CN106455579A - 用于治疗和预防耳鸣的方法和组合物 - Google Patents
用于治疗和预防耳鸣的方法和组合物 Download PDFInfo
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- CN106455579A CN106455579A CN201580024649.XA CN201580024649A CN106455579A CN 106455579 A CN106455579 A CN 106455579A CN 201580024649 A CN201580024649 A CN 201580024649A CN 106455579 A CN106455579 A CN 106455579A
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Abstract
本发明涉及用于治疗内耳病症的药物组合物和方法。具体地说,本发明提供一种通过施用包含c‑Jun N‑末端激酶的肽抑制剂的药物组合物来治疗和/或预防有需要的受试者中的急性内耳耳鸣的方法。
Description
相关申请的交叉引用
本申请要求于2014年4月23日提交的美国临时专利申请序列号61/983,394的优先权和权益,所述专利的公开内容出于所有目的以引用的方式整体并入本文。
发明领域
本发明涉及耳科学和神经耳科学的领域。具体地说,本发明涉及用于改善、治疗和/或预防内耳病症(如急性内耳耳鸣)的药物组合物和方法。所述药物组合物可包含c-JunN-末端激酶(JNK)的肽抑制剂。
发明背景
耳鸣是在没有外部声学刺激下对声音的感知,这是一种非常常见的病症。根据一些最近的估计,大约25%的美国成年人经历过耳鸣,其中有近8%经常发生(Shargorodsky等,2010)。欧洲人口研究估计,7%-14%的人群曾向他们的医生谈及耳鸣,而潜在的致残耳鸣则出现在1%-2.4%的人群中(Vesterager,1997)。耳鸣可能严重影响睡眠或放松的能力,或导致疲劳、刺激、紧张、绝望、挫败或抑郁(Chan,2009;Stouffer等,1990)。
许多耳鸣患者准备尝试各种各样的治疗以寻找有效的缓解(Tyler,2012)。虽然诸如耳鸣再训练疗法(Jastreboff,2007)或认知行为疗法(Cima等,2012)的手段可以为某些患者提供缓解,但是没有针对耳鸣护理的通用标准或审批过的耳鸣药物(Langguth等,2012),从而引起患者和医生的相当大的失望(Hall等,2011)。因此,本领域中需要可以有效改善或预防与各种病状相关的耳鸣的发展的另外的治疗剂。
发明概要
本发明提供了一种改善或减少有需要的受试者中由耳蜗损伤诱发的耳鸣(例如急性内耳耳鸣)的发生的方法。在一个实施方案中,所述方法包括向受试者施用包含治疗有效量的JNK的肽抑制剂或其药学上可接受的盐的药物组合物。待改善、治疗、抑制和/或预防的耳鸣可以是急性、亚急性或慢性的。在具体实施方案中,受试者是人。
在一些实施方案中,待改善、治疗、抑制和/或预防的耳鸣是由选自以下各项的耳蜗损伤所诱发:急性听觉创伤、老年性耳聋、缺血、缺氧、气压伤、中耳炎、暴露于耳毒性药物、传导性听力损失或突发性耳聋。在一个实施方案中,耳鸣与听力损失有关。在某些实施方案中,听力损失可能是重度或极重度听力损失(例如,发病48小时内的听力损失为至少60dB)。在一些实施方案中,在可能诱发耳蜗损伤的事件时或之后不久,向受试者施用JNK肽抑制剂。例如,在一个实施方案中,在诱发耳蜗损伤的事件后的几天至一周内向受试者施用JNK肽抑制剂。
用于本发明药物组合物和方法中的JNK肽抑制剂通常是长度不超过50个氨基酸的肽,并且包含对应于来自c-Jun蛋白或JNK相互作用蛋白(JIP)(例如JIP-1(也称为胰岛-脑蛋白1)、JIP-2(也称为胰岛-脑蛋白2)和JIP-3)的JNK结合结构域的氨基酸序列。例如,在一些实施方案中,JNK肽抑制剂包含与SEQ ID NO:1-4和13-45的序列具有实质性序列同源性的氨基酸序列。在某些实施方案中,JNK肽抑制剂中的所有手性氨基酸均呈D构型。在其他实施方案中,JNK肽抑制剂中的所有手性氨基酸均呈L构型。在一个实施方案中,JNK肽抑制剂包含或由SEQ ID NO:2或SEQ ID NO:3的序列组成。在另一个实施方案中,JNK肽抑制剂包含或由SEQ ID NO:14或SEQ ID NO:16的序列组成。在仍另一个实施方案中,JNK肽抑制剂包含或由SEQ ID NO:18或SEQ ID NO:20的序列组成。
包含JNK肽抑制剂的药物组合物可被配制为凝胶。在一些此类实施方案中,药物组合物包含透明质酸。药物组合物可局部地施用于受试者,例如,通过圆窗膜或卵圆窗膜施用至内耳。在某些实施方案中,将包含JNK肽抑制剂的药物组合物递送至中耳。在其他实施方案中,通过鼓室内注射向受试者施用包含JNK肽抑制剂的药物组合物。
具体实施方案
本发明部分地基于这样的发现:耳蜗细胞中的c-Jun N-末端激酶(JNK)的抑制降低耳鸣的响度,并且造成耳鸣完全缓解的更频繁发生,特别是在患有严重听力损失的患者中。
JNK是参与细胞外应激损伤和炎症后细胞凋亡的有丝分裂原活化蛋白激酶的应激活化组的成员(Manning,2003)。其抑制阻止转录复合体的形成以及沿编码炎症分子的基因的凋亡途径或活化的进一步进展。JNK信号传导途径已牵涉于创伤性损伤或耳蜗炎症后耳蜗中的损伤细胞(例如毛细胞和螺旋神经节神经元)的凋亡(Zine等,2004;Abi-Hachem等,2010;Hu等,2002;Ma等,2000;Barkdull等,2007)。据报道JNK的抑制在耳蜗损伤的各种模型中是耳保护性的,并且防止听力损失(Wang等,2003;Wang等2007;和Coleman等2007;Grindal等,2010;以及Eshraghi等,2011)。然而,JNK信号级联在耳鸣的发展中的作用还不太清楚。
