CN105636984A - 用于治疗慢性炎症和预防胃肠道癌或纤维化的cd40信号转导抑制剂和其他化合物,该其他化合物是胆汁酸、胆汁酸衍生物、tgr5受体激动剂、fxr激动剂或其组合 - Google Patents
用于治疗慢性炎症和预防胃肠道癌或纤维化的cd40信号转导抑制剂和其他化合物,该其他化合物是胆汁酸、胆汁酸衍生物、tgr5受体激动剂、fxr激动剂或其组合 Download PDFInfo
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Abstract
本发明提供了用于治疗有此需要的个体中慢性炎性疾病的CD40信号转导抑制剂和其他化合物,所述其他化合物是胆汁酸、胆汁酸衍生物、TGR5受体激动剂、FXR受体激动剂或其组合。还提供了用于预防癌症和/或纤维化的CD40信号转导抑制剂和其他化合物,所述其他化合物是胆汁酸、胆汁酸衍生物、TGR5受体激动剂、FXR受体激动剂或其组合。
Description
本发明涉及药物领域。本发明具体涉及用于治疗个体的方式和方法,所述个体患有慢性炎症或处于罹患慢性炎症的风险中。本发明还涉及预防癌症和纤维化的方式和方法。更具体地,本发明涉及用于治疗具有炎症组分的自身免疫疾病或慢性炎症或用于预防胃肠道癌或纤维化,优选肝、肾或胃肠道纤维化的CD40信号转导抑制剂和其胆汁酸或胆汁酸衍生物,CD40信号转导抑制剂如CD40结合抗体,其抑制CD40受体的激活。
作为组织对损伤的应答,炎症的特征在于急性期期间增加的血流和血管通透性以及流体、白细胞和炎性介质(如细胞因子)的累积。在亚急性/慢性期(后文中称作慢性期)中,其特征在于针对组织损伤位点处存在的病原体发展出特异性体液和细胞免疫应答。在急性和慢性炎症过程期间,多种可溶性因子参与通过提高的细胞粘附分子表达和化学趋向性来进行白细胞招募。许多这类可溶性介质调控归巢细胞(如成纤维细胞、内皮细胞、组织巨噬细胞和肥大细胞)和新招募的炎性细胞(如单核细胞、淋巴细胞、嗜中性粒细胞和嗜酸性粒细胞)的激活,且一些这类介质导致炎症过程的***性作用(如发烧、低血压、急性期蛋白质的合成、白细胞增多、恶病质)(C.A.Feghali等,1997,FrontiersinBioscience2,第12-26页)。除可溶性因子外,还存在细胞-细胞介导的信号转导通路,包括CD40信号转导通路,其与慢性炎症的维持和严重程度相关。大多数涉及的可溶性和细胞相关因子具有多效性作用。
炎性应答可由微生物的组分以及大分子(如蛋白质和多糖)和小化学物质(其被识别为外来物)触发。炎性应答和机制旨在保护个体免受感染并消除外来物质,但在一些情况中仍能够导致组织损伤和疾病。在一些情况下,甚至自身(自体)分子也能引发炎性应答,这类反应被称作自身免疫应答且这些反应导致的疾病被统称为自身免疫疾病(Abbas等,CellularandMolecularImmunology(《细胞和分子免疫学》)7E)。
在本发明中,发现CD40信号转导抑制剂和其他化合物可在慢性炎性疾病的治疗和癌症或纤维化的预防中有利地结合。所述其他化合物优选是胆汁酸、胆汁酸衍生物、TGR5受体激动剂、FXR受体激动剂或其组合。本发明目前提供了用于治疗有此需要的个体中慢性炎性疾病的CD40信号转导抑制剂和其他化合物,所述其他化合物是胆汁酸、胆汁酸衍生物、TGR5受体激动剂、FXR受体激动剂或其组合。本发明还提供了用于预防癌症和/或纤维化的CD40信号转导抑制剂和其他化合物,所述其他化合物是胆汁酸、胆汁酸衍生物、TGR5受体激动剂、FXR受体激动剂或其组合。在优选的实施方式中,所述纤维化是肝、肾或胃肠道纤维化。
胆汁酸和胆汁酸衍生物除其促进提高膳食脂肪的处理的微胶粒形成的主要功能外还调节多种不同作用。这些辅助作用包括抗炎症作用。这些和其他作用被认为受胆汁酸或衍生物与特异性胆汁酸受体之间的结合等所介导。胆汁酸受体的优选示例是受体TGR5和FXR。TGR5是一种G蛋白偶联受体,也称作G蛋白偶联胆汁酸受体1(GPBAR1)、G蛋白偶联受体19(GPCR19)、胆汁酸的膜型受体(M-BAR)。TGR5是一种由GPBAR1基因编码的人中的蛋白质。TGR5由单个外显子编码,其映射至小鼠中的染色体1C3和人中的染色体2q35。TGR5广泛表达,但在不同的组织中的表达水平不同,其中在肝、肠、棕色脂肪组织和脾中高表达。不同的胆汁酸不同地作用于TGR5和FXR激活,表明这两种受体在调节胆汁酸作用方面具有不同的功能(XiaosongChen等(2011)Exp.DiabetesRes.Vol2011:第1-5页)。法尼醇X受体(FXR)(也称作胆汁酸受体或BAR(基因名NR1H4))是核受体家族的成员。FXR的功能是胞内胆汁酸(胆固醇分解代谢的终产物)水平的主要感应器和胆汁酸诱导的转录程序的主要执行物。胆汁酸与FXR的配体结合结构域直接相互作用并增强或拮抗FXR的反式激活功能。与其作为胆汁酸受体发挥功能一致的是,FXR在正常生理状态下通常接触胆汁酸的组织中的表达最丰富:肝、肠和肾。经由FXR或TGR5的信号转导调控若干代谢通路,不仅调节BA合成和肠肝循环,还调节甘油三酯、胆固醇、葡萄糖和能量内稳态(综述于Fiorucci等(2009)TrendsPharmacolSci.卷30:第570-580页)。
胆汁酸长期以来被认为对先天免疫的细胞施加直接调控作用。这类胆汁酸的一个示例是鹅去氧胆酸(CDCA),一种重要胆汁酸和FXR配体。CDCA负调节LPS初免的巨噬细胞中的IL1b、IL6和TNF释放(Calmus1992)。FXR激活被证明拮抗NFκB活性并从而拮抗促炎性基因表达(Wang2008,Vavassori2009)。
用于本发明的优选的TGR5激动剂描述于HiroyukiSato等(2008).J.Med.Chem.51,1831-1841等。Sato等最近报道,鹅去氧胆酸的23-烷基-取代和6,23-烷基-双取代的衍生物(如6R-乙基-23(S)-甲基鹅去氧胆酸)是TGR5的强力和选择性激动剂。具体而言,其显示,天然胆汁酸的C23-(S)位置的甲基化赋予TGR5对于FXR激活的显著选择性,而6R-烷基取代提高了全部两种受体处的效力。天然产物和非类固醇化合物的文库的筛选导致公开了6-甲基-2-氧代-4-噻吩-2-基-1,2,3,4-四氢嘧啶-5-羧酸苄酯(WO2004067008)和齐墩果酸作为结构上多样的TGR5激动剂。最近,合成了多种胆汁酸和胆汁酸衍生物。例如,对映体鹅去氧胆酸(CDCA)和石胆酸(LCA)。Sato等(2008)描述了多种其他的TGR5激动剂且通过引用纳入本文以参考TGR激动剂。该文章描述了TGR5选择性激动剂和TGR5、FXR双重激动剂。TGR激动剂和FXR激动剂具有多种性质。对于本发明,某一化合物是TGR5激动剂的前提是其在Sato等(2008)描述的TGR5激动剂试验中是活性的。对于本发明,某一化合物是FXR激动剂的前提是其在Sato等(2008)描述的FXR激动剂试验中是活性的。某一化合物是TGR5,FXR双重激动剂的前提是其在Sato等(2008)描述的TGR5和FXR激动剂试验中是活性的。该参考文献也通过引用纳入本文以描述TGR5和FXR激动剂测试。优选的本发明的TGR5激动剂描述于(Gioiello等(2012)ExpertOpin.Ther.Patents.