus tacrolimus 1.0 mg/kg QD, respectively. Eight animals in group-3 received ASP0028 1.2 mg/kg plus tacrolimus 1.0 mg/kg QD. The allograft median survival time (MST) in group-2 and group-3 were significantly extended to 41 and 61.5 days, versus that of 28 days 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.