CN107661500A - Vap‑1抑制剂用于治疗纤维变性疾病的用途 - Google Patents
Vap‑1抑制剂用于治疗纤维变性疾病的用途 Download PDFInfo
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- CN107661500A CN107661500A CN201710879422.4A CN201710879422A CN107661500A CN 107661500 A CN107661500 A CN 107661500A CN 201710879422 A CN201710879422 A CN 201710879422A CN 107661500 A CN107661500 A CN 107661500A
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Abstract
本发明涉及VAP‑1的抑制剂,及其作为药物在治疗纤维变性疾病中的用途。此外,本发明涉及基于在体液中可溶性VAP‑1或SSAO活性的升高水平诊断纤维变性疾病的方法,并涉及用于所述诊断方法的试剂盒。
Description
本申请是申请日为2010年9月7日、发明名称为“VAP-1抑制剂用于治疗纤维变性疾病的用途”的中国专利申请201080050348.1(国际申请号PCT/FI2010/050689)的分案申请。
发明领域
本发明涉及VAP-1的抑制剂及其作为抗纤维变性剂的用途。此外,本发明涉及诊断纤维变性疾病的方法以及用于所述诊断方法的试剂盒。
发明背景
纤维变性疾病通常在创伤或慢性炎症后作为受干扰的伤口愈合过程的结果存在。纤维变性病理在定期暴露于化学和生物损害的器官,例如肝、肺、皮肤和肾中特别常见。无论病症是急性的还是慢性的,它们都具有共同的特征,即异常的成纤维细胞活化和胞外基质(ECM)的积累,导致器官功能的丧失,因为瘢痕组织替代了正常组织。该疾病是渐进的,常常是不可逆,具有差的预后和存活率。
不考虑损伤的原因,纤维变性瘢痕的组成与损伤非常类似。纤维变性严重程度的诊断和验证从预后观点看极其重要。治疗的决策过程高度取决于对纤维变性的评估、其进程以及并发症的发作。在肝纤维变性中,经皮的肝活组织检查是分级和分期肝病的金标准。然而,这是侵入性操作,通常具有与疼痛和不适相关的某些不可避免的风险和并发症。死亡率(归因于该操作的并发症)为1:1000至1:10 000(Crockett等人,2006)。
发现血清单胺氧化酶活性水平在患与纤维变性相关的肝硬化、慢性肝炎和肝癌的患者中升高,但发现在患炎性***疾病例如类风湿性关节炎或***性红斑狼疮的患者中是正常的(McEwen和Castell 1967,J Lab Clin Med.70:36-47;Ito等人1971Digestion.4:49-58;Ma Lin等人,1976,Proc Soc Exp Biol Med.151:40-3)。然而,已经考虑将升高的血清单胺氧化酶活性仅作为标志物或者作为对组织损伤的应答,并且其在纤维变性的发病机理中的作用还未知。
常规的治疗方法使用皮质类固醇和免疫抑制药物,主要靶向纤维变性的炎症过程。然而,不幸的是这些药剂具有很少的临床效果或者没有临床效果,并且存在治疗纤维变性疾病的新药物的明显需求。
发明简述
本发明的一些目的涉及作为抗纤维变性剂的VAP-1抑制剂、VAP-1抑制剂用于生产治疗纤维变性疾病的药物的用途,以及在需要其的人类受试者中预防、治疗或者减轻纤维变性疾病的方法,所述方法包括将有效量的VAP-1抑制剂施用给所述患者。
本发明另外的目的是提供在受试者中诊断纤维变性疾病的方法。该方法包括a)提供来自所述受试者的体液样品,b)在所述样品中测定可溶性VAP-1(sVAP-1)的量或者SSAO活性,c)基于sVAP-1的所述量或者SSAO活性诊断纤维变性。根据需要,可以将sVAP-1的量或者SSAO活性与参照体液中sVAP-1的量或者SSAO活性比较。
本发明另外的目的是提供在诊断纤维变性疾病的方法中使用的试剂盒。
在上述目的的一些实施方案中,VAP-1抑制剂是抗VAP-1抗体,例如包含选自SEQID NO 1-3的1-3个CDR共有序列的完全人的抗VAP-1抗体和/或包含选自SEQ ID NO 24-26的1-3个CDR共有序列的轻链多肽。在一些其他的实施方案中,所述抗VAP-1抗体具有包含选自SEQ ID NO 4-8的第一CDR序列、选自SEQ ID NO 9-13的第二CDR序列和选自SEQ ID NO14-18的第三CDR序列的重链多肽和/或包含选自SEQ ID NO 27-31的第一CDR序列、选自SEQID NO 32-36的第二CDR序列和选自SEQ ID NO 37-41的第三CDR序列的轻链多肽。
在一些另外的实施方案中,所述抗VAP-1抗体具有包含选自SEQ ID NO 19-23的氨基酸序列的重链可变区和包含选自SEQ ID NO 42-46的氨基酸序列的轻链可变区。又在一些另外的实施方案中,所述抗体是重组的完全人重组抗体,其包含在SEQ ID NO 47中所述的重链多肽和在SEQ ID NO 48中所述的轻链多肽。
在上述目的的一些其他实施方案中,VAP-1抑制剂是SSAO抑制剂,例如选自肼衍生物、丙烯基胺和炔丙基胺、4-取代的-2-丁炔基胺、卤代烯丙基胺、吡咯啉衍生物、炔丙基二胺、烯丙基胺、二胺、4,5,6,7-四氢咪唑并[4,5-c]吡啶衍生物、氨基硫羰基衍生物、羧酰胺、磺酰胺、噻唑和/或胍衍生物、肟衍生物、二肼、芳基烷基胺(arylalkylamine)、唑烷酮、卤代烷基胺、苯磷硫胺和咪唑并吡啶衍生物。
在上述目的的一些另外的实施方案中,纤维变性疾病选自肝纤维变性和诱发其的炎症疾病,即急性和慢性肝炎、胆道疾病和中毒性肝损伤、肺纤维变性、肾纤维变性,包括糖尿病性肾病导致的肾纤维变性,骨髓纤维变性、胰纤维变性、硬皮病、***疾病、瘢痕、皮肤纤维变性、心脏纤维变性、器官移植、血管狭窄、再狭窄、动脉纤维变性、关节纤维变性(arthrofibrosis)、***纤维变性、肌肉纤维变性、腹膜后纤维变性、甲状腺纤维变性、***纤维变性、膀胱纤维变性、胸膜纤维变性和COPD,所述COPD是这样的疾病,其中气管壁随成肌纤维细胞和胶原的积累而纤维变性,并且与所有纤维变性组织一样,是收缩的。
本发明的其他特定实施方案描述于所附权利要求中。
本发明的其他目的、细节和优点从以下附图、详细说明和实施例中看是显而易见的。
附图简述
以下,本发明将参照附图通过优选的实施方案更加详细地描述,附图中
图1显示施用VAP-1抗体BTT-1029导致了对CCI4诱导的肝纤维变性的几乎完全保护。来自用矿物油(MO,对照组)、CCI4或CCI4与VAP-1抗体平行注射的WT和VAP-1敲除小鼠的Sirus red染色。使用Image J阈值分析进行纤维变性瘢痕的定量测量。显示了3组实验的平均值±SEM。放大倍数×10。
图2显示尽管进行了CCl4-纤维变性诱导,但VAP-1抗体处理的肝和VAP-1敲除肝都显示明显缺少肝炎和坏死区域。显示了在×20放大倍数下,突出坏死肝细胞(箭头)和正在进行的肝炎(箭头)的苏木精和伊红染色。
图3显示VAP-1抗体阻止了在纤维变性组织中胶原蛋白IV和弹性蛋白表达的增加。使用Image J阈值分析进行胶原蛋白IV、弹性蛋白和层粘连蛋白染色的定量测量。显示了3组实验的平均值±SEM。
图4图解了mRNA水平表明VAP-1对肝星形细胞和成纤维细胞的调节作用。显示了弹性蛋白、aSMA、VAP-1和TIMP1的定量RT-PCR分析。数据显示为来自测量了3次的3只小鼠的平均值±SEM。*p<0.05、**<0.01、***<0.001(ANOVA)。
图5显示应答CCI4诱导的肝纤维变性增加的血清中可溶性VAP-1和SSAO活性。图5A图解了用时间分辨荧光DELFIA测定法分析的血清中CCI4诱导的肝纤维变性对可溶性VAP-1水平的影响。图5B显示用放射化学测定法,在来自CCI4诱导的WT肝的血清中发现的SSAO活性的增加水平。
图6显示了在VAP-1敲除小鼠和VAP-1抗体处理的C57BL/6小鼠中拯救的由CCI4诱导的肾小球病变。显示了在×40放大倍数下,突出肾小球的苏木精和伊红染色。
图7图解了在VAP-1敲除小鼠和VAP-1抗体处理的小鼠中胶原蛋白积累显著降低(由于CCI4诱导的肾小球纤维变性)。显示了来自用矿物油(MO,对照组)、CCI4或CCI4与VAP-1抗体平行注射的WT和VAP-1敲除小鼠的Sirus red染色。使用Image J阈值分析进行纤维变性瘢痕的定量测量。显示了3组实验的平均值±SEM。放大倍数×40。
图8图解了与运载体处理的小鼠比较,来自VAP-1抗体(BTT-1029)处理的烟草烟暴露的小鼠的支气管肺泡灌洗液中总细胞数的降低。
图9图解了与运载体处理的小鼠比较,来自对照罗氟司特处理的烟草烟暴露的小鼠的支气管肺泡灌洗液中总细胞数的降低。
图10显示与NaCl 0.9%处理的对照组比较,在***处理组和两个SSAO抑制剂(BTT-2089)处理组中血管中层形成的显著减少。
图11显示与NaCl 0.9%处理的对照组比较,在***处理组和两个SSAO抑制剂(BTT-2089)处理组中新内膜形成的显著减少。
图12显示苏木精根皮红藏红花(hematoxylin phloxine saffron)(HPS)染色的血管区段的实例。当与对照组比较时,在SSAO抑制剂处理组C和D中管腔尺寸是增加的。A-NaCl0.9%组;B–***;C-BTT208910mg/kg;D-BTT-2089 30mg/kg。
