CN104519912A - 液体因子viii制剂 - Google Patents
液体因子viii制剂 Download PDFInfo
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- CN104519912A CN104519912A CN201380042462.3A CN201380042462A CN104519912A CN 104519912 A CN104519912 A CN 104519912A CN 201380042462 A CN201380042462 A CN 201380042462A CN 104519912 A CN104519912 A CN 104519912A
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Abstract
本发明涉及凝血因子VIII的液体含水制剂,其包含因子VIII分子、浓度高于10 mM的钙盐、以及浓度至少100 mM的糖类和/或多元醇,其中该制剂具有5.5-7.5的pH。本发明进一步提供了用于优化凝血因子VIII液体制剂的方法,该方法包含步骤:(i)提供一种或更多种液体制剂,其包含待测试的因子VIII;(ii)添加蛋白质变性剂到所述液体制剂中,并孵育所得溶液预定的时间段;(iii)分析(ii)的孵育溶液中解离的因子VIII的存在;以及(iv)选择一种或更多种具有所需低水平的解离的因子VIII的制剂。
Description
背景
在患有凝血病的对象中,诸如患有血友病A的人类中,致使凝血级联的各个步骤发生功能障碍,这是由于例如凝血因子的缺乏或存在不足。凝血级联一部分的这类功能障碍将导致血液凝固不充分,以及潜在地危及生命的出血,或内脏损害,诸如关节损害。患有血友病A的个体可以接受凝血因子置换疗法,诸如外源性因子VIII(FVIII)。
目前市场上的所有因子VIII产品都作为静脉输液用冻干制剂供应。在使用前,执行输液的人必须用液体重构粉末。这是耗时的,可以是多步骤的手动操作,并需要用户可见地监视溶解,这可以需要几分钟并可引起一些剂量变化。因此,因子VIII分子的稳定的、随时可用的液体制剂(优选地与方便的递送系统相结合)是高度期望的。具有很高浓度的稳定赋形剂的液体制剂可引起注射部位的局部刺激以及可能的静脉炎,这是由于注射的液体与周围组织之间的渗透压之间的较大差别。因此具有接近生理条件的渗透浓度的液体制剂是特别期望的。
蛋白质在水性溶液中具有许多可能的降解途径。因此必须微调液体蛋白质制剂以便获得实际使用所需的保质期期间的稳定性。典型的所需保质期是在2-8 ℃的储存温度下2年以便允许生产、储存和配送。在发现赋形剂、pH值和可改善液体制剂稳定性的其他可能因素的过程中,只使用目标储存条件是不切实际的,因为必须孵育样品很长的时间以便观察假定的稳定效应。因此,稳定性研究常常是在加速(应激)条件下进行的。这些应激条件包括,例如,高温、高湿度、强光照、极端pH值、经涡旋或振荡增加的气/水界面、和/或重复的冻融循环。由于这些应激条件,关键问题就是来自加速稳定性研究的数据是否以及多大程度上可以外推到实时条件下的那些数据。
因此,避免长期储存且避免应激条件的用于进行可靠的稳定性研究的方法是非常期望的。
因子VIII液体制剂的稳定性以前已在学术文献以及专利和专利申请中描述过了。
Fatouros等(International Journal of Pharmaceutics 155, 121-131
(1997))描述了氧、金属离子、pH和离子强度对液体溶液中的B结构域缺失的因子VIII稳定性的影响。该工作的一部分也在US5962650中描述了。
Fatouros等(Pharmaceutical Research 14, 1679-1684 (1997)和International Journal of Pharmaceutics 194, 69-79 (2000))描述了表面活性剂以及具体而言的非常高浓度的碳水化合物的稳定效应。该工作的一部分也在US5919908中描述了。
WO2011/027152描述了用tris和苯甲酸钾的组合缓冲的因子VIII的液体制剂,其含有EDTA和钙(钙相对于EDTA过量)以及另外的赋形剂。
概述
本发明涉及FVIII的液体药物制剂,该制剂可以用来治疗患有血友病A的对象。
本发明人现已发现,对于因子VIII分子,包括衍生物诸如PEG化因子VIII分子和具有延长作用的其他衍生物,获得了在冷藏温度下改善稳定性的液体制剂,这是通过10 mM以上例如15 mM或更高的钙浓度结合100 mM或更高的多元醇浓度而获得的。由于钙和某些多元醇的这些浓度的高度稳定效应,可以获得具有低浓度NaCl和低渗透浓度的稳定液体制剂。
因此,在一方面,本发明涉及凝血因子VIII的液体含水制剂,其中该制剂包含因子VIII分子、一种或更多种提供超过10 mM钙离子浓度的钙盐、以及浓度至少100 mM的一种或更多种多元醇,其中该制剂具有5.5-7.5之间的pH。
在一方面,本发明涉及凝血因子VIII的液体含水制剂,其中该制剂包含因子VIII分子、浓度至少15 mM的钙盐、以及浓度至少100 mM的糖类和/或多元醇;其中该制剂具有5.5-7.5的pH。
本发明人现已进一步发现,赋形剂对多价蛋白质的液体制剂的稳定效应可以通过加速测定法来精确确定,其中已包括化学性蛋白质变性剂并将样品短时间孵育。
因此,在另一方面,本发明涉及用于优化凝血因子VIII的液体制剂和识别因子VIII的稳定液体制剂的方法,该方法包含以下步骤:(i)提供一种或更多种液体制剂,其包含FVIII以及应评估其对FVIII的稳定效应的一种或更多种赋形剂;(ii)添加所选的蛋白质变性剂(例如盐酸胍或尿素)到所述液体制剂中并孵育所得一种或多种溶液预定的时间段;(iii)分析(ii)的孵育溶液中解离的因子VIII的存在;以及(iv)选择一种或更多种具有所期望低水平的解离的因子VIII的制剂。
描述
本发明的FVIII分子的稳定的液体药物制剂推进了改善的(易用的)递送系统的使用。所描述的稳定化原理也可以用于在制备期间(上游纯化步骤、储存和处理)稳定因子VIII分子。
凝血因子
VIII
分子
因子VIII(FVIII)是主要由肝细胞产生的大的复合糖蛋白。FVIII具有大约300
kDa的大小,包括信号肽,并且包含由同源性所定义的几个明显的结构域。有三个A结构域、独特的B结构域和两个C结构域。Al(a1区)和A2(a2区)C末端以及A3结构域的N末端(a3区)的小的酸性区域在它与其他凝血蛋白的相互作用中发挥重要作用,所述的其他凝血蛋白包括凝血酶和von Willebrand因子(vWF或VWF),FVIII的载体蛋白。详细的结构域结构由此可以列为A1-a1-A2-a2-B-a3-A3-C1-C2。
FVII在血浆中作为两条链进行循环,在B-a3交界处分开,即作为A1-a1-A2-a2-B/a3-A3-C1-C2异二聚体。蛋白结构是由二价金属离子结合所稳定的。A1-a1-A2-a2-B链被称为重链(HC)而a3-A3-C1-C2链被称为轻链(LC)。
内源FVIII分子作为具有各种大小的B结构域的分子集合而在体内循环,最短的具有740位处的C末端,即在A2-a2的C末端。这些具有不同长度B结构域的FVIII分子都具有完全的促凝活性。用凝血酶激活后,FVIII将在Al-a1的C末端372位处、在A2-a2的C末端740位处以及a3和A3之间的1689位处裂解,后一裂解将释放a3区并伴随对VWF的亲和力的丧失。凝血酶裂解(激活)的FVIII分子被称为FVIIIa。激活使得FVIIIa能够与磷脂表面如活化血小板和活化因子IX(FIXa)相互作用,即形成了tenase复合物,使因子X(FX)能够有效活化。
术语“因子VIII(a)”和“FVIII(a)”包括FVIII和FVIIIa两者。
“FVIII(a)”包括可能存在的、和从一个个体到另一个发生的FVIII(a)的天然等位基因变体。FVIII(a)可以是血浆来源的或重组生产的,其使用熟知的生产和纯化方法。糖基化的程度和部位、酪氨酸硫酸化以及其他翻译后修饰可以不同,这取决于所选的宿主细胞及其生长条件。
人FVIII由2351个氨基酸(包括信号肽)和2332个氨基酸(无信号肽)组成。详细的结构域结构,A1-a1-A2-a2-B-a3-A3-C1-C2具有相应的氨基酸残基(参见SEQ ID NO 1):A1
(1-336),a1 (337-372),A2 (373-710),a2
(711-740),B (741-1648),a3 (1649-1689),A3
(1690-2020),C1 (2021-2173)和C2 (2174-2332)。“天然FVIII”是来源于如SEQ ID NO:1(氨基酸1-2332)所示的全长序列的人FVIII分子。B结构域跨越SEQ ID NO 1的氨基酸741-1648。
包括在本发明制剂中的因子VIII分子还可以是B结构域截短/缺失的FVIII分子,其中余下的结构域对应SEQ ID NO:1的氨基酸号1-740和1649-2332所述的序列。
由此可见,这些FVIII分子是在转化的宿主细胞中产生的重组分子,优选哺乳动物来源的宿主细胞。然而,余下的结构域(即三个A结构域、两个C结构域以及a1、a2和a3区)可能约1%、2%、3%、4%或5%地稍微不同于SEQ ID NO:1所示的氨基酸序列(氨基酸1-740和1649-2332)。
包括在本发明制剂中的FVIII分子还可以是FVIII的生物活性片段,也就是说,其中除B结构域外的结构域已被缺失或截短的FVIII,但其中缺失/截短形式的FVIII分子保持其支持血块形成的能力。FVIII活性可以使用本领域中熟知的技术在体外评估。FVIII活性测定的例子可以在实施例部分找到。
可以在余下的结构域中引入氨基酸修饰(取代、缺失等),例如为了改变因子VIII与各种其他组分的结合能力,诸如Von Willebrand因子(vWF)、低密度脂蛋白受体相关蛋白(LPR)、各种受体、其他凝血因子、细胞表面等,或者为了引入和/或消除糖基化位点等。不消除FVIII活性的其他突变也可在FVIII分子/类似物中提供来用于本发明的制剂中。
本文使用的术语“FVIII类似物”是指这样的FVIII分子(全长或B结构域截短/缺失的),其中与SEQ ID NO:1相比,一个或更多个氨基酸已被取代或缺失,或者对于B结构域截短/缺失的FVII分子来说,是SEQ ID NO 1的相应部分。
FVIII类似物还包括FVIII分子,其中亲本多肽的一个或更多个氨基酸残基已被缺失或用其他氨基酸残基取代,和/或其中添加了另外的氨基酸残基到亲本FVIII多肽中。
而且,因子VIII分子/类似物可以在例如截短的B结构域和/或在分子的一个或更多个其他结构域中包含其他修饰(“FVIII衍生物”)。这些其他修饰可以是缀合到因子VIII分子上的各种分子的形式,诸如多聚化合物、肽化合物、脂肪酸衍生的化合物等。
本文使用的术语“FVIII衍生物”是指FVIII分子(全长或B结构域截短/缺失的)或FVIII类似物,其中亲本FVIII多肽的一个或更多个氨基酸已被化学修饰,例如通过烷基化、PEG化(包括糖基聚乙二醇化(glycopegylation),其中PEG被连接到一个或更多个多肽的聚糖上,例如按照US
20100261872所述)、酰化、酯形成或酰胺形成等,以缀合不同官能团到FVIII多肽的主链上,例如迁延(protractive)基团或延长半衰期的部分。术语“FVIII衍生物”还包括融合蛋白,其中FVIII分子(全长或B结构域截短/缺失的)被融合至另一多肽,例如白蛋白或Fc结构域或Fc衍生物。
在本发明的上下文中,术语“糖基聚乙二醇化的FVIII”旨在命名这样的因子VIII分子(包括全长FVIII和B结构域截短/缺失的FVIII),其中一个或更多个PEG基团已经通过多肽的一个或多个多糖侧链(一个或多个聚糖)连接到FVIII多肽上。
术语“迁延基团”/“延长半衰期的部分”在本文中应理解为是指连接到一个或更多个氨基酸侧链官能团(诸如-SH、-OH、-COOH、-CONH2、-NH2)或者一个或更多个N-和/或O-聚糖结构上的一个或更多个化学基团,并且当缀合到这些蛋白质/肽上时,可以增加许多治疗性蛋白质/肽的体内循环半衰期。
迁延基团/延长半衰期的部分的例子包括:生物相容性脂肪酸及其衍生物,羟烷基淀粉(HAS)例如羟乙基淀粉(HES),多聚(Glyx-Sery)n(高氨基酸多聚体(HAP)),透明质酸(HA),肝素前体(Heparosan)多聚体(HEP),磷脂酰胆碱基多聚体(PC多聚体),Fleximer®多聚体(Mersana Therapeutics, MA, USA),右旋糖酐(Dextran),聚唾液酸(PSA),聚乙二醇(PEG),Fc结构域,转铁蛋白,白蛋白,弹性蛋白样肽,XTEN®多聚体(Amunix, CA, USA),白蛋白结合肽,von
Willebrand因子片段(vWF片段),羧基端肽(CTP肽,Prolor Biotech, IL),及其任意组合(参见例如McCormick,
C.L., A.B.Lowe,和N. Ayres,
Encyclopedia of Polymer Science and Technology中的Water-Soluble
Polymers.2002, John Wiley & Sons, Inc.)。衍生化的方式不是关键的,并可以从上文进行阐明。
术语“Fc融合蛋白”在本文中意在包含融合到可以来源于任何抗体同种型的Fc结构域上的FVIII。IgG Fc结构域将通常是优选的,这是由于IgG抗体的相对长的循环半衰期。Fc结构域可以另外进行修饰以便调节某些效应器的功能,诸如例如补体结合和/或结合到某些Fc受体上。FVIII与Fc结构域(其具有结合FcRn受体的能力)的融合通常会导致与wt FVIII半衰期相比延长的融合蛋白循环半衰期。
由此可见,用于本发明的FVIII分子还可以是FVIII类似物的衍生物,诸如,例如,FVIII类似物的融合蛋白、PEG化或糖基聚乙二醇化的FVIII类似物、或者缀合到肝素前体(heparosan)多聚体上的FVIII类似物。
本文使用的术语“FVIII变体”是指FVIII类似物和FVIII衍生物的组。
用于本发明制剂中的FVIII分子的例子包含例如描述于WO2010045568、WO2009062100、WO2010014708、WO2008082669、WO2007126808、US20100173831、US20100173830、US20100168391、US20100113365、US20100113364、WO200331464、WO2009108806、WO2010102886、WO2010115866、WO2011101242
(PCT/EP2011/051438)、WO2011101284
(PCT/EP2011/051959)、WO2011101277
(PCT/ EP2011/051889)、WO2011131510
(PCT/ EP2011/055686)、WO2012007324
(PCT/EP2011/061349)、WO2011101267
(PCT/EP2011/051723)和WO2013083858中的FVIII分子。
可以用于本发明制剂中的FVIII分子的例子包括
Advate®、Helixate®、Kogenate®、Xyntha® 的活性成分,以及在WO2008/135501和WO2009/007451中描述的FVIII分子。
包括在本发明制剂中的FVIII分子还可以是FVIII衍生物或FVIII类似物或其组合,它们表现出相对于野生型FVIII基本上相同的或改善的生物活性,当与生色测定法(FVIII活性测定)中的人FVIII相比较时。FVIII活性测定法的例子可以在实施例部分找到。
生物活性
包含在根据本发明的制剂中的FVIII分子能够在凝血级联中以功能上类似于或等效于人FVIII的方式起作用,经由与FIXa的相互作用诱导了活化血小板上FXa的形成,并帮助血块的形成。FVIII活性可以使用本领域中熟知的技术在体外评估。血块分析法、FX活化测定法(通常称为生色测定法)、凝血酶生成测定法和全血凝血弹性描记术(thromboelastography)是这样的体外技术的例子。用于本发明制剂中的FVIII分子可以具有天然人FVIII至少约10%、至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%、100%或比100%更高的FVIII活性,当与生色测定法(FVIII活性测定)中的人FVIII相比是。FVIII活性测定法的例子可以在实施例部分找到。
B
结构域
FVIII的B结构域跨越SEQ
ID NO:1的氨基酸741-1648。B结构域在几个不同位点被裂解,产生了循环血浆FVIII分子中的大异质性。高度糖基化的B结构域的确切功能是未知的。已知的是B结构域对于凝血级联中的FVIII活性来说是可有可无的。因此重组FVIII经常是以B结构域缺失/截短分子的形式产生的。明显缺乏功能是有事实支持的,即B结构域缺失/截短的FVIII似乎具有与全长天然FVIII相同的体内特性。尽管如此,有迹象表明B结构域可能减少了与细胞膜的结合,至少是在无血清条件下。
B
结构域缺失
/
截短的因子
VIII
分子
内源性全长FVIII是作为单链前体分子合成的。在分泌之前,前体被裂解成重链和轻链。重组的B结构域缺失的FVIII可以通过两种不同的策略来产生。要么将不带B结构域的重链和轻链作为两条不同的多肽链各自合成(双链策略),要么将B结构域缺失的FVIII作为单个前体多肽链合成(单链策略),将该单个前体多肽链以与全长FVIII前体相同的方式裂解成重链和轻链。
在由单链策略产生的B结构域缺失的FVIII前体多肽中,重链和轻链部分常常通过接头分开。为了最大程度地减少在B结构域缺失的FVIII中引入免疫原性表位的风险,接头序列可以来源于FVIII的B结构域。作为最低要求,接头必须包含蛋白酶的识别位点,该蛋白酶将B结构域缺失的FVIII前体多肽裂解成重链和轻链。在全长FVIII的B结构域中,氨基酸1644-1648构成该识别位点。在B结构域缺失的FVIII活化时,导致接头去除的凝血酶裂解位点位于重链中。因此,接头的大小和氨基酸序列不可能通过凝血酶活化来影响它从余下FVIII分子中去除。B结构域的缺失/截短是生产FVIII的优点。然而,可以在接头中包括B结构域的一部分而不会降低生产率。B结构域对生产率的负面影响尚未被归因于B结构域的任何具体大小或序列。
降解
液体制剂中的因子VIII通过几种机制降解,包括重链和轻链之间的氧化和解离。轻链和重链的解离可以通过熟知的技术在体外评估,例如通过如在实施例部分描述的尺寸排阻色谱法(SEC)。
