Abstract

FTY720 (fingolimod, Gilenya®) is a sphingosine analog prodrug that induces lymphocyte sequestration in secondary lymphoid organs, resulting in peripheral lymphopenia. Lymphopenia by FTY720 is characterized by a dosedependent and sustained reduction of circulating T and B lymphocytes within hours of administration, accounting for a 70% reduction of CD4+ T cells, 90% reduction of CD8+ T-cells, and >50% reduction of CD19% B-cells, with a single administration. Mechanistically, lymphocyte sequestration following FTY720 administration in vivo is due to blockade of lymphocyte egress into efferent lymph. The induction of lymphopenia by FTY720 requires the generation of its active phosphate intermediate, FTY720-P, a step catalyzed by phosphorylation of FTY720 by the ubiquitous sphingosine-kinase 2. In turn, FTY720-P becomes a potent subnanomolar agonist on four of the five sphingosine-1 phosphate (S1P) receptors (S1P1,3,4,5). Clinically, FTY720 has recently become the first oral therapy to be approved for the treatment of relapsingremitting multiple sclerosis. As a research tool, FTY720 has been critical in providing mechanistic insights into lymphocyte trafficking in physiology and disease. Although FTY720-P displays similar potency across S1P receptors, it is the S1P1 subtype, a class-A-type Gi-coupled GPCR, that is the sole mediator of FTY720-P’s ability to induce lymphopenia. S1P1 is broadly expressed in mammals, with relatively high expression found in neuronal, immune and endothelial cells, and has proven to be critical for vascular development in rodents. The aim of this review is to highlight FTY720’s efficacy as an immunosuppressant, examine its mechanisms of action, and the emergence of mono-selective S1P1 agonist therapies for autoimmune diseases.

Keywords: Chemical agonist, drug selectivity, FTY720, GPCR, lymphopenia, S1P