图13显示用抗VAP-1抗体或同种型匹配的对照抗体染色的来自正常、NASH肝硬化和ALD肝硬化肝的组织。VAP-1染色显示,与正常或同种型对照比较,在NASH肝硬化和ALD肝硬化肝中更深,并且反映了纤维变性区域中VAP-1表达的增加。
图14显示用抗VAP-1、抗CD31和抗胶原蛋白IV抗体染色的来自正常的和NASH肝硬化肝的组织。VAP-1染色用箭头显示,并且其主要仅存在于NASH肝硬化肝中,并反映了纤维变性区域中VAP-1表达的增加。
图15显示用抗VAP-1、抗CD90和抗CD3抗体染色的来自NASH肝硬化肝的组织。VAP-1染色用箭头显示,并且其存在于NASH肝硬化肝中,并反映了纤维变性区域中VAP-1表达的增加。
图16显示用抗VAP-1和抗平滑肌肌动蛋白抗体染色的肝星形细胞,以及用抗VAP-1、抗CD90和抗胶原蛋白IV抗体染色的肝肌成纤维细胞。VAP-1染色用箭头显示,并且其存在于肝星形细胞和肝肌成纤维细胞中。
图17是sVAP-1水平与相应的组织学纤维变性阶段的散点图。直线表示中值。
图18显示将sVAP-1用作为单独的生物标志物以预测显著的肝纤维变性(F2-4)(图18A)、晚期的纤维变性(F3-4)(图18B)和肝硬化(F4)(图18C)的受者作用特征(ROC)曲线。
图19显示从sVAP-1水平、糖尿病状态和AST/ALT比率(0.837+sVAP-1(ng/ml)×0.001+糖尿病(是=1否=0)×0.591+logAST/ALT×0.8)计算的纤维变性得分的受者作用特征(ROC)曲线,以预测显著的肝纤维变性(F2-4)(图19A)、晚期的纤维变性(F3-4)(图19B)和肝硬化(F4)(图19C)。
发明详述
本发明基于令人意外的发现,即血管黏着蛋白-1(VAP-1)(也称为氨基脲敏感的胺氧化酶(SSAO)并由人类基因AOC3定义)在纤维变性组织的形成中起着直接的作用。到目前为止,VAP-1已经显示出通过介导白细胞迁移进入组织,参与多种炎症疾病,但还没有显示出直接参与纤维变性本身的发病机理。
术语“纤维变性”指在器官或组织中形成了或者存在过多的***。其可能以对刺激例如组织损伤或者炎症的修复或者替代应答的形式发生。
本发明的一个目的是研究VAP-1抑制剂在保护多种器官免于纤维变性损伤中的作用。例如,在小鼠中由四氯化碳造成的慢性纤维变性肝损伤中、在慢性阻塞性肺病(COPD)的烟草烟诱导的小鼠模型中和在血管重构、血管狭窄和新内膜变厚(纤维变性)的小鼠模型中,已经获得了极好的结果。因此,可以实际上将VAP-1抑制剂作为抗纤维变性剂。
在一个方面,本发明的实施方案因此提供了通过给需要该治疗的人类患者使用有效水平的VAP-1抑制剂,在人类身体中,体内减轻或治疗纤维变性的方法。术语“治疗”意图包括以这样的目的将VAP-1抑制剂施用给受试者,所述目的可以包括预防、改善、防止或者治愈涉及纤维变性的疾病,例如肝纤维变性和诱发其的炎症疾病,即急性和慢性肝炎、胆道疾病和中毒性肝损伤、肺纤维变性、肾纤维变性,包括糖尿病性肾病导致的肾纤维变性、骨髓纤维变性、胰纤维变性、硬皮病、***疾病、瘢痕、皮肤纤维变性、心脏纤维变性、器官移植、血管狭窄、再狭窄、动脉纤维变性、关节纤维变性(arthrofibrosis)、***纤维变性、肌肉纤维变性、腹膜后纤维变性、甲状腺纤维变性、***纤维变性、膀胱纤维变性、胸膜纤维变性和COPD,所述COPD是这样的疾病,其中气管壁随肌成纤维细胞和胶原的积累而纤维变性,并且与所有纤维变性组织一样,是收缩的。
VAP-1抑制剂的“有效水平”意为至少改善纤维变性的有害作用的水平。可以通过治疗纤维变性相关疾病的临床领域的普通技术人员容易地确定VAP-1抑制剂的施用量和方案。优选地,VAP-1抑制剂是单克隆抗VAP-1抗体,其以每周一次至每三月一次的间隔,以0.01至20mg/kg,更优选地以0.1至15mg/kg,最优选地以1.0至10mg/kg的剂量静脉内提供。备选地,以每周一次至每三月一次的间隔,以0.1至20mg/kg,优选地以0.2至10mg/kg,最优选地0.5至5mg/kg的剂量皮下提供VAP-1抑制剂。
可以以约0.1μg/kg至约300mg/kg的剂量之内,优选地1.0μg/kg至10mg/kg之间的有效量施用本发明化合物,其是SSAO的抑制剂。本发明化合物可以以每日一次的剂量或者按千克体重施用,并且可以以每日两次、三次或四次的分份剂量施用总的每日剂量。
可以以备选的方式配制上述方面,即,以致本发明的一些实施方案提供VAP-1抑制剂作为抗纤维变性剂,用于预防、治疗和/或缓解纤维变性疾病,例如肝纤维变性和诱发其的炎症疾病,即急性和慢性肝炎、胆道疾病和中毒性肝损伤、肺纤维变性、肾纤维变性,包括糖尿病性肾病导致的肾纤维变性、骨髓纤维变性、胰纤维变性、硬皮病、***疾病、瘢痕、皮肤纤维变性、心脏纤维变性、器官移植、血管狭窄、再狭窄、动脉纤维变性、关节纤维变性(arthrofibrosis)、***纤维变性、肌肉纤维变性、腹膜后纤维变性、甲状腺纤维变性、***纤维变性、膀胱纤维变性、胸膜纤维变性和COPD,所述COPD是这样的疾病,其中气管壁随肌成纤维细胞和胶原的积累而纤维变性,并且与所有纤维变性组织一样,是收缩的。因此,可以将VAP-1抑制剂用于生产所述纤维变性疾病的药物。
术语“VAP-1抑制剂”指具有阻断VAP-1的功能或其SSAO活性的能力的任意化合物。可以将VAP-1抑制剂分成两种主要种类:阻断性抗体和SSAO抑制剂。
如本文中所用,术语“抗VAP-1抗体”(Ab)或“单克隆VAP-1抗体”(MAb)意为包括能与VAP-1蛋白质特异结合的完整抗体以及抗体片段,例如Fab和F(ab’)2片段。
在本发明的多种方面中使用的合适的抗VAP-1抗体是本领域可得到的,并且可以通过技术人员已知的方法产生另外的抗体。例如,美国专利5,580,780描述了单克隆抗体(mAb),1B2,其识别人VAP-1并可以在冰冻切片测定中阻断淋巴细胞与扁桃体HEV结合。MAb1B2是鼠IgM-抗体,并且对于人VAP-1是特异的。国际专利公开WO 03/093319公开了嵌合的抗VAP-1单克隆抗体BTT-1002,其与对应的鼠抗体比较,具有降低的免疫原性。然而,作为嵌合抗体,将其应用于人类治疗受到损害,这归因于其免疫原性以及由此产生的针对其的抗体。
在此处引用作为参考的国际专利公开WO 2008/129124公开了具有降低的免疫原性和细胞因子释放的完全人类抗VAP-1抗体。优选的完全人类单克隆抗VAP-1抗体的实例包括这样的抗体,其具有包含选自SEQ ID NO 1-3的1-3个CDR共有序列的重链多肽和/或包含选自SEQ ID NO 24-26的1-3个CDR共有序列的轻链多肽。其他优选的抗VAP-1抗体包括这样的抗体,其具有包含选自SEQ ID NO 4-8的第一CDR序列、选自SEQ ID NO 9-13的第二CDR序列和选自SEQ ID NO 14-18的第三CDR序列的重链多肽和/或包含选自SEQ ID NO 27-31的第一CDR序列、选自SEQ ID NO 32-36的第二CDR序列和选自SEQ ID NO 37-41的第三CDR序列的轻链多肽。
在本发明的其他实施方案中,完全人类抗VAP-1抗体是表示为8C10的抗体,并包含SEQ ID NO 19中所述的重链可变区和SEQ ID NO 42中所述的轻链可变区。还在其他实施方案中,抗VAP-1抗体是表示为8A4的抗体,并且其包含SEQ ID NO 20中所述的重链可变区和SEQ ID NO 43中所述的轻链可变区。在另外的实施方案中,抗VAP-1抗体是表示为3F10的抗体,并包含SEQ ID NO 21中所述的重链可变区和SEQ ID NO 44中所述的轻链可变区。又在另外的实施方案中,抗VAP-1抗体是表示为5F12的抗体,并包含SEQ ID NO 22中所述的重链可变区和SEQ ID NO 45中所述的轻链可变区。甚至又在另外的实施方案中,抗VAP-1抗体是表示为4B3的抗体,并包含SEQ ID NO 23中所述的重链可变区和SEQ ID NO 46中所述的轻链可变区。还可以将这些抗体提供为重组抗体,例如重组r8C10(BTT-1023),其包含SEQ IDNO 47中所述的重链多肽和SEQ ID NO 48中所述的轻链多肽。
用于本发明实施方案的合适的SSAO抑制剂的实例包括但不限于,肼衍生物例如烯丙基肼类,特别是苯基烯丙基肼类;和羟胺(即氨氧基)衍生物。烯丙基肼类的更特定的实例包括但不限于,2-(苯基-烯丙基)-肼、N-[2-(4’-氟苯基)-烯丙基]-肼和(E)-1-氟-2-苯基-3-肼基丙烯,而羟胺衍生物的更特定的实例包括但不限于,2-氨氧基-1-苯基-乙醇和2-氨氧基-1-(3’,4’-二甲氧基-苯基)-乙醇。此类SSAO抑制剂描述于WO2006/094201和WO2005/014530中,所述WO2006/094201和WO2005/014530在此处引用作为参考。其他合适的肼衍生物包括乙酰肼类,例如但不限于描述于此处引用作为参考的WO 2009/145360中的2-(4-{2-[5-(4-乙酰哌嗪-1-yl)吡啶-2-基]乙基}苯基)乙酰肼;和肼醇类,例如但不限于描述于此处引用作为参考的WO 02/02090中的(1R,2S)-2-(1-甲基肼基)-1-苯基-1-丙醇、(1R,2S)-2-(1-甲基肼基)-1,2-二苯基乙醇、1-(1’-甲基肼基)-3-(间甲氧基苯氧基)-2-丙醇和(1S,2R)-2-(1-甲基肼基)-1,2-二苯基乙醇(BTT-2079);和肼茚满类,例如但不限于描述于在此处引用作为参考的WO 03/006003和WO2005/080319中的(1S,2S)-2-(1-甲基肼基)-1-茚满醇。
