CN108495642A - 包含细菌菌株的组合物 - Google Patents
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- CN108495642A CN108495642A CN201680065752.3A CN201680065752A CN108495642A CN 108495642 A CN108495642 A CN 108495642A CN 201680065752 A CN201680065752 A CN 201680065752A CN 108495642 A CN108495642 A CN 108495642A
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Abstract
本发明提供了包含细菌菌株的组合物,其用于治疗和预防发炎性和自身免疫性疾病。
Description
发明领域
本发明属于包含从哺乳动物消化道分离的细菌菌株的组合物和此类组合物用于治疗疾病的用途的领域。
发明背景
虽然认为人类肠道在子宫内是无菌的,但在出生后其立刻暴露于大量的母体和环境微生物。此后,出现微生物定殖和演替的动态期,其受例如分娩模式、环境、饮食和宿主基因型等因素影响,所有因素都影响肠微生物丛的组成,特别是在童年期间。随后,微生物丛稳定化并变成成人样[1]。人类肠微生物丛含有超过500-1000个基本上属于两大细菌分类脆弱拟杆菌(Bacteroidete)和厚壁门菌(Firmicute)的不同种系型[2]。由人类肠的细菌定殖产生的成功共生关系产生多种代谢、结构、保护和其它有益功能。定殖肠部的增强代谢活性确保降解以其它方式无法摄取的饮食组分,同时释放副产物,为宿主提供重要的营养物来源。类似地,充分认识到肠微生物丛的免疫重要性,且在免疫系统减弱的无菌动物中例示,其免疫系统在引入共生细菌后在功能上复原[3-5]。
微生物丛组成的显著变化已经在例如发炎性肠病(IBD)等肠胃病症中证明。举例来说,在IBD患者中梭菌属(Clostridium)XIVa簇细菌的水平降低,而大肠杆菌数目增加,表明肠内共生体与病原性共生体的平衡的变化[6-9]。有趣地,此微生物生态失调也与效应T细胞群体的不平衡相关。
认识到某些细菌菌株对动物肠可能具有潜在的积极作用,已经提议各种菌株用于治疗各种疾病(参见例如[10-13])。也已经提议某些菌株,包括大部分乳杆菌属(Lactobacillus)和双歧杆菌属(Bifidobacterium)菌株,用于治疗不直接与肠相关的各种发炎性和自身免疫性疾病(综述参见[14]和[15])。然而,不同疾病和不同细菌菌株之间的关系和特定细菌菌株对肠和在全身水平下和对任何特定类型疾病的准确作用尚未很好地表征。
已经发现来自酿脓链球菌(Streptococcus pyogenes)、干酪乳杆菌(Lactobacillus casei)和包括扭曲真杆菌在内的多种真杆菌属菌株的细胞壁碎片诱发慢性多发性关节炎和关节发炎(参见[16])。
本领域中需要治疗发炎性和自身免疫性疾病的新方法。还需要待表征的肠细菌的潜在作用,以可以研发使用肠细菌的新疗法。
发明概要
本发明人已经研发用于治疗和预防发炎性和自身免疫性疾病的新疗法。具体来说,本发明人已经研发用于治疗和预防由IL-17或Th17通路介导的疾病和病状的新疗法。具体来说,本发明人已经确定来自真杆菌属(Eubacterium)的细菌菌株可以有效治疗和预防由IL-17或Th17通路介导的疾病和病状。如实施例中所描述,经口施用包含扭曲真杆菌(Eubacterium contortum)的组合物可以降低葡萄膜炎的小鼠模型中包括Th17发炎反应在内的发炎反应的严重度。
因此,在第一实施方案中,本发明提供了一种包含真杆菌属的细菌菌株的组合物,其用于治疗或预防由IL-17或Th17通路介导的疾病或病状的方法中。本发明人已经确定用来自此物种的细菌菌株治疗在由IL-17和Th17通路介导的发炎性和自身免疫性疾病的小鼠模型中可以提供临床益处,可以降低包括IL-17在内的作为Th17通路的一部分的细胞因子的水平,并且可以减轻Th17发炎反应。
在特定实施方案中,本发明提供了一种包含真杆菌属的细菌菌株的组合物,其用于治疗或预防选自由以下组成的群组的疾病或病状的方法中:葡萄膜炎;癌症,例如乳癌、肺癌、肝癌、结肠癌或卵巢癌;多发性硬化;关节炎,例如类风湿性关节炎、骨关节炎、牛皮癣性关节炎或幼年特发性关节炎;视神经脊髓炎(德维克氏病(Devic's disease));强直性脊柱炎;脊柱关节炎;牛皮癣;系统性红斑狼疮;发炎性肠病,例如克罗恩氏病(Crohn’sdisease)或溃疡性结肠炎;乳糜泻;哮喘,例如过敏性哮喘或中性粒细胞性哮喘;慢性阻塞性肺病(COPD);巩膜炎;血管炎;白塞氏病(Behcet's disease);动脉粥样硬化;异位性皮炎;肺气肿;牙周炎;过敏性鼻炎;以及同种异体移植排斥。来自真杆菌属的细菌菌株展示的对Th17发炎反应和对由IL-17和Th17通路介导的疾病的作用可以为由IL-17和Th17通路介导的其它疾病和病状,例如上列疾病和病状提供治疗益处。
在特别优选的实施方案中,本发明提供了一种包含真杆菌属的细菌菌株的组合物,其用于治疗或预防例如后葡萄膜炎等葡萄膜炎的方法中。本发明人已经确定用真杆菌属菌株治疗可以降低葡萄膜炎的小鼠模型中的发病率和疾病严重度,并且可以预防或减少视网膜损伤。在优选实施方案中,本发明提供了一种包含扭曲真杆菌物种的细菌菌株的组合物,其用于葡萄膜炎的治疗中。使用扭曲真杆菌的组合物可以特别有效地治疗葡萄膜炎。
在其它优选实施方案中,本发明提供了一种包含真杆菌属的细菌菌株的组合物,其用于治疗或预防例如中性粒细胞性哮喘或过敏性哮喘等哮喘的方法中。用真杆菌属菌株治疗可以减少中性粒细胞和嗜酸细胞募集到肺中,此可以帮助治疗或预防哮喘。在某些实施方案中,组合物用于治疗或预防中性粒细胞性哮喘或嗜酸性粒细胞性哮喘的方法中。本发明的组合物可以特别有效地治疗或预防中性粒细胞性哮喘和嗜酸性粒细胞性哮喘。实际上,在某些实施方案中,组合物用于在哮喘治疗或预防中降低中性粒细胞性发炎反应的方法中,或组合物用于在哮喘治疗或预防中降低嗜酸性粒细胞性发炎反应的方法中。在优选实施方案中,本发明提供了一种包含扭曲真杆菌物种的细菌菌株的组合物,其用于治疗哮喘且尤其治疗嗜酸性粒细胞性哮喘或过敏性哮喘。扭曲真杆菌还可以在哮喘模型中对中性粒细胞具有特别深远的作用,并且用扭曲真杆菌治疗可以特别有效地治疗中性粒细胞性哮喘。
在其它优选实施方案中,本发明提供了一种包含真杆菌属的细菌菌株的组合物,其用于治疗或预防类风湿性关节炎的方法中。用真杆菌属菌株治疗可以在类风湿性关节炎的小鼠模型中提供临床益处且减少关节肿胀。在优选实施方案中,本发明提供了一种包含扭曲真杆菌物种的细菌菌株的组合物,其用于治疗类风湿性关节炎。使用扭曲真杆菌的组合物可以特别有效地治疗类风湿性关节炎。
在其它优选实施方案中,本发明提供了一种包含真杆菌属的细菌菌株的组合物,其用于治疗或预防多发性硬化的方法中。用真杆菌属菌株治疗可以降低多发性硬化的小鼠模型中的发病率和疾病严重度。在优选实施方案中,本发明提供了一种包含扭曲真杆菌物种的细菌菌株的组合物,其用于治疗多发性硬化。使用扭曲真杆菌的组合物可以特别有效地治疗多发性硬化。
在其它优选实施方案中,本发明提供了一种包含真杆菌属的细菌菌株的组合物,其用于治疗或预防例如乳癌、肺癌或肝癌等癌症的方法中。包含真杆菌属的细菌菌株的组合物可以减少乳癌、肺癌和肝癌的小鼠模型中的肿瘤生长。在某些实施方案中,组合物用于在癌症治疗中减小肿瘤尺寸或预防肿瘤生长的方法中。在某些实施方案中,本发明提供了一种包含扭曲真杆菌物种的细菌菌株的组合物,其用于癌症治疗中。
在某些实施方案中,本发明的组合物用于在由IL-17或Th17通路介导的疾病或病状的治疗或预防中减少IL-17产生或减少Th17细胞分化的方法中。具体来说,本发明的组合物可以用于在哮喘、类风湿性关节炎、多发性硬化、葡萄膜炎或癌症的治疗或预防中减少IL-17产生或减少Th17细胞分化。优选地,本发明提供了包含扭曲真杆菌的细菌菌株的组合物,其用于在哮喘、类风湿性关节炎、多发性硬化、葡萄膜炎或癌症的治疗或预防中减少IL-17产生或减少Th17细胞分化。
在某些实施方案中,组合物用于具有高水平的IL-17或Th17细胞的患者中。真杆菌属菌株展示的与Th17发炎反应强烈相关的对葡萄膜炎的作用意味着真杆菌属菌株可能特别有益于此类患者。
在本发明的优选实施方案中,组合物中的细菌菌株属于扭曲真杆菌。也可使用密切相关的菌株,例如具有与扭曲真杆菌的细菌菌株的16s rRNA序列至少95%、96%、97%、98%、99%、99.5%或99.9%一致的16s rRNA序列的细菌菌株。优选地,细菌菌株具有与SEQID NO:1、2、3或4至少95%、96%、97%、98%、99%、99.5%或99.9%一致的16s rRNA序列。优选地,序列一致性是针对SEQ ID NO:4。优选地,用于本发明的细菌菌株具有由SEQ IDNO:4表示的16s rRNA序列。
在某些实施方案中,本发明的组合物用于经口施用。经口施用本发明的菌株可以有效地治疗IL-17或Th17通路介导的疾病和病状。此外,经口施用便于患者和开业医师且允许传递到肠和/或部分或全部定殖肠部。
在某些实施方案中,本发明的组合物包含一种或多种药学上可接受的赋形剂或载剂。
在某些实施方案中,本发明的组合物包含已冻干的细菌菌株。冻干是一项制备允许传递细菌的稳定组合物的有效和便利的技术。
在某些实施方案中,本发明提供了一种包含如上所述的组合物的食品。
在某些实施方案中,本发明提供了一种包含如上所述的组合物的疫苗组合物。
另外,本发明提供了一种治疗或预防由IL-17或Th17通路介导的疾病或病状的方法,其包括施用包含真杆菌属的细菌菌株的组合物。
在研发以上发明时,本发明人已经鉴别和表征特别适用于疗法的细菌菌株。本发明的扭曲真杆菌菌株展示有效治疗本文中描述的疾病,例如葡萄膜炎。因此,在另一个方面中,本发明提供了一种扭曲真杆菌菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或其衍生物的细胞。本发明还提供了包含此类细胞的组合物或此类细胞的生物纯培养物。本发明还提供了一种扭曲真杆菌菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或其衍生物的细胞,其用于治疗中,尤其用于本文中描述的疾病。
图示简单说明
图1:葡萄膜炎的小鼠模型-对照组中TEFI评分。数据呈现为平均值±SEM。
图2:葡萄膜炎的小鼠模型-第28天的TEFI评分。数据呈现为平均值±SEM。
发明详述
细菌菌株
本发明的组合物包含真杆菌属的细菌菌株。所述实施例证明此种属细菌可用于治疗或预防葡萄膜炎和由IL-17或Th17通路介导的疾病和病状。优选的细菌菌株属于扭曲真杆菌物种。
本发明提供了一种真杆菌属,例如扭曲真杆菌,其用于治疗中,例如用于治疗或预防发炎性和/或自身免疫性疾病。类似地,本发明提供了一种包含真杆菌属,例如扭曲真杆菌的细菌菌株的组合物,其用于治疗中,例如用于治疗或预防发炎性和/或自身免疫性疾病。在某些实施方案中,本发明的组合物包含真杆菌属,例如扭曲真杆菌,并且不含任何其它细菌种属。在某些实施方案中,本发明的组合物包含真杆菌属的单一物种,例如扭曲真杆菌,并且不含任何其它细菌物种。在某些实施方案中,本发明的组合物包含真杆菌属的单一菌株,例如扭曲真杆菌,并且不含任何其它细菌菌株或物种。
用于本发明的真杆菌属物种的实例包括扭曲真杆菌、裂变真杆菌(Eubacteriumfissicatena)、粘真杆菌(Eubacterium limosum)、直肠真杆菌(Eubacterium rectale)和产气真杆菌(Eubacterium aerofaciens)。真杆菌属是革兰氏阳性的专性厌氧的不形成孢子的棒状杆菌,其不产生丙酸或乳酸作为主要酸产物[17]。扭曲真杆菌的模式菌株是ATCC25540=DSM 3982[17]。扭曲真杆菌菌株DSM 3982的16S rRNA基因序列的GenBank登记号是FR749945、FR749946和L34615(本文中公开为SEQ ID NO:1-3)。示例性扭曲真杆菌菌株描述于[17]中。
在一些实施方案中,用于本发明中的真杆菌属物种不是凸腹真杆菌(Eubacteriumventriosum)。在一些实施方案中,用于本发明中的真杆菌属物种不是挑剔真杆菌(Eubacterium eligens)。在一些实施方案中,用于本发明中的组合物不包含凸腹真杆菌。在一些实施方案中,用于本发明中的组合物不包含挑剔真杆菌。
在所述实施例中测试的扭曲真杆菌细菌在本文中称为菌株MRX050。测试的MRX050菌株的16S rRNA序列在SEQ ID NO:4中提供。菌株MRX050由4D Pharma Research有限公司(Life Sciences Innovation Building,Aberdeen,AB25 2ZS,Scotland)在2016年11月15日寄存在国际寄存局NCIMB有限公司(Ferguson Building,Aberdeen,AB21 9YA,Scotland)并分配登记号NCIMB 42689。术语“MRX050”和“MRx0050”在本文中可互换使用。
还预期与所述实施例中测试的菌株密切相关的细菌菌株有效治疗或预防葡萄膜炎和由IL-17或Th17通路介导的疾病和病状。在某些实施方案中,用于本发明的细菌菌株具有与扭曲真杆菌的细菌菌株的16s rRNA序列至少95%、96%、97%、98%、99%、99.5%或99.9%一致的16s rRNA序列。优选地,用于本发明的细菌菌株具有与SEQ ID NO:1、2、3或4至少95%、96%、97%、98%、99%、99.5%或99.9%一致的16s rRNA序列。优选地,序列一致性是针对SEQ ID NO:4。优选地,用于本发明的细菌菌株具有由SEQ ID NO:4表示的16srRNA序列。