卷22:第1399-1414页)。特别优选(Gioiello等(2012)ExpertOpin.Ther.Patents.卷22:第1399-1414页)的表1、表2、表3、图1、图2或图3中描述的TGR5激动剂。还优选本申请的表1、表2、图2、图3、图4或图5中描述的TGR5激动剂。一种优选的TGR5激动剂是UDCA(图5)。还优选描述于WO2008/002573;WO2008/091540;WO2010/059859;WO2010/059853或WO2010/014836中的TGR5激动剂。优选的FXR激动剂是WO2010/059853;WO2007/095174;WO2008/002573或WO2002/072598中所述的激动剂。优选的FXR激动剂是参考文献ModicaS.DecipheringthenuclearbileacidreceptorFXRparadigm(解码核胆汁酸受体FXR范例).NRS2010;8:第1-28页的图3的激动剂。优选的FXR激动剂是图6的FXR激动剂。
TGR5激动剂还描述于US2012/0115832。该参考文献也因此通过引用纳入本文,具体用于描述多种TGR5激动剂。
FXR激动剂还描述于WO2005/082925和US2008/0182832。这些参考文献也因此通过引用纳入本文,具体用于描述多种FXR激动剂。一种优选的FXR激动剂是WO2010/059853;WO2007/095174;或WO2002/072598中描述的激动剂。
CD40分子是一种50kDaI型膜糖蛋白且表达于B细胞、单核细胞/巨噬细胞、树突细胞(DC)和激活的内皮细胞上1-6。在某些条件下,CD40还可发现于成纤维细胞、表皮细胞、角质细胞和其他细胞上7。CD40配体(CD40L,CD154)是一种32kDaII型内在膜糖蛋白,其瞬时表达于激活的CD4+T细胞和少量激活的CD8+T细胞上8,9。此外,CD40L还发现于激活后的多种其他细胞类型上,包括肥大细胞、嗜碱性粒细胞、B细胞、嗜酸性粒细胞、DC和血小板10,11。CD40通路被认为是炎性应答的起始和效应阶段中的关键转换。
CD40和CD40L的结合(也称作CD40和CD40L的连接)起始表达CD40的细胞内的信号级联。通过CD40的信号转导通常受结合CD40或CD40L的抗体的抑制。该CD40-CD40L相互作用可使用针对CD40或CD40L的单克隆抗体(Mab)来抑制。激活的血小板上CD40L的表达已导致使用高剂量水平的IgG1抗人CD40LMab治疗期间的血栓栓塞事件以及这些Mab研发的终止12,13。通过CD40结合抗体抑制CD40信号转导因此似乎是人中较富有吸引力的方法。使用不同的携带CD40的细胞类型的多个体外研究中证明了Mab5D12(抗人CD40)的抑制活性14,15且使用多种非人灵长类动物疾病模型在体内验证了嵌合5D12(ch5D12)CD40抑制活性16,17。ch5D12是一种分子工程改造的人IgG4抗体,含有鼠5D12的重链和轻链的可变结构域且被构建为在用于人时降低鼠5D12Mab的免疫原性潜力并提高鼠5D12Mab的体内半衰期。
同许多受体类似,CD40受体在不存在CD40L或等同物的情况下不进行信号转导。CD40信号转导抑制剂因此在不存在激活因子时不抑制受体的信号转导。因此,在否则CD40受体将有活性的条件下(即不存在抑制剂的情况下),CD40信号转导抑制剂抑制信号转导。激活CD40信号转导的生理方式是向表达CD40的细胞提供CD40L。这可以通过提供表达CD40L的细胞或通过提供可溶性CD40L来实现。当某一化合物将表达CD40的细胞中的CD40转导的激活降低50%或更多时,认为该化合物是CD40信号转导抑制剂。在这类测试中,该化合物优选在添加激活CD40受体的化合物或细胞之前添加。然而,无需总是如此。该试验中激活CD40受体的化合物优选是CD40L,通过提供表达CD40L的细胞或通过提供可溶性CD40L。目前可获得多种CD40结合抗体,其可在结合后激活CD40受体的信号转导。这类抗体也被称作CD40激动剂。
CD40信号转导抑制剂可以是CD40结合分子、CD40L结合分子或其组合。该CD40或CD40L结合分子通常是抗体或其片段或衍生物或模拟物。多种抗体CD40信号转导抑制剂是本领域已知的。优选的CD40信号转导抑制剂是将表达CD40的细胞中的CD40信号转导抑制50%或更多的CD40结合抗体,优选在前文所述的测试中。在优选的实施方式中,该CD40信号转导抑制剂是CD40结合CD40抑制剂。在优选的实施方式中,该CD40信号转导抑制剂是结合并抑制人CD40的激活的单克隆抗体或其抗原结合部分。该抗体优选包含选自下组的可变结构域氨基酸序列:CD40结合抗体5D12、ch5D12以及PG102和ASKP1240(EP1391464)。其他抗体优选包含选自US2011/0243932的CD40结合抗体的可变结构域氨基酸序列。非限制性但优选的示例是前述CD40结合抗体5D12、ch5D12以及PG102、US2011/0243932和ASKP1240。PG102和其他CD40信号转导抑制性CD40结合抗体描述于WO2007/129895。这类抗体在上文所述测试中结合CD40并抑制CD40受体信号转导至少50%。特别优选的CD40信号转导抑制剂是ch5D12、PG102、HCD122(CHIR-12.12,卢卡单抗(lucatumumab)),US2011/0243932和ASKP1240(EP1391464)。在特别优选的实施方式中,该CD40信号转导抑制剂是PG102(可变区的氨基酸序列描述于图1)。已在临床试验中测试了多种CD40抗体(一项卢卡单抗的1期研究,静脉内给予具有复发的或顽固性多发性骨髓瘤的患者的全人抗CD40拮抗剂单克隆抗体(WilliamBensinger等,BritishJournalofHaematology,卷159,第1期,第58-66页,2012年10月)以及复发的慢性淋巴细胞性白血病中抗CD40人源化单克隆抗体卢卡单抗(HCD122)的一项I期研究(LeukLymphoma.2012年11月;53(11):2136-42,2012年6月12日))。
其他CD40信号转导抑制剂结合CD40L。这些抑制剂通常阻止CD40L结合CD40。这类CD40L结合抑制剂优选是CD40L结合抗体或其片段或衍生物或类似物。优选的作为CD40信号转导抑制剂的CD40L结合抗体是MR-1、IDEC131(E60400)、IDEChu5C8(BG9588)(参见Vincenti(2002),Am.J.ofTransplantation卷2,第898-903页并在本文中引用)。IDEC分子针对人CD40L而MR-1针对小鼠CD40L。
目前存在多种不同的具有与抗体类似的结合性质的蛋白质。这些分子进一步称作抗体等同物或抗体部分或衍生物或模拟物。在本发明的上下文中,这类抗体等同物和部分和模拟物和衍生物被认为在本发明的方式、用途和方法中与抗体等同。这类抗体等同物的非限制性示例是非抗体骨架蛋白结合物,例如但不限于,抗卡林素(anticalin)、C型凝集素结构域结合物、艾维素(avimer)、阿德素(Adnectin)和DARPin(设计的锚蛋白重复蛋白)(参考文献SheridanC.NatureBiotechnology2007,(25),365-366)。
