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

作者：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^*

来源：Transplant Immunology, 2017, 40: 57-65.

DOI：10.1016/j.trim.2017.01.002

• Kidney transplantation
• Nonhuman primates
• Immunosuppressive drugs
• FTY720
• Lymphocyte subsets

FTY720, a SIP-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 S1P(1)/S1P(5)-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 s 1 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 615 days, versus that of 28 days in group-I (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(+)/rreg 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.

• 出版日期2017-2
• 单位中国人民解放军军事医学科学院