因子VIII分子的解离是在SEC中观察到比单体因子VIII更长洗脱时间的峰的出现。这个峰已被归于游离轻链(Fatouros等, International Journal of Pharmaceutics 155, 121页, 1997)。因此,FVIII分子的解离可以通过例如测定游离轻链的水平来进行评估。
实施方案
在本发明的一个实施方案中,因子VIII是重组制备的全长人FVIII。在另一实施方案中,因子VIII是重组制备的B结构域截短的FVIII。在本发明的一个实施方案中,因子VIII是具有如SEQ
ID NO:1所示序列的全长人FVIII。
在本发明的一个实施方案中,FVIII分子是FVIII序列类似物;在另一实施方案中,FVIII分子是在血块测定法中显示出相对于野生型FVIII基本上相同的或改善的生物活性的FVIII序列类似物,例如在下面的实验部分中所描述的。
在一个实施方案中,FVIII分子是由编码SEQ ID NO 2给出的氨基酸序列的载体所产生的B结构域截短的FVIII分子,该分子包含21个氨基酸残基的接头序列(SFSQNSRHPSQNPPVLKRHQR)(SEQ ID NO 6)。
在一个实施方案中,FVIII分子是双链的B结构域截短的FVIII分子,由通过非共价相互作用保持在一起的重链-接头序列(A1-a1-A2-a2-L)和轻链序列(a3-A3-C1-C2)所组成。接头(L)是20个氨基酸残基的接头序列(SFSQNSRHPSQNPPVLKRHQ)(SEQ
ID NO 3);重链(A1-a1-A2-a2)和轻链(a3-A3-C1-C2)分别对应SEQ
ID NO:1的氨基酸号1-740和1649-2332所述的序列。
在一个实施方案中,FVIII连接到迁延基团上。在一系列实施方案中,因子VIII为(i)PEG化的FVIII、(ⅱ)FVIII融合蛋白、(ⅲ)融合白蛋白的FVIII、或(iv)融合Fc区的FVIII。
在另一实施方案中,因子VIII是糖基聚乙二醇化的FVIII,诸如糖基聚乙二醇化的重组制备的全长人FVIII或糖基聚乙二醇化的B结构域截短的FVIII。在一个实施方案中,FVII连接到多糖(例如HEP、HES、HAS、PSA)上。在另一实施方案中,因子VIII连接到聚唾液酸(PSA)或者肝素前体(HEP)上。
在一个实施方案中,FVIII分子是具有修饰的循环半衰期的B-结构域截短的FVIII分子,所述分子通过在截短的B结构域中的O-连接的寡糖与亲水性聚合物共价缀合,其中FVIII的活化导致了共价缀合的聚合物的去除。在其不同的具体实施方案中,亲水性聚合物是聚乙二醇(PEG)、PSA和HEP。
在一个实施方案中,FVIII分子是具有修饰的循环半衰期的B-结构域截短的因子VIII分子,所述分子通过在截短的B结构域中的O-连接的寡糖与亲水性聚合物共价缀合,其中:(ⅰ)因子VIII的活化导致了共价缀合的亲水性聚合物的去除;以及(ii)FVIII前体多肽的重链和轻链部分是通过接头分开的,其中接头序列来源于FVIII的B结构域。在一个实施方案中,B结构域的长度为20-30个氨基酸。在一个实施方案中,亲水性聚合物是多糖;在一个实施方案中,所述多糖是PSA;在另一实施方案中,所述多糖是HEP。在一个实施方案中,亲水性聚合物是PEG。在不同的实施方案中,PEG的大小是从约10,000至约160,000 Da或者约40,000
Da。在一系列实施方案中,所使用的PEG具有2-160
kDa、或2-80 kDa、或5-80
kDa;或者5-60 kDa;或者10-80
kDa、或10-60 kDa、或20-60
kDa范围的大小。在不同的实施方案中,PEG是2 kDa、5 kDa、10 kDa、20 kDa、40 kDa、或80 kDa的PEG。
在一个具体系列的实施方案中,连接到如上所述迁延基团上的FVIII分子是双链的B结构域截短的FVIII分子,由通过非共价相互作用保持在一起的重链-接头序列(A1-a1-A2-a2-L)和轻链序列(a3-A3-C1-C2)所组成,其中接头(L)是20个氨基酸残基的接头序列(SFSQNSRHPSQNPPVLKRHQ)(SEQ
ID NO 3);重链(A1-a1-A2-a2)和轻链(a3-A3-C1-C2)分别对应SEQ
ID NO:1的氨基酸号1-740和1649-2332所述的序列。在其具体实施方案中,所描述的FVIII被连接到(i)一个或更多个PEG基团、(ⅱ)一个或更多个PSA基团、(ⅲ)一个或更多个HEP基团、或(iv )一个或更多个迁延基团上,其选自PEG、PSA和HEP。在进一步的具体实施方案中,一种或更多种迁延PEG/PSA/HEP基团已经由多肽的一个或多个多糖侧链(一个或多个聚糖)连接到FVIII多肽上;在进一步的实施方案中,所述迁延基团已通过位于接头序列(SEQ ID 3)内的聚糖连接到FVIII多肽上。在进一步的实施方案中,PEG基团是20-60 kDa的PEG或40 kDa的PEG。
在一个实施方案中,本发明制剂中的FVIII是双链的B结构域截短的FVIII分子,由通过非共价相互作用保持在一起的重链-接头序列(A1-a1-A2-a2-L)和轻链序列(a3-A3-C1-C2)所组成,其中接头(L)是20个氨基酸残基的接头序列(SFSQNSRHPSQNPPVLKRHQ)(SEQ
ID NO 3);重链(A1-a1-A2-a2)和轻链(a3-A3-C1-C2)分别对应SEQ
ID NO:1的氨基酸号1-740和1649-2332所述的序列,其中一个或更多个PEG基团已通过位于接头序列(SEQ ID 3)内的聚糖连接到FVIII多肽上。在进一步的实施方案中,PEG基团是20-60 kDa的PEG或40 kDa的PEG。
在一个实施方案中,本发明制剂中的FVIII是双链的B结构域截短的FVIII分子,由通过非共价相互作用保持在一起的重链-接头序列(A1-a1-A2-a2-L)和轻链序列(a3-A3-C1-C2)所组成,其中接头(L)是20个氨基酸残基的接头序列(SFSQNSRHPSQNPPVLKRHQ)(SEQ
ID NO 3);重链 (A1-a1-A2-a2) 和轻链 (a3-A3-C1-C2)分别对应SEQ ID NO: 1的氨基酸号1-740和1649-2332所述的序列,其中一个或更多个HEP基团已通过位于接头序列(SEQ ID 3)内的聚糖连接到FVIII多肽上。
在一个实施方案中,本发明制剂中的FVIII是双链的B结构域截短的FVIII分子,由通过非共价相互作用保持在一起的重链-接头序列(A1-a1-A2-a2-L)和轻链序列(a3-A3-C1-C2)所组成,其中接头(L)是20个氨基酸残基的接头序列(SFSQNSRHPSQNPPVLKRHQ)(SEQ
ID NO 3);重链 (A1-a1-A2-a2) 和轻链 (a3-A3-C1-C2)分别对应SEQ ID NO: 1的氨基酸号1-740和1649-2332所述的序列,其中一个或更多个PSA基团已通过位于接头序列(SEQ ID 3)内的聚糖连接到FVIII多肽上。
在一个实施方案中,本发明制剂中的FVIII是SEQ
ID NO 2给出的B结构域截短的FVIII分子,其中一个或更多个PEG基团已通过位于接头序列(SEQ ID 3)内的聚糖连接到FVIII多肽上。在进一步的实施方案中,PEG基团是20-60 kDa的PEG或40 kDa的PEG。
在一个实施方案中,本发明制剂中的FVIII是SEQ
ID NO 2给出的B结构域截短的FVIII分子,其中一个或更多个HEP基团已通过位于接头序列(SEQ ID 3)内的聚糖连接到FVIII多肽上。
在一个实施方案中,本发明制剂中的FVIII是SEQ
ID NO 2给出的B结构域截短的FVIII分子,其中一个或更多个PSA基团已通过位于接头序列(SEQ ID 3)内的聚糖连接到FVIII多肽上。
含水制剂
本发明制剂中的因子VIII的浓度一般在10-10,000
IU/mL的范围内。在不同的实施方案中,本发明制剂中的FVIII分子的浓度在10-8000 IU/mL、或10-6000
IU/mL、或10-4000 IU/mL、或10-2500 IU/mL、或30-4000
IU/mL、或30-2500 IU/mL、或50-2500 IU/mL、或50-1250
IU/mL、或100-2500 IU/mL的范围内。
一个IU(国际单位)定义为在1 mL新鲜的、汇集的正常人体血浆中发现的FVIII的量。
在本发明的一个实施方案中,药物制剂是含水溶液。术语“含水制剂”定义为包含至少50 %w/w水的制剂。同样地,术语“含水溶液”定义为包含至少50 %w/w水的溶液。
盐
根据本发明的制剂包含钙盐。制剂还可以含有钠盐。
在一个实施方案中,制剂含有至少15 mM的钙盐。在一个系列的实施方案中,制剂包含15-100
mM的钙盐,或15-80 mM或15-60
mM或15-45 mM或15-30
mM或15-25 mM或15-20
mM;或者至少20 mM的钙盐,或20-100
mM,或20-80 mM,或20-60
mM,或20-45 mM,或20-45
mM,或20-40 mM,或20-30
mM,或25-35 mM,或者至少30 mM,或30-45 mM,或约30 mM。在一个具体实施方案中,制剂含有25-35 mM的钙盐。
钙盐可以是,例如,选自氯化钙、乙酸钙、乳酸钙、苯甲酸钙及其混合物,以及本领域技术人员所熟知的其他可溶性钙盐。在一个实施方案中,钙盐是氯化钙。
在一个实施方案中,制剂不含EDTA。
在一个实施方案中,制剂含有至少5 mM的钠盐。在一个系列的实施方案中,制剂包含5-500
mM的钠盐,或15-150 mM或15-125
mM或15-100 mM;或者至少20 mM的钙盐,或20-150 mM或20-130 mM或20-100 mM;或者至少30 mM,或30-150 mM或50-150 mM。在一个实施方案中,钠盐的浓度为100 mM,或5-100
mM,或50-100 mM,或低于50 mM,或5-50 mM。
一种或多种用于pH调节的钠盐,一般以NaOH的形式,以特定钠浓度被包括。
钠盐可以是,例如,选自氯化钠、乙酸钠、乳酸钠、苯甲酸钠及其混合物,以及本领域技术人员所熟知的其他可溶性钠盐。
在本发明的一个实施方案中,钠盐是氯化钠;在另一实施方案中,所述盐是乙酸钠。在第三个实施方案中,本发明的制剂含有氯化钠和乙酸钠的混合物。
缓冲液
根据本发明的制剂可以包含缓冲体系。缓冲液(或缓冲物质)可以选自乙酸盐、苯甲酸盐、碳酸盐、柠檬酸盐、甘氨酰甘氨酸、组氨酸或组氨酸衍生物、Hepes、甘氨酸、磷酸盐、磷酸氢盐、以及三(羟甲基)-氨基甲烷(TRIS)、N,N-二羟乙基甘氨酸、三(羟甲基)-甲基甘氨酸、琥珀酸盐、天冬氨酸、谷氨酸或其混合物。在本发明的一个实施方案中,缓冲物质的浓度为1-100 mM,诸如,例如,1-50 mM,或1-25 mM,或1-20 mM,或5-20 mM或5-15 mM。
在本发明的一个实施方案中,制剂包含组氨酸,优选L-组氨酸。在其一个实施方案中,组氨酸的浓度为1-100
mM,诸如,例如,1-50 mM,或1-25
mM,或1-20 mM,或5-20
mM或5-15 mM。
本发明的液体制剂通常具有5.5至7.5的pH。在不同的实施方案中,制剂具有6.0-7.0或6.2-6.8或6.3-6.7的pH。
糖类和
/
或多元醇
本发明的制剂进一步包含糖类(糖)和/或多元醇(糖醇)。糖类可以是,例如,选自单糖、二糖或多糖,以及水溶性葡聚糖(包括例如单糖果糖、葡萄糖、甘露糖,二糖乳糖、蔗糖、海藻糖,以及多糖右旋糖酐、棉子糖、水苏糖)。多元醇可以是,例如,选自糖醇(包括例如甘露醇、山梨醇、肌醇、半乳糖醇、卫矛醇、木糖醇和阿糖醇),多羟糖醇(alditol)(例如甘油(丙三醇)、1,2-丙二醇(丙二醇)、1,3-丙二醇、1,3-丁二醇),聚乙二醇,或其混合物。
如果制剂中包含多于一种的糖类和/或多元醇,所述浓度意在指向制剂中存在的“糖类和/或多元醇”的总量。
在本发明的一个实施方案中,FVIII制剂包含来自以下组的一种或更多种糖类和/或糖醇:蔗糖、山梨醇、甘油、棉子糖、水苏糖、甘露醇、山梨醇或其混合物。
在一个实施方案中,FVIII制剂包含至少200 mM浓度的糖类和/或糖醇。
在一个实施方案中,根据本发明的FVIII制剂包含一种或更多种糖类,并且不包含多元醇。在另一实施方案中,制剂包含单一的糖类组分,并且不包含多元醇。在具体的上述实施方案中,糖类是蔗糖。
在一个实施方案中,制剂包含一种或更多种多元醇,并且不包含糖类。在另一实施方案中,制剂包含单一的多元醇组分,并且不包含糖类。在具体的上述实施方案中,糖类是山梨醇或甘露醇。
在本发明的一个实施方案中,制剂所包含的糖类和/或糖醇的浓度将导致计算的制剂渗透浓度(“X”) 等于或低于1.50 Osm/L。在本发明的一个实施方案中,制剂因此包含从100
mM浓度至X mM浓度的糖类和/或糖醇,其中X定义为使计算的制剂渗透浓度达到1.50 Osm/L的值(mM)。在另一实施方案中,制剂包含从200
mM浓度至X mM浓度的糖类和/或糖醇,其中X定义为使计算的制剂渗透浓度达到1.50 Osm/L的值(mM)。
当计算给定制剂的渗透浓度,并由此确定所述制剂的X值时,制剂中的所有组分都被包括在计算中(例如CaCl2、NaCl、缓冲物质、甲硫氨酸)。渗透浓度的计算描述于本申请中(见下面的“渗透浓度”部分)。然而,渗透浓度的理论计算是本领域技术人员所熟知的。
在本发明的一个实施方案中,制剂包含至少100 mM浓度的糖类和/或多元醇,或至少200 mM,或100-1800 mM,或300-1800 mM,或100-1500
mM,或200-1800 mM,或200-1500 mM,或100-1000
mM,或200-1000 mM,或300-1000 mM,或200-800
mM,或300-800 mM,或400-800
mM,或500-800 mM,或500-700
mMM。
在一个实施方案中,本发明的制剂包含蔗糖。在一个实施方案中,蔗糖的浓度为100-1000 mM,或150-1750 mM,或200-1000
mM,或300-1000 mM,或200-800 mM,或300-800
mM,或440-730 mM,或400-800
mM,或500-800 mM,或500-700
mM;在另一实施方案中,蔗糖的浓度为50-600 mg/mL,或100-600 mg/mL,或100-450
mg/mL或150-450 mg/mL或150-250 mg/mL(100
mg/mL的蔗糖对应292 mM)。
在另一实施方案中,本发明的制剂包含山梨醇。在不同的实施方案中,山梨醇的浓度为至少400 mM,或400-1500 mM,或者100-800
mg/mL,或100-650 mg/mL,或150-650 mg/mL,或150-500
mg/mL,或150-250 mg/mL(100 mg/mL的山梨醇对应549 mM)。
其他赋形剂
本发明的制剂可以进一步含有另外的赋形剂。用于根据本发明的药物制剂中的标准赋形剂的例子是防腐剂、抗氧化剂和表面活性剂。
在本发明的一个实施方案中,可以添加诸如甲硫氨酸(或者其他含硫氨基酸或含硫氨基酸类似物)的还原剂以抑制甲硫氨酸残基氧化为甲硫氨酸亚砜。通过“抑制”是为了生产期间以及随时间的甲硫氨酸氧化物类的最小程度积累。抑制甲硫氨酸氧化将导致多肽固有分子形式的更多保留。要加入的量应当是这样的量,其足以抑制甲硫氨酸残基氧化而使得甲硫氨酸亚砜的量是管理机构可接受的。通常地,这意味着制剂包含不超过约10%至约30%的甲硫氨酸亚砜。通常地,这可以通过添加甲硫氨酸而使得所添加的甲硫氨酸与因子VIII的甲硫氨酸残基的比为至少约1:1来实现。
在本发明的一个实施方案中,制剂包含甲硫氨酸,例如L-甲硫氨酸。在其一个实施方案中,甲硫氨酸的浓度为0.05-100
mM,诸如,例如,0.1-10 mM或0.1-2
mM或0.2-0.5 mM。
在本发明的一个实施方案中,制剂进一步包含表面活性剂。典型的表面活性剂(括号[]中给出商品名的例子)是聚氧乙烯脱水山梨醇脂肪酸酯诸如聚氧乙烯(20)脱水山梨醇单月桂酸酯[Tween
20]、聚氧乙烯(20)脱水山梨醇单棕榈酸酯[Tween
40]或聚氧乙烯(20)脱水山梨醇单油酸酯[Tween
80],泊洛沙姆诸如聚氧丙烯-聚氧乙烯嵌段共聚物[Pluronic
F68/poloxamer 188],聚乙二醇辛基苯基醚[Triton X-100]或者聚氧乙烯乙二醇十二烷基醚[Brij 35]。表面活性剂在药物制剂中的使用是本领域技术人员所熟知的。为了方便起见,参考Remington:
The Science and Practice of Pharmacy,第19版,1995。
在本发明的一个实施方案中,制剂包含山梨聚糖单油酸酯[Tween 80]。在其一个实施方案中,脱水山梨醇单油酸酯[Tween
80]的浓度为0.01-0.5 mg/mL,诸如,例如,0.05-0.3 mg/mL或0.05-0.2
mg/mL,或者约0.1 mg/mL。
在本发明的一个实施方案中,制剂包含poloxamer 188。在其一个实施方案中,poloxamer 188的浓度为0.01-5
mg/mL,诸如,例如,0.05-3 mg/mL或0.25-2 mg/mL,或者约0.5
mg/mL。
在本发明的一个实施方案中,制剂中含有FVIII、L-组氨酸、Tween® 80、L-甲硫氨酸、NaCl、蔗糖和CaCl2;在本发明的另一实施方案中,制剂含有FVIII、10 mM
L-组氨酸,0.1 mg/ml Tween® 80、0.37 mM L-甲硫氨酸、78 mM
NaCl、188 mg/ml蔗糖,和30 mM
CaCl2,pH 6.7;在另一实施方案中,制剂包含FVIII、20-40
mM CaCl2、500-800 mM蔗糖或150-250 mg/mL山梨醇。在任一这些实施方案的具体实施方案中,所述的FVIII是:
(ⅰ)包含对应SEQ ID NO 1的氨基酸号1-740和1649-2332所述序列的结构域的FVIII分子;或者
(ii)SEQ
ID NO 2给出的B结构域截短的FVIII分子;或者
(ii)双链的B结构域截短的FVIII分子,由通过非共价相互作用保持在一起的重链-接头序列(A1-a1-A2-a2-L)和轻链序列(a3-A3-C1-C2)所组成。接头(L)是20个氨基酸残基的接头序列(SFSQNSRHPSQNPPVLKRHQ)(SEQ
ID NO 3),重链 (A1-a1-A2-a2) 和轻链(a3-A3-C1-C2)分别对应SEQ
ID NO 1的氨基酸号1-740和1649-2332所述的序列;或者
(iv)SEQ
ID NO 2给出的B结构域截短的FVIII分子,其中一个或更多个PEG基团已通过位于接头序列(SEQ ID 3)内的聚糖连接到FVIII多肽上;或者
(v)双链的B结构域截短的FVIII分子,由通过非共价相互作用保持在一起的重链-接头序列(A1-a1-A2-a2-L)和轻链序列(a3-A3-C1-C2)所组成,其中接头(L)是20个氨基酸残基的接头序列(SFSQNSRHPSQNPPVLKRHQ)(SEQ