抗体部分或衍生物的非限制性示例含有抗体或其等同物的重链和/或轻链的可变结构域。这类蛋白质的非限制性示例是VHH、纳米抗体、人结构域抗体(dAb)、单域抗体、鲨鱼抗原反应性蛋白(ShArp)、小模块免疫药物(SMIPTM)、单抗体(monobody)和/或IMab(参考文献SheridanC.NatureBiotechnology2007,(25),365-366)。优选的抗体部分或衍生物至少具有抗体或其等同物的重链和轻链的可变结构域。这类结合分子的非限制性示例是F(ab)片段和单链Fv片段。存在许多不同的具有特定IG折叠的抗体,其经操纵以特异性结合靶标。这类操纵的蛋白质被认为是抗体的等同物或模拟物。在优选的实施方式中,CD40或CD40L结合分子是抗体。抗体可以是天然的抗体或合成的抗体。在优选的实施方式中,抗体包含抗体的CDR1、CDR2、CDR3区。然而,本发明也包括人工生成CDR样区,例如可通过噬菌体展示进行选择的那些。在优选的实施方式中,所述抗体是人、人源化或人样抗体。特别优选的是(除其特异性外)不进一步与免疫***相互作用的结合分子。在抗体的情况中,所述抗体优选包含IgG4恒定区,或IgG4样恒定区。例如,可以突变IgG1分子的恒定区使得其在结合其靶标后不再激活补体***。
用于本发明的抗体可以来自任何动物来源,包括鸟类和哺乳动物(例如人、鼠、驴、绵羊、兔、山羊、豚鼠、骆驼、马或鸡)。本发明的抗体优选是人或人源化单克隆抗体。本发明中,“人”抗体包括具有人免疫球蛋白的氨基酸序列的抗体且包括分离自人免疫球蛋白文库的抗体(包括但不限于,与人免疫球蛋白序列同源的免疫球蛋白序列的合成文库)或分离自小鼠(其表达来自人基因的抗体)的抗体。对于一些应用,包括人中抗体的体内治疗性或诊断性应用和体外检测试验,优选使用人或嵌合抗体。完全人抗体特别适用于人对象的治疗性治疗。人抗体可由本领域已知的多种方法制备,包括上文所述的噬菌体展示方法,其使用衍生自人免疫球蛋白序列或与人免疫球蛋白序列同源的合成序列的抗体文库。还参见美国专利号4,444,887和4,716,111;以及PCT公开号WO98/46645、WO98/50433、WO98/24893和W098/16654,其各自通过引用全文纳入本文。待用于本发明的方法的抗体包括经修饰的衍生物,即通过共价连接任何类型的分子与该抗体。此外,该衍生物可含有一种或多种非经典氨基酸。在本发明的某些实施方式中,与未修饰的抗体相比,待用于本发明的方法的抗体在哺乳动物(优选人)中具有延长的半衰期。可通过本领域技术人员已知的技术生成具有增加的体内半衰期的抗体或其抗原结合片段(参见例如PCT公开号WO97/34631)。在某些实施方式中,待用于本发明的方法的抗体是单链抗体。单链抗体的设计和构建是本领域熟知的。在某些实施方式中,待用于本发明的抗体结合胞内表位,即是胞内抗体。胞内抗体至少包含能够免疫特异性结合抗原的抗体的一部分且优选不含有编码用于其分泌的序列。这类抗体将在胞内结合其抗原。在一个实施方式中,该胞内抗体包含单链Fv(″sFv")。在其他实施方式中,该胞内抗体优选不编码可操作的分泌性序列且因此保留在细胞内。胞内抗体的生成是本领域技术人员熟知的且描述于例如美国专利号6,004,940;6,072,036;5,965,371,其通过引用全文纳入本文。在一个实施方式中,胞内抗体表达于细胞质中。在其他实施方式中,胞内抗体定位于多个胞内位置。在这类实施方式中,特异性定位序列可与胞内核苷酸(intranucleotide)多肽相连以将胞内抗体导入特定位置。待用于本发明的方法的抗体或其片段可通过用于抗体合成的本领域已知的任意方法生产,具体而言可通过化学合成或优选通过重组表达技术。单克隆抗体可使用本领域已知的多种技术制备,包括使用杂交瘤、重组和噬菌体展示技术或其组合。例如,可使用杂交瘤技术来生产单克隆抗体,包括本领域已知的那些。可用于制备本发明的抗体的噬菌体展示方法的示例包括W097/13844;以及美国专利号5,580,717,5,821,047、5,571,698、5,780,225和5,969,108中公开的那些,其各自通过引用全文纳入本文。如以上参考文献中描述的那样,噬菌体选择后,可分离来自噬菌体的抗体编码区域并用于生成全抗体,包括人抗体,或任何需要的抗原结合片段,并在任何需要的宿主中表达,包括哺乳动物细胞、昆虫细胞、植物细胞、酵母和细菌,例如下文所述。重组生产Fab、Fab′和F(ab′)2片段的技术也可使用本领域已知的方法进行,例如PCT公开号WO92/22324中公开的那些。还可以生产治疗上有用的IgG、IgA、IgM和IgE抗体。对于生产人抗体和人单克隆抗体的技术以及生产这类抗体的方案的详细讨论,参见例如PCT公开号WO98/24893。本发明中引用的所有参考文献都通过引用全文纳入本文。此外,诸如梅达来科斯公司(Medarex,Inc.)(新泽西州普林斯顿)、艾比基尼科斯公司(Abgenix,Inc.)(加利福尼亚州弗里蒙特)和金法目公司(Genpharm)(加利福尼亚州圣何塞)的公司可参与使用与上文所述技术类似的技术来提供针对所选抗原的人抗体。用于生产抗体、其衍生物或类似物(例如本发明的抗体的重链或轻链或其部分或本发明的单链抗体)的重组表达需要构建含有编码该抗体的多核苷酸的表达载体并在合适的宿主细胞中或甚至在体内表达所述载体。一旦获得本发明的编码抗体分子或抗体的重链或轻链或其部分的多核苷酸(优选但非必需含有重链或轻链可变结构域),即可使用本领域熟知的技术通过重组DNA技术生产用于生产抗体分子的载体。因此,本发明描述了通过表达含有编码核苷酸序列的抗体的多核苷酸来制备蛋白质的方法。本领域技术人员熟知的方法可用于构建含有抗体编码序列和适当转录和翻译控制信号的表达载体。这些方法包括,例如,体外重组DNA技术、合成技术和体内遗传重组。本发明因此提供了可复制的载体,其包含的核苷酸序列编码本发明的抗体分子、抗体的重链或轻链、抗体的重链或轻链可变结构域或其部分、或重链或轻链CDR,其可操作地连接启动子。这类载体可包含编码抗体分子的恒定区的核苷酸序列(参见例如PCT公开号WO86/05807;PCT公开号WO89/01036;和美国专利号5,122,464)且抗体的可变结构域可克隆至这类载体中用于表达整个重链、整个轻链或整个重链和轻链。通过常规技术将表达载体转移至宿主细胞中并随后通过常规技术培养转染的细胞以产生本发明的抗体。因此,本发明包括以下宿主细胞:其包含的多核苷酸编码本发明的抗体或其片段、或其重链或轻链、或其部分、或本发明的单链抗体,其可操作地连接异源性启动子。在优选的实施方式中,为表达双链抗体,可在宿主细胞中共表达编码重链和轻链的载体以表达整个免疫球蛋白分子,如下文详述的那样。可利用多种宿主表达载体***来表达本发明中定义的抗体分子。在哺乳动物宿主细胞中,可利用多种基于病毒的表达***。在使用腺病毒作为表达载体的情况中,感兴趣的抗体编码序列可与腺病毒转录/翻译复合物(例如晚期启动子和三联体前导序列)相连。该嵌合抗体可随后通过体外或体内重组***腺病毒基因组中。***病毒基因组的非必需区域(如区域E1或E3)可导致在感染的宿主中有活力且能够表达抗体分子的重组病毒。