CN105073110A - 通过诱导分化成调节性t细胞和促进调节性t细胞增殖来抑制免疫应答的药物组合物 - Google Patents
通过诱导分化成调节性t细胞和促进调节性t细胞增殖来抑制免疫应答的药物组合物 Download PDFInfo
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Abstract
本发明涉及(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺的新制药用途,更具体而言,本发明涉及包含所述化合物作为活性成分的药物组合物,其用于抑制免疫应答,和/或用于由未分化的T细胞诱导分化成调节性T细胞和/或促进调节性T细胞增殖。
Description
技术领域
本发明涉及(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺的新制药用途。更具体地,本发明涉及通过四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺对诱导分化和促进调节性T细胞增殖的作用,以及对活化的调节性T细胞的免疫调节作用来预防或治疗多种免疫疾病(包括移植物抗宿主病(GVHD))的方法;用于在这样的方法中使用的药物组合物;以及通过使用所述药物组合物来获得用于预防或治疗免疫疾病的调节性T细胞的方法。
背景技术
免疫是指通过识别和移除存在于体内的外来抗原物质的对外来物质的自身保护作用。可将免疫应答大致分为细胞介导免疫应答和体液免疫应答。在体液免疫应答中,B细胞分泌的抗体识别外来抗原并将其中和,通过结合至被识别为非自身的其它细胞表面来帮助巨噬细胞的吞噬作用,或通过激活补体系统来增加特异性免疫应答。在细胞介导免疫应答中,细胞毒性T细胞(Tc细胞)通过分泌细胞因子(如IL-2和IFN-γ)来直接使外来抗原失活或活化巨噬细胞。这样,在免疫应答中,区分自身和非自身抗原的能力是绝对重要的。
然而,在移植同种异体的或异种的细胞、组织或器官的具体情况中,需要抑制免疫应答来预防对有益的外来移植物的排斥。例如,为了治疗血癌(例如白血病)、骨髓瘤、淋巴瘤和再生障碍性贫血,已将同种异体骨髓移植或造血干细胞移植用作有效的治疗方法。然而,在通过将宿主识别为非自身抗原的免疫排斥应答的情况中,来自于供体的移植物可对受体的组织、皮肤、器官等造成损伤,在最坏情况中甚至死亡。这样,将其中移植物通过引起免疫排斥应答来损伤宿主的组织的疾病称作移植物抗宿主病(GVHD)。例如,在干细胞移植的情况中是指移植到骨髓的新细胞(移植物)将患者(宿主)的组织识别为外来的,使得同种异体供体的干细胞损伤受体的组织、皮肤、消化器官、或诸如肝的器官等。在移植物抗宿主病的发病机制中,患者的抗原呈递细胞激活移植的骨髓细胞中的T细胞,以使其分化成Th1细胞并增加如IL-2和IFN-γ的细胞因子的分泌,从而激活细胞毒性T细胞和天然杀伤细胞,它们攻击患者的器官导致移植物抗宿主病。移植物抗宿主病的主要原因是同种异体骨髓移植或造血干细胞移植。具体地,已报道移植物抗宿主病是由造血干细胞移植引起,并且15-30%的患者死亡。因此,为了防止移植物抗宿主病的发生并确保移植物长时间存活,应避免受体的识别外来抗原的免疫系统或者应抑制免疫应答。
此外,在诸如变态反应的免疫过敏性反应中,在个体的免疫反应造成比入侵的外来物质更大的损伤的情况下,必须抑制免疫反应。这样的过敏性疾病的实例为变应性鼻炎、哮喘、特应性皮炎等。此外,自身免疫病是指其中免疫系统对个体身体的部分过度敏感,使得区分自身和非自身的能力欠缺,损伤自己身体的疾病。自身免疫病也需要抑制免疫应答的治疗。这样的自身免疫病的实例为风湿性关节炎、胰岛素依赖性糖尿病、多发性硬化、狼疮、银屑病、炎性肠病、溃疡性结肠炎、重症肌无力、多肌炎、皮肌炎、自身免疫性血细胞减少症、血管炎综合征、系统性红斑狼疮等。在全世界,免疫过敏性反应引起的疾病已经增加,但是导致这样的疾病的根源还未充分研究。因此,抑制免疫反应已经被广泛用作用于治疗患有免疫疾病(如移植排斥、移植物抗宿主病、过敏性疾病和自身免疫病)的患者的有用疗法。现在,已研发许多用于抑制免疫反应的化学免疫抑制剂,并且环孢菌素A表现最好的临床效果,并已被广泛用于自身免疫病(包括移植物抗宿主病、移植排斥和多种炎性疾病)。当以高剂量使用环孢菌素A时,其完全抑制T细胞的激活来治疗疾病,但是具有显示相当大的副作用(包括肾毒性)的缺点。因此,推荐将其以低剂量使用。此外,为了帮助克服由于低剂量使用而降低的药物效果,已进行与2或3个其它免疫抑制剂的联合给药。然而,对于联合给药,存在两个化合物的作用机制和毒性位点不同的先决条件。因此,需要研发能够替代常规免疫抑制剂的更有效的免疫抑制剂。
