Immunosuppressants that prevents acute rejection has dramatically improved graft survival in organ transplantation. For instance, calcineurin inhibitors (CNIs) improve the survival of patients receiving transplants. However, CNIs also cause adverse effects such as renal toxicities. Adverse effects that lead to poor quality of life are still major issues associated with immunosuppression. A study from Akira Okimoto discovered and identified a selective sphingosine-1-phosphate (S1P) agonist, ASP1126.

Most immunosuppressive drugs inhibit the activation or proliferation of lymphocytes that have infiltrated an organ allograft. Inversely, S1P-receptor agonists exert their immunosuppressive effects through a unique mechanism, in which they bind to the S1P1 receptor on lymphocytes and inhibit their egress from secondary lymphoid organs. S1P represents a biologically active sphingolipid that acts through the members of a family of 5 G protein-coupled receptors (S1P1 to S1P5). Among these, S1P1 is a major regulator of lymphocyte trafficking. Fingolimod phosphate acts as a nonselective S1P-receptor agonist, exerts its immunomodulatory effect. Here, the authors describe the pharmacologic profile of a novel S1P1 agonist, ASP1126.

Especially, ASP1126 is a selective and orally active S1P agonist, with EC50 values of 7.12 nM, 517 nM for hS1P1 and hS1P3, respectively. Moreover, ASP1126 decreases the number of peripheral lymphocytes, naive T cells, central memory T cells and effector memory T cells in the peripheral blood.

Furthermore, in Vivo, ASP1126 (1 and 5 mg/kg, orally once daily for 14 days) significantly prolongs allograft survival. Likewise, ASP1126 in combination with 0.02 mg/kg tacrolimus notably improves graft survival time.

To sum up, ASP1126 has the potential to be applied in clinical transplantation with an improved safety profile.

Okimoto A, et al. ASP1126, a Novel Sphingosine-1-Phosphate-Selective Agonist With a Favorable Safety Profile, Prolongs Allograft Survival in Rats and Nonhuman Primates in Combination With Tacrolimus With a Broad Safety Margin for Bradycardia. Transplant Proc. 2019 Jul – Aug;51(6):2081-2098.