还可能需要特定的起始信号以有效地翻译***的抗体编码序列。这些信号包括ATG起始密码子和相邻序列。此外,该起始密码子必须与所需编码序列的阅读框同相以确保翻译整个***物。这些外源性翻译控制信号和起始密码子可以是多种来源的,其是天然的和合成的。可通过纳入适当转录增强元件、转录终止子等来增强表达的效率。一旦通过重组表达生成待用于本发明的方法的抗体分子,即可通过本领域已知的用于纯化免疫球蛋白分子的任何方法来进行纯化,例如通过色谱(例如,离子交换、亲和力、特别是通过蛋白A后对特异性抗原的亲和力,和尺寸柱色谱)、离心、差别性溶解度,或通过任何其他用于纯化蛋白质的标准方法。此外,本发明的抗体或其片段可与本发明所述或本领域已知的异源性多肽序列融合以促进纯化。如上文所述,根据另一个方面,本发明提供了一种用于治疗的上文所定义的抗体或其等同物或衍生物。对于治疗性治疗,抗体或其等同物或衍生物可在体外生成并应用于有此需要的对象。可通过任何合适的途径向对象给予抗体或其等同物或衍生物,优选以适用于这类途径的药物组合物的形式和有效地进行所需治疗的剂量给予。本领域技术人员可简单地确定用于降低疾病进展速率或用于消除疾病病症所需的抗体的治疗有效剂量。或者,可通过上文所述的体内抗体生产方法由对象自身来生产抗体。合适地,用于这类体内生产的载体是病毒载体,优选对于本发明所述特定靶细胞具有靶细胞选择性的病毒载体。因此,根据另一个方面,本发明提供了上文所定义的抗体或其等同物或衍生物在制造用于治疗对象以实现所述治疗效果的药物中的应用。该治疗包括以足够实现所需治疗效果的剂量给予药物。该治疗可包括重复给予抗体。根据另一个方面,本发明提供了一种治疗人的方法,包括以足够实现所需治疗效果的剂量给予上文所定义的抗体或其等同物或衍生物。
该慢性炎性疾病优选是具有炎性组分的自身免疫疾病。该慢性炎性疾病优选是肝、肾、胃肠道、心血管***或代谢***的慢性炎性疾病。优选的肝的慢性炎性疾病是胆管消失综合征(VBDS)、原发性胆汁性肝硬化(PBC)、胆汁酸腹泻(慢性腹泻)、原发性硬化性胆管炎(PSC)、自身免疫肝炎、肝移植相关移植物抗宿主病、门静脉高压、非酒精性脂肪性肝炎(NASH)或非酒精性脂肪性肝病(NAFLD)。优选的所述慢性炎性胃肠道疾病是胰腺的慢性炎症、克罗恩病或溃疡性结肠炎。慢性炎性心血管疾病是动脉粥样硬化且优选的代谢***的慢性炎性疾病是肥胖、胰岛素耐受、代谢综合征、I型糖尿病或II型糖尿病。
该慢性炎性或自身免疫疾病优选是肝、肾、胃肠道、心血管***或代谢***的慢性炎性或自身免疫疾病。优选的肝的慢性炎性或自身免疫疾病是原发性胆汁性肝硬化(PBC)、胆汁酸腹泻(慢性腹泻)、原发性硬化性胆管炎(PSC)、自身免疫肝炎、肝移植相关移植物抗宿主病、门静脉高压、非酒精性脂肪性肝炎(NASH)或非酒精性脂肪性肝病(NAFLD)。优选的所述慢性炎性或自身免疫胃肠道疾病是胰腺的慢性炎症、克罗恩病或溃疡性结肠炎。慢性炎性心血管疾病是动脉粥样硬化且优选的代谢***的慢性炎性或自身免疫疾病是肥胖、胰岛素耐受、代谢综合征、I型糖尿病或II型糖尿病。
考虑到慢性炎症通常与严重的疾病(如癌症和纤维化)相关,且考虑到本发明至少缓解慢性炎症,CD40信号转导抑制剂和其他化合物还可在经治疗的个体中用于至少延缓癌症的发生和用于至少减少纤维化。至少与不接受癌症预防或纤维化预防治疗的相同或相似个体相比时是这样的。现有的纤维化通常是不可逆的。因此预防纤维化指的是预防如果不进行治疗将发生的纤维化。
该胆汁酸或胆汁酸衍生物优选是胆汁酸,或上文所述的衍生物。目前可能在体外合成多种胆汁酸和胆汁酸衍生物。因此,本发明使用的胆汁酸衍生物不仅指衍生自胆汁酸的化合物,也指具有与衍生自胆汁酸的化合物相同结构的合成的化合物。鹅去氧胆酸衍生物是优选的胆汁酸衍生物。该胆汁酸衍生物优选是6-α-乙基鹅去氧胆酸或23-取代的胆汁酸。
优选的胆汁酸是熊去氧胆酸或鹅去氧胆酸。
该胆汁酸或胆汁酸衍生物优选是FXR和/或TGR5信号转导激活因子。这类化合物在本领域中还称作FXR激动剂或TGR5激动剂。如先前所述,多种TGR5信号转导激活因子也是FXR信号转导激活因子。
本发明还提供了一种治疗患有慢性炎症的个体的方法,所述方法包括向有此需要的个体给予CD40信号转导抑制剂和其他化合物,所述其他化合物是胆汁酸、胆汁酸衍生物、TGR5受体激动剂、FXR受体激动剂或其组合。
本发明还提供了包含CD40信号转导抑制剂和其他化合物的试剂盒,所述其他化合物是胆汁酸、胆汁酸衍生物、TGR5受体激动剂、FXR受体激动剂或其组合。该试剂盒优选用于治疗有此需要的个体中的慢性炎性疾病或用于预防有此需要的个体中的癌症和/或纤维化。
附图简要说明
图1.抗体PG102的氨基酸序列。
图2.A.多种胆汁酸骨架修饰。B.胆汁酸衍生物结构和强度。C.诺华公司(Novartis)的胆汁酸衍生物(来自Gioiello等(2012)ExpertOpin.Ther.Patents.卷22:第1399-1414页)。
图3.多种TGR激动剂,结构和效力(来自Gioiello等(2012)ExpertOpin.Ther.Patents.卷22:第1399-1414页)。
图4.多种天然TGR5激动剂和效力(来自Gioiello等(2012)ExpertOpin.Ther.Patents.卷22:第1399-1414页)。
图5.TGR5和FXR激动剂。
图6.来自ModicaS.DecipheringthenuclearbileacidreceptorFXRparadigm(解码核胆汁酸受体FXR范例).NRS2010;8:第1-28页的FXR激动剂。
图7.PG102和6-ECDCA对细胞因子分泌的抑制。使用A)megaCD40L或B)megaCD40L和LPS刺激PBMC以诱导细胞因子分泌。向培养物中添加6-ECDCA和/或PG102并评估其对于培养物上清液中TNF、IL-6、IL-8、IL-1β和IL-12p70水平的影响。
图8.实验期间的小鼠体重。从第3天至第8天通过在饮用水中给予2,5%(重量/体积)DSS来诱导小鼠中的结肠炎。每天测量体重并以相对于第1天体重的形式表示。
图9:口服强饲(oralgavage)后4小时血浆中FITC浓度所测定的肠道通透性。在DSS治疗后8天通过口服强饲向小鼠给予FITC。FITC给药后4小时,处死小鼠并测定血液中的荧光量作为肠道通透性的标志物。
图10:结肠的长度。在实验的终点处处死小鼠并分离结肠。测量结肠的长度作为结肠炎症的测量值。
图11:脾中粒细胞的分析。在实验的终点处处死小鼠并分离脾。使用针对GR-1和CD11b的抗体对脾细胞进行染色并通过FACS分析测定粒细胞的相对贡献。
图12:使用PMA和离子霉素刺激后脾细胞的TNF释放。在实验的终点处处死小鼠并分离脾。使用PMA和离子霉素对脾细胞刺激4.5小时并通过ELISA测量TNF释放。
实施例1
PG102和合成的FXR激动剂(如GW4064和6-ECDCA)对于THP1细胞的促炎性细胞因子分泌的抑制作用。
材料和方法:
