CN111479587A - FXIIa抑制剂在治疗肾纤维化和/或慢性肾脏疾病中的应用 - Google Patents
FXIIa抑制剂在治疗肾纤维化和/或慢性肾脏疾病中的应用 Download PDFInfo
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Abstract
本发明涉及用于治疗或预防慢性肾脏疾病、肾纤维化、肾小球硬化、肾瘢痕形成、天然或移植肾脏中的缺血/再灌注损伤和/或急性肾损伤的因子XII(FXII)的抑制剂,用于治疗或预防慢性肾脏疾病、肾纤维化、肾小球硬化、肾瘢痕形成、天然或移植肾脏中的缺血/再灌注损伤、急性肾损伤、因肾脏移植/同种异体移植的排斥引起的肾纤维化和/或因排斥或复发性原发疾病引起的肾脏移植/同种异体移植的纤维化的包含因子XII的一种抑制剂的试剂盒,以及用于治疗或预防慢性肾脏疾病、肾纤维化、肾小球硬化、肾瘢痕形成、天然或移植肾脏中的缺血/再灌注损伤和/或急性肾损伤的包含因子XII的一种抑制剂的抗因子XII(FXII)抗体或其抗原结合片段。
Description
领域
本公开内容涉及治疗或预防肾部或肾脏疾病的方法。
背景
超过10%的美国成年人(约三千万)患有慢性肾脏疾病(CKD)。这种患病率以及缺乏适当的治疗方法要求开发CKD的新的治疗策略。肾纤维化被认为是大多数慢性肾脏疾病的最终表现,与它们的主要病因无关。肾脏实质的近99%由肾小管间质组成。基于增加的细胞死亡和/或降低的增殖/再生的肾小管上皮细胞(TEC)的损失代表了导致肾脏疾病趋向于慢性化和纤维化的最初和决定性机制。TEC的死亡以及成纤维细胞的过度活化及其分化为成肌纤维细胞促进细胞外基质(ECM)的不受控制的产生和累积,从而通过纤维化瘢痕组织替代功能性肾单位。
单侧输尿管阻塞(UUO)的实验模型已被广泛用于研究肾小管间质纤维化的发病机制,因为输尿管阻塞后纤维化的演变具有高度可再现性,并以快速的方式概括了人肾纤维化中发生的致病事件的序列。与特发性肺纤维化不同,浸润性巨噬细胞是肾间质纤维化的主要特征之一。巨噬细胞可通过以下机制影响肾脏损伤:i)通过释放大量促炎性介质来增强炎症反应;ii)巨噬细胞来源的活性氧和TNF-α可以触发TEC的凋亡和坏死,从而扩大了肾脏的损害,和iii)巨噬细胞过度生产促纤维化细胞因子和生长因子可能刺激成纤维细胞的增殖及其分化为α-平滑肌肌动蛋白(SMA)阳性的成肌纤维细胞,从而导致伤口异常愈合,并最终导致纤维化。越来越多的证据表明,巨噬细胞浸润的程度与肾脏损害的严重程度密切相关。巨噬细胞在肾脏疾病发病机理中的有害作用也得到了研究的支持,这些研究表明,巨噬细胞的消耗会阻止新月型肾小球肾炎的发展,而骨髓衍生的巨噬细胞的过继转移会在同一疾病模型中加重肾脏损伤。UUO模型例如在Chevalier等人,Kidney International(2009),75,1145-1152(doi:10.1038/ki.2009.86)中描述。
接触系统或血浆激肽释放酶-激肽系统由三种丝氨酸蛋白酶组成:Hageman因子(凝血因子XII、FXII)、因子XI(FXI)和血浆激肽释放酶(PKLK),以及非酶辅因子高分子量激肽原(HK)。接触系统的活化在FXII暴露于带负电的表面例如高岭土、硫酸右旋糖酐、内毒素、细胞外RNA、聚磷酸盐和肝素时发生。在这种环境下,FXII被转化为双链活性蛋白酶FXIIa。FXIIa通过活化因子XI(FXI)来启动内在的凝血途径。但是,最近的数据支持FXII对于生理性止血不可或缺的观点,并证明FXII在病理性血栓形成中起着至关重要的作用。此外,FXIIa将前激肽释放酶转化为激肽释放酶,其进而活化额外的FXII,并从高分子量的激肽原(HK)中释放缓激肽(BK)。另外,FXII以uPAR依赖性方式刺激内皮细胞的增殖。
现有技术出版物WO 2006/066878涉及抗FXII抗体用于抑制凝血因子XII的用途,以及相应的抗体或抑制剂在治疗或预防与静脉或动脉血栓形成相关的疾病中的用途,即用作抗血栓形成剂。现有技术出版物WO 2011/121123A1涉及因子XII抑制剂在治疗间质性肺疾病中的用途。Ewa Jablonska的论文“Role of Instrinsic Coagulation Pathway inthe Pathogenesis of Idiopathic Pulmonary Fibrosis”(2010年11月29日,VVBLaufersweiler,Giessen(ISBN:978-3-8359-5693-3))涉及特发性肺纤维化(IPF)发病机制中的凝血途径背景下的FXI/FXII。现有技术出版物WO 2015/193457A1涉及因子XII抑制剂在治疗神经创伤性疾病中的用途。Vorlova等人Thromb.Haemost.2017Jan 5;117(1):176-187(doi:10.1160/TH16-06-0466;Epub 2016Oct 27)讨论了靶向FXII作为治疗心血管疾病的方法。
迄今为止,尚未评估FXII在肾纤维化和/或慢性肾脏疾病(CKD)发生中的作用。
正在进行或已经进行了关于肾部或肾纤维化的临床试验的已知小分子或药物与不同的靶标和/或机制相关(Nanthakumar等人,Nature Reviews 2015,693-720,doi:10.1038/nrd4592)。虽然吡非尼酮能够预防啮齿动物的肾纤维化,但尚未在肾脏患者中证实这些益处。在一项针对77位肾脏疾病患者的研究中,吡非尼酮改善了肾功能,但未能显著降低蛋白尿,这表明吡非尼酮改善了肾功能,但未改善足状突细胞损伤。已经确定了几种介导肾纤维化的关键信号传导途径,但是目前在大型临床试验中,没有靶向这些途径的药物被证明对肾脏疾病的抗纤维化治疗有效,并且不断提出新的靶标(Nugent等人,frontiersin physiology 2015(6),Article 132,doi:10.3389/fphys.2015.00132)。
在一项研究中,研究了人C1抑制剂(C1 INH)对小鼠中局部缺血再灌注损伤(IRI)的早期炎症反应以及随后进展为纤维化的影响,其中观察到在再灌注之前接受C1-INH的动物与媒介物(PBS)治疗的对应动物相比,具有显著改善的生存率以及优越的肾功能。在此背景下的发现结果被发现指示在缺血性损伤之前静脉内递送C1-INH保护肾脏免于炎症性损伤和随后进展为纤维化。作者得出的结论是,在IRI的背景下,早期补体阻滞构成预防缺血性急性肾损伤后的纤维化的有效策略(Danobeitia J.S,Ziemelis M,Ma X,Zitur LJ,ZensT,Chlebeck PJ,等人(2017),Complement inhibition attenuates acute kidney injuryafter ischemia-reperfusion and limits progression to renal fibrosis in mice;PLoS ONE 12(8):e0183701.https://doi.org/10.1371/journal.pone.0183701)。
尽管进行了上述努力,但目前尚无批准的用于治疗肾纤维化和/或慢性肾脏疾病(CKD)的药物。因此,存在对于抗纤维化策略的未满足的临床需求,其将优选地预防不受控制的TEC死亡、促进肾小管增殖/再生并抑制成纤维细胞活化。
概述
为了满足上述需求,本发明提供了
-因子XII(FXII)的抑制剂,
-试剂盒,以及
-抗因子XII(FXII)抗体或其抗原结合片段,
其用于治疗和预防受试者特别是人或动物受试者的慢性肾脏疾病和/或肾纤维化,特别地其中慢性肾脏疾病和/或肾纤维化是以下一种或多种的结果和/或与之相关:肾小球硬化,肾瘢痕形成,肾脏中的局部缺血/再灌注损伤,急性肾损伤,肾脏移植/同种异体移植排斥反应,复发性原发疾病(recurrent underlying disease),和/或与FXII/FXIIa介导的补体形成相关的炎症性肾脏疾病,选自肾炎、狼疮性肾炎、C3-肾小球肾炎、致密沉积病、非典型溶血尿毒症综合征、链球菌感染后肾小球肾炎、过敏性紫癜性肾炎、抗体介导的肾脏移植排斥反应。
在本发明的上下文中以及在整个说明书和权利要求书中,术语“因子XII的抑制剂”应理解为不包括C1INH,即“前提是因子XII的抑制剂不是C1 INH”。
在产生本发明的过程中,发明人已经使用上述单侧输尿管阻塞(UUO)实验模型研究了抑制因子XII(FXII)在肾纤维化小鼠模型中的作用。发明人发现在实验性肾纤维化中的FXII抑制
(i)显著降低细胞外基质蛋白的丰度,
(ii)在早期不影响巨噬细胞的累积或细胞因子的产生,
(iii)在疾病的早期和晚期导致凋亡的肾小管上皮细胞的数量显著减少,
(iv)在疾病的早期和晚期导致增殖的肾小管上皮细胞的数量增加,以及
(v)减轻体重减轻。
本发明人通过将FXII抑制剂施用至公认的肾纤维化动物模型证明了这些效果,所述动物模型以加速的方式概括了在人肾纤维化中发生的致病事件的序列。
本发明人的发现为通过抑制FXII治疗或预防受试者的肾纤维化和/或慢性肾脏疾病(CKD)的方法提供了基础。本发明人的发现还为用于治疗或预防受试者的肾纤维化和/或CKD的FXII抑制剂提供了基础。
例如,本公开内容提供了用于治疗受试者的肾纤维化和/或CKD的方法,其包括向受试者施用FXII抑制剂。在另一个实例中,本公开内容提供了用于预防受试者的肾纤维化的方法,该方法包括向受试者施用FXII抑制剂。
在一个替代实例中,本公开内容提供了用于治疗受试者的肾纤维化的FXII抑制剂。在另一个实例中,本公开内容提供了用于预防受试者的肾纤维化的FXII抑制剂。
本发明人还发现它们可以减少受试者的肾纤维化的进展。因此,本公开内容另外提供了用于减少受试者的肾纤维化的进展的方法或FXII抑制剂。例如,本公开内容提供了用于降低受试者的肾纤维化的风险或预防受试者的肾纤维化的方法或FXII抑制剂。
在一个实例中,FXII的抑制剂是直接抑制剂。在一个实例中,FXII的抑制剂结合FXII和/或FXIIa。在一个实例中,FXII的抑制剂结合FXII和/或FXIIa并抑制FXII和/或FXIIa的活性。例如,FXII的抑制剂与FXIIa结合并抑制FXIIa的活性。在另一个实例中,FXII的抑制剂与FXII结合并抑制FXII的活化。在一个实例中,FXII和/或FXIIa的活性分别被抑制至少约50%、60%、65%、70%、75%、80%、85%、90%或95%。例如,FXII和/或FXIIa的活性分别被抑制约60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%。用于确定FXII和/或FXIIa的活性的方法是本领域已知的和/或在本文中描述。
在一个实例中,FXII的抑制剂是丝氨酸蛋白酶抑制剂。例如,FXII抑制剂是Infestin-4。在另一个实例中,FXII抑制剂是SPINK-1。在另一个实例中,FXII抑制剂是Infestin-4或SPINK-1变体。
在一个实例中,FXII的抑制剂不是丝氨酸蛋白酶抑制剂。例如,FXII的抑制剂不是Infestin-4。例如,FXII的抑制剂不是Infestin-4的变体。在一个实例中,FXII的抑制剂不是SPINK-1。例如,FXII的抑制剂不是SPINK-1的变体。
在一个实例中,用于本公开内容的方法或FXII抑制剂包括施用FXII抑制剂,其中该抑制剂包含:
(i)野生型Infestin-4多肽序列(SEQ ID NO:1)或包含以下的多肽序列:
(a)经修饰以在SEQ ID NO:1的N末端氨基酸位置2-13之外包含1-5个氨基酸突变的SEQ ID NO:1;和/或
(b)与SEQ ID NO:1具有至少70%的同一性,并保留来自SEQ ID NO:1的六个保守的半胱氨酸残基;或
(ii)野生型SPINK-1多肽序列(SEQ ID NO:2),或包含以下的多肽序列:
(a)经突变以用SEQ ID NO:1的位置2-13的N末端氨基酸替换位置2-13的N末端氨基酸的SEQ ID NO:2;任选地进一步修饰以包含1-5个额外的氨基酸突变,这些突变增加多肽序列与SEQ ID NO:1的序列的同源性;和/或
(b)与SEQ ID NO:2具有至少70%的同一性,并保留来自SEQ ID NO:2的六个保守的半胱氨酸残基;或
(iii)SPINK-1突变体K1(SEQ ID NO:3)、K2(SEQ ID NO:4)或K3(SEQ ID NO:5)中的一种。
在一个实例中,FXII的抑制剂包含丝氨酸蛋白酶抑制剂Infestin-4的序列。例如,FXII的抑制剂包含SEQ ID NO:1所示的序列。
在一个实例中,FXII的抑制剂包含修饰的Infestin-4。例如,FXII的抑制剂包含经修饰以在SEQ ID NO:1的N末端氨基酸位置2-13之外包含1-5个氨基酸突变的SEQ ID NO:1所示的序列。
在另一个实例中,FXII的抑制剂包含与SEQ ID NO:1所示的序列具有至少70%同一性并且保留来自SEQ ID NO:1的六个保守的半胱氨酸残基的序列。例如,FXII的抑制剂与SEQ ID NO:1具有约75%的同一性,或与SEQ ID NO:1具有约80%的同一性,或与SEQ IDNO:1具有约85%的同一性,或与SEQ ID NO:1具有约90%的同一性,或与SEQ ID NO:1具有约95%的同一性,或与SEQ ID NO:1具有约98%的同一性,或与SEQ ID NO:1具有约99%的同一性。