用于本发明实施方案的合适的SSAO抑制剂的其他实例包括但不限于,丙烯基-和炔丙基胺、4-取代的-2-丁炔基胺、卤代烯丙基胺(特别地2-和3-卤代烯丙基胺)、吡咯啉衍生物、炔丙基二胺、烯丙基胺和二胺。以上SSAO抑制剂的更特定实例包括但不限于5-苯氧基戊-2,3-二烯基胺、4-(4-甲氧基苯基)丁-3-炔基胺、4-苯基丁-3-炔基胺、2-苯基-3-氟烯丙基胺、S-(E)-4-(4-氨基-2-氟代丁-2-烯基氧基)-N-(1-苯乙基)苯甲酰胺、(E)-3-氟-4-(4-(甲基磺酰基)苯氧基)丁-2-烯-1-胺、(E)-3-氟-4-(2-甲基苯并[d]噻唑-5-基氧基)丁-2-烯-1-胺、(E)-4-(4-氨基-2-氟代丁-2-烯基氧基)-N-(1-苯乙基)苯磺酰胺和(E)-2-(4-氟代苯乙基)-3-氟代烯丙基胺(BTT-2089、mofegeline)。此类化合物描述于WO 2007/005737、WO 2005/082343、WO 2009/066152、WO 2009/055002和Palfreyman等人,J Neural Transm.(1994),41,407-414)中,所述文献在此处引用作为参考。
用于本发明实施方案的合适的SSAO抑制剂的其他实例包括但不限于,描述于在此处引用作为参考的WO2006/013209和US2007/066646中的4,5,6,7-四氢咪唑并[4,5-c]吡啶衍生物(在WO 02/38153中所述,在此处引用作为参考)、羧酰胺例如N-羟基-2-(2-(2-甲基-1H-吲哚-3-基)乙酰胺基)乙酰胺和5-氨基-2-羟基-N-(2-羟基苄基)苯甲酰胺和磺酰胺例如N2-{[4-(1,1-二甲基丙基)苯基]磺酰基}-N1-羟基丝氨酰胺。
此外,噻唑和/或胍衍生物,特别地2-酰基氨基***衍生物适合于在本发明的多种实施方案中使用。此类SSAO抑制剂的更特定实例包括但不限于N-{4-[2-(4-{[氨基(亚氨基)甲基]氨基}苯基)乙基]-1,3-***-2-基}乙酰胺、N-{4-[2-(4-{[氨基(亚氨基)甲基]氨基}苯基)乙基]-5-[4-(甲基磺酰基)苄基]-1,3-***-2-基}乙酰胺、N-{4-[2-(4-{[2-氨基-1H-咪唑-4-基)甲基]苯基}乙基)***-2-基]-乙酰胺、2-(4-{2-[2-(乙酰基氨基-1,3-***-4-基]乙基}苯基)-N-[氨基(亚氨基)甲基]乙酰胺。此类化合物描述于WO2004/087138、WO2004/067521、WO2006/028269、WO2006/011631和WO2005/089755中,所述全部文献在此处引用作为参考。
此外,多种肟衍生物是SSAO抑制剂,并可以因此用于本发明的多种实施方案。此类肟衍生物包括但不限于,描述于WO 2010/029379中的5-溴-1,3-苯并二间二氧杂环戊烯-4-甲酰基咪唑肟、6-乙氧基-1,3-二甲基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲酰基咪唑肟、1,3-二甲基-6-(甲硫基)-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲酰基咪唑肟,所述WO 2010/029379在此处引用作为参考。
还可以将在WO 2010/015870、WO 2005/072738、Lyles G.A.,Int.J.Biochem.CellBiol.第28卷第259-276页(1996)和McDonald等人,Annual reports in Med.Chem.第42卷第229-243页(2007)中公开的二肼、芳烷基胺、唑烷酮、卤代烷基胺和苯磷硫胺(维生素B1)作为SSAO抑制剂用于本发明的多种实施方案,所述文献在此处引用作为参考。
适合在本发明实施方案的多个方面和实施方案中使用的其他SSAO抑制剂包括在此处引用作为参考的WO 2010/064020中描述的咪唑并吡啶衍生物。
此外,在本发明的多种实施方案中使用的合适的SSAO抑制剂包括具有抑制或阻断VAP-1的SSAO活性能力的任一立体异构体、立体异构体的混合物、E或Z形式、E或Z形式的混合物、前体药物、代谢物、晶体形式、非晶体形式、水合物、溶剂合物或其盐。
可以用本领域已知的SSAO测定法筛选并鉴定其他合适的SSAO抑制剂。该测定法包括VAP-1 SSAO活性测定法,其使用基本上如用于单胺氧化酶和相关酶所述的偶联比色方法(Holt,A.,等人,Anal.Biochem.244:384-392(1997))。还可以使用Amplex Red试剂(10-乙酰基-3,7-二羟基吩嗪),对H2O2高度敏感的和稳定的探针,独立地测量内皮细胞的SSAO活性(Zhou M,Panchuk-Voloshina N.Anal Biochem.253(2):169-74(1997))。此外,可以使用[7-14C]-苄胺盐酸盐作为底物,通过放射化学方法测定胺氧化酶活性(Jaakkola等人,AmJ Pathol:155(6):1953-65(1999))。作为VAP-1 SSAO酶的来源,可以使用在细胞系例如中国仓鼠卵巢(CHO)细胞中表达的重组人类VAP-1 SSAO(Smith,D.J.,等人,J.Exp.Med.188:17-27(1998))。其他合适的SSAO VAP-1酶来源可以是来自不同物种例如灵长类动物和啮齿动物的血清和组织样品。
对于根据本发明实施方案的用途,可以将VAP-1抑制剂提供为药物组合物,其包含可药用载体或稀释剂,以及作为活性成分的VAP-1抑制剂。组合物含有足以(完全地或部分地)拮抗需要此种拮抗的患者中患者的SSAO活性或者与VAP-1的生物学配体的天然VAP-1结合的量的VAP-1抑制剂。
可以通过治疗纤维变性相关疾病的临床领域的普通技术人员容易地确定VAP-1抑制剂的施用量和方案。一般地,VAP-1抑制剂治疗的剂量是变化的,这取决于所考虑的事项,例如:待治疗患者的年龄、性别和一般健康状况;若存在的话,同时治疗的种类;治疗的频率和想要的效果的性质;组织损伤的程度;症状的持续时间;以及可由各个医师调整的其他变量。可以以一次或多次应用施用想要的剂量,以获得想要的结果。可以以单位剂量形式提供根据本发明实施方案的药物组合物。
可以在用于施用的任意合适药物载体中施用药物组合物。它们可以以任意形式使用,只要其实现预防、减轻、防止或者治愈人类或动物患者中纤维变性疾病的状况。
用于肠胃外和局部施用的药物组合物包括无菌水性溶剂或非水性溶剂、混悬剂和乳剂。非水性溶剂的实例是丙二醇、聚乙二醇、植物油、鱼油和可注射的有机酯。水性载体包括水、水-醇溶液,包括盐水和缓冲的中等肠胃外运载体,包括氯化钠溶液、林格葡萄糖溶液、葡萄糖加氯化钠溶液、含乳糖的林格溶液或不挥发的油。静脉内运载体包括流体和营养补充剂、电解质补充剂,例如那些基于林格葡萄糖的电解质补充剂等等。根据实施方案的含水组合物可以包含合适的缓冲剂,例如取决于靶向的pH范围,包含磷酸、柠檬酸、乙酸、碳酸或甘氨酸的钠和钾缓冲液。氯化钠作为张度调节剂的用途也是有用的。组合物可以包括其他赋形剂,例如稳定剂或防腐剂。有用的稳定剂包括表面活性剂(聚山梨醇酯20&80、泊洛沙姆407)、聚合物(聚乙二醇、聚维酮)、碳水化合物(蔗糖、甘露醇、葡萄糖、乳糖)、醇(山梨醇、甘油、丙二醇、乙二醇)、合适的蛋白质(白蛋白)、合适的氨基酸(甘氨酸、谷氨酸)、脂肪酸(乙醇胺)、抗氧化剂(抗坏血酸、半胱氨酸等)、螯合剂(EDTA盐、组氨酸、天冬氨酸)或金属离子(Ca、Ni、Mg、Mn)。其中有用的防腐剂是苯甲醇、氯代丁醇、苯扎氯铵和可能地对羟基苯甲酸酯。
可以以浓缩形式或者以根据需要重构的粉末形式提供药物组合物。在此类情况下,可以将粉末制剂用于上述注射/输注赋形剂的溶液。在冻干的情况下,优选的是某些冷冻保护剂,包括聚合物(聚维酮、聚乙二醇、葡聚糖)、糖(蔗糖、葡萄糖、乳糖)、氨基酸(甘氨酸、精氨酸、谷氨酸)和白蛋白。如果将用于重构的溶液加入到包装中,其可以由例如,用于注射的纯水或者氯化钠溶液或者葡聚糖或葡萄糖溶液组成。
可以通过化学或者通过基因工程方法,将治疗上有用的抗VAP-1抗体与其他试剂缀合,所述其他试剂提供抗体靶向期望的作用位点。备选地,可以通过化学或者通过基因工程方法,将其他化合物与抗体缀合,以增强或者提供抗体的其他特性,特别是增强抗体促进由VAP-1结合介导的有害作用的减轻的能力。
可以通过化学或者通过基因工程方法标记抗VAP-1抗体,以提供可检测的抗体。此类标记的抗体对于在人类中成像纤维变性位点,特别是对于在体内免疫闪烁(immunoscintigraphic)成像纤维变性位点是有用的工具。对于成像目的,抗体片段的用途可能要优于抗纤维变性治疗的完整抗体方法,并且衍生自完全人类抗体的片段应当比其嵌合等同物或小鼠等同物更安全。
本发明的一些方面涉及诊断纤维变性疾病。关于本发明,已经发现体液(例如血清或血浆)中升高水平的可溶性VAP-1(sVAP-1)和因此升高的SSAO活性与纤维变性的程度相关。因此,本发明的一些实施方案提供了用于诊断纤维变性疾病的工具和方法,所述纤维变性疾病为例如肝纤维变性和诱发其的炎症疾病,即急性和慢性肝炎、胆道疾病和中毒性肝损伤、肺纤维变性、肾纤维变性,包括糖尿病性肾病导致的肾纤维变性、骨髓纤维变性、胰纤维变性、硬皮病、***疾病、瘢痕、皮肤纤维变性、心脏纤维变性、器官移植、血管狭窄、再狭窄、动脉纤维变性、关节纤维变性(arthrofibrosis)、***纤维变性、肌肉纤维变性、腹膜后纤维变性、甲状腺纤维变性、***纤维变性、膀胱纤维变性、胸膜纤维变性和COPD,所述COPD是这样的疾病,其中气管壁随肌成纤维细胞和胶原的积累而纤维变性,并且与所有纤维变性组织一样,是收缩的。