细胞:THP1是来源于急性单核细胞性白血病患者的人单核细胞细胞系(TsuchiyaS等(1980).Int.J.Cancer26(2):171-6)。Jurkat细胞系描述于SchneiderU等(1977).IntJCancer19(5):621-6。简言之,在第1天,在附加有10%胎牛血清(吉布可公司(Gibco),参考号10270-106)和50μg/mL庆大霉素(英杰公司(Invitrogen),货号15750-045)的伊氏改良的达氏培养基(IMDM,BW公司(BioWhittaker),货号BE12-722F)中培养THP-1和Jurkat39.8/50人细胞。随后,使THP1细胞未经处理或使用以下物质进行预处理:
●使用rhuIFNγ(1000U/mL,PT公司(PeproTech))预处理48小时以上调CD40表达
●使用FXR激动剂(GW4064(西格玛公司(Sigma)G5172)或6-ECDCA(开曼公司(Cayman),11031)预处理18小时
在生物试验的第3天,根据以下方案清洗和培养THP-1细胞:
*表达CD40L的人T细胞。THP1细胞和J39.8/50细胞将以1∶1比例培养
**PG102;泛遗传公司(PanGenetics),批次PANY001,2011年6月
以以下顺序在圆底细胞培养板(NunclonTM)中对所有条件进行三次重复:50μL的THP-I细胞(相当于2x104个细胞/孔),50μL的测试样品和50μLJ39.8/50细胞。总体积为每孔150μl。在37℃下和潮湿的5%CO2气氛中将细胞孵育48小时。
在第5天时,在培养48小时后,收集70μL的细胞培养物上清液并转移至低结合圆底微量滴定板中。根据生产商的说明书使用多重细胞因子试验(路明克斯公司(Luminex))测定收获的细胞培养物上清液中的多种细胞因子,包括TNF、IL-6、IL-1β和IL-10。
将计算不同的测试条件中使用测试样品实现的细胞因子分泌的抑制百分比。
实施例2
PG102和合成的FXR激动剂6-ECDCA对于外周血单核细胞(PBMC)的促炎性细胞因子分泌的协同抑制作用。
材料和方法:
使用Fycoll密度梯度离心(Histopaque;西格玛诊断公司(SigmaDiagnostics))从肝素化的人血中新鲜地分离PBMC。PBMC以5X10E5个细胞/mL的浓度在圆底96孔板中含有10%FCS的RPMI中培养。使用两种不同的刺激来从PBMC中诱导细胞因子分泌:
1.在IFN-γ(250U/mL)存在的情况下将PBMC培养24小时以诱导CD40的上调。随后使用megaCD40L(100ng/mL,恩佐生命科学公司(EnzoLifeSciences))对CD40通路激活24小时。
2.在IFN-γ存在的情况下将PBMC培养24小时以诱导CD40的上调。随后使用megaCD40L(100ng/mL)和LPS(100ng/mL)对细胞刺激24小时。
在存在或不存在可变浓度的PG102(5、10和100ng/mL)和/或6-ECDCA(0.1、1和5μM)的条件下培养刺激的PBMC。与刺激同时添加PG102。相反地,在添加刺激前3小时添加6-ECDCA。在培养的终点处,收集上清液并储存于-80℃下直至进行细胞因子分析。使用BD细胞计数珠阵列(CBA)人炎性细胞因子试剂盒(BD科学公司(BDBiosciences))来测量培养物上清液中的IL-1β、IL-8、IL-6、TNF和IL-12p70水平。根据生产商的说明书进行试验。简言之,将感兴趣的细胞因子的捕获珠与上清液或人炎性细胞因子标准品和PE检测试剂混合。将样品在黑暗中和室温下孵育3小时。随后,清洗样品并在FACSCANTOII细胞计数仪(BD科学公司)上分析。使用FCAP阵列软件(BD科学公司)来分析数据。
结果:
刺激CD40-CD154通路后,生成了大量的TNF(733pg/mL)、IL-6(5,3ng/mL)和IL-8(19,5ng/mL)。在这些刺激条件下也生成了IL-12p70(50pg/mL)。IL-1β(7pg/mL)几乎无法检测。PG102以剂量依赖的方式抑制PBMC的细胞因子释放,100ng/mLPG102分别抑制89%、87%、78%、88%和93%的TNF、IL-6、IL-8、IL-1β和IL-12p70释放。以0.1或1μM的浓度单独使用的6-ECDCA并不抑制这些细胞因子的释放。然而,5μM的6-ECDCA分别抑制14%、18%、17%、35%和20%的TNF、IL-6、IL-8、IL-1β和IL-12p70释放。向培养物中添加PG102和6-ECDCA的组合对细胞因子释放的抑制高于单独的PG102或6-ECDCA,也高于不存在PG102时以对细胞因子释放没有抑制作用的浓度(1μM)使用6-ECDCA。在图7A中,细胞因子分泌的抑制百分比描述为单独的PG102(5ng/mL)、单独的6-ECDCA(1μM)以及PG102(5ng/mL)和6-ECDCA(1μM)的组合。
或者,与Toll样受体刺激(LPS)联用通过CD40途径刺激PBMC。LPS是革兰氏阴性细菌外膜的主要组分并在人中引发强免疫应答。类似于CD40通路的刺激,LPS与TLR4受体的结合导致NF-κB的激活和促炎性细胞因子的生成。在这些刺激条件下,所有评估的细胞因子都大量分泌(TNF:9ng/mL;IL-6:23ng/mL;IL-8:23ng/mL;IL-1β:100pg/mL;IL-12p70:1500pg/mL)。单独的PG102能够剂量依赖地抑制TNF、IL-12p70和IL-1b分泌,但IL-8和IL-6分泌几乎不受影响。清楚地,与CD40通路的独有刺激相比,PG102在这些刺激条件下效力较低。PG102(100ng/mL)将TNF、IL-6、IL-8、IL-1β和IL-12p70分别抑制38%、0%、17%、43%和67%。先前已证明6-ECDCA以剂量依赖的方式抑制LPS诱导的TNF生成(GadaletaRM等,Gut2011;60(4):463-72)。这里,我们证明,对于单独的CD40通路激活或CD40通路与TLR-4通路激活组合所诱导的促炎性细胞因子释放,6-ECDCA无法非常有效地对其进行抑制。6-ECDCA(5μM)将TNF、IL-6、IL-8、IL-1β和IL-12p70分别抑制21%、0%、9%、12%和22%。与单独的PG102或6-ECDCA相比,PG102和6-ECDCA组合更有效地抑制TNF、IL-6、IL-8、IL-1β和IL-12p70释放。这示于图7B,其中分别以5ng/mL和1μM的浓度使用PG102和6-ECDCA。
该数据显示,PG102与6-ECDCA联用抑制该研究中分析的所有促炎性细胞因子的分泌,比单独的PG102或6-ECDCA更有效。特别地,当细胞因子诱导刺激较强时,PG102与6-ECDCA的组合对促炎性细胞因子的分泌具有协同抑制作用。这些数据显示,PG102与6-ECDCA联用可阻断炎症(不依赖于刺激),这表明其同微生物组分或自身免疫过程是否导致促炎性细胞因子释放不相关。该数据还显示,联用时可以使用较低浓度的这些试剂以允许较好的安全性概况同时不损失有效性。
实施例3
DSS诱导的结肠炎小鼠模型中MR-1和合成的FXR激动剂6-ECDCA的协同抑制作用
材料和方法:
