CN104822392A - 抑制活化的t-细胞中il-22表达的方法 - Google Patents
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Abstract
本发明涉及抑制活化的和分化的人T-细胞中促炎细胞因子白介素-22(IL-22)表达上调的方法,所述的上调是由施用治疗有效量的磷酸二酯酶4(PDE4)抑制剂诱导的。该方法包括与PDE4抑制剂的施用依次或同时施用足以抑制IL-22表达上调的量的维生素D受体激动剂。
Description
发明领域
本发明涉及抑制活化和分化的人T-细胞中白介素-22表达的方法以及该方法中所用的药物组合物。
发明背景
磷酸二酯酶是在细胞中催化环AMP和/或环GMP分别水解成5-AMP和5-GMP的酶,因此它们对细胞调节cAMP或cGMP水平至关重要。在目前鉴定的11种磷酸二酯酶中,磷酸二酯酶(PDE)4、PDE7和PDE8是选择性作用于cAMP。PDE4是cAMP在免疫和炎性细胞例如中性粒细胞、巨噬细胞和T-淋巴细胞中表达的最重要调节剂(Z.Huang和J.A.Mancini,Current Med.Chem.13,2006,第3253-3262页)。由于cAMP是调节炎性应答的一个重要的第二信使,发现PDE4通过调节促炎细胞因子例如TNFα、IL-2、IFN-γ、GM-CSF和LTB4而调节炎性细胞的炎性应答。因此,抑制PDE4成为治疗炎性疾病例如哮喘、慢性阻塞性肺病(COPD)、类风湿性关节炎、特应性皮炎、克隆病等的一个具有吸引力的靶标(M.D.Houslay等人,Drug Discovery Today 10(22),2005,第1503-1519页;N.Press&K.H.Banner,Progress in Medicinal Chemistry 47,2009,第37-74页)。由于特应性皮炎(AD)患者具有升高的PDE活性,PDE4抑制也成为AD的一种可行的治疗(Journal of Investigative Dermatology(1986),87(3),372-6;N.Ishii等人,J.Pharmacol.Exper.Ter.346,2013,第105-112页)。
PDE4基因家族至少由4种基因A、B、C和D组成,其具有高度的同源性(V.Boswell Smith和D.Spina,Curr.Opinion Investig.Drugs 6(11),2006,第1136-1141页)。这4种PDE4同种型在不同组织和细胞类型中差异表达。因此,PDE4B主要在单核细胞和中性粒细胞中表达,但在皮质和上皮细胞中不表达,而PDE4D在肺、皮质、小脑和T-细胞中表达(C.Kroegel和M.Foerster,Exp.Opinion Investig.Drugs 16(1),2007,第109-124页)。
很多PDE4抑制剂已经在炎性疾病、严重的哮喘、炎性肠病和COPD上研究它们的治疗效果。首先,茶碱是一种较弱的非选择性磷酸二酯酶抑制剂,用于治疗呼吸疾病,例如哮喘和COPD。然而,茶碱治疗会产生轻度和重度副作用,例如心律失常和惊厥,从而限制了茶碱的临床应用(Kroegel和Foerster,同上)。由于磷酸二酯酶4仍是抗炎治疗的一个具有吸引力的靶标,开发了数种更具选择性的PDE4抑制剂,并且在临床进行研究。由于剂量限制的副作用、严重的恶心和呕吐,临床开发的很多第一代PDE4抑制剂例如咯利普兰已停用。具有明显较少副作用的第二代PDE4抑制剂目前用于临床试验(Houslay,同上)。
表现出PDE4抑制活性的化合物被用作治疗剂,用于全身治疗炎性变应性疾病例如支气管哮喘、COPD、变应性鼻炎和肾炎;自身免疫疾病例如类风湿性关节炎、多发性硬化、克隆病和系统性红斑狼疮;中枢神经系统疾病例如抑郁、遗忘症和痴呆;与心力衰竭、休克和脑血管疾病等引起的缺血回流相关的器官病;胰岛素抵抗性糖尿病;创伤;和其它其中炎症在疾病的病因或进程中发挥作用的疾病。
