Abstract
Introduction: Prostaglandin D2 (PGD2) is a major Th2 inflammatory mediator involved in cell migration and activation through the prostaglandin D2 (DP2) receptor. PGD2 has multiple metabolites; some are selective for DP2. GB001 is an oral antagonist of DP2 in phase 2 clinical development for moderate-severe asthma (NCT03683576) and chronic rhinosinusitis (NCT03956862) that blocks receptor activation and intracellular signaling induced by PGD2. We aimed to evaluate GB001 potency against PGD2 metabolite induced DP2 activity.
Methods: G-protein activation assays (cAMP) were performed in CHO cells overexpressing human DP2. DP2 internalization on eosinophils in human whole blood was determined by flow cytometry. In both assays, cell lines and human whole blood were pretreated with GB001 and then incubated with PGD2 or one of the following metabolites at pre-determined EC80 concentrations: ∆12-PGD2, 15-deoxy-∆12,14-PGD2, dk-PGD2, PGJ2, ∆12-PGJ2, 15-deoxy-∆12,14-PGJ2, 9α,11β-PGF2.
Results: GB001 is a potent antagonist of PGD2 and PGD2 metabolite-induced activity. In the cAMP and DP2 internalization assays, GB001 had a potency of IC50=4.27nM ± 4.3 (n=2), IC50=1.63nM ± 1.1 (n=6), respectively. GB001 was active across all metabolites tested with potency ranging from 4 to 20nM in the cAMP assay and <2nM in the DP2 internalization assay.
Conclusion: GB001 is a potent antagonist of PGD2 metabolite-induced cAMP signaling and human eosinophil DP2 internalization. GB001 inhibition of PGD2 metabolite-induced migration and signaling may be beneficial in controlling PGD2-mediated inflammation.
Sponsored by GB001, Inc. a wholly owned subsidiary of Gossamer Bio, Inc.
Footnotes
Cite this article as: European Respiratory Journal 2020; 56: Suppl. 64, 2902.
This abstract was presented at the 2020 ERS International Congress, in session “Respiratory viruses in the "pre COVID-19" era”.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2020