在一个实例中,FXII的抑制剂包含丝氨酸蛋白酶抑制剂SPINK-1的序列。例如,FXII的抑制剂包含SEQ ID NO:2所示的序列。
在另一个实例中,FXII的抑制剂包含SEQ ID NO:2所示的序列,该序列经突变以用SEQ ID NO:1的位置2-13的N末端氨基酸替换位置2-13的N末端氨基酸;并任选地进一步修饰以包含1-5个额外的氨基酸突变,这些突变增加多肽序列与SEQ ID NO:1的序列的同源性。
在另一个实例中,FXII的抑制剂包含与SEQ ID NO:2所示的序列具有至少70%同一性并且保留来自SEQ ID NO:2的六个保守的半胱氨酸残基的序列。例如,FXII的抑制剂与SEQ ID NO:2具有约75%的同一性,或与SEQ ID NO:2具有约80%的同一性,或与SEQ IDNO:2具有约85%的同一性,或与SEQ ID NO:2具有约90%的同一性,或与SEQ ID NO:2具有约95%的同一性,或与SEQ ID NO:2具有约98%的同一性,或与SEQ ID NO:2具有约99%的同一性。
在一个实例中,FXII的抑制剂是包含可变区片段(Fv)的蛋白质。例如,该蛋白质选自:
(i)单链Fv片段(scFv);
(ii)二聚体scFv(di-scFv);或
(iv)双抗体(即双特异性抗体);
(v)三抗体(即三特异性抗体);
(vi)四抗体(即四特异性抗体);
(vii)Fab;
(viii)F(ab’)2;
(ix)Fv;
(x)与抗体的恒定区、Fc或重链恒定结构域(CH)2和/或CH3连接的(i)至(ix)之一;或
(xi)抗体。
在一个实例中,FXII的抑制剂是抗体。例如,该抗体是抗FXII抗体。在另一个实例中,该抗体是抗FXIIa抗体。
示例性抗体是全长和/或裸抗体。
在一个实例中,FXII的抑制剂是重组、嵌合、CDR嫁接、人源化、同人源化、灵长类化、去免疫化或人的蛋白质。
在一个实例中,所述抗体是IgG抗体。
在一个实例中,抗FXII抗体包含重链可变区(VH),其包含SEQ ID NO:6所示的序列。
在一个实例中,抗FXII抗体包含轻链可变区(VL),其包含SEQ ID NO:7所示的序列。
在一个实例中,抗FXII抗体包含含有SEQ ID NO:6所示的序列的VH和含有SEQ IDNO:7所示的序列的VL。
在一个实例中,抗FXII抗体包含可变区,该可变区包含SEQ ID NO:6和SEQ ID NO:7的VH和/或VL的互补决定区(CDR)。
在一个实例中,蛋白质或抗体是由编码任何前述蛋白质或抗体的核酸编码的蛋白质或抗体的任何形式,例如缺少编码的C末端赖氨酸残基的变体、脱酰胺的变体和/或糖基化的变体和/或包含焦谷氨酸(例如在蛋白质的N末端)的变体和/或缺少N末端残基的变体。
在一个实例中,抗FXII抗体包含:
(i)包含以下的VH:
(a)SEQ ID NO:6所示的序列;或
(b)包含SEQ ID NO:8所示的序列的CDR1;包含SEQ ID NO:10所示的序列的CDR2;和包含SEQ ID NO:12所示的序列的CDR3;或(c)包含SEQ ID NO:8所示的序列的CDR1;包含SEQ ID NO:9所示的序列的CDR2;和包含SEQ ID NO:11所示的序列的CDR3;和/或
(ii)包含以下的VL:
(a)SEQ ID NO:7所示的序列;或
(b)包含SEQ ID NO:13所示的序列的CDR1;包含SEQ ID NO:14所示的序列的CDR2;和包含SEQ ID NO:16所示的序列的CDR3;或
(c)包含SEQ ID NO:13所示的序列的CDR1;包含SEQ ID NO:14所示的序列的CDR2;和包含SEQ ID NO:15所示的序列的CDR3。
在一个实例中,抗FXII抗体包含:
(i)包含以下的VH:
(a)CDR1,其包含SEQ ID NO:8所示的序列;
(b)CDR2,其包含SEQ ID NO:10所示的序列;和
(c)CDR3,其包含SEQ ID NO:12所示的序列;和/或
(ii)包含以下的VL:
(a)CDR1,其包含SEQ ID NO:13所示的序列;
(b)CDR2,其包含SEQ ID NO:14所示的序列;和
(c)CDR3,其包含SEQ ID NO:16所示的序列。
在一个实例中,抗FXII抗体包含:
(i)包含以下的VH:
(a)CDR1,其包含SEQ ID NO:8所示的序列;
(b)CDR2,其包含SEQ ID NO:9所示的序列;和
(c)CDR3,其包含SEQ ID NO:11所示的序列;和/或
(ii)包含以下的VL:
(a)CDR1,其包含SEQ ID NO:13所示的序列;
(b)CDR2,其包含SEQ ID NO:14所示的序列;和
(c)CDR3,其包含SEQ ID NO:15所示的序列。
在一个实例中,抗FXII抗体包含:
(i)包含以下的VH:
(a)SEQ ID NO:8所示的CDR1;
(b)SEQ ID NO:10所示的CDR2,其中位置3的X为D,位置4的X为I,位置5的X为P,位置6的X为T,位置7的X为K,和位置8的X为G;和
(c)SEQ ID NO:11所示的CDR3;和/或
(ii)包含以下的VL:
(a)SEQ ID NO:13所示的CDR1;
(b)SEQ ID NO:14所示的CDR2;和
(c)SEQ ID NO:15所示的CDR3。
例如,抗FXII抗体包含含有SEQ ID NO:18所示的序列的VH和含有SEQ ID NO:19所示的序列的VL。
在一个实例中,抗FXII抗体包含λ轻链恒定区。
在一个实例中,抗FXII抗体包含IgG4或稳定化的IgG4恒定区。例如,根据Kabat的系统,稳定化的IgG4恒定区在铰链区的位置241处包含脯氨酸(Kabat等人,Sequences ofProteins of Immunological Interest Washington DC United States Department ofHealth and Human Services,1987年和/或1991年)。
在一个实例中,抗FXII抗体在组合物中。例如,该组合物包含蛋白质,该蛋白质包含本文所述的抗体可变区或VH或VL或抗体。在一个实例中,组合物另外包含蛋白质或抗体的一种或多种变体。例如,其包含缺失编码的C末端赖氨酸残基的变体、脱酰胺的变体和/或糖基化的变体和/或包含焦谷氨酸(例如在蛋白质的N末端)的变体和/或缺少N末端残基(例如抗体或V区中的N末端谷氨酰胺)的变体和/或包含全部或部分分泌信号的变体。编码的天冬酰胺残基的脱酰胺变体可能导致生成异天冬氨酸和天冬氨酸同种型,或甚至导致涉及相邻氨基酸残基的琥珀酰胺。编码的谷氨酰胺残基的脱酰胺变体可能导致谷氨酸。当提及特定氨基酸序列时,意图包括包含此类序列和变体的异质混合物的组合物。
在一个实例中,在本文所述的任何方法或FXII抑制剂中,FXII抑制剂连接至融合伴侣。例如,融合伴侣包含聚乙二醇(PEG)或半衰期延长多肽。
在一个实例中,FXII的抑制剂直接连接至融合伴侣。在另一个实例中,FXII的抑制剂通过接头连接至融合伴侣。例如,FXII抑制剂直接连接至半衰期延长多肽。在另一个实例中,FXII的抑制剂通过接头与半衰期延长多肽连接。在一个实例中,FXII的抑制剂直接连接至PEG。在另一个实例中,FXII的抑制剂通过接头与PEG连接。
在一个实例中,接头是介入中间的肽接头。例如,接头是可裂解的接头。
在一个实例中,半衰期延长多肽选自白蛋白、afamin、甲胎蛋白、维生素D结合蛋白、人白蛋白、免疫球蛋白和IgG的Fc。例如,半衰期延长多肽是白蛋白。
在一个实例中,FXII的抑制剂是包含通过接头肽与FXII抑制剂连接的人白蛋白的融合蛋白。
在一个实例中,肠胃外施用FXII抑制剂。例如,静脉内、皮下或鞘内施用FXII的抑制剂。在一个实例中,皮下施用FXII抑制剂。在另一个实例中,静脉内施用FXII的抑制剂。
在本文描述的任何方法的一个实例中,FXII抑制剂以一个或多个剂量施用至受试者。例如,FXII抑制剂以:
(i)单个剂量;或
(ii)多个剂量;或
(ii)作为连续输注或敷用
施用至受试者。
在一个实例中,FXII抑制剂以单个剂量施用至受试者。
在一个实例中,以多个剂量向受试者施用FXII抑制剂。例如,FXII的抑制剂以两个剂量,或三个剂量,或四个剂量,或五个剂量或更多个剂量的形式施用至受试者。例如,每个剂量的FXII抑制剂的施用间隔数小时。例如,每个剂量的FXII抑制剂的施用间隔约1小时,或约2小时,或约3小时,或约4小时,或约6小时,或约8小时,或约12小时,或约16小时,或约20小时,或约24小时。
例如,每个剂量的FXII抑制剂的施用间隔数天。例如,每个剂量的FXII抑制剂的施用间隔约1天,或约2天,或约3天,或约4天,或约5天,或约6天,或约7天。
在一个实例中,每个剂量的FXII抑制剂的施用间隔至少14天或至少28天。
例如,每个剂量的FXII抑制剂的施用间隔数周。例如,每个剂量的FXII抑制剂的施用间隔约1周或约2周或约3周或约4周或约5周或约6周。
在一个实例中,每个剂量的FXII抑制剂的施用间隔至少一个月。
在一个实例中,在整个施用过程中,FXII抑制剂的施用之间的时间长度是相同的。在一个实例中,在整个施用过程中,FXII抑制剂的施用之间的时间长度是不同的。例如,FXII抑制剂在治疗开始时每周一次施用,然后在预定次数的剂量后每月一次施用。在一个实例中,FXII抑制剂的施用之间的时间长度是可变的。
在一个实例中,FXII抑制剂作为连续剂量施用至受试者。例如,FXII抑制剂在一段时间内作为连续输注施用至受试者。例如,FXII抑制剂在约1分钟至约24小时之间的时间段内施用。例如,FXII抑制剂在约10分钟至约12小时,或约10分钟至约6小时,或约10分钟至约5小时,或约10分钟至约4小时,或约10分钟至约3小时,或约10分钟至约2小时,或约10分钟至约1小时,或约30分钟的时间内施用。
在一个实例中,FXII抑制剂被多次施用。例如,FXII的抑制剂被施用一次或多次。例如,施用FXII抑制剂直至治疗或预防了肾纤维化。例如,将FXII抑制剂施用数天至数月。例如,将FXII抑制剂施用约一天,或约2天,或约3天,或约4天,或约5天,或约6天,或约1周,或约2周,或约4周,或约6周,或约2个月。
在一个实例中,以治疗或预防有效量施用FXII抑制剂。例如,FXII抑制剂以约0.01mg/kg至约1000mg/kg的剂量施用至受试者。例如,FXII抑制剂以约0.01mg/kg体重,或约0.1mg/kg体重,或约1mg/kg体重,或约50mg/kg体重,或约100mg/kg体重,或约200mg/kg体重,或约500mg/kg体重,或约1000mg/kg体重的剂量施用。例如,FXII抑制剂以约0.001mg/kg至约100mg/kg体重,或约0.01mg/kg至约100mg/kg,或约0.01mg/kg至约50mg/kg,或约0.1mg/kg至约30mg/kg,或约0.1mg/kg至约10mg/kg,或约0.1mg/kg至约5mg/kg,或约0.1mg/kg至约2mg/kg或约0.1mg/kg至约1mg/kg的剂量施用。在一个实例中,FXII抑制剂以约0.01mg/kg至约1000mg/kg,或约0.1mg/kg至约1000mg/kg,或约1mg/kg至约1000mg/kg,或约1mg/kg至约500mg/kg,或约10mg/kg至约200mg/kg,或约10mg/kg至约100mg/kg,或约50mg/kg至约500mg/kg,或约50mg/kg至约200mg/kg,或约100mg/kg至约200mg/kg的剂量施用。在一个实例中,FXII抑制剂以约10mg/kg的剂量施用。在一个实例中,FXII抑制剂以约20mg/kg的剂量施用。
在一个实例中,受试者患有肾纤维化和/或慢性肾脏疾病(CKD)。在一个实例中,已经诊断出该受试者患有肾纤维化和/或CKD。在一个实例中,受试者正在接受针对肾纤维化和/或CKD的治疗。在一个实例中,受试者正在接受针对肾纤维化和/或CKD相关病症(例如糖尿病性肾病,高血压性肾病,肾小球肾炎,肾小球硬化症,间质性肾炎)的治疗。在一个实例中,患者正在接受针对天然或同种异体肾纤维化和/或CKD的治疗。例如,受试者正在接受使用ACE抑制剂、降压药、皮质类固醇、免疫抑制剂(硫唑嘌呤、MMF、环磷酰胺、利妥昔单抗)的治疗。
在一个实例中,受试者正在接受透析或血液透析形式的治疗。在一个实例中,受试者正在接受使用RAAS抑制剂的治疗。
在本文所述使用的任何方法或FXII抑制剂的一个实例中,受试者处于发展肾纤维化和/或CKD的风险中。在这方面,FXII的抑制剂以防止或预防性方式使用,或者可以说以主要的预防性方式使用。处于发展肾纤维化和/或CKD的风险中的示例性受试者患有糖尿病。例如,糖尿病是2型糖尿病。
处于患肾纤维化和/或CKD的风险中的受试者的其他或替代特征包括以下特征中的一种或多种:
·糖尿病性肾病
·高血压性肾病