在一些实施方案中,基于体液中升高的sVAP-1水平和/或SSAO活性的纤维变性疾病的诊断可以与纤维变性疾病现存的几组预测性生物标志物的分析组合。这可以改进现存生物标志物的诊断能力。换言之,可以单独地或者与其他临床和生物化学的标志物组合使用sVAP-1水平/SSAO活性作为新的非侵入性测试,以预测纤维变性的存在。
可以通过以下方法测定体液样品例如血清中sVAP-1的水平:用于定量可溶性VAP-1的时间分辨一步免疫荧光测定法(time-resolved one-step immunofluorometricassay)(TR-IFMA)(DELFIA)使用生物素缀合的小鼠抗人VAP-1抗体TK8-14(BiotieTherapies Corp.)作为链霉抗生物素蛋白包被的微量滴定板上的捕获物。使用铕缀合的小鼠抗人VAP-1抗体TK8-18(Biotie Therapies Corp.)作为示踪物进行结合的可溶性VAP-1的检测。通过在615nm测量时间分辨荧光(Victor3多标记计数器)检测标记。荧光计数与样品中存在的可溶性VAP-1的多少直接相关。然后与参照的标准曲线比较,分析样品数据。
在本发明的一些实施方案中,基于在获自需要该诊断的和/或怀疑患纤维变性的受试者的体液中SSAO活性诊断纤维变性。用于该目的的一种合适方法已经由Li等人在J.Chromatogr.B,810(2004)277-282中公开。测定SSAO活性的其他工具和方法是本领域已知的。
此外,本发明的一些方面提供了用于诊断纤维变性的试剂盒。在一些实施方案中,试剂盒包含用于评估sVAP-1的量的一种或多种试剂,例如特异性抗VAP-1抗体,例如上述抗VAP-1抗体之一。在其他实施方案中,试剂盒包含用于评估在体液例如血清或血浆中SSAO活性的一种或多种试剂。例如,试剂盒可以包含VAP-1 SSAO的底物,例如苄胺、甲胺、氨基丙酮或者其他脂肪族或芳族单胺,以及合适的SSAO酶活性测定缓冲液,以及用于测定SSAO活性的一套试剂和方法。可以使用偶联的测定法检测SSAO活性,其中测量在单胺底物上由于SSAO活性的作用产生的过氧化氢,或者其可以通过使用14C标记的胺底物例如苄胺,监测水溶性胺至有机溶剂可溶性醛的转变来直接测量。
对于本领域技术人员显而易见的是,因为技术进步,可以以多种方式实施本发明概念。本发明及其实施方案并不受限于以下所描述的实施例,但可以在权利要求的范围内进行改变。
实施例1.VAP-1抑制剂在肝纤维变性的小鼠模型中的作用
本研究的目的是在小鼠中评估VAP-1抑制剂对纤维变性肝损失的作用。
根据Home Office规范,在Birmingham大学的生物医学服务单位,在常规条件下维持并饲养全部小鼠。每笼饲养4只小鼠,并在实验前使它们适应饲养环境一周。在研究中使用8-10周龄的雌性C57BL/6和VAP-1-/-小鼠(缺少VAP-1的AOC3基因敲除小鼠)。C57BL/6小鼠获自Birmingham大学的生物医学服务单位的原种群体,而VAP-1-/-(AOC3基因敲除)小鼠获自合同培养者Taconic,丹麦。
通过以1ml/kg的剂量,每两周一次腹膜内施用溶解于矿物油中的四氯化碳(CCl4;Aldrich Chemical)8周,建立慢性肝纤维变性的小鼠模型,而对照组仅接受矿物油。在CCl4施用之前和期间,用小鼠抗小鼠VAP-1抗体BTT-1029处理的小鼠接受每周一次的静脉内注射两周。在CCl4的最终剂量后96小时,处死动物。通过在异氟烷麻醉期间的心脏穿刺抽取血液样品,之后通过颈椎脱位处死小鼠。解剖肝脏并切成4块用于不同的处理。
使用SPSS for Windows 11.0版进行统计学方差分析。将单向方差分析然后Fisher’s至少显著差异事后检验(Fisher’s least significant difference post hoctest)用于分析具有两个以上变量组的样品的显著性。
将肝样本固定在4%多聚甲醛中,包埋在石蜡中并切成4μm切片。用于组织病理学分析的切片是根据标准步骤染色的Sirus red(Sirius red)或者H&E。对于免疫荧光染色,将固定的小鼠肝通过浸没在30%蔗糖中、快速冷冻来进行低温保护,并在低温恒温器中切成7μm。简言之,用含0.1%Triton X-100(PBST)的磷酸缓冲盐水洗涤切片10分钟,并用在0.1%PBST中的10%山羊血清室温温育1小时。用在血清-PBST中稀释的针对弹性蛋白、胶原蛋白IV和层粘连蛋白(Abcam)的一级抗体温育后,将载玻片在PBST中洗涤三次并用二级抗体室温温育1小时。
如所预期,CCl4在C57BL/6小鼠中诱导了严重的纤维变性损伤。8周时,野生型小鼠显示出Sirus red原纤维的肝脏含量8倍的增加,所述Sirus red原纤维具有肝细胞坏死和进行性的肝炎。有趣地,在VAP-1缺陷型小鼠和BTT-1029处理的野生型小鼠二者中,纤维变性损伤显著降低。这些小鼠仅表现出少量的Sirus red原纤维,并且肝脏组织学显示几乎正常(完全没有坏死区域和仅轻微的肝炎)(图1和2)。此外,存在显著更少数量的成熟巨噬细胞,与野生型比较,再次显示出较轻微的损伤(数据未显示)。
通过qRT-PCR评估肝中与肝星形细胞活化相关的基因的mRNA水平。为此,使用Qiagen RNAeasy Mini试剂盒(#74104)从小鼠肝中提取总RNA。使用随机引物(Promega)和来自Invitrogen的Superscript III,将RNA反转录成cDNA模板。qRT-PCR的参数如下:变性95℃10分钟,55个循环的扩增95℃10秒,55℃30秒,72℃1秒。使用参照基因GAPDH和来自Roche的探针,用Roche LightCycler480***测量Quantitative Real-time PCR。使用“E-方法”(Roche)定量表达水平。
数据显示,VAP-1通过调节肝星形细胞(HSC)在肝纤维变性发展中起作用。认为活化的HSC是纤维变性肝中合成ECM组分、包括弹性蛋白的主要来源。施用了CCl4的野生型肝显示出αSMA和弹性蛋白mRNA水平的明显增加,表明表达αSMA的HSC的积累和弹性蛋白的沉积(图4)。与野生型肝比较,在BTT-1029处理的野生型和VAP-1-/-肝中,αSMA和弹性蛋白二者的mRNA水平显著更低。弹性蛋白和胶原蛋白IV表达的差异还通过共聚焦显微术证实,然而层粘连蛋白水平保持不变(图3)。
总之,BTT-1029处理通过降低肝星形细胞的活化,诱导了已建立的肝纤维变性的几乎完全保护,因此限制了纤维变性病变中成纤维细胞的发展。在VAP-1-/-小鼠中也显示出同样的作用,表现出对CCl4诱导的损伤的几乎完全保护。结果显示,VAP-1通过对肝星形细胞的调节作用在肝纤维变性的发展中作为关键成员。VAP-1 SSAO是铜胺氧化酶,并因此与赖氨酰氧化酶类似,所述赖氨酰氧化酶是另一种铜胺氧化酶,负责交联ECM蛋白质例如弹性蛋白和胶原蛋白。仍可能的是,VAP-1的SSAO活性还对ECM蛋白质中交联的形成具有直接作用。
此外,使用[7-14C]苄胺盐酸盐(spec.act.57mCi/mmol)作为底物通过放射化学方法测定血清和肝组织样品的SSAO活性(图5)。在37℃,用5μM氯吉兰和帕吉林,并用具有1mM氨基脲的非特异结合管预温育血清(40mg/ml蛋白质)或组织制备物(2mg/ml蛋白质)30分钟。在37℃,在终体积200μl含[7-14C]苄胺盐酸盐作为底物的0.2mM磷酸钠缓冲液(pH 7.4)中进行测定1小时。如之前在Jaakkola等人,1999(American Journal of Pathology,155,6)中所述终止并处理催化性酶活性反应测定。使用牛血清白蛋白作为标准品,根据Bradford等人(Bradford,M.M.,1976,Anal.Biochem.72,248)测定蛋白质浓度。
结果显示,除了防止了CCl4诱导的肝纤维变性外,BTT-1029处理还明显降低了所述肝样品中的SSAO活性。
实施例2.VAP-1抑制剂在肾损伤的小鼠模型中的肾保护作用
高暴露于四氯化碳对肝和肾均造成了伤害。因此收集来自在实施例1中所述的经CCl4处理动物的肾,并分析VAP-1抑制剂对肾病的作用。
将肾固定在4%多聚甲醛中,包埋在石蜡中并切成4μm切片。在Sirus red和H&E染色的切片上进行组织病理学分析。根据标准方法进行染色。通过使用Image J软件的阈值分析定量Sirus red原纤维的量。
使用SPSS Windows,版本11.0进行统计学方差分析。将单向方差分析然后TukeyHSD’s最小显著差异事后检验(Tukey HSD’s least significant difference post hoctest)用于分析具有两个以上变量组的样品中的显著性。
施用了CCl4的小鼠显示出具有节段性和整体性改变的局部肾小球改变。H&E染色显示出多种病变,例如肾小球系膜细胞过多、尖端区域的粘连和硬化。然而,主要观察到了肾小球簇的整体崩解,并且仅留下了肾小球的片段(数据未显示)。有趣地,VAP-1敲除小鼠和BTT-1029处理的小鼠完全没有肾小球病变(图6)。
通过Sirus red染色,评估作为纤维变性的指征的肾小球周围胶原的积累。在C57BL/6小鼠中施用CCl4,诱导了肾小球簇周围胶原积累的几乎两倍增加。有趣地,缺少VAP-1或者施用了VAP-1抑制剂的小鼠与对照类似,显示出胶原沉积的显著减少(图7)。结果清楚显示了VAP-1在CCl4诱导的肾病中的保护性作用。