还预期作为菌株MRX050(尤其以NCIMB 42689寄存的MRX050)和ATCC 25540的生物型的细菌菌株有效治疗或预防葡萄膜炎和由IL-17或Th17通路介导的疾病和病状。生物型是具有相同或极类似的生理和生物化学特性的密切相关菌株。
作为菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或ATCC 25540的生物型且适合用于本发明中的菌株可以通过对菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或ATCC25540的其它核苷酸序列进行测序来鉴别。举例来说,基本上全基因组可以测序,且用于本发明的生物型菌株可以在其全基因组的至少80%上(例如在至少85%、90%、95%或99%上或在其全基因组上)具有至少95%、96%、97%、98%、99%、99.5%或99.9%序列一致性。举例来说,在一些实施方案中,生物型菌株在其基因组的至少98%上具有至少98%序列一致性或在其基因组的99%上具有至少99%序列一致性。用于鉴别生物型菌株的其它适合序列可以包括hsp60或重复序列,例如BOX、ERIC、(GTG)5或REP或[18]。生物型菌株可以具有与菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或ATCC 25540的对应序列至少95%、96%、97%、98%、99%、99.5%或99.9%序列一致的序列。在一些实施方案中,生物型菌株具有与以NCIMB 42689寄存的菌株MRX050的对应序列至少95%、96%、97%、98%、99%、99.5%或99.9%序列一致的序列并且包含与SEQ ID NO:4至少99%一致(例如至少99.5%或至少99.9%一致)的16S rRNA序列。在一些实施方案中,生物型菌株具有与以NCIMB 42689寄存的菌株MRX050的对应序列至少95%、96%、97%、98%、99%、99.5%或99.9%序列一致的序列并且具有SEQ ID NO:4的16S rRNA序列。
或者,作为菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或ATCC 25540的生物型且适用于本发明中的菌株可以通过使用菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或ATCC 25540和限制片段分析和/或PCR分析,例如通过使用荧光增强的片段长度多态现象(fluorescent amplified fragment length polymorphism,FAFLP)和重复DNA组件(rep)-PCR指纹或蛋白质剖析或部分16S或23s rDNA测序来鉴别。在优选实施方案中,此类技术可以用于鉴别其它扭曲真杆菌菌株。
在某些实施方案中,作为菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或ATCC25540的生物型且适用于本发明中的菌株是当通过增强的核蛋白体DNA限制分析(amplified ribosomal DNA restriction analysis,ARDRA)分析时,例如当使用Sau3AI限制酶(关于示例性方法和指导参见例如[19])时提供与菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或ATCC 25540相同模式的菌株。或者,生物型菌株被确定是具有与菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或ATCC 25540相同的碳水化合物发酵模式的菌株。
适用于本发明的组合物和方法的其它扭曲真杆菌菌株,例如菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或ATCC 25540的生物型,可以使用任何适当方法或策略,包括实施例中描述的分析鉴别。举例来说,用于本发明中的菌株可以通过在厌氧YCFA中培养和/或将细菌施用到II型胶原蛋白诱发的关节炎小鼠模型并接着评估细胞因子水平来鉴别。具体来说,具有与菌株MRX050(尤其以NCIMB42689寄存的MRX050)或ATCC 25540类似的生长模式、代谢类型和/或表面抗原的细菌菌株可用于本发明。适用菌株将具有与菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或ATCC 25540可比的免疫调节活性。具体来说,生物型菌株将对葡萄膜炎疾病模型引起与实施例中所示的作用可比的作用,其可以通过使用实施例中描述的培养和施用方案来鉴别。
本发明的一种尤其优选的菌株是菌株MRX050菌株(尤其以NCIMB 42689寄存的MRX050)。它是实施例中测试的示例性菌株并且展示有效治疗疾病。因此,本发明提供扭曲真杆菌菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或其衍生物的细胞,例如分离细胞。本发明还提供了一种组合物,其包含扭曲真杆菌菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或其衍生物的细胞。本发明还提供了一种扭曲真杆菌菌株MRX050(尤其以NCIMB42689寄存的MRX050)的生物纯培养物。本发明还提供了扭曲真杆菌菌株MRX050(尤其以NCIMB 42689寄存的MRX050)或其衍生物的细胞,其用于治疗中,尤其用于本文中描述的疾病。扭曲真杆菌菌株MRX050(尤其以NCIMB 42689寄存的MRX050)的衍生物可以是子代菌株(子代)或从原始培养(亚克隆)的菌株。
本发明菌株的衍生物可以例如在基因水平下修饰,而不消除生物活性。具体来说,本发明的衍生菌株是治疗活性的。衍生菌株将具有与扭曲真杆菌菌株MRX050(尤其以NCIMB42689寄存的MRX050)可比的免疫调节活性。具体来说,衍生物菌株将对葡萄膜炎疾病模型引起与实施例中所示的作用可比的作用,其可以通过使用实施例中描述的培养和施用方案来鉴别。菌株MRX050(尤其以NCIMB 42689寄存的MRX050)的衍生物一般将是菌株MRX050(尤其以NCIMB 42689寄存的MRX050)的生物型。
对扭曲真杆菌菌株MRX050的细胞的提及涵盖具有与菌株MRX050相同的安全性和治疗功效特性的任何细胞,并且本发明涵盖此类细胞。对以NCIMB 42689寄存的MRX050的提及仅仅指寄存的MRX050菌株。
在优选实施方案中,本发明组合物中的细菌菌株能存活且能够部分或全部定殖肠部。
治疗用途
如实施例中证明,本发明的细菌组合物有效减少Th17发炎反应。具体来说,用本发明的组合物治疗实现由IL-17和Th17通路介导的病状的动物模型中的临床改善并且可以实现IL-17A水平和其它Th17通路细胞因子减少。因此,本发明的组合物可用于治疗或预防发炎性和自身免疫性疾病和尤其由IL-17介导的疾病或病状。具体来说,本发明的组合物可用于减少或预防IL-17发炎反应升高。
Th17细胞是产生例如IL-17A、IL17-F、IL-21和IL 22的T辅助细胞子集。Th17细胞分化和IL-17表达可能由IL-23驱动。这些细胞因子和其它因子形成Th17通路的重要部分,Th17通路是公认的发炎信号传导通路,其促进且引起大量的发炎性和自身免疫性疾病(如例如[20-25]中所述)。Th17通路活化的疾病是Th17通路介导的疾病。Th17通路介导的疾病可以通过抑制Th17通路改善或减轻,Th17通路可以通过减少Th17细胞分化或降低其活性或减少Th17通路细胞因子的水平来抑制。由Th17通路介导的疾病可以通过Th17细胞产生的细胞因子,例如IL-17A、IL-17F、IL-21、IL-22、IL-26、IL-9的水平增加表征([26]中评述)。由Th17通路介导的疾病可以通过Th-17相关基因,例如Stat3或IL-23R的表现增加表征。由Th17通路介导的疾病可以与增加的Th17细胞水平相关。
IL-17是一种促发炎细胞因子,其促进若干发炎性和自身免疫性疾病和病状的发病机理。如本文所用,IL-17可以指IL-17家族的任何成员,包括IL-17A、IL-17B、IL-17C、IL-17D、IL-17E和IL-17F。IL-17介导的疾病和病状特征在于罹患所述疾病或病状的组织中IL-17的高表达和/或IL-17阳性细胞的累积或存在。类似地,IL-17介导的疾病和病状是因高IL-17水平或IL-17水平增加而加重且因低IL-17水平或IL-17水平减少而减轻的疾病和病状。IL-17发炎反应可以是局部或全身性的。
可能由IL-17或Th17通路介导的疾病和病状的实例包括葡萄膜炎;癌症,例如乳癌、肺癌、肝癌、结肠癌或卵巢癌;多发性硬化;关节炎,例如类风湿性关节炎、骨关节炎、牛皮癣性关节炎或幼年特发性关节炎;视神经脊髓炎(德维克氏病);强直性脊柱炎;脊柱关节炎;牛皮癣;系统性红斑狼疮;发炎性肠病,例如克罗恩氏病或溃疡性结肠炎;乳糜泻;哮喘,例如过敏性哮喘或中性粒细胞性哮喘;慢性阻塞性肺病(COPD);巩膜炎;血管炎;白塞氏病;动脉粥样硬化;异位性皮炎;肺气肿;牙周炎;过敏性鼻炎;以及同种异体移植排斥。在优选实施方案中,本发明的组合物用于治疗或预防这些病状或疾病中的一种或多种。在其它优选实施方案中,这些病状或疾病由IL-17或Th17通路介导。在一些实施方案中,通过本发明治疗的疾病或病状不是结肠直肠癌和/或结肠炎。
在一些实施方案中,疾病或病状的发病机理影响肠。在一些实施方案中,疾病或病状的发病机理不影响肠。在一些实施方案中,疾病或病状的发病机理不局限在肠。在一些实施方案中,治疗或预防除肠以外的部位。在一些实施方案中,治疗或预防肠以及除肠以外的部位。在某些实施方案中,疾病或病状是全身性的。
在某些实施方案中,本发明的组合物用于在由IL-17或Th17通路介导的疾病或病状的治疗或预防中减少IL-17产生或减少Th17细胞分化的方法中。在某些实施方案中,本发明的组合物用于治疗或预防发炎性或自身免疫性疾病,其中所述治疗或预防通过减少Th17发炎反应或预防其升高来实现。在某些实施方案中,本发明的组合物用于治疗患有发炎性或自身免疫性疾病的患者中,其中所述患者具有高水平的IL-17或升高的Th17细胞或展现Th17发炎反应。在某些实施方案中,患者可以经诊断患有慢性发炎性或自身免疫性疾病或病状,或本发明的组合物可以用于预防发展成为慢性发炎性或自身免疫性疾病或病状的发炎性或自身免疫性疾病或病状。在某些实施方案中,疾病或病状可能对用TNF-α抑制剂治疗不起反应。本发明的这些用途可以应用于前段中列出的任何特定疾病或病状。
IL-17和Th17通路常常与慢性发炎性和自身免疫性疾病相关,因此本发明的组合物可能特别适用于治疗或预防如上列出的慢性疾病或病状。在某些实施方案中,组合物用于患有慢性疾病的患者中。在某些实施方案中,组合物用于预防慢性疾病发展。
本发明的组合物可用于治疗由IL-17或Th17通路介导的疾病和病状且对付Th17发炎反应,因此本发明的组合物可能特别适用于治疗或预防慢性疾病、治疗或预防患者的对其它疗法(例如用TNF-α抑制剂治疗)起反应的疾病,和/或治疗或预防与IL-17和Th17细胞相关的组织损伤和症状。举例来说,已知IL-17活化软骨和骨组织中基质破坏并且IL-17对软骨细胞和成骨细胞中基质产生具有抑制作用,因此本发明的组合物可用于治疗或预防骨质侵蚀或软骨破坏。
在某些实施方案中,用本发明的组合物治疗减少IL-17水平、尤其IL-17A水平或预防其升高。在某些实施方案中,用本发明的组合物治疗减少TNFα、IFN-γ或IL-6水平或预防其升高。这些细胞因子的水平的此类减少或预防水平升高可用于治疗或预防发炎性和自身免疫性疾病和病状,尤其由IL-17或Th17通路介导的疾病和病状。
葡萄膜炎
在优选实施方案中,本发明的组合物用于治疗或预防葡萄膜炎。所述实施例证明本发明的组合物可以降低葡萄膜炎的动物模型的发病率和疾病严重度,因此其可用于治疗或预防葡萄膜炎。葡萄膜炎是葡萄膜发炎且会引起视网膜组织破坏。其可以呈不同解剖形式(前部、中间、后部或扩散)存在且由不同但相关的病因引起,包括全身性自身免疫性病状。IL-17和Th17通路主要与葡萄膜炎相关,因此本发明的组合物治疗葡萄膜炎的功效表明本发明的组合物可以特别有效治疗和预防由IL-17或Th17通路介导的疾病和病状。参考文献[27-34]描述葡萄膜炎患者中升高血清水平的介白素-17A,IL17A遗传变异体与全葡萄膜炎特定相关,Th17相关的细胞因子在实验自身免疫性葡萄膜炎的发病机理中的作用,在单相实验自身免疫性葡萄膜炎期间Th17细胞与调节T细胞之间的不平衡,葡萄膜炎和活动性亚当=白塞和沃格特-小柳-原田(Vogt-Koyanagi-Harada,VKH)疾病患者中IL-17A上调,用苏金单抗(secukinumab)(抗IL-17A抗体)治疗非感染性葡萄膜炎,和葡萄膜炎眼睛中的Th17。
在某些实施方案中,葡萄膜炎是后葡萄膜炎。后葡萄膜炎主要存在视网膜和脉络膜发炎,并且所述实施例证明本发明的组合物有效减少视网膜发炎和损伤。