本发明人已惊奇地发现,用肽抑制剂来抑制JNK可以降低由耳蜗损伤(包括与急性听觉创伤或特发性突发感音神经性听力损失相关的耳鸣)诱发的耳鸣的严重性和发生。不受理论的束缚,认为用本文所述的肽抑制剂来抑制JNK保护了耳蜗感觉细胞(例如,内毛细胞或螺旋神经节神经元)的形态,从而防止它们产生导致耳鸣感觉的听觉神经纤维的异常兴奋。与被设计成减少或防止谷氨酸受体的异常活性或在受损感觉细胞触发的异常活性(例如,谷氨酸兴奋性毒性)后恢复兴奋性-抑制性平衡的试剂不同,JNK肽抑制剂首先保护感觉细胞免受永久损伤,以使得它们不触发这种异常活动。因此,本发明提供了一种改善或减少有需要的人中由耳蜗损伤诱发的急性内耳耳鸣的发生的方法。在一个实施方案中,所述方法包括向人施用包含治疗有效量的JNK的肽抑制剂或其药学上可接受的盐的药物组合物。
如本文所用,“改善耳鸣”是指在施用本发明的药物组合物之后患者所经历的耳鸣的一个或多个方面的改善。例如,如果耳鸣的响度、耳鸣的频率和/或患者感觉到的耳鸣的持续时间减少或者耳鸣完全消失,则患者的耳鸣将被认为是改善的。评估患者中耳鸣的严重性和存在的方法是本领域技术人员已知的,并且可以包括但不限于经过验证的心理调查问卷,如耳鸣致残量表(Tinnitus Handicap Inventory)、耳鸣反应问卷以及耳鸣功能指数。参见,例如Figueiredo等,2009;Kamalski等,2010;以及Meikle等,2011,其各自以引用的方式整体并入本文。
在一些实施方案中,待改善、治疗和/或预防的耳鸣是由耳蜗损伤诱发的。耳蜗损伤可能导致耳蜗中细胞,包括外毛细胞、内毛细胞和螺旋神经节神经元的损伤或改变其活性。耳蜗损伤可由以下造成:急性听觉创伤、老年性耳聋、缺血、缺氧、气压伤、中耳炎、暴露于耳毒性药物、传导性听力损失或突发性耳聋。待使用本发明方法改善、治疗和/或预防的耳鸣可以是急性、亚急性或慢性的。
如本文所用,术语“耳毒性药物”是指特征为对第八神经或对听力和平衡器官具有有害作用的任何化合物。可以产生耳鸣作为副作用的此类耳毒性药物包括但不限于:氨基糖苷类抗生素、抗炎药、镇静剂、抗抑郁药、奎宁药物以及化疗剂(例如顺铂)。
在某些实施方案中,待改善、治疗和/或预防的耳鸣与听力损失有关。因此,在一些实施方案中,施用了本发明的药物组合物的受试者患有或被诊断患有听力损失。在一个实施方案中,听力损失是急性感音神经性听力损失。在另一个实施方案中,急性感音神经性听力损失是由急性听觉创伤诱发的。在仍另一个实施方案中,听力损失是特发性突发感音神经性听力损失。在具体实施方案中,施用了本发明的药物组合物的受试者已经或被诊断患有重度或极重度听力损失。如本文所用,重度或极重度听力损失”是指在通过本领域已知的标准技术所测量在发病48小时内听力损失为至少60dB。在实施例1中描述了用于评估受试者中听力损失的严重程度的一种示例性方法。在一些实施方案中,患有严重或极重度听力损失的受试者在发病48小时内已被或被诊断为具有至少60dB的听力损失。本发明人已发现,本文所述的药物组合物特别适用于改善或减少在发病48小时内具有至少60dB的听力损失的受试者中耳鸣的发生。在其他实施方案中,施用了本发明的药物组合物的受试者已被或被诊断为患有中度急性听力损失。如本文所用,“中度听力损失”是指在发作48小时后持续的至少40dB的急性听力损失。
在本发明方法的一些实施方案中,在引起耳鸣发生的耳蜗损伤后四周内向受试者施用包含JNK的肽抑制剂的药物组合物。在其他实施方案中,在诱发耳鸣的耳蜗损伤后两周内向受试者施用药物组合物。在仍然其他实施方案中,在诱发耳鸣的耳蜗损伤后一周内向受试者施用药物组合物。在某些优选实施方案中,在耳蜗损伤后三至五天内向受试者施用药物组合物。例如,在一个具体实施方案中,在耳蜗损伤后约三天向受试者施用药物组合物。在某些其他实施方案中,在诱发耳鸣的耳蜗损伤后两天内向受试者施用药物组合物。
在其他实施方案中,本发明的药物组合物作为预防手段施用于受试者以减少耳鸣的发展。例如,在一个实施方案中,在受试者暴露于潜在的耳蜗损伤之前或期间,向受试者施用药物组合物。举例来说,可以在暴露于耳毒性药物或过度强烈的噪声之前向受试者施用本发明的药物组合物。
在某些实施方案中,在本发明的药物组合物和方法中使用的JNK的肽抑制剂包含来源于胰岛-脑1蛋白或胰岛-脑2蛋白(分别被称为JNK相互作用蛋白(JIP)1和2)的JNK结合结构域的氨基酸序列。参见Bonny等,2001,该文献以引用的方式整体并入本文。已显示JIP蛋白家族在JNK信号级联中起到支架蛋白的作用。参见Weston和D avis,Science 292:2439-2440,2001。例如,在此类实施方案中,JN K肽抑制剂包含或由与DQSRPVQPFLNLTTPRKPR(SEQ ID NO:1)、RPKRPTTLNLFPQVPRSQD(SEQ ID NO:4)、DTYRPKRPTTLNLFPQVPRSQDT(SEQ ID NO:13)、TDQSRPVQPFLNLTTPRKPR YTD(SEQ ID NO:15)、HKHRPTTLRLTTLGAQDS(SEQ ID NO:17)、SDQAGLTTLRLTTPRHKH(SEQ ID NO:19)、RPKRPTTLNLF(SEQ ID NO:21)或FLNLTTPRKPR(SEQ ID NO:23)的序列具有实质性序列同源性的氨基酸序列组成。在其他实施方案中,JNK肽抑制剂包含或由与RPKRPKTLNLF(SEQ ID NO:25)、FLNLTKPR KPR(SEQ ID NO:27)、RPKRPTFLNLF(SEQ ID NO:29)、FLNL FTPRKPR(SEQ ID NO:31)、RPKRPTSLNLF(SEQ ID NO:33)、FLNLSTPRKPR(SEQ ID NO:35)、RPKRPTTLNLD(SEQ IDNO:37)、DLNLTTPRKPR(SEQ ID NO:39)、PKRPTTLNLF(SEQ ID NO:41)或FLNLTTPRKP(SEQ IDNO:43)的序列具有实质性序列同源性的氨基酸序列组成。在一些实施方案中,JNK肽抑制剂包含来源于(JNK)相互作用蛋白-3(JIP3)(Genbank登记号NP_055948.2)的J NK结合结构域的氨基酸序列。在某些实施方案中,JNK肽抑制剂包含或由选自SEQ ID NO:1、4、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41及43的序列组成。
