CN116723863A - 用于治疗出血性病症的组合物和方法 - Google Patents
用于治疗出血性病症的组合物和方法 Download PDFInfo
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Abstract
本公开涉及使用如PEG化抗VWF适体BT200等VWF靶向剂治疗出血性病症,特别是A型血友病(轻度、中度或重度血友病)和1型或2型或3型冯维勒布兰德氏病(VWD)。
Description
相关申请交叉引用
本申请要求以下美国临时专利申请的优先权权益:于2020年11月24日提交的第63/117,545号;于2021年3月1日提交的第63/155,012号;以及于2021年6月30日提交的第63/216,601号;所述美国临时专利申请中的每一个通过全文引用的方式并入本文。
序列表的引用
本申请与电子格式的序列表一起提交。序列表以于2021年11月24日创建的大小为40,029字节的以20591009PCTSEQLST.txt命名的文件提供。序列表的电子格式的信息通过引用其整体并入本文。
技术领域
本公开涉及用于如遗传性出血性病症(例如,A型血友病和冯维勒布兰德氏病(vonWillebrand disease,VWD))等出血性病症的治疗的药剂、组合物和方法。所述方法使用与VWF结合的药剂以及其药物组合物和调配物。
背景技术
出血性病症是血液无法正常凝结的一组异质性病状。因此,患有出血性病症的患者在受伤、创伤或外科手术后将经历广泛性出血。一些患者可能会出现重度且自发性的出血。出血性病症可以是遗传性的或后天性的。遗传性出血性病症通常是由涉及凝血的因子(即凝血因子(coagulation factor);也称为凝血因子(clotting factor))缺陷以及血管和血小板异常引起的。由凝血蛋白缺陷引起的遗传性出血性病症包含A型血友病和B型血友病,1型、2型(包含2a、2b、2m和2n亚型)和3型冯维勒布兰德氏病(VWD),和其它罕见出血性病症。血小板引起的出血性病症包含血小板计数较少的遗传性血小板减少症巨血小板综合征(Bernard-Soulier syndrome)和血小板无力症(Glanzmann's thrombasthenia)。
凝血是一个复杂的过程,包含一系列组分的顺序相互作用,尤其是纤维蛋白原、因子II(FII)、因子V(FV)、因子VII(FVII)、因子VIII(FVIII)、因子IX(FIX)、因子X(FX)、因子XI(FXI)、因子XII(FXII)和冯维勒布兰德氏因子(von Willebrand Factor,VWF)。凝血组分与血液中的血小板相互作用以维持正常止血。
任何凝血组分的缺陷和/或凝血组分与血小板之间的调节中断都可能导致出血性病症。凝血因子的遗传缺陷,例如编码这些因子的基因突变会导致罕见遗传性出血,例如血友病。血友病是一种X连锁遗传性出血性病症,其发病率约为10,000例活产中有一例。血友病是由凝血因子VIII(FVIII)(A型血友病)或凝血因子IX(FIX)(B型血友病)缺陷引起的(例如,Samuelson等人综述的,《血液综述(Blood Rev.)》,2019,35:43-50)。编码FVIII的基因突变可以导致A型血友病。A型血友病的临床表现通常以自发性和长期出血为特征,范围从轻度、中度到重度不等。
冯维勒布兰德氏因子(VWF)是一种大血浆糖蛋白,在血浆中循环,并且在正常止血中发挥重要作用。VWF介导血小板粘附于血管损伤部位暴露的内皮下胶原蛋白,以促进血小板介导的栓塞形成。VWF还通过与因子VIII(FVIII)和血小板表面糖蛋白结合来发挥其止血功能,并且将FVIII定位在血小板栓塞和随后血栓形成的部位。与FVIII复合的VWF还稳定血浆中的FVIII蛋白,并且保护其免受循环中激活的蛋白C的蛋白水解降解。因此,FVIII-VWF复合物延长了FVIII的循环寿命。
VWF的缺陷(deficiency和/或defect)可以导致冯维勒布兰德氏病(VWD)。VWD最常见的症状包含粘膜皮肤出血、血肿和创伤或外科手术后出血,类似于A型血友病,因为缺陷VWF辅因子导致FVIII快速降解。VWD是最常见的遗传性出血性病症,估计患病率为约1%。约有1:10,000个体出现临床相关的出血症状。VWD可能是由VWF的定量和/或定性缺陷引起的。VWF的定量缺陷通常与重度1型和3型VWD相关联。2型VWD通常由VWF的定性缺陷(即VWF的功能缺陷)引起。例如,2b型VWD的特征在于VWF与血小板糖蛋白Ib的结合亲和力增加,这导致一些VWD患者消耗VWF和血小板减少症,从而导致重度出血表型。
目前,A型血友病使用血浆源性或重组FVIII的蛋白质替代疗法进行治疗。尽管FVIII替代/替代物可以显著改善患有血友病的患者的生活,但血友病患者仍有重度出血和慢性关节损伤的风险,因为预防性治疗受到半衰期短、可用性有限和纯化FVIII蛋白成本高的限制。VWD患者出血的治疗和预防重点是将血浆VWF和FVIII水平增加到足够的止血水平。目前的治疗包含通过施用去氨加压素(DDAVP)和输注含有VWF的因子浓缩物(例如,VWF/FVIII浓缩物)或重组VWF制剂来刺激内源性VWF的释放。治疗的选择取决于疾病的类型和出血的严重程度。
本公开提供了用于治疗出血性病症的VWF靶向剂,尤其是A型血友病,包含轻度、中度和重度血友病,以及1型、2型(例如2a型、2b型、2m型和2n型)和3型冯维勒布兰德氏病(VWD)。VWF靶向剂包含VWF结合适体以及其变体。
发明内容
在本公开的一方面,提供了用于治疗患者的出血性病症的方法。所述方法包括向所述患者施用药学上有效量的包括VWF靶向剂的组合物。
根据本公开,所述患者被诊断患有出血性病症。所述出血性病症是一种遗传性出血性病症,包含A型血友病(例如,轻度、中度或重度血友病)、VWD(例如,1型VWD、2a型、2b型、2m型和2n型VWD以及3型VWD)、遗传性血小板减少症和罕见出血性病症。所述出血性病症也可能是后天性的,例如抑制剂诱导的血小板减少症。在一个实施例中,所述患者被诊断患有A型血友病。所述患者可能患有轻度血友病、中度血友病或重度血友病。在另一个实施例中,所述患者被诊断患有1型、如2a型、2b型和2n型等2型或3型VWD。
在一些实施例中,所述VWF靶向剂是与VWF结合的VWF结合剂。所述VWF靶向剂是抗体、纳米抗体、肽、寡核苷酸、RNA(例如,siRNA、microRNA)、合成多核苷酸(例如,适体)或小分子。
在一些实施例中,所述VWF结合剂是选自以下的合成多核苷酸:SEQ IDNo.:3、BT99(SEQ ID No.:4)、BT100(SEQ ID No.:5)、BT200(SEQ ID No.:6)、ARC15105(SEQ ID No.:7)、ARC1779(SEQ ID No.:8)或其变体。
在一些实施例中,患有出血性病症的所述患者可以接受单剂量或多剂量的所述VWF靶向剂。在一个实施例中,所述患者接受多剂量的所述VWF结合剂。
在一个优选实施例中,所述VWF靶向剂是BT200,其为一种PEG化适体,与人VWF的A1结构域特异性结合。在一个实施例中,BT200以范围为1.0mg至10.0mg或1.0mg至6.0mg的剂量施用。
另一方面,本公开提供了用于增加受试者的血液系统中VWF的循环水平的方法。所述方法包括向所述受试者施用包括VWF靶向剂的组合物。所述VWF靶向剂与VWF结合并增加循环中的VWF水平。在一些实施例中,所述VWF靶向剂是与VWF结合的VWF结合剂。作为非限制性实例,所述VWF结合剂是选自以下的合成多核苷酸:SEQ ID No.:3、BT99(SEQ ID No.:4)、BT100(SEQ ID No.:5)、BT200(SEQ ID No.:6)、ARC15105(SEQ IDNo.:7)、ARC1779(SEQ IDNo.:8)或其变体。在一个优选实施例中,所述VWF靶向剂是BT200,其为一种PEG化适体,与人VWF的A1结构域特异性结合。BT200以范围为1.0mg至10.0mg或1.0mg至6.0mg的剂量施用。在一些实施例中,所述受试者被诊断患有VWD,例如,1型VWD,2型VWD,包含2a型、2b型和2n型,以及3型VWD。在其它实施例中,所述受试者被诊断患有包含1型、2型和3型的VWD,并且接受因子替代治疗。
在又另一方面,本公开提供了用于延长受试者的血液系统中FVIII的循环寿命的方法。所述方法包括向所述受试者施用包括VWF靶向剂的组合物。所述VWF靶向剂与VWF结合并增加循环中的FVIII水平。在一些实施例中,所述VWF靶向剂是与VWF结合的VWF结合剂。作为非限制性实例,所述VWF结合剂是选自以下的合成多核苷酸:SEQ ID No.:3、BT99(SEQ IDNo.:4)、BT100(SEQ ID No.:5)、BT200(SEQ ID No.:6)、ARC15105(SEQ IDNo.:7)、ARC1779(SEQ ID No.:8)或其变体。在一个优选实施例中,所述VWF靶向剂是BT200,其为一种PEG化适体,与人VWF的A1结构域特异性结合。BT200以范围为1.0mg至10.0mg或1.0mg至6.0mg的剂量施用。在一些实施例中,所述受试者被诊断患有A型血友病,例如轻度、中度或重度血友病。在一些实例中,所述受试者被诊断患有A型血友病,并且接受因子替代治疗。在其它实施例中,所述受试者被诊断患有1型VWD或2型VWD(包含2a型、2b型和2n型)或3型VWD。在一些实例中,所述受试者被诊断患有VWD,并且接受VWF替代治疗。
附图说明
图1显示了健康志愿者共同施用BT200和去氨加压素对VWF和FVIII水平的加和效应。
图2是显示皮下注射BT200后,患有2b型VWD的患者的血小板计数的直方图。
图3显示了皮下注射BT200后,患有2b型VWD的患者的增加的FVIII水平和活性(aPTT FS)。
图4A示出了皮下注射BT200后增加的VWF水平;图4B示出了患有2b型VWD的患者皮下注射BT200后增加的VWF活性。
图5示出了患有轻度A型血友病的患者在BT200预防性治疗后增加的因子VIII活性(%)。
具体实施方式
以下描述中阐述了本公开的一个或多个实施例的细节。虽然与本文所描述的那些材料和方法类似或等同的任何材料和方法均可以用于实践或测试本公开,但是现在描述了优选的材料和方法。根据描述,本公开的其它特征、目的和优点将变得显而易见。在描述中,单数形式还包含复数形式,除非上下文另有明确说明。除非另外定义,否则本文所使用的所有技术术语和科学术语均具有与本公开所属领域的普通技术人员通常所理解的含义相同的含义。在冲突的情况下,将以本说明书为准。
本公开涉及用于治疗如遗传性出血性病症(例如,A型血友病和VWD)等出血性病症的方法、药剂和药物组合物以及其调配物。一种用于治疗患者的出血性病症的方法,所述方法包括向所述患者施用治疗有效量的药物组合物,所述药物组合物包括靶向冯维勒布兰德氏因子(VWF)的药剂。
特别地,本文中的药剂涉及可以靶向血液中的VWF的任何分子。VWF靶向剂可以与VWF结合以介导VWF止血功能。VWF靶向剂可以是抗体、纳米抗体、肽、寡核苷酸、RNA(例如,siRNA、microRNA)、适体以及其变体或小分子。根据本公开,VWF靶向剂是源自与VWF特异性结合的适体的合成多核苷酸。靶向剂可以用一种或多种化学修饰和缀合物进一步修饰。所述药剂和VWF复合物保护循环的VWF不被清除,由此增加血液中VWF和FVIII的水平,以增加凝血。
定义
为了更清楚和简洁地描述要求保护的公开的主题,为特定术语提供了以下定义,所述特定术语用于以下描述和所附权利要求中。贯穿本说明书,特定术语的例示应该被认为是非限制性实例。
药物组合物:如本文所使用的,术语“药物组合物”有时可以与术语“药物调配物”互换使用。其是指活性化合物与药学上可接受的载体或赋形剂(惰性或活性)的组合,使组合物适用于体外、体内或离体诊断或治疗用途。在本公开的上下文中,活性化合物可以是一种或多种可以用于治疗出血性病症的化合物。
药学上可接受的赋形剂:如本文所使用的,术语“药学上可接受的赋形剂”意指可用于制备通常安全、无毒并且在生物学上和其它方面均合乎需要的药物组合物的载体或赋形剂,并且包含对于兽医用途以及人类药物用途而言是可接受的载体或赋形剂。如在说明书和权利要求中所使用的,“药学上可接受的载体或赋形剂”包含一种和多于一种此类载体或赋形剂两者。如本文所使用的,术语“药学上可接受的载体”涵盖任何标准药学载体,如磷酸盐缓冲盐溶液、水和乳液(如油/水或水/油乳液)以及各种类型的润湿剂。在一些实例中,组合物和调配物还可以包含稳定剂和防腐剂。术语“药学上可接受的”是指生理上可耐受的并且当向人施用时通常不产生不良反应的分子实体和组合物。优选地,如本文所使用的,术语“药学上可接受的”意指由联邦或州政府的管理机构批准的或在美国药典或其它普遍认可的药典中列出的可用于动物,并且更具体地用于人,或通常公认为用于胃肠外产品安全的药物。
治疗有效量:如本文所使用的,术语“治疗有效量”是指足以产生治疗应答的化合物的量。与本公开相关,术语“治疗有效量”可以指足以产生治疗应答的抗VWF适体的量。治疗应答可以是用户(例如,临床医生)将识别为对疗法具有有效应答的任何应答。所需的精确量将因受试者而异,这取决于受试者的物种、年龄和一般状况、特定的治疗剂、其施用模式和/或途径等。然而,应理解的是,本公开的化合物和组合物的总日用量可以在合理的医学判断的范围内由主治医师决定。
预防(preventing、prevention或prevent)如本文所使用的,术语“预防”(“prevent”、“preventing”和“prevention”)以及其语法变体可以互换使用。这些术语是指部分或完全延迟或阻止病症或病状和/或一种或多种其伴随症状的发作或复发或者阻止受试者获得或重新获得病症或病状或降低受试者获得或重新获得病症或病状或一种或多种其伴随症状的风险的方法。
治疗(treating、treatment或treat):如本文所使用的,术语“治疗”(“treating”、“treatment”和“to treat”)以及其语法变型是指向受试者施用有效量的药物组合物,使得疾病的至少一种症状逆转、治愈、缓解、改善、减轻、减少或达到有益或期望的临床结果,如疾病程度的减轻,疾病的稳定(例如,不恶化)状态、疾病进展的延迟或减缓、疾病状态的改善或缓和以及缓解(部分或全部;以及可检测或不可检测)。
受试者:如本文所使用的,术语“受试者”可以与术语“个体”和“患者”互换使用,并且指脊椎动物,优选地哺乳动物,更优选地人。
注射剂:如本文所使用的,术语“注射剂”或“可注射调配物”是指可以被抽入注射器并向受试者(例如,人)皮下、腹腔内或肌内注射的组合物。
肠胃外施用:如本文所使用的,药物调配物的术语“肠胃外施用”是指通过除局部或口服(即非局部和非口服途径)以外的途径向受试者施用。肠胃外途径的实例包含皮下、肌内、血管内(包含动脉内或静脉内)、腹膜内、眶内、眼球后、眼球周、鼻内、肺内、鞘内、脑室内、椎管内、脑池内、囊内、胸骨内或病灶内施用。肠胃外施用可以是例如,通过持续或间歇和/或脉动的团注或连续输注,并且可以通过针或导管或其它管道。
皮下施用:如本文所使用的,术语“皮下施用”是指药物组合物的常用施用途径,包含但不限于皮下注射和输注。输注可以是连续的或使用输液泵或任何其它可商购获得的装置喷射。
止血和凝血组分
凝血是一个复杂而动态的生物过程,涉及凝血组分的顺序相互作用,所述凝血组分包含凝血因子:因子II(FII)、因子V(FV)、因子VII(FVII)、因子VIII(FVIII)、因子IX(FIX)、因子X(FX)、因子XI(FXI)、因子XII(FXII)和辅因子冯维勒布兰德氏因子(VWF)。
因子VIII(FVIII)(也称为抗血友病因子A)是一种大血浆糖蛋白,是液相凝血级联反应的关键组分。FVIII主要由肝细胞和血管内皮细胞产生。人FVIII是最大的凝血因子之一,包含三个A-结构域、一个独特的B-结构域和两个C-结构域,并且通过FXa和凝血酶的蛋白水解切割被激活,以产生激活的FVIII异源三聚体(FVIIIa)。FVIIIa在凝血级联反应中作为凝血酶原酶和腾那斯(tenase)复合物的非酶辅因子,在存在FIXa、磷脂和钙离子的情况下加速FX激活(Fay等人,《血液综述(Blood Reviews)》,2004,18:1-15)。FVIII的半衰期为约12小时。为了避免过度凝血,FVIIIa必须在激活后不久通过蛋白C(APC)介导的切割进行失活。FVIIIa的失活是一个快速的过程,这解释了FVIIIa在血液中半衰期短的原因。如本文所使用的,术语“因子VIII(a)”和“FVIII(a)”包含FVIII和FVIIIa两者。类似地,术语“因子VIII”和“FVIII”可以包含FVIII和FVIIIa两者。
血浆中存在的FVIII与冯维勒布兰德氏因子(VWF)相关,形成非共价FVIII-VWF复合物。冯维勒布兰德氏因子(VWF)是一种大多聚体糖蛋白,并且在止血和血栓形成中起着关键作用。人VWF前原蛋白(GeneBank参考号NP_000543.2;SEQ ID No.:1)(由cDNA编码:GeneBank参考号NM_000552.3;SEQ ID No.:2)被加工成包括具有不同功能的多个亚结构域的成熟多肽(Hassan和Saxena,《血液凝固和纤溶(Blood Coagul.Fibrinolysis)》,2012,23(1):11-22)。VWF是FVIII的载体蛋白,其将FVIII与血小板表面糖蛋白结合,并且将FVIII定位在血小板栓塞和随后血栓形成的位点。VWF还通过形成非共价结合的VWF-FVIII复合物在循环中充当FVIII的稳定剂,所述复合物保护FVIII不被激活的蛋白C(APC)降解,由此防止FVIII过早蛋白水解(Koppelman等人,《血液(Blood.)》,1996;87:2292–2300)。另外,VWF阻断FVIII与脂蛋白相关受体的相互作用,并且由此增加FVIII在循环中的半衰期。