在某些实施方案中,用本发明的组合物治疗减少视网膜损伤。在某些实施方案中,本发明的组合物在葡萄膜炎治疗中用于减少或预防视网膜损伤。在某些实施方案中,组合物用于治疗处于视网膜损伤风险中的严重葡萄膜炎患者。在某些实施方案中,用本发明的组合物治疗减少视神经盘发炎。在某些实施方案中,本发明的组合物用于治疗减少或预防视神经盘发炎。在某些实施方案中,用本发明的组合物治疗减少发炎细胞浸透视网膜组织。在某些实施方案中,本发明的组合物用于减少发炎细胞浸透视网膜组织。在某些实施方案中,用本发明的组合物治疗维持或改善视力。在某些实施方案中,本发明的组合物用于维持或改善视力。
在某些实施方案中,组合物用于治疗或预防与非感染性或自身免疫性疾病,例如白塞氏病、克罗恩氏病、富克斯异色性虹膜睫状体炎(Fuchs heterochromiciridocyclitis)、肉芽肿病伴多血管炎、HLA-B27相关葡萄膜炎、幼年特发性关节炎、结节病、脊柱关节炎、交感性眼炎、小管间质性肾炎和葡萄膜炎症候群或沃格特-小柳-原田症候群相关的葡萄膜炎。IL-17A已经显示与例如白塞氏病和沃格特-小柳-原田疾病相关。
葡萄膜炎的治疗或预防可以指例如减轻症状严重度或预防复发。
癌症
在优选实施方案中,本发明的组合物用于治疗或预防癌症。IL-17和Th17通路在癌症发展和进展中具有重要作用,因此本发明的组合物可用于治疗或预防癌症。
虽然IL-17和Th17细胞在癌症中的作用未完全了解,但已知IL-17和Th17细胞的许多促肿瘤作用。举例来说,Th17细胞和IL-17可以促进血管生成,增加肿瘤细胞的增殖和存活,并活化肿瘤促进转录因子[35-37]。
在某些实施方案中,用本发明的组合物治疗减小肿瘤尺寸或减少肿瘤生长。在某些实施方案中,本发明的组合物用于减小肿瘤尺寸或减少肿瘤生长。本发明的组合物可以有效减小肿瘤尺寸或生长。在某些实施方案中,本发明的组合物用于具有实体肿瘤的患者中。在某些实施方案中,本发明的组合物在癌症治疗中用于减少或预防血管生成。IL-17和Th17细胞在血管生成中具有重要作用。在某些实施方案中,本发明的组合物用于预防转移。
在优选实施方案中,本发明的组合物用于治疗或预防乳癌。本发明的组合物可以有效治疗乳癌,并且IL-17和Th17细胞在乳癌中具有重要作用[38]。在某些实施方案中,本发明的组合物用于在乳癌治疗中减小肿瘤尺寸,减少肿瘤生长,或减少血管生成。在优选实施方案中,癌症是乳癌。在优选实施方案中,癌症是IV期乳癌。
在某些实施方案中,本发明的组合物用于治疗或预防肺癌。本发明的组合物可以有效治疗肺癌,并且IL-17和Th17细胞在肺癌中具有重要作用[39]。在某些实施方案中,本发明的组合物用于在肺癌治疗中减小肿瘤尺寸,减少肿瘤生长,或减少血管生成。在优选实施方案中,癌症是肺癌。
在某些实施方案中,本发明的组合物用于治疗或预防肝癌。本发明的组合物可以有效治疗肝癌,并且IL-17和Th17细胞在肝癌中具有重要作用[40]。在某些实施方案中,本发明的组合物用于在肝癌治疗中减小肿瘤尺寸,减少肿瘤生长,或减少血管生成。在优选实施方案中,癌症是肝癌(肝细胞癌)。
在某些实施方案中,本发明的组合物用于治疗或预防癌瘤。本发明的组合物可以特别有效治疗癌瘤。在某些实施方案中,本发明的组合物用于治疗或预防非免疫原性癌。本发明的组合物可以有效治疗非免疫原性癌。
在其它实施方案中,本发明的组合物用于治疗或预防急性成淋巴细胞性白血病(acute lymphoblastic leukemia,ALL)、急性骨髓性白血病、肾上腺皮质癌、基细胞癌瘤、胆管癌、膀胱癌、骨肿瘤、骨肉瘤/恶性纤维组织细胞瘤、脑干神经胶质瘤、脑肿瘤、小脑星形细胞瘤、大脑星形细胞瘤/恶性神经胶质瘤、室管膜瘤、髓母细胞瘤、幕上原始神经外胚层肿瘤、乳癌、支气管腺瘤/类癌瘤、伯基特氏淋巴瘤(Burkitt's lymphoma)、类癌瘤肿瘤、子宫颈癌、慢性淋巴细胞性白血病、慢性骨髓性白血病、慢性脊髓增生病、结肠癌、皮肤T细胞淋巴瘤、子宫内膜癌、室管膜瘤、食道癌、尤因肉瘤(Ewing's sarcoma)、眼内黑色素瘤、视网膜母细胞瘤、胆囊癌、胃癌、胃肠道类癌肿瘤、胃肠基质肿瘤(gastrointestinal stromaltumor,GIST)、生殖细胞肿瘤、儿童期视觉通路和下丘脑神经胶质瘤、霍奇金氏淋巴瘤(Hodgkin lymphoma)、黑色素瘤、胰岛细胞癌瘤、卡波西氏肉瘤(Kaposi sarcoma)、肾细胞癌、喉癌、白血病、淋巴瘤、间皮瘤、神经母细胞瘤、非霍奇金淋巴瘤、口咽癌、骨肉瘤、卵巢癌、胰腺癌、甲状旁腺癌、咽癌、垂体腺瘤、浆细胞瘤形成、前列腺癌、肾细胞癌瘤、视网膜母细胞瘤、肉瘤、睾丸癌、甲状腺癌或子宫癌。
本发明的组合物在与其它治疗剂组合使用时会特别有效。本发明组合物的免疫调节作用会在与更直接抗癌剂组合时有效。因此,在某些实施方案中,本发明提供了一种组合物,其包含真杆菌属的细菌菌株和抗癌剂。在优选实施方案中,抗癌剂是免疫检查点抑制剂、靶向抗体免疫疗法、CAR-T细胞疗法、溶瘤病毒或抑制细胞生长药物。在优选实施方案中,组合物包含选自由以下组成的群组的抗癌剂:Yervoy(易普利单抗(ipilimumab),BMS);Keytruda(派姆单抗(pembrolizumab),Merck);Opdivo(纳武单抗(nivolumab),BMS);MEDI4736(AZ/MedImmune);MPDL3280A(Roche/Genentech);曲美目单抗(Tremelimumab)(AZ/MedImmune);CT-011(皮利珠单抗(pidilizumab),CureTech);BMS-986015(利鲁单抗(lirilumab),BMS);MEDI0680(AZ/MedImmune);MSB-0010718C(Merck);PF-05082566(Pfizer);MEDI6469(AZ/MedImmune);BMS-986016(BMS);BMS-663513(优瑞路单抗(urelumab),BMS);IMP321(Prima Biomed);LAG525(Novartis);ARGX-110(arGEN-X);PF-05082466(Pfizer);CDX-1127(瓦利路单抗(varlilumab);CellDex Therapeutics);TRX-518(GITR Inc.);MK-4166(Merck);JTX-2011(Jounce Therapeutics);ARGX-115(arGEN-X);NLG-9189(英多莫德(indoximod),NewLink Genetics);INCB024360(Incyte);IPH2201(Innate Immotherapeutics/AZ);NLG-919(NewLink Genetics);抗VISTA(JnJ);依帕斯塔特(Epacadostat)(INCB24360,Incyte);F001287(Flexus/BMS);CP 870893(University ofPennsylvania);MGA271(Macrogenix);依玛珠单抗(Emactuzumab)(Roche/Genentech);加尼斯替(Galunisertib)(Eli Lilly);优库路单抗(Ulocuplumab)(BMS);BKT140/BL8040(Biokine Therapeutics);巴维昔单抗(Bavituximab)(Peregrine Pharmaceuticals);CC90002(Celgene);852A(Pfizer);VTX-2337(VentiRx Pharmaceuticals);IMO-2055(Hybridon,Idera Pharmaceuticals);LY2157299(Eli Lilly);EW-7197(Ewha Women'sUniversity,Korea);威罗菲尼(Vemurafenib)(Plexxikon);达拉菲尼(Dabrafenib)(Genentech/GSK);BMS-777607(BMS);BLZ945(Memorial Sloan-Kettering CancerCentre);Unituxin(地土昔单抗(dinutuximab),United Therapeutics Corporation);Blincyto(布尔莫单抗(blinatumomab),Amgen);Cyramza(雷莫芦单抗(ramucirumab),EliLilly);Gazyva(欧努珠单抗(obinutuzumab),Roche/Biogen);Kadcyla(阿多曲妥珠单抗恩他新(ado-trastuzumab emtansine),Roche/Genentech);Perjeta(帕妥珠单抗(pertuzumab),Roche/Genentech);Adcetris(布瑞西单抗维多新(brentuximab vedotin),Takeda/Millennium);Arzerra(奥法木单抗(ofatumumab),GSK);Vectibix(帕尼单抗(panitumumab),Amgen);Avastin(贝伐单抗(bevacizumab),Roche/Genentech);Erbitux(西妥昔单抗(cetuximab),BMS/Merck);Bexxar(托西莫单抗(tositumomab)-I131,GSK);Zevalin(替伊莫单抗(ibritumomab tiuxetan),Biogen);Campath(阿仑单抗(alemtuzumab),Bayer);Mylotarg(吉妥珠单抗奥唑米星(gemtuzumab ozogamicin),Pfizer);Herceptin(曲妥珠单抗(trastuzumab),Roche/Genentech);Rituxan(利妥昔单抗(rituximab),Genentech/Biogen);伏洛昔单抗(volociximab)(Abbvie);艾那维单抗(Enavatuzumab)(Abbvie);ABT-414(Abbvie);埃罗妥珠单抗(Elotuzumab)(Abbvie/BMS);ALX-0141(Ablynx);奥扎利单抗(Ozaralizumab)(Ablynx);埃替单抗(Actimab)-C(Actinium);埃替单抗-P(Actinium);米拉珠单抗-多柔比星(Milatuzumab-dox)(Actinium);Emab-SN-38(Actinium);伊土莫单抗(Naptumonmab estafenatox)(ActiveBiotech);AFM13(Affimed);AFM11(Affimed);AGS-16C3F(Agensys);AGS-16M8F(Agensys);AGS-22ME(Agensys);AGS-15ME(Agensys);GS-67E(Agensys);ALXN6000(萨玛利单抗(samalizumab),Alexion);ALT-836(Altor Bioscience);ALT-801(Altor Bioscience);ALT-803(Altor Bioscience);AMG780(Amgen);AMG 228(Amgen);AMG820(Amgen);AMG172(Amgen);AMG595(Amgen);AMG110(Amgen);AMG232(阿达木单抗(adecatumumab),Amgen);AMG211(Amgen/MedImmune);BAY20-10112(Amgen/Bayer);瑞洛土单抗(Rilotumumab)(Amgen);戴诺素单抗(Denosumab)(Amgen);AMP-514(Amgen);MEDI575(AZ/MedImmune);MEDI3617(AZ/MedImmune);MEDI6383(AZ/MedImmune);MEDI551(AZ/MedImmune);帕莫西单抗(Moxetumomab pasudotox)(AZ/MedImmune);MEDI565(AZ/MedImmune);MEDI0639(AZ/MedImmune);MEDI0680(AZ/MedImmune);MEDI562(AZ/MedImmune);AV-380(AVEO);AV203(AVEO);AV299(AVEO);BAY79-4620(Bayer);拉安土单抗(Anetumab ravtansine)(Bayer);万替珠单抗(vantictumab)(Bayer);BAY94-9343(Bayer);西罗珠单抗(Sibrotuzumab)(Boehringer Ingleheim);BI-836845(Boehringer Ingleheim);B-701(BioClin);BIIB015(Biogen);欧努珠单抗(Biogen/Genentech);BI-505(Bioinvent);BI-1206(Bioinvent);TB-403(Bioinvent);BT-062(Biotest)BIL-010t(Biosceptre);MDX-1203(BMS);MDX-1204(BMS);奈西莫单抗(Necitumumab)(BMS);CAN-4(Cantargia AB);CDX-011(Celldex);CDX1401(Celldex);CDX301(Celldex);U3-1565(Daiichi Sankyo);帕曲土单抗(patritumab)(Daiichi Sankyo);替加土单抗(tigatuzumab)(Daiichi Sankyo);尼妥珠单抗(nimotuzumab)(Daiichi Sankyo);DS-8895(Daiichi Sankyo);DS-8873(DaiichiSankyo);DS-5573(Daiichi Sankyo);MORab-004(Eisai);MORab-009(Eisai);MORab-003(Eisai);MORab-066(Eisai);LY3012207(Eli