JNK抑制剂肽还可来源于c-Jun蛋白。例如,包含对应于氨基酸33-79的c-Jun上的JNK结合区的合成肽在美国专利号6,514,745中描述为天然存在的c-Jun的竞争性抑制剂,以便通过JNK减少c-Jun活化的量。通过γ-氨基丁酸(GABA)间隔基(例如,Ac-YGRKKRRQRRR-gaba-ILKQSMTLNLADPVGSLKPHLRAKN-N H2(SEQ ID NO:45))融合的人c-Junδ结构域(氨基酸33-57)序列和HIV-TAT蛋白转导结构域(氨基酸47-57)组成的细胞可渗透的37聚体肽显示在体外和完整细胞中特异性地破坏c-Jun/JNK复合体形成,以及通过JNK的c-Jun的后续磷酸化和活化。参见Holzberg等,J Biol Chem.278(41):40213-23,2003。因此,在一个实施方案中,在本发明的药物组合物和方法中使用的JNK抑制剂包含或由SEQ ID NO:45组成。
在一些实施方案中,JNK抑制剂肽结合至JNK。在其他实施方案中,JNK肽抑制剂抑制JNK信号级联的一个或多个组分的活化,如转录因子(例如c-Jun、ATF-2、ELK-1或p53)的活化。可用于本发明的药物组合物和方法中的其他合适的JNK肽抑制剂是描述于美国专利号6,410,693;6,610,820;8,236,924;8,080,517;以及8,183,339中的那些,所述专利各自以引用的方式整体并入本文。
包含本文所述的氨基酸序列的JNK肽抑制剂可以是约15、约20、约25、约30、约35、约40、约45、约50或更多个氨基酸。在一些实施方案中,JNK肽抑制剂包含不多于50个氨基酸。在其他实施方案中,JNK肽抑制剂包含不多于35个氨基酸。在某些实施方案中,JNK肽抑制剂包含约20个氨基酸至约50个氨基酸或者约25个氨基酸至约40个氨基酸。
JNK抑制剂肽可以是L-氨基酸、D-氨基酸或两者的组合的聚合物。例如,在一些实施方案中,这些肽为D逆向-反转肽。术语“逆向-反转异构体”是指线性肽的异构体,其中序列的方向是反向的,术语“D-逆向-反转异构体”是指线性肽的异构体,其中序列的方向是反向的并且每个氨基酸残基的手性是反转的。参见,例如,Jameson等,Nature,368,744-746(1994);Brady等,Nature,368,692-693(1994)。组合D-对映体和反向合成的净结果是,交换每个酰胺键中的羰基和氨基的位置,同时保留每个α碳上的侧链基团的位置。除非另外特别说明,假定本发明的任何给定的L-氨基酸序列可以通过合成相应的天然L-氨基酸序列的反向序列而制成D逆向-反转肽。
在一些实施方案中,JNK肽抑制剂包含氨基酸序列,其中所有手性氨基酸均呈D构型。在其他实施方案中,JNK肽抑制剂包含氨基酸序列,其中所有手性氨基酸均呈L构型。除甘氨酸之外的所有氨基酸均可以两种异构体形式存在,因为在中心碳原子周围形成两种不同的对映体的可能性。因此,“手性氨基酸”是指具有附接至中心碳原子的四个不同取代基的氨基酸。
可以用于本发明的药物组合物和方法中的JNK肽抑制剂还包括本文所述的JNK抑制剂肽的衍生物、片段、同系物、类似物以及保守变体。如本文所用,保守变体是指氨基酸序列中不会不利地影响肽的生物学功能的改变。当改变的序列防止或破坏与肽相关的生物学功能时,取代、插入或缺失被认为对肽有不利影响。例如,可以改变肽的总电荷、结构或疏水/亲水特性,而不会不利地影响生物活性。因此,氨基酸序列可以被改变,例如以使得肽更疏水或亲水,而不会不利地影响肽的生物活性。
保守取代通常包括以下组内的取代:甘氨酸和丙氨酸;缬氨酸、异亮氨酸和亮氨酸;天冬氨酸和谷氨酸;天冬酰胺和谷氨酰胺;丝氨酸和苏氨酸;赖氨酸和精氨酸;以及苯丙氨酸和酪氨酸。因此,包括在本发明中的是具有突变序列的肽,使得它们例如在序列上和功能上与具有相应亲本序列的蛋白质保持同源。此类突变可以是例如涉及保守氨基酸变化的突变,例如,具有广泛相似分子特性的氨基酸之间的变化。例如,脂族基丙氨酸、缬氨酸、亮氨酸以及异亮氨酸中的交换可以被认为是保守的。在一些实施方案中,用甘氨酸取代这些中的一种也可以被认为是保守的。其他保守交换包括脂族基天冬氨酸和谷氨酸中;酰胺基天冬酰胺和谷氨酰胺中;羟基丝氨酸和苏氨酸中;芳族基苯丙氨酸、酪氨酸和色氨酸中;碱性基团赖氨酸、精氨酸和组氨酸中;以及含硫基团甲硫氨酸和半胱氨酸中的那些。在一些实施方案中,在甲硫氨酸和亮氨酸组中的取代也可以被认为是保守的。优选的保守取代基是天冬氨酸-谷氨酸;天冬酰胺-谷氨酰胺;缬氨酸-亮氨酸-异亮氨酸;丙氨酸-缬氨酸;苯丙氨酸-酪氨酸;以及赖氨酸-精氨酸。
本文所述的肽抑制剂的衍生物、片段和类似物被定义为至少4个连续氨基酸的序列,其长度足以允许表位的特异性识别。片段的长度小于JNK抑制剂肽所来源的相应全长多肽的长度。如果衍生物或类似物含有修饰的核酸或氨基酸,那么所述衍生物和类似物可以是全长的或不是全长的。在一些实施方案中,JNK抑制剂肽的衍生物或类似物包括,例如包括在相同大小的氨基酸序列上或当与比对序列比较时(其中通过本领域已知的计算机同源性程序完成比对)与这些肽至少约30%、50%、70%、80%,或95%、98%或甚至99%实质上同源的区域的分子。例如,可使用序列分析软件(Sequence Analysis Software Packageof the Genetics Computer Group,University of Wisconsin Biotechnology Center,1710University Avenue,Madison,Wis.53705)(其中参数是默认的)来测量序列同一性。在一个实施方案中,JNK肽抑制剂包含与SEQ ID NO:1至4和13-45中任一个至少80%同一的序列。在另一个实施方案中,JNK肽抑制剂包含与SEQ ID NO:1至4和13-45中任一个至少90%同一的序列。在仍另一个实施方案中,JNK肽抑制剂包含与SEQ ID NO:1至4和13-45中任一个至少95%同一的序列。