ID NO 3);重链 (A1-a1-A2-a2) 和轻链(a3-A3-C1-C2)分别对应SEQ
ID NO: 1的氨基酸号1-740和1649-2332所述的序列,其中一个或更多个PEG基团已通过位于接头序列(SEQ ID 3)内的聚糖连接到FVIII多肽上;或者
(vi)具有修饰的循环半衰期的B-结构域截短的FVIII分子,所述分子通过在截短的B结构域中的O-连接的寡糖与亲水性聚合物共价缀合,其中FVIII的活化导致了共价缀合的聚合物的去除。在其不同的具体实施方案中,亲水性聚合物是聚乙二醇(PEG)、PSA和HEP;
(vii)具有修饰的循环半衰期的B-结构域截短的因子VIII分子,所述分子通过在截短的B结构域中的O-连接的寡糖与亲水性聚合物共价缀合,其中:(ⅰ)因子VIII的活化导致了共价缀合的亲水性聚合物的去除;以及(ii)FVIII前体多肽的重链和轻链部分是通过接头分开的,其中接头序列来源于FVIII的B结构域。在一个实施方案中,B结构域的长度为20-30个氨基酸;或者
(vi)Advate®的活性成分,或者
(vii)Helixate®的活性成分;或者
(viii)Kogenate®的活性成分,或者
(ix)Xyntha®的活性成分,或者
(x)按照Thim
L.等(Haemophilia 2010;
16:349-359)所述制备的FVIII分子;或者
(xi)按照WO
2009108806中所述制备的FVIII分子。
抗氧化
抗氧化作用可以通过置换与产物接触的氧气(空气)来实现。在具体的实施方案中,制剂不包括抗氧化剂;而是通过排除空气或者通过置换与产物接触的氧气(空气)来控制FVIII的氧化易感性。这可以例如通过用氮、氦或氩任一种来饱和液体制剂,并在用气体置换产物上的空气后密封最终容器来实现。氧气(空气)的置换可以例如作为“脱气”过程进行,其中对制剂进行一个或更多个循环的(ⅰ)暴露于惰性气体(氩、氦或氮)和/或(ii)将含有制剂的腔室排空到低于大气压的压强。在一个具体的实施方案中,将制剂无菌过滤,分配在小瓶中,并通过暴露于纯N2(通过短暂排空腔室到0.1巴压强而散布)三个循环进行脱气,以及然后用纯N2在顶部空间密封小瓶。
当然抗氧化剂的使用也可以与空气排除相结合。此外,制剂可以进行避光保护;当然所述保护可以与空气排除和抗氧化剂使用的其中一种或两种相结合。
因此,本发明还提供了含有本文所定义的液体含水药物制剂以及任选的惰性气体的气密容器(例如小瓶或药筒(cartridge)(诸如用于笔式涂药器(pen applicator)的药筒))。惰性气体可以选自氮气、氦气或氩气。在本发明上下文中,术语“气密容器”意指具有低的氧气(空气)透过性的容器。
容器(例如小瓶或药筒或注射器)通常由玻璃或塑料制成,特别是玻璃,任选地由橡胶隔膜或允许保持了药物制剂完整性的渗透的其他封闭装置进行封闭。在进一步的实施方案中,容器是封闭在密封袋中的小瓶或药筒,例如密封的塑料袋,诸如层状的(例如金属(诸如铝)层压的塑料袋)。
施用和治疗
在本发明的一个实施方案中,制剂是用于施用给对象的药物制剂。制剂通常通过肠胃外施用进行施用,其可以通过经由注射器(任选笔式注射器)的皮下、肌内、腹膜内或者静脉内注射进行。备选地,肠胃外施用可以通过输液泵来进行。
本发明还包括治疗血友病A的方法,该方法包含给有此需要的对象施用根据本发明的制剂。
本文使用的术语“对象”包括任何人患者或非人脊椎动物。
本文使用的术语“治疗(treating)”或“治疗(treatment)”是指有此需要的任何人或其他脊椎动物对象的医学疗法。所述对象预期已由执业医生或执业兽医进行过体检,该医生或兽医已给出初步的或明确的诊断表明所述具体治疗的使用对所述人或其他脊椎动物的健康是有益的。所述治疗的时间和目的可以随不同个体而变化,根据对象的健康现状。因此,所述治疗可以是预防性的、姑息的、对症的和/或根治性的。就本发明而言,预防性的、姑息的、对症的和/或根治性治疗可以代表本发明单独的方面。
所述血友病A可以是重型、中型或轻型。血友病A的临床严重程度是由血液中的FVIII功能单元的浓度来确定的,并分类为轻型、中型或重型。重型血友病是由<0.01
U/ml的凝血因子水平(对应于正常水平的<1%)所定义的,而中型和轻型患者分别具有1-5%和>5%的水平。
渗透浓度
渗透浓度,原名容量渗透摩尔浓度(osmolarity),是溶质浓度的量度,定义为每升(L)溶液的溶质渗透摩尔(Osm)数(osmol/L或Osm/L)。摩尔浓度(molarity)测量每单位体积溶液的溶质摩尔数,而容量渗透摩尔浓度测量每单位体积溶液的溶质微粒的渗透摩尔数。重量渗透摩尔浓度(Osmolality)是每千克溶剂中的溶质渗透摩尔(osmol/kg或Osm/kg)的量度。摩尔浓度和容量渗透摩尔浓度在理论上是温度依赖性的。这是因为水会随温度而改变其体积。然而,如果溶质的浓度低,那么容量渗透摩尔浓度和重量渗透摩尔浓度被认为是等价的。
渗透浓度的理论计算是本领域技术人员所熟知的。简言之,对溶液中的每种组分计算渗透系数f、分子在水中解离的微粒数n以及摩尔浓度的积,并将所有组分的结果求和。
因此,溶液的渗透浓度可以由下面的表达式进行计算:Osm/L = ∑i fi
ni Ci,其中指数i代表特定组分的身份;fi是具体组分的渗透系数;n是分子在水中解离的微粒数;C是组分的摩尔浓度。如前面提到的,摩尔浓度具有少量的温度依赖性;为该目的,我们指25℃时的浓度。
评估注射后溶液可能施加的渗透压的备选方式是通过评估重量渗透摩尔浓度,其中评估了相对于溶剂质量的组分含量。如果溶液密度和溶解组分的干质量是已知的,那么重量渗透摩尔浓度和渗透浓度可以很容易地相互转换。重量渗透摩尔浓度可以通过多种方法进行测量,最常见的是凝固点降低法。例如,对于水,添加到1 kg水中的1 Osmol的溶质将降低1.86℃的凝固点。用于通过凝固点降低法来测量溶液的重量渗透摩尔浓度的方法描述于例如欧洲药典2.2.35和美国药典785章中。
下表列出了一些重要赋形剂的渗透系数和微粒数n。对于其他组分,f=1的值提供了用于实用目的的足够好的近似,以及对于用于肠胃外使用的药物制剂而言,基本上所有相关化合物的n值都是熟知的。
赋形剂 | f | n |
NaCl | 0.93 | 2 |
CaCl2 | 0.86 | 3 |
乙酸钠 | 0.95 | 2 |
蔗糖 | 1.02 | 1 |
甘油 | 1.01 | 1 |
组氨酸 | 1.0 | 1 |
L-甲硫氨酸 | 1.0 | 1 |
Poloxamer-188 | 1.0 | 1 |
山梨聚糖80 | 1.0 | 1 |
在本发明的不同实施方案中,制剂具有低于1.50 Osm/L、低于1.20
Osm/L、低于1.00 Osm/L、或低于0.90
Osm/L.的计算渗透浓度。
为确定赋形剂在
FVIII
制剂中的稳定效应的加速测定法
本发明人现已进一步发现,赋形剂对多价蛋白质的液体制剂的稳定效应可以通过加速测定法来精确确定,其中已包括化学性蛋白质变性剂并将样品短时间孵育。
因此,因子VIII分子(包括类似物和衍生物)的液体制剂与蛋白质变性剂的孵育和接着进行的分析(例如通过实施例部分描述的尺寸排阻色谱法(SEC))是快速研究制剂的有用工具。样品还可以通过例如实施例部分描述的生色测定法来分析活性。根据本发明的方法提供了快速且可靠的方式来进行加速稳定性研究。该方法提供了避免长期储存样品和/或避免使测试样品经受应激条件的方式。应激条件可能使所获得的结果难以外推到实时条件下的那些结果。根据本发明的方法提供了快速且准确的方式来识别具有低的游离轻链形成的FVIII制剂的样品,即提供了快速且准确的方式来识别稳定制剂。
需要几个月甚至几年的时间来获得给定制剂的实时稳定性数据,而本方法提供了短时间内获得的数据,通常是一周或更短的时间内,通常甚至在24-48小时内。
化学性蛋白质变性剂是通过对蛋白质结构的破坏稳定性来表征的,它是由于溶液的组成而不是由于外部应激诸如极端的温度、机械应力或光。化学性蛋白质变性剂的例子是离液剂诸如盐酸胍、尿素、硫脲、乙醇和本领域技术人员所熟知的其他化合物。低于5.5或高于8.0的pH条件也可以用作因子VIII的化学变性剂。
在本发明的一个实施方案中,变性剂是盐酸胍(GuHCl)。在另一实施方案中,变性剂是尿素。在一个系列的实施方案中,变性剂是浓度为0.1-1.0
M的盐酸胍,诸如,例如,0.2-0.8 M或0.2 M或0.4 M。在另一系列的实施方案中,变性剂是浓度为1-5 M的尿素,诸如,例如,1-3 M或1-2 M。
制剂可以通过探测完整因子VIII分子的存在的任何方法进行分析。特别合适的是色谱法,其对完整因子VIII分子和对任一解离的轻链或解离的重链提供各自的信号,或者对所有三种提供各自的信号。
在一个实施方案中,制剂通过尺寸排阻色谱法进行分析。在另一实施方案中,制剂通过场流分级法进行分析。在另一实施方案中,制剂通过离子交换色谱法进行分析。在另一实施方案中,制剂通过疏水作用色谱法进行分析。在另一实施方案中,制剂通过分析超速离心法进行分析。可以类似地使用本领域技术人员所熟知的其他分离方法。
孵育时间和温度
添加变性剂到FVIII制剂中之后,含有变性剂的制剂通常在约5℃下孵育至少1小时,更优选24小时或更长的时间。在不同的实施方案中,温育时间为12-240小时,12-120小时,或24-120小时,或24-60小时。
实施方案列表
在下面提到本发明的许多不同的实施方案:
实施方案1:凝血因子VIII的液体含水制剂,所述制剂包含因子VIII多肽、浓度至少15 mM的钙盐、浓度至少10 mM的钠盐;其中所述制剂具有6.0-7.5的pH。
实施方案2:实施方案1所述的制剂,所述制剂包含浓度20-45 mM的钙盐。
实施方案3:根据实施方案1或实施方案2所述的制剂,其中所述盐是氯化钙。
实施方案4:根据实施方案1-3任一项所述的制剂,其中所述钠盐的浓度为至多100 mM。
实施方案5:根据实施方案1-4任一项所述的制剂,其中所述钠盐是氯化钠或乙酸钠。
实施方案6:根据实施方案1-5任一项所述的制剂,所述制剂进一步含有浓度至少200 mM的糖类或糖醇。
实施方案7:根据实施方案6所述的制剂,其中所述制剂含有浓度至少200 mM和至多800
mM的蔗糖。
实施方案8:根据实施方案6所述的制剂,其中所述制剂含有浓度至少400 mM的山梨醇。
实施方案9:根据实施方案1-8任一项所述的制剂,其中所述因子VIII多肽是重组的全长FVIII或者重组的B结构域截短的FVIII。
实施方案10:根据实施方案9所述的制剂,其中所述因子VIII多肽被连接到迁延基团上。
实施方案11:根据实施方案10所述的制剂,其中所述因子VIII多肽是PEG化FVIII、或融合白蛋白的FVIII、或融合Fc区的FVIII。
实施方案12:根据实施方案10所述的制剂,其中所述因子VIII多肽是糖基聚乙二醇化的B结构域截短的FVIII。
实施方案13:根据实施方案1-12任一项所述的制剂,所述制剂具有6.0至7.0、或6.4至7.0的pH。
实施方案14:用于优化凝血因子VIII液体制剂的方法,所述方法包含步骤:
(i)提供包含待待测试的因子VIII的各种液体制剂;
(ii)添加蛋白质变性剂到所述液体制剂中,并孵育所得溶液预定的时间段;
(iii)分析(ii)所孵育的溶液中游离FVIII轻链的存在;
(iv)选择具有所需低水平游离轻链的一种或更多种制剂。
实施方案15:用于识别凝血因子VIII的稳定液体制剂的方法,所述方法包含步骤:
(i)提供包含待待测试的因子VIII的各种液体制剂;
(ii)添加蛋白质变性剂到所述液体制剂中,并孵育所得溶液预定的时间段;
(iii)分析(ii)所孵育的溶液中游离FVIII轻链的存在;
(iv)选择具有所需低水平游离轻链的一种或更多种制剂。
实施方案16:根据实施方案14或实施方案15所述的方法,其中所述蛋白质变性剂是盐酸胍或尿素。
实施方案17:根据实施方案14-16任一项所述的方法,其中所述因子VIII多肽是重组的全长FVIII或者重组的B结构域截短的FVIII。
实施方案18:根据实施方案17所述的方法,其中所述因子VIII多肽被连接到迁延基团上。
实施方案19:根据实施方案18所述的方法,其中所述因子VIII多肽是PEG化FVIII、或融合白蛋白的FVIII、或融合Fc区的FVIII。
实施方案20:根据实施方案19所述的方法,其中所述因子VIII多肽是糖基聚乙二醇化的B结构域截短的FVIII。
更多的实施方案是:
实施方案21:凝血因子VIII的液体含水制剂,所述制剂包含因子VIII多肽、浓度至少15 mM的钙盐、浓度至少100 mM的多元醇,其中所述制剂具有5.5-7.0的pH。
实施方案22:实施方案21所述的制剂,所述制剂包含浓度15-100 mM或20-45
mM的钙盐。
实施方案23:根据实施方案21或实施方案22所述的制剂,其中所述盐是氯化钙。
实施方案24:根据实施方案21-23任一项所述的制剂,其中计算的渗透浓度为至多1500 mOsm/L、或1000 mOsm/L、或900
mOsm/L。
实施方案25:根据实施方案21-24任一项所述的制剂,所述制剂进一步包含钠盐。
实施方案26:根据实施方案25的制剂,其中所述钠盐是氯化钠或乙酸钠或其混合物。
实施方案27:根据实施方案21-26任一项所述的制剂,其中所述多元醇是糖类或糖醇。
实施方案28:根据实施方案27所述的制剂,其中所述制剂含有浓度至少200 mM和至多800
mM的蔗糖。
实施方案29:根据实施方案27所述的制剂,其中所述制剂含有浓度至少400 mM的山梨醇。
实施方案30:根据实施方案21-29任一项所述的制剂,其中所述因子VIII多肽是重组的全长FVIII或者重组的B结构域截短的FVIII。
实施方案31:根据实施方案21-30任一项所述的制剂,其中所述因子VIII多肽被连接到迁延基团上。
实施方案32:根据实施方案31所述的制剂,其中所述因子VIII多肽是PEG化FVIII、或融合白蛋白的FVIII、或融合Fc区的FVIII。
实施方案33:根据实施方案31或实施方案32所述的制剂,其中所述因子VIII多肽是糖基聚乙二醇化的B结构域截短的FVIII。
实施方案34:根据实施方案21-33任一项所述的制剂,所述制剂具有6.0至7.0、或6.4至7.0的pH。
实施方案35:用于优化凝血因子VIII液体制剂的方法,所述方法包含步骤:
(i)提供包含待测试的因子VIII的各种液体制剂;
(ii)添加蛋白质变性剂到所述液体制剂中,并孵育所得溶液预定的时间段;
(iii)分析(ii)所孵育的溶液中游离FVIII轻链的存在;
(iv)选择具有所需低水平游离轻链的一种或更多种制剂。
实施方案36:用于识别凝血因子VIII的稳定液体制剂的方法,所述方法包含步骤:
(i)提供包含待待测试的因子VIII的各种液体制剂;
(ii)添加蛋白质变性剂到所述液体制剂中,并孵育所得溶液预定的时间段;
(iii)分析(ii)所孵育的溶液中游离FVIII轻链的存在;
(iv)选择具有所需低水平游离轻链的一种或更多种制剂。
实施方案37:根据实施方案35或实施方案36所述的方法,其中所述蛋白质变性剂是盐酸胍或尿素。
实施方案38:根据实施方案35-37任一项所述的方法,其中所述因子VIII多肽是重组的全长FVIII或者重组的B结构域截短的FVIII。
实施方案39:根据实施方案38所述的方法,其中所述因子VIII多肽被连接到迁延基团上。
实施方案40:根据实施方案39所述的方法,其中所述因子VIII多肽是PEG化FVIII、或融合白蛋白的FVIII、或融合Fc区的FVIII。
实施方案41:根据实施方案39或实施方案40所述的方法,其中所述因子VIII多肽是糖基聚乙二醇化的B结构域截短的FVIII。
实验
缩略语列表
SEC 尺寸排阻层析法
LC 轻链
GuHCl 盐酸胍
BDD-FVIII B结构域缺失/截短的因子VIII
GP-BDD-FVIII 糖基聚乙二醇化的B结构域截短/缺失的因子VIII
实施例1 - 重组的B结构域截短/缺失的FVIII的生产
B结构域截短/缺失的FVIII(“BDD-FVIII”)(SEQ ID NO 2):
BDD-FVIII的制备由例如Thim L.等人描述(Haemophilia
2010; 16:349-359)。
糖基聚乙二醇化的B结构域截短/缺失的FVIII(“GP-BDD-FVIII”):
GP-BDD-FVIII的制备描述于例如国际公开WO 2009/108806中。
FVIII-Fc/白蛋白融合蛋白:
融合蛋白的制备是通过在HEK细胞中瞬时表达,接着通过在亲和柱、F25琼脂糖和Poros 50 HQ上的三步纯化,其中因子VIII因子分别被融合到Fc结构域(SEQ ID NO 4)或白蛋白(SEQ ID NO 5)上。
SEQI ID NO 5 - 白蛋白融合:
实施例2 - FVIIIa活性测定:生色测定法
用Coatest® SP FVIII试剂(Chromogenix)在生色FVIII测定中如下评估rFVIII化合物的FVIII活性(FVIII:C):将rFVIII样品和FVIII标准品(例如纯化的野生型rFVIII,根据来自NIBSC的第七版国际FVIII标准进行校正)稀释在Coatest®测定缓冲液(50 mM
Tris、150 mM NaCl、1 % BSA, pH 7.3,含防腐剂)中。将五十µl的样品、标准品和缓冲液阴性对照按一式两份添加到96孔微量滴定板(Nunc)中。将来自Coatest® SP试剂盒的因子IXa/因子X试剂、磷脂试剂和CaCl2以5:1:3(体积:体积:体积)混合,并将75 µl该混合物添加到孔中。在室温下孵育15 min后,添加50 µl的因子Xa底物S-2765/凝血酶抑制剂I-2581混合物,并将试剂在室温下孵育10分钟后,添加pH为3的25 µl的1 M柠檬酸。用Spectramax®微量滴定板读数器(Molecular
Devices)测定415 nm处的吸光度,620
nm处的吸光度用作参照波长。从所有样品中减去阴性对照的值,并通过绘制的吸光度值对FVIII浓度的线性回归制备校正曲线。
实施例3 - FVIIIa活性测定:一阶段血块测定法
rFVIII化合物的FVIII活性(FVIII:C)进一步在如下的一阶段FVIII血块测定法中进行评估:将rFVIII样品和和FVIII标准品(例如纯化的野生型rFVIII根据来自NIBSC的第七版国际FVIII标准进行校正)在HBS/BSA缓冲液(20 mM hepes,150
mM NaCl,pH 7.4,含1 % BSA)中稀释到约10
U/ml,接着在含有VWF(Dade
Behring)的FVIII缺乏的血浆中进行10倍稀释。随后将样品在HBS/BSA缓冲液中进行稀释。APTT凝结时间是使用单因素程序使用ACL300R或ACL5000仪器(Instrumentation Laboatory)进行测量的。将含有VWF(Dade Behring)的FVIII缺乏的血浆用作测定血浆并将SynthASil®(Hemosil®,