表现出PDE4抑制活性的化合物还可以有益于预防、治疗或改善多种皮肤疾病或病症,例如增生性和炎性皮肤障碍,并且特别是银屑病、表皮炎症、脱发、皮肤萎缩、类固醇诱导的皮肤萎缩、皮肤老化、光皮肤老化、痤疮、皮炎、特应性皮炎、脂溢性皮炎、接触性皮炎、荨麻疹、瘙痒症和湿疹。
发生银屑病的一个病因是活化的免疫细胞例如Th1和Th17细胞的皮肤渗透,所述的细胞表达细胞因子,其在银屑病斑块中诱导自身永久存在的炎性循环。特别是,细胞因子TNFα、IL-17和IL-22表现出对银屑病发生和进程至关重要。使用已经活化和分化成Th1/Th17表型的人外周血T-细胞的体外分析被开发用于评价试验化合物的抗炎作用,通过测量它们对细胞因子表达的作用。
在进行本发明研究的过程中,令人惊讶地发现当在Th1/Th17分析中试验PDE4抑制剂时,它们上调促炎细胞因子IL-22的表达,在较小程度上上调IL-17的表达。在银屑病和特应性皮炎的患者中IL-22的表达上调很高,强化了它在慢性皮肤炎性病症中的作用。通过非造血源细胞例如上皮细胞(包括角质细胞、内皮细胞和成纤维细胞)表达的受体,IL-22在诱导角质细胞的修饰的增殖和分化以及炎性分子例如MCH I类、IL-6和IL-8的表达中发挥重要作用,从而促进皮肤炎症。化合物(作为抗炎药物,具有治疗功效)引起促炎细胞因子预料不到的上调为与另一种能下调IL-22表达的治疗活性化合物的同时治疗提供了基本原理。
发明概述
使用活化的人T-细胞分化成Th1/Th17细胞的体外分析发现维生素D受体激动剂卡泊三醇能强烈抑制IL-22的表达。当卡泊三醇与一系列PDE4抑制剂一起在该分析中试验时,PDE4抑制剂介导的IL-22上调被抵消,而PDE4抑制剂对其它促炎细胞因子特别是TNFα的抑制作用被预料不到地保留。
因此,一方面,本发明涉及在活化的和分化的人T-细胞中抑制促炎细胞因子白介素-22(IL-22)的表达上调的方法,所述的上调是通过施用治疗有效量的磷酸二酯酶4(PDE4)抑制剂诱导,该方法包括与PDE4抑制剂的施用依次或同时施用足以抑制IL-22表达上调的量的维生素D受体激动剂。
另一方面,本发明涉及用于治疗炎性疾病或病症的药物组合物,其包含治疗有效量的PDE4抑制剂和足以抑制施用PDE4抑制剂诱导的促炎细胞因子IL-22的表达上调的量的维生素D受体激动剂,以及可药用载体或介质。
附图简述
图1是显示浓度为1μM的7种PDE4抑制剂在临床开发中上调Th1/Th17细胞中IL-22表达的图。
图2是显示在Th1/Th17细胞中化合物A剂量依赖上调IL-22表达的图。
图3是显示浓度为120nM的卡泊三醇和浓度为5.6μM的化合物A在Th1/Th17细胞中单独和组合使用时对TNFα(图3a)和IL-22(图3b)表达的作用图。“MC 903”是卡泊三醇。
图4是显示浓度为100nM的卡泊三醇和浓度为1μM的5种不同PDE4抑制剂在Th1/Th17细胞中单独或组合使用时对IL-22表达的作用图。“MC 903”是卡泊三醇。
图5是显示浓度为100nM的卡泊三醇和浓度为1μM的7种不同PDE4抑制剂在Th1/Th17细胞中单独和组合使用时对IL-22表达的作用图。“Calcip”是卡泊三醇。
图6是显示浓度为1μM的化合物A单独或与浓度为100nM的4种不同维生素D类似物在Th1/Th17细胞中对IL-22表达的作用图。
图7是显示存在或不存在浓度为1μM的化合物A时不同浓度的卡泊三醇(MC903)在Th1/Th17细胞中对IL-22表达的作用图。
发明详述
定义
在本文中,术语“维生素D受体激动剂”(或缩写成“维生素D激动剂”)旨在表示刺激维生素D受体的活性的生物活性化合物。维生素D受体激动剂可以选自天然维生素D衍生物或合成的维生素D类似物。骨化三醇、卡泊三醇、马沙骨化醇和他卡西醇是维生素D受体激动剂的实例,发现其下调本文公开的Th1/Th17分析中IL-22的表达(参见图6)。
“卡泊三醇”是下式的维生素D类似物
发现卡泊三醇存在两种结晶形式,无水物和一水合物。WO 94/15912中公开了卡泊三醇一水合物及其制备。术语“卡泊三醇”旨在包括所有形式的化合物。
“罗氟司特”是化合物3-(环丙基甲氧基)-N-(3,5-二氯吡啶-4-基)4-(二氟甲氧基)苯甲酰胺。