Lilly);LY2875358(Eli Lilly);LY2812176(Eli Lilly);LY3012217(Eli Lilly);LY2495655(Eli Lilly);LY3012212(Eli Lilly);LY3012211(Eli Lilly);LY3009806(Eli Lilly);西妥木单抗(cixutumumab)(Eli Lilly);法拉维单抗(Flanvotumab)(Eli Lilly);IMC-TR1(Eli Lilly);雷莫芦单抗(Eli Lilly);塔巴木单抗(Tabalumab)(Eli Lilly);扎诺利单抗(Zanolimumab)(EmergentBiosolution);FG-3019(FibroGen);FPA008(Five Prime Therapeutics);FP-1039(FivePrime Therapeutics);FPA144(Five Prime Therapeutics);卡妥索单抗(catumaxomab)(Fresenius Biotech);IMAB362(Ganymed);IMAB027(Ganymed);HuMax-CD74(Genmab);HuMax-TFADC(Genmab);GS-5745(Gilead);GS-6624(Gilead);OMP-21M18(登西珠单抗(demcizumab),GSK);马帕木单抗(mapatumumab)(GSK);IMGN289(ImmunoGen);IMGN901(ImmunoGen);IMGN853(ImmunoGen);IMGN529(ImmunoGen);IMMU-130(Immunomedics);米拉珠单抗-多柔比星(Immunomedics);IMMU-115(Immunomedics);IMMU-132(Immunomedics);IMMU-106(Immunomedics);IMMU-102(Immunomedics);依帕珠单抗(Epratuzumab)(Immunomedics);克利瓦单抗(Clivatuzumab)(Immunomedics);IPH41(InnateImmunotherapeutics);达拉土单抗(Daratumumab)(Janssen/Genmab);CNTO-95(Intetumumab,Janssen);CNTO-328(西妥昔单抗(siltuximab),Janssen);KB004(KaloBios);莫加利单抗(mogamulizumab)(Kyowa Hakko Kirrin);KW-2871(依美昔单抗(ecromeximab),Life Science);索奈珠单抗(Sonepcizumab)(Lpath);马土西单抗(Margetuximab)(Macrogenics);恩利珠单抗(Enoblituzumab)(Macrogenics);MGD006(Macrogenics);MGF007(Macrogenics);MK-0646(达洛珠单抗(dalotuzumab),Merck);MK-3475(Merck);Sym004(Symphogen/Merck Serono);DI17E6(Merck Serono);MOR208(Morphosys);MOR202(Morphosys);Xmab5574(Morphosys);BPC-1C(恩斯土单抗(ensituximab),Precision Biologics);TAS266(Novartis);LFA102(Novartis);BHQ880(Novartis/Morphosys);QGE031(Novartis);HCD122(卢卡木单抗(lucatumumab),Novartis);LJM716(Novartis);AT355(Novartis);OMP-21M18(登西珠单抗,OncoMed);OMP52M51(Oncomed/GSK);OMP-59R5(Oncomed/GSK);万替珠单抗(Oncomed/Bayer);CMC-544(奥英妥珠单抗(inotuzumab ozogamicin),Pfizer);PF-03446962(Pfizer);PF-04856884(Pfizer);PSMA-ADC(Progenics);REGN1400(Regeneron);REGN910(奈瓦库单抗(nesvacumab),Regeneron/Sanofi);REGN421(恩替库单抗(enoticumab),Regeneron/Sanofi);RG7221、RG7356、RG7155、RG7444、RG7116、RG7458、RG7598、RG7599、RG7600、RG7636、RG7450、RG7593、RG7596、DCDS3410A、RG7414(帕萨珠单抗(parsatuzumab))、RG7160(伊佳珠单抗(imgatuzumab))、RG7159(欧宾珠单抗(obintuzumab))、RG7686、RG3638(欧奈珠单抗(onartuzumab))、RG7597(Roche/Genentech);SAR307746(Sanofi);SAR566658(Sanofi);SAR650984(Sanofi);SAR153192(Sanofi);SAR3419(Sanofi);SAR256212(Sanofi),SGN-LIV1A(林妥珠单抗(lintuzumab),Seattle Genetics);SGN-CD33A(SeattleGenetics);SGN-75(马维珠单抗(vorsetuzumab mafodotin),Seattle Genetics);SGN-19A(Seattle Genetics);SGN-CD70A(Seattle Genetics);SEA-CD40(Seattle Genetics);替伊莫单抗(Spectrum);MLN0264(Takeda);加尼妥单抗(ganitumab)(Takeda/Amgen);CEP-37250(Teva);TB-403(Thrombogenic);VB4-845(Viventia);Xmab2512(Xencor);Xmab5574(Xencor);尼妥珠单抗(YM Biosciences);卡路单抗(Carlumab)(Janssen);NY-ESO TCR(Adaptimmune);MAGE-A-10TCR(Adaptimmune);CTL019(Novartis);JCAR015(JunoTherapeutics);KTE-C19CAR(Kite Pharma);UCART19(Cellectis);BPX-401(BellicumPharmaceuticals);BPX-601(Bellicum Pharmaceuticals);ATTCK20(UnumTherapeutics);CAR-NKG2D(Celyad);Onyx-015(Onyx Pharmaceuticals);H101(ShanghaiSunwaybio);DNX-2401(DNAtrix);VCN-01(VCN Biosciences);Colo-Ad1(PsiOxusTherapeutics);ProstAtak(Advantagene);Oncos-102(Oncos Therapeutics);CG0070(Cold Genesys);Pexa-vac(JX-594,Jennerex Biotherapeutics);GL-ONC1(Genelux);T-VEC(Amgen);G207(Medigene);HF10(Takara Bio);SEPREHVIR(HSV1716,VirttuBiologics);OrienX010(OrienGene Biotechnology);Reolysin(Oncolytics Biotech);SVV-001(Neotropix);Cacatak(CVA21,Viralytics);Alimta(Eli Lilly)、顺铂(cisplatin)、奥沙利铂(oxaliplatin)、伊立替康(irinotecan)、亚叶酸(folinic acid)、甲氨蝶呤(methotrexate)、环磷酰胺(cyclophosphamide)、5-氟尿嘧啶(5-fluorouracil)、Zykadia(Novartis)、Tafinlar(GSK)、Xalkori(Pfizer)、Iressa(AZ)、Gilotrif(Boehringer Ingelheim)、Tarceva(Astellas Pharma)、Halaven(Eisai Pharma)、Veliparib(Abbvie)、AZD9291(AZ)、阿雷替尼(Alectinib)(Chugai)、LDK378(Novartis)、盖纳特皮(Genetespib)(Synta Pharma)、Tergenpumatucel-L(NewLink Genetics)、GV1001(Kael-GemVax)、替瓦替尼(Tivantinib)(ArQule);Cytoxan(BMS);Oncovin(Eli Lilly);阿霉素(Adriamycin)(Pfizer);Gemzar(Eli Lilly);Xeloda(Roche);Ixempra(BMS);Abraxane(Celgene);Trelstar(Debiopharm);Taxotere(Sanofi);Nexavar(Bayer);IMMU-132(Immunomedics);E7449(Eisai);Thermodox(Celsion);Cometriq(Exellxis);Lonsurf(Taiho Pharmaceuticals);Camptosar(Pfizer);UFT(Taiho Pharmaceuticals);和TS-1(Taiho Pharmaceuticals)。
在一些实施方案中,一个或多个真杆菌属细菌菌株是本发明组合物中的唯一治疗活性剂。在一些实施方案中,组合物中的细菌菌株是本发明组合物中的唯一治疗活性剂。
哮喘
在优选实施方案中,本发明的组合物用于治疗或预防哮喘。本发明的组合物可以减少敏化和用房尘螨提取物激发后中性粒细胞和/或嗜酸性粒细胞募集到气道中,因此其可用于治疗或预防哮喘。哮喘是一种特征为气道发炎和限制的慢性疾病。哮喘发炎可以由IL-17和/或Th17细胞介导,因此本发明的组合物可以特别有效预防或治疗哮喘。哮喘发炎可以由嗜酸性粒细胞和/或中性粒细胞介导。
在某些实施方案中,哮喘是嗜酸性粒细胞或过敏性哮喘。嗜酸性粒细胞和过敏性哮喘的特征是外周血和气道分泌物中嗜酸性粒细胞数目增加且病理学上与基底膜区域变厚和药理学上与皮质类固醇反应相关[41]。减少或抑制嗜酸性粒细胞募集或活化的组合物可用于治疗或预防嗜酸性粒细胞和过敏性哮喘。
在其它实施方案中,本发明的组合物用于治疗或预防中性粒细胞性哮喘(或非嗜酸性粒细胞性哮喘)。高中性粒细胞数目与可能对皮质类固醇治疗不敏感的严重哮喘有关。减少或抑制中性粒细胞募集或活化的组合物可用于治疗或预防中性粒细胞性哮喘。
嗜酸性粒细胞和中性粒细胞性哮喘并非互斥病状且一般帮助对付任一嗜酸性粒细胞和中性粒细胞反应的治疗可用于治疗哮喘。
增加的IL-17水平和Th17通路活化与严重哮喘有关,因此本发明的组合物可用于预防严重哮喘的发展或用于治疗严重哮喘。
在某些实施方案中,本发明的组合物用于在哮喘治疗或预防中降低嗜酸性粒细胞发炎反应的方法中,或用于在哮喘治疗或预防中降低中性粒细胞性发炎反应的方法中。如上所指出,哮喘中高水平嗜酸性粒细胞在病理学上与基底膜区域变厚相关,因此在哮喘治疗或预防中减少嗜酸性粒细胞发炎反应也许能特别地对付所述疾病的此特征。此外,与升高的嗜酸性粒细胞组合或其不存在的升高的嗜中性粒细胞与严重哮喘和慢性气道变窄有关。因此,减少中性粒细胞性发炎反应可能特别适用于对付严重哮喘。
在某些实施方案中,组合物减少过敏性哮喘中细支气管支气管周浸透,或用于在过敏性哮喘的治疗中减少细支气管支气管周浸透。在某些实施方案中,组合物减少中性粒细胞性哮喘中细支气管支气管周和/或血管周浸透,或用于在过敏性中性粒细胞性哮喘的治疗中减少细支气管支气管周和/或血管周浸透。
在某些实施方案中,用本发明的组合物治疗减少TNFα水平或预防其升高。
在某些实施方案中,本发明的组合物用于减少嗜酸性粒细胞和/或中性粒细胞性发炎反应的哮喘治疗方法中。在某些实施方案中,待治疗的患者已经或先前已经被鉴别为具有高水平的嗜中性粒细胞或嗜酸性粒细胞,例如如通过采血或唾液分析来鉴别。
本发明的组合物在施用于新生儿或孕妇时可用于预防新生儿中哮喘发展。组合物可用于预防儿童中哮喘发展。本发明的组合物可用于治疗或预防成年发作型哮喘。本发明的组合物可用于管理或减轻哮喘。本发明的组合物可能特别适用于减少与由例如房尘螨等过敏原加重的哮喘相关的症状。
治疗或预防哮喘可以指例如减轻症状严重度或减小对患者而言成问题的恶化频率或触发范围。
关节炎
在优选实施方案中,本发明的组合物用于治疗或预防类风湿性关节炎(rheumatoid arthritis,RA)。本发明的组合物可以减少小鼠模型中RA临床征象,减少软骨和骨骼破坏,并且减少IL-17发炎反应,因此其可用于治疗或预防RA。RA是一种主要影响关节的全身性发炎病症。RA与引起关节肿胀、滑液增生和软骨和骨骼破坏的发炎反应有关。IL-17和Th17在RA中可能具有关键作用,例如因为IL-17抑制软骨细胞和成骨细胞中基质产生,并且活化基质金属蛋白酶的产生和功能,且因为RA疾病活动与IL-17水平和Th-17细胞数相关[42,43],因此本发明的组合物可特别有效预防或治疗RA。