Instrumentation Laboratory)用作PTT试剂。在凝结仪器中,将稀释的样品或标准品与FVIII缺乏的血浆和PTT试剂在37℃下进行混合。添加氯化钙,通过测量浊度来确定直到血块形成的时间。样品中的FVIII:C是基于FVIII标准品的稀释液的血块形成时间的标准曲线计算出的。
实施例4 - FVIII降解:通过尺寸排阻色谱法(SEC)确定FVIII游离轻链
rFVIII化合物解离成游离重链和轻链是通过SEC方法评估的。柱子是Sepax
ZenixTM SEC-300,且洗脱液是pH 7.0的10mM Tris、10mM CaCl2、300 mM NaCl和5%异丙醇。因子VIII分子的降解是在SEC中观察到比单体因子VIII更长洗脱时间的峰的出现。这个峰已被归于游离轻链(游离LC)。
工作实施例
实施例5
制备一系列糖基聚乙二醇化的因子VIII(GP-BDD-FVIII)的制剂,在所有制剂中具有下列组分:28
µg/mL的糖基聚乙二醇化的因子VIII,18
mg/mL NaCl,0.1 mg/mL聚山梨酯80,0.6 mg/mL蔗糖,0.055 mg/mL甲硫氨酸,1.5 mg/mL组氨酸,0.13 mg/mL CaCl2,pH 6.5。此外,每种制剂含有另外的如下表1中所列出的多元醇稳定剂:
表1
制剂1 | 无另外的稳定剂 |
制剂2 | 0.3 M蔗糖 |
制剂3 | 1.0 M蔗糖 |
制剂4 | 1.0 M甘油 |
制剂5 | 0.3 M棉子糖 |
制剂6 | 0.3 M水苏糖 |
将样品在5℃下孵育5周,并通过SEC(如上)分析游离轻链。此外,制备了具有相同配方但还含有0.2 M
GuHCl的一组样品,并在5℃下孵育24h,以及然后通过SEC分析游离轻链。在两个实验中的游离轻链峰的相对面积列于下表2中:
表2
可以看出,通过快速方法用化学变性剂正确识别出了5 ℃下5周期间具有最低的游离轻链形成的制剂3。
实施例6
为了研究糖基聚乙二醇化的因子VIII(GP-BDD-FVIII)的液体制剂中的最佳钙浓度,用约250
U/mL的糖基聚乙二醇化的因子VIII、18
mg/mL NaCl、0.05 mg/mL聚山梨酯80、1.5 mg/mL蔗糖、1 mg/mL甲硫氨酸和1.5 mg/mL组氨酸制备pH 6.9的制剂。氯化钙浓度列于下表3中:
表3
将溶液无菌过滤,分配在小瓶中,并通过暴露于纯N2(通过短暂排空腔室到0.1巴压强而散布)3个循环进行脱气,并用纯N2在顶部空间密封小瓶。在30 ℃下8周和5 ℃下26周后通过SEC HPLC(如上)分析样品,并在5 ℃下37周后分析活性(生色测定法,如上)。此外,用相同钙浓度和130 µg/ml的糖基聚乙二醇化的因子VIII、0.2 M GuHCl、18
mg/mL NaCl、0.1 mg/mL聚山梨酯80、3 mg/mL蔗糖、0.055 mg/mL甲硫氨酸和1.5 mg/mL组氨酸,pH 6.9下建立快速筛选实验。将样品在5 ℃下孵育24h。
下表4列出了在不同条件下获得的游离轻链的相对量和因子VIII活性。
表4
在5 ℃下,从3增加到10 mM的钙浓度清楚地得到了超过37周的更好活性观察结果以及超过26周的更低游离轻链形成。这只能在24h后通过用化学变性剂测定法进行预测,而在30 ℃下的加速稳定性仅显示了边际差异。通过从10增加到30 mM的钙获得了进一步的稳定。此外,通过化学变性剂测定法很好地预测了这一点,但没有通过30 ℃下的加速稳定性进行预测。
实施例7
通过用130 µg/mL的糖基聚乙二醇化的因子VIII(GP-BDD-FVIII)、0.4 M
GuHCl、18 mg/mL NaCl、3.9 mM CaCl2、0.1
mg/mL聚山梨酯80、3
mg/mL蔗糖、0.055 mg/mL甲硫氨酸和1.5 mg/mL组氨酸以及不同浓度的另外的糖类制备pH
6.9的制剂来研究糖类的稳定效应。将样品在5 ℃下孵育24h,并通过SEC(如上)进行分析。用不同稳定剂获得的游离轻链的相对面积列于下表5中:
表5
稳定剂 | 游离轻链,5℃下24h,0.4 M GuHCl |
无稳定剂 | 5.1% |
0.2 M蔗糖 | 2.6% |
0.4 M蔗糖 | 1.9% |
0.6 M蔗糖 | 0.9% |
0.8 M蔗糖 | 0.7% |
0.15 M棉子糖 | 3.2% |
0.3 M棉子糖 | 1.9% |
0.45 M棉子糖 | 1.2% |
0.1 M水苏糖 | 4.2% |
0.2 M水苏糖 | 2.5% |
0.3 M水苏糖 | 2.0% |
可以看出,所有三种糖类都有效地稳定了因子VIII的液体制剂。
实施例8
在0.35 M GuHCl存在下的多因素实验中研究了pH、NaCl浓度、乙酸钠(NaOAc)浓度、氯化钙浓度和蔗糖浓度对糖基聚乙二醇化的因子VIII(GP-BDD-FVIII)的液体稳定性的影响。
所有样品都含有150 µg/mL的GP-BDD-FVIII和0.1 mg/mL聚山梨酯80。其他组分在下表6中给出。所有这些制剂都具有低于900 mOsm/L的计算渗透浓度,没有考虑GuHCl的含量,它不是所研发的药物制剂的一部分。将样品在5 ℃下孵育5天,并通过SEC(如上所述)进行分析。游离轻链峰的相对面积也列于表中。
表6
可以看出,在不含NaCl和NaOAc、和含有10 mM CaCl2、以及不含蔗糖(制剂37、40和43)时观察到了游离轻链的最高形成。增加钙浓度到30 mM、添加蔗糖至300或600 mM以及添加NaCl或NaOAc都降低了游离轻链的形成。用200 mM NaOAc、30 mM CaCl2和600
mM蔗糖(制剂30、33和36)观察到了最慢的游离轻链形成。
含有200 mM NaCl、30 mM
CaCl2和600 mM蔗糖的样品(制剂12、15和18)几乎同样好。不同pH值之间的差异在实验的变化范围内。这些结果证实了30 mM钙和300或优选600 mM蔗糖的稳定效应,并且还表明完全不含钠对于因子VIII在含水溶液中的稳定性是不利的。
实施例9
为了评估NaCl或NaOAc的最佳浓度,进行了用尿素作为化学变性剂的实验。由于GuHCl本身是盐,它可能会干扰其他盐的最佳浓度的确定。
所有样品都含有100 µg/mL的糖基聚乙二醇化的FVIII(GP-BDD-FVIII)、1.6 M尿素、30mM CaCl2、570
mM蔗糖和0.1 mg/mL聚山梨酯80。在5 ℃下96小时后的组氨酸、NaCl和乙酸钠(醋NaOAc)的浓度、连同游离轻链的相对面积列在下表7中。游离LC的含量通过SEC(如上)测量。该表还列出了如上所述计算的渗透浓度,没有考虑尿素的含量,它不是所研发的药物制剂的一部分。
表7
可以看出,游离轻链的形成在不含任何钠盐的制剂中是最高的。10 mM NaCl或10 mM
NaOAc的添加改善了稳定性。进一步添加NaCl达160 mM不会进一步稳定并可能轻微破坏稳定,而添加NaOAc达160 mM轻微地稳定。
实施例10
制备了GP-BDD-FVIII的许多制剂。所有制剂都含有10 mM L-组氨酸、0.02
mg/ml聚山梨酯80、0.5
mg/mL poloxamer 188、0.37 mM L-甲硫氨酸、310 mM NaCl和0.6
mg/ml蔗糖,并将pH调节至6.4。制剂含有约250 U/ml的GP-BDD-FVIII的,以及不同浓度的CaCl2。将溶液无菌过滤,分配在小瓶中,并通过暴露于纯N2(通过短暂排空腔室到0.1巴压强而散布)3个循环进行脱气。用N2在顶部空间封闭小瓶,并在5 ℃下孵育。孵育4周和8周后,将样品通过尺寸排阻色谱法(SEC,如上)进行分析。下表8显示了不同制剂的这个峰的相对面积:
表8
可以看出,游离轻链的量在15 mM CaCl2时增加得比10 mM
CaCl2时更慢,在20mM CaCl2时更慢,以及在30 mM CaCl2时甚至更慢。30、45、60和100 mM CaCl2之间的游离轻链形成的变化是在实验不确定性范围之内的。
实施例11
制备了一系列融合到Fc结构域(SEQ
ID NO 4)或白蛋白(SEQ ID NO 5)上的因子VIII制剂。这些蛋白质具有公认较长的持续作用时间。pH
7.3的Fc融合蛋白制剂含有约200
U/ml因子VIII衍生物、10 mM咪唑、0.1 mg/ml聚山梨酯80、0.5 M甘油、0.25 M NaCl和0.6 M GuHCl。pH
7.3的白蛋白融合蛋白制剂含有约500 U/ml因子VIII衍生物、10 mM咪唑、0.1 mg/ml聚山梨酯80、0.5 M甘油、0.25 M NaCl和0.6 M GuHCl。此外,制剂含有不同浓度的蔗糖和CaCl2。将制剂在5 ℃下孵育约24h,并通过尺寸排阻色谱法(SEC,如上)进行分析。下表9列出了所测得的CaCl2和蔗糖浓度以及相对轻链面积
表9
可以看出,加速测定法也适用于这些因子VIII衍生物。还可以看出,30 mM的钙浓度和500 mM的蔗糖浓度对因子VIII衍生物的液体稳定性具有有利影响。
实施例12
制备了一系列BDD-FVIII制剂。所有制剂都有以下组分:约2500
IU/ml BDD-FVIII、310 mM NaCl、20 mM组氨酸、6 mg/ml蔗糖、0.11 mg/ml甲硫氨酸、0.2
mg/ml聚山梨酯80和0.4 M盐酸胍。制剂进一步含有3-100 mM范围的不同浓度的氯化钙。将制剂在5 ℃下孵育约24小时,并通过尺寸排阻色谱法(SEC,如上)进行分析。下表10列出了不同浓度CaCl2的轻链相对积分:
表10
可以看出,通过增加钙浓度10 mM以上来稳定BDD-FVIII,与30-100 mM的值是大约等效的。
实施例13
制备了一系列BDD-FVIII制剂。所有制剂都有以下组分:约500
IU/ml BDD-FVIII、310 mM NaCl、7 mM组氨酸、2 mg/ml蔗糖、0.04 mg/ml甲硫氨酸、0.07
mg/ml聚山梨酯80和0.6 M盐酸胍。制剂进一步含有1-30 mM范围的不同浓度的氯化钙。将样品在5 ℃下孵育4天,并通过生色测定法(Coatest® SP
FVIII,如上)来测定因子VIII活性。所测得的活性列于下表中:
表11
可以看出,加速稳定性筛选也可以使用生物活性测定法来进行。
实施例14
制备了一系列BDD-FVIII制剂。所有制剂都有以下组分:约2000
IU/ml BDD-FVIII、0.6 M GuHCl、30 mM CaCl2、570
mM蔗糖、0.1 mg/ml聚山梨酯80、40 mM NaCl和10 mM组氨酸。pH值在5.5和7.2之间变化。所有制剂都具有约743 mOsm/L的计算渗透浓度,没有考虑GuHCl的含量,它不是所研发的药物制剂的一部分。将制剂在5 ℃下孵育3天,并通过尺寸排阻色谱法(SEC,如上)进行分析。下表列出了不同pH值的轻链相对积分:
表12
可以看出,pH值约6.5是最有利的。
实施例15
制备了GP-BDD-FVIII的两种制剂。两种制剂都含有约290 U/ml的GP-BDD_FVIII、10 mM组氨酸、30 mM CaCl2、1.5 mg/ml普朗尼克 F68、600 mM蔗糖,并调节pH至6.7。一种制剂不含NaCl,另一种含78 mM NaCl。不含NaCl的制剂具有约700 mOsm/L的计算渗透浓度,含78 mM的NaCl的制剂具有约845 mOsm/L的计算渗透浓度。将溶液无菌过滤,分配在小瓶中,并通过暴露于纯N2(通过短暂排空腔室到0.1巴压强而散布)3个循环进行脱气,并用纯N2在顶部空间密封小瓶。将样品在5 ℃或-80 ℃下孵育52周,并用生色测定法测量活性。下表列出了结果。
表13
可以看出,在两种制剂中的活性都保留得非常好,储存在5 ℃下的样品显示出了与储存在-80 ℃下的参照基本相同的活性。
实施例16
制备了GP-BDD-FVIII的八种制剂。所有制剂含有约300 U/ml的GP-BDD-FVIII、30 mM CaCl2、0.1
mg/ml聚山梨酯80和500
mM蔗糖。制剂含有不同浓度的组氨酸、NaCl、醋酸钠,并调节至不同的pH值,如在下表中所详述的。将溶液无菌过滤,分配在小瓶中,并通过暴露于纯N2(通过短暂排空腔室到0.1巴压强而散布)3个循环进行脱气,并用纯N2在顶部空间密封小瓶。将样品在5 ℃或-80 ℃下孵育32周,并用生色法测定活性。结果也列在表中
表14
可以看出,储存在5 ℃下的样品显示出了与储存在-80℃下的参照几乎相同的活性,pH 6.4-6.9时的活性保留得特别好。
实施例17
制备了GP-BDD-FVIII的八种制剂。所有制剂都含有约290 U/ml的GP-BDD
FVIII、0.3 mM 甲硫氨酸、30 mM
CaCl2、0.1 mg/ml聚山梨酯80和10 mM组氨酸,并具有6.5的pH。制剂含有不同浓度的蔗糖和NaCl,如下表中所详述的。将溶液无菌过滤,分配在小瓶中,并通过暴露于纯N2(通过短暂排空腔室到0.1巴压强而散布)3个循环进行脱气,并用纯N2在顶部空间密封小瓶。将样品在5 ℃或-80 ℃下孵育32周,并用生色法测量活性。结果也列在表中
表15
可以看出,储存在5 ℃下的样品显示出了与储存在-80℃下的参照几乎相同的活性,除了含9 mM蔗糖的制剂。显然,更高的蔗糖浓度赋予了制剂的高稳定性,甚至在NaCl浓度比前面稳定液体因子VIII制剂中所描述的值低得多的情况下。
实施例18
制备了全长因子VIII(Kogenate™)的四种制剂。所有制剂含有500 IU/ ml因子VIII、0.6 M GuHCl、20 mM组氨酸,38 mM NaCl、0.1
mg/ml聚山梨酯80,pH
6.9。此外,制剂含有不同量的CaCl2和蔗糖。将制剂在5 ℃下孵育约24h,并通过SEC色谱法测定游离LC含量。结果列在下表中
表16
可以看出,通过增加的钙和蔗糖浓度防止轻链从重链上解离也稳定了全长因子VIII,并且当钙和蔗糖的浓度都增加时是特别稳定的。
实施例19
制备了GP-BDD-FVIII的六种制剂。所有制剂都含有30 mM CaCl2和0.055
mg/ml L-甲硫氨酸。其他组份列在下表中。将溶液无菌过滤,分配在小瓶中,并通过暴露于纯N2(通过短暂排空腔室到0.1巴压强而散布)3个循环进行脱气,并用纯N2在顶部空间密封小瓶。将制剂在-80 ℃或5 ℃下储存9个月,并通过生色测定法测量活性。结果列在表中。
表17
可以看出,活性在5 ℃下9个月后保留得很好。
实施例20
制备了BDD-FVIII的两种制剂。两种制剂都含有30 mM
CaCl2、10 mM组氨酸、570 mM蔗糖、78 mM NaCl、0.1 mg/ml聚山梨酯80和0.055 mg/ml L-甲硫氨酸,并调节pH至6.7。制剂具有下表中所列的不同浓度的因子VIII。将溶液无菌过滤,分配在小瓶中,并通过暴露于纯N2(通过短暂排空腔室到0.1巴压强而散布)3个循环进行脱气,并用纯N2在顶部空间密封小瓶。将制剂在-80 ℃或5 ℃下储存9个月,并通过生色测定法测量活性。结果列在表中。
表18
可以看出,活性在5 ℃下9个月后保留得很好。
尽管本发明的某些特征已经在本文中阐明和描述,但是许多修改、替换、改变和等价方案对于本领域普通技术人员来说将是容易想到的。因此应理解的是,所附权利要求旨在覆盖所有落在本发明的真正精神内的修改和变化。
序列表
<110> Novo Nordisk A/S
<120> 液体FVIII制剂
<130> 8565.204-WO
<160> 6
<170> BiSSAP 1.0
<210> 1
<211> 2332
<212> PRT
<213> 人工序列
<220>
<221> 来源
<222> 1..2332
<223> /分子类型="蛋白质"
/注释="野生型人凝血因子VIII"
/生物体="人工序列"
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His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser
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Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His
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Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu
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Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly
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Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met
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1325
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1335
1340
Lys His Leu Thr Pro Ser Thr Leu Thr Gln Ile Asp Tyr Asn Glu Lys
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1355
1360
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1370
1375
Ser His Ser Ile Pro Gln Ala Asn Arg Ser Pro Leu Pro Ile Ala Lys
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1385
1390
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1405
Phe Gln Asp Asn Ser Ser His Leu Pro Ala Ala Ser Tyr Arg Lys Lys
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1420
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1450
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1500