“替托司特(Tetomilast)”是化合物6-[2-(3,4-二乙氧基苯基)噻唑-4-基]吡啶-2-甲酸。
“GSK-256066”是化合物6-[3-(N,N-二甲基氨基甲酰基)苯基磺酰基]-4-(3-甲氧基苯基氨基)-8-甲基喹啉-3-甲酰胺盐酸盐。
“Oglemilast”是化合物N-(3,5-二氯吡啶-4-基)-4-(二氟甲氧基)-8-甲基磺酰基酰氨基)二苯并(b,d)呋喃-1-甲酰胺。
“阿普司特(Apremilast)”是化合物(+)-N-[2-[1(S)-(3-乙氧基-4-甲基苯基)-2-(甲基磺酰基)乙基]-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]乙酰胺。
“AN2728”是化合物4-(1-羟基-1,3-二氢-2,1-苯并氧杂硼杂环戊烷-5-基氧基)苄腈。
化合物A是化合物2-{6-[2-(2,3-二氯吡啶-4-基)乙酰基]-2,3-二甲氧基苯氧基}-N-丙基乙酰胺。
化合物B是化合物N-苄基-2-{6-[2-(3,5-二氯吡啶-4-基)乙酰基]-2,3-二甲氧基苯氧基}乙酰胺。
化合物C是化合物2-(3,5-二氯吡啶-4-基)1-{2-[2-(4-氟苯基)乙氧基]-3,4-二甲氧基苯基}乙酮。
化合物D是化合物2-(3,5-二氯吡啶-4-基)-1-{9-甲氧基-螺[2H-1,5-苯并二氧杂-3(4H),3’-氧杂环丁烷]-6-基}乙酮。
化合物E是化合物2-{6-[2-(3,5-二氯吡啶-4-基)乙酰基]-2,3-二甲氧基苯氧基}-N-(2-二甲基氨基乙基)乙酰胺。
术语“上调IL-22表达”旨在表示上调分化的但未处理的T-细胞(Th1/Th17)中IL-22表达,并且进一步上调用PDE4抑制剂处理的分化的T-细胞中IL-22表达。
实施方案
在银屑病皮肤损害中,树突细胞和T-细胞相互作用并且与角质细胞相互作用,通过复合细胞因子网络连接固有和适应性免疫应答,其在分子水平定义为银屑病。银屑病皮肤的固有免疫细胞特别是炎性树突细胞中产生的重要的细胞因子是TNFα以及IL-12和IL-23,它们在T-细胞分别分化或发展成Th1或Th17细胞中发挥重要作用。Th1细胞传统上特征在于产生IFN-γ,而Th17细胞产生标记性细胞因子IL-17、IL-22和IL-26。这些重要调节剂在银屑病的发病机理中的重要性已经被临床上用生物学对抗TNFα、IL-17和IL-12/IL-23的成功靶向证实。
考虑到Th17亚组在银屑病和其它慢性免疫介导的炎性疾病例如银屑病关节炎、风湿性关节炎、多发性硬化和炎性肠病中的主要作用,建立了体外细胞分析方法,使用活化的人T-细胞通过确定的细胞因子环境分化成Th1/Th17细胞,其通过活化系/表型特异性转录因子编制分化程序,同时抑制负责诱导其它辅助T-细胞亚组的因子(参见下面实施例1)。产生的Th1/Th17细胞用于试验不同剂量水平和两种活性成分的剂量比例的效果,通过比较单独或同时应用不同试验浓度产生的促炎细胞因子IL-6、IL-8、IL-17、IL-22和TNF-α的表达水平进行。
在一个实施方案中,维生素D受体激动剂可以选自卡泊三醇、骨化三醇、阿法骨化醇、他卡西醇、马沙骨化醇和帕立骨化醇。在用于局部应用的目前倍受喜欢的实施方案中,维生素D受体激动剂是卡泊三醇或卡泊三醇一水合物。
由于PDE4抑制剂引起的IL-22上调似乎是一类作用,参见下面图1,PDE4抑制剂可以选自多种已知的PDE4抑制剂,例如选自罗氟司特、GSK256066、oglemilast、替托司特、阿普司特、AN2728、化合物A、化合物B、化合物C、化合物D和化合物E。在目前倍受喜欢的实施方案中,PDE4抑制剂是化合物A(2-{6-[2-(2,3-二氯吡啶-4-基)乙酰基]-2,3-二甲氧基苯氧基}-N-丙基乙酰胺)和化合物D(2-(3,5-二氯吡啶-4-基)-1-{9-甲氧基-螺[2H-1,5-苯并二氧杂-3(4H),3’-氧杂环丁烷]-6-基}乙酮)。
