Efficacy of IDOR-1117-2520, a novel, orally available CCR6 antagonist in a preclinical model of skin dermatitis. Efficacy of IDOR-1117-2520, a novel, orally available CCR6 antagonist in a preclinical model of skin dermatitis

Background and Purpose: The chemokine receptor CCR6 is important in guiding pathogenic T17 cells that are implicated in numerous autoimmune diseases including psoriasis to sites of inflammation via the chemokine CCL20. On this basis, pharmacological interventions that inhibit CCR6+ immune cell migration provide a novel therapeutic approach for such diseases. However, the translatability from pre-clinical models to human diseases of such an intervention has so far not been assessed in detail. Here, we evaluate the translatability of a preclinical model of Aldara induced skin inflammation to psoriasis with a particular focus on immune cell trafficking and assess the efficacy of the novel, orally available CCR6 antagonist IDOR-1117-2520 in this model. Experimental Approach: Here, we evaluated the in vivo therapeutic effects of IDOR-1117-2520, a novel, highly selective, potent, and orally available CCR6 small molecule inhibitor, in the Aldara mouse model of skin inflammation. To understand in detail CCR6 inhibition on the inflammatory response, flow cytometry, RNA sequencing, and transcriptome-based cell type deconvolution approaches were used to characterize immune cell migration patterns and to compare the results to publicly available human psoriasis transcriptomics data. Key Results: IDOR-1117-2520 dose dependently reduced infiltration of CCR6 + immune cells into inflamed skin and was equally efficacious as IL-17 and IL-23 inhibition in reducing inflammation in the skin. Pathway analysis highlighted the strong molecular similarities in immune response between human psoriasis and the Aldara mouse model. Genes associated with the IL-17/IL-23 pathway were prominently expressed in both human psoriasis and in the mouse model. CCR6 inhibition modulated multiple pathways associated with inflammation beyond the proximal IL-17/IL-23 pathway. A chemokine-chemokine receptor interaction map implicated the CCL20-CCR6 as the dominant axis in recruiting pathogenic T17 cells in this model system, as well as in human psoriasis. Conclusion and Implications: These results suggest that IDOR-1117-2520 could provide a promising novel targeted therapeutic approach to treating psoriasis and, potentially, other autoimmune diseases with an involvement of CCR6/CCL20 axis and the IL-17/IL-23 pathway. The data provide rationale for the further development of IDOR-1117-2520, which is currently being evaluated in a clinical phase 1 trial (ISRCTN28892128). Overall design: We evaluated the in vivo therapeutic effects of IDOR-1117-2520, a novel, highly selective, potent, and orally available CCR6 small molecule inhibitor, in the Aldara mouse model of skin inflammation. RNAseq was used to understand in detail CCR6 inhibition on the inflammatory response. RNAseq was performed on the Aldara model ear punch on samples treated with IDOR-1117-2520 at selected timepoints.

背景与研究目的：趋化因子受体CCR6（chemokine receptor CCR6）可通过趋化因子CCL20（chemokine CCL20），将参与包括银屑病在内的多种自身免疫性疾病的致病性T17细胞引导至炎症部位。基于此，抑制CCR6阳性免疫细胞迁移的药理学干预手段，可为这类疾病提供全新的治疗策略。然而，此类干预手段从临床前模型向人类疾病的转化可行性，迄今尚未得到详尽评估。本研究旨在评估艾达乐（Aldara）诱导的皮肤炎症临床前模型向银屑病的转化可行性，重点关注免疫细胞迁移情况，并评估新型口服CCR6拮抗剂IDOR-1117-2520在该模型中的疗效。实验方法：本研究在艾达乐诱导的小鼠皮肤炎症模型中，评估了新型高选择性、强效且可口服的CCR6小分子抑制剂IDOR-1117-2520的体内治疗效果。为详尽解析CCR6抑制对炎症应答的调控机制，本研究采用流式细胞术（flow cytometry）、RNA测序（RNA sequencing）以及基于转录组的细胞类型反卷积技术，对免疫细胞迁移模式进行表征，并将结果与公开的人类银屑病转录组数据进行比对。主要结果：IDOR-1117-2520可剂量依赖性地减少CCR6阳性免疫细胞向炎症皮肤的浸润，且在减轻皮肤炎症方面的效果与白细胞介素17（IL-17）、白细胞介素23（IL-23）抑制相当。通路分析显示，人类银屑病与艾达乐小鼠模型的免疫应答存在高度相似的分子特征。IL-17/IL-23通路相关基因在人类银屑病及小鼠模型中均显著表达。CCR6抑制可调控近端IL-17/IL-23通路之外的多种炎症相关通路。趋化因子-趋化因子受体相互作用图谱显示，CCL20-CCR6轴是本模型系统及人类银屑病中招募致病性T17细胞的核心通路。结论与意义：本研究结果表明，IDOR-1117-2520可为银屑病及潜在的其他涉及CCR6/CCL20轴与IL-17/IL-23通路的自身免疫性疾病，提供极具潜力的新型靶向治疗策略。本研究数据为IDOR-1117-2520的进一步开发提供了理论依据，该药物目前正处于I期临床试验（ISRCTN28892128）阶段。整体实验设计：本研究在艾达乐诱导的小鼠皮肤炎症模型中，评估了新型高选择性、强效且可口服的CCR6小分子抑制剂IDOR-1117-2520的体内治疗效果。采用RNA测序技术详尽解析CCR6抑制对炎症应答的调控机制。对艾达乐模型小鼠的耳组织样本（经IDOR-1117-2520处理的不同时间点样本）进行RNA测序。