此外,VWF与FVIII之间的相互作用在FVIII功能、免疫原性和清除中起着至关重要的作用,其中VWF基本上是作为FVIII的伴侣。VWF在正常生理条件下和患有血友病的患者中对FVIII具有重要的保护作用。在用FVIII替代疗法治疗后已经形成了FVIII抑制剂(例如,FVIII替代物的抗体)的血友病患者中,VWF可以保护外源性FVIII免于与抑制性抗体结合(Gensana等人,《血友病(Hemophilia.)》,2001;7:369–374)。
VWF的血浆水平可以影响出血(低水平的VWF)或血栓形成(较高水平的VWF)的风险。血浆VWF的定量缺陷(低水平)(如<50%)与出血风险增加相关,而VWF的高血浆水平(如>150%)会增加血栓形成风险(例如,静脉血栓栓塞疾病、缺血性中风、冠状动脉疾病、心肌梗塞和外周血管疾病的风险更高)。
出血和出血性病症
凝血过程中的缺陷可能会增加出血的风险,例如,凝血因子缺陷和血小板数量或功能缺陷会导致出血性病症。出血可以发生在身体内部(内出血)、皮肤下方或来自皮肤表面(外出血)。
如本文所使用的,术语“出血性病症”是指当血液无法正常凝结时导致的一组异质性病状。在正常凝血中,血小板粘在一起并在受伤的血管部位形成栓塞。血液中的凝血因子相互作用以形成纤维蛋白凝块,本质上是凝胶栓塞,其将血小板固定在适当的位置并允许受伤部位愈合,同时防止血液从血管中流出。无法形成血栓可以是非常危险的,会导致过度出血。出血可能是由于血小板过少或异常、凝血因子异常或含量低、凝血因子功能失调(例如,编码凝血因子的基因突变)或血管异常导致的。出血严重程度可以根据指南进行评估,如Rodeghiero等人综述的评估工具,ISTH/SSC出血评估工具:标准化问卷和一份关于遗传性出血疾病新出血评分的建议(ISTH/SSC bleeding assessment tool:a standardizedquestionnaire and a proposal for a new bleeding score for inherited bleedingdisorders),《血栓形成与止血杂志(J Thromb Haemost.)》2010年9月;8(9):2063-5.doi:10.1111/j.1538-7836.2010.03975.x)。患有出血性病症的人可能有内部出血和外部出血两者。出血性病症的常见症状包含但不限于受伤、外科手术、创伤或月经后的持续出血;过度瘀伤;关节、肌肉和软组织出血;胃肠道出血;无已知或可识别原因的自发性出血。
出血性病症可以是遗传性的或后天性的。如本文所使用的,术语“遗传性出血性病症”(也称为“先天性出血性病症”)是指一组由凝血组分遗传缺陷引起的罕见病症。最常见的出血性病症包含血友病(例如,A型血友病和B型血友病)和VWD(例如,1型、2型和3型)。A型血友病或B型血友病是一种罕见的遗传性出血性病症,根据患者血浆中残留因子活性的多少,其范围可以是轻度、中度到重度。A型血友病的发病率约为每5000名活产男性中就有1人,B型血友病的发病率为每25000名活产男性中就有1人。总的来说,其是世界上最常见的遗传性出血性病症之一。冯维勒布兰德氏病(VWD)是美国最常见的遗传性出血性病症,影响高达1%的美国人口。
出血也可能是由于血液中血小板(血小板(thrombocyte))计数低,这种病状被称为血小板减少症。成年人的正常血小板计数范围为每微升血液150,000个至450,000个血小板。血小板计数低于每微升150,000个血小板即低于正常水平(血小板减少症)。直到计数变得非常低——低于每微升10,000个或20,000个血小板前,严重出血的风险不会发生。当计数低于每微升50,000个血小板时,有时会出现轻度出血。如果血小板计数非常低,每微升少于10,000个或20,000个血小板时,可能会发生严重出血的风险。在极少数情况下,血小板数量可能非常低,从而发生危险的内出血。血小板减少症可能发生在各种情况下,如遗传性出血性病症和后天性病症(例如,药物副作用)。血小板计数低(血小板减少症)可能是由于骨髓产生的血小板不足,不能维持血液中足够血小板和/或容纳了过多血小板的脾脏异常。
导致血小板计数低(血小板减少症)的病症包含例如,血栓性血小板减少性紫癜(TTP);弥散性血管内凝血(DIC);免疫性血小板减少症(ITP);自身免疫性疾病;癌症、重度肝病和骨髓缺陷导致脾脏肿大病症;病毒或细菌感染;以及对药物的副反应。
A型血友病
经典血友病或A型血友病(也称为因子FVIII缺乏症)是一种遗传性出血性病症,由染色体X连锁的FVIII缺乏症引起,并且几乎只影响男性。编码FVIII的基因(即F8基因)的突变导致A型血友病。遗传突变可以导致FVIII的缺失或合成减少或蛋白质合成异常(Hong等人,《血栓形成研究(Thrombosis Res.)》,2007,119:1-13)。X染色体缺陷是由本身不是血友病患者的女性携带者传播的。由于染色体的随机激活,一些女性携带者可能从无症状到有症状不等,这取决于她们的FVIII失活程度。
由于没有足够的FVIII,血液无法正常凝结,A型血友病的临床表现是出血倾向增加,例如,小切口或受伤有过度出血的风险。另外,患有血友病的人可能会出现内出血,随着时间的推移,所述内出血可以损害关节(包含膝关节、踝关节、肘关节和髋关节)、肌肉、器官和组织(例如,皮肤下的软组织)。血友病出血强度取决于FVIII缺乏症的水平。A型血友病有三种形式:个体患者中的轻度、中度或重度(表1),这是基于缺陷的血浆FVIII(IU)确定的(Bolton Maggs和Pasi,《柳叶刀(Lancet)》,2003,361:1801-1809)。
表1:三种形式的血友病
*IU:国际单位
对于轻度遗传性出血性病症,其它健康个体也会出现出血症状。尽管患有轻度出血性病症的患者在日常生活中可能不经常出血,但止血挑战后可能会出现问题,包含但不限于创伤、拔牙和外科手术。
A型血友病的治疗主要集中在通过因子替代物增加缺乏凝血因子VIII的血液活性,以抑制和/或预防患者的活动性出血。目前可用的治疗剂包含人血浆源性冻干FVIII浓缩物和由基因工程化细胞产生的重组凝血因子。FVIII浓缩物在血浆中的半衰期很短,成人平均为约12小时,患有A型血友病的个体患者的半衰期介于6小时与29小时之间,并且年幼儿童的半衰期甚至更短。血友病的FVIII替代物治疗通常需要频繁静脉注射治疗剂。
对于患有重度A型血友病的患者,预防性治疗需要增加剂量和给药间隔。
目前正在开发若干技术来延长FVIII在血液中的半衰期。由于绝大多数血浆FVIII在与VWF的高亲和力复合物中循环,FVIII大部分被清除,而不与VWF偶联。研究表明,血友病患者的FVIII受血浆VWF水平的显著影响。例如,Valentino已经表明,具有升高VWF水平的患者的FVIII半衰期显著更长(Valentino等人,《血友病》,2014,20:607-615)。靶向VWF伴侣以增加血浆FVIII-VWF复合物水平可以提供延长FVIII在血浆中半衰期的替代策略。
根据本公开,VWF靶向剂可以与VWF结合并延长VWF的半衰期,由此延长FVIII的半衰期。
冯维勒布兰德氏病(VWD)
尽管已被公认的是因子VIII缺乏(A型血友病)和因子IX缺乏(B型血友病),但冯维勒布兰德氏病(VWD)更为常见。VWF的缺陷(例如,数量减少、功能缺陷或完全缺失)会导致不同类型的VWD。VWD可以影响男性和女性两者。相反,VWF浓度或功能异常升高也会导致严重的医疗病症,如静脉血栓栓塞疾病(VTE)。基于血液中VWF和FVIII活性的水平,VWD分为三种不同类型(1型、2型和3型)。
3型VWD是VWF完全缺乏的最严重和最不常见的形式。患有3型VWD的患者的血液中几乎没有或没有VWF。在没有VWF作为载体的情况下,血液中FVIII的量也降低到低水平。3型VWD患者很难形成血小板栓塞和纤维蛋白凝块两者。3型VWD患者的关节和肌肉有自发性出血,其鼻子和嘴经常出血。患有3型VWD的女性可能有很长的月经期以及大量出血。
2型VWD与VWF的定性缺陷相关,并且在一些患者中可能与3型VWD一样严重,其包含四种亚型:2a型、2b型、2m型和2n型。2a型是由于VWF蛋白的错误大小导致的VWF多聚化缺陷引起的。异常的VWF多聚体使血小板无法形成良好的血小板栓塞。在2b型中,VWF蛋白具有异常活性,具有自发血小板结合的变体。VWF的附着会导致身体迅速清除血小板,这会导致血液中血小板和VWF两者的短缺。2m型是由配体与完整多聚体结合的VWF缺陷引起的。在2n型中,VWF在FVIII结合方面存在缺陷,不能作为FVIII的载体和保护剂。血液中FVIII的水平较低,因为缺乏足够的VWF来防止其降解。2n型VWD患者可能表现为轻度血友病,伴有一些相同的症状。2b型VWD尤其是由VWF的A1结构域的突变引起的,所述突变导致与血小板上GPIb受体结合的A1结构域组成性激活,导致VWF、FVIII和血小板的消耗性缺乏。
1型VWD是最温和且最常见的形式,占VWD的高达85%(由Robertson等人综述,《北美儿科临床(Pediatr Clin North Am.)》,2008,55(2):377-392),其与VWF的定量损失相关,但具有质量正常的VWF。由于血液中没有足够的VWF,1型中所见的FVIII水平可能较低。少数患有1型VWD的患者可能会出现重度出血。VWD 1型是一个非常异质的遗传缺陷家族,在最后一次计数时有85个独特的SNP,并且只有部分VWF缺乏。例如,1型VWD的维琴察型变体(Vicenza variant)的特征在于低血浆VWF水平和超正常VWF多聚体,这是由VWF清除率增加引起的(Alessandra等人,《血液》2002,99(1):180-184)。
其它罕见出血性病症
其它凝血因子缺乏可以导致罕见的出血性病症,例如罕见因子缺乏,包含因子I、II、V、VII、X、XI、XII和XIII缺乏。在其它遗传性病症中,可能会获得其它出血性病症,例如血小板病症,这是后天性出血性病症的最常见原因。
目前,A型血友病和VWD的标准治疗涉及频繁静脉输注FVIII和VWF制剂或浓缩物,所述制剂或浓缩液包括源自人供体血浆的FVIII和VWF复合物、重组FVIII制剂或重组VWF制剂。在重度A型血友病患者中,FVIII注射用于预防性治疗。由于FVIII的血浆半衰期短,必须向患者每周静脉施用约3次。VWD可以通过用含有血浆或重组来源的VWF的浓缩物进行替代疗法。增加VWF功能半衰期的一种方法是通过VWF的PEG化,其通过具有增加的半衰期来聚乙二醇化VWF,也将间接增强血浆中存在的FVIII的半衰期(PCT申请公开号:WO2006/071801;所述文献的内容通过全文引用的方式并入)。VWF抗原在特定位点处的PEG化可以保护VWF免受血浆中巨噬细胞介导的清除(Fazavaza等人,《血栓形成与止血杂志》,2020;18:1278-1290;所述文献的内容通过全文引用的方式并入)。
非常期望创造新的治疗,所述治疗可以增加患有出血性病症(例如,血友病和VWD)的患者的FVIII和VWF的功能半衰期,同时可以减少药物的施用频率或通过其它不那么麻烦和痛苦的施用方式施用。
本公开的发明人令人惊讶地发现,用PEG缀合修饰的VWF靶向适体可以在单剂量治疗后增加血液中的VWF和FVIII水平。VWF靶向核酸在任何浓度下都不会干扰血浆中FVIII的功能,并且在相对较低的浓度下也不会干扰VWF在血浆中的功能。
根据本公开,提供VWF靶向剂以结合血浆中的VWF并阻断其清除,由此增加VWF-FVIIII复合物在血浆中的半衰期。VWF靶向剂可以用于治疗遗传性出血性疾病,特别是A型血友病和VWD(例如,1型维琴察亚型(Vicenza subtype)、2型,包含2a、2b、2m和2n亚型,以及3型)。
VWF靶向剂
如本文所使用的,术语“靶向剂”是指与所关注的分子特异性结合并相互作用的药剂。VWF靶向剂是一种直接与VWF结合或通过另一种药剂间接与VWF结合以调节VWF生物活性(例如,VWF与FVIII的相互作用以及VWF和FVIII-VWF复合物的半衰期)的药剂(也称为“VWF结合剂”)。一般来说,靶向剂可以是抗体、纳米抗体、肽、寡核苷酸、RNA(例如,siRNA、microRNA)、合成多核苷酸(例如,适体)或可以与VWF结合的小分子。VWF靶向剂还包含与VWF结合由此阻断清除机制的药剂。在一些实施例中,VWF靶向剂可以用于治疗出血性病症,特别是A型血友病和VWD。VWF靶向剂也可以用于阻断血液中的VWF清除。
在一些实施例中,VWF靶向剂可以是基于核酸的,特别是与VWF结合的适体以及其变体。在一些实例中,VWF结合剂是适体或其盐。适体是短(即通常长度为12个至80个核苷酸)单链核酸聚合物,以高亲和力和特异性与VWF结合。适体是一种合成多核苷酸,可以使用指数富集的配体系统进化(SELEX)过程分离。
适体
适体是一种与特定靶分子结合并调节靶活性、结构或功能的生物分子。适体通常被称为“化学抗体”,具有与抗体类似的特征。适体可以是基于核酸的或基于氨基酸的,即核酸适体或肽适体。核酸适体通过经典的沃森-克里克碱基配对(Watson-Crick basepairing)以外的相互作用对靶分子具有特异性结合亲和力。核酸适体能够与选定的靶标特异性结合,并且通过结合阻断其靶标的能力。本公开的适体是合成寡核苷酸。典型的核酸适体大小约为10kDa至15kDa,以亚纳摩尔亲和力与其靶标结合,并且区分密切相关的靶标。核酸适体的靶标可以是但不限于蛋白质、核酸分子、肽、小分子和整个细胞。
核酸适体可以是核糖核酸(RNA)、脱氧核糖核酸(DNA)或混合的核糖核酸和脱氧核糖核酸(DNA/RNA杂合)。适体可以是单链的。适体的合适核苷酸长度范围为约15个至约150个核苷酸(nt),并且在各种其它优选实施例中,长度为15nt至30nt、20nt至25nt、20nt至45nt、30nt至100nt、30nt至60nt、25nt至70nt、25nt至60nt、40nt至60nt、25nt至40nt、30nt至40nt,15nt、16nt、17nt、18nt、19nt、20nt、21nt、22nt、23nt、24nt、25nt、26nt、27nt、28nt、29nt、30nt、31nt、32nt、33nt、34nt、35nt、36nt、37nt、38nt、39nt、40nt、41nt、42nt、43nt、44nt、45nt、46nt、47nt、48nt、49nt或50nt中的任一个或30nt至50nt、40nt至70nt或50nt至100nt。然而,序列可以被设计为具有足够的灵活性,使得其可以适应适体与靶标的相互作用。
如本文所使用的,术语“核酸”、“多核苷酸”、“寡核苷酸”可互换使用。核酸分子是由至少两个共价连接在一起的核苷酸组成的核苷酸聚合物。核酸分子是DNA(脱氧核糖核苷酸)、RNA(核糖核苷酸)以及重组RNA和DNA分子或使用核苷酸类似物产生的DNA或RNA的类似物。核酸可以是单链的或双链的、线性的或环状的。所述术语还包括核酸片段,如可以使用公开的提取方法回收的天然存在的RNA或DNA,或在体外人工合成的人工DNA或RNA分子(即合成多核苷酸)。核酸的分子量也不受限制,可以任选的在从若干个碱基对(bp)至几百个碱基对的范围内,例如约2个核苷酸至约1,0000个核苷酸,或约10个核苷酸至5,000个核苷酸,或约10个核苷酸至约1,000个核苷酸。
术语“核苷酸(nt)”是指核酸的单体,一种包含杂环碱基、糖和一个或多个磷酸酯基团的化合物。碱基是嘌呤和嘧啶的衍生物,并且糖是戊糖(脱氧核糖或核糖中的任一种)。
如本文所使用的,术语“修饰”是指将核酸(例如,寡核苷酸)与化学试剂进行化学反应的技术。核酸可以在碱基部分、糖部分或磷酸酯主链中被修饰。修饰包含但不限于2'-位糖修饰、5-位嘧啶修饰、8位嘌呤修饰、环外胺处的修饰、4-硫代尿苷的取代、5-溴或5-碘-尿嘧啶的取代、主链修饰、硫代磷酸酯或烷基磷酸酯修饰、甲基化、罕见碱基配对组合,如异碱基异胞苷和异胍等。修饰也可以包含3'和5'修饰,如加帽。核酸分子也可以通过与具有期望的生物属性的部分缀合来修饰。此类部分可以包含但不限于化合物、肽和蛋白质、碳水化合物、抗体、酶、聚合物、药物和荧光团。在一些实例中,多核苷酸与亲脂性化合物缀合,如胆固醇、二烷基甘油、二酰基甘油或非免疫原性高分子量化合物或聚合物,如PEG(聚乙二醇)或其它水溶性药学上可接受的聚合物,包含但不限于聚酰胺基胺(PAMAM)和多糖,如葡聚糖,或聚噁唑啉(POZ)。所述修饰可以旨在例如增加核酸分子的体内稳定性,或增强或介导分子的递送。
适体可以是单价的或多价的。适体可以是单体、二聚体、三聚体、四聚体或其它更高的多聚体。个体适体单体可以连接以形成多聚体适体融合分子。作为非限制性实例,连接寡核苷酸(即接头)可以被设计为含有与随机适体的5'臂和3'臂区域互补的序列,以形成二聚体适体。对于三聚体或四聚体适体,将对小的三聚体或四聚体(即Holliday连接样)DNA纳米结构进行工程化,以包含与随机适体的3'臂区域互补的序列,从而通过杂交产生多聚体适体融合。另外,3至5或5至10dT富集核苷酸可以作为适体结合基序之间的单链区被工程化到接头多核苷酸中,这提供了多个适体的灵活性和自由度,以协调和协同与细胞配体或受体的多价相互作用。可替代地,多聚体适体也可以通过将生物素化适体与链霉亲和素混合而形成。