本发明方法适合于治疗炎性疾病或病症。在下面实施例1中描述的细胞分析中,共施用卡泊三醇和化合物A显示出导致Th1/Th2细胞中很多广泛的因子抑制。化合物A抑制TNFα和IL-6以及卡泊三醇抑制IL-22、IL-17和IL-8通过组合治疗得以维持。更有益的是,共施用卡泊三醇导致化合物A和其它PDE4抑制剂介导的IL-22表达下调。因此,可以认为共施用PDE4抑制剂和维生素D受体激动剂可以导致显著增强PDE4抑制剂的抗炎作用,为甾体治疗提供一种具有吸引力的替代疗法。下面图7给出的结果表明在比影响角化细胞增殖所需的浓度还低的浓度下可以获得卡泊三醇对IL-22表达的作用。这表明PDE4抑制剂和维生素D受体激动剂的组合可以用于治疗其中需要抗炎作用而不伴随影响角化细胞增殖的病症。
可以用PDE4抑制剂和维生素D受体激动剂的组合治疗的炎性疾病或病症的实例是炎性变应性疾病例如支气管哮喘、COPD、变应性鼻炎和肾炎;自身免疫病例如类风湿性关节炎、多发性硬化、克隆病和系统红斑狼疮;与心力衰竭、休克和脑血管疾病等引起的缺血回流相关的器官病;胰岛素抵抗性糖尿病;创伤;和其它其中炎症在疾病的病因或进程中发挥作用的疾病。特别感兴趣的使用本发明方法治疗免疫介导的炎性疾病例如银屑病、银屑病关节炎、类风湿性关节炎、多发性硬化和炎性肠病。
在目前倍受喜欢的实施方案中,本发明方法可以用于治疗炎性皮肤疾病或病症。可以很好地用PDE4抑制剂和维生素D受体激动剂组合治疗的炎性皮肤疾病或病症的实例是银屑病、表皮炎症、脱发、皮肤萎缩、甾体诱导的皮肤萎缩、皮肤老化、光皮肤老化、痤疮、皮炎、特应性皮炎、脂溢性皮炎、接触性皮炎、荨麻疹、瘙痒和湿疹。使用本发明方法治疗其中IL-22表达上调发挥重要作用的炎性皮肤疾病或病症是特别令人感兴趣的,例如银屑病或特应性皮炎。
基于下面图7中所示的结果,目前假定足以抑制PDE4抑制剂引起的IL-22表达上调的维生素D受体激动剂的浓度可以比PDE4抑制剂的治疗有效浓度低10倍以上。目前假定维生素D受体激动剂的浓度可以比PDE4抑制剂的浓度低25倍以上、低50倍以上、低100倍以上、低250倍以上、低500倍以上、低750倍以上或低1000倍以上。
因此,当在分析中PDE4抑制剂的浓度为1μM时,足以抑制PDE4抑制剂引起的IL-22表达上调的维生素D受体激动剂的浓度可以是100nM或更低。维生素D受体激动剂的浓度的通常范围为100nM-100pM(PDE4抑制剂的浓度为1μM)。更特别的是,维生素D受体激动剂的浓度可以是75nM、50nM、40nM、30nM、25nM、20nM、10nM、5nM、1nM、0.5nM或0.1nM。
用于本发明方法的药物组合物包括治疗有效量的PDE4抑制剂和足以抑制施用PDE4抑制剂诱导的IL-22表达上调的量的维生素D受体激动剂以及可药用载体或介质。
适合的组合物包括例如适合口服(包括持续或定时释放)、经皮、眼、局部、真皮、鼻或口腔施用形式的那些。当用于治疗炎性皮肤疾病或病症时,局部施用所要求的组合物是特别适合的。
组合物可以通过药剂学领域中熟知的任何方法制备,例如Remington,The Science and Practice of Pharmacy,第20版,2000中所公开的。所有方法包括将活性成分与载体混合的步骤,所述的载体构成一种或多种赋形剂。通常,组合物是通过活性成分用于液体载体或细分的固体载体或两者均匀且彻底混合制备,然后,如果需要,将产品制成所需的剂型。
适合于口服施用的本发明组合物可以是分离的单元形式例如胶囊剂、小药囊、片剂或锭剂,每种包含预设量的活性成分;粉末或颗粒形式;在水性液体或非水液体中的溶液或混悬液形式,所述的非水液体例如乙醇或甘油;或水包油乳剂或油包水乳剂形式。此类油类可以是食用油,例如棉花籽油、芝麻油、椰子油或花生油。用于水性混悬液的适合的分散剂或助悬剂包括合成的或天然的树胶例如黄蓍胶、藻酸盐、阿拉伯胶、右旋糖酐、羧甲基纤维素钠、明胶、甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素、卡波姆和聚乙烯吡咯烷酮。活性成分还可以以大丸剂、药糖剂或糊剂形式施用。
