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Abstract Details

In Vitro Assessment of the Binding and Functional Reponses of Ozanimod and Its Circulating Metabolites Across Human Sphingosine 1-Phosphate Receptors
Multiple Sclerosis
P6 - Poster Session 6 (12:00 PM-1:00 PM)
Ozanimod is an S1P receptor modulator, which binds with high affinity selectively to S1P receptor subtypes 1 (S1P1) and 5 (S1P5), in clinical development for the treatment of relapsing multiple sclerosis. Ozanimod is extensively metabolized in humans to form a number of circulating active metabolites, including 2 major active metabolites CC112273 and CC1084037.
To characterize the binding affinity, functional potency, and relative intrinsic activity of ozanimod and its clinically circulating metabolites across the human sphingosine 1-phosphate (S1P) receptors.
Competitive radioligand binding was performed using tritium-labeled ozanimod to determine if its metabolites compete for the same binding site within S1P1 and S1P5. The in vitro pharmacology and selectivity profile of ozanimod and its metabolites was also investigated using GTPγS binding assays in Chinese hamster ovary cell membranes expressing recombinant human S1P1-5, as well as assessing agonist-mediated S1P1 and S1P5 internalization in over-expressing cell lines and intracellular signaling in primary cultures of human astrocytes.
Ozanimod and its functionally active metabolites bind to the same orthosteric binding site within S1P1 and S1P5. The active metabolites display the same selectivity profile to ozanimod and are agonists for S1P1 and S1P5 but inactive at S1P2, S1P3, and S1P4 at clinically relevant concentrations. Agonism at S1P1 induces receptor internalization whereas S1P5 does not appear to internalize. Ozanimod and the most predominant metabolite, CC112273, elicit functional intracellular signaling in human astrocytes, and pharmacological characterization performed using more readily available mouse astrocytes determined this to be S1P1, and not S1P5 mediated.
Ozanimod and its functionally active metabolites bind to the same orthosteric binding site within S1P1 and S1P5 and are pharmacologically identical. As such, all circulating metabolites will likely contribute to the observed clinical efficacy in patients with relapsing multiple sclerosis.
Julie Selkirk
No disclosure on file
Grace Yan No disclosure on file
Nathan Ching No disclosure on file
Kate Paget No disclosure on file
Morgan Brand No disclosure on file
Richard Hargreaves, PhD No disclosure on file