·肾小球肾炎
·狼疮肾炎
·肾血管炎
·肾小球硬化
·间质性肾炎
·常染色体显性多囊肾
·Alport综合征
·镇痛剂肾病
·与缺血再灌注或排斥反应相关的肾脏同种异体移植损伤
在一个实例中,用FXIIa抑制剂治疗处于发展肾纤维化和/或慢性肾脏疾病(CKD)的风险的患有高血压性肾病(肾硬化)的受试者,以抑制纤维发生。
在一个实例中,用FXII抑制剂治疗处于发展肾纤维化和/或慢性肾脏疾病(CKD)的风险的患有慢性肾小球肾炎的受试者,以预防肾纤维化。
在一个实例中,用FXII抑制剂治疗处于发展肾纤维化和/或慢性肾脏疾病(CKD)的风险的患有Alport综合征的受试者,以减少肾纤维化。
患有肾血管炎的患者在肾小球和肾小管间质中均具有严重的肾脏炎症,其中急性期炎症标志物水平升高:循环中C-反应蛋白和IL-6的水平升高。
在本文描述的任何方法的一个实例中,FXII抑制剂在肾纤维化和/或CKD发作之前或之后施用至受试者。例如,FXII的抑制剂是预防性或治疗性施用的。在一个实例中,将抑制剂预防性地施用至受试者。在一个实例中,将抑制剂治疗性地施用至受试者。
在美国,由于终末期肾纤维化,无论原发的肾脏疾病如何,每年大约有100,000名CKD患者需要开始肾脏替换治疗。本公开内容提供了通过执行本文描述的方法来降低必须经历透析和/或肾脏移植的风险的方法。
FXII抑制剂以足以引起以下作用的量施用至患有糖尿病肾病的患者:减少蛋白尿并减慢肾小球滤过率(GFR)的损失。
FXII抑制剂在发展肾纤维化和/或CKD之前在患有早期肾小球硬化的患者中施用,以预防终末期肾脏疾病引起的肾纤维化。在一组患者中,在发展肾纤维化和/或CKD发生后施用FXII抑制剂,以研究是否可以减缓GFR的进一步损失。
在一组患有糖尿病性肾病的患者中,在肾纤维化和/或慢性肾脏疾病(CKD)的症状发作后施用FXIIa抑制剂以检查是否可以减少蛋白尿。在另一组患有糖尿病性肾病的患者中,以缓和或减轻肾纤维化和/或CKD的一种或多种症状(例如蛋白尿和GFR损失)的剂量施用FXII抑制剂。
肾纤维化和/或CKD的临床体征和症状是本领域技术人员已知的。它们包括:
-高血压
-容量负荷过度
-贫血
-继发性或三发性甲状旁腺功能亢进
-代谢性酸中毒
-高钾血症
-瘙痒
-尿毒症脑病
本文所述的治疗方法或FXII抑制剂可另外减少为预防和/或治疗肾纤维化和/或CKD而施用皮质类固醇和其他免疫抑制剂(硫唑嘌呤、MMF、环磷酰胺、利妥昔单抗)的需要。
本公开内容还提供了用于在有需要的受试者中治疗或预防肾纤维化和/或CKD的包含FXII抑制剂的组合物。本公开内容还提供了FXII抑制剂在制备用于治疗或预防受试者的肾纤维化和/或CKD的药物中的用途。
本公开内容还提供了一种试剂盒,其包含至少一种FXII抑制剂,其与用于在受试者中治疗或预防肾纤维化和/或CKD的说明书一起包装。任选地,试剂盒另外包含治疗活性化合物或药物。
本公开内容还提供了试剂盒,其包含至少一种FXII抑制剂,其与向患有肾纤维化和/或CKD或处于患有肾纤维化和/或CKD的风险中的受试者施用FXII抑制剂的说明书一起包装,任选地,与治疗活性化合物或药物一起。
肾纤维化和/或慢性肾脏疾病(CKD)和FXII抑制剂的示例性作用在本文中描述,并且将其作必要的变通后用于前五个段落中示出的本公开内容的实例。
本发明人还产生了适合用于治疗人受试者的FXII的抑制剂,例如抗FXII抗体或其抗原结合片段。该抑制剂是一种亲和力成熟的人抗体,其已被修饰以使框架区中的大多数(但不是全部)残基与种系人抗体中的残基相同,从而降低了免疫原性的可能性。该抗体还能够抑制FXIIa并具有良好的可制造性特征。因此,本公开内容还提供了抗FXII抗体或其抗原结合片段,其中所述抗FXII抗体包含含有SEQ ID NO:18所示的序列的VH和含有SEQ IDNO:19所示的序列的VL。
在一个实例中,抗FXII抗体包含λ轻链恒定区。在一个实例中,抗FXII抗体包含IgG4或稳定化的IgG4恒定区。例如,根据Kabat的系统,稳定化的IgG4恒定区在铰链区的位置241处包含脯氨酸(Kabat等人,Sequences of Proteins of Immunological InterestWashington DC United States Department of Health and Human Services,1987年和/或1991年)。
在一个实例中,抗FXII抗体包含含有SEQ ID NO:20所示的序列的重链和含有SEQID NO:21所示的序列的轻链。在一个实例中,本发明提供了一种组合物,其包含抗FXII抗体或抗原结合片段和载体,例如药学上可接受的载体。在一个实例中,组合物另外包含蛋白质或抗体的一种或多种变体。例如,其包括缺少编码的C末端赖氨酸残基的变体、脱酰胺的变体和/或糖基化的变体和/或包含焦谷氨酸(例如在蛋白质的N末端)的变体和/或缺少N末端残基(例如抗体或V区中的N末端谷氨酰胺)的变体和/或包含全部或部分分泌信号的变体。编码的天冬酰胺残基的脱酰胺变体可能导致生成异天冬氨酸和天冬氨酸同种型,甚至导致涉及相邻氨基酸残基的琥珀酰胺。编码的谷氨酰胺残基的脱酰胺变体可能导致谷氨酸。当提及特定氨基酸序列时,旨在包括包含此类序列和变体的异质混合物的组合物。
本公开内容还提供了用于医学用途的抗FXII抗体或其抗原结合片段。
本公开内容还提供了用于治疗或预防受试者的疾病的方法,该方法包括施用抗FXII抗体或其抗原结合片段,其中该疾病选自与FXII/FXIIa介导的补体活化相关的肾脏疾病。
与FXII/FXIIa介导的补体活化相关的炎症性肾脏疾病:
-狼疮肾炎
-C3-肾小球肾炎
-致密沉积病
-非典型溶血尿毒症综合征
-链球菌感染后肾小球肾炎
-过敏性紫癜性肾炎
-抗体介导的肾脏移植排斥反应
将患有上述与FXII/FXIIa诱导的补体活化相关的肾脏疾病的患者选择用于使用FXII/FXIIa抑制剂进行治疗。
对于患有遗传性肾炎的患者,没有肾脏炎症和随后的纤维化的有效治疗。这些患者将接受使用FXIIa抑制剂或抗FXII抗体的治疗。
接受体外治疗(血液透析、血浆置换、级联过滤和脂质去除)的患者暴露于含有带负电荷的人造膜的装置中,这可能导致FXII/FXIIa介导的激肽形成和补体活化。在受试者的血液在对所述人受试者进行的医学程序期间和/或之后与人造表面接触期间和/或之后,在所述医学程序之前和/或期间和/或之后施用所述抗体或其抗原结合片段,其中
(i)人造表面暴露于至少100%的受试者血液体积并且人造表面至少为1.0m2,或
(ii)人造表面是在受试者体外的体外循环的一部分,或
(iii)人造表面是透析设备的一部分,例如透析膜、管路系统、捕沫器和滴注室(血液暴露于空气中)。
本公开内容还提供了涂覆有本发明的抗体或抗原结合片段的医疗装置,其中该装置是透析机、用于血液氧合的体外膜氧合系统、用于辅助泵血的装置、血液透析装置、用于体外过滤血液的装置、用于收集血液的储存库、腔内导管、支架和/或任何上述装置的附件,包括管道、套管、离心泵、阀、端口、和/或转向器。
本公开内容还提供了一种方法,所述方法包括将抗FXII抗体或其抗原结合片段施用至接受体外程序的患者,其中医疗程序包括与以下至少一种接触:
(a)血液透析,
(b)血浆置换,
(c)脂质去除。
本公开内容还提供了用于治疗或预防与增加的肾血管通透性相关的疾病(包括进行性肾病综合征、蛋白消耗性糖尿病性肾病)的方法,其中该方法包括施用抗FXII抗体或其抗原结合片段。
附图的简要说明
图1A是在损伤后第10天在来自IgG-和3F7-处理的小鼠的对照和阻塞的(UUO)肾脏中确定的肾小管损伤评分的图示。
图1B显示了在损伤后第10天,来自IgG-和3F7-处理的小鼠的对照和阻塞的(UUO)肾脏的PAS染色切片。
图2A-C是在损伤后第10天,在来自IgG-或3F7-处理的小鼠的对照和阻塞的(UUO)肾脏中,通过qPCR(图2A)、蛋白质印迹(图2B)和免疫组织化学(图2C)评估的α-SMA的表达的图示。
图3A-C是在损伤后第10天,在来自IgG-或3F7-处理的小鼠的对照和阻塞的(UUO)肾脏中,通过qPCR(图3A)、蛋白质印迹(图3B)和免疫组织化学(图3C)评估的纤连蛋白的表达的图示。
图4A-C是在损伤后第10天,在来自IgG-或3F7-处理的小鼠的对照和阻塞的(UUO)肾脏中,通过qPCR(图4A)、羟基脯氨酸含量(图4B)和免疫组织化学(图4C)评估的胶原蛋白I(Col I)的表达的图示。
图5A和5B是在损伤后第10天在来自IgG-或3F7-处理的小鼠的对照和阻塞的(UUO)肾脏中巨噬细胞(F4/80阳性细胞)的累积的图示。
图6显示了在损伤后第3天来自IgG-和3F7-处理的小鼠的对照和阻塞的(UUO)肾脏的代表性的裂解的胱天蛋白酶3染色的切片。
图7显示了在损伤后第3天来自IgG-和3F7-处理的小鼠的对照和阻塞的(UUO)肾脏的代表性的Ki67染色的切片。
图8显示了在损伤后第3天来自IgG-和3F7-处理的小鼠的对照和阻塞的(UUO)肾脏的代表性的PAS染色的切片。
图9表示在损伤后第10天,具有对照和阻塞的(UUO)肾脏的IgG-和3F7-处理的小鼠的体重减轻。
图10表示在损伤后第10天,具有对照和阻塞的(UUO)肾脏的IgG-和3F7-处理的小鼠的肾脏/体重比。
序列表的简述
SEQ ID NO:1是野生型Infestin-4的氨基酸序列。
SEQ ID NO:2是野生型SPINK-1的氨基酸序列。
SEQ ID NO:3是SPINK-1突变体K1的氨基酸序列。
SEQ ID NO:4是SPINK-1突变体K2的氨基酸序列。
SEQ ID NO:5是SPINK-1突变体K3的氨基酸序列。
SEQ ID NO:6是来自抗FXII抗体3F7的VH的氨基酸序列。
SEQ ID NO:7是来自抗FXII抗体3F7的VL的氨基酸序列。
SEQ ID NO:8是来自抗FXII抗体的VH CDR1的氨基酸序列。
SEQ ID NO:9是来自抗FXII抗体的VH CDR2的氨基酸序列。
SEQ ID NO:10是来自抗FXII抗体的VH CDR2的氨基酸序列。
SEQ ID NO:11是来自抗FXII抗体的VH CDR3的氨基酸序列。
SEQ ID NO:12是来自抗FXII抗体的VH CDR3的氨基酸序列。
SEQ ID NO:13是来自抗FXII抗体的VL CDR1的氨基酸序列。
SEQ ID NO:14是来自抗FXII抗体的VL CDR2的氨基酸序列。
SEQ ID NO:15是来自抗FXII抗体的VL CDR3的氨基酸序列。
SEQ ID NO:16是来自抗FXII抗体的VL CDR3的氨基酸序列。
SEQ ID NO:17是来自抗FXII抗体的VL CDR1的氨基酸序列。
SEQ ID NO:18是抗FXII抗体gVR115的VH的氨基酸序列。
SEQ ID NO:19是抗FXII抗体gVR115的VL的氨基酸序列。
SEQ ID NO:20是抗FXII抗体gVR115的重链的氨基酸序列。
SEQ ID NO:21是抗FXII抗体gVR115的轻链的氨基酸序列。
SEQ ID NO:22是人因子XII的氨基酸序列。
SEQ ID NO:23是成熟形式的人白蛋白的氨基酸序列。
SEQ ID NO:24是Infestin-4变体的氨基酸序列。
SEQ ID NO:25是Infestin-4变体的氨基酸序列。
描述
一般原则
在本说明书通篇中,除非另有明确说明或上下文另有要求,否则对单个步骤、物质的组合物、步骤组或物质的组合物组的引用应视为包含一个和多个(即一个或多个)那些步骤、物质的组合物、步骤组或物质的组合物组。
本领域技术人员将认识到,除了具体描述的内容以外,本公开内容还可以进行变化和修改。应当理解,本公开内容包括所有这样的变化和修改。本公开内容还单独地或共同地包括在本说明书中提及或指示的所有步骤、特征、组合物和化合物,以及所述步骤或特征的任何和所有组合或任何两个或更多个。
本公开内容的范围不受本文描述的具体实例的限制,这些实例仅旨在示例的目的。功能等效的产品、组合物和方法显然在本公开内容的范围内。
除非另有明确说明,否则本文中的本公开内容的任何实例均应作必要的变通而应用于本公开内容的任何其他实例。
除非另有明确定义,否则本文中使用的所有技术和科学术语均应具有本领域普通技术人员通常理解的相同含义(例如,在细胞培养、分子遗传学、免疫学、免疫组织化学、蛋白质化学和生物化学中)。