同时,T细胞(在免疫系统中发挥核心作用的细胞组之一)在胸腺中成熟,并归类为CD4阳性辅助性T细胞(Th细胞)和CD8阳性细胞毒性T细胞。通过一系列分化过程,辅助性T细胞分化成具有本质特性的T细胞—Th1(T辅助型1)、Th2(T辅助型2)、Th17(T辅助型17)、调节性T细胞(Treg细胞)等。调节性T细胞具有通过抑制异常激活的免疫细胞的功能来控制炎症反应的特性,因此已知免疫疾病可以通过增加调节性T细胞的活性的作用来治疗。调节性T细胞使用CD4+CD25+作为标志物,并表达转录因子Foxp3。调节性T细胞在免疫耐受性和自身免疫病中的重要性在具有Foxp3突变的scurfy小鼠中是明显的。具有Foxp3突变的scurfy小鼠由于CD4+T细胞的过度激活以及炎症细胞因子的过度产生在出生后仅一个月就死亡(SakaguchiS.等人,Cell2008,133:775-787),在人类中其是Foxp3基因突变遗传性疾病,引起多种自身免疫病(如1型糖尿病、变态反应、炎性肠病等)的IPEX(X连锁多内分泌腺病肠病伴免疫失调综合征(immunodysregulationpolyendocrinopathyenteropathyX-linkedsyndrome))的原因(ItohM.等人,JImmunol1999,162:5317-5326)。因此,可以预期能够通过激活调节性T细胞或给药具有调节性T细胞作为活性成分的药物来治疗多种免疫疾病(包括自身免疫病和慢性炎性疾病)。然而,与其它由胸腺产生的T淋巴细胞相比,调节性T细胞是具有免疫抑制功能的已分化细胞,并且它们已经被胸腺中的自身抗原刺激。调节性T细胞包含约5%的胸腺T淋巴细胞和约10-15%的存在于终末器官的CD4+T淋巴细胞。因此,很难获得治疗有效量的调节性T细胞,并且需要有效地获得大量调节性T细胞的方法。
同时,第10-2009-0018593号韩国专利申请公开提供具有抑制细胞坏死活性的新型吲哚或吲唑化合物以及用于治疗坏死相关疾病的包含其的治疗剂。然而,上述专利文件仅公开了上述吲哚或吲唑化合物抑制细胞坏死和与一些坏死相关疾病(如肝疾病、神经变性疾病等)相关的活性,从未提及上述化合物与调节性T细胞的关系、对抑制免疫应答的效能或将其用于治疗免疫过敏性反应相关疾病的可能性。
因此,本发明人旨在提供能够替代或辅助常规的免疫抑制剂的具有优异的免疫抑制效能的化合物。因此本发明人发现第10-2009-0018593号韩国专利申请公开的化合物(具体为(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺,已知其为细胞坏死抑制剂)促进未成熟T细胞分化成调节性T细胞并增殖,并且表现出优异的免疫抑制效能,因此可被广泛地应用于移植排斥、移植物抗宿主病、过敏性疾病、自身免疫病等的治疗,以完成本发明。
发明内容
技术问题
因此,本发明的目的是提供用于抑制免疫应答的药物组合物,其包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体。
本发明的另一目的是提供用于预防和治疗免疫疾病的药物组合物,其包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体,所述免疫疾病例如移植排斥、移植物抗宿主病、过敏性疾病、自身免疫病和炎性疾病。
本发明的另一目的是提供用于诱导未成熟T细胞分化成调节性T细胞和/或促进调节性T细胞增殖的组合物,其包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体。
本发明的另一目的是提供用于通过诱导分化成调节性T细胞和促进增殖来获得调节性T细胞的方法,其包括用包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体的组合物处理未成熟T细胞的步骤。
本发明的另一目的是提供用于预防或治疗免疫疾病(例如移植排斥、移植物抗宿主病、过敏性疾病、自身免疫病和炎性疾病)的药物组合物,其包含通过用包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体的组合物处理未成熟T细胞获得的调节性T细胞。
解决问题的技术方案
为了实现上述目的,本发明提供用于通过诱导分化成调节性T细胞和/或促进增殖来激活调节性T细胞以用于抑制免疫应答的药物组合物,其包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体。
作为一个方面,本发明提供用于抑制免疫应答的药物组合物,其包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体。
作为另一方面,本发明提供用于通过激活调节性T细胞来抑制免疫应答以预防或治疗免疫疾病(例如移植排斥、移植物抗宿主病、过敏性疾病、自身免疫病和炎性疾病)的药物组合物,其包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体。
作为另一方面,本发明提供用于诱导未成熟T细胞分化成调节性T细胞和/或促进调节性T细胞增殖的组合物,其包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体。
作为另一方面,本发明提供用于通过诱导分化成调节性T细胞和促进增殖来获得调节性T细胞的方法,其包括用包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体的组合物处理未成熟T细胞的步骤。