在某些实施方案中,本发明的组合物用于在RA治疗或预防中降低IL-17水平或预防IL-17水平升高。在某些实施方案中,用本发明的组合物治疗减少IL-17水平、尤其IL-17A水平或预防其升高。在某些实施方案中,用本发明的组合物治疗减少IFN-γ或IL-6水平或预防其升高。
在某些实施方案中,用本发明的组合物治疗减少关节肿胀。在某些实施方案中,本发明的组合物用于关节肿胀的患者或经鉴别处于关节肿胀风险中的患者中。在某些实施方案中,本发明的组合物用于减少RA中的关节肿胀的方法中。
在某些实施方案中,用本发明的组合物治疗减少软骨破坏或骨骼破坏。在某些实施方案中,本发明的组合物用于在RA治疗中减少或预防软骨或骨骼破坏。在某些实施方案中,组合物用于治疗患有严重RA的处于软骨或骨骼破坏风险中的患者。
增加的IL-17水平和Th17细胞数与RA中软骨和骨组织破坏有关[42,43]。已知IL-17活化软骨和骨组织中基质破坏并且IL-17对软骨细胞和成骨细胞中基质产生具有抑制作用。因此,在某些实施方案中,本发明的组合物用于在RA治疗中预防骨质侵蚀或软骨破坏。在某些实施方案中,组合物用于治疗展现骨质侵蚀或软骨破坏的患者或经鉴别处于骨质侵蚀或软骨破坏风险中的患者。
TNF-α也与RA相关,但TNF-α不参与所述疾病后期的发病机理。相比之下,IL-17在整个慢性疾病阶段具有作用[44]。因此,在某些实施方案中,本发明的组合物用于治疗慢性RA或晚期RA,例如包括关节破坏和软骨丧失的疾病。在某些实施方案中,本发明的组合物用于治疗先前已接受抗TNF-α疗法的患者。在某些实施方案中,尚未治疗的患者不或不再对抗TNF-α疗法起反应。
本发明的组合物可用于调节患者的免疫系统,因此,在某些实施方案中,本发明的组合物用于预防已经被鉴别为处于RA风险中或已经被诊断患有早期RA的患者的RA。本发明的组合物可用于预防RA发展。
本发明的组合物可用于管理或减轻RA。本发明的组合物可能特别适用于减少与关节肿胀或骨组织破坏相关的症状。治疗或预防RA可指例如减轻症状严重度或减小对患者而言成问题的恶化频率或触发范围。
多发性硬化
在优选实施方案中,本发明的组合物用于治疗或预防多发性硬化。本发明的组合物可以减少多发性硬化小鼠模型(EAE模型)的发病率和疾病严重度,因此其可用于治疗或预防多发性硬化。多发性硬化是一种与特别脑和脊柱中神经元髓鞘破坏相关的发炎病症。多发性硬化是一种慢性疾病,其逐步丧失活动能力且连串进展。IL-17和Th17细胞在多发性硬化中可能具有关键作用,例如因为IL-17水平可能与多发性硬化病变相关,IL-17会破坏血脑屏障内皮细胞紧密接头,且Th17细胞会迁移到中枢神经系统中并引起神经元丧失[45,46]。因此,本发明的组合物可以特别有效预防或治疗多发性硬化。
在某些实施方案中,用本发明的组合物治疗降低发病率或疾病严重度。在某些实施方案中,本发明的组合物用于降低发病率或疾病严重度。在某些实施方案中,用本发明的组合物治疗预防运动功能衰退或改善运动功能。在某些实施方案中,本发明的组合物用于预防运动功能衰退或用于改善运动功能。在某些实施方案中,用本发明的组合物治疗预防出现瘫痪。在某些实施方案中,本发明的组合物在多发性硬化治疗中用于预防瘫痪。
本发明的组合物可用于调节患者的免疫系统,因此,在某些实施方案中,本发明的组合物用于预防已经被鉴别为处于多发性硬化风险中或已经被诊断患有早期多发性硬化或“复发缓解型”多发性硬化的患者的多发性硬化。本发明的组合物可用于预防出现硬化症。
本发明的组合物可用于管理或减轻多发性硬化。本发明的组合物可能特别适用于减少与多发性硬化相关的症状。治疗或预防多发性硬化可以指例如减轻症状严重度或减小对患者而言成问题的恶化频率或触发范围。
施用模式
优选地,本发明的组合物待施用于胃肠道,以能够传递到肠和/或使本发明的细菌菌株部分或全部定殖肠部。一般地,虽然本发明的组合物经口施用,但其可以直肠、鼻内或通过颊或舌下途径施用。
在某些实施方案中,本发明的组合物可以呈泡沫、喷雾或凝胶形式施用。
在某些实施方案中,本发明的组合物可以呈栓剂,例如直肠栓剂,例如呈可可豆油(可可脂)、合成硬脂(例如suppocire、witepsol)、甘油基-明胶、聚乙二醇或肥皂甘油组合物的形式施用。
在某些实施方案中,本发明的组合物通过管,例如鼻饲管、口胃管、胃管、空肠造口管(J型管)、经皮内窥镜胃造口术(percutaneous endoscopic gastrostomy,PEG)或端口,例如通向胃、空肠和其它适合进入埠的胸壁端口施用胃肠道。
本发明的组合物可以施用一次,或其可以作为治疗方案一部分连续施用。在某些实施方案中,本发明的组合物将每日施用。
在本发明的某些实施方案中,根据本发明的治疗伴随有患者肠微生物丛的评估。如果本发明的菌株传递和/或部分或全部定殖未实现,使得功效未观测到,那么可以重复治疗,如果传递和/或部分或全部定殖成功且观测到功效,那么可以停止治疗。
在某些实施方案中,本发明的组合物可以施用于怀孕动物,例如哺乳动物,例如人类,以预防发炎性或自身免疫性疾病在其子女中在子宫内和/或其出生后出现。
本发明的组合物可以施用于经诊断患有由IL-17或Th17通路介导的疾病或病状或已经被鉴别为处于由IL-17或Th17通路介导的疾病或病状风险中的患者。组合物也可以作为预防措施施用以预防健康患者中由IL-17或Th17通路介导的疾病或病状出现。
本发明的组合物可以施用于已经被鉴别为具有异常肠微生物丛的患者。举例来说,患者可以具有减少或缺乏的真杆菌属的定殖。
本发明的组合物可以作为食品,例如营养增补剂施用。
一般地,本发明的组合物用于治疗人类,不过其可以用于治疗动物,包括单胃哺乳动物,例如家禽、猪、猫、犬、马或兔。本发明的组合物可用于增强动物的生长和效能。若施用于动物,则可以使用经口管饲法。
组合物
一般地,本发明的组合物包含细菌。在本发明的优选实施方案中,组合物呈冻干形式配制。举例来说,本发明的组合物可以包含含有本发明的细菌菌株的颗粒或明胶胶囊,例如硬明胶胶囊。
优选地,本发明的组合物包含冻干细菌。细菌冻干是公知程序且相关指导可于例如参考文献[47-49]中获得。
或者,本发明的组合物可以包含活的活性细菌培养物。
在一些实施方案中,本发明组合物中的细菌菌株尚未灭活,例如尚未热灭活。在一些实施方案中,本发明组合物中的细菌菌株尚未杀死,例如尚未热杀死。在一些实施方案中,本发明组合物中的细菌菌株尚未减毒,例如尚未热减毒。举例来说,在一些实施方案中,本发明组合物中的细菌菌株尚未杀死、灭活和/或减毒。举例来说,在一些实施方案中,本发明组合物中的细菌菌株是活的。举例来说,在一些实施方案中,本发明组合物中的细菌菌株能存活。举例来说,在一些实施方案中,本发明组合物中的细菌菌株能够部分或完全定殖肠部。举例来说,在一些实施方案中,本发明组合物中的细菌菌株能存活并能够部分或完全定殖肠部。
在一些实施方案中,组合物包含活的细菌菌株与已经杀死的细菌菌株的混合物。
在优选实施方案中,本发明的组合物经囊封以能够传递细菌菌株到肠。囊封保护组合物免于降解,直到通过例如用化学或物理刺激,例如压力、酶活性或物理性崩解(其可以通过pH值改变而触发)进行破裂,在目标位置传递。可以使用任何适当囊封法。示例性囊封技术包括截留在多孔基质内、附着或吸附在固体载体表面上、通过絮凝或利用交联剂而自我凝聚以及机械容纳在微孔膜或微胶囊后。关于可用于制备本发明的组合物的囊封的指导可以于例如参考文献[50]和[51]中获得。
组合物可以经口施用且可以呈片剂、胶囊或散剂形式。囊封产品是优选的,因为扭曲真杆菌是厌氧菌。其它成分(例如维生素C)可以作为除氧剂和益生基质包括以改善活体内传递和/或部分或全部定殖和存活。或者,本发明的益生组合物可以作为食品或营养产品,例如基于牛奶或乳清的发酵乳制品,或作为药品经口施用。
组合物可以配制为益生菌。
本发明的组合物包括治疗有效量的本发明的细菌菌株。治疗有效量的细菌菌株足以对患者发挥有益作用。治疗有效量的细菌菌株可以足够传递到患者肠和/或部分或全部定殖患者肠部。
例如适合于成年人的细菌日剂量可以是约1×103到约1×1011菌落形成单位(colony forming unit,CFU);例如约1×107到约1×1010CFU;在另一实例中,约1×106到约1×1010CFU。
在某些实施方案中,组合物含有相对于组合物的重量,约1×106到约1×1011CFU/g,例如约1×108到约1×1010CFU/g的量的细菌菌株。剂量可以是例如1g、3g、5g和10g。
通常,益生菌,例如本发明的组合物,任选与至少一种适合益生化合物组合。益生化合物通常是不易消化的碳水化合物,例如寡糖或多糖,或糖醇,其在上部消化道中不降解或吸收。已知的益生菌包括商业产品,例如菊糖和反式半乳寡糖。
在某些实施方案中,本发明的益生菌组合物包括相对于组合物总重量,约1到约30重量%(例如5到20重量%)的量的益生菌化合物。碳水化合物可以选自由以下组成的群:果寡糖(或FOS)、短链果寡糖、菊糖、异麦芽寡糖、果胶、木寡糖(或XOS)、几丁寡糖(或COS)、β-葡聚糖、阿拉伯胶改性和抗性淀粉、聚葡萄糖、D-塔格糖、阿拉伯胶纤维、角豆树、燕麦和柑桔纤维。在一个方面中,益生菌是短链果糖-寡糖(下文中简单起见展示为FOSs-c.c);所述FOSs-c.c是不可消化的碳水化合物,一般由甜菜糖转变获得并且包括三个葡萄糖分子键结的蔗糖分子。
本发明的组合物可以包含药学上可接受的赋形剂或载剂。此类适合赋形剂的实例可以见于参考文献[52]中。用于治疗用途的可接受的载剂或稀释剂是医药技术中众所周知的并且描述于例如参考文献[53]中。适合载剂的实例包括乳糖、淀粉、葡萄糖、甲基纤维素、硬脂酸镁、甘露糖醇、山梨糖醇等等。适合稀释剂的实例包括乙醇、甘油和水。医药载剂、赋形剂或稀释剂的选择可以针对预期施用途径和标准医药实践来选择。药物组合物可以包含任何适合粘合剂、润滑剂、悬浮剂、包被剂、增溶剂作为载剂、赋形剂或稀释剂或除载剂、赋形剂或稀释剂之外可以包含所述物质。适合粘合剂的实例包括淀粉、明胶、天然糖(例如葡萄糖、无水乳糖、自由流动乳糖、β-乳糖、玉米甜味剂)、天然和合成树胶(例如阿拉伯胶、黄蓍胶)或海藻酸钠、羧甲基纤维素和聚乙二醇。适合润滑剂的实例包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等等。防腐剂、稳定剂、染料和甚至调味剂可以提供于药物组合物中。防腐剂的实例包括苯甲酸钠、山梨酸和对羟基苯甲酸酯。也可以使用抗氧化剂和悬浮剂。
本发明的组合物可以配制为食品。举例来说,除本发明的治疗作用之外,食品可以提供营养益处,例如营养增补剂中。类似地,食品可以被配制成增强本发明组合物的口味,或通过使其更类似于常见食品而非药物组合物,使得组合物食用起来更具吸引力。在某些实施方案中,本发明的组合物被配制为基于牛奶的产品。术语“基于牛奶的产品”意指具有变化脂肪含量的任何基于牛奶或乳清的液体或半固体产品。基于牛奶的产品可以是例如奶牛奶、山羊奶、绵羊奶、脱脂乳、全乳、无任何加工下奶粉与乳清重组的牛奶或加工产品,例如酸奶酪、凝乳、凝块、酸牛奶、酸全乳、酪乳和其它酸牛奶产品。另一重要组包括乳制饮料,例如乳清饮料、发酵牛奶、炼乳、婴儿或婴孩牛奶;增香乳、冰淇淋;含牛奶的食品,例如甜食。
在一些实施方案中,本发明的组合物包含真杆菌属的一个或多个细菌菌株并且不含来自任何其它种属的细菌或仅仅包含最低限度量或生物学上不相干量的来自另一种属的细菌。因此,在一些实施方案中,本发明提供一种包含真杆菌属的一个或多个细菌菌株的组合物,其不含来自任何其它种属的细菌或仅仅包含最低限度量或生物学上不相干量的来自另一种属的细菌,并且其用于治疗中。
在某些实施方案中,本发明的组合物含有单一细菌菌株或物种且不含有任何其它细菌菌株或物种。此类组合物可以仅仅包含最低限度量或生物学上不相干量的其它细菌菌株或物种。此类组合物可以是基本上不含其它生物体物种的培养物。因此,在一些实施方案中,本发明提供了一种包含真杆菌属的单一细菌菌株或物种的组合物,其不含来自任何其它种属的细菌或仅仅包含最低限度量或生物学上不相干量的来自另一种属的细菌,并且其用于治疗中。
在一些实施方案中,本发明的组合物包含超过一个细菌菌株或物种。举例来说,在一些实施方案中,本发明的组合物包含超过一个来自同一物种的菌株(例如超过1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、15个、20个、25个、30个、35个、40个或45个菌株)并且任选地不含来自任何其它物种的细菌。在一些实施方案中,本发明的组合物包含少于50个来自同一物种的菌株(例如少于45个、40个、35个、30个、25个、20个、15个、12个、10个、9个、8个、7个、6个、5个、4个或3个菌株)并且任选地不含来自任何其它物种的细菌。在一些实施方案中,本发明的组合物包含1-40个、1-30个、1-20个、1-19个、1-18个、1-15个、1-10个、1-9个、1-8个、1-7个、1-6个、1-5个、1-4个、1-3个、1-2个、2-50个、2-40个、2-30个、2-20个、2-15个、2-10个、2-5个、6-30个、6-15个、16-25个或31-50个来自同一物种的菌株并且任选地不含来自任何其它物种的细菌。在一些实施方案中,本发明的组合物包含超过一个来自同一种属的物种(例如超过1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、12个、15个、17个、20个、23个、25个、30个、35个或40个物种)并且任选地不含来自任何其它种属的细菌。在一些实施方案中,本发明的组合物包含少于50个来自同一种属的物种(例如少于50个、45个、40个、35个、30个、25个、20个、15个、12个、10个、8个、7个、6个、5个、4个或3个物种)并且任选地不含来自任何其它种属的细菌。在一些实施方案中,本发明的组合物包含1-50个、1-40个、1-30个、1-20个、1-15个、1-10个、1-9个、1-8个、1-7个、1-6个、1-5个、1-4个、1-3个、1-2个、2-50个、2-40个、2-30个、2-20个、2-15个、2-10个、2-5个、6-30个、6-15个、16-25个或31-50个来自同一种属的物种并且任选地不含来自任何其它种属的细菌。本发明包含上述细菌的任何组合。