如本文所使用的,术语“多聚体适体”或“多价适体”是指包括多个单体单元的适体,其中每个单体单元可以是其自身的适体。多价适体具有多价结合特征。多聚体适体可以是同源多聚体或异源多聚体。术语“同源多聚体”是指包括多个相同类型的结合单元的多聚体适体,即每个单元与同一靶分子的相同结合位点结合。术语“异源多聚体”是指包括不同类型的多个结合单元的多聚体适体,即每个结合单元与同一靶分子的不同结合位点结合,或每个结合单元与不同靶分子上的结合位点结合。因此,异源多聚体可以指在不同结合位点处与一个靶分子结合的多聚体适体或与不同靶分子结合的多聚体适体。与不同靶分子结合的异源多聚体也可以称为多特异性多聚体。
可以使用称为体外选择的过程产生针对靶分子(例如,VWF)的适体(Ellington和Szostak,《自然(Nature)》,1990;346:818-822)或SELEX(Tuerk和Gold,《科学(Science)》,1990,249:505-510)。这种方法允许与靶分子具有高度特异性结合的核酸分子的体外进化。SELEX方法在例如以下中进行了描述:美国专利第7,087,735号、美国专利第5,475,096号和美国专利第5,270,163号;所述美国专利中每一个的内容通过全文引用的方式并入本文。核酸适体可以使用本领域众所周知的方法合成。例如,所公开的适体可以使用本领域已知的标准寡核苷酸合成技术来合成。
VWF适体
根据本公开,VWF靶向剂是多核苷酸、其盐或其衍生物,所述靶向剂靶向VWF以例如调节血浆中VWF与FVIII之间的相互作用。在一些实施例中,VWF靶向剂是与VWF特异性结合的适体。因此,抗VWF适体也被称为“VWF结合剂”。
当合成多核苷酸与VWF结合时,可以阻断血液中的清除机制,由此增加血液中VWF抗原的水平。所述阻断可以增加血液中因子VIII的水平,因为FVIII-VWF复合物受到保护,不会被蛋白质降解。
在一些实施例中,与VWF结合的合成多核苷酸可以是15个至50个核苷酸的长度,或20个至30个核苷酸的长度(例如,20个核苷酸、21个核苷酸、22个核苷酸、23个核苷酸、24个核苷酸、25个核苷酸、26个核苷酸、27个核苷酸、28个核苷酸、29个核苷酸和30个核苷酸的长度)。所述合成多核苷酸可以进一步包括双链区。双链区可以是约6个至约9个核苷酸。双链区由6个核苷酸、或7个核苷酸、或8个核苷酸或9个核苷酸形成。此外,双链区由在序列末端处或附近的3'和5'核苷酸中的6个或更多个形成。
在一些实施例中,合成多核苷酸可以被化学修饰。每个核苷酸可以含有至少一个化学修饰。此类化学修饰可以在合成多核苷酸的糖、核碱基或核苷间接头处。对糖的修饰可以包括但不限于2'-氨基、2'-O-烷基、2'-氟和2'-O-甲基修饰。作为非限制性实例,靶向VWF的合成多核苷酸包括2'-O-甲基修饰。在一些实施例中,末端帽结构可以结合到合成多核苷酸的3'和/或5'末端。帽结构包含在合成多核苷酸的5'末端处的5'-5'反向核苷酸帽和在合成多核酸的3'末端处的3'-3'反向核苷酸盖。帽结构可以是反向脱氧胸苷或氨基(NH2)。
可以进一步修饰合成多核苷酸以在合成多核苷酸的5'或3'末端处包括一种或多种缀合物,如PEG(聚乙二醇)部分。PEG部分可以是任何大小或分支构型。PEG的大小可以在约5kD至约200kD的范围内。PEG可以是具有连接在一起的多个PEG链的直链PEG或支链PEG。3'-和5'-短PEG缀合物不干扰结合特异性,并且其不影响合成多核苷酸的靶亲和力。
在一个实施例中,VWF结合剂是合成多核苷酸,其包括SEQ ID No.:3(5'GCCAGGGACCUAAGACACAUGUCCCUGGC-3')的至少21个连续核苷酸;所述序列源自与VWF特异性结合的适体。在一个实施例中,VWF结合剂可以是合成多核苷酸,其包括SEQ ID No.:3的至少21个连续核苷酸。另外,合成多核苷酸可以表现出具有至少6个核苷酸、或至少7个核苷酸、或至少8个核苷酸或至少9个核苷酸的双链区。在一个实施例中,6个或更多个核苷酸的双链区在合成多核苷酸的末端处或附近(例如,在1个至10个核苷酸内)。
在一些实施例中,合成多核苷酸在序列的3'末端包括反向脱氧胸苷。作为非限制性实例,VWF靶向剂是合成多核苷酸,其包括以下结构:
mGmCmCmAmGmGmGmAmCmCmUmAmAmGmAmCmAmCmAmUmGmUmCmCmCmUmGmGmC-idT(SEQ IDNo.:4)(BT99),其中“NH”是5'-己胺接头磷酰胺,“idT”是反向脱氧胸苷,“mN”是含有2'-O-甲基的残基。
在一些实施例中,合成多核苷酸在序列的3'末端处包括反向脱氧胸苷,并且在序列的5'末端处包括氨基(NH2)。作为非限制性实例,VWF靶向剂是合成多核苷酸,其包括以下结构:
NH2-mGmCmCmAmGmGmGmAmCmCmUmAmAmGmAmCmAmCmAmUmGmUmCmCmCmUmGmGmC-idT(SEQ ID No.:5)(BT100),其中“NH”是5'-己胺接头磷酰胺,“idT”是反向脱氧胸苷,“mN”是含有2'-O-甲基的残基。
在一些实施例中,与VWF结合的合成多核苷酸进一步包括在序列的5'末端处缀合的PEG部分。作为非限制性实例,VWF靶向剂是合成多核苷酸,其包括以下结构:
PEG40K-NH-mGmCmCmAmGmGmGmAmCmCmUmAmAmGmAmCmAmCmAmUmGmUmCmCmCmUmGmGmC-idT(SEQ ID No.:6)(BT200),其中“NH”是5'-己胺接头磷酰胺,“idT”是反向脱氧胸苷,“mN”是含有2'-O-甲基的残基,“PEG”是聚乙二醇,并且PEG40K是分子量约为40KDa的PEG化部分。
PEG化BT200与血浆中VWF的A1结构域特异性结合,干扰其调节和功能(Zhu等人,《血栓形成与止血杂志》,2020年5月;18(5):1113-1123;所述文献的内容通过全文引用的方式并入本文)。一种机制是BT200与VWF的结合可以通过抑制VWF与巨噬细胞低密度脂蛋白受体相关蛋白-1(LRP1)的相互作用来保护核酸-蛋白复合物免受清除(Fazavana等人,《血栓形成与止血杂志》,2020,1278-1290)。在此方面,BT200可以用作抗出血剂。本公开的发明人发现,在低剂量下,BT200阻断了VWF抗原从循环中的清除,并且导致VWF抗原(VWF-Ag)和FVIII两者的浓度持续增加,但对两者的活性的影响可忽略不计。在较高剂量下,BT200阻断VWF的清除并抑制VWF的活性,但不抑制FVIII活性。因此,BT200可以用于纠正遗传性出血性病症(例如,1型、2b型和3型VWD)患者的VWF和/或FVIII缺乏。
通过皮下注射的BT200显示出延长的半衰期,在循环中持续7天至12天,提供良好的皮下生物利用度(Zhu等人,《血栓形成与止血杂志》,2020,1113-1123)。
在其它实施例中,VWF结合剂是包括以下序列的适体:
PEG40K-NH-mGmGmGmAmCmCmUmAmAmGmAmCmAmCmAmUmGmUmCmCmC-idT(ARC15105)(SEQ ID No.:7)或序列:
PEG20K-NH-mGmCmGmUdGdCdAmGmUmGmCmCmUmUmCmGmGmCdCmGsdTmGdCdGdGdTmGmCdCmUdCdCmGmUdCmAmCmGmCidT(ARC1779)(SEQ ID No.:8),其中“NH”是5'-己胺接头磷酰胺,“idT”是反向脱氧胸苷,“mN”是含有2'-O-甲基的残基,“dN”是脱氧核苷酸残基,“sdT”是硫代磷酸脱氧胸苷残基且“PEG”是聚乙二醇,并且PEG20K是分子量约为20KDa的PEG化部分。
在一些实施例中,VWF结合剂可以包含与SEQ ID No.:3具有至少50%、55%、60%、65%、70%、75%、80%、90%、95%、96%、97%、98%、99%或100%序列同一性的合成多核苷酸。
表2:VWF适体和变体
药物组合物
在本公开的另一方面,提供了包含本公开的任一种抗VWF适体的药物组合物和调配物。VWF结合剂以适合向有需要的受试者施用的调配物形式调配。适用于本公开的药物组合物,特别是基于核酸的组合物的调配物在国际专利公开第WO2013/090648号(申请PCT/US2012/069610)中教导,所述国际专利公开的内容通过全文引用的方式并入本文。制备调配物的方法在本领域中是众所周知的,例如在《雷明顿:药物科学与实践(Remington:TheScience and Practice of Pharmacy)》(第20版,A.R.Gennaro AR.编辑),利平科特·威廉斯·威尔金斯出版公司(Lippincott Williams&Wilkins),2000中;所述文献的内容通过全文引用的方式并入本文。
本公开的药物组合物可以包括至少一种VWF靶向剂作为活性成分,例如BT200。
所述组合物进一步包含至少一种药学上可接受的载体、稀释剂或赋形剂,例如盐水或蒸馏水。任选地,所述组合物可以包含赋形剂,所述赋形剂稳定适体药剂,由此维持所述药剂的治疗活性。在一些实施例中,所述组合物可以包括有助于适体药剂扩散的赋形剂,如盐、糖和醇。
作为非限制性实例,赋形剂可以包含糖类,如蔗糖、海藻糖、果糖、半乳糖、甘露醇、葡聚糖和葡萄糖;多元醇,如甘油和山梨醇;蛋白质,如白蛋白;疏水性分子,如油;亲水性聚合物,如聚乙二醇;异构体,如非对映异构体和对映异构体、异构体的混合物,包含外消旋混合物、盐、溶剂化物以及其多晶型物。
在一些实施例中,组合物可以是液体溶液或悬浮液的形式。在一些情况下,组合物是无菌的,用于注射。
在一些实施例中,本公开的VWF靶向剂被调配用于口服施用。调配物可以是片剂或胶囊形式。在一些实施例中,本公开的VWF药剂被调配用于鼻内施用。鼻内调配物可以是粉末、滴鼻剂或气雾剂的形式。在一些实施例中,本公开的VWF药剂被调配用于肠胃外施用。调配物仅包含药学上可接受的赋形剂、稀释剂、载体和佐剂,其在所用浓度下向人肠胃外施用是安全的,符合与联邦药物管理局(Federal Drug Administration)或其它外国国家当局认为安全的赋形剂、稀释剂、载体和佐剂相同或相似的标准。药物调配物可以是即用型溶液形式、浓缩形式或冻干制剂,其可以用指导量的适合肠胃外注射的稀释剂(如水、盐溶液或缓冲溶液)重组。在一些实例中,所述调配物是一种稳定的水性药物调配物,在其整个保质期内保持在其物理、化学、微生物、治疗和毒理学规范范围内。在一些实施例中,本公开的VWF靶向剂被调配用于吸入。
在一些实施例中,本公开的VWF靶向剂可以被调配用于活性剂的受控释放。作为非限制性实例,用于受控释放的调配物可以包括生物相容性聚合物。聚合物的选择取决于特定治疗方案中所需的药物释放速率。适于持续释放的生物相容性聚合物包含但不限于可生物降解的聚合物,如聚酰胺,例如聚(氨基酸)和聚(肽);聚酯,如聚(乳酸)、聚(乙醇酸)、聚(乳酸-共-乙醇酸)和聚(己内酯);聚(酸酐);聚原酸酯;聚碳酸酯以及其化学衍生物;共聚物以及其混合物。生物相容性聚合物可以包含不可降解的聚合物,如多糖;聚醚(例如,聚(环氧乙烷)、聚(乙二醇)和聚(四亚甲基氧化物));乙烯基聚合物(例如,聚丙烯酸酯、丙烯酸、聚(乙烯醇)、聚(吡咯烷酮),和聚(乙酸乙烯酯));聚氨酯;纤维素基聚合物(例如,纤维素、烷基纤维素、羟烷基纤维素、纤维素醚、纤维素酯、硝化纤维素和乙酸纤维素);聚硅氧烷和其它硅酮衍生物。药剂的持续释放可以持续两个月以上、持续一个月、持续三周、持续两周、持续一周、持续六天、持续五天、持续四天、持续三天、持续两天或持续一天。用于持续释放的组合物中的药剂的量可以占调配物的约0.1%至约30%、或约0.1%至约10%、或约1%至约10%、或约0.5%至约5%(w/w),例如调配物的约0.1%(w/w)、约0.2%(w/w)、约0.5%(w/w)、约1.0%(w/w)、约2.0%(w/w)、约5.0%(w/w)、约10%(w/w)、约12%(w/w)、约15%(w/w)、约20%(w/w)、约25%(w/w)或约30%(w/w)。
在一些实施例中,VWF靶向剂被调配为可注射的热敏凝胶调配物。如本文所使用的,术语“热敏凝胶调配物”意指在低温下以流动粘性液体的形式存在,但在较高温度下形成刚性半固体凝胶的调配物。具体地,所述调配物在室温或较低温度下为液体,但一旦注射即为凝胶,从而在注射部位产生药物储库。调配物可以含有热敏聚合物。如本文所使用的,术语“凝胶”是指当热敏聚合物溶液的温度升高到或高于聚合物的凝胶化温度时自发出现的半固相。示例性热敏聚合物可以包含PLGA-PEG-PLGA三嵌段共聚物、泊洛沙姆(poloxamer)、普朗尼克酸(Pluronic acid)F127和聚氧乙烯-聚氧丙烯(PEO-PPO)嵌段共聚物。在一些实施例中,调配物的凝胶化温度为约30℃至约40℃。
在一些实施例中,VWF靶向剂可以用脂质体调配物封装。如本文所使用的,术语“脂质体”意指由至少一个脂质双层膜组成的调配物,所述脂质双层膜包围水性内部区室。脂质体可以是具有单个膜并且直径范围通常介于0.02μm与0.05μm之间的小单层囊泡(SUV),或通常大于0.05μm的大单层囊泡(LUV),或具有多个通常同心的膜层且通常大于0.1μm的寡层大囊泡。脂质体被调配成携带包含在水性内部空间内或分配到脂质双层中的VWF药剂。
在一些实施例中,VWF靶向剂可以调配为可植入的固体调配物,或涂覆到植入物(例如,支架)的表面。
药物调配物中VWF靶向剂的浓度取决于多种因素,包含待施用的药物的剂量和施用途径。
治疗、施用和剂量
一方面,本公开的VWF靶向剂可以用于治疗出血性病症,并且更具体地用于治疗遗传性出血性病症,例如A型血友病(轻度、中度和重度血友病)和VWD(1型、2b型和3型)。
在一些实施例中,本公开的VWF靶向剂可以用于出血性病症的疗法和预防性治疗。如本文所使用的,术语“预防性治疗”通常指通过向患有出血性病症患者定期输注凝血因子浓缩物来避免出血的预防性治疗。患有重度形式的出血性病症(例如,重度血友病和3型VWD)的患者接受预防性治疗后,出血风险可能会降低,并且关节损伤减少。
在一些实施例中,本公开的VWF靶向剂可以与凝血因子替代疗法(也称为凝血因子替代物)组合使用。例如,VWF靶向剂可以与FVIII替代疗法组合使用,用于治疗患者的A型血友病,如轻度血友病、中度血友病和重度血友病。在一个优选实施例中,患者被诊断患有重度血友病。
定期进行FVIII预防治疗可以显著防止患有A型血友病的患者,特别是患有重度血友病的患者的自发性出血症状。血浆源性FVIII浓缩物和重组FVIII制剂是A型血友病目前可用的治疗。由于FVIII在血液中的短循环半衰期需要定期静脉输注FVIII以维持治疗性血浆FVIII水平,因此临床给药计划对患者依从性具有重要意义。最近的工作重点是开发延长FVIII替代物半衰期的新方法,例如重组FVIII的修饰。然而,使用修饰的重组FVIII分子的临床研究表明,与野生型重组FVIII相比,半衰期的增加更为温和(≈1.5倍)(Pipe等人,《血液》,2016,128:2007-2016)。
最近有报道称,VWF肽可以有效延长VWF缺陷小鼠的内源性FVIII存活期,并且延长血浆VWF载体片段的半衰期可以显著延长VWF缺陷小鼠的FVIII半衰期(Yee等人,《血液》,2014,124:445-452)。可以升高VWF水平的药剂可以用于延长FVIII在血液中的半衰期,由此升高FVIII活性低的患者(例如,血友病和VWD)的FVIII水平。本发明人进行的研究表明,施用VWF结合剂BT200可以以剂量依赖的方式增加血液中的VWF和FVIII水平。BT200与VWF结合并阻止VWF在血液中清除。升高的VWF形成FVIII-VWF复合物,由此增加血液中的FVIII水平。
在一些实施例中,本公开的VWF靶向剂可以与重组FVIII制剂或血浆源性FVIII浓缩物组合使用,以延长FVIII在血友病患者的血液中的半衰期。患者可能患有轻度、中度或重度血友病。特别地,患者患有重度血友病。
在一些实施例中,本公开的VWF靶向剂可以与VWF替代疗法组合用于治疗VWD,特别是3型VWD和2型VWD以及1型VWD。在一些实例中,VWF靶向剂可以与VWF替代制剂组合使用。VWF替代制剂可以是含有FVIII和VWF两者的血浆源性因子浓缩物(即FVIII/VWF浓缩物)和重组VWF制剂。作为非限制性实例,重组VWF制剂可以是Vonicog alfa,rVWF,其在表达VWF和FVIII两者的基因改变的CHO细胞中产生(Turecek等人,《血液学(Hamostaseologie)》,2009,29(增刊):S32-38)。
在其它实例中,本VWF靶向剂可以与DDAVP治疗组合使用。VWF靶向剂可以稳定并增加由DDAVP刺激释放的内源性VWF和FVIII水平。
在一些实施例中,本公开的VWF靶向剂可以用于维持血液中足够的VWF水平以保护FVIII不被降解。VWF可以是内源性的,由体内产生VWF的细胞释放,或是外源性的,用体外VWF替代物输注。FVIII可以是内源性的或外源性的。
在一些实施例中,VWF靶向剂可以用于增加患有2b型VWD的患者,特别是伴有由于血小板聚集而形成的血小板减少症的2b型VWD患者的血小板计数。本VWF靶向剂(如BT200)可以提高血液中的血小板计数。