作为另一方面,本发明提供用于预防和治疗免疫疾病(例如移植排斥、移植物抗宿主病、过敏性疾病、自身免疫病和炎性疾病)的药物组合物,其包含通过用包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体的组合物处理未成熟T细胞获得的调节性T细胞。
制备本发明的化合物((四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺)的方法可指在第10-2009-0018593号韩国专利申请公开中公开的方法。上述专利文件以其整体援引加入本文。
本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺可形成药学上可接受的盐。这样的“药学上可接受的盐”包括包含药学上可接受的阴离子的无毒酸加成盐—例如与无机酸(如硫酸、盐酸、硝酸、磷酸、氢溴酸、氢碘酸等)的盐;与有机羧酸(如酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡糖酸、苯甲酸、乳酸、反丁烯二酸、顺丁烯二酸、水杨酸等)的盐;或与磺酸(如甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、萘磺酸等)的盐。另外,还包括药学上可接受的碱加成盐—例如与碱金属或碱土金属(如锂、钠、钾、钙、镁等)的盐;与氨基酸(如赖氨酸、精氨酸、胍等)的盐;或与二环己胺、N-甲基-D-葡糖胺、三(羟甲基)甲胺、二乙醇胺、胆碱、三乙胺等的有机盐。可通过任何常规方法将本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺转化成它们的盐,并且本领域技术人员在无额外解释下可容易地实施盐形成。
术语“异构体”在本说明书中意指与所述化合物或其盐具有相同的化学式或分子式,但光学上或立体上与之不同的那些。本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺的结构中可具有不对称的碳中心,因此可以旋光异构体(R或S异构体)、外消旋体、非对映异构体的混合物、或单个非对映异构体等的形式存在。本发明也涵盖所有异构体及其混合物。
在下文中,除非另外说明,本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺包括其药学上可接受的盐和异构体。
本发明的特征在于提供包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体的组合物,其用于抑制免疫应答。
在本说明书中,术语“免疫抑制”或“免疫应答抑制”是指抑制由外来或自身抗原对身体造成的不利免疫应答。
本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺可用于抑制在所有细胞、组织和器官的移植中可发生的免疫排斥应答。例如,它可用于抑制在移植皮肤、血液、角膜、肝、肺、肠、胰、心脏、肾、骨髓、干细胞、前体细胞等时的免疫排斥应答,并可优选地用于抑制由皮肤移植物、骨髓移植、干细胞移植、输血和器官移植引起的免疫排斥应答。
因此,本发明的药物组合物通过抑制对移植的器官、组织或细胞的免疫应答来用于治疗和预防移植排斥和/或移植物抗宿主病。
在本说明书中,“治疗”意指当施用于显示疾病症状开始的个体时中断或延迟疾病进展,并且“预防”意指当施用于未显示疾病症状开始,但有疾病症状开始的风险的个体时中断或延迟疾病开始的迹象。
另外,本发明的药物组合物可用于治疗和预防由免疫过敏性反应引起的多种免疫过敏相关疾病,优选过敏性疾病、自身免疫病和炎性疾病。过敏性疾病的实例为变应性鼻炎、哮喘、特应性皮炎等。另外,自身免疫病的实例为风湿性关节炎、胰岛素依赖性糖尿病、多发性硬化、狼疮、银屑病、炎性肠病、溃疡性结肠炎、重症肌无力、多肌炎、皮肌炎、自身免疫性血细胞减少症、血管炎综合征、系统性红斑狼疮等。
在本发明的具体实施例中,为确定本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺对抑制免疫应答的作用,通过将供体小鼠的骨髓和脾细胞移植到辐射照射的受体小鼠来制备同种异体的免疫应答小鼠模型,并给药本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺来测量是否发生免疫移植排斥。结果是其中用本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺治疗的组的生存率与未治疗组相比相当大地提高,并在体重和移植物抗宿主反应的评价中观察到显著的结果(图1和2)。在组织学观察中,作为大肠H&E染色的结果观察到其中未用本发明的化合物治疗的疾病小鼠模型中的大肠的绒毛和粘膜被破坏,但是其中用本发明的化合物治疗的组与正常的大肠相似(图3)。
另外,作为通过在同种异体免疫应答小鼠模型中氧化性应激来观察免疫应答的结果,观察到与未用本发明的化合物治疗的组相比,在其中用本发明的化合物治疗的组中,细胞中活性氧簇(ROS)的产生比率以剂量和时间依赖性的方式被显著抑制(图4),并且高速泳动族蛋白B1(在下文中称作“HMGB1”)(其为免疫调节功能的标志物)的表达被显著抑制(图5)。
