S1P Receptor Modulation is Potentially Neuroprotective Through Activity on Th1 and Th17 Cell Expansion/Migration, Monocyte Migration, and Microglia Expansion
D. Guimond*, M. Boyett, C. Lopez, S. Sawa-Ballweber, C. Villescaz, K. Dines, G. J. Opiteck, F. L. Scott, K. R. Taylor Meadows
Receptos, a wholly owned subsidiary of Celgene, San Diego, CA, United States
Hypothesis: Ozanimod (RPC1063) is an oral, once-daily immunomodulator that selectively targets sphingosine 1-phosphate receptor 1 (S1PR1) and S1PR5 and has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis. Ozanimod down-regulates S1PR1, resulting in retention of autoreactive T and B cells in secondary lymphoid organs, and penetrates the blood-brain barrier where it may have direct effects on S1PR1 and S1PR5 on CNS cells. Using the experimental autoimmune encephalomyelitis (EAE) mouse model, the direct effects of ozanimod on modulation of Th1 and Th17 cell subsets were investigated. In addition, the model was used to elucidate ozanimod activity on monocyte migration into the spinal cord (SC) as well as microglia expansion within the SC.
Methods: C57BL/6 mice were immunized with MOG35-55 and pertussis toxin to initiate immune cell activation, migration to the SC and neurodegeneration. Mice were treated with ozanimod via oral gavage.
Results: In EAE, activated Th1 and Th17 cells, and monocytes expand in the periphery 7-14 days post-immunization and migrate into the SC on days 14-18. Microglia expand in the SC on days 18-21. Ozanimod diminished Th1 and Th17 cell expansion in the periphery by 60-70% compared with vehicle-treated mice, and reduced the number of Th1 and Th17 cells in the SC by ≥80% vs. vehicle. Ozanimod also decreased monocyte infiltration into the SC by 65% compared with vehicle and reduced microglia expansion by 75% vs. vehicle. Immunohistochemistry of the SC at study termination demonstrated that ozanimod reduced overall inflammation and demyelination in EAE.
Conclusion: Ozanimod reduces the peripheral expansion of Th1 and Th17 T-cell subsets and results in significant reduction in migration of both subsets into the SC in EAE. In addition, monocyte migration and resident microglia expansion are reduced with ozanimod treatment. Together, these data demonstrate that ozanimod directly modulates and reduces immune cells that drive CNS inflammation and neurodegeneration in a mouse model of multiple sclerosis.
Funded by Celgene Corporation.