除非另有说明,否则本公开内容中使用的重组蛋白、细胞培养物和免疫学技术是本领域技术人员众所周知的标准程序。这样的技术在诸如以下来源的整个文献中进行了描述和解释:J.Perbal,A Practical Guide to Molecular Cloning,John Wiley and Sons(1984),J.Sambrook等人Molecular Cloning:A Laboratory Manual,Cold Spring HarborLaboratory Press(1989),T.A.Brown(editor),Essential Molecular Biology:APractical Approach,Volumes 1and 2,IRL Press(1991),D.M.Glover and B.D.Hames(editors),DNA Cloning:A Practical Approach,Volumes 1-4,IRL Press(1995and1996),和F.M.Ausubel等人(editors),Current Protocols in MolecularBiology,Greene Pub.Associates and WileyInterscience(1988,包括到目前为止的所有更新),Ed Harlow and David Lane(editors)Antibodies:A Laboratory Manual,ColdSpring Harbor Laboratory,(1988),和J.E.Coligan等人(editors)Current Protocolsin Immunology,John Wiley&Sons(包括到目前为止的所有更新)。
本文的可变区及其部分、免疫球蛋白、抗体及其片段的描述和定义可通过KabatSequences of Proteins of Immunological Interest,National Institutes ofHealth,Bethesda,Md.,1987年和1991年,Bork等人,J Mol.Biol.242,309-320,1994,Chothia and Lesk J.Mol Biol.196:901-917,1987,Chothia等人Nature 342,877-883,1989和/或Al-Lazikani等人,J Mol Biol 273,927-948,1997中的讨论来进一步阐明。本文对蛋白质或抗体的任何讨论应理解为包括该蛋白质或抗体的在制造和/或储存过程中产生的任何变体。例如,在制造或储存期间,抗体可以被脱酰胺(例如在天冬酰胺或谷氨酰胺残基处)和/或具有改变的糖基化和/或具有被转化为焦谷氨酰胺的谷氨酰胺残基和/或具有被去除或“剪断”的N末端或C末端残基和/或具有部分或全部的未完全处理并因此保留在抗体的末端的信号序列。应当理解,包含特定氨基酸序列的组合物可以是所述的或编码的序列和/或所述或编码序列的变体的异质混合物。
术语“和/或”,例如“X和/或Y”应被理解为表示“X和Y”或“X或Y”,并且应被理解为对两种含义或任一含义提供明确的支持。
在整个说明书中,单词“包括(comprise)”或诸如“包含(comprises)”或“含有(comprising)”的变体将被理解为暗示包括陈述的元素、整数或步骤或元素、整数或步骤的组,但不排除任何其他元素、整数或步骤或元素、整数或步骤的组。
如本文中所使用的,术语“源自”应被认为指示可以从特定来源获得指定的整数,尽管不必直接从该来源获得。
选择的定义
术语“肾部(renal)”和“肾脏(kidney)”在本文可互换使用。
凝血因子XII,也称为Hageman因子或FXII,其是血浆蛋白。它是因子XIIa的酶原形式,其是丝氨酸蛋白酶(或丝氨酸内肽酶)类别的一种酶。在人中,因子XII由F12基因编码。仅出于命名而非限制的目的,人因子XII的示例性序列在NCBI参考序列:NP_000496.2;NCPI蛋白登录号为NP_000496和SEQ ID NO:22中示出。因子XII的其他序列可以使用本文提供的序列和/或在公众可获得的数据库中确定和/或使用标准技术确定(例如,如Ausubel等人,(editors),Current Protocols in Molecular Biology,Greene Pub.Associates andWiley-Interscience(1988,包括目前为止的所有更新)或Sambrook等人,MolecularCloning:A Laboratory Manual,Cold Spring Harbor Laboratory Press(1989)所述)。
如本文所用,术语“因子XII抑制剂”或“FXII抑制剂”或“FXII的抑制剂”是指因子XII(在活化之前,即其酶原)和活化的因子XII(FXIIa)中的一种或两种的抑制剂,以及FXII的活化的抑制剂。因此,“FXII的抑制剂”可以包括FXII和FXIIa(也称为αFXIIa)(包括FXIIa裂解产物FXIIaα和FXIIaβ(也称为FXIIf))中的一种或两种以及FXII的活化的抑制剂。FXII抑制剂包括野生型抑制剂的功能变体和片段。功能性变体或片段是保留野生型分子抑制FXII、FXIIa或FXII活化的至少50%(例如,约50%,或约60%,或约70%,或约80%,或约90%,或约95%,或约99%,或约100%)的能力的分子。在一个实例中,FXII抑制剂是非内源性抑制剂;也就是说,它们不是在人体或动物体内天然存在的抑制剂。
如本文所用,术语“直接FXII抑制剂”或“直接抑制剂”是指通过与FXII(或FXIIa)接触(例如结合)起作用的抑制剂,即FXII抑制剂结合FXII和/或FXIIa并且抑制其活性和/或活化。相反,间接抑制剂可在不接触FXII(或FXIIa)蛋白的情况下起作用。例如,反义RNA可以用来减少FXII基因的表达,或者一种小分子可以通过与下游FXIIa反应伴侣(如因子XI)的相互作用来抑制FXIIa的作用;这些不会直接与FXII蛋白相互作用。因此,与直接抑制剂相对应的,间接抑制剂在FXII蛋白的上游或下游起作用。在一个实例中,FXII抑制剂对FXII或FXIIa具有特异性,特别是对人FXII或FXIIa具有特异性。
如本文所用,术语“因子XII的抑制剂”或“因子XII抑制剂”应还被理解为不涵盖C1-INH,即“前提是因子XII的抑制剂不是C1INH”。
如本文所用,在提及蛋白质或其抗原结合位点与抗原的相互作用时术语“结合”是指该相互作用取决于抗原上特定结构(例如,抗原决定簇或表位)的存在。例如,抗体识别并结合特定的蛋白质结构,而不是一般的蛋白质。如果抗体与表位“A”结合,则在包含标记的“A”和蛋白质的反应中包含表位“A”(或游离的未标记的“A”)的分子的存在将减少与抗体结合的标记的“A”的量。
如本文所用,术语“特异地结合”或“特异性结合”应被理解为是指蛋白质或其抗原结合位点更频繁地、更迅速地、以更长的持续时间和/或以更大的亲和力与特定的抗原或表达该抗原的细胞(与其他抗原或细胞相比)反应或缔合。例如,蛋白质或其抗原结合位点以实质上更大的亲和力(例如1.5倍或2倍或5倍或10倍或20倍或40倍或60倍或80倍至100倍或150倍或200倍)与FXII(或FXIIa)结合,相对于其与其他凝血因子或通常被多反应性天然抗体(即已知与人中天然存在的多种抗原结合的天然存在的抗体)所识别的抗原的结合而言。通常,但并非必须,结合是指特异性结合,并且每个术语应理解成给另一个术语提供明确的支持。
术语“酰胺分解活性”是指FXII的抑制剂催化另一种多肽中的至少一个肽键的水解的能力。如本文所用,术语“同一性”或“相同”是指相同的或构成保守取代的氨基酸的百分比数。同源性可以使用序列比较程序如GAP(Deveraux等人,1984,Nucleic AcidsResearch 12,387-395,其通过引用并入本文)确定。以这种方式,可以通过将缺口插入比对中(例如通过GAP使用的比较算法来确定此类缺口)来比较与本文引用的那些序列的长度相似或基本上不同的长度的序列。
“半衰期延长多肽”或“HLEP”是多肽融合伴侣,其可以增加FXII抑制剂在患者或动物中的体内半衰期。实例包括白蛋白和免疫球蛋白及其片段,例如Fc结构域或衍生物,其可以直接地或通过可裂解或不可裂解的接头与FXII抑制剂融合。Ballance等人(WO 2001/79271)描述了融合多肽,其包含与人血清白蛋白融合的多种不同的治疗性多肽。如本文所用,术语“白蛋白”和“血清白蛋白”涵盖人白蛋白(HA)及其变体。仅出于命名而非限制的目的,白蛋白的完全成熟形式以及来自其他物种的白蛋白和其变体的示例性序列示于SEQ IDNO:23。如本文所用,“白蛋白”是指具有白蛋白的一种或多种功能活性(例如生物学活性)的白蛋白多肽或氨基酸序列或白蛋白变体。在某些实例中,白蛋白用于稳定或延长FXII抑制剂的治疗活性。白蛋白可以源自任何脊椎动物,尤其是任何哺乳动物,例如人、猴子、牛、绵羊或猪。也可以使用非哺乳动物白蛋白,其包括但不限于来自鸡和鲑鱼的白蛋白。与白蛋白连接的多肽的白蛋白部分可以来自与治疗性多肽部分不同的动物。白蛋白融合蛋白的实例参见WO 2008/098720,其通过引用整体并入本文。
术语“重组”应理解为是指人工遗传重组的产物。因此,在包含抗体可变区的重组蛋白的情况下,该术语不涵盖受试者体内天然存在的抗体,该抗体是在B细胞成熟过程中发生的天然重组的产物。但是,如果这样的抗体是分离的,则可以认为其是包含抗体可变区的分离的蛋白。类似地,如果使用重组方式分离并表达编码蛋白质的核酸,则所得蛋白质为重组蛋白质。重组蛋白还包括当其在例如表达其的细胞、组织或受试者体内时,通过人工重组手段表达的蛋白。
术语“蛋白质”应被认为包括单个多肽链,即通过肽键连接的一系列连续氨基酸或彼此共价或非共价连接的一系列多肽链(即多肽复合物)。例如,可以使用合适的化学键或二硫键将一系列多肽链共价连接。非共价键的例子包括氢键、离子键、范德华力和疏水相互作用。
从上段将理解术语“多肽”或“多肽链”是指通过肽键连接的一系列连续氨基酸。
本领域技术人员将意识到,“抗体”通常被认为是包含由多个多肽链组成的可变区的蛋白质,例如,包含轻链可变区(VL)的多肽和包含重链可变区(VH)的多肽。抗体通常还包含恒定结构域,其中一些结构域可以排列成恒定区,在重链的情况下,该恒定区包括恒定片段或可结晶片段(Fc)。VH和VL相互作用形成Fv,该Fv包含能够与一种或几种紧密相关的抗原特异性结合的抗原结合区。通常,来自哺乳动物的轻链是κ轻链或λ轻链,而来自哺乳动物的重链是α、δ、ε、γ或μ。抗体可以是任何类型(例如IgG、IgE、IgM、IgD、IgA和IgY)、类别(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类。术语“抗体”还涵盖人源化抗体、灵长类化抗体、人抗体、同人源化抗体和嵌合抗体。“抗FXII抗体”包括结合和/或抑制FXII酶原和活化蛋白(FXIIa)(包括FXIIaα和FXIIaβ裂解片段)中的一种或两种的抗体。在一些实例中,抗体特异性结合FXIIa或FXIIa的α或β链片段。
术语“全长抗体”、“完整抗体”或“整个抗体”可互换使用,是指与抗体的抗原结合片段相反,其基本完整形式的抗体。具体而言,完整抗体包括具有包含Fc区的重链和轻链的抗体。恒定结构域可以是野生型序列恒定结构域(例如,人野生型序列恒定结构域)或其氨基酸序列变体。
如本文所用,“可变区”是指如本文所定义的抗体的轻链和/或重链的能够与抗原特异性结合并且包括互补决定区(CDR)(即CDR1、CDR2和CDR3)以及框架区(FR)的氨基酸序列的部分。示例性的可变区包含三个或四个FR(例如,FR1、FR2、FR3和任选地FR4)以及三个CDR。在衍生自IgNAR的蛋白质的情况下,蛋白质可能缺少CDR2。VH是指重链的可变区。VL是指轻链的可变区。
如本文所用,术语“互补决定区”(同义CDR,即CDR1、CDR2和CDR3)是指抗体可变结构域的氨基酸残基,其存在对于抗原结合是必需的。每个可变结构域通常具有三个CDR区域,分别标识为CDR1、CDR2和CDR3。在执行本公开内容时可以根据Kabat Sequences ofProteins of Immunological Interest,National Institutes of Health,Bethesda,Md.,1987年和1991年或其他编号系统例如Chothia and Lesk J.Mol Biol.196:901-917,1987;Chothia等人Nature 342,877-883,1989;和/或Al-Lazikani等人,J Mol Biol 273:927-948,1997;Lefranc等人,Devel.And Compar.Immunol.,27:55-77,2003的IMGT编号系统;或Honnegher and Plükthun J.Mol.Biol.,309:657-670,2001的AHO编号系统,来定义分配给CDR和FR的氨基酸位置。
“框架区”(FR)是除CDR残基之外的那些可变结构域残基。
