376 Establishment of a novel in vivo mouse model of the IL-17 signaling pathway suitable for explorations of PK/PD relationships

Abstract

The IL-17 signaling pathway is a key driver of psoriasis and a validated target for treatment of the disease. The purpose of the present study was to establish a mechanistic in vivo mouse model of IL-17 signaling, suitable for modelling of PK/PD relationships for new psoriasis therapies inhibiting this pathway. To obtain an IL-17 induced response in skin, which is the relevant tissue for psoriasis translations, an intradermal cytokine injection model was selected, with proximal biomarkers of clinical relevance as the primary endpoints. The biomarkers were measured in ear tissue lysate 0.5-24 hours after cytokine injection, analyzing both mRNA and protein levels. When IL-17A was injected intradermally in one ear of BalbC mice, a clear upregulation of several proximal biomarkers was seen, including CXCL1 and CCL20. However, the response was only evident at very high concentrations of IL-17A. To obtain a response with lower, clinically relevant IL-17 levels, TNFa - which is known to act in synergy with IL-17 - was co-injected with IL-17A. TNFa significantly potentiated the response of IL-17A, resulting in robust upregulation of proximal biomarkers at IL-17A concentrations that were within the concentration range reported in skin samples from psoriasis patients. The upregulated biomarkers included CXCL1 and CCL20, with the peak response observed 1-4 hours after the intradermal cytokine injection. To confirm that the biomarker response was dependent on IL-17A, we determined the therapeutic effect of an anti-IL17A antibody. Indeed, antibody doses ranging from 1 to 10 mg/kg inhibited the biomarker response. In conclusion, we have established a mechanistic mouse model of the IL-17 signaling axis which enables in-depth investigations of the PK/PD relationships of therapeutic interventions targeting this signaling pathway.