本VWF靶向剂可以增加血液中的血小板计数。因此,VWF靶向剂可以用于治疗血小板减少症,即患者血液中血小板计数低的病状。血小板减少症可能发生在各种情况下,例如骨髓病症、药物的副作用、与癌症和重度肝病相关联的脾脏肿大、自身免疫性疾病、暴露于有毒化学品的情况以及感染。
特别地,BT200可以维持血液中VWF和FVIII水平的持续升高。
在一些实施例中,本VWF靶向剂、组合物和方法可以用于治疗凝血组分中的其它罕见缺陷。罕见的遗传性出血性病症(RBD)包含例如,凝血因子纤维蛋白原、FII、FV、组合的FV和FVIII、FVII、FX、FXI、FXIII的缺乏,以及维生素K依赖性因子(VKCFD)的先天性缺乏。
根据本公开,所述方法包括向受试者施用治疗有效量的药物组合物,所述药物组合物包括至少一种VWF靶向剂。在一些实例中,靶向剂是VWF结合剂。所述VWF结合剂是抗体、纳米抗体、肽、寡核苷酸、RNA(例如,siRNA、microRNA)、合成多核苷酸(例如,适体)或小分子。在一些实施例中,VWF结合剂是选自由以下组成的组的合成多核苷酸:SEQ ID No.:3、BT99(SEQ ID No.:4)、BT100(SEQ ID No.:5)、BT200(SEQ ID No.:6)、ARC15105(SEQ IDNo.:7)和ARC1779(SEQ ID No.:8)以及其变体。在一个优选实施例中,VWF结合剂是BT200(SEQ ID No.:6)。
VWF靶向剂可以增加用所述药剂治疗的受试者的血液中FVIII和VWF的水平。VWF靶向剂也可以提高受试者的血小板计数。
作为非限制性实例,VWF靶向剂是BT200(SEQ ID No.:6)。
根据本公开,讨论并确定了治疗方案,如剂量、剂量-应答关系、负荷和维持剂量以及给药时间表(如间隔和时间)、施用途径、调配物等。
在一些实施例中,VWF靶向剂可以以任何施用途径向有需要的受试者施用。药剂和组合物可以被调配成通过肠胃外施用或肠内施用或其它适当途径施用。肠胃外施用可以通过注射或通过插入留置导管进行,包含但不限于静脉内(IV)、肌内(IM)、皮下(SC)、表皮注射、硬膜外注射、脑内(进入脑)施用、脑室内(进入脑室)施用、外羊膜施用、鼻内施用、动脉内、心内、骨内输注(IO)、腹膜内输注或注射、透皮扩散、肠内和胃肠道途径、局部施用和口服途径。
作为非限制性实例,VWF靶向剂通过皮下注射施用。
药物的治疗有效剂量因患者而异,并且取决于患者的年龄和病状以及递送途径等因素。此类剂量可以根据本领域技术人员已知的常规药理学程序来确定。可能影响有效治疗受试者所需剂量的因素包含但不限于疾病或病症的严重程度、先前的治疗、受试者的总体健康状况和/或年龄以及存在的其它疾病。此外,用治疗有效量的本文所公开的治疗性多核苷酸治疗受试者可以包含单个治疗或可以包含一系列治疗。本文所公开的用于治疗的治疗性多核苷酸的有效剂量可以在特定治疗过程中增加或减少。如本文所描述的,剂量的变化可以由诊断测定的结果产生并变得显而易见。
在一些实施例中,VWF靶向剂的治疗有效量或剂量可以在约0.001μg/kg或0.01μg/kg至约250mg/kg或500mg/kg体重的范围内,其它范围包含但不限于约0.01μg/kg至100mg/kg体重、约0.01μg/kg至50mg/kg体重、约0.1μg/kg至20mg/kg体重、约0.1μg/kg至10mg/kg体重、约1μg/kg至100mg/kg体重、约1μg/kg至50mg/kg体重、约10μg/kg至100mg/kg体重、约10μg/kg至50mg/kg体重、约20μg/kg至100mg/kg体重、约20μg/kg至50mg/kg体重、约1mg/kg至100mg/kg体重、约1mg/kg至50mg/kg体重或约20mg/kg至50mg/kg体重。本领域技术人员将理解,某些因素可能影响有效治疗受试者所需的剂量,这些因素包含但不限于疾病或病症的严重性、之前的治疗、所述受试者的总体健康和/或年龄以及存在的其它疾病。
在一些实施例中,药物组合物可以以单剂量向有需要的受试者施用。BT200的单剂量可以是0.1mg、0.2mg、0.5mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5.0mg、5.5mg、6.0mg、6.5g,7.0mg、7.5mg、8.0mg、8.5mg、9.0mg、10.0mg、11.0mg、12.0mg、13.0mg、14.0mg、15.0mg、16.0mg、17.0mg、18.0mg、19.0mg、20.0mg、21.0mg、22.0mg、23.0mg、24.0mg、25.0mg、26.0mg、27.0mg、28.0mg、29.0mg、30.0mg、31.0mg、32.0mg、33.0mg、34.0mg、35.0mg、36.0mg、37.0mg、38.0mg、39.0mg、40.0mg、41.0mg、42.0mg、43.0mg、44.0mg、45.0mg、46.0mg、47.0mg、48.0mg、49.0mg、50.0mg、51.0mg、52.0mg、53.0mg、54.0mg、55.0mg、56.0mg、57.0mg、58.0mg、59.0mg、60.0mg、61.0mg、62.0mg、63.0mg、64.0mg、65.0mg、66.0mg、67.0mg、68.0mg、69.0mg、70.0mg、71.0mg、72.0mg、73.0mg、74.0mg、75.0mg、76.0mg、77.0mg、78.0mg、79.0mg、80.0mg、81.0mg、82.0mg、83.0mg、84.0mg、85.0mg、86.0mg、87.0mg、88.0mg、89.0mg、90.0mg、91.0mg、92.0mg、93.0mg、94.0mg、95.0mg、96.0mg、97.0mg、98.0mg、99.0mg或100.0mg。
在一个优选实施例中,BT200的单剂量为约1.0mg至10.0mg,或约1.0mg至6.0mg。
在一些实施例中,药物组合物可以多个剂量向有需要的受试者施用。本文提供的给药方案是安全且有效的,可以防止出血。作为非限制性实例,患者可以每周用本VWF靶向剂治疗一次。还应理解,用于治疗的药剂的有效剂量可以在特定治疗过程中增加或减少。本公开的药剂可以同时或单独施用。
在一个优选实施例中,提供了多次给药方案,包含BT200的负荷剂量和BT200的连续维持剂量。负荷剂量和维持剂量范围可以是但不限于0.1mg至10.0mg的BT200或1.0mg至6.0mg的BT200。
作为非限制性实例,BT200可以以0.1mg、0.2mg、0.5mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5.0mg、5.5mg、6.0mg、6.5mg、7.0mg、8.0mg、9.0mg、10.0mg、15mg或20mg给药。在一些实施例中,BT200可以以3.0mg、6.0mg、9.0mg或10.0mg给药。
在一些实施例中,VWF靶向剂或其药物调配物可以约每天、约每隔一天、约每3天、约每4天、约每5天、约每6天、约每7天、约每8天至10天、约每11天至14天或约每三周向有需要的患者施用。在一个实施例中,VWF药剂或其药物调配物可以约每7天施用一次。
在一些实施例中,VWF靶向剂或其药物调配物可以单次施用。在其它实例中,VWF靶向剂或其药物调配物的施用可以持续约1周、约2周、约3周、约4周、约5周、约两个月、约三个月至四个月、约四个月至六个月或约一年。在一些实例中,VWF药剂或其药物调配物的施用约为每7天一次,持续约5周。在某些实施例中,施用可以在例如约4周或约5周之后是间歇性的。作为非限制性实例,有需要的受试者可以每周治疗一次,持续约5周,并且然后在接下来的几年中治疗约3次至约4次。在一些实施例中,VWF药剂或其药物调配物可以间歇性地向受试者施用,以维持血管的通畅性,或将VWF保持在某些水平。包含给药时间表和使用方法与其它出血预防疗法的组合。
根据本公开,VWF靶向剂可以每隔一天施用一次、每三天施用一次、每五天施用一次、每周施用一次或每隔一周施用一次。在一个优选实施例中,VWF靶向剂可以以至少一个负荷剂量和至少一个维持剂量施用。负荷剂量和维持剂量可以相同或不同。作为非限制性实例,VWF靶向剂或其药物调配物可以每7天施用2个负荷剂量和3个维持剂量。
等效物和范围
本领域技术人员应当认识到或仅使用常规实验就能够确定根据本文所描述的本公开的具体实施例的很多等效物。本公开的范围不旨在限于以上描述,而是如所附权利要求中所阐述的。
在权利要求中,冠词如“一个/种(a/an)”以及“所述”可以意指一个或多个,除非指明与上下文相反或另外地根据上下文是显而易见的。如果组成员中的一个、多于一个或全部存在于、使用于或以其它方式相关于给出的产品或流程,则在所述组的一个或多个成员之间包含“或”的权利要求书或说明书被认为是满意的,除非指明与上下文相反或另外地根据上下文是显而易见的。本公开包含其中所述基团中的恰好一个成员存在于、使用于或以其它方式相关于给出的产品或流程的实施例。本公开包含实施例,在所述实施例中,所述组中多于一个或全部成员存在于、使用于或以其它方式关联给定的产品或过程。
还应注意,术语“包括”旨在开放式的,并且允许但不需要包含另外的元素或步骤。因此,当在本文中使用术语“包括”时,还涵盖并且公开了术语“由……组成”。
在给出范围时,端点被包含在内。此外,应当理解,除非从本领域的普通技术人员的上下文和理解中另外指示或以其它方式显而易见,否则表达为范围的值可以假定在本公开的不同实施例中到范围下限的单位的十分之一的任何特定值或子范围,除非上下文另外明确指出。
另外,应当理解,落入现有技术的本公开的任何特定实施例可以明确地从权利要求书中的任何一项或多项中排除。由于本领域的普通技术人员认为此类实施例是已知的,因此即使本文未明确阐述排除,也可以排除此类实施例。本公开的组合物的任何特定实施例(例如,任何抗生素、治疗性成分或活性成分;任何生产方法;任何使用方法等)可以由于任何原因而从任何一项或多项权利要求中排除,无论是否与现有技术的存在有关。
应当理解,已经使用的词语是描述性而不是限制性词语,并且可以在所附权利要求书的范围内进行改变而不脱离本公开在更广泛方面的真实范围和精神。
尽管已经相对于几个所描述实施例以一定长度和一定特定性描述了本公开,但是本公开并不旨在应当限于任何这种细节或实施例或者任何特定实施例,而是应当参考所附权利要求书进行解释,以便根据现有技术提供对这种权利要求书的尽可能广泛的解释并且因此有效地涵盖本公开的预期范围。
实例
实例1:用于治疗出血性病症的BT200的给药窗口
在健康志愿者中以范围为0.18mg至48mg的剂量单次给药BT200后,测量因子VIII和VWF的血液水平。给药一周后,因子VIII和VWF抗原的血液水平以剂量和时间依赖的方式增加(如表3(因子VIII)和表4(VWF抗原)所示)。在表3和表4的描述列中,描述包含队列编号、给予的治疗和患者标识符。例如,“1-BT200-A”意指给予BT200的队列1的患者A,“1-对照-A”意指对照组的患者A。
表3.因子VIII活性
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表4.VWF抗原
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在接受治疗的个体中也测试了VWF的功能。在三种不同的活性测试中:多板聚集仪、血小板功能分析仪和ELISA用于VWF的游离A1结构域,与未治疗的个体相比没有观察到任何影响。在接受BT200治疗的志愿者中,因子VIII的功能也有所增加。
对健康志愿者的研究表明,0.6mg BT200的低剂量在给药后48小时约使基线FVIII活性翻倍,并且在给药1周内维持近一半的增加。然而,在同一时间段内,使用测定(一种使用未稀释全血的高灵敏度功能测定)未观察到对VWF功能的影响。
结果还表明,10倍剂量的6mg BT200在单次给药后2周内维持基线FVIII的翻倍,而测定没有发现任何VWF功能抑制的证据。
这些观察表明,BT200可以剂量依赖性地增强VWF/FVIII水平。
单剂量施用后,健康志愿者的BT200的消除半衰期约为5天至12天,表明皮下注射后BT200的半衰期长且耐受性好。BT200施用后未观察到脱靶不良反应。
BT200和去氨加压素的共同施用对血液中的VWF和FVIII水平有加和效应(如图1所示)。
实例2:患者的剂量应答的个体剂量滴定
一组多达25名患有重度先天性A型血友病(无抑制剂)、轻度中度A型血友病、FVIII水平低于正常的A型血友病杂合子携带者、1型VWD、“维琴察”型或2b型VWD的患者纳入了研究,以评估剂量滴定和剂量应答。
患者通过皮下(SC)注射在第1天、第4天和第7天(±2天)给药3mg BT200。然后在第14天、第21天和第28天,根据患者患有的出血性病症,在3mg与9mg之间滴定BT200剂量。在患有A型血友病或1型VWD的患者中测量FVIII活性。在患有2b型VWD的患者中测量血小板计数和/或FVIII活性。
五名患有2b型VWD的患者(3名男性:2名女性)(表5),在第1天和第4天给药3mgBT200,然后每周给药6mg至9mg BT200(第7天、第14天、第21天和第28天)。患者的中值年龄为61岁(范围为24岁至72岁)。五名患者中有四名出现血小板减少症,并且两名患者因反复出现重度出血而接受常规重组VWF替代疗法。在疗法前、疗法期间和疗法后通过VWF参数、FVIII活性和血小板计数以及其它临床结果参数来测量功效。通过Friedman ANOVA进行统计分析。
表5:患有2b型VWF的患者
患者 | 年龄:性别 | 突变 |
#1 | 54;女性 | 3922C>T杂合 |
#2 | 61;男性 | C3916C>T |
#3 | 24;男性 | C3916C>T |
#9 | 72;男性 | 3946G>A杂合 |
#10 | 61;女性 | C3939G>C |
结果表明,患者在首次皮下注射BT200(首次剂量3mg BT200)后4天内出现有临床意义的应答。血小板计数从基线时的中值60上升到28天时的159/nL(p=0.012),即在所有患有血小板减少症的患者中高达4倍,并且在这些患者中有3/4回归正常(图2)。所有血小板减少症患者在第一剂量的BT200后96小时后,血小板计数增加。FVIIIc的血浆水平从67%(44%至91%)翻倍达到134%(114%至200%)(p<0.001),并且在FVIIIc活性低于正常的患者中回归正常(从基线时的44%到最后剂量后1周的135%)。这反映在均匀延长的激活部分凝血活酶时间(aPTT-FS)从43秒缩短到32秒(p=0.002)(图3)并且凝血酶产生增加。BT200施用使循环VWF抗原水平从64%(32%至106%)增加到143%(103%至351%,p<0.001)(图4A)。在所有患者中,VWF胶原蛋白结合活性(VWF:CBA)增加了2倍至4倍,在所有血小板减少症患者中,VWF瑞斯托菌素(ristocetin)辅因子(VWF:RCo)活性和VWF:GpIbM活性增加了2倍至3倍,但在一名没有血小板减少症的患者中仅增加了少量(n=5时,所有p值均<0.05)(图4B)。增加的瑞斯托菌素BT200耐受性非常好,没有任何相关的不良反应。
这些临床观察结果表明,BT200特异性纠正了2b型VWD的潜在病理生理学,使患有血小板减少症的患者的血小板计数迅速而强烈地增加,并且使所有患者的VWF和FVIIIc升高。据推测,BT200可能通过增加所有患者的循环VWF和FVIII水平以及血小板减少症患者的血小板计数对2b型VWD患者具有潜在益处。
患有A型血友病的患者在相同给药时间表下用BT200治疗,表现出增加的FVIII活性(图5)。
这些结果表明BT200具有7天至12天的延长的半衰期。BT200可以诱导VWF水平和活性的持续增加,以及通过增加的aPTT缩短和增加的凝血酶产生来测量的FVIII水平和活性增加。
实例3:BT200增加FVIII疗法的半衰期
患者用FVIII疗法治疗(Refacto AF/三名患者;Elocta/一名患者;Afstyla/两名患者;Kovaltry/一名患者;以及Advate/一名患者)。BT200治疗之前FVIII疗法的半衰期是基于本领域已知的历史值。对患者给药分次负荷剂量,并且在负荷剂量后给药每周剂量(表6)。BT200治疗后每名患者的每种FVIII疗法的半衰期在BT200治疗一个月后测量。所有FVIII值均通过显色测定(患者#014、017、020至024)或通过一阶段凝血测定(患者#027)产生。平均增加为3.1倍(中值=2.8倍)(表6)。这些观察结果表明,BT200可以增加市场上几乎所有FVIII产品的半衰期。
表6:BT200增加FVIII疗法的半衰期
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序列表
<110> 邦德治疗有限公司(BAND THERAPEUTICS, LLC)
<120> 用于治疗出血性病症的组合物和方法
<130> 2059.1009PCT
<140> PCT/USXX/XXXXX
<141> 2021-11-24
<150> 63/117,545
<151> 2020-11-24
<150> 63/155,012
<151> 2021-03-01
<150> 63/216,601
<151> 2021-06-30
<160> 8
<170> PatentIn 3.5版
