Efficacy and immunomodulatory actions of ONO-4641, a novel selective agonist for sphingosine 1-phosphate receptors 1 and 5, in preclinical models of multiple sclerosis

Clin Exp Immunol. 2013 Jan;171(1):54-62. doi: 10.1111/j.1365-2249.2012.04669.x.

Abstract

ONO-4641 is a next-generation sphingosine 1-phosphate (S1P) receptor agonist selective for S1P receptors 1 and 5. The objective of the study was to characterize the immunomodulatory effects of ONO-4641 using preclinical data. ONO-4641 was tested in both in-vitro pharmacological studies as well as in-vivo models of transient or relapsing-remitting experimental autoimmune encephalomyelitis (EAE). In vitro, ONO-4641 showed highly potent agonistic activities versus S1P receptors 1 and 5 [half maximal effective concentration (EC(50) ) values of 0·0273 and 0·334 nM, respectively], and had profound S1P receptor 1 down-regulating effects on the cell membrane. ONO-4641 decreased peripheral blood lymphocyte counts in rats by inhibiting lymphocyte egress from secondary lymphoid tissues. In a rat experimental autoimmune encephalomyelitis (EAE) model, ONO-4641 suppressed the onset of disease and inhibited lymphocyte infiltration into the spinal cord in a dose-dependent manner at doses of 0·03 and 0·1 mg/kg. Furthermore, ONO-4641 prevented relapse of disease in a non-obese diabetic mouse model of relapsing-remitting EAE. These observations suggest that ONO-4641 may provide therapeutic benefits in the treatment of multiple sclerosis.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Female
  • Immunologic Factors / therapeutic use*
  • Lymphocyte Count
  • Lymphocytes / drug effects
  • Mice
  • Mice, Inbred NOD
  • Multiple Sclerosis / drug therapy*
  • Rats
  • Rats, Inbred Lew
  • Receptors, Lysosphingolipid / agonists*
  • Spinal Cord / drug effects

Substances

  • Immunologic Factors
  • Receptors, Lysosphingolipid