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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.

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.
AuthorsT Komiya, K Sato, H Shioya, Y Inagaki, H Hagiya, R Kozaki, M Imai, Y Takada, T Maeda, H Kurata, M Kurono, R Suzuki, K Otsuki, H Habashita, S Nakade
JournalClinical and experimental immunology (Clin Exp Immunol) Vol. 171 Issue 1 Pg. 54-62 (Jan 2013) ISSN: 1365-2249 [Electronic] England
PMID23199323 (Publication Type: Journal Article)
Copyright© 2012 ONO Pharmaceutical Co., Ltd Clinical and Experimental Immunology © 2012 British Society for Immunology.
Chemical References
  • Immunologic Factors
  • Receptors, Lysosphingolipid
Topics
  • 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)

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