如本文所用,术语“可变区片段”或“Fv”应理解为是指包含VL和VH的任何蛋白质,无论是由多个多肽还是由单个多肽组成,其中VL和VH缔合形成具有抗原结合位点(即能够与抗原特异性结合)的复合物。形成抗原结合位点的VH和VL可以在单个多肽链中或在不同的多肽链中。此外,本公开内容的Fv(以及本公开内容的任何蛋白质)可以具有多个抗原结合位点,其可以或可以不结合相同的抗原。该术语应理解为包括直接源自抗体的片段以及与使用重组方法产生的这种片段相对应的蛋白质。在一些实例中,VH不连接至重链恒定结构域(CH)和/或VL不连接至轻链恒定结构域(CL)。示例性的包含Fv的多肽或蛋白质包括Fab片段、Fab'片段、F(ab')片段、scFv、双抗体、三抗体、四抗体或更高级的复合物,或与恒定区或其结构域例如CH2或CH3结构域相连的任何前述物质,例如微型抗体或抗体。“Fab片段”由抗体的单价抗原结合片段组成,并且可以通过用木瓜蛋白酶消化完整抗体以产生由完整的轻链和部分重链组成的片段来产生,或者可以使用重组方法生产。可以通过用胃蛋白酶处理完整抗体然后还原以产生由完整轻链和部分重链(包含VH和单个恒定结构域)组成的分子来获得抗体的“Fab'片段”。以这种方式处理的每个抗体获得两个Fab'片段。Fab片段也可以通过重组方式产生。抗体的“F(ab')2片段”由通过两个二硫键结合在一起的两个Fab'片段的二聚体组成,并且通过用胃蛋白酶处理整个抗体分子而无需随后还原来获得。“Fab2”片段是包含使用例如亮氨酸拉链或CH3结构域连接的两个Fab片段的重组片段。“单链Fv”或“scFv”是含有抗体的Fv的重组分子,其中轻链的可变区和重链的可变区通过合适的柔性多肽接头共价连接。从前面的讨论中将明显的是,该术语涵盖包含VH和VL的抗体或其抗原结合片段。
如本文所用,两个多肽序列之间的术语“序列同一性”或“同一性”表示在序列之间(优选在由SEQ ID NO.1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、24、25编码的氨基酸序列的整个长度上)相同的氨基酸的百分比。优选地,本发明的多肽序列具有分别至少约70%、75%、80%、85%、90%、95%、96%、97%、98%或99%的序列同一性。
如本文所用,术语“预防(preventing)”、“防止(prevent)”或“阻止(prevention)”包括施用本公开内容的化合物从而停止或阻碍病症的至少一种症状的发展或进展。
如本文所用,术语“治疗(treating)”、“医治(treat)”或“疗治(treatment)”包括施用本文所述的蛋白质从而减轻或消除特定疾病或病症的至少一种症状或减慢疾病或病症的进展。如本文所用,术语“受试者”应理解为是指包括人在内的任何动物,例如哺乳动物。示例性受试者包括但不限于人和非人灵长类动物。例如,受试者是人。
预防和治疗肾纤维化和慢性肾脏疾病
本文的公开内容提供了通过向受试者施用因子XII的抑制剂来治疗肾纤维化和/或慢性肾脏疾病(CKD)的方法。
本公开内容还提供了用于预防受试者的肾纤维化和/或CKD的方法,其包括向受试者施用因子XII的抑制剂。
CKD是一种进行性疾病,其可以细分为I至V阶段。根据疾病的严重程度,可以通过向受试者施用因子XII的抑制剂来减缓和/或预防从一个阶段到另一个阶段的进展。
本文公开的治疗和预防方法适用于天然肾脏和移植/同种异体移植的肾脏。
在一个实例中,受试者患有以下肾脏疾病的一种或多种:
-肾纤维化
-糖尿病性肾病,肾小球肾炎
-狼疮肾炎
-肾血管炎
-肾小球硬化
-高血压性肾病(肾硬化)
-间质性肾炎
-常染色体显性多囊肾
-Alport综合症
-镇痛剂肾病
-与缺血再灌注或排斥反应相关的肾脏同种异体移植损伤。
在一个实例中,受试者已患有或正在患有与肾部或肾脏纤维化相关的病症。例如,受试者已患有或正在患有糖尿病。
本公开内容的方法可以容易地应用于与肾纤维化和/或CKD相关的任何形式的肾脏疾病。
在一个实例中,受试者处于发展肾纤维化和/或CKD的风险中,但是尚未发生肾纤维化的发作。如果受试者具有比对照群体高的发展肾纤维化和/或CKD的风险,则该受试者处于风险中。对照群体可以包括从没有患有过糖尿病或其他与肾纤维化相关的肾脏疾病或不具有糖尿病或其他与肾纤维化相关的肾脏疾病的家族病史的一般群体中随机选择的一个或多个受试者(例如,年龄、性别、种族和/或种族特点匹配的)。
如果发现与肾纤维化和/或CKD相关的“风险因素”与该受试者相关(GFR降低、蛋白尿、糖尿病、高血压、肥胖、肾脏移植患者中人白细胞抗体的存在),则该受试者可被认为处于肾纤维化和/或CKD的风险中。风险因素可以包括与给定疾病相关的任何活动、特性、事件或性质,例如,通过对受试者群体进行统计或流行病学研究。因此,即使鉴定潜在风险因素的研究并未明确包括受试者,也可以将该受试者归类为处于肾纤维化的风险中。
如上文和以下实施例部分所讨论的,本公开内容的方法实现以下一种或多种效果:
使用FXIIa抑制剂的治疗
(i)显著降低细胞外基质蛋白的丰度,
(ii)在早期和晚期均不影响巨噬细胞的累积或细胞因子的产生,
(iii)在早期和晚期导致凋亡的肾小管上皮细胞的数量明显减少,
(iv)在早期和晚期导致增殖的肾小管上皮细胞的数量增加(=再生),和/或
(v)减轻体重减轻。
对本领域技术人员明显的是,受试者的肾脏疾病例如肾纤维化的症状或作用的“减轻”或“减弱”将与也患有肾脏疾病例如肾纤维化但尚未接受本文所述方法的治疗的另一受试者或与治疗前的该受试者进行比较。并不一定需要同时比较两个受试者。可以依靠人口数据。例如,评估未接受本文所述方法的治疗的患有肾纤维化的受试者群体(任选地,与所治疗的受试者相似的受试者群体,例如年龄、体重、糖尿病状态)并将平均值与用本文所述方法治疗的受试者或受试者群体的结果进行比较。
因子XII的抑制剂
在一个实例中,FXII的抑制剂是直接FXII抑制剂,例如特异性FXII抑制剂。例如,如果以1:1的摩尔比使用,特异性FXII抑制剂抑制血浆丝氨酸蛋白酶或除FXII和/或FXIIa以外的其他内源性蛋白质小于或等于约25%。例如,当FXII/FXIIa抑制剂以相应血浆丝氨酸蛋白酶与所述抑制剂的1:1的摩尔比使用时,所述FXII/FXIIa抑制剂的特异性抑制剂抑制除FXII和/或FXIIa以外的血浆丝氨酸蛋白酶小于或等于约25%。在一个实例中,如果以1:1的摩尔比使用,FXII抑制剂酶抑制除FXII和/或FXIIa以外的血浆丝氨酸蛋白小于或等于约20%,或小于或等于约15%,或小于或等于约10%,或小于或等于约5%,或小于或等于约1%。例如,特异性FXII抗体抑制血浆丝氨酸蛋白酶FXIa约5%,其中FXIa与所述抗体的摩尔比为1:1,而相同的FXII抗体抑制FXIIa至少约80%或至少约90%。
在一个实例中,如果以相应血浆丝氨酸蛋白酶与抑制剂的1:1的摩尔比使用,另一种血浆丝氨酸蛋白酶被抑制超过约50%。在本公开内容的另一个实例中,如果以相应血浆丝氨酸蛋白酶与抑制剂的1:1的摩尔比使用,则另外两种血浆丝氨酸蛋白酶被抑制超过约50%。
丝氨酸蛋白酶抑制剂
在一个实例中,FXII的抑制剂是丝氨酸蛋白酶抑制剂。例如,FXII的抑制剂包含对应于Infestin-4或其变体的序列。在一个实例中,FXII的抑制剂包含对应于SPINK-1或其变体的序列。
Infestin-4
在一个实例中,本公开内容提供了包含Infestin结构域4(称为“Infestin-4”)的FXII抑制剂。Infestin是一类丝氨酸蛋白酶抑制剂,其来源于食血昆虫Triatomainfestans的中肠,Triatoma infestans是克氏锥虫(Trypanosoma cruzi)的主要载体,其已知导致Chagas病。(Campos ITN等人32Insect Biochem.Mol.Bio.991-997,2002;CamposITN等人577FEBS Lett.512-516,2004;WO 2008/098720)。该昆虫使用这些抑制剂来防止摄入的血液的凝结。Infestin基因编码4个结构域,这些结构域产生可以抑制凝血途径中的不同因子的蛋白质。特别地,结构域4编码一种蛋白质(Infestin-4),其是FXIIa的强抑制剂。已经在小鼠中施用了Infestin-4,而没有引起出血并发症(WO 2008/098720;Hagedorn等人,Circulation 2010;121:1510-17)。
在一个实施方案中,FXII的抑制剂包括Infestin-4。如本文所用,术语“Infestin-4”涵盖保留抑制FXII能力的野生型肽的变体或片段。仅出于命名而非限制的目的,在SEQID NO:1中示出了Infestin-4的示例性序列。
在一个实例中,选择Infestin-4是因为其抑制FXIIa的能力。在一个实例中,Infestin-4包括Infestin-4的变体,其中该变体包含Infestin结构域4,以及任选地Infestin结构域1、2和/或3。在一个实例中,Infestin-4是加(His)6-标签的Infestin-4构建体。
在另一个实例中,Infestin-4是包含与infestin-4连接或结合的融合伴侣的融合蛋白,所述融合伴侣例如是半衰期延长多肽(例如白蛋白,IgG的Fc结构域或PEG)。在一个实例中,接头将融合伴侣连接至Infestin-4。在各种实施方案中,Infestin-4是在Hagedorn等人,Circulation 2010;117:1153-60中描述的rHA-Infestin-4蛋白。在一个实例中,组合物包含通过柔性接头结合于Hagedorn等人,Circulation 2010;117:1153-60中描述的rHA-Infestin-4蛋白的白蛋白。在另一个实例中,使用了FXII的其他Infestin-4抑制剂,其实例描述在WO 2008/098720和Hagedorn等人,Circulation 2010;117:1153-60中,两者均通过引用整体并入本文。
在一个实例中,FXII的抑制剂是Infestin-4的变体。如本文所用,Infestin-4的术语“变体”是指具有一个或多个氨基酸突变的多肽,其中“突变”被定义为针对野生型Infestin-4序列(SEQ ID NO:1)的取代、缺失或添加。Infestin-4的术语“变体”还包括野生型或突变的Infestin-4序列的功能片段。
在一个实例中,野生型Infestin-4序列的一种或多种突变基本上不改变该多肽抑制FXII的功能性能力。例如,一种或多种突变没有完全或基本上消除多肽抑制FXII的能力。例如,变体保留野生型Infestin-4的抑制能力的至少约20%,或约30%,或约40%,或约50%,或约60%,或约70%,或约80%,或约90%,或约95%,或约98%,或约99%,或更多。
在一个实例中,FXII的抑制剂包含Infestin-4变体,其包含来自如SEQ ID NO:1所示的野生型Infestin-4序列的氨基末端的残基2-13。例如,Infestin-4变体包含SEQ IDNO:24所示的氨基酸序列。
在一个实例中,FXII的抑制剂包含Infestin-4变体,其包含SEQ ID NO:1的残基2-13,并且还在SEQ ID NO:1的残基2-13之外包含与野生型Infestin-4序列(SEQ ID NO:1)相比的至少一个氨基酸突变。例如,Infestin-4变体包含至少两个氨基酸突变,或至少三个氨基酸突变,或至少四个氨基酸突变,或至少五个氨基酸突变。例如,FXII的抑制剂包含含有经修饰以在SEQ ID NO:1的N末端氨基酸位置2-13之外包含1-5个氨基酸突变的SEQ ID NO:1的多肽序列。
在一个实例中,FXII的抑制剂是Infestin-4变体,其保留了来自野生型Infestin-4序列的六个保守的半胱氨酸残基。在一个实例中,六个保守的半胱氨酸残基是野生型Infestin-4序列(SEQ ID NO:1)的位置6、8、16、27、31和48处的氨基酸。在一个实例中,Infestin-4变体在位置48处包含最后的保守的半胱氨酸。在另一个实例中,半胱氨酸残基的确切位置以及彼此之间的相对位置可以因Infestin-4变体序列的插入或缺失而从野生型Infestin-4序列的位置6、8、16、27、31和48发生改变。
在一个实例中,Infestin-4变体与野生型Infestin4序列至少约70%相同。例如,Infestin-4与野生型Infestin-4序列具有至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%或至少约99%的同一性。例如,FXII的抑制剂包含多肽序列,该多肽序列包含与SEQ ID NO:1至少70%相同的序列,并保留来自SEQ ID NO:1的六个保守的半胱氨酸残基。
在一个实例中,FXII的抑制剂是Infestin-4变体,其保留了来自野生型Infestin-4序列的六个保守的半胱氨酸残基和/或具有与野生型Infestin-4序列至少约70%相同的序列。
在一个实例中,FXII的抑制剂是包含经修饰以在SEQ ID NO:1的N末端氨基酸位置2-13之外含有1-5个氨基酸突变的SEQ ID NO:1;和与SEQ ID NO:1至少70%相同,并保留来自SEQ ID NO:1的六个保守的半胱氨酸残基的Infestin-4变体。
实施例
方法
为了评估3F7抗体在治疗实验性肾纤维化中的功效,采用了肾损伤和纤维化的UUO模型。在该模型中,小鼠在输尿管阻塞后7-10天内发展出严重的间质性肾纤维化。
为了阻塞左输尿管,用氯胺酮/甲苯噻嗪(分别为50和5mg/kg;Pfizer,Germany的Ketavet和Bayer,Germany的Rompun)麻醉2个月大的C57Bl/6小鼠。将左侧剃毛,并在左侧肾脏上方制造中线切口。用缝合线将左输尿管打结两次,直到终点和切口闭合。在手术过程中,通过将小鼠置于37℃的加热垫上来维持体温。小鼠分为两组:单侧输尿管阻塞(UUO)小鼠接受媒介物(IgG,作为同种型对照,每只小鼠1mg,n=5)或抗FXIIa抗体(3F7,每只小鼠1mg,n=10)。从UUO建立后的第一天开始施加3F7。结扎后立即将该物质静脉内注射到尾静脉中,然后每天注射一次,直到处死小鼠进行分析为止。对侧肾脏作为对照(Schaefer L.等人,J Pathol,2002)。在UUO后第3或10天处死小鼠。左输尿管阻塞后3或10天分析血浆和肾脏。