当具体的多肽被称为与具有确定长度的参考多肽有特定百分比同一性时,该同一性百分比是相对于参考肽。因此,举例来说,与100个氨基酸长度的参考多肽50%同一的肽可以是与参考多肽的50个氨基酸长的部分完全同一的50个氨基酸的多肽。它也可能是100个氨基酸长的多肽,其在它的整个长度上与参考多肽50%同一。当然,其他多肽将满足相同的标准。
JNK肽抑制剂的另一种变型是将1至15个氨基酸或氨基酸类似物连接至本文所述的JNK肽抑制剂的N-末端或C-末端氨基酸。JNK肽抑制剂的类似物可以通过向活性肽抑制剂的N-末端、C-末端或N-末端和C-末端两者添加1至15个另外的氨基酸来制备,其中此类氨基酸添加不会不利地影响肽结合JNK的能力。
JNK抑制剂肽通过本领域熟知的方法获得或产生,例如化学合成或遗传工程方法。例如,可使用肽合成仪来合成包括所需区或结构域的JNK肽抑制剂。可选地,可通过将编码JNK肽抑制剂的载体插入适合的宿主细胞中并在促进表达的条件下培养宿主细胞,通过重组表达来合成JNK肽抑制剂。合适的宿主细胞包括但不限于哺乳动物细胞、昆虫细胞、酵母细胞以及细菌细胞。JNK肽抑制剂还可使用本领域已知的无细胞翻译系统来合成。
在某些实施方案中,JNK肽抑制剂是包含与蛋白质转导结构域(PTD)融合的JNK结合结构域的嵌合肽。PTD在大小上是异质的并且缺乏序列同源性,尽管大多数具有正电荷并且是两亲性的。在某些实施方案中,PTD可以是抗微生物肽,如protegrin 1、Bactenecin 7、Buforin以及Maginin;富含精氨酸的RNA和DNA结合肽的宿主(例如,HIV-1反式激活蛋白(TAT)和果蝇同源结构域转录因子触角足(也称为Penetratin);嵌合PTD,如Transportan;来源于噬菌体展示文库的富含赖氨酸和精氨酸的肽;聚精氨酸;以及最近的β-高赖氨酸低聚物。参见Fisher等,2001;Lindsay,2002;Tung等,2002;Bogoyevitch等,2002;以及Garcia-Echeverria等,2003,所述文献各自以引用的方式整体并入本文。在某些实施方案中,PTD是本文所述的任何PTD的反向、逆向-反转和对映体形式。可融合至JNK结合结构域的示例性PTD包括来源于HIV TAT蛋白(例如GRKKRRQRRRPP(SEQ ID NO:5)或PPRRRQRRKKRG(SEQ ID NO:6))、触角蛋白(例如RQIKIWFQNRRMKWKK(SEQ ID NO:7)或RRMKWKK(SEQ ID NO:8))、SynB1(例如RGGRLSYSRRRFSTSTGR(SEQ ID NO:9))、SynB3(RRLSYSRRRF(SEQ ID NO:10))、SynB5(RGGRLAYLRRRWAVLGR(SEQ ID NO:11))或聚精氨酸(RRRRRRRR(SEQ ID NO:12))的PTD。PTD序列可以融合至JNK结合结构域肽的N-末端或C-末端。可在PTD序列与JNK结合结构域序列之间插入1至10个氨基酸的接头。在一些实施方案中,使用具有两个脯氨酸残基的接头。
在具体实施方案中,融合至JNK结合结构域的PTD来源于TAT蛋白。在此类实施方案中,嵌合肽可包含或由以下序列组成:
DQSRPVQPFLNLTTPRKPRPPRRRQRRKKRG(SEQ ID NO:2);
GRKKRRQRRRPPRPKRPTTLNLFPQVPRSQD(SEQ ID NO:3);
GRKKRRQRRRPPDTYRPKRPTTLNLFPQVPRSQDT(SEQ ID NO:14);
TDQSRPVQPFLNLTTPRKPRYTDPPRRRQRRKKRG(SEQ ID NO:16);
GRKKRRQRRRPPHKHRPTTLRLTTLGAQDS(SEQ ID NO:18);
SDQAGLTTLRLTTPRHKHPPRRRQRRKKRG(SEQ ID NO:20);
GRKKRRQRRRPPRPKRPTTLNLF(SEQ ID NO:22);
FLNLTTPRKPRPPRRRQRRKKRG(SEQ ID NO:24);
GRKKRRQRRRPPRPKRPKTLNLF(SEQ ID NO:26);
FLNLTKPRKPRPPRRRQRRKKRG(SEQ ID NO:28);
GRKKRRQRRRPPRPKRPTFLNLF(SEQ ID NO:30);
FLNLFTPRKPRPPRRRQRRKKRG(SEQ ID NO:32);
GRKKRRQRRRPPRPKRPTSLNLF(SEQ ID NO:34);
FLNLSTPRKPRPPRRRQRRKKRG(SEQ ID NO:36);
GRKKRRQRRRPPRPKRPTTLNLD(SEQ ID NO:38);
DLNLTTPRKPRPPRRRQRRKKRG(SEQ ID NO:40);
GRKKRRQRRRPPPKRPTTLNLF(SEQ ID NO:42);或
FLNLTTPRKPPPRRRQRRKKRG(SEQ ID NO:44)。
在本发明方法中采用的药物组合物包含治疗有效量的JNK肽抑制剂或其药学上可接受的盐以及药学上可接受的载体或赋形剂。包含在本发明药物组合物中的JNK肽抑制剂可以是游离形式或盐的形式,其中所述盐是药学上可接受的。这种药学上可接受的盐的实例包括但不限于与有机酸(例如乙酸、乳酸、柠檬酸、苹果酸、反丁烯二酸、酒石酸、硬脂酸、抗坏血酸、琥珀酸、苯甲酸、甲磺酸、甲苯磺酸或双羟萘酸)、无机酸(例如,盐酸、硝酸、焦磷酸、硫酸或磷酸)以及聚合酸(例如,单宁酸、羧甲基纤维素、聚乳酸、聚乙醇酸或聚乳酸-乙醇酸的共聚物)形成的那些盐。在一个具体实施方案中,JNK肽抑制剂作为乙酸盐存在于药物组合物中。