在一些实施方案中,组合物包含微生物菌群。举例来说,在一些实施方案中,组合物包含真杆菌属细菌菌株作为微生物菌群的一部分。举例来说,在一些实施方案中,真杆菌属细菌菌株与一个或多个(例如至少2个、3个、4个、5个、10个、15个或20个)来自其可以一起体内共生在肠中的其它种属的其它细菌菌株组合存在。举例来说,在一些实施方案中,组合物包含扭曲真杆菌的细菌菌株与来自不同种属的细菌菌株组合。在一些实施方案中,微生物菌群包含两个或更多个从例如人等单一生物体的粪便样品获得的细菌菌株。在一些实施方案中,未发现微生物菌群在自然界中在一起。举例来说,在一些实施方案中,微生物菌群包含从至少两个不同生物体的粪便样品获得的细菌菌株。在一些实施方案中,两个不同生物体来自于相同物种,例如两个不同人。在一些实施方案中,两个不同生物体是人类婴儿和成年人。在一些实施方案中,两个不同生物体是两个不同成年人。在一些实施方案中,两个不同生物体是人和非人哺乳动物。
在一些实施方案中,本发明的组合物另外包含具有与以NCIMB 42689寄存的菌株MRX050相同的安全和治疗功效特征,但不是以NCIMB 42689寄存的MRX050或者不是扭曲真杆菌或者不是真杆菌属的细菌菌株。
在本发明的组合物包含超过一个细菌菌株、物种或种属的一些实施方案中,个别的细菌菌株、物种或种属可以分开、同时或连续施用。举例来说,组合物可以包含超过一个细菌菌株、物种或种属全部,或细菌菌株、物种或种属可以分开存储并且分开、同时或连续施用。在一些实施方案中,超过一个细菌菌株、物种或种属分开存储,但是在使用前混合在一起。
在一些实施方案中,从成年人粪便获得用于本发明的细菌菌株。在本发明的组合物包含超过一个细菌菌株的一些实施方案中,从成年人粪便获得所有细菌菌株,或者如果存在其它细菌菌株,那么其仅仅以最低限度量存在。细菌可以在从成年人粪便获得并且用于本发明的组合物后培养。
如上所提及,在一些实施方案中,本发明的细菌菌株是本发明的组合物中的唯一治疗活性剂。在一些实施方案中,组合物中的细菌菌株是本发明组合物中的唯一治疗活性剂。
根据本发明使用的组合物可能需要或可能不需要销售批准。
在某些实施方案中,本发明提供了以上药物组合物,其中所述细菌菌株是冻干的。在某些实施方案中,本发明提供了以上药物组合物,其中所述细菌菌株进行喷雾干燥。在某些实施方案中,本发明提供了以上药物组合物,其中细菌菌株是冻干的或喷雾干燥并且其中其是活的。在某些实施方案中,本发明提供以上药物组合物,其中细菌菌株是冻干的或喷雾干燥并且其中其能存活。在某些实施方案中,本发明提供以上药物组合物,其中细菌菌株是冻干的或喷雾干燥并且其中其能够部分或完全定殖肠部。在某些实施方案中,本发明提供以上药物组合物,其中细菌菌株是冻干的或喷雾干燥并且其中其能成活并能够部分或完全定殖肠部。
在一些情况下,冻干或喷雾干燥的细菌菌株在施用之前复原。在一些情况下,复原是通过使用本文中描述的稀释剂。
本发明的组合物可以包含药学上可接受的赋形剂、稀释剂或载剂。
在某些实施方案中,本发明提供了一种药物组合物,其包含:如本发明中使用的细菌菌株;和药学上可接受的赋形剂、载剂或稀释剂;其中细菌菌株在施用有于需要的受试者时量足够治疗病症;并且其中病症选自由以下组成的群组:葡萄膜炎;癌症,例如乳癌、肺癌、肝癌、结肠癌或卵巢癌;多发性硬化;关节炎,例如类风湿性关节炎、骨关节炎、牛皮癣性关节炎或幼年特发性关节炎;视神经脊髓炎(德维克氏病);强直性脊柱炎;脊柱关节炎;牛皮癣;系统性红斑狼疮;发炎性肠病,例如克罗恩氏病或溃疡性结肠炎;乳糜泻;哮喘,例如过敏性哮喘或中性粒细胞性哮喘;慢性阻塞性肺病(COPD);巩膜炎;血管炎;白塞氏病;动脉粥样硬化;异位性皮炎;肺气肿;牙周炎;过敏性鼻炎;以及同种异体移植排斥。
在某些实施方案中,本发明提供药物组合物,其包含:如本发明中使用的细菌菌株;和药学上可接受的赋形剂、载剂或稀释剂;其中细菌菌株的量足够治疗或预防由IL-17或Th17通路介导的疾病或病状。在优选实施方案中,所述疾病或病状选自由以下组成的群组:葡萄膜炎;癌症,例如乳癌、肺癌、肝癌、结肠癌或卵巢癌;多发性硬化;关节炎,例如类风湿性关节炎、骨关节炎、牛皮癣性关节炎或幼年特发性关节炎;视神经脊髓炎(德维克氏病);强直性脊柱炎;脊柱关节炎;牛皮癣;系统性红斑狼疮;发炎性肠病,例如克罗恩氏病或溃疡性结肠炎;乳糜泻;哮喘,例如过敏性哮喘或中性粒细胞性哮喘;慢性阻塞性肺病(COPD);巩膜炎;血管炎;白塞氏病;动脉粥样硬化;异位性皮炎;肺气肿;牙周炎;过敏性鼻炎;以及同种异体移植排斥。
在某些实施方案中,本发明提供以上药物组合物,其中细菌菌株的量是相对于组合物的重量每克约1×103到约1×1011菌落形成单位。
在某些实施方案中,本发明提供以上药物组合物,其中组合物以1g、3g、5g或10g的剂量施用。
在某些实施方案中,本发明提供以上药物组合物,其中组合物通过选自由口腔、直肠、皮下、鼻、颊和舌下组成的群组的方法施用。
在某些实施方案中,本发明提供以上药物组合物,其包含选自由乳糖、淀粉、葡萄糖、甲基纤维素、硬脂酸镁、甘露糖醇和山梨糖醇组成的群组的载剂。
在某些实施方案中,本发明提供以上药物组合物,其包含选自由乙醇、甘油和水组成的群组的稀释剂。
在某些实施方案中,本发明提供以上药物组合物,其包含选自由以下组成的群组的赋形剂:淀粉、明胶、葡萄糖、无水乳糖、自由流动的乳糖、β-乳糖、玉米甜味剂、阿拉伯胶、黄蓍胶、海藻酸钠、羧甲基纤维素、聚乙二醇、油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠和氯化钠。
在某些实施方案中,本发明提供以上药物组合物,其进一步包含防腐剂、抗氧化剂和稳定剂中的至少一种。
在某些实施方案中,本发明提供以上药物组合物,其包含选自由苯甲酸钠、山梨酸和对羟基苯甲酸酯组成的群组的防腐剂。
在某些实施方案中,本发明提供以上药物组合物,其中当组合物存储在密封容器中约4℃或约25℃下且容器置于具有50%相对湿度的气氛中时,在至少约1个月、3个月、6个月、1年、1.5年、2年、2.5年或3年时期后如以菌落形成单位测量,至少80%细菌菌株残留。
在一些实施方案中,本发明的组合物提供于包含如本文描述的组合物的密封容器中。在一些实施方案中,密封容器是小袋或瓶子。在一些实施方案中,本发明的组合物提供于包含如本文描述的组合物的注射器中。
在一些实施方案中,本发明的组合物可以呈药物制剂提供。举例来说,组合物可以呈片剂或胶囊提供。在一些实施方案中,胶囊是明胶胶囊(“明胶胶囊”)。
在一些实施方案中,本发明的组合物经口施用。经口施用可能涉及吞咽,以便化合物进入胃肠道,和/或经颊、经舌或舌下施用,通过此,化合物直接从口腔进入血流。
适合于经口施用的药物制剂包括固体塞、固体微粒、半固体和液体(包括多相或分散系统),例如片剂;含有微米粒子或纳米粒子的软胶囊或硬胶囊、液体(例如水溶液)、乳液或粉末;糖锭(包括填充液体);咀嚼片;凝胶;快速分散的剂型;薄膜;卵形囊剂;喷雾;和经颊/粘膜粘着贴片。
在一些实施方案中,药物制剂是肠制剂,即适合于通过经口施用递送本发明的组合物至肠的抗胃制剂(例如对胃pH值有抗性)。当细菌或组合物的另一组分对酸敏感,例如在胃条件下倾向于降解时,肠制剂可能特别有用。
在一些实施方案中,肠制剂包含肠衣。在一些实施方案中,制剂是肠衣剂型。举例来说,制剂可以是肠衣片剂或肠衣胶囊等等。肠衣可以是常规肠衣,例如用于片剂、胶囊等等进行经口递送的常规包衣。制剂可以包含膜衣,例如肠聚合物、例如酸不溶性聚合物的薄膜层。
在一些实施方案中,肠制剂本质上是肠溶性的,例如胃具有抗性,无需肠衣。因此,在一些实施方案中,制剂是不包含肠衣的肠制剂。在一些实施方案中,制剂是由热胶凝材料制成的胶囊。在一些实施方案中,热胶凝材料是纤维素材料,例如甲基纤维素、羟甲基纤维素或羟丙基甲基纤维素(HPMC)。在一些实施方案中,胶囊包含不含任何成膜聚合物的壳。在一些实施方案中,胶囊包含壳并且壳包含羟丙基甲基纤维素且不包含任何成膜聚合物(例如参见[54])。在一些实施方案中,制剂是本质上肠胶囊(例如来自Capsugel的)。
在一些实施方案中,制剂是软胶囊。软胶囊是由于添加例如丙三醇、山梨糖醇、麦芽糖醇和聚乙二醇等在胶囊壳中存在的软化剂而具有一定弹性和柔软度的胶囊。软胶囊可以例如根据明胶或淀粉产生。基于明胶的软胶囊从多个供应商购得。取决于施用方法,例如经口或经直肠,软胶囊可以具有多种形状,其可以例如是圆形、卵形、长方形或鱼雷形状。软胶囊可以通过常规方法产生,例如通过谢勒法(Scherer process)、阿可法(Accogelprocess)或液滴或吹制法产生。
培养方法
用于本发明的细菌菌株可以使用如例如参考文献[55-57]中详述的标准微生物学技术培养。
用于培养的固体或液体培养基可以是YCFA琼脂或YCFA培养基。YCFA培养基可以包括(每100ml,近似值):酪胨(1.0g)、酵母提取物(0.25g)、NaHCO3(0.4g)、半胱氨酸(0.1g)、K2HPO4(0.045g)、KH2PO4(0.045g)、NaCl(0.09g)、(NH4)2SO4(0.09g)、MgSO4·7H2O(0.009g)、CaCl2(0.009g)、刃天青(0.1mg)、氯化血红素(1mg)、生物素(1μg)、钴胺素(1μg)、对氨基苯甲酸(3μg)、叶酸(5μg)和吡哆胺(15μg)。
用于疫苗组合物中的细菌菌株
本发明人已经确定本发明的细菌菌株可用于治疗或预防由IL-17或Th17通路介导的疾病或病状。此可能是本发明的细菌菌株作用于宿主免疫系统的结果。因此,当作为疫苗组合物施用时,本发明的组合物也可用于预防由IL-17或Th17通路介导的疾病或病状。在某些此类实施方案中,本发明的细菌菌株能存活。在某些此类实施方案中,本发明的细菌菌株能够部分或完全定殖肠部。在某些此类实施方案中,本发明的细菌菌株能存活并且能够部分或完全定殖肠部。在其它此类实施方案中,本发明的细菌菌株可以是杀死的、灭活的或减毒的。在某些此类实施方案中,组合物可以包含疫苗佐剂。在某些实施方案中,组合物用于通过注射,例如通过皮下注射施用。
通则
除非另外指明,否则本发明的实施将采用在本领域技能内的常规化学、生物化学、分子生物学、免疫学和药理学方法。此类技术在文献中充分解释。参见例如参考文献[58]和[59-65]等。
术语“包含”涵盖“包括”以及“由……组成”,例如“包含”X的组合物可以仅仅由X组成,或可以包括其它某物,例如X+Y。
关于数值x的术语“约”是任选选用的并且意指例如x±10%。
词语“基本上”不排除“完全”,例如“基本上不含”Y的组合物可完全不含Y。必要时,本发明的定义中可以省略词语“基本上”。
提及两种核苷酸序列之间的序列一致性百分比意指在比对时,比较两种序列中相同的核苷酸百分比。此比对和同源性或序列一致性百分比可以使用本领域中已知的软件程序,例如参考文献[66]的部分7.7.18中描述的软件程序确定。优选比对通过Smith-Waterman同源性搜索算法使用仿射空位搜索(其中开放空位罚分是12且空位延伸罚分是2、BLOSUM 62矩阵)来确定。Smith-Waterman同源性搜索算法在参考文献[67]中公开。
除非特别陈述,否则包括多个步骤的工艺或方法可以在方法开始或结束包括其它步骤,或可以包括其它插入步骤。此外,适当时步骤可以组合,省去或以替代次序进行。
本文中描述本发明的多个实施方案。应了解每个实施方案中说明的特征都可以与其它所说明的特征组合以提供其它实施方案。具体来说,本文中强调为适合、典型或优选的实施方案可以彼此组合(除非其互斥时)。
用于进行本发明的模式
实施例1-葡萄膜炎的小鼠模型中细菌接种物的功效
概述
本研究使用光感受器间类视黄醇结合蛋白(IRBP)诱发的葡萄膜炎的小鼠模型测试细菌施用对葡萄膜炎的作用。葡萄膜炎是一种由眼内发炎和视网膜组织破坏引起的威胁视力的病状。此疾病可以在啮齿类动物中在实验性自身免疫性葡萄膜视网膜炎(experimental autoimmune uveoretinitis,EAU)模型中进行研究[68]。EAU是一种器官特异性病症,其中Th1/Th17细胞是针对视网膜抗原并且产生细胞因子,所述细胞因子活化存在和渗透的单核细胞,导致组织破坏。可以通过用包括光感受器间类视黄醇结合蛋白肽(IRBPp)在内的视网膜抗原挑战,在小鼠中诱发EAU。通常在第8-9天发病,并在14-15天后达到峰值。临床疾病的征象可以使用局部内窥镜眼底成像(topical endoscopic fundalimaging,TEFI)监测。
菌株
MRX050:扭曲真杆菌
本实施例中使用的菌株已经以NCIMB 42689寄存。
生物治疗剂提供于丙三醇原液中。微生物生长培养基(YCFA)用于培养此剂。
小鼠
小鼠是品系C57BL/6并且在研究开始时是6周龄。使用72个小鼠(+36个卫星动物)。从研究去除不健康的动物。动物圈养在恒温监测保藏室(22±4℃)中无特异病原(spf)条件下。在使用前使动物适应标准畜舍条件,历时最少一周。在整个时间段内监测动物的健康状态,并且在研究开始前评定各动物用于实验的适合性。在研究持续时间期间,小鼠以每笼至多10个动物成组圈养。在整个适应和研究时期期间,经过辐射的颗粒饲料(实验室饲料,欧盟啮齿类动物饲料22%,5LF5)和水随意取用。饲料或水的任何成分不能干扰研究。
