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* = Presenting author

P080 IL-10 induction properties of the TLR-9 agonist cobitolimod – a candidate for treatment of active ulcerative colitis in late stage of clinical development

Admyre C.1, Zargari A.1, Atreya R.2, Knittel T.*1

1Index Pharmaceuticals, Stockholm, Sweden 2University of Erlangen-Nürnberg, Department of Medicine 1, Erlangen, Germany

Background

Cobitolimod (DIMS0150, Kappaproct®) is an oligonucleotide that acts as a Toll-Like Receptor 9 (TLR-9) agonist and is able to induce clinical remission in patients with active ulcerative colitis (UC) after topical administration. To gain further insights into the mechanism of action of cobitolimod we studied the stimulatory properties of cobitolimod in induction of IL-10 in vitro.

Methods

Peripheral blood mononuclear cells (PBMCs) were isolated from buffy coats of healthy blood donors and were cultured with increasing concentrations of cobitolimod (0.1–100 μM). In control experiments a CpG reverted form of cobitolimod (IDX0526) was tested. The IL-10 levels were analyzed by ELISpot and ELISA assays. Furthermore, PBMCs isolated from whole blood of patients with UC were exposed to cobitolimod.

Results

PBMCs from different healthy donors all showed a dose dependent IL-10 induction as analyzed by ELISpot in response to cobitolimod. In agreement with the results obtained by ELISpot data, cobitolimod resulted in a dose dependent increase of IL-10 levels in the supernatant using the ELISA measure. Cobitolimod gave rise to the highest IL-10 response at 100 μM and was not effective at lower concentrations (0.1 μM to 1 μM), In PBMCs derived from patients with UC cobitolimod induced IL-10 expression levels in a dose dependent manner and to a similar extent as observed in healthy individuals.

Conclusion

The data illustrate that cobitolimod induces IL-10 expression in PBMCs derived from healthy individuals and ulcerative colitis patients and that this induction was dose-dependent. The in vitro dose response relationship provides further support for the upcoming clinical phase IIb study named CONDUCT in which different doses of cobitolimod will be administered at different frequencies to patients with moderate to severe, treatment refractory, active UC.