用于本发明的任何施用途径的药物组合物含有治疗有效量的JNK肽抑制剂、以及(必要时)无机或有机、固体或液体药学上可接受的载体或赋形剂。适于向内耳局部施用的药物组合物包括水溶液或悬浮液,例如在单独或与载体一起含有活性成分的冻干制剂的情况下,可在使用前制备。它们还包括凝胶,其可以是生物可降解的或生物不可降解的,水性或非水性的,或基于微球的。形成凝胶的生物相容性聚合物的实例包括但不限于透明质酸、透明质酸盐、卵磷脂凝胶、(聚)丙氨酸衍生物、普朗尼克(pluronics)、聚(乙二醇)、泊洛沙姆、壳聚糖、木葡聚糖、胶原、纤维蛋白、聚酯、聚(丙交酯)、聚(乙交酯)或它们的共聚物PLGA、乙酸异丁酸蔗糖酯以及单油酸甘油酯。优选的是凝胶,其可易于施用至中耳中,在延长的时间内释放肽抑制剂并且允许高百分比的肽抑制剂递送至内耳中。
优选地用作本发明药物组合物中的生物相容性聚合物的透明质酸是广泛分布在身体所有器官的结缔组织的细胞外基质中的生理物质。它以不同的分子量存在,并且据报道是非抗原性的。此外,它具有优异的生物相容性并且还是可生物降解的。透明质酸是天然存在的多糖,即一种由包含糖醛酸钠-N-乙酰葡糖胺的重复二糖单元的长链聚合物构成的糖胺聚糖。透明质酸的主要特性是它结合水,且因此形成高粘度的可降解凝胶。透明质酸溶液的粘度随着浓度和分子量而增加。JNK肽抑制剂可溶解或悬浮在透明质酸凝胶中。在一些实施方案中,药物组合物包含约0.5%至约1%的透明质酸。在其他实施方案中,药物组合物包含约0.7%至约0.9%的透明质酸。
药物组合物可被灭菌和/或可含有佐剂,例如防腐剂、稳定剂、润湿剂和/或乳化剂、用于调节渗透压的盐和/或缓冲剂。在一些实施方案中,药物组合物包含将组合物的pH缓冲为约6.0至约7.4的缓冲剂。在某些实施方案中,药物组合物包含磷酸盐缓冲剂。在相关实施方案中,磷酸盐缓冲剂将组合物的pH缓冲至约6.2。
如果需要,本发明的药物组合物可含有其他药理活性物质或其他组分,如抗生素(例如氟喹诺酮类)、抗炎剂(例如类固醇)、可的松、止痛剂、安替比林、苯佐卡因、普鲁卡因等。药物组合物可以通过药学领域熟知的任何方法制备,例如通过常规混合、制粒、成型、溶解或冻干方法制备,并且含有约0.01%至100%,优选约0.1%至50%(冻干物高达100%)的活性成分。
包含JNK肽抑制剂的药物组合物可以口服、静脉内、皮下、腹膜内、肌内、直肠或局部施用于受试者。在某些实施方案中,局部施用至内耳是优选的,因为全身施用的治疗有效剂量可能诱导不希望的副作用。在本发明中施用的唯一要求在于治疗有效量的包含JNK肽抑制剂的药物组合物能够到达患病个体的耳蜗细胞。
可通过各种递送技术来完成药物组合物向内耳的施用。此类技术包括使用装置或药物载体以有靶向方式将JNK肽抑制剂运输和/或递送至圆窗或卵圆窗的膜,在此它扩散至内耳中或主动输注。实例是otowicks(参见,例如Silverstein的美国专利号6,120,484,其通过引用并入本文)、圆窗导管(参见,例如美国专利号5,421,818;5,474,529;5,476,446;6,045,528;全部授予Arenberg,或Lenarz的美国专利号6,377,849和美国专利公开号2002/0082554,这些专利均以引用方式并入本文)、微植入物(参见,例如Jukarainen等的WO2004/064912)或各种类型的凝胶、泡沫体、纤维蛋白或其他药物载体,将其放置在圆窗龛或卵圆窗中,并且装载有化合物以供持续释放(参见,例如Manning的WO 97/38698;Silverstein等,Otolaryngology--Head and Neck Surgery 120(5):649-655(1999);Balough等,Otolaryngology--Head and Neck Surgery 119(5):427-431(1998),所述文献各自以引用的方式整体并入本文。其他合适的递送技术包括使用插入耳蜗管或耳蜗的任何其他部位中的装置(参见,例如Kuzma的美国专利号6,309,410,其通过引用并入本文)。包含JNK肽抑制剂的药物组合物也可以通过鼓室内注射施用于内耳,其中组合物被注射至目标内中耳界面组织结构区域上的中耳,如圆窗龛内(参见,例如Light J.和Silverstein H.,CurrentOpinion in Otolaryngology&Head and Neck Surgery 12:378-383(2004))。注射可直接通过鼓膜,通过插入鼓膜中的通气管或通过鼓膜的开口(例如通过鼓膜瓣)进行。待注射的制剂的体积通常在约200与约500微升之间。在具体实施方案中,向内耳施用的方法是通过穿过圆窗膜的扩散,其相对容易从中耳空间进入,并允许内耳保持完整,由此避免了耳蜗内液渗漏的任何潜在问题。因此,在一些实施方案中,药物组合物被递送至中耳。
不能通过任何上述装置注射或输注的药物组合物可借助于外科器械穿过鼓膜中的小开口沉积至目标内中耳界面结构上。
可在如本文所述由耳蜗损伤诱发耳鸣之前、期间或之后施用药物组合物。待施用的量可根据施用方法、治疗持续时间、待治疗的受试者的状况、耳鸣的严重性、使用的具体JNK肽抑制剂而变化,并最终将由主治医师决定。治疗的持续时间可在约1小时至数天、数周或数月之间,并且可延长至长期治疗。在长期治疗的情况下,可能必须施用重复剂量的药物组合物。
将治疗有效量或剂量定义为在受治疗个体中有效抑制或减轻耳鸣的量或剂量。治疗有效量或剂量也是有效抑制或减轻患病个体的耳鸣的量。在一个实施方案中,JNK肽抑制剂的治疗有效量或剂量是在施用组合物后有效减轻患病个体对耳鸣的感觉的量或剂量。在另一个实施方案中,JNK肽抑制剂的治疗有效量或剂量是在施用组合物后有效降低耳鸣响度的量或剂量。在另一个实施方案中,JNK肽抑制剂的治疗有效量或剂量是在施用组合物后有效降低耳鸣发作频率的量或剂量。在仍另一个实施方案中,JNK肽抑制剂的治疗有效量或剂量是在施用组合物后有效缩短耳鸣发作持续时间的量或剂量。