<210> 1
<211> 2813
<212> PRT
<213> 智人(Homo sapiens)
<400> 1
Met Ile Pro Ala Arg Phe Ala Gly Val Leu Leu Ala Leu Ala Leu Ile
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Leu Pro Gly Thr Leu Cys Ala Glu Gly Thr Arg Gly Arg Ser Ser Thr
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Ala Arg Cys Ser Leu Phe Gly Ser Asp Phe Val Asn Thr Phe Asp Gly
35 40 45
Ser Met Tyr Ser Phe Ala Gly Tyr Cys Ser Tyr Leu Leu Ala Gly Gly
50 55 60
Cys Gln Lys Arg Ser Phe Ser Ile Ile Gly Asp Phe Gln Asn Gly Lys
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Arg Val Ser Leu Ser Val Tyr Leu Gly Glu Phe Phe Asp Ile His Leu
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Phe Val Asn Gly Thr Val Thr Gln Gly Asp Gln Arg Val Ser Met Pro
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Tyr Ala Ser Lys Gly Leu Tyr Leu Glu Thr Glu Ala Gly Tyr Tyr Lys
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Leu Ser Gly Glu Ala Tyr Gly Phe Val Ala Arg Ile Asp Gly Ser Gly
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Asn Phe Gln Val Leu Leu Ser Asp Arg Tyr Phe Asn Lys Thr Cys Gly
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Leu Cys Gly Asn Phe Asn Ile Phe Ala Glu Asp Asp Phe Met Thr Gln
165 170 175
Glu Gly Thr Leu Thr Ser Asp Pro Tyr Asp Phe Ala Asn Ser Trp Ala
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Leu Ser Ser Gly Glu Gln Trp Cys Glu Arg Ala Ser Pro Pro Ser Ser
195 200 205
Ser Cys Asn Ile Ser Ser Gly Glu Met Gln Lys Gly Leu Trp Glu Gln
210 215 220
Cys Gln Leu Leu Lys Ser Thr Ser Val Phe Ala Arg Cys His Pro Leu
225 230 235 240
Val Asp Pro Glu Pro Phe Val Ala Leu Cys Glu Lys Thr Leu Cys Glu
245 250 255
Cys Ala Gly Gly Leu Glu Cys Ala Cys Pro Ala Leu Leu Glu Tyr Ala
260 265 270
Arg Thr Cys Ala Gln Glu Gly Met Val Leu Tyr Gly Trp Thr Asp His
275 280 285
Ser Ala Cys Ser Pro Val Cys Pro Ala Gly Met Glu Tyr Arg Gln Cys
290 295 300
Val Ser Pro Cys Ala Arg Thr Cys Gln Ser Leu His Ile Asn Glu Met
305 310 315 320
Cys Gln Glu Arg Cys Val Asp Gly Cys Ser Cys Pro Glu Gly Gln Leu
325 330 335
Leu Asp Glu Gly Leu Cys Val Glu Ser Thr Glu Cys Pro Cys Val His
340 345 350
Ser Gly Lys Arg Tyr Pro Pro Gly Thr Ser Leu Ser Arg Asp Cys Asn
355 360 365
Thr Cys Ile Cys Arg Asn Ser Gln Trp Ile Cys Ser Asn Glu Glu Cys
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Pro Gly Glu Cys Leu Val Thr Gly Gln Ser His Phe Lys Ser Phe Asp
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Asn Arg Tyr Phe Thr Phe Ser Gly Ile Cys Gln Tyr Leu Leu Ala Arg
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Asp Cys Gln Asp His Ser Phe Ser Ile Val Ile Glu Thr Val Gln Cys
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Ala Asp Asp Arg Asp Ala Val Cys Thr Arg Ser Val Thr Val Arg Leu
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Pro Gly Leu His Asn Ser Leu Val Lys Leu Lys His Gly Ala Gly Val
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Ala Met Asp Gly Gln Asp Val Gln Leu Pro Leu Leu Lys Gly Asp Leu
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Arg Ile Gln His Thr Val Thr Ala Ser Val Arg Leu Ser Tyr Gly Glu
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Asp Leu Gln Met Asp Trp Asp Gly Arg Gly Arg Leu Leu Val Lys Leu
500 505 510
Ser Pro Val Tyr Ala Gly Lys Thr Cys Gly Leu Cys Gly Asn Tyr Asn
515 520 525
Gly Asn Gln Gly Asp Asp Phe Leu Thr Pro Ser Gly Leu Ala Glu Pro
530 535 540
Arg Val Glu Asp Phe Gly Asn Ala Trp Lys Leu His Gly Asp Cys Gln
545 550 555 560
Asp Leu Gln Lys Gln His Ser Asp Pro Cys Ala Leu Asn Pro Arg Met
565 570 575
Thr Arg Phe Ser Glu Glu Ala Cys Ala Val Leu Thr Ser Pro Thr Phe
580 585 590
Glu Ala Cys His Arg Ala Val Ser Pro Leu Pro Tyr Leu Arg Asn Cys
595 600 605
Arg Tyr Asp Val Cys Ser Cys Ser Asp Gly Arg Glu Cys Leu Cys Gly
610 615 620
Ala Leu Ala Ser Tyr Ala Ala Ala Cys Ala Gly Arg Gly Val Arg Val
625 630 635 640
Ala Trp Arg Glu Pro Gly Arg Cys Glu Leu Asn Cys Pro Lys Gly Gln
645 650 655
Val Tyr Leu Gln Cys Gly Thr Pro Cys Asn Leu Thr Cys Arg Ser Leu
660 665 670
Ser Tyr Pro Asp Glu Glu Cys Asn Glu Ala Cys Leu Glu Gly Cys Phe
675 680 685
Cys Pro Pro Gly Leu Tyr Met Asp Glu Arg Gly Asp Cys Val Pro Lys
690 695 700
Ala Gln Cys Pro Cys Tyr Tyr Asp Gly Glu Ile Phe Gln Pro Glu Asp
705 710 715 720
Ile Phe Ser Asp His His Thr Met Cys Tyr Cys Glu Asp Gly Phe Met
725 730 735
His Cys Thr Met Ser Gly Val Pro Gly Ser Leu Leu Pro Asp Ala Val
740 745 750
Leu Ser Ser Pro Leu Ser His Arg Ser Lys Arg Ser Leu Ser Cys Arg
755 760 765
Pro Pro Met Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu
770 775 780
Gly Leu Glu Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met
785 790 795 800
Ser Met Gly Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg
805 810 815
His Glu Asn Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln
820 825 830
Gly Lys Glu Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr
835 840 845
Cys Val Cys Arg Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp
850 855 860
Ala Thr Cys Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly
865 870 875 880
Leu Lys Tyr Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp
885 890 895
Tyr Cys Gly Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys
900 905 910
Gly Cys Ser His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu
915 920 925
Val Glu Gly Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys
930 935 940
Arg Pro Met Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg
945 950 955 960
Tyr Ile Ile Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg
965 970 975
His Leu Ser Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val
980 985 990
Cys Gly Leu Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr
995 1000 1005
Ser Ser Asn Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn
1010 1015 1020
Ser Trp Lys Val Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro
1025 1030 1035
Leu Asp Ser Ser Pro Ala Thr Cys His Asn Asn Ile Met Lys Gln
1040 1045 1050
Thr Met Val Asp Ser Ser Cys Arg Ile Leu Thr Ser Asp Val Phe
1055 1060 1065
Gln Asp Cys Asn Lys Leu Val Asp Pro Glu Pro Tyr Leu Asp Val
1070 1075 1080
Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile Gly Asp Cys Ala
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Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val Cys Ala Gln
1100 1105 1110
His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys Pro Gln
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Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys Glu
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Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln
1145 1150 1155
His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys
1160 1165 1170
His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln
1175 1180 1185
Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly
1190 1195 1200
Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp
1205 1210 1215
Pro Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr
1220 1225 1230
Cys Glu Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr
1235 1240 1245
Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser
1250 1255 1260
Glu Pro Pro Leu His Asp Phe Tyr Cys Ser Arg Leu Leu Asp Leu
1265 1270 1275
Val Phe Leu Leu Asp Gly Ser Ser Arg Leu Ser Glu Ala Glu Phe
1280 1285 1290
Glu Val Leu Lys Ala Phe Val Val Asp Met Met Glu Arg Leu Arg
1295 1300 1305
Ile Ser Gln Lys Trp Val Arg Val Ala Val Val Glu Tyr His Asp
1310 1315 1320
Gly Ser His Ala Tyr Ile Gly Leu Lys Asp Arg Lys Arg Pro Ser
1325 1330 1335
Glu Leu Arg Arg Ile Ala Ser Gln Val Lys Tyr Ala Gly Ser Gln