片剂可以通过压制或模制活性成分与一种或多种赋形剂而制备。压制片剂可以通过在适合的机器中压制自由流动形式例如粉末或颗粒的活性成分,任选与粘合剂混合,例如乳糖、葡萄糖、淀粉、明胶、阿拉伯胶、黄蓍胶、藻酸钠、羧甲基纤维素、甲基纤维素、羟丙基甲基纤维素、聚乙二醇、石蜡等;润滑剂例如油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等;崩解剂例如淀粉、甲基纤维素、琼脂、膨润土、交联羧甲基纤维素钠、淀粉乙醇酸钠、交聚维酮等;或分散剂例如聚山梨酯80。模制片剂可以通过在适合的机器中模制粉末活性成分和用惰性液体稀释剂润湿的适合的载体的混合物而制备。
对于口服施用,PDE4抑制剂施用量可以是0.01-2mg/kg体重,更特别的是0.1-1.5mg/kg体重或0.25-1.25mg/kg体重或0.5-1mg/kg体重。维生素D激动剂的量应当相应调整,并且施用量可以是0.00001-0.001mg/kg。
经皮组合物可以是糊剂或贴剂形式。
适合于眼施用的组合物可以是活性成分的无菌水性制剂,其可以是微晶形式,例如水性微晶混悬液形式。脂质体制剂或生物可降解的聚合物体系例如Encyclopedia of Pharmaceutical Technology,第2卷,1989中所公开的,也可以用于本发明活性成分,用于眼施用。
适合于局部或眼施用的组合物包括液体或半固体制剂,例如搽剂、洗剂、凝胶剂、软膏剂、气雾剂、喷雾剂、薄膜剂、水包油或油包水乳剂例如乳膏剂或糊剂;或溶剂剂或混悬剂例如滴剂。用于眼治疗的组合物优选另外包含环糊精。
对于局部施用,PDE4抑制剂通常可以以占组合物重量的约0.01至约20%的量存在,例如占组合物重量的约0.1%至约10%,但也可以以占组合物重量至多约50%的量存在。维生素D受体激动剂的量应当相应调整,并且维生素D受体激动剂通常可以占组合物重量的约0.0001至约2.0%的量存在于组合物中。
适合于鼻或口腔施用的组合物包括散剂、自行喷雾剂(self-propelling)和喷雾(spray)制剂,例如气雾剂和喷雾剂(atomisers)。这类制剂在例如Modern Pharmaceutics,第2版,G.S.Banker and C.T.Rhodes(编辑),第427-432页,Marcel Dekker,New York;Modern Pharmaceutics,第3版,G.S.Banker and C.T.Rhodes(Eds.),第618-619页和第718-721页,MarcelDekker,New York and_Encyclopedia of Pharmaceutical Technology,第10卷,J.Swarbrick and J.C.Boylan(编辑),第191-221页,Marcel Dekker,New York中有更详细的公开。
除了上述成分,本发明组合物可以包括一种或多种另外的成分,例如稀释剂、缓冲剂、矫味剂、着色剂、表面活性剂、增稠剂、防腐剂,例如羟基苯甲酸甲酯(包括抗氧化剂)、乳化剂等。
实施例
实施例1
在体外分析中使用活化的和分化的人T-细胞评价卡泊三醇和PDE4抑制剂的抗炎作用
文献已经记录了外周血T细胞分化成特定T细胞亚群的可塑性。因此,预期可以通过体外培养一定时间建立不同系的炎性T-细胞群,并且用作体外基于细胞的分析,其中可以评价炎性T细胞的表型和抗炎药的作用。
特别感兴趣的是建立一个方案用于产生人Th1/Th17细胞,用于试验新疗法对银屑病和/或其它Th17相关疾病的功效。
材料和方法
首先使用STEMCELL的分离系统从健康供体的人外周血中阴性分离CD4+T细胞。
随后,通过用特异性抗体交联细胞表面蛋白质CD3和CD28来活化CD4+T细胞。
然后,为了诱导Th1/Th17分化,将活化的CD4+T细胞以密度2-5×106个细胞/mL培养基在烧瓶中培养,培养基是X-VIVO 15无血清培养基,在含生长和分化因子混合物的存在下,包含下列:
·rhIL-2,10ng/mL
·rhTGF-β,10ng/mL
·rhIL-1β,10ng/mL
·rhIL-6,10ng/mL