通过在饮用水中给予2.5%(重量/体积)硫酸葡聚糖钠(DSS;MW.36000-50000Da,MP生物化学公司(MPBiochemicalsInc))持续8天在C57/B16野生型小鼠中诱导结肠炎。通过使用6-乙基-鹅去氧胆酸(6-ECDCA)进行治疗来实现FXR的药理学激活。在开始DSS治疗前通过口服强饲给予6-ECDCA(10mg/kg/天)或载剂持续3天,并持续直至DSS治疗结束。在DSS治疗的第2天(6-ECDCA治疗的第4天),向小鼠腹膜内(i.p.)注射250μg的针对小鼠CD40L的仓鼠抗体、MR-1或对照IgG(LEAFTM纯化的亚美尼亚仓鼠IgG同种型对照抗体,生物传奇公司(Biolegend))。
实验中使用5个治疗组(n=10只小鼠/组):
1.-DSS,+载剂,通过口服强饲(o.g.)+对照IgG腹膜内
2.+DSS,+载剂,口服强饲+对照IgG腹膜内
3.+DSS,+载剂,口服强饲+抗CD40L腹膜内
4.+DSS,+6-ECDCA,口服强饲+对照IgG腹膜内
5.+DSS,+6-ECDCA,口服强饲+抗CD40L腹膜内
评估每天的体重变化并以相对于第1天体重的形式表示第2-11天的体重。对于肠道通透性试验,在DSS治疗的8天后通过口服强饲向小鼠给予FITC。FITC给药后4小时,处死小鼠并测定血液中的荧光量作为通透性的标志物。分离结肠并测量结肠长度。收集脾并分离细胞。使用抗体混合物对细胞进行染色以通过FACS分析测定脾中免疫细胞的组成。基于GR-1和CD11b表达鉴定粒细胞并表示为脾中活细胞的百分比。最后,使用PMA和离子霉素对脾细胞体外刺激4.5小时。收集培养物上清液并使用ELISA测量TNF。
结果:
先前已证明FXR受体激动剂6-ECDCA干扰化学诱导的肠道炎症,具有结肠炎症状的改善、表皮通透性的抑制和减少的杯状细胞损失(GadaletaRM等,Gut2011;60(4):463-72)。MR-1(一种拮抗性抗CD40L抗体)在使用同系CD45RB高CD4+T细胞重建的SCID小鼠中实验性结肠炎模型中有效(LiuZ等,J.Immunol2000;164(11):6005-11)。在本研究中,6-ECDCA的剂量方案与Gadaleta等报道的相同。实际上,在本研究中6-ECDCA也干扰DSS诱导的结肠炎疾病过程。相反,最适度地给予MR-1(仅给予一次,在结肠炎诱导后一天)以允许CD40通路阻滞和FXR受体激活的组合的协同作用。在诊所中降低CD40通路阻滞的剂量和频率降低了副作用和不希望的免疫抑制的风险。来自本研究的结果显示,应用的MR-1剂量方案单独给予时不足以干扰结肠炎疾病过程,但与FXR受体激动剂6-ECDCA联用时能够干扰结肠炎疾病过程。
如预期的那样,DSS导致第7天(DSS给药开始后4天)时开始的体重降低。该体重降低在第5组中最小,该组中的小鼠接受6-ECDCA和MR-1(图8)。此外,在接受DSS的小鼠中,肠道通透性在组合治疗组中的损伤最小(图9)。结肠缩短是炎症的标志。DSS主要导致结肠炎症并因此导致结肠缩短。接受组合DSS+6-ECDCA+αCD40L的小鼠的结肠长度与未接受DSS的小鼠的结肠长度没有显著不同(图10)。6-ECDCA似乎导致脾中粒细胞的增加,该作用因组合6-ECDCA与αCD40L而降低(图11)。图12显示,与分离自其他DSS治疗组(第2-4组)的小鼠相比,分离自接受6-ECDCA和αCD40L的小鼠的脾细胞在体外刺激后生成较少的TNF。总之,虽然MR-1不具有作用,但在多个结果测量上,在该小鼠结肠炎模型中,与单独使用6-ECDCA相比,MR-1和6-ECDCA联用的效果更好。因此,在胃肠道(包括肝)的自身免疫疾病中应用FXR受体激活和抗CD40阻滞时,该联用将允许使用较温和的剂量方案,其中使用较低浓度的各试剂和较低的剂量频率。FXR受体激活和CD40阻滞的组合有助于改进的安全性概况和更有效的炎症抑制。
参考文献
1.RanheimEA,KippsTJ.ActivatedTcellsinduceexpressionofB7/BB1onnormalorleukemicBcellsthroughaCD40-dependentsignal(激活的T细胞通过CD40依赖性信号诱导正常或白血病B细胞上的B7/BB1的表达).JExpMed(1993);177:925-35.
2.HasboldJ,Johnson-LegerC,AtkinsCJ,ClarkEA,KlausGGB.PropertiesofmouseCD40:cellulardistributionofCD40andBcellactivationbymonoclonalanti-mouseCD40antibodies(小鼠CD40的性质:CD40的细胞分布和通过单克隆抗小鼠CD40抗体进行的B细胞激活).EurJImmunol(1994);24:1835-42.
3.AldersonMR,ArmitageRJ,ToughTW,StrockbineL,FanslowWC,SpriggsMK.CD40expressionbymonocytes:regulationbycytokinesandactivationofmonocytesbytheligandforCD40(单核细胞的CD40表达:通过细胞因子进行调控和通过CD40的配体激活单核细胞).JExpMed(1993);178:669-74.
4.KienerPA,Moran-DavisP,RankinBM,WahlAF,AruffoA,HollenbaughD.StimulationofCD40withpurifiedsolublegp39inducesproinflammatoryresponsesinhumanmonocytes(使用纯化的可溶性gp39刺激CD40在人单核细胞中诱导促炎性应答).JImmunol(1995);155:4917-25.
5.ShuU,KiniwaM,WuCY等,ActivatedTcellsinduceinterleukin-12productionbymonocytesviaCD40-CD40ligandinteraction(激活的T细胞经由CD40-CD40配体相互作用诱导单核细胞生产白介素-12).EurJImmunol(1995);25:1125-8.
6.CellaM,ScheideggerD,Palmer-LehmannK,LaneP,LanzavecchiaA,AlberG.LigationofCD40ondendriticcellstriggersproductionofhighlevelsofinterleukin-12andenhancesTcellstimulatorycapacity:T-ThelpviaAPCactivation(树突细胞上CD40的连接触发生成高水平白介素-12并增强T细胞刺激能力:经由APC激活的T-T辅助).JExpMed(1996);184:747-52.
7.vanKootenC,BanchereauJ.FunctionsofCD40onBcells,dendriticcellsandothercells(B细胞、树突细胞和其他细胞上CD40的功能).CurrOpinImmunol(1997);9:330-7.
8.CayabyabM,PhillipsJH,LanierLL.CD40preferentiallycostimulatesactivationofCD4+Tlymphocytes(CD40优先共刺激CD4+T淋巴细胞的激活).JImmunol(1994);152:1523-31.