1340 1345 1350
Val Ala Ser Thr Ser Glu Val Leu Lys Tyr Thr Leu Phe Gln Ile
1355 1360 1365
Phe Ser Lys Ile Asp Arg Pro Glu Ala Ser Arg Ile Thr Leu Leu
1370 1375 1380
Leu Met Ala Ser Gln Glu Pro Gln Arg Met Ser Arg Asn Phe Val
1385 1390 1395
Arg Tyr Val Gln Gly Leu Lys Lys Lys Lys Val Ile Val Ile Pro
1400 1405 1410
Val Gly Ile Gly Pro His Ala Asn Leu Lys Gln Ile Arg Leu Ile
1415 1420 1425
Glu Lys Gln Ala Pro Glu Asn Lys Ala Phe Val Leu Ser Ser Val
1430 1435 1440
Asp Glu Leu Glu Gln Gln Arg Asp Glu Ile Val Ser Tyr Leu Cys
1445 1450 1455
Asp Leu Ala Pro Glu Ala Pro Pro Pro Thr Leu Pro Pro Asp Met
1460 1465 1470
Ala Gln Val Thr Val Gly Pro Gly Leu Leu Gly Val Ser Thr Leu
1475 1480 1485
Gly Pro Lys Arg Asn Ser Met Val Leu Asp Val Ala Phe Val Leu
1490 1495 1500
Glu Gly Ser Asp Lys Ile Gly Glu Ala Asp Phe Asn Arg Ser Lys
1505 1510 1515
Glu Phe Met Glu Glu Val Ile Gln Arg Met Asp Val Gly Gln Asp
1520 1525 1530
Ser Ile His Val Thr Val Leu Gln Tyr Ser Tyr Met Val Thr Val
1535 1540 1545
Glu Tyr Pro Phe Ser Glu Ala Gln Ser Lys Gly Asp Ile Leu Gln
1550 1555 1560
Arg Val Arg Glu Ile Arg Tyr Gln Gly Gly Asn Arg Thr Asn Thr
1565 1570 1575
Gly Leu Ala Leu Arg Tyr Leu Ser Asp His Ser Phe Leu Val Ser
1580 1585 1590
Gln Gly Asp Arg Glu Gln Ala Pro Asn Leu Val Tyr Met Val Thr
1595 1600 1605
Gly Asn Pro Ala Ser Asp Glu Ile Lys Arg Leu Pro Gly Asp Ile
1610 1615 1620
Gln Val Val Pro Ile Gly Val Gly Pro Asn Ala Asn Val Gln Glu
1625 1630 1635
Leu Glu Arg Ile Gly Trp Pro Asn Ala Pro Ile Leu Ile Gln Asp
1640 1645 1650
Phe Glu Thr Leu Pro Arg Glu Ala Pro Asp Leu Val Leu Gln Arg
1655 1660 1665
Cys Cys Ser Gly Glu Gly Leu Gln Ile Pro Thr Leu Ser Pro Ala
1670 1675 1680
Pro Asp Cys Ser Gln Pro Leu Asp Val Ile Leu Leu Leu Asp Gly
1685 1690 1695
Ser Ser Ser Phe Pro Ala Ser Tyr Phe Asp Glu Met Lys Ser Phe
1700 1705 1710
Ala Lys Ala Phe Ile Ser Lys Ala Asn Ile Gly Pro Arg Leu Thr
1715 1720 1725
Gln Val Ser Val Leu Gln Tyr Gly Ser Ile Thr Thr Ile Asp Val
1730 1735 1740
Pro Trp Asn Val Val Pro Glu Lys Ala His Leu Leu Ser Leu Val
1745 1750 1755
Asp Val Met Gln Arg Glu Gly Gly Pro Ser Gln Ile Gly Asp Ala
1760 1765 1770
Leu Gly Phe Ala Val Arg Tyr Leu Thr Ser Glu Met His Gly Ala
1775 1780 1785
Arg Pro Gly Ala Ser Lys Ala Val Val Ile Leu Val Thr Asp Val
1790 1795 1800
Ser Val Asp Ser Val Asp Ala Ala Ala Asp Ala Ala Arg Ser Asn
1805 1810 1815
Arg Val Thr Val Phe Pro Ile Gly Ile Gly Asp Arg Tyr Asp Ala
1820 1825 1830
Ala Gln Leu Arg Ile Leu Ala Gly Pro Ala Gly Asp Ser Asn Val
1835 1840 1845
Val Lys Leu Gln Arg Ile Glu Asp Leu Pro Thr Met Val Thr Leu
1850 1855 1860
Gly Asn Ser Phe Leu His Lys Leu Cys Ser Gly Phe Val Arg Ile
1865 1870 1875
Cys Met Asp Glu Asp Gly Asn Glu Lys Arg Pro Gly Asp Val Trp
1880 1885 1890
Thr Leu Pro Asp Gln Cys His Thr Val Thr Cys Gln Pro Asp Gly
1895 1900 1905
Gln Thr Leu Leu Lys Ser His Arg Val Asn Cys Asp Arg Gly Leu
1910 1915 1920
Arg Pro Ser Cys Pro Asn Ser Gln Ser Pro Val Lys Val Glu Glu
1925 1930 1935
Thr Cys Gly Cys Arg Trp Thr Cys Pro Cys Val Cys Thr Gly Ser
1940 1945 1950
Ser Thr Arg His Ile Val Thr Phe Asp Gly Gln Asn Phe Lys Leu
1955 1960 1965
Thr Gly Ser Cys Ser Tyr Val Leu Phe Gln Asn Lys Glu Gln Asp
1970 1975 1980
Leu Glu Val Ile Leu His Asn Gly Ala Cys Ser Pro Gly Ala Arg
1985 1990 1995
Gln Gly Cys Met Lys Ser Ile Glu Val Lys His Ser Ala Leu Ser
2000 2005 2010
Val Glu Leu His Ser Asp Met Glu Val Thr Val Asn Gly Arg Leu
2015 2020 2025
Val Ser Val Pro Tyr Val Gly Gly Asn Met Glu Val Asn Val Tyr
2030 2035 2040
Gly Ala Ile Met His Glu Val Arg Phe Asn His Leu Gly His Ile
2045 2050 2055
Phe Thr Phe Thr Pro Gln Asn Asn Glu Phe Gln Leu Gln Leu Ser
2060 2065 2070
Pro Lys Thr Phe Ala Ser Lys Thr Tyr Gly Leu Cys Gly Ile Cys
2075 2080 2085
Asp Glu Asn Gly Ala Asn Asp Phe Met Leu Arg Asp Gly Thr Val
2090 2095 2100
Thr Thr Asp Trp Lys Thr Leu Val Gln Glu Trp Thr Val Gln Arg
2105 2110 2115
Pro Gly Gln Thr Cys Gln Pro Ile Leu Glu Glu Gln Cys Leu Val
2120 2125 2130
Pro Asp Ser Ser His Cys Gln Val Leu Leu Leu Pro Leu Phe Ala
2135 2140 2145
Glu Cys His Lys Val Leu Ala Pro Ala Thr Phe Tyr Ala Ile Cys
2150 2155 2160
Gln Gln Asp Ser Cys His Gln Glu Gln Val Cys Glu Val Ile Ala
2165 2170 2175
Ser Tyr Ala His Leu Cys Arg Thr Asn Gly Val Cys Val Asp Trp
2180 2185 2190
Arg Thr Pro Asp Phe Cys Ala Met Ser Cys Pro Pro Ser Leu Val
2195 2200 2205
Tyr Asn His Cys Glu His Gly Cys Pro Arg His Cys Asp Gly Asn
2210 2215 2220
Val Ser Ser Cys Gly Asp His Pro Ser Glu Gly Cys Phe Cys Pro
2225 2230 2235
Pro Asp Lys Val Met Leu Glu Gly Ser Cys Val Pro Glu Glu Ala
2240 2245 2250
Cys Thr Gln Cys Ile Gly Glu Asp Gly Val Gln His Gln Phe Leu
2255 2260 2265
Glu Ala Trp Val Pro Asp His Gln Pro Cys Gln Ile Cys Thr Cys
2270 2275 2280
Leu Ser Gly Arg Lys Val Asn Cys Thr Thr Gln Pro Cys Pro Thr
2285 2290 2295
Ala Lys Ala Pro Thr Cys Gly Leu Cys Glu Val Ala Arg Leu Arg
2300 2305 2310
Gln Asn Ala Asp Gln Cys Cys Pro Glu Tyr Glu Cys Val Cys Asp
2315 2320 2325
Pro Val Ser Cys Asp Leu Pro Pro Val Pro His Cys Glu Arg Gly
2330 2335 2340
Leu Gln Pro Thr Leu Thr Asn Pro Gly Glu Cys Arg Pro Asn Phe
2345 2350 2355
Thr Cys Ala Cys Arg Lys Glu Glu Cys Lys Arg Val Ser Pro Pro
2360 2365 2370
Ser Cys Pro Pro His Arg Leu Pro Thr Leu Arg Lys Thr Gln Cys
2375 2380 2385
Cys Asp Glu Tyr Glu Cys Ala Cys Asn Cys Val Asn Ser Thr Val
2390 2395 2400
Ser Cys Pro Leu Gly Tyr Leu Ala Ser Thr Ala Thr Asn Asp Cys
2405 2410 2415
Gly Cys Thr Thr Thr Thr Cys Leu Pro Asp Lys Val Cys Val His
2420 2425 2430
Arg Ser Thr Ile Tyr Pro Val Gly Gln Phe Trp Glu Glu Gly Cys
2435 2440 2445
Asp Val Cys Thr Cys Thr Asp Met Glu Asp Ala Val Met Gly Leu
2450 2455 2460
Arg Val Ala Gln Cys Ser Gln Lys Pro Cys Glu Asp Ser Cys Arg
2465 2470 2475
Ser Gly Phe Thr Tyr Val Leu His Glu Gly Glu Cys Cys Gly Arg
2480 2485 2490
Cys Leu Pro Ser Ala Cys Glu Val Val Thr Gly Ser Pro Arg Gly
2495 2500 2505
Asp Ser Gln Ser Ser Trp Lys Ser Val Gly Ser Gln Trp Ala Ser
2510 2515 2520
Pro Glu Asn Pro Cys Leu Ile Asn Glu Cys Val Arg Val Lys Glu
2525 2530 2535
Glu Val Phe Ile Gln Gln Arg Asn Val Ser Cys Pro Gln Leu Glu
2540 2545 2550
Val Pro Val Cys Pro Ser Gly Phe Gln Leu Ser Cys Lys Thr Ser
2555 2560 2565
Ala Cys Cys Pro Ser Cys Arg Cys Glu Arg Met Glu Ala Cys Met
2570 2575 2580
Leu Asn Gly Thr Val Ile Gly Pro Gly Lys Thr Val Met Ile Asp
2585 2590 2595
Val Cys Thr Thr Cys Arg Cys Met Val Gln Val Gly Val Ile Ser
2600 2605 2610
Gly Phe Lys Leu Glu Cys Arg Lys Thr Thr Cys Asn Pro Cys Pro
2615 2620 2625
Leu Gly Tyr Lys Glu Glu Asn Asn Thr Gly Glu Cys Cys Gly Arg
2630 2635 2640
Cys Leu Pro Thr Ala Cys Thr Ile Gln Leu Arg Gly Gly Gln Ile
2645 2650 2655
Met Thr Leu Lys Arg Asp Glu Thr Leu Gln Asp Gly Cys Asp Thr
2660 2665 2670
His Phe Cys Lys Val Asn Glu Arg Gly Glu Tyr Phe Trp Glu Lys
2675 2680 2685
Arg Val Thr Gly Cys Pro Pro Phe Asp Glu His Lys Cys Leu Ala
2690 2695 2700
Glu Gly Gly Lys Ile Met Lys Ile Pro Gly Thr Cys Cys Asp Thr
2705 2710 2715
Cys Glu Glu Pro Glu Cys Asn Asp Ile Thr Ala Arg Leu Gln Tyr
2720 2725 2730
Val Lys Val Gly Ser Cys Lys Ser Glu Val Glu Val Asp Ile His
2735 2740 2745
Tyr Cys Gln Gly Lys Cys Ala Ser Lys Ala Met Tyr Ser Ile Asp
2750 2755 2760
Ile Asn Asp Val Gln Asp Gln Cys Ser Cys Cys Ser Pro Thr Arg
2765 2770 2775
Thr Glu Pro Met Gln Val Ala Leu His Cys Thr Asn Gly Ser Val
2780 2785 2790
Val Tyr His Glu Val Leu Asn Ala Met Glu Cys Lys Cys Ser Pro
2795 2800 2805
Arg Lys Cys Ser Lys
2810
<210> 2
<211> 8833
<212> DNA
<213> 智人(Homo sapiens)
<400> 2
agctcacagc tattgtggtg ggaaagggag ggtggttggt ggatgtcaca gcttgggctt 60
tatctccccc agcagtgggg actccacagc ccctgggcta cataacagca agacagtccg 120