实施例1–减少的萎缩肾小管数量/减少的肾小管扩张
如上文方法部分所述,在UUO后10天将小鼠处死,并通过目标器官的形态和生化变化表征纤维化程度。石蜡包埋样品的连续切片(2μm)用PAS染色。肾小管间质病变的严重程度使用先前描述(Moreth K.等人,J Clin Invest,2010)的活动指数从0到5分级(正常,轻度,中度,晚期或严重)。对于每只动物,评估皮质和髓质中至少15个肾小管间质区域,并对针对肾小管扩张和萎缩进行分级。计算每只小鼠的肾小管损伤得分作为每张图像的加总的个体得分的平均值。结果显示在图1A和1B中,其中图1A表示在损伤后第10天在IgG-处理和3F7-处理的小鼠的对照和阻塞的(UUO)肾脏中确定的肾小管损伤评分,其中图1B显示在损伤后第10天IgG-和3F7-处理的小鼠的对照和阻塞的(UUO)肾脏的PAS染色的切片。从图1A和1B可以看出,用3F7抗体处理的小鼠在用3F7抗体处理的小鼠的阻塞的肾脏中相对于IgG处理的对照显著减少了萎缩的肾小管的数量和减少了肾小管扩张。
实施例2–对α-SMA表达的减弱作用
在UUO期间,同种型(IgG)处理的对照肾脏显示α-SMA的表达的显著增加,如UUO后10天通过qPCR、蛋白质印迹和免疫组织化学评估的。3F7抗体对FXIIa的抑制显著降低UUO肾脏中的α-SMA表达,如可以从表示通过蛋白质印迹(图2B)和免疫组织化学(图2C)评估的α-SMA的表达的图2B和C所见的。在用3F7抗体处理的UUO肾脏中α-SMA mRNA表达没有降低,如通过qPCR评估的(图2A)。
实施例3–对细胞外基质蛋白表达的减弱作用
类似地,UUO极大地增加了细胞外基质蛋白、纤连蛋白(FN)和胶原蛋白I(Col I)的表达,而用3F7抗体治疗显著降低了UUO后10天阻塞的肾脏中这些成分的丰度,如可以从表示通过qPCR(图3A)、蛋白质印迹(图3B)和免疫组织化学(图3C)评估的FN的表达的图3A-C和表示通过qPCR评估的Col I的表达(图4A)、羟基脯氨酸含量的测量(图4B)和免疫组织化学(图4C)的图4A-C所见的。
实施例4–关于对F4/80阳性巨噬细胞的作用的研究
为了确定所观察到的FXIIa抑制的有益作用是否是炎症抑制的结果,发明人还检查了UUO后10天UUO肾脏中的巨噬细胞浸润和细胞因子水平。发明人发现,UUO诱导了F4/80阳性巨噬细胞在肾脏中的累积,而使用3F7抗体的处理对它们在阻塞的器官中的数量没有影响。该结果在图5A和5B中表示。此外,在用IgG-和3F7-处理的UUO动物之间,TNF-α和IL-6的水平没有差异(数据未显示)。
实施例5–凋亡细胞的数量的减少
由于在UUO后10天发生纤维化而非炎症反应,发明人还分析了损伤后3天的阻塞的肾脏。令人惊讶地,施用3F7抗体既不影响UUO肾脏中的巨噬细胞累积也不影响细胞因子的产生(数据未显示)。但是,在这个时间点,与受IgG攻击的UUO同窝仔相比,观察到3F7处理的UUO小鼠中凋亡(裂解的胱天蛋白酶-3阳性)的肾小管上皮细胞数量的显著减少,如可以从图6中显示的损伤后第3天来自IgG-或3F7-处理的小鼠的对照和阻塞的(UUO)肾脏的代表性胱天蛋白酶-3染色的切片所见的。
此外,与注射IgG的小鼠相比,接受3F7的动物中增殖的(Ki67阳性)肾小管上皮细胞的数量增加,如可以从图7中显示的损伤后第3天来自IgG-或3F7-处理的小鼠的对照和阻塞的(UUO)肾脏的代表性Ki67染色的切片所见的。
这导致功能性肾小管的数量增加和收缩的和萎缩性肾小管的明显减少,如可以从图8中显示的损伤后第3天来自IgG-或3F7-处理的小鼠的对照和阻塞的肾脏的代表性PAS染色的切片所见的。改善的肾小管形态与细胞外基质成分的减少的累积高度相关(数据未显示)。
这些发现非常令人惊讶,因为它们与在肺纤维化的博来霉素模型中观察到的结果不同,在博莱霉素模型中,在肺损伤早期,凋亡的和增殖的肺泡上皮细胞的数量在3F7-和IgG-处理的小鼠之间没有差异。
实施例6–减轻体重减轻
如可以从图9所见的,UUO后的体重减轻在3F7处理的小鼠中与IgG处理的小鼠相比减少。从可以图10所见的,肾脏/体重比也是如此。
综上所述,这些实施例表明,在肾纤维化的UUO模型中抑制FXIIa防止功能性肾小管的丢失、减少肾纤维化的演变并减轻体重减轻。
实施例7–3F7对基因表达的影响
基因表达分析
方法
按照试剂盒说明,使用LIRAK试剂盒(Agilent)扩增纯化的总RNA进行Cy3标记。每个反应使用200ng总RNA。将Cy标记的aRNA与点样在微阵列载玻片(Agilent Technologies,设计ID074809)上的8×60K 60-聚体寡核苷酸杂交过夜。按照Agilent杂交方案进行杂交,然后洗涤和干燥载玻片。使用InnoScan 900(Innopsys,Carbonne,France)以2μm/像素的分辨率扫描干燥的载玻片。使用Mapix 6.5.0软件执行图像分析,并将所有斑点的计算值另存为GenePix结果文件。使用R软件和BioConductor的limma软件包评估存储的数据。取对数平均点信号用于进一步分析。使用NormExp程序对阴性对照斑点进行数据的背景校正,并在取平均值之前进行分位数归一化。使用适中的t统计量对基因进行差异表达排序。使用基因集测试对t值的排序进行途径分析。
实验与结果
为了确定抗FXII抗体(3F7)处理对原位分子特征的影响,本发明人对来自用抗FXII抗体(3F7)或IgG同种型对照处理的动物的UUO肾匀浆样品进行了基因表达分析。抗FXII抗体处理组中的五个最下调的基因表明抑制的:1)细胞凋亡:harakiri(Hrk),2)Wnt/β-连环蛋白信号传导:dickkopf相关蛋白2(Dkk2),3)细胞生长:核受体亚家族2E组成员1(Nr2e1),CWF19样细胞周期控制因子1(Cwf19l1),和4)谷氨酸转运:溶质载体家族1成员3(Slc1a3)。抗FXII抗体处理组中的四个最上调的基因表明FXII抑制对以下的影响:1)ECM细胞和细胞间通信:桥粒芯蛋白1γ(Dsg1c),2)血管生成:血管生成素样7(Angptl7),3)离子稳态:anoctamin 2(Ano2),和4)转录调控:调控因子X6(Rfx6)(表1)
表1
用抗FXII抗体处理后,肾脏匀浆物中调节的编码基因:
不想受任何特定作用理论的束缚,本文报道的实验结果表明3F7处理对基因表达有影响,这可以解释在实验动物中所报道的作用,例如凋亡细胞数量的减少(参见上述实施例5),或上述防止功能性肾小管的损失、肾纤维化的减少的演变以及减轻的体重减轻。
序列表
<110> 杰特有限公司
<120> FXIIa抑制剂在治疗肾纤维化和/或慢性肾脏疾病中的应用
<130> 2017_P003_A274
<150> EP 17207595.4
<151> 2017-12-15
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Ser Gly Ser Ser Glu Met Thr Val His His Tyr Val Tyr
1 5 10
<210> 18
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 来自抗FXII抗体gVR115的VH的氨基酸序列
<400> 18
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Tyr
20 25 30
Ile Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asp Ile Pro Thr Lys Gly Thr Val Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Leu Pro Arg Ser Gly Tyr Leu Ile Ser Pro His Tyr Tyr
100 105 110
Tyr Tyr Ala Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser
115 120 125
Ser
<210> 19
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 来自抗FXII抗体gVR115的VL的氨基酸序列
<400> 19
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Arg Asn
20 25 30
Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ala Ser Leu
85 90 95
Arg Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 20
<211> 456
<212> PRT
<213> 人工序列
<220>
<223> 来自抗FXII抗体gVR115的重链的氨基酸序列
<400> 20
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Tyr
20 25 30
Ile Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asp Ile Pro Thr Lys Gly Thr Val Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Leu Pro Arg Ser Gly Tyr Leu Ile Ser Pro His Tyr Tyr
100 105 110
Tyr Tyr Ala Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser
115 120 125
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
130 135 140
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
145 150 155 160
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
165 170 175
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
180 185 190
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
195 200 205
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
210 215 220
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
225 230 235 240
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
245 250 255
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
260 265 270
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
275 280 285
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
290 295 300
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
305 310 315 320
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
325 330 335
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
340 345 350
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
355 360 365
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
370 375 380
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
385 390 395 400
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
405 410 415
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
420 425 430