实施例3.VAP-1抑制剂在COPD小鼠模型中的作用
应用烟草烟诱导的COPD小鼠模型评估VAP-1抑制剂对COPD的治疗的作用。
将C57BL/6J小鼠每日一次暴露于烟草烟(TS)11个连续日,在最后TS暴露后24小时,产生了肺部炎症。11天后,应答包括巨噬细胞、上皮细胞、嗜酸性粒细胞、嗜中性粒细胞和淋巴细胞的显著增加。
将小鼠随机分成研究组(n=10),并在第-1天、第3天、第6天和第9天TS暴露后4小时用运载体(5ml/kg PBS pH 7.4+0.1%多山醇酯80)或小鼠单克隆抗VAP-1抗体(3mg/kg或9mg/kg在运载体中的BTT-1029)静脉内处理。另一组(n=10)静脉内接受运载体,并暴露于空气相同长度的时间。另外两组小鼠(n=10)在每次TS暴露前1小时每日一次口服地接受另一运载体(在无菌水中的0.5%的羧甲基纤维素钠盐(CMC))或参照化合物(在0.5%CMC中的5mg/kg罗氟司特)。最后一组(n=10)接受口服运载体(0.5%CMC),并暴露于空气等同长度的时间。
将全部结果表示为每一动物的各个时间点和每一组计算的平均值。如果正态检验为阳性,则首先将数据进行单向方差分析(ANOVA),然后是用于多重比较的Bonferroni校正(Bonferroni correction for multiple comparison),以测试处理组之间的显著性。认为“p”值≤0.05为统计学显著。
将全部数据都进行等方差性的Bartlets检验,并对于大多数研究,方差一般是相等的,然而,如在本研究中发生,一些处理组偶尔会给出阳性结果。因此,还使用非参数分析。由于数据是正态分布,引用参数分析(ANOVA)。
使用以下公式,在Excel电子表格为细胞数据内自动计算抑制百分比:
当在研究的第-1天、第3天、第6天&第9天,在TS暴露后4小时以9mg/kg和3mg/kg静脉内给予BTT-1029时,在BAL中显著降低了TS诱导的细胞增加(分别38%和33%抑制,二者都p<0.001)(图8)。这由巨噬细胞(分别29%和22%抑制,p<0.01&p<0.05)、嗜中性粒细胞(66%和59%抑制,二者都p<0.001)、淋巴细胞(69%和54%抑制,二者都p<0.001)和嗜酸性粒细胞(分别93%和65%抑制,p<0.001和p<0.01)的明显降低组成。
参照化合物罗氟司特,当在TS暴露前1小时每日一次口服给予时,也显著降低了细胞的总数(41%,p<0.001)(图9)。这种抑制包含嗜中性粒细胞(63%,p<0.001)、上皮细胞(51%,p<0.01)和淋巴细胞(65%,p<0.001)的降低。在该研究中,罗氟司特并没有显著降低在BAL中发现的巨噬细胞和嗜酸性粒细胞的数量。
实施例4.VAP-1抑制剂在血管壁中对新内膜和血管中层纤维变性的作用
新内膜和血管中层增厚是动脉粥样病变发展中的早期和重要阶段,并且是再狭窄的基本组分。其伴随着血管壁的新内膜和血管中层的纤维变性改变。本研究通过在接受了中等西式饮食的ApoE3Leiden小鼠的股动脉中评价全身递送(通过每日腹腔内注射)小分子SSAO抑制剂(莫非吉兰,BTT-2089)对套(cuff)诱导的新内膜增厚(套诱导的狭窄)的作用,来评价阻断SSAO在纤维变性疾病中的作用。
方法:在手术套放置前,用轻度高胆固醇血饮食喂饲40只雄性ApoE3*Leiden小鼠(12周龄)3周。处理为用1)运载体;2)饮用水中9mg/l的***;3)每日腹膜内注射10mg/kg的BTT-2089;4)每日腹膜内注射30mg/kg的BTT-2089,都在手术前1天开始,并在实验期间一直持续。在第0天进行手术,即在小鼠的两个股动脉周围都放置了非收缩性套(2-3mm长)。两周后处死每组的10只小鼠用于组织形态学测量分析,以定量加速的动脉粥样硬化病变和新内膜形成的抑制。与NaCl 0.9%处理的对照组比较,在***处理的阳性对照组中观察到了血管中层和新内膜形成的显著降低(图10和11)。这反映为当与对照组比较时,在SSAO抑制剂处理组中HPS染色的血管区段的实例中增加的管腔大小(图12)。
在相同的模型中,用来自与BTT-2089不同的化学种类的另一SSAO抑制剂进行第二次研究。通过每日腹膜内注射,以10mg/kg的水平给予这种基于肼的抑制剂(BTT-2079),并与30mg/kg的BTT-2089比较。除省略了***对照组外,在全部其他方面,本研究以相同的方式进行。以每日腹膜内30mg/kg莫非吉非(BTT-2089)抑制SSAO也具有有利的作用,并显示出SSAO抑制后新内膜形成和管腔狭窄百分比的显著降低。用每日腹膜内10mg/kg的SSAO抑制剂BTT-2079处理的组也导致了新内膜形成的显著降低。在全部组之间没有发现血管壁直径、血管中层和管腔面积的显著改变。10mg/kg的BTT-2079和30mg/kg的BTT-2089的内膜血管中层比率与对照组比较显著更低,但与对照组比较,管腔狭窄百分比仅在30mg/kg的BTT-2089组中显著更低。血管完整性未受影响。
这些研究表明,当与对照处理组比较时,***性施用SSAO抑制剂在ApoE 3Leiden小鼠套模型中导致了较少的新内膜增厚(新内膜纤维变性)。
实施例5.VAP-1抑制剂在肺纤维变性的小鼠模型中的作用
建立了博来霉素诱导的肺纤维变性,并将可繁殖的小鼠模型用于研究肺纤维变性。
通过Alzet微型渗透泵,用博来霉素(100mg/kg)全身性处理8周龄的雄性C57BL/6J小鼠7天,以诱发肺损伤。在泵植入后7-21天,没有观察到肺毒性。在第21天,如通过组织病理学评价,在肺中存在12-15%的纤维变性。这随后是临床性肺损伤,其可以通过增加的呼吸频率和体重的明显降低观察到,并最终导致在42天内(如果没有提前处死)死亡。
将小鼠随机分成研究组,并通过从第0天至第28天每三天一次静脉内注射用运载体、VAP-1抑制剂或参照化合物处理。在第21天,将每一研究组的一半小鼠处死,而在第28天处死另一半。
在尸体解剖时,固定(10%中性缓冲***)肺,并进行组织病理学处理,用于分级纤维变性病变。用H&E和Masson’s Trichrome染色组织切片,以鉴定纤维变性。用计算机辅助的图像分析定量每一只小鼠纤维变性肺面积与总肺面积的比率。
将单向方差分析然后合适的事后检验用于具有两个以上变量组的样品中显著性的分析。
如通过与对照比较,评分的统计学显著降低所证明,可以显示出肺纤维变性的降低。
实施例6.VAP-1抑制剂在糖尿病肾疾病的小鼠模型中的肾保护作用
糖尿病可以引起与渐进性肾纤维变性相关的糖尿病肾病(DN),最终降低功能性肾质量。为了评估抗VAP-1抗体和SSAO抑制剂对肾纤维变性的作用,应用糖尿病肾疾病的已建立的Db/db糖尿病小鼠模型。
大体上根据Guide for the Care and Use of Laboratory Animals(NationalAcademy Press,Washington,D.C.,1996)进行这些实验的全部方面(饲养、实验和动物的处理)。
评价测试品(SSAO抑制剂BTT-2079)在糖尿病肾病的小鼠模型中可能的肾保护作用。当完全建立了糖尿病时,将测试物质和运载体每日一次腹膜内(IP)施用给15周龄的db/db小鼠(BKS Cg-Lepr db/Lepr db)42个连续日。将Db/m小鼠用作为瘦正常对照(leannormal control)。与db/m小鼠比较,db/db小鼠显示出升高的血浆肌酸酐(表明受损的肾功能),以及高血糖和血脂异常(LDL、总胆固醇和甘油三酯)。糖尿病小鼠与肥胖、多尿、蛋白尿和增加的分次尿钠***(fractional urinary Na+excretion)(FENa)有关,表明受损的肾小管Na+再吸收。一种肾小球滤过率的估计——内源肌酸酐清除(CCr)在糖尿病小鼠中比db/m小鼠中更低。
如下所述,将雄性db/db非胰岛素依赖的糖尿病小鼠分配到处理组。
表1.实验设计的概述
在生命期结束时,进行尸体解剖,包括收集并保存组织。将来自全部32只动物的右肾固定在10%中性缓冲的***中。修剪纵切面并加工成石蜡块,切片成3微米,并用高碘酸席夫(PAS)染色,通过光学显微镜评价。根据在以下方法中所述的半定量评分方案,在每个肾的50个肾小球中对肾小球膜基质扩张(mesangial matrix expansion)打分。
根据以下***评分来自每一个肾的50个肾小球的肾小球膜基质扩张。
最低的:等级1,基质占据了0-25%的肾小球体积 |
轻微的:等级2,基质占据了25-50%的肾小球体积 |
中度的:等级3,基质占据了50-75%的肾小球体积 |
重度的:等级4,基质占据了75-100%的肾小球体积 |
通过合计每组中全部动物的肾小球膜基质得分并除以组中动物的总数的总和,得出每组的平均肾小球膜基质扩张得分。组均肾小球膜基质扩张得分显示于下表中。
表2.组均肾小球膜基质扩张得分
组别 | 处理 | 组均肾小球膜基质扩张得分 |
1 | 运载体 | 54.6 |
2 | 运载体 | 96.5 |
5 | BTT-2079,5mg/kg | 82.4 |
6 | BTT-2079,15mg/kg | 65.4 |
在正常动物中可以看到极少的肾小球膜基质,但肾小球膜基质的扩张是多种疾病例如糖尿病的特征。肾小球膜基质包括基底膜和相关的多阴离子蛋白聚糖,以及其他用高碘酸席夫(PAS)方法染色成红色至紫色的分子。因此,肾小球中PAS阳性物质的量是对存在的肾小球膜基质的量的度量。
