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.
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Authors | T 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 |
Journal | Clinical and experimental immunology
(Clin Exp Immunol)
Vol. 171
Issue 1
Pg. 54-62
(Jan 2013)
ISSN: 1365-2249 [Electronic] England |
PMID | 23199323
(Publication Type: Journal Article)
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Copyright | © 2012 ONO Pharmaceutical Co., Ltd Clinical and Experimental Immunology © 2012 British Society for Immunology. |
Chemical References |
- Immunologic Factors
- Receptors, Lysosphingolipid
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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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