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Asn His Tyr Gly Thr Gln Ile Pro Lys Glu Glu Trp Lys
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Glu Arg Leu Cys Ser Gln Asn Pro Pro Val Leu Lys Arg His Gln Arg
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Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile Tyr
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Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr Arg
1685
1690
1695
His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser
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1705
1710
Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro
1715
1720
1725
Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr
1730
1735
1740
Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly
1745
1750
1755
1760
Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Arg
1765
1770
1775
Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser Tyr
1780
1785
1790
Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val Lys
1795
1800
1805
Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met Ala
1810
1815
1820
Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp
1825
1830
1835
1840
Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu Leu
1845
1850
1855
Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val Thr
1860
1865
1870
Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys Ser
1875
1880
1885
Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys Asn
1890
1895
1900
Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His Ala
1905
1910
1915
1920
Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala Gln
1925
1930
1935
Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn
1940
1945
1950
Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys
1955
1960
1965
Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe Glu
1970
1975
1980
Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys
1985
1990
1995
2000
Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val
2005
2010
2015
Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile
2020
2025
2030
Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro
2035
2040
2045
Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr
2050
2055
2060
Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile
2065
2070
2075
2080
Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser Leu
2085
2090
2095
Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys Trp
2100
2105
2110
Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe Gly
2115
2120
2125
Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro Ile
2130
2135
2140
Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg Ser
2145
2150
2155
2160
Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser
Cys Ser Met
2165
2170
2175
Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln
Ile Thr Ala
2180
2185
2190
Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys Ala
2195
2200
2205
Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val Asn
2210
2215
2220
Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val
2225
2230
2235
2240
Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr
2245
2250
2255
Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp Thr
2260
2265
2270
Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp
2275
2280
2285
Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg
2290
2295
2300
Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg
2305
2310
2315
2320
Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr
2325
2330
<210> 2
<211> 1445
<212> PRT
<213> 人工序列
<220>
<221> 来源
<222> 1..1445
<223> /分子类型="蛋白质"
/注释="B结构域截短的FVIII-BDD-FVIII"
/生物体="人工序列"
<400> 2
Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr
1
5
10
15
Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro
20
25
30
Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys
35
40
45
Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro
50
55
60
Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val
65
70
75
80
Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val
85
90
95
Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala
100
105
110
Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val
115
120
125
Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn
130
135
140
Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser
145
150
155
160
His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu
165
170
175
Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu
180
185
190
His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp
195
200
205
His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser
210
215
220
Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg
225
230
235
240
Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His
245
250
255
Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu
260
265
270
Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile
275
280
285
Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly
290
295
300
Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met
305
310
315
320
Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg
325
330 335
Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp
340
345
350
Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe
355
360
365
Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His
370
375
380
Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu
385
390
395 400
Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro
405
410
415
Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr
420
425 430
Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile
435
440
445
Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile
450
455 460
Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile
465
470
475
480
Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys
485
490
495
His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys
500
505
510
Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys
515
520 525
Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala
530
535
540
Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp
545
550 555
560
Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe
565
570
575
Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln
580
585
590
Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp
Pro Glu Phe
595
600
605
Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser
610
615
620
Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu
625
630
635
640
Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr
645 650
655
Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro
660
665
670
Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp
675 680
685
Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala
690
695
700
Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu
705
710
715
720
Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala
725
730
735
Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Gln Asn
740 745
750
Pro Pro Val Leu Lys Arg His Gln Arg Glu Ile Thr Arg Thr Thr Leu
755
760
765
Gln Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu
770
775
780
Met Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser
785
790
795
800
Pro Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val
805
810
815
Glu Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg
820
825
830
Asn Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe
835
840
845
Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu
850
855
860
Leu Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val
865 870
875
880
Glu Asp Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr
885
890
895
Ser Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly
900
905
910
Ala Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr
915
920
925
Phe Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp
930
935
940
Cys Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val
945
950
955
960
His Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu
965
970
975
Asn Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe
980
985
990
Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met
995
1000
1005
Glu Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr
1010
1015
1020
Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp
1025
1030
1035
1040
Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr
1045
1050
1055
Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser
1060
1065
1070
Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu
1075
1080
1085
Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser
1090
1095
1100
Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His
1105
1110
1115
1120
Ala Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr
1125
1130
1135
Pro Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala
1140
1145
1150
Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr
1155
1160
1165
Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile
1170
1175
1180
Lys Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln
1185
1190
1195
1200
Gly Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile
1205
1210
1215
Met Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser
1220
1225
1230
Thr Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile
1235
1240
1245
Lys His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr
Ile Arg Leu
1250
1255
1260
His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met
Glu Leu Met
1265
1270
1275
1280
Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met
Glu Ser Lys
1285
1290
1295
Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe
Thr Asn Met
1300
1305
1310
Phe Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg
1315
1320
1325
Ser Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln
1330
1335
1340
Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly
1345
1350
1355
1360
Val Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe
Leu Ile Ser
1365
1370
1375
Ser Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys
1380
1385
1390
Val Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn
1395
1400
1405
Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile
His Pro Gln
1410
1415
1420
Ser Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu
Gly Cys Glu
1425
1430
1435
1440
Ala Gln Asp Leu Tyr
1445
<210> 3
<211> 20
<212> PRT
<213> 人工序列
<220>
<221> 来源
<222> 1..20
<223> /分子类型="蛋白质"
/注释="接头 - 20 氨基酸"
/生物体="人工序列"
<400> 3
Ser Phe Ser Gln Asn Ser Arg His Pro Ser Gln Asn Pro Pro Val Leu
1
5
10
15
Lys Arg His Gln
20
<210> 4
<211> 1702
<212> PRT
<213> 人工序列
<220>
<221> 来源
<222> 1..1702
<223> /分子类型="蛋白质"
/注释="FVIII-Fc融合蛋白"
/生物体="人工序列"
<400> 4
Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr
1
5
10
15
Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro
20
25
30
Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys
35
40
45
Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro
50
55
60
Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val
65
70 75
80
Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val
85
90
95
Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala
100
105
110
Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val
115
120
125
Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn
130
135
140
Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser
145
150
155
160
His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu
165 170
175
Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu
180
185
190
His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp
195 200
205
His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser
210
215
220
Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg
225
230
235
240
Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His
245
250
255
Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu
260
265
270
Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile
275
280
285
Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly
290 295
300
Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met
305
310
315
320
Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg
325
330
335
Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp
340
345
350
Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe
355
360
365
Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His
370
375
380
Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu
385 390
395
400
Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro
405
410
415
Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr
420
425
430
Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile
435
440
445
Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile
450
455
460
Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile
465
470
475
480
Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys
485
490
495
His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys
500
505
510
Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys
515
520
525
Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala
530
535
540
Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp
545
550
555
560
Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe
565
570
575
Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln
580
585
590
Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp
Pro Glu Phe
595
600
605
Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser
610
615
620
Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu
625
630
635
640
Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr
645
650
655
Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro
660
665
670
Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp
675
680
685
Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala
690
695
700
Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu
705
710
715
720
Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala
725
730
735
Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Gln Asn
740
745
750
Pro Pro Val Leu Lys Arg His Gln Arg Glu Ile Thr Arg Thr Thr Leu
755
760
765
Gln Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu
770
775
780
Met Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser
785
790
795
800
Pro Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val
805
810
815
Glu Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg
820
825
830
Asn Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe
835
840
845
Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu
850
855
860
Leu Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val
865
870
875
880
Glu Asp Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr
885
890
895
Ser Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly
900
905
910
Ala Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr
915
920
925
Phe Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp
930
935
940
Cys Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val
945
950
955
960
His Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu
965
970
975
Asn Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe
980
985
990
Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met
995
1000
1005
Glu Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr
1010
1015
1020
Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp
1025
1030
1035
1040
Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr
1045
1050
1055
Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser
1060
1065
1070
Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu
1075
1080
1085
Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser
1090
1095
1100
Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His
1105
1110
1115
1120
Ala Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr
1125
1130
1135
Pro Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala
1140
1145
1150
Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr
1155
1160
1165
Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile
1170
1175
1180
Lys Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln
1185
1190
1195
1200
Gly Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile
1205
1210
1215
Met Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser
1220
1225
1230
Thr Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile
1235
1240
1245
Lys His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr
Ile Arg Leu
1250
1255
1260
His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met
Glu Leu Met
1265
1270
1275 1280
Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met
Glu Ser Lys
1285
1290
1295
Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe
Thr Asn Met
1300
1305
1310
Phe Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg
1315
1320
1325
Ser Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln
1330
1335
1340
Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly
1345
1350
1355
1360
Val Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe
Leu Ile Ser
1365
1370 1375
Ser Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys
1380
1385
1390
Val Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn
1395
1400 1405
Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile
His Pro Gln
1410
1415
1420
Ser Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu
1425
1430 1435
1440
Ala Gln Asp Leu Tyr Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly
1445
1450
1455
Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Glu Pro Arg
1460
1465
1470
Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn
1475
1480
1485
Ala Glu Gly Glu Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp
1490
1495
1500
Val Leu Met Ile Ser Leu Ser Pro Met Val Thr Cys Val
Val Val Asp
1505
1510
1515
1520
Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn
1525 1530
1535
Val Glu Val Leu Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn
1540
1545
1550
Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp
1555
1560
1565
Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Ala Leu Pro
1570
1575
1580
Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala
1585
1590
1595
1600
Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met
Thr Lys Lys
1605
1610
1615
Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile
1620
1625
1630
Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn
1635
1640
1645
Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys
1650
1655
1660
Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys
1665
1670
1675
1680
Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe
1685
1690
1695
Ser Arg Thr Pro Gly Lys
1700
<210> 5
<211> 2054
<212> PRT
<213> 人工序列
<220>
<221> 来源
<222> 1..2054
<223> /分子类型="蛋白"
/注释="FVIII-白蛋白融合蛋白"
/生物体="人工序列"
<400> 5
Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr
1
5
10
15
Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro
20
25
30
Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys
35
40
45
Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro
50
55
60
Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val
65
70
75
80
Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val
85
90
95
Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala
100
105
110
Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val
115
120
125
Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn
130
135
140
Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser
145
150
155
160
His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu
165
170
175
Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu
180
185
190
His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp
195
200
205
His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser
210
215
220
Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg
225
230
235
240
Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His
245
250
255
Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu
260
265
270
Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile
275
280
285
Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly
290
295
300
Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met
305
310
315
320
Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg
325
330
335
Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp
340
345
350
Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe
355
360
365
Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His
370
375
380
Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu
385
390
395 400
Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro
405
410
415
Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr
420
425 430
Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile
435
440
445
Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile
450
455
460
Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile
465
470
475
480
Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys
485
490 495
His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys
500
505
510
Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys
515
520
525
Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala
530
535
540
Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp
545
550
555
560
Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe
565
570
575
Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln
580
585
590
Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp
Pro Glu Phe
595
600
605
Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser
610
615 620
Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu
625
630
635
640
Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr
645
650
655
Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro
660
665
670
Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp
675
680
685
Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala
690
695
700
Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu
705
710 715
720
Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala
725
730
735
Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Gln Asn
740
745
750
Pro Pro Val Leu Lys Arg His Gln Arg Glu Ile Thr Arg Thr Thr Leu
755
760
765
Gln Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu
770
775
780
Met Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser
785
790
795
800
Pro Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val
805
810
815
Glu Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg
820
825
830
Asn Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe
835
840
845
Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu
850
855
860
Leu Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val
865
870
875
880
Glu Asp Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr
885
890
895
Ser Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly
900
905
910
Ala Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr
915
920
925
Phe Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp
930 935
940
Cys Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val
945
950
955
960
His Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu
965
970
975
Asn Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe
980
985
990
Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met
995
1000
1005
Glu Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr
1010
1015
1020
Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp
1025
1030
1035
1040
Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr
1045
1050
1055
Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser
1060
1065
1070
Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu
1075
1080
1085
Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser
1090
1095
1100
Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His
1105
1110
1115
1120
Ala Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr
1125
1130
1135
Pro Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala
1140
1145
1150
Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr
1155
1160
1165
Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile
1170
1175
1180
Lys Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln
1185
1190
1195
1200
Gly Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile
1205
1210
1215
Met Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser
1220
1225
1230
Thr Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile
1235
1240
1245
Lys His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr
Ile Arg Leu
1250
1255
1260
His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met
Glu Leu Met
1265
1270
1275
1280
Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met
Glu Ser Lys
1285
1290
1295
Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe
Thr Asn Met
1300
1305
1310
Phe Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg
1315