·rhIL-23,20ng/mL
·抗-IL-4抗体,1μg/mL
·抗-IL-13抗体,1μg/mL
培养基每两天更换,并且T细胞培养至多5-7天,使得完全分化成Th1/Th17细胞。
一旦T细胞分化成Th1/Th17细胞,将细胞从分化介质中冲洗并且放置在分析介质(X-VIVO 15培养基,仅包含10ng/mL rhIL-2)中,在孔中最终浓度1-1.5×106个细胞/mL,每孔0.250mL细胞悬浮液(0.25-0.375×106个细胞/孔/样品),包含和不含试验化合物,处理24小时。在终点时,通过测量细胞培养上清液中释放的表型相关细胞因子的水平来评价抗炎药的作用。每个处理使用一式两份和不同供体的细胞。
结果
在体外培养和分化中Th1/Th17表型的特征
CD4+T细胞体外培养至多7天。通过细胞培养基上清液的细胞因子分析来评价细胞Th1/Th17表型。特别是,在分化压力下培养5-7天后,将T细胞从分化介质中冲洗并且放置在基础培养基中,最终浓度为1-1.5×106个细胞/mL。基础培养基代表生长介质但没有任何分化压力,其是仅包含2mM glutamax、1×pen/strep和10ng/mL rhIL-2的X-VIVO15培养基。
还在供体之间观察到Th1/Th17表型的变异;然而,变异通常很小,同时没有分化成Th1/Th17也是很少发生的(该种情况小于1%)。
分化的人Th1/Th17细胞的细胞因子表达分析显示细胞能很好地表达Th1相关的细胞因子IFNγ以及Th17相关的细胞因子IL-17和IL-22。
在炎症Th1/Th17细胞模型中评价卡泊三醇和化合物A的组合
分化5-6天后,将所有细胞小心洗涤并且放置在包含IL-2(X-VIVO+10ng/mL IL-2)的生长培养基中,终浓度为1-1.5×106个细胞/mL。向完全分化的人Th1/Th17细胞中单独或组合加入卡泊三醇(12nM、100nM和120nM)和化合物A(0.5μM、1μM和5.6μM)的稀释液。分析一式两份,并且包括未分化的人T细胞(阴性对照)和处理或未处理的分化的人Th1/Th17细胞。所有细胞在类似的条件下在包含0.1%DMSO以及存在或不存在试验化合物的分析培养基中培养。
Th1/Th17细胞在存在或不存在试验化合物下处理24小时。
从所有样品中收集上清液并且评价细胞因子表达(IL-6、IL-8、IL-17、IL-22和TNF-α)。使用MSD试剂盒测量所有细胞因子(以pg/mL表示),除了IL-22是用ELISA测量。
结果
数据分析和图像是用Excel或GraphPad Prism处理。统计学分析是用1way ANOVA分析,用Dunnett’s Multiple Comparison Test校正。
在进行的所有分析中,单独的卡泊三醇强烈抑制IL-22的表达(参见图3b)、IL-8的表达,一定程度上抑制IL-17的表达,但对TNF-α和IL-6的表达没有任何效果。
单独的化合物A(参见图2和3b)和其它试验的PDE4抑制剂(参见图1、4和5)增加IL-22的表达,并且一定程度增加IL-17的表达,而化合物A强烈降低TNFα的表达(参见图3a),并且较弱降低IL-6的表达,但对IL-8没有任何作用。
当卡泊三醇和化合物A共施用时,组合治疗导致人Th1/Th17细胞中广泛的细胞因子抑制。组合治疗维持了化合物A对TNFα和IL-6的抑制,以及卡泊三醇对IL-22、IL-17和IL-8的抑制(图3a和3b分别为TNFα和IL-22)。在这些试验中,卡泊三醇与PDE4抑制剂的比例为1:50。
结论
·在人Th1/Th17细胞中单独的化合物A显著抑制TNFα(图3a)和IL-6表达,并且显著增加IL-22表达(图3b)。
·上调IL-22表达的能力是剂量依赖的(图2),并且在数种PDE4抑制剂中观察到(图1)。
·在人Th1/Th17细胞中单独的卡泊三醇显著抑制IL-22表达(图3b),并且抑制IL-8,在一定程度上抑制IL-17表达。
·卡泊三醇和化合物A的组合治疗导致在人Th1/Th17细胞中广泛的细胞因子抑制。组合治疗维持了化合物A对TNF-α和IL-6的抑制,以及卡泊三醇对IL-22、IL-17和IL-8的抑制。
