Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: CR6086 is a novel small molecule acting as a potent and selective antagonist of the prostaglandin E2 (PGE2) receptor EP4 subtype (EP4 receptor). Recent studies have shown that PGE2-EP4 signaling acts directly on type 3 innate lymphoid cells (ILCs) and T cell differentiation, and may therefore play a key role in the altered immune response observed in autoimmune diseases such as rheumatoid arthritis (RA). The objectives of this study were: (1) to evaluate the efficacy and immunomodulatory effects of systemic treatment with CR6086 in comparison to classical NSAID or DMARD treatment on experimental arthritis in mice; (2) to confirm the efficacy of EP4 receptor targeting in a translational setting using human RA synovial tissue.
Methods: In female C57Bl/6 mice, antigen-induced arthritis (AIA) was elicited by two immunizations with methylated bovine serum albumin (mBSA) as an antigen in Freund’s complete adjuvant, and subsequently by intra-articular injection with mBSA into the right knee joint. Treatment was started two hours after the onset of arthritis, in 6 treatment groups: CR6086 (20 or 60 mg/kg/day), Naproxen (60 mg/kg/day), Dexamethasone (5 mg/kg/day), Etanercept (10 mg/kg every other day) or vehicle control. The effects of treatment were studied in vivo by 99mTechnetium measurements to detect joint swelling in the arthritic knee joint. At day 7 of treatment, mice were sacrificed and joints were isolated for histological analysis of inflammation and destruction. Synovial tissue was collected at day 3 to assess local cytokine and chemokine production by Luminex, and synovial gene expression by RT-QPCR. Furthermore, synovial explants of RA patients were cultured ex vivo in the presence or absence of CR6086 (300nM), Etanercept (10 µg/mL), or Tofacitinib (300nM), and the effect on spontaneous cytokine and chemokine production was analyzed by Luminex.
Results: Treatment with the EP4 receptor antagonist CR6086 significantly and dose-dependently reduced antigen-induced arthritis, as scored by macroscopic and histological scoring. Interestingly, CR6086 at 60 mg/kg/day was more effective than Naproxen, a classical NSAID, in reducing clinical inflammation scores and histological joint pathology. Furthermore, CR6086 at this dose was as effective as Dexamethasone in reducing histological inflammation, and even more potent in protecting from severe bone erosions. Regarding the immunomodulatory actions of CR6086, our study showed that CR6086 treatment reduced cytokines like IL-1beta, IL-17A, and to a lesser extent IL-6 and IFNgamma. The ex vivo experiment with human synovial tissue showed a beneficial, inhibitory effect of CR6086 on spontaneous secretion of cytokines and chemokines by synovial explants in two RA donors. In these two “responders”, a comparable inhibitory effect of Etanercept was observed, whereas Tofacitinib was clearly less effective than CR6086.
Conclusion: These findings provide support for the potential therapeutic effects of the EP4 receptor antagonist CR6086 in RA patients, and point to the PGE2-EP4 receptor pathway as a rational target for the development of novel DMARDs with immunomodulatory and anti-inflammatory properties.
To cite this abstract in AMA style:Koenders MI, Helsen MM, Walgreen B, van den Berg WB, Caselli G, Letari O, van der Kraan PM. The EP4 Receptor Antagonist CR6086 Is More Effective Than Classical NSAID and DMARD Treatment in a Murine Model of Arthritis and in Human RA Synovial Explants [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/the-ep4-receptor-antagonist-cr6086-is-more-effective-than-classical-nsaid-and-dmard-treatment-in-a-murine-model-of-arthritis-and-in-human-ra-synovial-explants/. Accessed March 3, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-ep4-receptor-antagonist-cr6086-is-more-effective-than-classical-nsaid-and-dmard-treatment-in-a-murine-model-of-arthritis-and-in-human-ra-synovial-explants/