以200×放大倍数评价来自每一动物的50个肾小球,并使用上述评分***为扩张的肾小球膜基质打分。通过合计对每一动物评价的每一肾小球的评分,计算组均肾小球膜基质扩张得分。然后合计组中全部动物的肾小球膜基质扩张得分并除以每组动物的数量,以获得组均肾小球膜基质扩张得分。基于这些数据,相对于db/db非胰岛素依赖的糖尿病小鼠(组2)中的组均肾小球膜基质扩张得分,用5mg/kg和15mg/kg的BTT-2079的治疗以剂量相关的方式降低了肾小球膜基质扩张得分。
为了评估抗VAP-1抗体和SSAO抑制剂对肾纤维变性的作用,应用了用于糖尿病肾病的其他成熟的小鼠模型1)链脲菌素诱导的糖尿病小鼠模型2)单侧输尿管梗阻,肾纤维变性模型。
1)链脲菌素诱导的糖尿病小鼠模型。在链脲菌素(STZ)注射前6h禁食6-7周龄(体重20-25g)的雄性小鼠。为了诱导糖尿病,将新鲜混合的STZ(柠檬酸钠缓冲液中的7mg/ml)以55mg/kg腹膜内注射到每一预先饥饿的小鼠中。为了完成该疾病的诱导,重复该步骤,以使每一小鼠连续5天都接受一次STZ注射。最后的STZ注射后一周,将未禁食血糖低于280mg/dL的小鼠排除于实验之外,因为这些小鼠通常不会发展成足以造成显著肾损伤的糖尿病。
用合适体积的运载体或测试物质,每隔一天腹膜内给药全部小鼠连续3周。全部动物都随意地给予正常的实验室食物和水。
通过酶学方法(Mutarotase-GOD)测定血液样品的血清化学物水平。通过测量尿白蛋白分泌和肌酸酐清除通过生物化学方法评估肾损伤,并另外地通过Masson三色染色和高碘酸席夫染色通过组织学方法评估肾损伤。
2)单侧输尿管梗阻-肾纤维变性模型。在手术前5天和手术后7天,用运载体或测试物质腹膜内给药全部小鼠。以合适的量每隔一天注射抑制剂和运载体,以抑制SSAO。全部动物都随意地给予正常的实验室食物和水。
用异氟烷(2-氯-2-(二氟甲氧基)-1,1,1-三氟-乙烷)吸入麻醉6-7周龄(体重20-25g)的雄性小鼠,并在手术前皮下注射0,05-0,1mg/kg丁丙诺啡。将小鼠进行单侧输尿管梗阻(UUO)或假手术。在UUO手术小鼠中,用4-0丝缝线在两点结扎左输尿管并在结扎线之间切断,以预防逆行的泌尿道感染。手术后7天处死小鼠。
通过测量尿白蛋白分泌和肌酸酐清除通过生物化学方法评估肾损伤,并另外地通过Masson三色染色和高碘酸席夫染色通过组织学方法评估肾损伤。
将单向方差分析和Dunnett’s检验用于全部研究,以确定处理组和运载体组之间的显著性差异。*P<0.05时认为差异显著。
如通过与对照比较评分的显著降低,可以显示出肾纤维变性的降低。
实施例7.糖尿病肾病的抗纤维变性治疗
糖尿病肾病是晚期肾病和纤维变性的常见原因,特别是间质纤维变性是糖尿病肾病的主要病理学特征。临床研究可以测定VAP-1的抑制剂是否可以减轻患糖尿病的患者的肾病,以延长肾功能。
将具有20-75ml/分钟/1.73m2之间的肾小球滤过率(GFR)、大于300mg/天的蛋白尿和血压低于或等于140/90的,正在使用血管紧张素转化酶(ACE)或血管紧张素受体拮抗剂(ARA)的患1型和2型糖尿病的成年患者招募入研究中。在合适的剂量方案(每日一次或者更少)的情况下,使患者接受有效水平的VAP-1抑制剂或者安慰剂1年。将患者随机分配成安慰剂组或者VAP-1抑制剂组。在研究期间,定期监测患者的参数,例如空腹血液和尿液葡萄糖水平、血压和临床化学。可以抽取另外的血液样品以测量血清VAP-1 SSAO的水平,其可能在糖尿病中升高并与该疾病的进程相关。此外,可以评价血清样品中的甲胺水平。升高的甲胺是抑制VAP-1 SSAO活性的生物标志物。要求患者在家定期检查他们的血压和血糖并记录获得的值,以监测他们的糖尿病状态。通过以合适的量施用胰岛素,可以以此方式较好的控制患者的糖尿病。
按当前治疗糖尿病肾病的标准可以维持患者,所述当前治疗糖尿病肾病的标准可以包括用ACE抑制剂和/或ARA治疗、血压目标低于130/80的抗高血压治疗和适当地设定HbA1C的目标的严格血糖过多控制。
通过GFR评估肾功能,并且研究的初级终点可以是肾功能从研究期的基线至终点的改变。次级终点可以包括尿白蛋白分泌在研究期的改变百分比。
实施例8.VAP-1作为纤维变性疾病的诊断标志物
本文通过免疫组织化学显示,肝VAP-1表达在具有非常高水平的纤维变性隔(septa)的肝硬化中是增加的(图13-15)。多色共聚焦显微镜显示,在肝星形细胞和肝肌成纤维细胞上VAP-1的表达(图16)。将培养的人肝星形细胞(HSC)用于确认HSC在体外表达和分泌sVAP-1。这些结果提示了VAP-1在纤维发生中的可能作用。
在明确定义的一组患非酒精性脂肪肝疾病(NAFLD)(具有匹配的和分级的肝组织学(Kleiner分类))的138名患者中测量血清sVAP-1水平。相对于肝组织学(脂肪变性、炎症和纤维变性)、代谢参数和肝损伤的血清学标志物,评估sVAP-1水平(表3)。
表3.在具有组织学分级和分期的NAFLD的138名患者中测量的人口统计学数据和参数的总结
BMI=体重指数,HOMA-IR=胰岛素抗性的稳态模型评估,AST=天冬氨酸转氨酶,ALT=丙氨酸转氨酶,ALP=碱性磷酸酶,GGT=γ-谷氨酰转移酶,CRP=C-反应蛋白。
与健康个体(300-500ng/ml)比较,sVAP-1水平在NAFLD群组(平均值+/-SD;945.9+/-457.6ng/ml)中显著升高。在那些具有显著的肝纤维变性群组(阶段F2-4)中观察到最高水平,并且在sVAP-1水平与纤维变性阶段之间存在明显的线性趋势(图17)。
单变量相关性分析确认了sVAP-1水平与组织学纤维变性阶段之间的显著相关性(r=0.43,p=0.0000003)(表4),并且在用后向消除的多元逻辑回归上,纤维变性阶段是对sVAP-1水平有贡献的最显著的独立因素(表5)。
表4.在单变量分析上与sVAP-1水平显著相关的因素
r值表示Pearson秩相关性。
表5.在用后向消除的多重回归后,与sVAP-1水平独立相关的因素
变量 | β系数 | P值 |
纤维变性阶段 | 0.31 | 0.0005 |
AST/ALT比率 | 0.24 | 0.009 |
ALP | 0.21 | 0.01 |
胆红素 | 0.20 | 0.02 |
脂肪变性等级 | 0.16 | 0.05 |
与显著的肝纤维变性(阶段F2-4)相关的因素的单变量和多变量分析显示,sVAP-1水平比肝损伤的标准生物化学标志物例如肝酶和AST/ALT比率更显著(表6和7)。
表6.在单变量分析上,与显著的纤维变性(F2-4)相关的因素
变量 | 优势比(95%CI) | P值 |
sVAP-1(连续的) | 1.003(1.001-1.004) | 0.00006 |
糖尿病 | 4.607(2.168-9.789) | 0.00007 |
年龄(每岁) | 1.041(1.010-1.072) | 0.008 |
AST/ALT | 6.144(1.525-24.756) | 0.01 |
高血压 | 2.628(1.265-5.458) | 0.01 |
白蛋白 | 0.913(0.836-0.996) | 0.04 |
表7.在用后向消除的多重回归后,与纤维变性独立相关的因素
在群组中,如果将sVAP-1水平用作为独立的生物标志物来预测显著的肝纤维变性(阶段F2-4)的存在,那么≥1000ng/ml的水平具有88.9%的阳性预测值。用于预测显著的纤维变性(F2-4)、晚期的纤维变性(F3-4)和肝硬化(F4)的受者作用特征曲线(AUROC)下面积分别为0.71(95%CI 0.62-0.80)、0.68(95%CI 0.58-0.78)和0.75(95%CI 0.58-0.92)(图18)。
此外,结果表明,通过将其与其他临床和生物化学参数组合,存在改进sVAP-1预测肝纤维变性的敏感性和特异性谱的可能。在多变量分析(sVAP-1、糖尿病状态和AST/ALT比率)上与肝纤维变性独立相关的因素的纤维变性评分(从回归等式中计算),具有0.79(95%CI 0.71-0.87)、0.80(95%CI 0.71-0.88)和0.89(95%CI 0.74-1.02)的预测显著的纤维变性(F2-4)、晚期的纤维变性(F3-4)和肝硬化(F4)的AUROC(图19)。
VAP-1蛋白质具有称为SSAO(氨基脲敏感的胺氧化酶)的单胺氧化酶酶活性。由于SSAO酶活性是VAP-1蛋白质的主要部分,所以还可以通过测量体液(例如血清或血浆)中SSAO活性的量测定体液中sVAP-1的水平。SSAP是在人类血清和血浆中作用于SSAO底物例如苄胺或甲胺的主要单胺氧化酶活性。因此,可以将SSAO活性用作为肝纤维变性的等同标志物。
序列表
<110> 生物结治疗公司,伯明翰大学
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<211> 9
<212> PRT
<213> 人
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> F, Y或R
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> N, G或S
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> S或N
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Y, F, W或S