这样,在同种异体免疫应答小鼠模型中确证本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺降低免疫移植排斥,并抑制ROS和HMGB1的产生和组织中的细胞坏死。此外,作为确定在细胞水平调节免疫应答可能性的结果,与其中未用本发明的化合物治疗的组相比,在其中用本发明的化合物治疗的组中,CD4+CD25+Foxp3+免疫调节性细胞(调节性T细胞)增加6倍或更多,并且CD4+IL-4细胞增加,但CD4+IFN-γ减少多于一半(图6)。IFN-γ是由移植的供体T细胞分泌的导致移植物抗宿主病的代表性细胞因子,并且可已知本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺通过上调调节性T细胞和IL-4来抑制移植的T细胞的激活。
从这样的实验结果可确证本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺增加调节性T细胞,通过增加的调节性T细胞的免疫抑制作用抑制移植的T细胞的激活,控制炎症反应,以及具有通过降低细胞中的活性氧簇(ROS)和HMGB1的表达来抑制免疫应答的效能。因此,本发明的化合物可有助于用作用于抑制免疫应答的药物组合物,并更广泛地应用于治疗需要抑制免疫应答的免疫疾病,例如移植排斥、移植物抗宿主病、过敏性疾病、自身免疫病、炎性疾病等。
可将用于免疫抑制的包含本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺的药物组合物与其它已知的免疫抑制剂联合使用。可联合的其它免疫抑制剂的实例为但不限于环孢菌素A、雷帕霉素、他克莫司、sacrolimus、甲氨蝶呤、硫唑嘌呤、吗替麦考酚酯和多种类固醇制剂。
作为本发明的另一方面提供用于诱导未成熟T细胞分化成调节性T细胞和/或促进调节性T细胞增殖的药物组合物,其包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体。
在本说明书中,术语“调节性T细胞”是指能够调节T细胞应答,使用CD4+CD25+作为标志物并表达转录因子Foxp3的细胞。调节性T细胞具有通过抑制非正常激活的免疫细胞的功能来控制炎症反应的性质,并且其抑制慢性炎症反应,使得可表现出对治疗免疫耐受和自身免疫病的效果。特别地,已知Foxp3因子在调节性T细胞的分化和激活中发挥重要作用。
因此,由本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺诱导的调节性T细胞可用于抑制在所有细胞、组织和器官的移植中可发生的免疫排斥应答。例如,它可用于抑制在移植皮肤、血液、角膜、肝、肺、肠、胰、心脏、肾、骨髓、干细胞、前体细胞等时的免疫排斥应答,并优选地可用于抑制由皮肤移植物、骨髓移植、干细胞移植、输血和器官移植引起的免疫排斥应答。因此,由本发明的化合物诱导的调节性T细胞可用于通过抑制对移植的器官、组织或细胞的免疫应答来治疗和预防移植排斥或移植物抗宿主病。另外,由本发明的化合物诱导的调节性T细胞可用于治疗和预防由免疫过敏性反应引起的多种免疫过敏相关疾病,优选过敏性疾病、自身免疫病和炎性疾病。自身免疫病的实例是风湿性关节炎、胰岛素依赖性糖尿病、多发性硬化、狼疮、银屑病、炎性肠病、溃疡性结肠炎、重症肌无力、多肌炎、皮肌炎、自身免疫性血细胞减少症、血管炎综合征、系统性红斑狼疮等。
在本发明的具体实施例中,确认本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺促进从小鼠脾细胞分离的CD4+T细胞分化成调节性T细胞(图7和8),并且与过去已知作为分化诱导剂的视黄醛或视黄酸相比,这样的效果是优异的。此外,确认在将本发明的化合物与视黄醛或视黄酸联合治疗的情况中,对于促进分化成调节性T细胞的效果更加提高(图9和10)。此外,在体外实验中,通过本发明的化合物处理来诱导的调节性T细胞表现出对于抑制T细胞和同种异体免疫应答细胞的增殖的效果,并且在体内移植物抗宿主病小鼠模型中,确认其对调节性T细胞的免疫调节功能的效果(图11-14)。
因此,本发明的化合物或包含其的组合物可有益地用于通过诱导未成熟T细胞分化成调节性T细胞和/或促进调节性T细胞增殖来大规模制备或富集(concentration)治疗有效量的调节性T细胞,以用于治疗免疫疾病和慢性炎性疾病。
优选地,包含本发明的化合物的用于诱导未成熟T细胞分化成调节性T细胞和/或促进调节性T细胞增殖的药物组合物还可包含用于分化成调节性T细胞的抗CD3抗体、抗CD28抗体和TGF-β,并且其还可包含作为常规分化诱导剂的视黄醛或视黄酸,以进一步改善对于促进分化和增殖的效果。
通过本发明的化合物分化的调节性T细胞表现CD4+、CD25+和Foxp3+的表型,并且在同种异体免疫应答细胞和GVHD小鼠中具有调节和抑制免疫应答的功能。
此外,本发明提供用于治疗免疫疾病(例如移植排斥、移植物抗宿主病、过敏性疾病、自身免疫病和炎性疾病)的组合物,其包含通过用本发明的化合物或包含其的组合物处理未成熟T细胞所获得的调节性T细胞。