如上所述,治疗有效量或剂量可根据特定JNK肽抑制剂的选择、待治疗耳鸣的严重性及其施用方法而变化。例如,较低剂量的对JNK具有较高结合亲和力的JNK肽抑制剂可能比以较低亲和力结合的JNK肽抑制剂更有效。另外,与局部施用于耳朵的圆窗膜或卵圆窗的相同药物组合物相比,将需要更高剂量的静脉内施用的JNK肽抑制剂。待递送的JNK肽抑制剂的治疗有效量或剂量可在约0.1mg至约3mg、约0.2mg至约2mg,或约0.3mg至约0.8mg范围内。在某些实施方案中,包含或由SEQ ID NO:2的序列组成的JNK肽抑制剂的治疗有效量或剂量为约0.2mg至约1mg。
治疗的持续时间也可以变化,这取决于需要治疗的耳鸣的严重性和具体形式(例如急性、亚急性或慢性耳鸣)。作为指导,较短的治疗持续时间是优选的,并且一旦治疗停止,耳鸣不再发生就足够了。对于短期治疗后耳鸣持续存在的个体,可采用更长的治疗持续时间。在一个实施方案中,将治疗有效量的JNK肽抑制剂以单剂量施用于受试者,例如单次鼓室内注射。在另一个实施方案中,在几天或几周时间内将治疗有效量的JNK肽抑制剂以多个剂量施用于受试者。在某些实施方案中,在连续三至五天的时间内将治疗有效量的JNK肽抑制剂以多次鼓室内注射施用于受试者。例如,在一个实施方案中,在连续三天内以三次鼓室内注射向受试者施用JNK肽抑制剂,每天注射一次。
在本发明的一些实施方案中,根据本发明的方法施用JNK肽抑制剂提供统计上显著的治疗效果。在一个实施方案中,统计上显著的治疗效果是基于由美国,例如FDA或其他国家的一个或多个管理机构提供的一个或多个标准或准则来确定。在其他实施方案中,根据从管理机构批准的临床试验设置和/或程序获得的结果来确定统计上显著的治疗效果。
在一些实施方案中,基于至少150、200、300、400、500、600、700、800、900、1000或2000的患者群体来确定统计上显著的治疗效果。在一些实施方案中,基于从随机化和双盲临床试验设置获得的数据来确定统计上显著的治疗效果。在一些实施方案中,基于p值小于或等于约0.05、0.04、0.03、0.02或0.01的数据来确定统计上显著的治疗效果。在一些实施方案中,基于置信区间大于或等于95%、96%、97%、98%或99%的数据来确定统计上显著的治疗效果。在一些实施方案中,基于本发明提供的方法的III期临床试验的结果来确定统计上显著的治疗效果。
通常,统计分析可以包括管理机构,例如,美国的FDA,欧洲的EMA或任何其他国家的管理机构所允许的任何合适的方法。在一些实施方案中,统计分析包括非层状分析、例如来自Kaplan-Meier、Jacobson-Truax、Gulliken-Lord-Novick、Edwards-Nunnally、Hageman-Arrindel和Hierarchical Linear Modeling(HLM)的对数秩分析、ANC OVA以及Cox回归分析,。
通过以下另外的实施例进一步说明了本发明,所述实施例不应解释为是限制性的。根据本公开,本领域技术人员应理解,在不脱离本发明的精神和范围的情况下可以在已公开并仍获得类似或相似结果的特定实施方案中做出许多改变。
实施例
实施例1.JNK的肽抑制剂在治疗内耳耳鸣中的功效
c-Jun N-末端激酶(JNK)参与应激损伤的毛细胞和螺旋神经节神经元的凋亡(Zine等,2004;Abi-Hachem等,2010),这是创伤性损伤(Hu等,2002)或耳蜗炎症(Ma等,2000;Barkdull等,2007)后耳蜗中细胞死亡的主要机制。AM-111是31个氨基酸的细胞可渗透的肽(SEQ ID NO:2,其中所有手性氨基酸均呈D构型,并且肽以相反的顺序合成),其是在生物相容性透明质酸凝胶中配制。嵌合肽含有来源于支架蛋白胰岛-脑1的效应结构域,所述支架蛋白胰岛-脑1在融合至转录(TAT)蛋白转导结构域的反式激活蛋白的细胞质中保留JNK(Bonny等,2001)。用AM-111的治疗显示在耳蜗损伤的各种模型中是耳保护性的:急性噪音创伤(Wang等,2003;Wang等2007;以及Coleman等2007)、急性迷路炎(Barkdull等,2007)、氨基糖苷类耳毒性(Wang等,2003)、细菌感染(Grindal等,2010)、耳蜗缺血(Omotehara等,2011)以及耳蜗植入创伤(Eshraghi等,2013)。AM-111的治疗谱的宽度提示JNK在急性感音神经性听力损失(ASNHL)中的关键作用。然而,先前没有报道AM-111对耳鸣的统计上显著的作用。
进行双盲、随机化、安慰剂对照的II期研究以评价AM-111在治疗ASNHL及相关耳鸣中的功效和安全性。符合条件的参与者年龄在18至60岁并患有ASNHL(单侧特发性突发感音神经性听力损失(ISSNHL)、单侧或双侧急性听觉创伤(AAT)),听力损失为至少30dB并且先前发作不超过48小时。相对于参考值来确定听力损失:在最受影响的3个连续测试频率(纯音平均值,PTA)处的平均听力阈值小于对侧耳朵的对应的平均听力阈值(Plontke等,2007)。在先前不对称听力或双侧ASNHL的情况下,将来自先前听力图的阈值或ISO-7029;2000标准值用作参考。在基线处确定的PTA频率对于所有评估保持固定。
排除标准包括以下病史:美尼尔氏病(Menière’s disease)、自身免疫或辐射诱发的听力80损失、内淋巴积水或波动性听力损失、疑似外淋巴瘘、膜破裂或蜗后性损伤、气压伤、3个连续频率中的空骨间隙>20dB、在过去6周内发生的先前的ASNHL事件、以及急性或慢性中耳炎或外耳炎。排除了在研究期间哺乳、怀孕或计划怀孕的妇女,或宣布不愿意或不能实施有效85避孕方法的有生育能力的妇女。在进行任何研究特异性程序之前,从每位患者处获得书面知情同意书。
