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Poster presentations: Basic Science 2020

P031 Therapeutic effect of OPS-2071 in a murine model of Crohn’s disease and in in vitro anti-inflammatory assays

H. Takagi1, M. Sato1, F. Kazuyuki1, I. Shibuya2, D. Oka1, N. Yamaya3, K. Inagaki1

1Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan, 2Pharmaceutical Planning Group, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan, 3Medical Regulatory Affairs Department, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan

Background

OPS-2071 is a novel fluoroquinolone that is currently in Phase 2 clinical trials for the evaluation of Crohn’s disease (CD) as an add-on therapy to standard of care. OPS-2071 has broad and potent antibacterial activity with low systemic absorption. It was previously investigated for the treatment of enteric infections, including Clostridium difficile. CD is an immune-mediated condition of unknown aetiology; however, studies suggest that an abnormal immune response against certain intestinal bacteria may trigger the development of chronic inflammation. In this study, we have evaluated the effect of OPS-2071 on both the murine T-cell-mediated colitis as well as its in vitro effect on the activity of immune cells.

Methods

Transfer of naïve T cells (CD4+CD62L+CD44−) into immunodeficiency mice induces autoimmune colitis. Two weeks following T-cell transfer, OPS-2071, sulfasalazine and anti-IL12/23 p40 antibody were administered for 3 weeks, followed by assessment of efficacy evaluation by histological score and inflammatory index. In vitro inhibitory action for TNF-α production was assayed using LPS-stimulated human peripheral blood cells and THP-1 macrophages. The effect on T-cell activation and cytokine production (TNF-α, IFN-γ) was examined using anti-CD2/CD3/CD28 antibody-loaded beads-stimulated human peripheral blood mononuclear cells. In vitro activity against bacteria considered to be a potential cause of IBD such as M. avium sub. paratuberculosis, Klebsiella pneumonia, etc., was also tested.

Results

OPS-2071 and anti-IL12/23 p40 antibody significantly reduced both histological score (control: 9.0, OPS: 4.7, anti-IL12: 4.3, p < 0.01) and inflammatory index (control: 58.3 ± 3.7 mg/cm, OPS: 25.9 ± 1.4 mg/cm, anti-IL12: 41.1 ± 2.4 mg/cm, p < 0.01) at a dose of 10 and 25 mg/kg, respectively. OPS-2071 suppressed TNF-α production in T cells, as well as macrophage activity in a dose-dependent fashion. OPS-2071 also suppressed human T-cell activation and proliferation. At high OPS-2071 concentrations, these effects were comparable to prednisolone. The minimum inhibitory concentration against IBD-related bacteria for: OPS-2071, ciprofloxacin, and metronidazole were 0.015–0.5, 0.25–8 and 0.03–>128 mg/ml, respectively.

Conclusion

OPS-2071 demonstrated significant therapeutic effect on colonic inflammation, suppressed TNF-α production in vitro and showed in vitro activity against bacteria related to CD. From these in vitro results, it can be concluded that OPS-2071 has anti-inflammatory activity, independent of its antibacterial activity. The dual effects demonstrated by this novel agent, OPS-2071, provided a rationale for exploring the impact of this compound on human CD in clinical trials.