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> L或R
<400> 26
Gln Gln Xaa Xaa Xaa Xaa Pro Xaa Thr
1 5
<210> 27
<211> 11
<212> PRT
<213> 人
<400> 27
Arg Ala Ser Gln Gly Ile Ser Arg Ala Leu Ala
1 5 10
<210> 28
<211> 11
<212> PRT
<213> 人
<400> 28
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 29
<211> 11
<212> PRT
<213> 人
<400> 29
Arg Ala Ser Gln Gly Ile Ser Arg Ala Leu Ala
1 5 10
<210> 30
<211> 11
<212> PRT
<213> 人
<400> 30
Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
1 5 10
<210> 31
<211> 12
<212> PRT
<213> 人
<400> 31
Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu Ala
1 5 10
<210> 32
<211> 7
<212> PRT
<213> 人
<400> 32
Asp Ala Ser Ser Leu Glu Ser
1 5
<210> 33
<211> 7
<212> PRT
<213> 人
<400> 33
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 34
<211> 7
<212> PRT
<213> 人
<400> 34
Asp Ala Ser Asn Leu Glu Arg
1 5
<210> 35
<211> 7
<212> PRT
<213> 人
<400> 35
Gly Ala Ser Ser Leu Gln Ser
1 5
<210> 36
<211> 7
<212> PRT
<213> 人
<400> 36
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 37
<211> 9
<212> PRT
<213> 人
<400> 37
Gln Gln Phe Asn Ser Tyr Pro Leu Thr
1 5
<210> 38
<211> 9
<212> PRT
<213> 人
<400> 38
Gln Gln Arg Ser Asn Trp Pro Leu Thr
1 5
<210> 39
<211> 9
<212> PRT
<213> 人
<400> 39
Gln Gln Phe Asn Ser Phe Pro Leu Thr
1 5
<210> 40
<211> 9
<212> PRT
<213> 人
<400> 40
Gln Gln Tyr Asn Ser Tyr Pro Arg Thr
1 5
<210> 41
<211> 9
<212> PRT
<213> 人
<400> 41
Gln Gln Tyr Gly Ser Ser Pro Leu Thr
1 5
<210> 42
<211> 107
<212> PRT
<213> 人
<400> 42
Val Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Arg Ala
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Gly Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 43
<211> 107
<212> PRT
<213> 人
<400> 43
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 44
<211> 107
<212> PRT
<213> 人
<400> 44
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Arg Ala
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Arg Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Phe Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 45
<211> 107
<212> PRT
<213> 人
<400> 45
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 46
<211> 108
<212> PRT
<213> 人
<400> 46
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 47
<211> 463
<212> PRT
<213> 人
<400> 47
Met Glu Phe Gly Leu Asn Trp Val Phe Leu Val Ala Leu Leu Arg Asp
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Phe Ser Tyr Ala Met His Trp Val Arg Gln Thr Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Ile Trp Phe Asp Gly Ser Asn Glu Asn Tyr Val
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Asp Ala Trp Ser Tyr Phe Asp Tyr Trp Gly Gln
115 120 125
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
130 135 140
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
145 150 155 160
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
165 170 175
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
180 185 190
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
195 200 205
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
210 215 220
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
225 230 235 240
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Ala Gly Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
275 280 285
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
340 345 350
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
450 455 460
<210> 48
<211> 236
<212> PRT
<213> 人
<400> 48
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys Val Ile Gln Leu Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Ser Arg Ala Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Gly Pro Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Phe Asn Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
Claims (31)
1.作为抗纤维变性剂的VAP-1抑制剂。
2.权利要求1的VAP-1抑制剂,其选自单克隆抗VAP-1抗体和SSAO抑制剂。
3.权利要求2的VAP-1抑制剂,其中所述抗体是包含选自SEQ ID NO 1-3的1-3个CDR共有序列的完全人类抗VAP-1抗体和/或包含选自SEQ ID NO 24-26的1-3个CDR共有序列的轻链多肽。
4.权利要求2的VAP-1抑制剂,其中所述抗体具有包含选自SEQ ID NO 4-8的第一CDR序列、选自SEQ ID NO 9-13的第二CDR序列和选自SEQ ID NO14-18的第三CDR序列的重链多肽和/或包含选自SEQ ID NO 27-31的第一CDR序列、选自SEQ ID NO 32-36的第二CDR序列和选自SEQ ID NO 37-41的第三CDR序列的轻链多肽。