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
435 440 445
Ser Leu Ser Leu Ser Leu Gly Lys
450 455
<210> 21
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 来自抗FXII抗体gVR115的轻链的氨基酸序列
<400> 21
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Arg Asn
20 25 30
Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ala Ser Leu
85 90 95
Arg Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro
100 105 110
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu
115 120 125
Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro
130 135 140
Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala
145 150 155 160
Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala
165 170 175
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg
180 185 190
Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr
195 200 205
Val Ala Pro Thr Glu Cys Ser
210 215
<210> 22
<211> 615
<212> PRT
<213> 智人
<220>
<223> 人因子XII的氨基酸序列
<400> 22
Met Arg Ala Leu Leu Leu Leu Gly Phe Leu Leu Val Ser Leu Glu Ser
1 5 10 15
Thr Leu Ser Ile Pro Pro Trp Glu Ala Pro Lys Glu His Lys Tyr Lys
20 25 30
Ala Glu Glu His Thr Val Val Leu Thr Val Thr Gly Glu Pro Cys His
35 40 45
Phe Pro Phe Gln Tyr His Arg Gln Leu Tyr His Lys Cys Thr His Lys
50 55 60
Gly Arg Pro Gly Pro Gln Pro Trp Cys Ala Thr Thr Pro Asn Phe Asp
65 70 75 80
Gln Asp Gln Arg Trp Gly Tyr Cys Leu Glu Pro Lys Lys Val Lys Asp
85 90 95
His Cys Ser Lys His Ser Pro Cys Gln Lys Gly Gly Thr Cys Val Asn
100 105 110
Met Pro Ser Gly Pro His Cys Leu Cys Pro Gln His Leu Thr Gly Asn
115 120 125
His Cys Gln Lys Glu Lys Cys Phe Glu Pro Gln Leu Leu Arg Phe Phe
130 135 140
His Lys Asn Glu Ile Trp Tyr Arg Thr Glu Gln Ala Ala Val Ala Arg
145 150 155 160
Cys Gln Cys Lys Gly Pro Asp Ala His Cys Gln Arg Leu Ala Ser Gln
165 170 175
Ala Cys Arg Thr Asn Pro Cys Leu His Gly Gly Arg Cys Leu Glu Val
180 185 190
Glu Gly His Arg Leu Cys His Cys Pro Val Gly Tyr Thr Gly Ala Phe
195 200 205
Cys Asp Val Asp Thr Lys Ala Ser Cys Tyr Asp Gly Arg Gly Leu Ser
210 215 220
Tyr Arg Gly Leu Ala Arg Thr Thr Leu Ser Gly Ala Pro Cys Gln Pro
225 230 235 240
Trp Ala Ser Glu Ala Thr Tyr Arg Asn Val Thr Ala Glu Gln Ala Arg
245 250 255
Asn Trp Gly Leu Gly Gly His Ala Phe Cys Arg Asn Pro Asp Asn Asp
260 265 270
Ile Arg Pro Trp Cys Phe Val Leu Asn Arg Asp Arg Leu Ser Trp Glu
275 280 285
Tyr Cys Asp Leu Ala Gln Cys Gln Thr Pro Thr Gln Ala Ala Pro Pro
290 295 300
Thr Pro Val Ser Pro Arg Leu His Val Pro Leu Met Pro Ala Gln Pro
305 310 315 320
Ala Pro Pro Lys Pro Gln Pro Thr Thr Arg Thr Pro Pro Gln Ser Gln
325 330 335
Thr Pro Gly Ala Leu Pro Ala Lys Arg Glu Gln Pro Pro Ser Leu Thr
340 345 350
Arg Asn Gly Pro Leu Ser Cys Gly Gln Arg Leu Arg Lys Ser Leu Ser
355 360 365
Ser Met Thr Arg Val Val Gly Gly Leu Val Ala Leu Arg Gly Ala His
370 375 380
Pro Tyr Ile Ala Ala Leu Tyr Trp Gly His Ser Phe Cys Ala Gly Ser
385 390 395 400
Leu Ile Ala Pro Cys Trp Val Leu Thr Ala Ala His Cys Leu Gln Asp
405 410 415
Arg Pro Ala Pro Glu Asp Leu Thr Val Val Leu Gly Gln Glu Arg Arg
420 425 430
Asn His Ser Cys Glu Pro Cys Gln Thr Leu Ala Val Arg Ser Tyr Arg
435 440 445
Leu His Glu Ala Phe Ser Pro Val Ser Tyr Gln His Asp Leu Ala Leu
450 455 460
Leu Arg Leu Gln Glu Asp Ala Asp Gly Ser Cys Ala Leu Leu Ser Pro
465 470 475 480
Tyr Val Gln Pro Val Cys Leu Pro Ser Gly Ala Ala Arg Pro Ser Glu
485 490 495
Thr Thr Leu Cys Gln Val Ala Gly Trp Gly His Gln Phe Glu Gly Ala
500 505 510
Glu Glu Tyr Ala Ser Phe Leu Gln Glu Ala Gln Val Pro Phe Leu Ser
515 520 525
Leu Glu Arg Cys Ser Ala Pro Asp Val His Gly Ser Ser Ile Leu Pro
530 535 540
Gly Met Leu Cys Ala Gly Phe Leu Glu Gly Gly Thr Asp Ala Cys Gln
545 550 555 560
Gly Asp Ser Gly Gly Pro Leu Val Cys Glu Asp Gln Ala Ala Glu Arg
565 570 575
Arg Leu Thr Leu Gln Gly Ile Ile Ser Trp Gly Ser Gly Cys Gly Asp
580 585 590
Arg Asn Lys Pro Gly Val Tyr Thr Asp Val Ala Tyr Tyr Leu Ala Trp
595 600 605
Ile Arg Glu His Thr Val Ser
610 615
<210> 23
<211> 609
<212> PRT
<213> 智人
<220>
<223> 人白蛋白成熟形式的氨基酸序列
<400> 23
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu
35 40 45
Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala
100 105 110
Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
130 135 140
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys
145 150 155 160
Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys
180 185 190
Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu
195 200 205
Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys
210 215 220
Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
245 250 255
Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile
275 280 285
Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu
290 295 300
Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp
305 310 315 320
Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser
325 330 335
Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val
355 360 365
Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
370 375 380
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
385 390 395 400
Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys
405 410 415
Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu
420 425 430
Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
450 455 460
Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
465 470 475 480
Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg
485 490 495
Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
515 520 525
Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
530 535 540
Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala
565 570 575
Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe
580 585 590
Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly
595 600 605
Leu
<210> 24
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> Infestin-4变体的氨基酸序列
<400> 24
Val Arg Asn Pro Cys Ala Cys Phe Arg Asn Tyr Val
1 5 10
<210> 25
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> Infestin-4变体的氨基酸序列
<400> 25
Asp Ser Leu Gly Arg Glu Val Arg Asn Pro Cys Ala
1 5 10
Claims (17)
1.因子XII(FXII)的抑制剂,其用于治疗或预防受试者特别是人或动物受试者的慢性肾脏疾病和/或肾纤维化。
2.根据权利要求1使用的FXII抑制剂,其中慢性肾脏疾病和/或肾纤维化是以下一种或多种的结果和/或与之相关:肾小球硬化,肾瘢痕形成,肾脏中的局部缺血/再灌注损伤,急性肾损伤,肾脏移植/同种异体移植排斥反应,复发性原发疾病,和/或与FXII/FXIIa介导的补体形成相关的炎症性肾脏疾病,选自肾炎、狼疮性肾炎、C3-肾小球肾炎、致密沉积病、非典型溶血尿毒症综合征、链球菌感染后肾小球肾炎、过敏性紫癜性肾炎、抗体介导的肾脏移植排斥反应。
3.根据权利要求1或2使用的FXII抑制剂,其中所述FXII抑制剂:
(i)结合FXII和/或FXIIa;或
(ii)结合FXII和/或FXIIa并抑制FXII和/或FXIIa的活性和/或抑制FXII的活化。
4.根据权利要求1至3中任一项使用的FXII抑制剂,其中所述FXII抑制剂是丝氨酸蛋白酶抑制剂或包含:
(i)SEQ ID NO:1的野生型Infestin-4多肽序列,或包含以下的多肽序列:
-经修饰以在SEQ ID NO:1的N末端氨基酸位置2-13之外包含1-5个氨基酸突变的SEQID NO:1;和/或
-与SEQ ID NO:1至少70%,80%或85%相同并且保留来自SEQ ID NO:1的六个保守的半胱氨酸残基的序列;或
(ii)SEQ ID NO:2的野生型SPINK-1多肽序列,或包含以下的多肽序列:
-经突变以用SEQ ID NO:1的位置2-13的N末端氨基酸替换位置2-13的N末端氨基酸的SEQ ID NO:2;和
-任选地进一步修饰以包含1-5个额外的氨基酸突变,这些突变增加多肽序列与SEQ IDNO:1的序列的同源性;和/或
-与SEQ ID NO:2至少70%相同并且保留来自SEQ ID NO:2的六个保守的半胱氨酸残基的序列;或
(iii)选自K1(SEQ ID NO:3)、K2(SEQ ID NO:4)和K3(SEQ ID NO:5)的SPINK-1突变体。
5.根据权利要求1至3中任一项使用的FXII抑制剂,其中所述FXII抑制剂是包含可变区片段(Fv)的蛋白质。
6.根据权利要求5使用的FXII抑制剂,其中所述FXII抑制剂是抗FXII抗体或其抗原结合片段。
7.根据权利要求6使用的FXII抑制剂,其中所述抗FXII抗体包含:
(i)包含以下的VH:
-SEQ ID NO:6所示的序列;或
-包含SEQ ID NO:8所示的序列的CDR1;包含SEQ ID NO:10所示的序列的CDR2;和包含SEQ ID NO:12所示的序列的CDR3;或
-包含SEQ ID NO:8所示的序列的CDR1;包含SEQ ID NO:9所示的序列的CDR2;和包含SEQ ID NO:11所示的序列的CDR3;和/或
(ii)包含以下的VL:
-SEQ ID NO:7所示的序列;或
-包含SEQ ID NO:13所示的序列的CDR1;包含SEQ ID NO:14所示的序列的CDR2;和包含SEQ ID NO:16所示的序列的CDR3;或
-包含SEQ ID NO:13所示的序列的CDR1;包含SEQ ID NO:14所示的序列的CDR2;和包含SEQ ID NO:15所示的序列的CDR3。
8.根据权利要求6使用的FXII抑制剂,其中所述抗FXII抗体包含:
(i)包含SEQ ID NO:18所示的序列的VH和包含SEQ ID NO:19所示的序列的VL或
(ii)包含SEQ ID NO:20所示的序列的重链和包含SEQ ID NO:21所示的序列的轻链。
9.根据权利要求6至8中任一项使用的FXII抑制剂,其中所述抗FXII抗体是单特异性、双特异性或三特异性IgG抗体。
10.根据权利要求1至9中任一项使用的FXII抑制剂,其中所述FXII抑制剂连接至融合伴侣,优选其中所述融合伴侣包含聚乙二醇(PEG)或半衰期延长多肽,优选其中所述半衰期延长多肽选自白蛋白、afamin、甲胎蛋白、维生素D结合蛋白、人白蛋白、免疫球蛋白和IgG的Fc。
11.根据权利要求10使用的FXII抑制剂,其中所述半衰期延长多肽通过接头与FXII抑制剂连接。
12.根据权利要求10或11使用的FXII抑制剂,其中所述FXII抑制剂是包含通过接头肽与FXII抑制剂连接的人白蛋白的融合蛋白。
13.根据权利要求1至12中任一项使用的FXII抑制剂,其中所述FXII抑制剂静脉内或皮下或鞘内施用至受试者。
14.根据权利要求1至13中任一项使用的FXII抑制剂,其中所述FXII抑制剂以(i)单个剂量或(ii)多个剂量或(iii)作为连续剂量施用至受试者。
15.根据权利要求1至14中任一项使用的FXII抑制剂,其中所述FXII抑制剂以约0.01至约100mg/kg体重的浓度施用至受试者,优选其中所述FXII抑制剂以约1至约20mg/kg体重的浓度施用至受试者。
16.根据权利要求1至15中任一项使用的FXII抑制剂,其中所述受试者处于发展慢性肾脏疾病和/或肾纤维化的风险中,特别地其中所述慢性肾脏疾病和/或肾纤维化是以下一种或多种的结果和/或与之相关:肾小球硬化,肾瘢痕形成,肾脏中的局部缺血/再灌注损伤,急性肾损伤,肾脏移植/同种异体移植排斥反应,复发性原发疾病,和/或与FXII/FXIIa介导的补体形成相关的炎症性肾脏疾病,选自肾炎、狼疮性肾炎、C3-肾小球肾炎、致密沉积病、非典型溶血尿毒症综合征、链球菌感染后肾小球肾炎、过敏性紫癜性肾炎、抗体介导的肾脏移植排斥反应。
17.用于治疗或预防受试者的慢性肾脏疾病和/或肾纤维化的试剂盒,特别地其中所述慢性肾脏疾病和/或肾纤维化是以下一种或多种的结果和/或与之相关:肾小球硬化,肾瘢痕形成,肾脏中的局部缺血/再灌注损伤,急性肾损伤,肾脏移植/同种异体移植排斥反应,复发性原发疾病,和/或与FXII/FXIIa介导的补体形成相关的炎症性肾脏疾病,选自肾炎、狼疮性肾炎、C3-肾小球肾炎、致密沉积病、非典型溶血尿毒症综合征、链球菌感染后肾小球肾炎、过敏性紫癜性肾炎、抗体介导的肾脏移植排斥反应,所述试剂盒包含:
-至少一种FXII抑制剂;
-使用试剂盒来治疗或预防受试者的慢性肾脏疾病和/或肾纤维化的说明书,以及
-任选地,至少一种其他治疗活性化合物或药物。
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EP2497489A1 (en) * | 2011-03-09 | 2012-09-12 | CSL Behring GmbH | Factor XII inhibitors for the treatment of silent brain ischemia and ischemia of other organs |
EP2548892A1 (en) * | 2011-07-22 | 2013-01-23 | CSL Behring GmbH | Inhibitory anti-Factor XII/XIIa monoclonal Antibodies and their uses |
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JP2003530839A (ja) | 2000-04-12 | 2003-10-21 | プリンシピア ファーマスーティカル コーポレイション | アルブミン融合タンパク質 |
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ES2753183T3 (es) | 2007-02-12 | 2020-04-07 | Csl Behring Gmbh | Aplicación terapéutica de inhibidores de la proteasa de serina de tipo Kazal |
EP2371857A1 (en) | 2010-04-01 | 2011-10-05 | CSL Behring GmbH | Factor XII inhibitors for treating interstitial lung disease |
AU2012289001B2 (en) * | 2011-07-22 | 2016-03-03 | Csl Behring Gmbh | Inhibitory anti -factor XII/XIIa monoclonal antibodies and their uses |
EP2623110A1 (en) | 2012-01-31 | 2013-08-07 | CSL Behring GmbH | Factor XII inhibitors for the treatment of neurological inflammatory disorders |
WO2014089493A1 (en) * | 2012-12-07 | 2014-06-12 | Vanderbilt University | Antibodies against factor xii and uses thereof |
EP3013366B1 (en) * | 2013-06-28 | 2021-08-25 | CSL Behring GmbH | Combination therapy using a factor xii inhibitor and a c1-inhibitor |
CA2950988C (en) | 2014-06-18 | 2024-02-06 | Csl Behring Gmbh | Therapy using a factor xii inhibitor in a neurotraumatic disorder |
WO2017120397A1 (en) | 2016-01-08 | 2017-07-13 | Alnylam Pharmaceuticals, Inc. | Polynucleotide agents targeting factor xii (hageman factor) (f12) and methods of use thereof |
CN109071629A (zh) | 2016-04-06 | 2018-12-21 | 杰特有限公司 | 治疗动脉粥样硬化的方法 |
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EP2497489A1 (en) * | 2011-03-09 | 2012-09-12 | CSL Behring GmbH | Factor XII inhibitors for the treatment of silent brain ischemia and ischemia of other organs |
EP2548892A1 (en) * | 2011-07-22 | 2013-01-23 | CSL Behring GmbH | Inhibitory anti-Factor XII/XIIa monoclonal Antibodies and their uses |
CN105188750A (zh) * | 2013-03-08 | 2015-12-23 | 德国杰特贝林生物制品有限公司 | 治疗和预防远端缺血-再灌注损伤 |
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CA3085478A1 (en) | 2019-06-20 |
JP7317827B2 (ja) | 2023-07-31 |
CN111479587B (zh) | 2024-01-09 |
US20210070879A1 (en) | 2021-03-11 |
BR112020011240A2 (pt) | 2020-11-24 |
EP3723804A1 (en) | 2020-10-21 |
EP3723804A4 (en) | 2021-10-20 |
JP2021506773A (ja) | 2021-02-22 |
WO2019113642A1 (en) | 2019-06-20 |
KR20200100116A (ko) | 2020-08-25 |
US11505619B2 (en) | 2022-11-22 |
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