本发明的药物组合物可包含药学上可接受的载体、稀释剂、赋形剂或其组合,如果需要,连同本发明的化合物。药物组合物便于将所述化合物向活有机体给药。有多种给药化合物的技术,并且它们包括但不限于口服、注射、气雾剂、肠胃外和局部给药。
在本说明书中,药学上可接受的载体意指不显著地刺激活有机体且不抑制要给药的化合物的生物活性和性质的载体或稀释剂。此外,添加剂可便于制剂的制备、可压性、外观和味道。例如,如果需要,可添加稳定剂、表面活性剂、滑动修饰剂(slipmodifier)、增溶剂、缓冲剂、甜味剂、碱性化合物、吸收剂、增味剂、粘合剂、助悬剂、硬化剂、抗氧化剂、抛光剂、香味成分、调味剂、色素、包衣剂、湿润剂、湿度调整剂、填充剂、消泡剂、清新剂、咀嚼剂、抗静电剂、着色剂、糖包衣剂、等渗剂、柔软剂、乳化剂、粘着剂、增稠剂、发泡剂、pH调节剂、赋形剂、分散剂、崩解剂、防水剂、杀菌剂、防腐剂、增溶助剂、溶剂、增塑剂等。
包含在本发明的药物组合物中的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺的剂量取决于医师的处方,其将患者的体重、性别、年龄、健康状况和饮食、疾病的特定本质、药剂的给药时间、给药方法、药剂的混合比率以及疾病的严重性等这样的因素考虑在内。然而,对于成人的治疗所需的剂量通常为每天约1.0mg到2,000mg,取决于给药的强度和频率。当经由肌内或静脉内途径向成人给药时,当以单个剂量单独给药时,每天约1.0mg到300mg的总剂量通常是足够的,但对于一些患者可能需要更高的每日剂量。
发明效果
本发明的药物组合物可有益地用作用于抑制免疫应答的药物组合物,并且更可广泛地应用于治疗移植排斥、移植物抗宿主病、过敏性疾病、自身免疫病等。此外,它能够有益地用于通过促进未成熟T细胞分化成调节性T细胞和增殖来大规模地获得治疗有效量的调节性T细胞,以用于治疗免疫疾病和慢性炎性疾病,并且根据本发明获得的调节性T细胞可广泛地应用于治疗需要抑制免疫应答的移植排斥、自身免疫病(如移植物抗宿主病)、慢性炎性疾病等。
附图简述
图1是其中未用化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺(在下文中称作“化合物A”)治疗的GVHD小鼠和其中用化合物A治疗的GVHD小鼠的照片。
图2是显示随着GVHD小鼠模型(其中供体小鼠的骨髓和脾细胞被移植入接受辐射的小鼠中)的移植后经过的天数,GVHD临床评分(A)、生存率(B)和体重(C)的图。■代表通过骨髓和脾细胞移植制备的GVHD小鼠,●代表其中未通过骨髓移植和脾细胞诱导GVHD的小鼠,△代表其中给药0.3mg/kg化合物A的GVHD小鼠模型,▼代表其中给药1mg/kg化合物A的GVHD小鼠模型。
图3是显示未用化合物A治疗的GVHD小鼠和用化合物A治疗的GVHD小鼠的各大肠的H&E染色结果的照片。
图4是显示未用化合物A治疗的GVHD小鼠和其中用各剂量的化合物A治疗的在治疗后第7天(A)和第14天(B)的GVHD小鼠的活性氧簇(ROS)产生比率的图。
图5是显示未用化合物A治疗的GVHD小鼠和其中用各剂量的化合物A治疗的在治疗后第7天(A)和第14天(B)的GVHD小鼠的HMGB1相对表达的图。
图6是由未用化合物A治疗的GVHD小鼠和用化合物A治疗的GVHD小鼠分离的脾的调节性T细胞(CD4+CD25+Foxp3+)和CD4+IFN-γ细胞的流式细胞仪分析的结果。
图7是显示由小鼠脾细胞(其中用抗-CD3(aCD3)和抗-CD28(aCD28)处理、向其中另外用TGF-β处理,以及向其中另外用40μM或80μM化合物A处理)分离的CD4+细胞分化成调节性T细胞(CD4+CD25+Foxp3+)的程度。
图8是分化的细胞(其为由小鼠脾细胞(其中用抗-CD3和抗-CD28处理、向其中另外用TGF-β处理,以及向其中另外用40μM或80μM化合物A处理)分离的CD4+细胞)Foxp3+表达程度的流式细胞仪分析的结果。
图9是各组中分化成调节性T细胞的效果的流式细胞仪分析的结果。在通过将由小鼠脾分离的CD4+细胞用抗-CD3和抗-CD28或附加用TGF-β处理来诱导分化成调节性T细胞的过程中,将组分为40μM化合物A处理组、80μM化合物A处理组、0.1μM视黄酸(在下文中称作“RA”)处理组、1μM视黄醛处理组、0.1μRA和40μM化合物A处理组、0.1μMRA和80μM化合物A处理组、1μM视黄醛和40μM化合物A处理组以及1μM视黄醛和80μM化合物A处理组。
图10是显示分化成调节性T细胞(CD4+CD25+Foxp3+)程度的图。在通过将由小鼠脾分离的CD4+细胞用抗-CD3、抗-CD28和TGF-β处理来诱导分化成调节性T细胞的过程中,将组分为化合物A单独处理组、视黄醛单独处理组、RA单独处理组、化合物A和视黄醛联合处理组以及化合物A和RA联合处理组。
图11是显示对于通过加入aCD3和aCD28诱导的调节性T细胞、通过加入aCD3、aCD28和TGF-β诱导的调节性T细胞(表示为“TGF-βTreg”)、通过加入aCD3、aCD28、TGF-β和RA诱导的调节性T细胞(表示为“RATreg”)、通过加入aCD3、aCD28、TGF-β和40μM化合物A诱导的调节性T细胞以及通过加入aCD3、aCD28、TGF-β和80μM化合物A诱导的调节性T细胞(表示为“化合物ATreg”),通过[3H]胸苷分析对T细胞增殖的抑制效果的结果的图。