gagctgtagc agacctgatt gagcctttgc agcagctgag agcatggcct agggtgggcg 180
gcaccattgt ccagcagctg agtttcccag ggaccttgga gatagccgca gccctcattt 240
gcaggggaag atgattcctg ccagatttgc cggggtgctg cttgctctgg ccctcatttt 300
gccagggacc ctttgtgcag aaggaactcg cggcaggtca tccacggccc gatgcagcct 360
tttcggaagt gacttcgtca acacctttga tgggagcatg tacagctttg cgggatactg 420
cagttacctc ctggcagggg gctgccagaa acgctccttc tcgattattg gggacttcca 480
gaatggcaag agagtgagcc tctccgtgta tcttggggaa ttttttgaca tccatttgtt 540
tgtcaatggt accgtgacac agggggacca aagagtctcc atgccctatg cctccaaagg 600
gctgtatcta gaaactgagg ctgggtacta caagctgtcc ggtgaggcct atggctttgt 660
ggccaggatc gatggcagcg gcaactttca agtcctgctg tcagacagat acttcaacaa 720
gacctgcggg ctgtgtggca actttaacat ctttgctgaa gatgacttta tgacccaaga 780
agggaccttg acctcggacc cttatgactt tgccaactca tgggctctga gcagtggaga 840
acagtggtgt gaacgggcat ctcctcccag cagctcatgc aacatctcct ctggggaaat 900
gcagaagggc ctgtgggagc agtgccagct tctgaagagc acctcggtgt ttgcccgctg 960
ccaccctctg gtggaccccg agccttttgt ggccctgtgt gagaagactt tgtgtgagtg 1020
tgctgggggg ctggagtgcg cctgccctgc cctcctggag tacgcccgga cctgtgccca 1080
ggagggaatg gtgctgtacg gctggaccga ccacagcgcg tgcagcccag tgtgccctgc 1140
tggtatggag tataggcagt gtgtgtcccc ttgcgccagg acctgccaga gcctgcacat 1200
caatgaaatg tgtcaggagc gatgcgtgga tggctgcagc tgccctgagg gacagctcct 1260
ggatgaaggc ctctgcgtgg agagcaccga gtgtccctgc gtgcattccg gaaagcgcta 1320
ccctcccggc acctccctct ctcgagactg caacacctgc atttgccgaa acagccagtg 1380
gatctgcagc aatgaagaat gtccagggga gtgccttgtc acaggtcaat cacacttcaa 1440
gagctttgac aacagatact tcaccttcag tgggatctgc cagtacctgc tggcccggga 1500
ttgccaggac cactccttct ccattgtcat tgagactgtc cagtgtgctg atgaccgcga 1560
cgctgtgtgc acccgctccg tcaccgtccg gctgcctggc ctgcacaaca gccttgtgaa 1620
actgaagcat ggggcaggag ttgccatgga tggccaggac gtccagctcc ccctcctgaa 1680
aggtgacctc cgcatccagc atacagtgac ggcctccgtg cgcctcagct acggggagga 1740
cctgcagatg gactgggatg gccgcgggag gctgctggtg aagctgtccc ccgtctatgc 1800
cgggaagacc tgcggcctgt gtgggaatta caatggcaac cagggcgacg acttccttac 1860
cccctctggg ctggcggagc cccgggtgga ggacttcggg aacgcctgga agctgcacgg 1920
ggactgccag gacctgcaga agcagcacag cgatccctgc gccctcaacc cgcgcatgac 1980
caggttctcc gaggaggcgt gcgcggtcct gacgtccccc acattcgagg cctgccatcg 2040
tgccgtcagc ccgctgccct acctgcggaa ctgccgctac gacgtgtgct cctgctcgga 2100
cggccgcgag tgcctgtgcg gcgccctggc cagctatgcc gcggcctgcg cggggagagg 2160
cgtgcgcgtc gcgtggcgcg agccaggccg ctgtgagctg aactgcccga aaggccaggt 2220
gtacctgcag tgcgggaccc cctgcaacct gacctgccgc tctctctctt acccggatga 2280
ggaatgcaat gaggcctgcc tggagggctg cttctgcccc ccagggctct acatggatga 2340
gaggggggac tgcgtgccca aggcccagtg cccctgttac tatgacggtg agatcttcca 2400
gccagaagac atcttctcag accatcacac catgtgctac tgtgaggatg gcttcatgca 2460
ctgtaccatg agtggagtcc ccggaagctt gctgcctgac gctgtcctca gcagtcccct 2520
gtctcatcgc agcaaaagga gcctatcctg tcggcccccc atggtcaagc tggtgtgtcc 2580
cgctgacaac ctgcgggctg aagggctcga gtgtaccaaa acgtgccaga actatgacct 2640
ggagtgcatg agcatgggct gtgtctctgg ctgcctctgc cccccgggca tggtccggca 2700
tgagaacaga tgtgtggccc tggaaaggtg tccctgcttc catcagggca aggagtatgc 2760
ccctggagaa acagtgaaga ttggctgcaa cacttgtgtc tgtcgggacc ggaagtggaa 2820
ctgcacagac catgtgtgtg atgccacgtg ctccacgatc ggcatggccc actacctcac 2880
cttcgacggg ctcaaatacc tgttccccgg ggagtgccag tacgttctgg tgcaggatta 2940
ctgcggcagt aaccctggga cctttcggat cctagtgggg aataagggat gcagccaccc 3000
ctcagtgaaa tgcaagaaac gggtcaccat cctggtggag ggaggagaga ttgagctgtt 3060
tgacggggag gtgaatgtga agaggcccat gaaggatgag actcactttg aggtggtgga 3120
gtctggccgg tacatcattc tgctgctggg caaagccctc tccgtggtct gggaccgcca 3180
cctgagcatc tccgtggtcc tgaagcagac ataccaggag aaagtgtgtg gcctgtgtgg 3240
gaattttgat ggcatccaga acaatgacct caccagcagc aacctccaag tggaggaaga 3300
ccctgtggac tttgggaact cctggaaagt gagctcgcag tgtgctgaca ccagaaaagt 3360
gcctctggac tcatcccctg ccacctgcca taacaacatc atgaagcaga cgatggtgga 3420
ttcctcctgt agaatcctta ccagtgacgt cttccaggac tgcaacaagc tggtggaccc 3480
cgagccatat ctggatgtct gcatttacga cacctgctcc tgtgagtcca ttggggactg 3540
cgcctgcttc tgcgacacca ttgctgccta tgcccacgtg tgtgcccagc atggcaaggt 3600
ggtgacctgg aggacggcca cattgtgccc ccagagctgc gaggagagga atctccggga 3660
gaacgggtat gagtgtgagt ggcgctataa cagctgtgca cctgcctgtc aagtcacgtg 3720
tcagcaccct gagccactgg cctgccctgt gcagtgtgtg gagggctgcc atgcccactg 3780
ccctccaggg aaaatcctgg atgagctttt gcagacctgc gttgaccctg aagactgtcc 3840
agtgtgtgag gtggctggcc ggcgttttgc ctcaggaaag aaagtcacct tgaatcccag 3900
tgaccctgag cactgccaga tttgccactg tgatgttgtc aacctcacct gtgaagcctg 3960
ccaggagccg ggaggcctgg tggtgcctcc cacagatgcc ccggtgagcc ccaccactct 4020
gtatgtggag gacatctcgg aaccgccgtt gcacgatttc tactgcagca ggctactgga 4080
cctggtcttc ctgctggatg gctcctccag gctgtccgag gctgagtttg aagtgctgaa 4140
ggcctttgtg gtggacatga tggagcggct gcgcatctcc cagaagtggg tccgcgtggc 4200
cgtggtggag taccacgacg gctcccacgc ctacatcggg ctcaaggacc ggaagcgacc 4260
gtcagagctg cggcgcattg ccagccaggt gaagtatgcg ggcagccagg tggcctccac 4320
cagcgaggtc ttgaaataca cactgttcca aatcttcagc aagatcgacc gccctgaagc 4380
ctcccgcatc accctgctcc tgatggccag ccaggagccc caacggatgt cccggaactt 4440
tgtccgctac gtccagggcc tgaagaagaa gaaggtcatt gtgatcccgg tgggcattgg 4500
gccccatgcc aacctcaagc agatccgcct catcgagaag caggcccctg agaacaaggc 4560
cttcgtgctg agcagtgtgg atgagctgga gcagcaaagg gacgagatcg ttagctacct 4620
ctgtgacctt gcccctgaag cccctcctcc tactctgccc cccgacatgg cacaagtcac 4680
tgtgggcccg gggctcttgg gggtttcgac cctggggccc aagaggaact ccatggttct 4740
ggatgtggcg ttcgtcctgg aaggatcgga caaaattggt gaagccgact tcaacaggag 4800
caaggagttc atggaggagg tgattcagcg gatggatgtg ggccaggaca gcatccacgt 4860
cacggtgctg cagtactcct acatggtgac tgtggagtac cccttcagcg aggcacagtc 4920
caaaggggac atcctgcagc gggtgcgaga gatccgctac cagggcggca acaggaccaa 4980
cactgggctg gccctgcggt acctctctga ccacagcttc ttggtcagcc agggtgaccg 5040
ggagcaggcg cccaacctgg tctacatggt caccggaaat cctgcctctg atgagatcaa 5100
gaggctgcct ggagacatcc aggtggtgcc cattggagtg ggccctaatg ccaacgtgca 5160
ggagctggag aggattggct ggcccaatgc ccctatcctc atccaggact ttgagacgct 5220
cccccgagag gctcctgacc tggtgctgca gaggtgctgc tccggagagg ggctgcagat 5280
ccccaccctc tcccctgcac ctgactgcag ccagcccctg gacgtgatcc ttctcctgga 5340
tggctcctcc agtttcccag cttcttattt tgatgaaatg aagagtttcg ccaaggcttt 5400
catttcaaaa gccaatatag ggcctcgtct cactcaggtg tcagtgctgc agtatggaag 5460
catcaccacc attgacgtgc catggaacgt ggtcccggag aaagcccatt tgctgagcct 5520
tgtggacgtc atgcagcggg agggaggccc cagccaaatc ggggatgcct tgggctttgc 5580
tgtgcgatac ttgacttcag aaatgcatgg tgccaggccg ggagcctcaa aggcggtggt 5640
catcctggtc acggacgtct ctgtggattc agtggatgca gcagctgatg ccgccaggtc 5700
caacagagtg acagtgttcc ctattggaat tggagatcgc tacgatgcag cccagctacg 5760
gatcttggca ggcccagcag gcgactccaa cgtggtgaag ctccagcgaa tcgaagacct 5820
ccctaccatg gtcaccttgg gcaattcctt cctccacaaa ctgtgctctg gatttgttag 5880
gatttgcatg gatgaggatg ggaatgagaa gaggcccggg gacgtctgga ccttgccaga 5940
ccagtgccac accgtgactt gccagccaga tggccagacc ttgctgaaga gtcatcgggt 6000
caactgtgac cgggggctga ggccttcgtg ccctaacagc cagtcccctg ttaaagtgga 6060
agagacctgt ggctgccgct ggacctgccc ctgcgtgtgc acaggcagct ccactcggca 6120
catcgtgacc tttgatgggc agaatttcaa gctgactggc agctgttctt atgtcctatt 6180
tcaaaacaag gagcaggacc tggaggtgat tctccataat ggtgcctgca gccctggagc 6240
aaggcagggc tgcatgaaat ccatcgaggt gaagcacagt gccctctccg tcgagctgca 6300
cagtgacatg gaggtgacgg tgaatgggag actggtctct gttccttacg tgggtgggaa 6360
catggaagtc aacgtttatg gtgccatcat gcatgaggtc agattcaatc accttggtca 6420