数种PDE4抑制剂单独或与卡泊三醇组合的作用
试验了在临床开发中的数种PDE4抑制剂(罗氟司特、替托司特、GSK256066、Oglemilast、阿普司特和AN2728)单独或与卡泊三醇组合时对人Th1/Th17细胞活性的作用。
如图5所示,相比介质处理的对照(虚线所示),单独用100nM卡泊三醇处理显著抑制人Th1/Th17细胞的IL-22表达和分泌。相反,相比介质处理的对照,单独用化合物A或所有试验的PDE4抑制剂处理增加了人Th1/Th17细胞的IL-22表达。
而且,用PDE4抑制剂和卡泊三醇的组合处理显著抑制了人Th1/Th17的IL-22表达和分泌,不管组合中存在哪种PDE4抑制剂。换而言之,在该研究中试验的临床开发中的所有PDE4抑制剂(罗氟司特、替托司特、GSK256066、Oglemilast、阿普司特和AN2728)都表现出与化合物A相当的功效,并且通过抑制PDE4活性介导IL-22表达上调可以被卡泊三醇抵消。
数种维生素D类似物单独或与化合物A组合的作用
试验了在临床使用中的数种维生素D类似物(卡泊三醇、骨化三醇、他卡西醇和马沙骨化醇)单独或与化合物A组合时对人Th1/Th17细胞活性的作用。
如图6所示,相比介质处理的对照(虚线所示),单独用100nM卡泊三醇处理显著抑制人Th1/Th17细胞的IL-22表达和分泌。类似地,单独用所有试验的维生素D类似物处理(所有试验为100nM)也显著抑制人Th1/Th17细胞的IL-22表达和分泌,并且作用与用100nM卡泊三醇处理后观察的作用相当。
相反,相比介质处理的对照,单独用化合物A处理增加了人Th1/Th17细胞的IL-22表达。
而且,化合物A和维生素D类似物的组合处理显著抑制了人Th1/Th17的IL-22表达和分泌,不管哪种维生素D类似物是组合的一部分。换而言之,在该研究中试验的临床使用的所有维生素D类似物(卡泊三醇、骨化三醇、他卡西醇和马沙骨化醇)在抵消抑制PDE4活性介导的IL-22表达上调中都表现出与卡泊三醇相当的功效。
存在和不存在化合物A时不同浓度的卡泊三醇的作用
存在或不存在浓度为1μM的化合物A时,试验了不同浓度的卡泊三醇(MC903)对人Th1/Th17细胞活性的作用。本研究的目的是确定抑制PDE4抑制剂介导的IL-22表达上调所需的卡泊三醇的最小浓度。
如图7所示,相比介质处理的对照(虚线所示),单独用100nM卡泊三醇处理抑制了人Th1/Th17细胞的IL-22表达和分泌,而单独用化合物A处理增加了人Th1/Th17细胞的IL-22表达。
用不同浓度的卡泊三醇(100nM、1nM、500pM和100pM)连同化合物A处理抑制了IL-22表达上调。该作用在浓度为10pM卡泊三醇下失效。
这些结果显示卡泊三醇对IL-22表达的作用可以在比影响角质细胞增殖所需的浓度(28nM)低很多的浓度下获得。这意味着PDE4抑制剂和维生素D受体激动剂的组合可以用于病症的治疗,其中需要抗炎作用而不伴随影响角质细胞增殖。
Claims (19)
1.抑制活化的和分化的人T-细胞中促炎细胞因子白介素-22(IL-22)表达上调的方法,所述的上调是由施用治疗有效量的磷酸二酯酶4(PDE4)抑制剂诱导的,该方法包括与PDE4抑制剂的施用依次或同时施用足以抑制IL-22表达上调的量的维生素D受体激动剂。
2.权利要求1的方法,其中维生素D受体激动剂选自卡泊三醇、骨化三醇、他卡西醇和马沙骨化醇。
3.权利要求2的方法,其中维生素D受体激动剂是卡泊三醇或卡泊三醇一水合物。
4.权利要求1-3的任意一项的方法,其中PDE4抑制剂选自罗氟司特、GSK256066、oglemilast、替托司特、阿普司特、AN2728、化合物A、化合物B、化合物C、化合物D和化合物E。
5.权利要求4的方法,其中PDE4抑制剂是2-{6-[2-(2,3-二氯吡啶-4-基)乙酰基]-2,3-二甲氧基苯氧基}-N-丙基乙酰胺(化合物A)或2-(3,5-二氯吡啶-4-基)-1-{9-甲氧基-螺[2H-1,5-苯并二氧杂-3(4H),3’-氧杂环丁烷]-6-基}乙酮(化合物D)。