实验概述
成年雌性C57BL/6小鼠随机分配至实验组并且适应一周。根据以下时程施用处理。在第0天,通过皮下注射,向动物施用含有200μg光感受器间类视黄醇结合蛋白肽1-20(IRBPp1-20)于补充有2.5mg/ml结核分枝杆菌(Mycobacterium Tuberculosis)H37Ra的完全弗氏佐剂(complete Freund’s adjuvant,CFA)中的乳液。同时在第0天,通过腹膜内注射,向动物施用1.5μg百日咳杆菌毒素(Bordetella Pertussis toxin)。从第-14天起,动物每周称重三次。从第-1天到第42天实验结束,使用局部内窥镜眼底成像(TEFI),针对葡萄膜炎的临床征象,每周监测动物两次。
施用时程
所有组都是n=12
经口施用的媒介物是YCFA培养基。
每日经口施用两次的施用体积是5ml/kg。
PO:经口施用,BID:每日两次,SC:皮下注射,IP:腹膜内注射,IRBP:光感受器间结合蛋白,CFA:完全弗氏佐剂,PTx:百日咳毒素
还使用用药物环孢菌素A处理来测试阳性对照组。
读出
体重.从第-14天起,动物一周称重三次。连续两个时刻体重损失等于或超过其初始(第0天)体重15%的动物被淘汰。
非特定的临床观测结果.从第-14天到实验结束,每日检查动物的非特定临床征象,包括姿势异常(弓背)、异常皮毛情况(竖毛)和异常活动水平(活动减少或增加)。
临床评分:通过局部内窥镜眼底成像(TEFI)进行视网膜成像.从第-1天到实验结束,每周针对葡萄膜炎的临床征象,对动物评分两次。在未麻醉但受约束的动物中,使用托吡卡胺(Tropicamide)1%、接着盐酸苯肾上腺素(Phenylephrine hydrochloride)2.5%进行瞳孔扩张后,使用TEFI捕捉视网膜影像。使用以下系统对视网膜影像评分。最大累积评分是20。
结果
研究结果展示在图1和2中。
临床评分:通过局部内窥镜眼底成像(TEFI)进行视网膜成像.通过针对非参数数据进行克鲁斯凯-沃利斯检验(Kruskal-Wallis test),接着针对实验日之间的多重比较进行邓恩事后检验(Dunn’s post-test),来分析从第0天到第28天在对照组中测量的TEFI评分数据。
与对照组中第0天相比,IRBP施用诱发从第14天(p<0.01)和在第28天(p<0.0001)测量的TEFI评分显著增加(图1)。
使用单因素ANOVA分析在实验组中在第28天测量的TEFI评分。正如所料,在阳性对照环孢霉素A组中观察到评分显著下降。相对于阴性对照物,MRX050处理的组的评分也存在统计上显著的下降(p<0.001)(图2)。
结论.如在IRBP诱发的葡萄膜炎的此模型中所预期,通过TEFI测定的临床评分从第14天起增加。到第28天,在MRX050处理的组中观察到发病率和疾病严重度惊人的和统计上显著的下降,此与阳性对照组中所见可比。具体地说,这些数据表明用菌株MRX050处理减少视网膜损伤、视神经盘发炎和/或视网膜组织被炎性细胞渗入(参见以上TEFI视网膜影像评分系统)。这些数据表明菌株MRX050可用于治疗或预防葡萄膜炎。
实施例2-稳定性测试
含有至少一种本文中描述的细菌菌株的本文中描述的组合物存储在密封容器中25℃或4℃下并且容器置于具有30%、40%、50%、60%、70%、75%、80%、90%或95%相对湿度的气氛中。1个月、2个月、3个月、6个月、1年、1.5年、2年、2.5年或3年后,至少50%、60%、70%、80%或90%的细菌菌株应残留,如以通过标准规方案测定的菌落形成单位测量。
序列
SEQ ID NO:1(扭曲真杆菌部分16S rRNA基因,模式菌株DSM 3982T,克隆1-FR749945)
SEQ ID NO:2(扭曲真杆菌部分16S rRNA基因,模式菌株DSM 3982T,克隆2-FR749946)
SEQ ID NO:3(扭曲真杆菌16S核糖体RNA ATCC 25540-L34615)
SEQ ID NO:4(扭曲真杆菌菌株MRX050的共有16S rRNA序列)
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序列表
<110> 4D 制药研究有限公司
<120> 包含细菌菌株的组合物
<130> P067606
<150> GB 1520638.6
<151> 2015-11-23
<160> 4
<170> SeqWin2010, 1.0版
<210> 1
<211> 1521
<212> DNA
<213> 扭曲真杆菌 (Eubacterium contortum)
<400> 1
gatcctggct caggatgaac gctggcggcg tgcttaacac atgcaagtcg agcgaagcgc 60
tttacttaga tttcttcgga ttgaagagtt ttgcgactga gcggcggacg ggtgagtaac 120
gcgtgggtaa cctgcctcat acagggggat aacagttaga aatgactgct aataccgcat 180
aagaccacgg taccgcatgg tacagtggga aaaactccgg tggtatgaga tggacccgcg 240
tctgattagc tagttggtaa ggtaacggct taccaaggcg acgatcagta gccgacctga 300
gagggtgacc ggccacattg ggactgagac acggcccaaa ctcctacggg aggcagcagt 360
ggggaatatt gcacaatggg ggaaaccctg atgcagcgac gccgcgtgaa ggatgaagta 420
tttcggtatg taaacttcta tcagcaggga agaaaatgac ggtacctgac taagaagccc 480
cggctaacta cgtgccagca gccgcggtaa tacgtagggg gcaagcgtta tccggattta 540
ctgggtgtaa agggagcgta gacggttatg taagtctgat gtgaaaaccc ggggctcaac 600
cccgggactg cattggaaac tatgtaacta gagtgtcgga gaggtaagtg gaattcctag 660
tgtagcggtg aaatgcgtag atattaggag gaacaccagt ggcgaaggcg gcttactgga 720
cgatgactga cgttgaggct cgaaagcgtg gggagcaaac aggattagat accctggtag 780
tccacgccgt aaacgatgaa tactaggtgt cgggtggcaa agccattcgg tgccgcagca 840
aacgcaataa gtattccacc tggggagtac gttcgcaaga atgaaactca aaggaattga 900
cggggacccg cacaagcggt ggagcatgtg gtttaattcg aagcaacgcg aagaacctta 960
cctgctcttg acatccccct gaccggcgtg taatggtgcc tttccttcgg gacaggggag 1020
acaggtggtg catggttgtc gtcagctcgt gtcgtgagat gttgggttaa gtcccgcaac 1080
gagcgcaacc cttatcttta gtagccagcg gtttggccgg gcactctaga gagactgcca 1140
gggataacct ggaggaaggt ggggatgacg tcaaatcatc atgcccctta tgagcagggc 1200
tacacacgtg ctacaatggc gtaaacaaag ggaggcgaag ccgtgaggtg gagcaaatcc 1260
caaaaataac gtctcagttc ggattgtagt ctgcaactcg actacatgaa gctggaatcg 1320
ctagtaatcg cgaatcagaa tgtcgcggtg aatacgttcc cgggtcttgt acacaccgcc 1380
cgtcacacca tgggagttgg taacgcccga agtcagtgac ccaaccgcaa ggagggagct 1440
gccgaaggtg ggaccgataa ctggggtgaa gtcgtaacaa ggtagccgta tcggaaggtg 1500
cggctggatc acctcctttc t 1521
<210> 2
<211> 1524
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<213> 扭曲真杆菌 (Eubacterium contortum)
<400> 2
tttgatcctg gctcaggatg aacgctggcg acgtgcttaa cacatgcaag tcgagcgaag 60
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aacgcgtggg taacctgcct catacagggg gataacagtt agaaatgact gctaataccg 180
cataagacca cagtaccgca tggtacagtg ggaaaaactc cggtggtatg agatggaccc 240
gcgtctgatt agctagttgg taaggtaacg gcttaccaag gcgacgatca gtagccgacc 300
tgagagggtg accggccaca ttgggactga gacacggccc aaactcctac gggaggcagc 360
agtggggaat attgcacaat gggggaaacc ctgatgcagc gacgccgcgt gaaggatgaa 420
gtatttcggt atgtaaactt ctatcagcag ggaagaaaat gacggtacct gactaagaag 480
ccccggctaa ctacgtgcca gcagccgcgg taatacgtag ggggcaagcg ttatccggat 540
ttactgggtg taaagggagc gtagacggtt atgtaagtct gatgtgaaaa cccggggctc 600
aaccccggga ctgcattgga aactatgtaa ctagagtgtc ggagaggtaa gtggaattcc 660
tagtgtagcg gtgaaatgcg tagatattag gaggaacacc agtggcgaag gcggcttact 720
ggacgatgac tgacgttgag gctcgaaagc gtggggagca aacaggatta gataccctgg 780
tagtccacgc cgtaaacgat gaatactagg tgtcgggtgg caaagccatt cggtgccgca 840
gcaaacgcaa taagtattcc acctggggag tacgttcgca agaatgaaac tcaaaggaat 900
tgacggggac ccgcacaagc ggtggagcat gtggtttaat tcgaagcaac gcgaagaacc 960
ttacctgctc ttgacatccc cctgaccggc gtgtaatggt gcctttcctt cgggacaggg 1020
gagacaggtg gtgcatggtt gtcgtcagct cgtgtcgtga gatgttgggt taagtcccgc 1080
aacgagcgca acccttatct ttagtagcca gcggtttggc cgggcactct agagagactg 1140
ccagggataa cctggaggaa ggtggggatg acgtcaaatc atcatgcccc ttatgagcag 1200
ggctacacac gtgctacaat ggcgtaaaca aagggaggcg aagccgtgag gtggagcaaa 1260
tcccaaaaat aacgtctcag ttcggattgt agtctgcaac tcgactacat gaagctggaa 1320
tcgctagtaa tcgcgaatca gaatgtcgcg gtgaatacgt tcccgggtct tgtacacacc 1380
gcccgtcaca ccatgggagt tggtaacgcc cgaagtcagt gacccaaccg caaggaggga 1440
gctgccgagg gtgggaccga taactggggt gaagtcgtaa caaggtagcc gtatcggaag 1500
gtgcggctgg atcacctcct ttct 1524
<210> 3
<211> 1483
<212> DNA
<213> 扭曲真杆菌 (Eubacterium contortum)
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nttttaacga gagtttgatc ctggctcagg atnaacgctg gcggcgtgct taacacatgc 60
