Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0395 - Species variation in sphingosine 1-phosphate receptor subtype 5 affects response to ozanimod in preclinical models of multiple sclerosis (ID 91)

Speakers
  • J. Selkirk
Authors
  • J. Selkirk
  • G. Yan
  • N. Ching
  • S. Biswas
  • K. Dines
  • S. Smith
  • C. Lopez
  • I. Ruiz
  • R. Hargreaves
Presentation Number
P0395
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity selectively to human S1P receptor subtypes 1 (S1P1) and 5 (S1P5). Ozanimod was recently approved in the US and EU for the treatment of relapsing forms of multiple sclerosis. While assessing the potency of ozanimod for mouse and rat S1P5, we observed reduced activity compared with the human homologue.

Objectives

To utilize and characterize observed species variation in the S1P5 response to ozanimod in order to understand the role of S1P receptors in the mouse experimental autoimmune encephalomyelitis (EAE) and cuprizone models of multiple sclerosis.

Methods

Using site-directed mutagenesis coupled with radioligand binding and GTPγS binding assays, we identified a single amino acid responsible for reduced potency of ozanimod at rodent S1P5. Together with pharmacokinetic exposure measurements, this allowed us to define the roles of S1P1 and S1P5 in key preclinical efficacy models.

Results

The mouse and rat amino acid sequence of S1P5 has an alanine at position 120, whereas in the human homologue there is a threonine at position 120. This amino acid change is key to the binding affinity of ozanimod to the rodent S1P5 receptor homologues. The potency of functional downstream signaling is also affected as this change mediates an approximate 100-fold rightward shift in the potency of ozanimod relative to that of human S1P5. Due to this observed reduced activity of ozanimod at mouse S1P5, central nervous system exposures achieved in preclinical EAE and cuprizone models demonstrated adequate target engagement of S1P1 but not of S1P5. Observed ozanimod efficacy readouts included a reduction in circulating absolute lymphocyte counts and clinical scoring in the EAE model, and neuroprotection but not remyelination in the cuprizone model.

Conclusions

Ozanimod has high affinity and potency for human S1P5; the observed reduced affinity and potency for rodent S1P5 has been identified to be due to a single amino acid substitution at position 120 in the rodent sequence. Findings using rodent models should be interpreted with caution as, depending on exposures achieved, they may reflect the effect of ozanimod on S1P1 receptor modulation only and possibly not S1P5 effects.

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