catcttcaca ttcactccac aaaacaatga gttccaactg cagctcagcc ccaagacttt 6480
tgcttcaaag acgtatggtc tgtgtgggat ctgtgatgag aacggagcca atgacttcat 6540
gctgagggat ggcacagtca ccacagactg gaaaacactt gttcaggaat ggactgtgca 6600
gcggccaggg cagacgtgcc agcccatcct ggaggagcag tgtcttgtcc ccgacagctc 6660
ccactgccag gtcctcctct taccactgtt tgctgaatgc cacaaggtcc tggctccagc 6720
cacattctat gccatctgcc agcaggacag ttgccaccag gagcaagtgt gtgaggtgat 6780
cgcctcttat gcccacctct gtcggaccaa cggggtctgc gttgactgga ggacacctga 6840
tttctgtgct atgtcatgcc caccatctct ggtctacaac cactgtgagc atggctgtcc 6900
ccggcactgt gatggcaacg tgagctcctg tggggaccat ccctccgaag gctgtttctg 6960
ccctccagat aaagtcatgt tggaaggcag ctgtgtccct gaagaggcct gcactcagtg 7020
cattggtgag gatggagtcc agcaccagtt cctggaagcc tgggtcccgg accaccagcc 7080
ctgtcagatc tgcacatgcc tcagcgggcg gaaggtcaac tgcacaacgc agccctgccc 7140
cacggccaaa gctcccacgt gtggcctgtg tgaagtagcc cgcctccgcc agaatgcaga 7200
ccagtgctgc cccgagtatg agtgtgtgtg tgacccagtg agctgtgacc tgcccccagt 7260
gcctcactgt gaacgtggcc tccagcccac actgaccaac cctggcgagt gcagacccaa 7320
cttcacctgc gcctgcagga aggaggagtg caaaagagtg tccccaccct cctgcccccc 7380
gcaccgtttg cccacccttc ggaagaccca gtgctgtgat gagtatgagt gtgcctgcaa 7440
ctgtgtcaac tccacagtga gctgtcccct tgggtacttg gcctcaactg ccaccaatga 7500
ctgtggctgt accacaacca cctgccttcc cgacaaggtg tgtgtccacc gaagcaccat 7560
ctaccctgtg ggccagttct gggaggaggg ctgcgatgtg tgcacctgca ccgacatgga 7620
ggatgccgtg atgggcctcc gcgtggccca gtgctcccag aagccctgtg aggacagctg 7680
tcggtcgggc ttcacttacg ttctgcatga aggcgagtgc tgtggaaggt gcctgccatc 7740
tgcctgtgag gtggtgactg gctcaccgcg gggggactcc cagtcttcct ggaagagtgt 7800
cggctcccag tgggcctccc cggagaaccc ctgcctcatc aatgagtgtg tccgagtgaa 7860
ggaggaggtc tttatacaac aaaggaacgt ctcctgcccc cagctggagg tccctgtctg 7920
cccctcgggc tttcagctga gctgtaagac ctcagcgtgc tgcccaagct gtcgctgtga 7980
gcgcatggag gcctgcatgc tcaatggcac tgtcattggg cccgggaaga ctgtgatgat 8040
cgatgtgtgc acgacctgcc gctgcatggt gcaggtgggg gtcatctctg gattcaagct 8100
ggagtgcagg aagaccacct gcaacccctg ccccctgggt tacaaggaag aaaataacac 8160
aggtgaatgt tgtgggagat gtttgcctac ggcttgcacc attcagctaa gaggaggaca 8220
gatcatgaca ctgaagcgtg atgagacgct ccaggatggc tgtgatactc acttctgcaa 8280
ggtcaatgag agaggagagt acttctggga gaagagggtc acaggctgcc caccctttga 8340
tgaacacaag tgtctggctg agggaggtaa aattatgaaa attccaggca cctgctgtga 8400
cacatgtgag gagcctgagt gcaacgacat cactgccagg ctgcagtatg tcaaggtggg 8460
aagctgtaag tctgaagtag aggtggatat ccactactgc cagggcaaat gtgccagcaa 8520
agccatgtac tccattgaca tcaacgatgt gcaggaccag tgctcctgct gctctccgac 8580
acggacggag cccatgcagg tggccctgca ctgcaccaat ggctctgttg tgtaccatga 8640
ggttctcaat gccatggagt gcaaatgctc ccccaggaag tgcagcaagt gaggctgctg 8700
cagctgcatg ggtgcctgct gctgcctgcc ttggcctgat ggccaggcca gagtgctgcc 8760
agtcctctgc atgttctgct cttgtgccct tctgagccca caataaaggc tgagctctta 8820
tcttgcaaaa ggc 8833
<210> 3
<211> 29
<212> RNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成寡核苷酸
<400> 3
gccagggacc uaagacacau gucccuggc 29
<210> 4
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成寡核苷酸
<220>
<223> 组合的DNA/RNA分子的描述:合成寡核苷酸
<220>
<221> modified_base
<222> (1)..(29)
<223> 2'-O-甲基核苷酸
<220>
<221> modified_base
<222> (30)..(30)
<223> 反向核苷酸
<400> 4
gccagggacc uaagacacau gucccuggct 30
<210> 5
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成寡核苷酸
<220>
<223> 组合的DNA/RNA分子的描述:合成寡核苷酸
<220>
<221> modified_base
<222> (1)..(29)
<223> 2'-O-甲基核苷酸
<220>
<221> modified_base
<222> (30)..(30)
<223> 反向核苷酸
<400> 5
gccagggacc uaagacacau gucccuggct 30
<210> 6
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成寡核苷酸
<220>
<223> 组合的DNA/RNA分子的描述:合成寡核苷酸
<220>
<221> modified_base
<222> (1)..(29)
<223> 2'-O-甲基核苷酸
<220>
<221> modified_base
<222> (30)..(30)
<223> 反向核苷酸
<400> 6
gccagggacc uaagacacau gucccuggct 30
<210> 7
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成寡核苷酸
<220>
<223> 组合的DNA/RNA分子的描述:合成寡核苷酸
<220>
<221> modified_base
<222> (1)..(21)
<223> 2'-O-甲基核苷酸
<220>
<221> modified_base
<222> (22)..(22)
<223> 反向核苷酸
<400> 7
gggaccuaag acacaugucc ct 22
<210> 8
<211> 40
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成寡核苷酸
<220>
<223> 组合的DNA/RNA分子的描述:合成寡核苷酸
<220>
<221> modified_base
<222> (1)..(4)
<223> 2'-O-甲基核苷酸
<220>
<221> modified_base
<222> (8)..(18)
<223> 2'-O-甲基核苷酸
<220>
<221> modified_base
<222> (20)..(20)
<223> 2'-O-甲基核苷酸
<220>
<221> misc_feature
<222> (20)..(21)
<223> 硫代磷酸酯键
<220>
<221> modified_base
<222> (22)..(22)
<223> 2'-O-甲基核苷酸
<220>
<221> modified_base
<222> (27)..(28)
<223> 2'-O-甲基核苷酸
<220>
<221> modified_base
<222> (30)..(30)
<223> 2'-O-甲基核苷酸
<220>
<221> modified_base
<222> (33)..(34)
<223> 2'-O-甲基核苷酸
<220>
<221> modified_base
<222> (36)..(39)
<223> 2'-O-甲基核苷酸
<220>
<221> modified_base
<222> (40)..(40)
<223> 反向核苷酸
<400> 8
gcgugcagug ccuucggccg tgcggtgccu ccgucacgct 40
Claims (35)
1.一种用于治疗受试者的遗传性出血性病症的方法,所述方法包括向所述受试者施用治疗有效量的包括VWF靶向剂的药物组合物。
2.根据权利要求1所述的方法,其中所述遗传性出血性病症是后天性血小板功能缺陷、先天性血小板功能缺陷、弥散性血管内凝血(DIC)、凝血酶原缺乏症、纤维蛋白原缺乏症、FV缺乏症、FVII缺乏症、FX缺乏症、FXI缺乏症(C型血友病)、FXIII缺乏症、FV和FVIII组合缺乏症(F5F8D)、VKCFD、血小板无力症(Glanzmann thrombasthenia)、A型血友病、B型血友病、免疫性血小板减少性紫癜(ITP)、1型冯维勒布兰德氏病(VWD)、2型冯维勒布兰德氏病(VWD)和3型冯维勒布兰德氏病(VWD)。
3.根据权利要求2所述的方法,其中所述遗传性出血性病症是A型血友病、1型VWD、2型VWD或3型VWD。
4.根据权利要求3所述的方法,其中所述遗传性出血性病症是A型血友病、轻度血友病、中度血友病或重度血友病。
5.根据权利要求3所述的方法,其中所述遗传性出血性病症是1型VWD、1型VWD的维琴察亚型、2a型VWD、2b型VWD、伴有血小板减少症的2b型VWD、2m型VWD、2n型VWD或3型VWD。
6.根据权利要求1至5中任一项所述的方法,其中所述VWF靶向剂是选自由以下组成的组的VWF结合剂:抗体、纳米抗体、肽、寡核苷酸、siRNA、microRNA、合成多核苷酸和小分子。
7.根据权利要求6所述的方法,其中所述VWF结合剂是选自由以下组成的组的合成多核苷酸:SEQ ID No.:3、BT99(SEQ ID No.:4)、BT100(SEQ ID No.:5)、BT200(SEQ ID No.:6)、ARC15105(SEQ ID No.:7)和ARC1779(SEQ ID No.:8)以及其变体。
8.根据权利要求7所述的方法,其中所述VWF结合剂是BT200(SEQ ID No.:6)或其变体。
9.根据权利要求8所述的方法,其中BT200增加血液中VWF的水平和活性、FVIII的水平和活性和/或血小板计数。
10.根据权利要求8所述的方法,其中BT200以范围为0.1mg至48.0mg、或0.1mg至20.0mg或1.0mg至10mg的剂量向所述受试者施用。
11.根据权利要求10所述的方法,其中BT200以范围为0.6mg至6.0mg的剂量向所述受试者施用。
12.根据权利要求8所述的方法,其中所述VWF结合剂通过皮下注射向所述受试者施用。
13.根据权利要求12所述的方法,其中所述VWF结合剂以多个剂量向所述受试者施用,并且其中每个剂量每隔一天施用一次、或每三天施用一次、或每五天施用一次、或每周施用一次或每隔一周施用一次。
14.根据权利要求1至13中任一项所述的方法,其中所述遗传性出血性病症的治疗是疗法治疗或预防性治疗。
15.根据权利要求3所述的方法,其中所述VWF靶向剂与凝血因子替代物治疗组合施用;所述凝血因子替代物是血浆源性FVIII/VWF浓缩物、重组FVIII制剂或重组VWF制剂。
16.一种用于预防受试者的慢性出血病状和/或自发性出血的方法,所述方法包括向所述受试者施用治疗有效量的包括VWF靶向剂的药物组合物。
17.根据权利要求16所述的方法,其中所述VWF靶向剂是选自由以下组成的组的VWF结合剂:抗体、纳米抗体、肽、寡核苷酸、siRNA、microRNA、合成多核苷酸和小分子。
18.根据权利要求17所述的方法,其中所述VWF结合剂是包括PEG化核酸的合成多核苷酸。
19.根据权利要求18所述的方法,其中所述VWF结合剂是BT200(SEQ ID No.:6)或其变体。
20.根据权利要求19所述的方法,其中BT200以范围为1.0mg至10.0mg的剂量或可替代地以范围为1.0mg至6.0mg的剂量施用。
21.一种用于阻断血液中VWF清除的方法,所述方法包括提供有效量的VWF靶向剂,所述VWF靶向剂是包括PEG化部分的合成多核苷酸。
22.根据权利要求21所述的方法,其中所述VWF靶向剂是BT200(SEQ ID No.:6)或其变体。
23.根据权利要求22所述的方法,其中BT200以范围为0.6mg至6.0mg、或1.0mg至6.0mg或1.0mg至10.0mg的量提供。
24.根据权利要求23所述的方法,其中BT 200增加血液中的VWF水平。
25.一种用于提高受试者血液中FVIII水平的方法,所述方法包括向所述受试者施用有效量的包括VWF靶向剂的组合物,所述VWF靶向剂是包括PEG化部分的合成多核苷酸。
26.根据权利要求25所述的方法,其中所述受试者被诊断患有A型血友病、1型VWD、2型VWD或3型VWD。
27.根据权利要求26所述的方法,其中所述VWF靶向剂是BT200(SEQ ID No.:6)。
28.根据权利要求27所述的方法,其中BT200增加FVIII凝血活性。
29.一种用于增加患者血液中血小板计数的方法,所述方法包括向所述患者施用有效量的包括BT200(SEQ ID No.:6)的组合物,其中所述患者具有低血小板计数(血小板减少症)。
30.根据权利要求29所述的方法,其中所述血小板减少症与导致低血小板计数的遗传病症、容纳异常血小板的脾脏肿大、对药物的副反应、自身免疫性疾病或病毒感染相关联。
31.根据权利要求30所述的方法,其中所述病症是2a型VWD、伴有血小板减少症的2b型VWD、2b型VWD、2m型VWD或2n型VWD。
32.一种用于用包括VWF结合剂BT200的药物组合物治疗患者的遗传性出血性病症的方法,所述方法包括:
a)评估所述患者的所述遗传性出血性病症和所述患者的基线凝血功能;
b)使用步骤a)的所述评估来确定用于初始治疗的BT200的最佳剂量;以及
c)在用初始剂量的BT200对所述患者进行一周的治疗后,提供每周剂量的BT200。
33.根据权利要求32所述的方法,其中所述遗传性出血性病症可以是A型血友病、重度血友病、1型VWD、2a型VWD、2b型VWD、2m型VWD、2n型VWD或3型VWD。
34.根据权利要求33所述的方法,其中所述评估包含血液中的FVIII活性、VWF抗原水平和/或血小板计数。
35.根据权利要求33所述的方法,其中用凝血因子替代物治疗所述患者。
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