9.HermannP,Van-KootenC,GaillardC,BanchereauJ,BlanchardD.CD40ligand-positiveCD8+TcellclonesallowBcellgrowthanddifferentiation(CD40配体阳性CD8+T细胞克隆允许B细胞生长和分化).EurJImmunol(1995);25:2972-7.
10.GrewalIS,FlavellRA.CD40andCD154incell-mediatedimmunity(细胞介导的免疫中的CD40和CD154).AnnuRevImmunol(1998);16:111-35.
11.HennV,SlupskyJR,GrafeM等,CD40ligandonactivatedplateletstriggersaninflammatoryreactionofendothelialcells(激活的血小板上的CD40配体触发内皮细胞的炎症反应).Nature(1998);391:591-4.
12.KawaiT,AndrewsD,ColvinRB,SachsDH,CosimiAB.ThromboemboliccomplicationsaftertreatmentwithmonoclonalantibodyagainstCD40ligand(使用针对CD40配体的单克隆抗体进行治疗后的血栓栓塞并发症).NatMed(2000);6:114.
13.KnosallaC,GollacknerB,CooperDK.Anti-CD154monoclonalantibodyandthromboembolismrevisited(重新审视抗CD154单克隆抗体和血栓栓塞).Transplantation(2002);74:416-17.
14.deBoerM,ConroyJ,MinHY,KwekkeboomJ.Generationofmonoclonalantibodiestohumanlymphocytecellsurfaceantigensusinginsectcellsexpressingrecombinantproteins(使用表达重组蛋白质的昆虫细胞生成针对人淋巴细胞表面抗原的单克隆抗体).JImmunolMeth(1992);152:15-23.
15.KwekkeboomJ,deRijkD,KasranA,BarcyS,deGrootC,deBoerM.HelpereffectorfunctionofhumanTcellsstimulatedbyanti-CD3Mabcanbeenhancedbyco-stimulatorysignalsandispartiallydependentonCD40-CD40ligandinteraction(由抗CD3Mab刺激的人T细胞的辅助效应功能可由共刺激信号增强并部分依赖于CD40-CD40配体相互作用).EurJImmunol(1994);24:508-17.
16.LamanJD,′tHartBA,Brok,HPM等,ProtectionofmarmosetmonkeysagainstEAEbytreatmentwithamurineantibodyblockingCD40(mu5D12)(通过使用封闭CD40的鼠抗体(mu5D12)进行治疗来保护绒猴免受EAE).EurJImmunol(2002);32:2218-28.
17.BoonL,LamanJD,Ortiz-BuijsseA等,Preclinicalassessmentofanti-CD40Mab5D12incynomolgusmonkeys(猕猴中抗CD40Mab5D12的临床前评估).Toxicology(2002);174:53-65.
表1多种获得专利的TGR5激动剂(来自Gioiello等(2012)ExpertOpin.Ther.Patents.卷22:第1399-1414页)
表2多种TGR5激动剂(来自Gioiello等(2012)ExpertOpin.Ther.Patents.卷22:第1399-1414页)
BA:胆汁酸;CA:胆酸;CDCA:鹅去氧胆酸;DCA:去氧胆酸;LCA:石胆酸。
Claims (15)
1.一种用于治疗有此需要的个体中慢性炎性或自身免疫疾病的CD40信号转导抑制剂和其他化合物,所述其他化合物是胆汁酸、胆汁酸衍生物、TGR5受体激动剂、FXR受体激动剂或其组合。
2.如权利要求1所述的CD40信号转导抑制剂和其他化合物,所述慢性炎性或自身免疫疾病是肝、肾、胃肠道、心血管***或代谢***的慢性炎性或自身免疫疾病。
3.如权利要求1或2所述的CD40信号转导抑制剂和其他化合物,所述肝的慢性炎性或自身免疫疾病是原发性胆汁性肝硬化(PBC)、胆汁酸腹泻(慢性腹泻)、原发性硬化性胆管炎(PSC)、自身免疫肝炎、肝移植相关移植物抗宿主病、门静脉高压、非酒精性脂肪性肝炎(NASH)或非酒精性脂肪性肝病(NAFLD)。
4.如权利要求1或2所述的CD40信号转导抑制剂和其他化合物,所述慢性炎性或自身免疫胃肠道疾病是胰腺的慢性炎症、克罗恩病或溃疡性结肠炎。
5.如权利要求1或2所述的CD40信号转导抑制剂和其他化合物,所述慢性炎性心血管疾病是动脉粥样硬化。
6.如权利要求1或2所述的CD40信号转导抑制剂和其他化合物,所述代谢***的慢性炎性或自身免疫疾病是肥胖、胰岛素耐受、代谢综合征、I型糖尿病或II型糖尿病。
7.用于预防癌症和/或纤维化的一种CD40信号转导抑制剂和其他化合物,所述其他化合物是胆汁酸、胆汁酸衍生物、TGR5受体激动剂、FXR受体激动剂或其组合。
8.如权利要求1-7中任一项所述的CD40信号转导抑制剂和其他化合物,所述胆汁酸或胆汁酸衍生物是FXR和/或TGR5信号转导激活因子(激动剂)。
9.如权利要求1-8中任一项所述的CD40信号转导抑制剂和其他化合物,所述胆汁酸衍生物包含鹅去氧胆酸衍生物,优选6-α-乙基鹅去氧胆酸或23-取代的胆汁酸。
10.如权利要求1-9中任一项所述的CD40信号转导抑制剂和其他化合物,所述胆汁酸是熊去氧胆酸或鹅去氧胆酸。
11.如权利要求1-10中任一项所述的CD40信号转导抑制剂和其他化合物,所述CD40信号转导抑制剂包含结合CD40的抗体或其片段或衍生物。
12.如权利要求11所述的CD40信号转导抑制剂和其他化合物,所述结合CD40的抗体包含抗体5D12、ch5D12、PG102、CHIR-12.12、ASKP1240或其衍生物的可变区。
13.一种治疗患有慢性炎症的个体的方法,所述方法包括向有此需要的个体给予CD40信号转导抑制剂和其他化合物,所述其他化合物是胆汁酸、胆汁酸衍生物、TGR5受体激动剂、FXR受体激动剂或其组合。
14.一种包含CD40信号转导抑制剂和其他化合物的试剂盒,所述其他化合物是胆汁酸、胆汁酸衍生物、TGR5受体激动剂、FXR受体激动剂或其组合。
15.如权利要求14所述的试剂盒,所述试剂盒用于治疗有此需要的个体中的慢性炎症或自身免疫疾病或者用于预防有此需要的个体中的癌症和/或纤维化。
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EP (1) | EP3008091A1 (zh) |
JP (1) | JP2016521744A (zh) |
KR (1) | KR20160034893A (zh) |
CN (1) | CN105636984A (zh) |
AU (1) | AU2014278833A1 (zh) |
CA (1) | CA2914924A1 (zh) |
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WO2016149299A1 (en) * | 2015-03-16 | 2016-09-22 | Epinova Therapeutics Corp. | Therapeutic compounds that suppress protein arginine methyltransferase activity for reducing tumor cell proliferation |
SG11201808607SA (en) * | 2016-03-28 | 2018-11-29 | Intercept Pharmaceuticals Inc | Medicine obtained by combining fxr agonist and arb |
CN112752578A (zh) * | 2018-09-25 | 2021-05-04 | 宜昌人福药业有限责任公司 | 作为免疫调节剂的tgr5信号传导的调节剂 |
IL291985A (en) | 2019-10-07 | 2022-06-01 | Kallyope Inc | gpr119 agonists |
MX2022014505A (es) | 2020-05-19 | 2022-12-13 | Kallyope Inc | Activadores de la ampk. |
EP4172162A1 (en) | 2020-06-26 | 2023-05-03 | Kallyope, Inc. | Ampk activators |
CN115569130B (zh) * | 2022-10-09 | 2024-02-09 | 东莞广州中医药大学研究院 | 环氧广藿香烯及其组合物在制备预防和/或治疗非酒精性脂肪肝药物中的应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1938045A (zh) * | 2003-11-04 | 2007-03-28 | 希龙公司 | 治疗自身免疫和炎性疾病以及器官移植排异的拮抗性抗-cd40抗体的应用 |
CN101325970A (zh) * | 2005-11-01 | 2008-12-17 | 诺华有限公司 | 抗cd40抗体的应用 |
CN102325784A (zh) * | 2008-11-19 | 2012-01-18 | 英特塞普特医药品公司 | G蛋白偶联受体5(tgr5)调节剂及其使用方法 |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4444887A (en) | 1979-12-10 | 1984-04-24 | Sloan-Kettering Institute | Process for making human antibody producing B-lymphocytes |
US4716111A (en) | 1982-08-11 | 1987-12-29 | Trustees Of Boston University | Process for producing human antibodies |
JP2532858B2 (ja) | 1985-04-01 | 1996-09-11 | セルテツク リミテツド | 形質転換したミエロ―マ細胞系 |
GB8601597D0 (en) | 1986-01-23 | 1986-02-26 | Wilson R H | Nucleotide sequences |