在基线处(第0天),将研究参与者随机化以2:1的比率接受AM-111(0.4或2.0mg/mL)或安慰剂。研究包括基线评估和在第3、7、30和90天的4次随访。基线评估包括一般身体检查、生命体征和育龄妇女的尿妊娠试验。在每次研究随访时,测定纯音听力阈值、60和80dB下的语音辨识及主观耳鸣响度。报告耳鸣的那些患者被要求在从0(无耳鸣)至10(极响)范围的数值标度上评价其“现在”的响度。
在局部麻醉下通过小的鼓膜切开术通过鼓室内(i.t.)注射在第0天施用约0.25mL的研究药物,其中将患者头部置于朝向未累及的耳倾斜45°的位置。患者保持在其躺着或仰卧的位置大约30分钟以允许活性物质扩散至耳蜗中。在双侧AAT的情况下,仅治疗受累及最严重的耳朵。从基线至第7天PTA恢复<10dB的受试者被给予每天两次(b.i.d.)接受口服泼尼松龙50mg(Ratiopharm,Ulm,Germany)持续5天的选择。先前的报告显示在第一个24小时内或第一周内开始的皮质类固醇治疗的结果没有差异(Huy等,2005)。
基于0.6的预期效应大小、5%的双侧I型误差率和80%的统计功效来确定样本大小。这产生计划的样本大小为每组群102名患者(68名AM-111,34名安慰剂),总共204名患者。
功效分析主要在修改的“意向治疗”(mITT)分析组(在第3±1天或最多第7+4天测量的PTA的治疗患者)上进行,并且其次在“每方案”(PP)分析组上进行。“安全群体”分析组包括接受研究药物注射的所有患者。基于在各个治疗组(mITT组)中观察到的前述值和平均变化,针对在第7天和第30天缺失的PTA值,以及在第7天缺失的语音辨识评分(SDS)值来进行随机填充。
对于连续效力终点,使用协方差(ANCOVA)模型分析,包括治疗组和初始频率范围作为类效应,以及各个终点的基线值作为协变量。对于完全恢复率,应用逻辑回归模型,包括治疗、初始频率范围和基线听力损失作为预测变量。初始频率范围包括在这些模型中,因为据报道自发恢复在较低频率下更明显(Huy等,2005)。使用Fisher精确检验法比较具有ASNHL相关耳鸣的治疗后缓解的受试者的百分比。
结果
筛选总共210名患者,并且入选2个群组的AM-111IIb期研究。每群组包含105名患者:70名分配给AM-111高剂量(2.0mg/mL)伴有35名分配给安慰剂,68名分配给AM-111低剂量(0.4mg/mL)组伴有37名分配给安慰剂。所有患者接受一次鼓室内注射研究药物,并且构成“安全群体”分析组(210名患者)。11名患者(5%)失访,而6名患者(3%)撤销同意。总共197名患者被包括在修改的“意向治疗”分析组中。排除的最常见原因是没有在规定的时间表(5名患者)内进行和服用禁用药物(5名患者)的研究访问。每个方案分析组中包括总共188名患者;排除的最常见原因是违反30dB最小听力损失标准(8名患者)。
大多数患者为男性(61%),患有ISSNHL(92%),并有耳鸣作为合并症(80%)。平均来说,在ASNHL发病后29小时对患者进行治疗。在最受影响的3个测试频率处的平均听力损失为52.2dB;平均SDS为52.3%(60dB)和67.6%(80dB)。在7%的患者中观察到临床相关的自发性眼球震颤(定义为>5次/30秒)。总体而言,治疗组的基线特征相似。
总共167名受试者在基线时具有ASNHL相关耳鸣(52名接受安慰剂的受试者和115名接受AM-111的受试者)。安慰剂、AM-111 0.4mg/mL和AM-111 2.0mg/mL组的基线发生率为73.2%、82.4%和84.3%。参见表1。ASNHL相关耳鸣的发生率下降最快,并且最显著的是AM-111 0.4mg/mL组(38.0%受累及的受试者在D90时有ASNHL相关耳鸣),其次是AM-1112.0mg/mL组(51.9%)和安慰剂组(56.0%)。参见表2。
表1.在基线时的耳鸣:关于ASNHL发作和主观响度的发生频率–安全群体分析组
N=受试者数量;ASNHL=急性感音神经性听力损失;SD=标准差
a排除在ASNHL后24小时内发生的耳鸣。
表2.患有ASNHL相关耳鸣的受试者的耳鸣频率的概述-安全群体分析组
通过听力损失严重程度(Jerger等,1980)分析PTA改善显示对于较小严重程度的意外强的自发恢复:截止第7天,安慰剂治疗的以轻度至中度听力损失(PTA<60dB;n=41)招募的患者已经恢复28.9dB或77%的初始损失,而对于严重或极重度听力损失(PTA≥60dB;n=30)的患者,仅为17.3dB或24%。ANCOVA显示治疗组与听力损失严重性亚组之间的统计上显著的相互作用项(p=0.04),这表明后者应该单独分析。轻度至中度的听力损失截止第90天基本上完全恢复(平均只有3dB或8.1%)。
在“严重至极重度听力损失”亚组中,与安慰剂相比,在90天内,AM-111 0.4mg/mL组中受试者的统计上显著更高的百分比实现了完全耳鸣缓解(56.0%对26.1%,p=0.045)。与安慰剂相比,AM-111 2.0mg/mL组中较高百分比的受试者也实现了完全耳鸣缓解,尽管这没有达到统计上的显著性(48.3%对26.1%,p=0.152)。在亚组“轻度至中度听力损失”中,在AM-111治疗组与安慰剂之间没有观察到统计上显著的差异。两个听力损失亚组中的每一个中AM-111对耳鸣的功效的结果总结在下表3中。
表3.治疗组和联合严重性亚组的治疗耳中完全ASNHL相关耳鸣缓解的受试者的频率-mITT分析组
使用Fisher精确检验法比较安慰剂与活性治疗组之间的频率。
研究结果显示,AM-111似乎是一种有前景的新型方法,用于以短期局部疗法来治疗ASNHL相关的耳鸣,特别是在患有与严重至极重度急性听力损失相关的耳鸣的患者中。
本文讨论和引用的所有出版物、专利和专利申请特此以引用的方式整体并入本文。应了解所公开的发明不限于所描述的具体方法、方案和材料,因为这些可以变化。还应了解本文所用的术语仅出于描述具体实施方案的目的,而不意图限制本发明的范围,本发明的范围将仅由随附权利要求限定。
