**5.2.2 S1P receptor antagonists**

204 Rheumatoid Arthritis – Treatment

Specific antibodies against S1P have been developed and are currently being tested in clinical studies for the treatment of cancer, fibrosis, inflammation, macular degeneration, diabetic retinopathy, glaucoma, and other diseases (Graler and Goetzl, 2004). The antibodies are thought to bind S1P and reduce the extracellular pool of bioactive S1P (Sabbadini, 2006). Indeed, a preclinical study using blocking S1P antibodies to prevent tumor progression was recently reported (Visentin et al., 2006). In this hallmark study, a specific monoclonal antibody recognizing S1P was administered to mice harboring human cancer xenografts. The intervention reduced, and in some cases completely eliminated, tumour formation and accompanying tumour angiogenesis. The results suggest that antibody-mediated inhibition of S1P signalling may be developed as a strategy for inhibiting pannus formation and

S1P and its receptors are powerful regulators of various critical functions of RA synoviocytes. Targeting these cells with specific S1P receptor agonists or antagonists can modulate specific inflammatory responses locally and systemically by altering cell migration, cytokine and chemokine secretion, and proliferation/survival. RP-001, a potent S1P1 receptor agonist with properties similar to those reported for FTY-720 on S1P1 receptor degradation and lymphocyte sequestration from the blood, was recently characterized (Cahalan et al., 2011). The short half-life of RP-001 *in vivo*, however, disqualifies this

The immunosuppressant drug FTY-720 (fingolimod) was originally described as a sphingosine analogue that is phosphorylated *in vivo* by SphK2 to a S1P agonist for all S1P receptors except S1P2 (Brinkmann et al., 2002; Mandala et al., 2002). Further studies revealed that FTY-720-P not only activates S1P receptors, it also down-regulates them and consequently renders cells unresponsive to S1P (Matloubian et al., 2004). FTY-720 has been suggested to play a major role in autoimmune disease, such as multiple sclerosis [reviewed in (Nicholas et al., 2011)]. Multiple sclerosis is a common neurological disability, in which autoreactive T-cells migrate across the blood–brain barrier and attack myelin sheaths, leading to demyelination and axonal damage. FTY-720 deprives thymocytes and lymphocytes by downregulating S1P receptors and interfering with S1P signalling necessary for their egress from secondary lymphoid tissues (Cyster, 2005; Graler and Goetzl, 2004; Kappos et al., 2006; Matloubian et al., 2004). The results of a Phase II clinical trial evaluating the efficacy and safety of FTY-720 for treating relapsing multiple sclerosis showed that the annualized relapse rate of the FTY-720 group was significantly decreased (Kappos et al., 2006). FTY-720 was recently FDA-approved for the treatment of multiple sclerosis (Strader

The effects of FTY-720 have been examined in several animal models of arthritis (Matsuura et al., 2000; Tsunemi et al., 2010; Wang et al., 2007). In the study of Wang et al. (2007), CIA rats were treated daily with FTY-720 for 28 days and the arthritis index was measured. Radiological analysis revealed that FTY-720-treated CIA rats had less joint damage in comparison to untreated CIA rats. Moreover, while histological assessment showed that CIA rats suffered from inflammatory cell infiltration and synovial hyperplasia in their joints,

**5.1.3 Depletion of extracellular S1P with S1P antibody** 

angiogenesis in RA.

**5.2 Targeting S1P receptors** 

compound for clinical use.

et al., 2011).

**5.2.1 S1P receptor agonists, FTY-720** 

Blocking S1P receptor activity by using S1P receptor antagonists may lead to promising therapeutic strategies for patients suffering from RA. Despite the lack of more comprehensive *in vivo* data, considerable progress has been made in the identification of the S1P receptors regulating synovial fibroblast migration, production of cytokines/chemokines and PGE2, proliferation, and survival. Several compounds targeting S1P receptors have also been used to decipher the biological roles of S1P receptors. The S1P1/3 antagonist VPC23019 and S1P3 antagonist CAY10444 blocked S1Pmediated synoviocyte migration and cytokine secretion, whereas the S1P2 antagonist JTE-013 attenuated S1P-mediated cytokine secretion (Kitano et al., 2006; Zhao et al., 2008). The pharmacokinetics, bioavailability and metabolic characteristics of these S1P antagonists are essential to advance *in vivo* studies and for therapeutic intervention. Indeed, pharmacological approaches have been developed to block the action of S1P in the context of cancer progression (reviewed in Peyruchaud, 2009).
