医学
效力
嗜酸性粒细胞趋化因子
药理学
IC50型
敌手
免疫学
杜皮鲁玛
哮喘
趋化因子
内科学
体外
免疫系统
受体
化学
生物化学
作者
Katerina Pardali,Fanyi Jiang,Mary P. FitzGerald,Gabriele Matschiner,David Keeling
出处
期刊:European Respiratory Journal
日期:2018-09-15
被引量:1
标识
DOI:10.1183/13993003.congress-2018.pa5248
摘要
Introduction: AZD1402 is an Anticalin protein in clinical development that has the potential to offer an inhaled treatment for asthma patients suffering from T2-driven disease through selective blockade of IL-4Rα. Aims and objective: To characterise the effect of AZD1402 on IL-4Rα signalling in human whole blood (WB) and establish a method to evaluate the functional impact of systemic exposure to AZD1402 following inhaled dosing. Methods: WB from healthy subjects was stimulated with IL-4 in the presence or absence of AZD1402. Phosphorylation of signalling components and released soluble biomarkers were quantified using FACS and multiplex ELISA, respectively. Results: Stimulation of human WB with IL-4 resulted in increased levels of phosphorylated STAT6 (pSTAT6) and in the release of eotaxin-3, TARC, and MDC. AZD1402, when added to WB samples (n=12), inhibited pSTAT6 in a concentration-dependent manner and with similar potency to the anti-IL-4Rα monoclonal antibody dupilumab (IC50 values 1.3 and 0.6 nM, respectively). Inhibition of the release of the soluble cytokines eotaxin-3, TARC, and MDC by AZD1402, at equivalent potencies to dupilumab, was observed (IC50 values of 1.9 nM, 1.2 nM, and 2.6 nM, respectively). The low level of variation observed render this method suitable to detect the presence of systemic (pharmacologically active) levels of AZD1402 following inhaled dosing. Conclusions: AZD1402, potently inhibits IL-4Rα signalling in human WB with IC50 values comparable to those of dupilumab. pSTAT6 responses in WB are used in the NCT03384290 Phase I trial to assess systemic exposure.
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