5.根据权利要求4的VAP-1抑制剂,其中所述抗体具有包含选自SEQ ID NO 19-23的氨基酸序列的重链可变区和包含选自SEQ ID NO 42-46的氨基酸序列的各个轻链可变区。
6.权利要求2的VAP-1抑制剂,其中所述抗体是包含SEQ ID NO 47中所述的重链多肽和SEQ ID NO 48中所述的轻链多肽的完全人类重组抗体。
7.权利要求2的VAP-1抑制剂,其中所述SSAO抑制剂选自肼衍生物、丙烯基胺和炔丙基胺、4-取代的-2-丁炔基胺、卤代烯丙基胺、吡咯啉衍生物、炔丙基二胺、烯丙基胺、二胺、4,5,6,7-四氢咪唑并[4,5-c]吡啶衍生物、氨基硫羰基衍生物、羧酰胺、磺酰胺、噻唑和/或胍衍生物、肟衍生物、二肼、芳基烷基胺、唑烷酮、卤代烷基胺、苯磷硫胺和咪唑并吡啶衍生物。
8.VAP-1抑制剂用于生产治疗纤维变性疾病的药物的用途。
9.权利要求8的用途,其中所述VAP-1抑制剂选自抗VAP-1抗体和SSAO抑制剂。
10.权利要求9的用途,其中所述抗体是包含选自SEQ ID NO 1-3的1-3个CDR共有序列的完全人类抗VAP-1抗体和/或包含选自SEQ ID NO 24-26的1-3个CDR共有序列的轻链多肽。
11.权利要求9的用途,其中所述抗体具有包含选自SEQ ID NO 4-8的第一CDR序列、选自SEQ ID NO 9-13的第二CDR序列和选自SEQ ID NO 14-18的第三CDR序列的重链多肽和/或包含选自SEQ ID NO 27-31的第一CDR序列、选自SEQ ID NO 32-36的第二CDR序列和选自SEQ ID NO 37-41的第三CDR序列的轻链多肽。
12.权利要求9的用途,其中所述抗体具有包含选自SEQ ID NO 19-23的氨基酸序列的重链可变区和包含选自SEQ ID NO 42-46的氨基酸序列的各个轻链可变区。
13.权利要求9的用途,其中所述抗体是包含SEQ ID NO 47中所述的重链多肽和SEQ IDNO 48中所述的轻链多肽的完全人类重组抗体。
14.权利要求9的用途,其中所述SSAO抑制剂选自肼衍生物、丙烯基胺和炔丙基胺、4-取代的-2-丁炔基胺、卤代烯丙基胺、吡咯啉衍生物、炔丙基二胺、烯丙基胺、二胺、4,5,6,7-四氢咪唑并[4,5-c]吡啶衍生物、氨基硫羰基衍生物、羧酰胺、磺酰胺、噻唑和/或胍衍生物、肟衍生物、二肼、芳基烷基胺、唑烷酮、卤代烷基胺、苯磷硫胺和咪唑并吡啶衍生物。
15.权利要求9的用途,其中所述纤维变性疾病选自肝纤维变性和诱发其的炎症疾病,即急性和慢性肝炎、胆道疾病和中毒性肝损伤、肺纤维变性、肾纤维变性,包括糖尿病性肾病导致的肾纤维变性,骨髓纤维变性、胰纤维变性、硬皮病、***疾病、瘢痕、皮肤纤维变性、心脏纤维变性、器官移植、血管狭窄、再狭窄、动脉纤维变性、关节纤维变性、***纤维变性、肌肉纤维变性、腹膜后纤维变性、甲状腺纤维变性、***纤维变性、膀胱纤维变性、胸膜纤维变性和COPD,所述COPD是这样的疾病,其中气管壁随肌成纤维细胞和胶原的积累而纤维变性,并且与所有纤维变性组织一样,是收缩的。
16.在需要其的人类受试者中预防、治疗或减轻纤维变性疾病的方法,所述方法包括向所述患者施用有效量的VAP-1抑制剂。
17.权利要求16的方法,其中所述VAP-1抑制剂选自抗VAP-1抗体和SSAO抑制剂。
18.权利要求17的方法,其中所述抗体是包含选自SEQ ID NO 1-3的1-3个CDR共有序列的完全人类抗VAP-1抗体和/或包含选自SEQ ID NO 24-26的1-3个CDR共有序列的轻链多肽。
19.权利要求17的方法,其中所述抗体具有包含选自SEQ ID NO 4-8的第一CDR序列、选自SEQ ID NO 9-13的第二CDR序列和选自SEQ ID NO 14-18的第三CDR序列的重链多肽和/或包含选自SEQ ID NO 27-31的第一CDR序列、选自SEQ ID NO 32-36的第二CDR序列和选自SEQ ID NO 37-41的第三CDR序列的轻链多肽。
20.权利要求17的方法,其中所述抗体具有包含选自SEQ ID NO 19-23的氨基酸序列的重链可变区和包含选自SEQ ID NO 42-46的氨基酸序列的各个轻链可变区。
21.权利要求17的方法,其中所述抗体是包含SEQ ID NO 47中所述的重链多肽和SEQID NO 48中所述的轻链多肽的完全人类重组抗体。
22.权利要求17的方法,其中所述SSAO抑制剂选自肼衍生物、丙烯基胺和炔丙基胺、4-取代的-2-丁炔基胺、卤代烯丙基胺、吡咯啉衍生物、炔丙基二胺、烯丙基胺、二胺、4,5,6,7-四氢咪唑并[4,5-c]吡啶衍生物、氨基硫羰基衍生物、羧酰胺、磺酰胺、噻唑和/或胍衍生物、肟衍生物、二肼、芳基烷基胺、唑烷酮、卤代烷基胺、苯磷硫胺和咪唑并吡啶衍生物。
23.权利要求16的方法,其中所述纤维变性疾病选自肝纤维变性和诱发其的炎症疾病,即急性和慢性肝炎、胆道疾病和中毒性肝损伤、肺纤维变性、肾纤维变性,包括糖尿病性肾病导致的肾纤维变性,骨髓纤维变性、胰纤维变性、硬皮病、***疾病、瘢痕、皮肤纤维变性、心脏纤维变性、器官移植、血管狭窄、再狭窄、动脉纤维变性、关节纤维变性、***纤维变性、肌肉纤维变性、腹膜后纤维变性、甲状腺纤维变性、***纤维变性、膀胱纤维变性、胸膜纤维变性和COPD,所述COPD是这样的疾病,其中气管壁随肌成纤维细胞和胶原的积累而纤维变性,并且与所有纤维变性组织一样,是收缩的。
24.诊断受试者中纤维变性疾病的方法,所述方法包括:
a)提供来自所述受试者的体液的样品,
b)测定所述样品中可溶性VAP-1(sVAP-1)的量或SSAO活性,
c)基于所述sVAP-1的量或SSAO活性诊断纤维变性。
25.权利要求24的方法,其中将所述sVAP-1的量或SSAO活性与参照体液中sVAP-1的量或SSAO活性比较。
26.权利要求24的方法,其中所述sVAP-1的量使用VAP-1特异性抗体测定。
27.权利要求24所述的方法,其中所述体液是血清或血浆。
28.权利要求24的方法,其中所述纤维变性疾病选自肝纤维变性和诱发其的炎症疾病,即急性和慢性肝炎、胆道疾病和中毒性肝损伤、肺纤维变性、肾纤维变性,包括糖尿病性肾病导致的肾纤维变性,骨髓纤维变性、胰纤维变性、硬皮病、***疾病、瘢痕、皮肤纤维变性、心脏纤维变性、器官移植、血管狭窄、再狭窄、动脉纤维变性、关节纤维变性、***纤维变性、肌肉纤维变性、腹膜后纤维变性、甲状腺纤维变性、***纤维变性、膀胱纤维变性、胸膜纤维变性和COPD,所述COPD是这样的疾病,其中气管壁随肌成纤维细胞和胶原的积累而纤维变性,并且与所有纤维变性组织一样,是收缩的。
29.权利要求24的方法,其中所述诊断包括测定纤维变性的程度。
30.用于权利要求24的方法的试剂盒,其包含用于评估体液中sVAP-1的量或SSAO活性的一种或多种试剂。
31.权利要求30的试剂盒,其用于评估sVAP-1的量,包含特异性抗VAP-1抗体。
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UA112154C2 (uk) * | 2009-09-08 | 2016-08-10 | Біоті Терапіс Корп. | Застосування повністю людського анти-vap-1-антитіла для лікування фіброзних станів |
JP5953035B2 (ja) * | 2011-11-28 | 2016-07-13 | 学校法人慶應義塾 | 病理診断支援装置、病理診断支援方法、及び病理診断支援プログラム |
PT2844637T (pt) | 2012-05-02 | 2018-04-17 | Boehringer Ingelheim Int | Inibidores de 3-haloalilamina substituídos de ssao e as suas utilizações |
WO2014024820A1 (ja) * | 2012-08-06 | 2014-02-13 | 塩野義製薬株式会社 | 新規慢性腎臓病治療用医薬組成物及び新規慢性腎臓病治療薬のスクリーニング方法 |
KR102205845B1 (ko) | 2013-10-28 | 2021-01-22 | 삼성전자주식회사 | 입자에 기반한 모델링 방법 및 장치 |
WO2015189534A1 (en) * | 2014-06-12 | 2015-12-17 | Proximagen Limited | Vap-1 inhibitors for treating muscular dystrophy |
JP2018080114A (ja) * | 2015-05-29 | 2018-05-24 | 株式会社アールテック・ウエノ | 抗ヒトvap−1モノクローナル抗体 |
EP3645039A4 (en) * | 2017-06-27 | 2021-05-05 | Neuracle Science Co., Ltd | USE OF ANTI-FAM19A5 ANTIBODIES TO TREAT FIBROSIS |
WO2023164548A1 (en) * | 2022-02-23 | 2023-08-31 | Yale University | Il-6 inhibitor as treatment for nephropathy |
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