P031 GPR84 inhibition as a novel therapeutic approach in IBD: mechanistic and translational studies
S. Dupont1, I. Arijs2, R. Blanqué1, D. Laukens3, K. Nys2, M.C. Ceccotti4, D. Merciris4, S. De Vos5, O. Maté6, I. Parent1, V. De Vriendt5, F. Labéguère7, R. Galien1, M. Devos3, P. Rutgeerts2, N. Vandeghinste8, S. Vermeire2, R. Brys*8
1Galapagos SASU, Translational Science, Romainville, France, 2Department of Clinical and Experimental Medicine, KU Leuven, Translational Research in GastroIntestinal Disorders, Leuven, Belgium, 3Ghent University Hospital, Department of Gastroenterology, Ghent, Belgium, 4Galapagos SASU, in vivo pharmacology, Romainville, France, 5Galapagos NV, Cell-based Assays, Mechelen, Belgium, 6Galapagos NV, Bioinformatics, Mechelen, Belgium, 7Galapagos SASU, Medicinal Chemistry, Romainville, France, 8Galapagos NV, Therapeutic Area Group, Mechelen, Belgium
GPR84 is a GPCR activated by medium chain fatty acids, mainly expressed in white blood cells. White blood cell migration is induced by GPR84 agonists. Recently, we reported that pharmacological GPR84 inhibition reduces disease activity in experimental colitis (Dupont et al., UEGW 2014). To gain mechanistic insights, the impact of GPR84 inhibition on colon gene expression profiles was investigated in experimental colitis. In addition, translational studies were engaged, measuring GPR84 expression levels in patient samples.
In vivo efficacy of GLPG1205, a GPR84 antagonist, was evaluated in a mouse chronic DSS (dextran sodium sulphate, 3 cycles)-induced colitis model using macroscopic and histopathological scorings and gene expression analysis (Affymetrix mouse genome 430 2.0 array). Blood and intestinal samples from ulcerative colitis (UC) and Crohn's disease (CD) patients were collected (before and after first Infliximab treatment, with response to treatment defined as complete mucosal healing) as well as from healthy controls. Gene expression was analysed (Affymetrix Human Genome U133 Plus 2.0 Array, QrtPCR and immunohistochemistry (IHC)).
Disease activity in a chronic DSS model was strongly reduced by GLPG1205 (10mg/kg, q.d.) and sulfasalazine (SSZ, 20 mg/kg, q.d.). Micro-array analysis of expression profiles in DSS-treated mice showed a strong negative correlation between GLPG1205 treatment and controls (R2=0.8), comparable to the impact of SSZ (R2=0.75). Comparison to human expression datasets showed an impact of GLPG1205 on several gene sets associated with IBD. Micro-array and QrtPCR data indicated an increase in GPR84 expression in inflamed UC colon and CD colon/ileum which was more pronounced in patients not responding to infliximab. Moreover IHC showed a positive GPR84 staining in mucosal inflammatory cells which was increased in active IBD mucosa and very pronounced in granuloma and pouchitis samples. Additionally, patient blood samples displayed increased GPR84 expression levels as well.
GLPG1205 has profound effects on experimental colitis that were confirmed at gene expression level and were comparable to SSZ. In patient biopsies, an increase in GPR84 expression was observed, reflecting infiltration of the mucosa by GPR84+ inflammatory cells. The increased GPR84 expression specifically in active disease conditions represents an advantage with regard to the safety profile of GPR84 inhibitors. As GPR84 expression is increased in circulating white blood cells of patients, GPR84 inhibition may impact disease through systemic effects as well.