图12是显示对于通过加入aCD3和aCD28诱导的调节性T细胞、通过加入aCD3、aCD28和TGF-β诱导的调节性T细胞(表示为“TGF-βTreg”)、通过加入aCD3、aCD28、TGF-β和RA诱导的调节性T细胞(表示为“RATreg”)、通过加入aCD3、aCD28、TGF-β和40μM化合物A诱导的调节性T细胞以及通过加入aCD3、aCD28、TGF-β和80μM化合物A诱导的调节性T细胞(表示为“化合物ATreg”),通过[3H]胸苷分析对同种异体免疫应答细胞增殖的抑制效果的结果的图。
图13是显示根据化合物A在同种异体免疫细胞中的浓度,诱导分化成调节性T细胞的效果的比较分析结果的图。
图14是显示根据化合物A在移植物抗宿主病(GVHD)小鼠模型中的浓度,促进分化成调节性T细胞的效果的比较分析结果的图。
发明实施方式
在下文中,用以下实施例更详细地说明本发明。然而,以下实施例仅意在便于本发明的理解,本发明的保护范围不受此限制。
实施例1:同种异体免疫应答小鼠模型的建立
彼此具有不同MHC种类的6-8周大的C57BL/6(H-2kb)小鼠和BALB/c(H-2kd)小鼠购自OrientBioCo.,Ltd.。在通过韩国加图立大学(TheCatholicUniversityofKorea)的实验动物部门管理委员会的规定后,将小鼠在其护理下使用。将受体小鼠BALB/c(H-2kd)用800cGy的全身辐射进行照射。在24小时内,将从供体小鼠C57BL/6(H-2kd)分离的5×106骨髓细胞和5×106脾细胞静脉移植入同种异体受体小鼠,以诱导移植物抗宿主排斥反应模型。观察骨髓移植的小鼠,并对以下进行评估:体重、姿势、活动、毛发状态和皮肤密度(用总计10分的量表,每个项目2分的评估标准)(表1)。
[表1]
评分 | 体重 | 姿势 | 活动 | 毛发状态 | 皮肤密度 |
0 | <10% | 正常 | 正常 | 正常 | 正常 |
1 | >10%到<25% | 轻微弯曲 | 略微减少 | 轻微混乱 | 脚和尾巴脱皮 |
2 | >25% | 严重弯曲 | 无刺激下不动 | 严重混乱 | 明显的皮肤起皮 |
实施例2:流式细胞仪(FACS分析)
将小鼠分成其中用(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺(LGLifeSciencesLtd.,Daejeon,韩国,在下文中称作“化合物A”)处理的GVHD组作为测试组,其中未用化合物A处理的GVHD组作为对照组。分离各组的脾,然后进行单细胞分离。通过使用荧光单克隆抗体和流式细胞仪分析CD4+CD25+Foxp3+(其为调节性T细胞的表型)的表达以及CD4+IFN-γ细胞和CD4+IL-4细胞。
实施例3:活性氧簇(ROS)的测量
将各组的动物处死,并分离它们的脾。分离单个细胞后,将获得的细胞用磷酸盐缓冲盐水(PBS)洗涤2次。将与3μM羧基-H2DCFDA试剂的反应在37℃下进行10分钟。用PBS洗涤后,用流式细胞仪在540nm下进行分析。
实施例4:RT-PCR
通过使用TRIzol试剂从细胞中提取总RNA。将1μgRNA与AMV逆转录酶和随机六聚体(hexamer)在45℃下反应1小时来合成cDNA。通过使用其中混合1μgcDNA作为模板、引物S、引物AS和蒸馏水的混合物以及SYBRGreen进行实时PCR。通过使用HMGB1(5'-GATGGGCAAAGGAGATCCTAAG-3'和5'-TCACTTTTTTGTCTCCCCTTTGGG-3')在95℃15秒、60℃10秒和72℃30秒的35个循环的条件下进行PCR。通过使用RadCFX96Real-TimeSystem(Bio-RadLaboratories)测量荧光数据。
实施例5:免疫细胞化学
从石蜡包埋组织获得4μm的连续切片,用二甲苯处理3次以移除石蜡,然后在95%、90%和70%乙醇中逐步水合。在0.5%过氧化氢中移除内源性过氧化物酶后,将标本用正常羊血清处理30分钟,然后与一级抗体(将其根据生产商的说明用PBS中的3%牛血清白蛋白(BSA)稀释)反应1小时。在一级抗体与针对在上述研究中显示表达差异的基因的蛋白质反应后,将标本用Tris缓冲盐水(TBS)洗涤3次,与5μg/ml在3%BSA中稀释的生物素化的抗小鼠/抗兔IgG反应30分钟,并用TBS洗涤三次。将标本放置于3μg/ml辣根过氧化物酶链酶亲和素中30分钟,通过使用DAB和过氧化氢进行显色,并用Meyer’s苏木素或1%甲基绿进行复染。
结果
1.通过本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺抑制小鼠模型中的免疫移植排斥。
在本发明中,通过GVHD小鼠模型观察本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺抑制免疫排斥应答的效果。结果是与未处理组相比,其中用本发明的化合物处理的组的生存率有相当大地提高,并且在体重和移植物抗宿主反应的评价中观察到显著的结果(图1和2)。在组织学观察中,作为大肠H&E染色的结果,观察到其中未用本发明的化合物治疗的疾病小鼠模型的大肠的绒毛和粘膜被破坏,但其中用本发明的化合物治疗的组与正常的大肠相似(图3)。
