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A1288 - Fevipiprant, a Potent Selective Antagonist of the Prostaglandin D2 Receptor 2, Modulates the Allergic Effector Unit Via Inhibition of Eosinophil Migration Towards Mast Cells
Author Block: R. Shamri1, V. J. Erpenbeck2, G. Dubois3, D. Sandham4, F. Levi-schaffer1; 1The Hebrew University of Jerusalem, Jerusalem, Israel, 2Translational Medicine, Novartis, Basel, Switzerland, 3Novartis, Horsham, United Kingdom, 4Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Cambridge, MA, United States.
Rationale: Prostaglandin D2 Receptor 2 (DP2; previously CRTh2), a receptor for prostaglandin D2 (PGD2), is expressed on adaptive and innate immune cells and plays a major role in the pathophysiology of asthma. PGD2, produced mainly by activated mast cells (MCs), serves as a chemoattractant for eosinophils and other immune cells. It is increased in asthmatic lungs after allergen challenge and chronically elevated in severe asthmatics. Consequently, the PGD2-DP2 pathway is a promising target of new therapies for asthma. Fevipiprant, a potent selective antagonist of the DP2 receptor [Sykes D et al 2016 Mol Pharmacol; 89: 593-605] reduces eosinophilic airway inflammation in patients with persistent asthma and raised sputum eosinophil counts [Gonem S et al 2016 Lancet Respir Med; 4:699-707] and is in development for treatment of uncontrolled asthma. Here, we report effects of Fevipiprant on the crosstalk between the two main effector cells of allergic inflammation that comprise the allergic effector unit [Elishmereni M et al 2013 Allergy; 68:171-179], i.e. MCs and eosinophils. Methods: Cord blood derived MCs and peripheral blood eosinophils were purified from healthy or asymptomatic, mildly allergic or asthmatic subjects not on medication during sampling, and co-cultured in vitro in the presence of Fevipiprant (0.001 μM-10 μM). The effect of Fevipiprant on crosstalk between the two cells was examined in migration, degranulation and viability assays. Results: Fevipiprant significantly inhibited eosinophil migration towards IgE-activated MCs in a dose-dependent manner, with a 60% reduction observed (from 28% of eosinophils migrating with medium down to 12% with the highest drug concentration). No drug-related effect on DP2 receptor surface expression on eosinophils in the absence of PGD2 was observed. As expected, Fevipiprant had no effect on eotaxin-mediated eosinophil migration. Other allergic effector unit activities, such as MC-induced eosinophil survival, or eosinophil-induced MC degranulation previously described, were not modulated by fevipiprant, suggesting no involvement of PGD2 signaling in these aspects of the co-culture system. Conclusions: Fevipiprant specifically inhibits PGD2-mediated MC-induced eosinophil recruitment, one of the early steps of allergic inflammation mediated by the allergic effector unit. These results demonstrate a potential mechanism by which this drug ameliorates lung inflammation.