探索用于非临床药效学研究的半抗原诱导小鼠特应性皮炎模型

Exploration of hapten-induced atopic dermatitis murine models for non-clinical pharmacodynamics study of drugs

特应性皮炎(atopic dermatitis, AD)是一种慢性、复发性、炎症性皮肤病,临床表现多样且难以治愈。目前多种治疗AD候选药物进入研发管线,为AD药物临床开发提供技术规范,国家药品监督管理局药品审评中心于2022年11月发布了《AD治疗药物临床试验技术指导原则》(征求意见稿)。非临床药效评价是受试药物进入临床试验前的重要研究内容,噁唑酮(oxazolone, OXA)和2,4-二硝基氟苯(2,4-dinitrofluorobenzene, DNFB)诱导的特应性皮炎小鼠模型是最常用的经典半抗原诱导AD小鼠模型,但在已有报道中,半抗原剂量、致敏部位、攻击次数和皮损严重程度评估方法都存在差异。本研究根据特应性皮炎患者病程和病理表现,结合AD治疗药物临床试验药效学评价要点构建AD小鼠模型,系统考察并比较不同构建方案(致敏部位、半抗原剂量和攻击次数等)与皮损指标间的关系,探索OXA和DNFB两种经典半抗原诱导AD小鼠的病变过程、模型强度和特点,为治疗AD候选药物的非临床药效学研究提供方法学依据。所有动物实验均经过中国医学科学院、北京协和医学院药物研究所实验动物管理与动物福利委员会批准(批准号:00007782和00007784)。

Atopic dermatitis(AD)is a chronic,relapsing,inflammatory dermatosis with a variety of clinical manifestations and difficult to cure.Currently,many AD drug candidates have entered the research and development pipeline.In order to provide technical specifications for the clinical development of AD drugs,the Center for Drug Evaluation of National Medical Products Administration released the"Technical Guidelines for Clinical Trials of Drugs for AD Treatment"(Draft for Comments)in November 2022.Non-clinical pharmacodynamics evaluation is an important research before the drug enters clinical trials.Oxazolone(OXA)-and 2,4-dinitro-fluorobenzene(DNFB)-induced models are the most popular classical hapten-induced AD murine models,but variations of modeling are existing in the methods from different studies,including sensitization sites,haptens'dosages,the period of challenges,and the skin lesions severity evaluation as well.In this study,the investigation of OXA-and DNFB-induced AD murine models with various conditions of modeling was performed to compare the characteristics of hapten-induced AD murine models in the pathological process and severity according to the appearance of AD patients,and the guidance of pharmacodynamics evaluation of AD-therapeutic drugs in clinical trials as well,which may provide a proposal for AD treatment drug candidates in the non-clinical pharmacodynamics evaluation.All animal experiments were approved by the Animal Care&Welfare Committee of Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College(approval No.:00007782 and 00007784).