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Ozanimod, a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity selectively to S1P receptor subtypes 1 (S1P 1 ) and 5 (S1P 5 ), is approved for the treatment of relapsing multiple sclerosis (MS) in multiple countries. Ozanimod profiling revealed a species difference in its potency for S1P 5 in mouse, rat, and canine compared with that for human and monkey. Site-directed mutagenesis identified amino acid alanine at position 120 to be responsible for loss of activity for mouse, rat, and canine S1P 5 , and mutation back to threonine as in human/monkey S1P 5 restored activity. Radioligand binding analysis performed with mouse S1P 5 confirmed the potency loss is a consequence of a loss of affinity of ozanimod for mouse S1P 5 and was restored with mutation of alanine 120 to threonine. Study of ozanimod in preclinical mouse models of MS can now determine the S1P receptor(s) responsible for observed efficacies with receptor engagement as measured using pharmacokinetic exposures of free drug. Hence, in the experimental autoimmune encephalomyelitis model, ozanimod exposures sufficient to engage S1P 1 , but not S1P 5 , resulted in reduced circulating lymphocytes, disease scores, and body weight loss; reduced inflammation, demyelination, and apoptotic cell counts in the spinal cord; and reduced circulating levels of the neuronal degeneration marker, neurofilament light. In the demyelinating cuprizone model, ozanimod prevented axonal degradation and myelin loss during toxin challenge but did not facilitate enhanced remyelination after intoxication. Since free drug levels in this model only engaged S1P 1, we concluded that S1P 1 activation is neuroprotective but does not appear to affect remyelination. SIGNIFICANCE STATEMENT: Ozanimod, a selective modulator of human sphingisone 1-phosphate receptor subtypes 1 and 5 (S1P 1/5 ), displays reduced potency for rodent and dog S1P 5 compared with human, which results from mutation of threonine to alanine at position 120. Ozanimod can thus be used as a selective S1P 1 agonist in mouse models of multiple sclerosis to define efficacies driven by S1P 1 but not S1P 5 . Based on readouts for experimental autoimmune encephalomyelitis and cuprizone intoxication, S1P 1 modulation is neuroprotective, but S1P 5 activity may be required for remyelination.

the journal of pharmacology and experimental therapeutics/the journal of pharmacology and experimental therapeutics

Deconstructing the Pharmacological Contribution of Sphingosine-1 Phosphate Receptors to Mouse Models of Multiple Sclerosis Using the Species Selectivity of Ozanimod, a Dual Modulator of Human Sphingosine 1-Phosphate Receptor Subtypes 1 and 5