aagtcgagcg aagcrcttta cttwgatttc ttcggawtga arggttttgy gactgagcgg 120
cggacgggtg agtaacgcgt gggtaacctg cctcatacag ggggataaca gttagaaatg 180
actgctaata ccgcataaga ccacrgtacc gcatggtaca gtggnaaaaa ctccggtggt 240
atgagatgga cccgcgtctg attagctagt tggtaaggta acggcttacn aaggcgacga 300
tcagtagccg acctgagagg gtgaccggcc acattgggac tgagacacgg ccnnaactcc 360
tacgggaggc agcagtgggg aatattgcac aatgggggaa accctgatgc agcgacgccg 420
cgtgaaggat gaagtatttc ggtatgtaaa cttctatcag cagggaagaa aatgacggta 480
cctgactaag aagccccggc taactacgtg ccagcagccn cggtaatacg tagggggnna 540
gcgttatccg gatttactgg gtgtaaaggg agcgtagacg gttatgtaag tctgatgtga 600
aaacccgggg ctcaaccccn nnnctgcatt ggaaactatg taactagagt gtcggagagg 660
taagtggaat tcctagtgta gcggtgaaat gcgtagatat taggaggaac accagtggcg 720
aaggcggctt actggacgat gactgacgtt gaggctcgaa agcgtgggga gcaaacagga 780
ttagataccc tggtagtcca cgccgtaaac gatgaatact aggtgtcggg tggcaaagcc 840
attcggtgcc gcagcaaacg caataagtat tccacctggg gagtacgttc gcaagaatga 900
aactcaaagg aattgacggg naccngcaca agcggtggag catgtggttt aattcgaann 960
aacgcgaaga accttacctg ctcttgacat ccccctgacc ggcgtgtaat ggtgccnttc 1020
cttcgggaca ggggngacag gtggtgcatg gttgtcgtca gctcgtgtcg tgagatgttg 1080
ggttaagtcc cnnaacgagc gcaaccctta tctttagtag ccagcggttt aggccggnna 1140
ctctagagag actgccaggn ataacctgga ggaaggtggg gatgacgnnn aatcatcatg 1200
ccccttatga gcaggnctac acacgtgcta caatggcgta aacaaaggga ggcgaagccg 1260
ygaggtggag caaatcccaa aaataacgtc tcagttcgga ttgtagtctg caactcgact 1320
acatgaagct ggaatcgcta gtaatcgcga atcagaatgt cgcggtgaat acgttcccnn 1380
gtcttgtaca caccgnccgt cacaccatgg gagttggtaa cgcccgaagt cagtgaccca 1440
accgcaagga gggagctgcc gaaggtggga ccgataactg ggg 1483
<210> 4
<211> 1407
<212> DNA
<213> 扭曲真杆菌 (Eubacterium contortum)
<400> 4
tgcagtcgag cgaagcagct ttacttagat ttcttcggat tgaaagagtt ttgcgactga 60
gcggcggacg ggtgagtaac gcgtgggtaa cctgcctcat acagggggat aacagttaga 120
aatgactgct aataccgcat aagaccacgg taccgcatgg tacagtggga aaaactccgg 180
tggtatgaga tggacccgcg tctgattagc tggttggtaa ggtaacggct taccaaggcg 240
acgatcagta gccgacctga gagggtgacc ggccacattg ggactgagac acggcccaaa 300
ctcctacggg aggcagcagt ggggaatatt gcacaatggg ggaaaccctg atgcagcgac 360
gccgcgtgaa ggatgaagta tttcggtatg taaacttcta tcagcaggga agaaaatgac 420
ggtacctgac taagaagccc cggctaacta cgtgccagca gccgcggtaa tacgtagggg 480
gcaagcgtta tccggattta ctgggtgtaa agggagcgta gacggttatg taagtctgat 540
gtgaaaaccc ggggctcaac cccgggactg cattggaaac tatgtaacta gagtgtcgga 600
gaggtaagtg gaattcctag tgtagcggtg aaatgcgtag atattaggag gaacaccagt 660
ggcgaaggcg gcttactgga cgatgactga cgttgaggct cgaaagcgtg gggagcaaac 720
aggattagat accctggtag tccacgccgt aaacgatgaa tactaggtgt cgggtggcaa 780
agccattcgg tgccgcagca aacgcaataa gtattccacc tggggagtac gttcgcaaga 840
atgaaactca aaggaattga cggggacccg cacaagcggt ggagcatgtg gtttaattcg 900
aagcaacgcg aagaacctta cctgctcttg acatccccct gaccggcgcg taatggtgcc 960
tttccttcgg gacaggggag acaggtggtg catggttgtc gtcagctcgt gtcgtgagat 1020
gttgggttaa gtcccgcaac gagcgcaacc cttatcttta gtagccagcg gtatggccgg 1080
gcactctaga gagactgcca gggataacct ggaggaaggt ggggatgacg tcaaatcatc 1140
atgcccctta tgagcagggc tacacacgtg ctacaatggc gtaaacaaag ggaggcgaag 1200
ccgcgaggtg gagcaaatcc caaaaataac gtctcagttc ggattgtagt ctgcaactcg 1260
actacatgaa gctggaatcg ctagtaatcg cgaatcagaa tgtcgcggtg aatacgttcc 1320
cgggtcttgt acacaccgcc cgtcacacca tgggagttgg taacgcccga agtcagtgac 1380
ccaaccgcaa ggagggagct gccgaag 1407
Claims (40)
1.一种包含真杆菌属的细菌菌株的组合物,其用于治疗或预防由IL-17或Th17通路介导的疾病或病状的方法中。
2.如权利要求1所述的组合物,其中所述组合物用于治疗或预防选自由以下组成的群组的疾病或病状的方法中:葡萄膜炎;癌症,例如乳癌、肺癌、肝癌、结肠癌或卵巢癌;多发性硬化;关节炎,例如类风湿性关节炎、骨关节炎、牛皮癣性关节炎或幼年特发性关节炎;视神经脊髓炎(德维克氏病);强直性脊柱炎;脊柱关节炎;牛皮癣;系统性红斑狼疮;发炎性肠病,例如克罗恩氏病或溃疡性结肠炎;乳糜泻;哮喘,例如过敏性哮喘或中性粒细胞性哮喘;慢性阻塞性肺病(COPD);巩膜炎;血管炎;白塞氏病;动脉粥样硬化;异位性皮炎;肺气肿;牙周炎;过敏性鼻炎;以及同种异体移植排斥。
3.如权利要求2所述的组合物,其中所述组合物用于治疗或预防葡萄膜炎的方法中。
4.如权利要求3所述的组合物,其中所述组合物用于减少或预防葡萄膜炎中的视网膜损伤的方法中。
5.如权利要求2所述的组合物,其中所述组合物用于治疗或预防例如肺癌、乳癌或肝癌等癌症的方法中。
6.如权利要求5所述的组合物,其中所述组合物用于减小肿瘤尺寸、减少肿瘤生长、预防转移或预防血管生成的方法中。
7.如权利要求2所述的组合物,其中所述组合物用于治疗或预防例如中性粒细胞性哮喘或过敏性哮喘等哮喘的方法中。
8.如权利要求7所述的组合物,其中所述组合物用于在哮喘治疗中减少中性粒细胞增多或嗜酸性粒细胞增多的方法中。
9.如权利要求2所述的组合物,其中所述组合物用于治疗或预防类风湿性关节炎的方法中。
10.如权利要求9所述的组合物,其中所述组合物用于减少类风湿性关节炎中的关节肿胀的方法中。
11.如权利要求2所述的组合物,其中所述组合物用于治疗或预防多发性硬化的方法中。
12.如权利要求11所述的组合物,其中所述组合物用于降低发病率或疾病严重度的方法中。
13.如任一前述权利要求所述的组合物,其中所述组合物用于在由IL-17或Th17通路介导的疾病或病状的治疗或预防中减少IL-17产生或减少Th17细胞分化的方法中。
14.如任一前述权利要求所述的组合物,其中所述组合物用于具有高水平的IL-17或Th17细胞的患者中。
15.如任一前述权利要求所述的组合物,其中所述细菌菌株属于扭曲真杆菌。
16.如权利要求1至14中任一项所述的组合物,其中所述细菌菌株具有与扭曲真杆菌的细菌菌株的16s rRNA序列至少95%、96%、97%、98%、99%、99.5%或99.9%一致的16srRNA序列。
17.如权利要求1至14中任一项所述的组合物,其中所述细菌菌株具有与SEQ ID NO:1、2、3或4至少95%、96%、97%、98%、99%、99.5%或99.9%一致的16s rRNA序列。
18.如权利要求17所述的组合物,其中所述细菌菌株具有与SEQ ID NO:4至少95%、96%、97%、98%、99%、99.5%或99.9%一致的16s rRNA序列,或者其中所述细菌菌株具有由SEQ ID NO:4表示的16s rRNA序列。
19.如权利要求1所述的组合物,其中所述组合物包含扭曲真杆菌物种的细菌菌株,其用于治疗或预防类风湿性关节炎的方法中。
20.如权利要求1所述的组合物,其中所述组合物包含扭曲真杆菌物种的细菌菌株,其用于治疗或预防例如中性粒细胞性哮喘或过敏性哮喘等哮喘的方法中。
21.如权利要求1所述的组合物,其中所述组合物包含扭曲真杆菌物种的细菌菌株,其用于治疗或预防多发性硬化的方法中。
22.如权利要求1所述的组合物,其中所述组合物包含扭曲真杆菌物种的细菌菌株,其用于治疗或预防葡萄膜炎的方法中。
23.如权利要求1所述的组合物,其中所述组合物包含扭曲真杆菌物种的细菌菌株,其用于治疗或预防癌症的方法中。
24.如任一前述权利要求所述的组合物,其中所述组合物用于经口施用。
25.如任一前述权利要求所述的组合物,其中所述组合物包含一种或多种药学上可接受的赋形剂或载剂。
26.如任一前述权利要求所述的组合物,其中所述细菌菌株是冻干的。
27.如任一前述权利要求所述的组合物,其中所述细菌菌株能存活并能够部分或完全定殖肠部。
28.如任一前述权利要求所述的组合物,其中所述组合物包含真杆菌属的单一菌株。
29.如任一前述权利要求所述的组合物,其包含真杆菌属细菌菌株作为微生物菌群的一部分。
30.一种包含如任一前述权利要求所述的组合物的食品,其供任一前述权利要求使用。
31.一种包含如任一前述权利要求所述的组合物的疫苗组合物,其供任一前述权利要求使用。
32.一种治疗或预防由IL-17或Th17通路介导的疾病或病状的方法,其包括向有需要的患者施用包含真杆菌属的细菌菌株的组合物。
33.一种以NCIMB 42689寄存的扭曲真杆菌菌株MRX050或其衍生物的细胞。
34.一种组合物,其包含如权利要求33所述的细胞。
35.如权利要求34所述的组合物,其包含药学上可接受的载剂或赋形剂。
36.一种以NCIMB 42689寄存的扭曲真杆菌菌株MRX050或其衍生物的生物纯培养物。
37.一种以NCIMB 42689寄存的扭曲真杆菌菌株MRX050或其衍生物的细胞,其用于治疗中。
38.如权利要求37所述的细胞,其中所述细胞用于如权利要求1至14中任一项所定义的方法中。
39.一种包含真杆菌属的一个或多个细菌菌株的组合物,其不含来自任何其它种属的细菌或仅仅包含最低限度量或生物学上不相干量的来自另一种属的细菌,并且其用于治疗中。
40.一种包含扭曲真杆菌物种的一个或多个细菌菌株的组合物,其用于治疗中。
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