本领域技术人员仅仅使用常规实验便可认识到或者能够确定本文所描述的发明的具体实施方案的很多等效方案。此类等效方案意图包含于下列权利要求书中。
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Claims (22)
1.一种改善或减少有需要的人中由耳蜗损伤诱发的急性内耳耳鸣发生的方法,所述方法包括向所述人施用药物组合物,所述药物组合物包含治疗有效量的c-Jun N-末端激酶(JNK)的肽抑制剂或其药学上可接受的盐,其中所述肽抑制剂的长度不超过50个氨基酸并且包含与SEQ ID NO:1至4和13至45中任一项的序列至少80%同一的序列。
2.如权利要求1所述的方法,其中所述肽抑制剂包含与DQSRPVQPFLNLTTPRKPR(SEQ IDNO:1)或RPKRPTTLNLFPQVPRSQD(SEQ ID NO:4)至少90%同一的序列。
3.如权利要求1所述的方法,其中所述肽抑制剂包含以下序列或由以下序列组成:DQSRPVQPFLNLTTPRKPRPPRRRQRRKKRG(SEQ ID NO:2)或GRKKRRQRRRPPRPKRPTTLNLFPQVPRSQD(SEQ ID NO:3)的序列。
4.如权利要求1至3中任一项所述的方法,其中所述肽抑制剂中所有的手性氨基酸均呈D构型。
5.如权利要求1至3中任一项所述的方法,其中所述肽抑制剂中所有的手性氨基酸均呈L构型。
6.如权利要求1所述的方法,其中所述耳蜗损伤是由以下造成:急性听觉创伤、老年性耳聋、缺血、缺氧、气压伤、中耳炎、暴露于耳毒性药物、传导性听力损失或突发性耳聋。
7.如权利要求1所述的方法,其中所述药物组合物在所述耳蜗损伤后四周内向所述人施用。
8.如权利要求1所述的方法,其中所述药物组合物在所述耳蜗损伤后一周内向所述人施用。
9.如权利要求1所述的方法,其中所述药物组合物在所述耳蜗损伤后三天内向所述人施用。
10.如权利要求1所述的方法,其中所述人已被或被诊断出在发病的48小时内具有至少60dB的急性听力损失。
11.如权利要求1所述的方法,其中所述人已被或被诊断出在发病48小时后持续的具有至少40dB的急性听力损失。
12.如权利要求1所述的方法,其中所述治疗有效量的肽抑制剂在施用所述组合物后有效减轻耳鸣的感觉。
13.如权利要求1所述的方法,其中所述治疗有效量的肽抑制剂在施用所述组合物后有效降低耳鸣的响度。
14.如权利要求1所述的方法,其中所述药物组合物经由圆窗膜或卵圆窗膜局部施用于内耳。
15.如权利要求1所述的方法,其中所述药物组合物通过鼓室内注射施用。
16.如权利要求1所述的方法,其中所述药物组合物被递送至中耳。
17.如权利要求1所述的方法,其中所述药物组合物是凝胶。
18.如权利要求1所述的方法,其中所述药物组合物包含约0.5%至约1%的透明质酸。
19.如权利要求1所述的方法,其中所述药物组合物包含将所述组合物的pH缓冲为6.0至7.4的磷酸盐缓冲剂。
20.如权利要求1所述的方法,其中所述肽抑制剂的治疗有效量为约0.2mg至约2mg。
21.如权利要求1所述的方法,其中所述肽抑制剂的治疗有效量为约0.3mg至约0.8mg。
22.如权利要求1所述的方法,其中所述治疗有效量的肽抑制剂是以多个剂量施用。
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US11331373B2 (en) | 2017-02-10 | 2022-05-17 | St. Jude Children's Research Hospital | Combination therapy for treating disorders of the ear |
US10561736B1 (en) | 2019-01-09 | 2020-02-18 | Spiral Therapeutics, Inc. | Apoptosis inhibitor formulations for prevention of hearing loss |
KR102643687B1 (ko) * | 2020-11-20 | 2024-03-05 | 가톨릭대학교 산학협력단 | 토끼풀 추출물을 활성 성분으로 포함하여 혈액순환을 증진하고 이명을 예방 또는 치료할 수 있는 조성물 |
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- 2015-04-23 US US14/694,122 patent/US20150306178A1/en not_active Abandoned
- 2015-04-23 EP EP15782753.6A patent/EP3139744A4/en not_active Withdrawn
- 2015-04-23 WO PCT/US2015/027252 patent/WO2015164580A1/en active Application Filing
- 2015-04-23 CN CN201580024649.XA patent/CN106455579A/zh active Pending
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JP2017513870A (ja) | 2017-06-01 |
AU2015249641A1 (en) | 2016-11-03 |
EP3139744A4 (en) | 2017-12-20 |
US20150306178A1 (en) | 2015-10-29 |
CA2945785A1 (en) | 2015-10-29 |
EP3139744A1 (en) | 2017-03-15 |
WO2015164580A1 (en) | 2015-10-29 |
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