GB8717430D0 (en) | 1987-07-23 | 1987-08-26 | Celltech Ltd | Recombinant dna product |
US5223409A (en) | 1988-09-02 | 1993-06-29 | Protein Engineering Corp. | Directed evolution of novel binding proteins |
US5780225A (en) | 1990-01-12 | 1998-07-14 | Stratagene | Method for generating libaries of antibody genes comprising amplification of diverse antibody DNAs and methods for using these libraries for the production of diverse antigen combining molecules |
US5427908A (en) | 1990-05-01 | 1995-06-27 | Affymax Technologies N.V. | Recombinant library screening methods |
GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
CA2405246A1 (en) | 1990-12-03 | 1992-06-11 | Genentech, Inc. | Enrichment method for variant proteins with alterred binding properties |
JPH07503124A (ja) | 1991-06-14 | 1995-04-06 | ゾーマ・コーポレーション | 微生物によって生産される抗体断片とそれらの複合体 |
DE69334095T2 (de) | 1992-07-17 | 2007-04-12 | Dana-Farber Cancer Institute, Boston | Verfahren zur intrazellulären Bindung von zielgerichteten Molekülen |
GB9601081D0 (en) | 1995-10-06 | 1996-03-20 | Cambridge Antibody Tech | Specific binding members for human transforming growth factor beta;materials and methods |
CA2249195A1 (en) | 1996-03-18 | 1997-09-25 | Board Of Regents, The University Of Texas System | Immunoglobin-like domains with increased half lives |
US5916771A (en) | 1996-10-11 | 1999-06-29 | Abgenix, Inc. | Production of a multimeric protein by cell fusion method |
EP2314625B1 (en) | 1996-12-03 | 2014-05-07 | Amgen Fremont Inc. | Transgenic mammals having human Ig loci including plural VH and Vkappa regions and antibodies produced therefrom |
US7227002B1 (en) | 1997-04-14 | 2007-06-05 | Micromet Ag | Human antibodies that bind human 17-A1/EpCAM tumor antigen |
US6235883B1 (en) | 1997-05-05 | 2001-05-22 | Abgenix, Inc. | Human monoclonal antibodies to epidermal growth factor receptor |
US20030059427A1 (en) | 2000-04-28 | 2003-03-27 | Force Walker R. | Isolation and characterization of highly active anti-CD40 antibody |
CA2440680C (en) | 2001-03-12 | 2010-06-01 | Roberto Pellicciari | Steroids as agonists for fxr |
CA2514547A1 (en) | 2003-01-28 | 2004-08-12 | Takeda Pharmaceutical Company Limited | Receptor agonists |
EP1568706A1 (en) | 2004-02-26 | 2005-08-31 | Intercept Pharmaceuticals, Inc. | Novel steroid agonist for FXR |
JP2010517931A (ja) | 2006-02-14 | 2010-05-27 | インターセプト ファーマシューティカルズ, インコーポレイテッド | Fxr媒介性の疾患または状態の予防または治療用のfxrリガンドとしての胆汁酸誘導体 |
EP1854810A1 (en) * | 2006-05-09 | 2007-11-14 | PanGenetics B.V. | Deimmunized antagonistic anti-human CD40 monoclonal antibody from the ch5D12 antibody |
SI2040713T1 (sl) | 2006-06-27 | 2014-11-28 | Intercept Pharmaceuticals, Inc. | Derivati žolčne kisline kot FXR ligandi za preprečevanje ali zdravljenje bolezni ali stanj, posredovanih s FXR |
AU2008209566C1 (en) | 2007-01-19 | 2013-02-14 | Intercept Pharmaceuticals, Inc. | 23-substituted bile acids as TGR5 modulators and methods of use thereof |
CA2732323C (en) | 2008-07-30 | 2017-06-27 | Intercept Pharmaceuticals, Inc. | Tgr5 modulators and methods of use thereof |
WO2010059859A1 (en) | 2008-11-19 | 2010-05-27 | Intercept Pharmaceuticals, Inc. | Tgr5 modulators and methods of use thereof |
BRPI1009920A2 (pt) * | 2009-05-01 | 2016-03-15 | Micropharma Ltd | composições bacterianas para profilaxina e tratamento de doença degenerativa. |
EP3178851B1 (en) | 2010-03-31 | 2020-04-29 | Boehringer Ingelheim International GmbH | Anti-cd40 antibodies |
-
2014
- 2014-06-13 WO PCT/NL2014/050390 patent/WO2014200349A1/en active Application Filing
- 2014-06-13 AU AU2014278833A patent/AU2014278833A1/en not_active Abandoned
- 2014-06-13 CA CA2914924A patent/CA2914924A1/en not_active Abandoned
- 2014-06-13 CN CN201480044800.1A patent/CN105636984A/zh active Pending
- 2014-06-13 US US14/897,295 patent/US20160151486A1/en not_active Abandoned
- 2014-06-13 EP EP14734941.9A patent/EP3008091A1/en not_active Ceased
- 2014-06-13 KR KR1020167000804A patent/KR20160034893A/ko not_active Application Discontinuation
- 2014-06-13 JP JP2016519472A patent/JP2016521744A/ja active Pending
- 2014-06-13 MX MX2015017035A patent/MX2015017035A/es unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1938045A (zh) * | 2003-11-04 | 2007-03-28 | 希龙公司 | 治疗自身免疫和炎性疾病以及器官移植排异的拮抗性抗-cd40抗体的应用 |
CN101325970A (zh) * | 2005-11-01 | 2008-12-17 | 诺华有限公司 | 抗cd40抗体的应用 |
CN102325784A (zh) * | 2008-11-19 | 2012-01-18 | 英特塞普特医药品公司 | G蛋白偶联受体5(tgr5)调节剂及其使用方法 |
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CA2914924A1 (en) | 2014-12-18 |
KR20160034893A (ko) | 2016-03-30 |
JP2016521744A (ja) | 2016-07-25 |
MX2015017035A (es) | 2016-04-25 |
EP3008091A1 (en) | 2016-04-20 |
US20160151486A1 (en) | 2016-06-02 |
WO2014200349A1 (en) | 2014-12-18 |
AU2014278833A1 (en) | 2016-01-07 |
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