6.权利要求1-5的任意一项的方法,用于治疗炎性疾病或病症。
7.权利要求6的方法,其中炎性疾病或病症选自炎性变应性疾病例如支气管哮喘、COPD、变应性鼻炎和肾炎;与心力衰竭、休克和脑血管疾病等引起的缺血回流相关的器官病;胰岛素抵抗性糖尿病;创伤;和免疫介导的炎性疾病例如银屑病、银屑病关节炎、类风湿性关节炎、多发性硬化、系统性红斑狼疮、克隆病和炎性肠病。
8.权利要求6或7的方法,其中炎性疾病或病症是炎性皮肤疾病或病症。
9.权利要求8的方法,其中炎性皮肤疾病或病症选自银屑病、表皮炎症、脱发、皮肤萎缩、甾体诱导的皮肤萎缩、皮肤老化、光皮肤老化、痤疮、皮炎、特应性皮炎、脂溢性皮炎、接触性皮炎、荨麻疹、瘙痒和湿疹。
10.用于治疗炎性疾病或病症的药物组合物,该药物组合物包含治疗有效量的PDE4抑制剂和足以抑制施用PDE4抑制剂诱导的促炎细胞因子IL-22表达上调的量的维生素D受体激动剂以及可药用载体或介质。
11.权利要求10的组合物,其中维生素D受体激动剂选自卡泊三醇、骨化三醇、他卡西醇和马沙骨化醇。
12.权利要求11的组合物,其中维生素D受体激动剂是卡泊三醇或卡泊三醇一水合物。
13.权利要求10-12的任意一项的组合物,其中PDE4抑制剂选自罗氟司特、GSK256066、oglemilast、替托司特、阿普司特、AN2728、化合物A、化合物B、化合物C、化合物D和化合物E。
14.权利要求13的组合物,其中PDE4抑制剂是2-{6-[2-(2,3-二氯吡啶-4-基)乙酰基]-2,3-二甲氧基苯氧基}-N-丙基乙酰胺(化合物A)或2-(3,5-二氯吡啶-4-基)-1-{9-甲氧基-螺[2H-1,5-苯并二氧杂-3(4H),3’-氧杂环丁烷]-6-基}乙酮(化合物D)。
15.权利要求10-14的任意一项的组合物,其中PDE4抑制剂以约0.01至约20%重量的量存在。
16.权利要求10-15的任意一项的组合物,其中维生素D受体激动剂以约0.0001至约2.0%重量的量存在。
17.权利要求10-16的任意一项的组合物,用于治疗炎性疾病或病症,所述的炎性疾病或病症选自炎性变应性疾病例如支气管哮喘、COPD、变应性鼻炎和肾炎;与心力衰竭、休克和脑血管疾病等引起的缺血回流相关的器官病;胰岛素抵抗性糖尿病;创伤;和免疫介导的炎性疾病例如银屑病、银屑病关节炎、类风湿性关节炎、多发性硬化、系统性红斑狼疮、克隆病和炎性肠病。
18.权利要求17的组合物,用于治疗炎性皮肤疾病或病症。
19.权利要求19的组合物,其中炎性皮肤疾病或病症选自银屑病、表皮炎症、脱发、皮肤萎缩、甾体诱导的皮肤萎缩、皮肤老化、光皮肤老化、痤疮、皮炎、特应性皮炎、脂溢性皮炎、接触性皮炎、荨麻疹、瘙痒和湿疹。
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- 2013-11-28 RU RU2015125680A patent/RU2663448C2/ru not_active IP Right Cessation
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RU2015125680A (ru) | 2017-01-10 |
US20150297616A1 (en) | 2015-10-22 |
EP2925364A1 (en) | 2015-10-07 |
HK1212894A1 (zh) | 2016-06-24 |
JP6367819B2 (ja) | 2018-08-01 |
WO2014083099A1 (en) | 2014-06-05 |
JP2016501209A (ja) | 2016-01-18 |
CN104822392B (zh) | 2017-09-08 |
RU2663448C2 (ru) | 2018-08-06 |
US9855285B2 (en) | 2018-01-02 |
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