2.通过(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺调节氧化性应激
ROS在调节身体中的细胞功能中扮演重要角色并有助于免疫系统中免疫细胞的防御作用。在坏死细胞中,ROS由线粒体产生,从而氧化HMGB1。最终,通过氧化的HMGB1引起免疫耐受。
因此,本发明人通过GVHD小鼠模型观察由氧化性应激引起的免疫应答。结果是与对照组相比,观察到在其中用本发明的化合物处理的组中,细胞中活性氧簇的产生比率以剂量和时间依赖的方式被明显抑制(图4)。
3.通过(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺抑制HMGB1生成
已公知HMGB1的释放可能具有调节炎症和免疫的功能。因此,在该研究中,将测试组(其中用本发明的化合物处理GVHD小鼠模型)和对照模型的动物处死,由脾细胞提取RNA,然后合成cDNA,并通过实时PCR进行HMGB1表达的比较研究。结果确认与对照组相比,在其中用本发明的化合物处理的组中HMGB1的释放以时间依赖性地方式被显著抑制(图5)。
4.通过(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺调节免疫应答
本发明人发现在GVHD小鼠模型中,通过本发明的化合物降低免疫移植排斥,抑制ROS和HMGB1的产生以及组织中的细胞坏死,因此他们意图观察在免疫疾病动物模型中调节免疫应答的可能性。因此,将测试组(其中用本发明的化合物处理)和对照组的小鼠处死,并将它们的脾分离,进行单细胞分离,并通过流式细胞仪探索免疫调节的功能。结果是与对照组相比,在其中用本发明的化合物处理的组中,CD4+CD25+Foxp3+免疫调节性细胞(调节性T细胞)增加6倍或更多。另外,CD4+IL-4细胞增加,并且CD4+IFN-γ减少多于一半(图6)。在GVHD模型中,高剂量辐射照射后,供体的移植的T细胞被通过宿主的抗原呈递细胞激活和增殖,以分泌已知作为引起GVHD的代表性细胞因子IFN-γ。上述实验结果表明本发明的化合物通过上调调节性T细胞和IL-4来抑制IFN-γ。因此,可已知本发明的化合物能够通过抑制移植的T细胞的激活来抑制免疫应答。
实施例6:在体外实验中确证通过(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧
代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺的诱导分化成调节性T细胞的效果
进行研究本发明的化合物对于淋巴细胞Th细胞分化的作用的实验。将从小鼠脾细胞分离的5×105CD4+T细胞分配入涂覆有1μg/ml的抗CD3(aCD3)的24孔板中,然后用1μg/ml抗CD8(aCD28)和5ng/ml的TGF-β处理3天以诱导分化成调节性T细胞。分化成调节性T细胞前,用浓度为40μM和80μM的本发明的化合物(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺(在下文中称作“化合物A”)(LGLifeSciencesLtd.,Daejeon,韩国)处理。对于流式细胞仪,向其中加入抗小鼠CD4PerCP、CD25APC和FoxP3PE荧光标记的抗体,并在4℃下反应30分钟。用PBS洗涤后,用流式细胞仪(FACSCaliburTM)进行测量。
这样,由于在通过用aCD3、aCD28和TGF-β刺激CD4+T细胞创造调节性T细胞分化环境后用化合物A处理,与其中未用化合物A处理的对照组相比,通过促进分化成调节性T细胞,Foxp3+的表达几乎翻倍,并且分化成调节性T细胞以化合物A浓度依赖的方式增加。特别地,可明白化合物A通过调节TGF-β信号来促进分化成Foxp3+Treg细胞(图7和8)。
实施例7:在体外实验中通过常规分化诱导剂视黄醛/视黄酸和化合物
A比较增殖调节性T细胞,以及确证联合疗法的效果
已知在TGF-β存在下,RA增加分化成Foxp3+Treg。从实施例6的实验结果,确证化合物A强烈地特别地增加Foxp3+的表达,因此进行其中将化合物A与常规已知的RA的效果比较的实验。
在将由小鼠脾细胞分离的5×105CD4+T细胞分配入涂覆有1μg/ml抗CD3(aCD3)的24孔板中,然后用1μg/ml抗CD8(aCD28)和5ng/ml的TGF-β处理3天以诱导分化成调节性T细胞的过程中,将组分成(1)40μM或80μM化合物A单独处理组、(2)0.1μM视黄酸(RA)单独处理组、(3)1μM视黄醛处理组、(4)0.1μMRA和40μM或80μM化合物A处理组以及(5)1μM视黄醛和40μM或80μM化合物A处理组,比较各组对于分化成调节性T细胞的效果。
如上,作为在aCD3、aCD28和TGF-β存在下用各单独的化合物或其组合处理CD4+细胞的结果,在用化合物A单独处理的情况中,Foxp3+的表达增加至与用视黄醛或RA处理的情况中相似的程度。另外,在用化合物A与RA或视黄醛的组合处理的情况中,与其中用各化合物单独处理的组相比,Foxp3+的表达增加。这些结果证实在Th细胞的分化中,化合物A促进分化成调节性T细胞(图9和10)。
实施例8:确证通过化合物A诱导的调节性T细胞对于抑制同种异体
免疫应答细胞增殖的效果
为了确证通过化合物A诱导的调节性T细胞(在下文中称作“iTreg”)的功能,评估iTreg细胞是否能够抑制T细胞增殖(aCD3+aCD28+刺激)以及同种异体免疫应答细胞的活性(B6CD4+和2000cGyB/cAPC的同种异体应答)。为此,(1)通过加入aCD3和aCD28诱导的Treg细胞,(2)通过加入aCD3、aCD28和TGF-β诱导的Treg细胞(称作“TGF-βTreg”),(3)通过加入aCD3、aCD28、TGF-β和RA诱导的Treg细胞(称作“RATreg”),(4)通过加入aCD3、aCD28、TGF-β和40μM化合物A诱导的Treg细胞(称作“化合物ATreg”),以及(5)通过加入aCD3、aCD28、TGF-β和80μM化合物A诱导的Treg细胞(称作“化合物ATreg”),并且通过混合的白细胞培养测试进行比较分析。
首先,进行T细胞增殖的分析。将1×105小鼠CD4+T细胞分配入涂覆有1μg/mlaCD3的96孔圆底板中,然后用1μg/ml的抗CD8(aCD28)刺激以创造CD4+T细胞增殖的环境。
第二,通过将1×105供体脾细胞和1×105的用20Gy辐射照射的受体脾细胞共孵育,诱导供体脾细胞对受体脾细胞的同种异体免疫应答。
将5组体外诱导的1×105调节性T细胞以与CD4+T细胞1:1的比率加入各孔中,并在37℃下孵育3-4天。然后,向其中加入[3H]胸苷,并在收获前孵育8-14小时。测量通过用Tomtec收获机过滤获得的细胞的放射性。
从实验结果,根据T细胞增殖和同种异体免疫应答,确证与TGF-βTreg和RATreg相比,通过化合物A诱导的Treg更有效地抑制T细胞的活性(图11和12)。
实施例9:在体外实验中确证通过化合物A对调节性T细胞分化的效
果。
将由C57BL/6脾细胞分离的1×106CD4+T细胞和在20Gy下照射的BALBc抗原呈递细胞(APCs)加入到48孔板中并在37℃下孵育5天。在诱导抗原呈递细胞对于脾细胞的同种异体免疫应答的条件下进行所述孵育,并在孵育前用不同浓度的化合物A进行处理用于比较分析。在5天孵育后收获细胞,并且对于流式细胞仪,向其中加入抗小鼠CD4PerCP、CD25APC和FoxP3PE荧光标记的抗体,并在4℃下反应30分钟。用PBS洗涤后,用流式细胞仪(FACSCaliburTM)进行测量。
结果确证调节性T细胞根据化合物A的浓度增加(图13)。
实施例10:在体内移植物抗宿主病(GVHD)小鼠模型中确证通过化合
物A增加调节性T细胞的作用
使用彼此具有不同的MHC类别的6-8周大的C57BL/6(H-2kb)小鼠和BALB/c(H-2kd)小鼠。将受体小鼠BALB/c(H-2kd)用8Gy下的全身辐射进行照射。在24小时内,将从供体小鼠C57BL/6(H-2kd)分离的5×106骨髓细胞和5×106脾细胞静脉移植入受体小鼠,以诱导移植物抗宿主排斥反应模型(GVHD模型)。向GVHD模型每周4次静脉注射化合物A,持续2周。处死小鼠,进行单细胞分离,并通过流式细胞仪研究脾中免疫调节的功能。结果确证在其中给药化合物A的组中,CD4+CD25+Foxp3+调节性T细胞增加。
Claims (11)
1.用于抑制免疫应答的药物组合物,其包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体。
2.权利要求1的用于抑制免疫应答的药物组合物,其用于抑制对皮肤、血液、角膜、肝、肺、肠、胰、心脏、肾、骨髓、干细胞或者前体细胞的移植的免疫排斥反应。
3.权利要求1的用于抑制免疫应答的药物组合物,其用于治疗和预防移植物抗宿主病、过敏性疾病、自身免疫病或炎性疾病。
4.用于诱导未成熟T细胞分化成调节性T细胞和/或促进调节性T细胞增殖的组合物,其包含(四氢吡喃-4-基)-[2-苯基-5-(1,1-二氧代-硫吗啉-4-基)甲基-1H-吲哚-7-基]胺、其药学上可接受的盐或异构体。
5.权利要求4的组合物,其还包含抗CD3抗体、抗CD28抗体和TGF-β。
6.权利要求4的组合物,其还包含视黄酸(RA)或视黄醛。
7.权利要求4的组合物,其中所述调节性T细胞具有CD4+、CD25+和Foxp3+的表型。
8.诱导分化成调节性T细胞的方法,其包括用权利要求4-7中任一项的组合物离体处理未成熟T细胞的步骤。
9.促进调节性T细胞增殖的方法,其包括用权利要求4-7中任一项的组合物离体处理未成熟T细胞的步骤。
10.通过诱导分化和促进调节性T细胞增殖来获得调节性T细胞的方法,其包括用权利要求4-7中任一项的组合物离体处理未成熟T细胞的步骤。
11.用于治疗免疫疾病的组合物,其包含通过权利要求10的方法获得的所述调节性T细胞,所述免疫疾病例如移植排斥、移植物抗宿主病、过敏性疾病、自身免疫病和炎性疾病。
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