1320
1325
Ser Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln
1330
1335
1340
Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly
1345
1350
1355
1360
Val Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe
Leu Ile Ser
1365
1370
1375
Ser Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys
1380
1385
1390
Val Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn
1395
1400
1405
Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile
His Pro Gln
1410
1415
1420
Ser Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu
1425
1430
1435
1440
Ala Gln Asp Leu Tyr Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly
1445
1450
1455
Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Asp Ala His
1460
1465
1470
Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe
1475
1480
1485
Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro
1490
1495
1500
Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys
1505
1510
1515
1520
Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His
1525
1530
1535
Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr
1540
1545
1550
Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn
1555
1560
1565
Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu
1570
1575
1580
Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu
1585
1590
1595
1600
Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro
1605
1610
1615
Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala
1620
1625
1630
Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu
1635
1640
1645
Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys
1650
1655
1660
Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe
1665
1670
1675
1680
Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
Lys Ala Glu
1685
1690 1695
Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr
1700
1705
1710
Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp
1715
1720
1725
Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu
1730
1735
1740
Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala
1745
1750
1755
1760
Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
Leu Ala Ala
1765
1770
1775
Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
Glu Ala Lys
1780
1785
1790
Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro
1795
1800
1805
Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr
1810
1815
1820
Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala
1825
1830
1835
1840
Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu
1845 1850
1855
Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe
1860
1865
1870
Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser
1875
1880
1885
Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser
1890
1895
1900
Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp
1905
1910
1915
1920
Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr
1925
1930
1935
Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn
1940
1945
1950
Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro
1955
1960
1965
Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr
1970
1975
1980
Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu
1985
1990
1995
2000
Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val
2005
2010
2015
Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp
2020
2025
2030
Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser
2035
2040
2045
Gln Ala Ala Leu Gly Leu
2050
<210> 6
<211> 21
<212> PRT
<213> 人工序列
<220>
<221> 来源
<222> 1..21
<223> /分子类型="蛋白"
/注释="接头 - 21 氨基酸"
/生物体="人工序列"
<400> 6
Ser Phe Ser Gln Asn Ser Arg His Pro Ser Gln Asn Pro Pro Val Leu
1
5
10
15
Lys Arg His Gln Arg
20
Claims (28)
1.凝血因子VIII的液体含水制剂,所述制剂包含
因子VIII分子;
浓度高于10 mM的钙盐;以及
浓度至少100 mM的糖类和/或多元醇;
其中所述制剂具有5.5-7.5的pH。
2.根据权利要求1的凝血因子VIII的液体含水制剂,所述制剂包含
因子VIII分子;
浓度至少15 mM的钙盐;以及
浓度至少100 mM的糖类和/或多元醇;
其中所述制剂具有5.5-7.5的pH。
3.权利要求1或权利要求2的制剂,其中所述钙盐以15-100
mM、或15-80 mM、或15-60 mM、或15-45 mM、或20-100 mM、或20-80 mM、或20-60 mM、或20-45 mM、或20-40 mM、或25-35 mM的浓度存在。
4.根据权利要求1或权利要求2或权利要求3的制剂,其中所述钙盐是乙酸钙或乳酸钙或苯甲酸钙或氯化钙,或者其两种或更多种的混合物。
5.根据权利要求4的制剂,其中所述盐是氯化钙。
6.根据权利要求1-5任一项的制剂,所述制剂进一步包含浓度至少5 mM的钠盐。
7.根据权利要求1-6任一项的制剂,其中所述钠盐以5-500 mM、或15-200 mM、或15-150 mM、或15-100 mM、或50-150 mM、或5-50 mM的浓度存在。
8.根据权利要求6或权利要求7的制剂,其中所述钠盐是氯化钠或乙酸钠或其混合物。
9.根据权利要求1-8任一项的制剂,其中所述多元醇是单糖或二糖或糖醇或其组合。
10.根据权利要求9的制剂,其中所述单糖或二糖和/或糖醇选自以下的组:蔗糖、山梨醇、甘油、棉子糖、水苏糖、甘露醇、山梨醇或其混合物。
11.根据权利要求9或权利要求10的制剂,其中所述单糖或二糖和/或糖醇以至少100 mM、或至少200 mM、或100-1800 mM、或300-1800 mM、或100-1500 mM、或200-1800 mM、或200-1500 mM、或100-1000 mM、或200-1000 mM、或300-1000 mM、或200-800 mM、或300-800 mM、或400-800 mM、或500-800 mM、或500-700 mM的浓度存在。
12.根据权利要求1-11任一项的制剂,其中所述制剂含有浓度50-600 mg/mL、或100-600 mg/mL、或100-450 mg/mL、或150-450 mg/mL、或150-300 mg/mL的蔗糖。
13.根据权利要求1-12任一项的制剂,其中所述制剂含有浓度至少400 mM的山梨醇。
14.根据权利要求13的制剂,其中所述山梨醇以100-800 mg/mL、或100-650 mg/mL、或150-650 mg/mL、或150-500 mg/mL、或150-250 mg/mL的浓度存在。
15.根据权利要求1-14任一项的制剂,其中所述制剂的计算渗透浓度为至多1500 mOsm/L、1200 mOsm/L、1000 mOsm/L、或900 mOsm/L。
16.根据权利要求1-15任一项的制剂,所述制剂具有5.5-7.5、或6.0至7.0、或6.3至6.7的pH。
17.根据权利要求1-16任一项的制剂,其中所述因子VIII分子是重组的全长FVIII或者重组的B结构域截短的FVIII。
18.根据权利要求1-16任一项的制剂,其中所述因子VIII分子是FVIII衍生物或者FVIII类似物。
19.根据权利要求18的制剂,其中所述因子VIII分子是PEG化FVIII,或者FVIII融合蛋白诸如融合白蛋白的FVIII、或融合Fc区的FVIII。
20.根据权利要求19的制剂,其中所述因子VIII分子是糖基聚乙二醇化的B结构域截短的FVIII。
21.根据权利要求1-17任一项的制剂,其中所述因子VIII分子是双链的B结构域截短的FVIII分子,其由通过非共价相互作用保持在一起的重链-接头序列(A1-a1-A2-a2-L)和轻链序列(a3-A3-C1-C2)所组成,其中所述接头(L)是20个氨基酸残基的接头序列(SFSQNSRHPSQNPPVLKRHQ)(SEQ ID NO 3);所述重链(A1-a1-A2-a2)和所述轻链(a3-A3-C1-C2)分别对应SEQ ID NO: 1的氨基酸编号1-740和1649-2332所述的序列。
22.根据权利要求1-20任一项的制剂,其中所述因子VIII分子是双链的B结构域截短的FVIII分子,其由通过非共价相互作用保持在一起的重链-接头序列(A1-a1-A2-a2-L)和轻链序列(a3-A3-C1-C2)所组成,其中所述接头(L)是20个氨基酸残基的接头序列(SFSQNSRHPSQNPPVLKRHQ)(SEQ ID NO 3);所述重链(A1-a1-A2-a2)和所述轻链(a3-A3-C1-C2)分别对应SEQ ID NO: 1的氨基酸编号1-740和1649-2332所述的序列,其中一个或更多个PEG基团已通过位于所述接头序列(SEQ ID 3)内的聚糖连接到所述FVIII多肽上。
23.用于优化凝血因子VIII液体制剂的方法,所述方法包含步骤:
(i)提供包含待测试的因子VIII的一种或更多种液体制剂;
(ii)添加蛋白质变性剂到所述液体制剂中,并孵育所得溶液预定的时间段;
(iii)分析(ii)所孵育的溶液中解离的因子FVIII的存在;
(iv)选择具有所需低水平的解离的因子FVIII的一种或更多种制剂。
24.用于识别因子VIII的稳定液体制剂的方法,所述方法包含步骤:
(i)提供包含待测试的因子VIII的一种或更多种液体制剂;
(ii)添加蛋白质变性剂到所述液体制剂中,并孵育所得溶液预定的时间段;
(iii)分析(ii)所孵育的溶液中解离的因子FVIII的存在;
(iv)选择具有所需低水平的解离的因子FVIII的一种或更多种制剂。
25.根据权利要求23或权利要求24的方法,其中所述蛋白质变性剂是盐酸胍或尿素。
26.根据权利要求23-25任一项的方法,其中所述因子VIII分子是重组的全长FVIII或者重组的B结构域截短的FVIII。
27.根据权利要求23-25任一项的方法,其中所述因子VIII分子是FVIII衍生物或者FVIII类似物。
28.根据权利要求26或权利要求27的方法,其中所述因子VIII多肽是糖基聚乙二醇化的B结构域截短的FVIII。
Applications Claiming Priority (9)
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EP12180239.1 | 2012-08-13 | ||
EP12180239 | 2012-08-13 | ||
US201261692744P | 2012-08-24 | 2012-08-24 | |
US61/692744 | 2012-08-24 | ||
US201361782743P | 2013-03-14 | 2013-03-14 | |
US61/782743 | 2013-03-14 | ||
EP13159832 | 2013-03-18 | ||
EP13159832.8 | 2013-03-18 | ||
PCT/EP2013/066847 WO2014026954A1 (en) | 2012-08-13 | 2013-08-13 | Liquid factor viii formulations |
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CN104519912A true CN104519912A (zh) | 2015-04-15 |
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US (1) | US20160000884A1 (zh) |
EP (1) | EP2882457A1 (zh) |
JP (1) | JP2015527350A (zh) |
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Cited By (9)
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CN107561296A (zh) * | 2017-10-13 | 2018-01-09 | 山东艾科达生物科技有限公司 | 一种测定凝血酶时间(tt)的试剂盒 |
WO2018032637A1 (zh) * | 2016-08-19 | 2018-02-22 | 安源医药科技(上海)有限公司 | 高糖基化人凝血因子viii融合蛋白及其制备方法与用途 |
CN109929029A (zh) * | 2017-12-15 | 2019-06-25 | 广东东阳光药业有限公司 | 一种提高重组人凝血因子viii高效表达的方法 |
WO2019219049A1 (zh) * | 2018-05-18 | 2019-11-21 | 北京辅仁瑞辉生物医药研究院有限公司 | 改进的fviii融合蛋白及其应用 |
CN111788220A (zh) * | 2018-01-12 | 2020-10-16 | 财团法人牧岩生命科学研究所 | 体内持续释放重组凝血因子ⅷ及其制备方法 |
CN113301911A (zh) * | 2018-10-23 | 2021-08-24 | 费城儿童医院 | 用于调节因子viii功能的组合物和方法 |
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US11981718B2 (en) | 2020-05-27 | 2024-05-14 | Ampsource Biopharma Shanghai Inc. | Dual-function protein for lipid and blood glucose regulation |
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HUE047933T2 (hu) | 2013-03-15 | 2020-05-28 | Bioverativ Therapeutics Inc | Faktor VIII polipeptid készítmények |
CA2956412A1 (en) * | 2014-08-04 | 2016-02-11 | Csl Limited | Factor viii formulation |
AU2016348658A1 (en) * | 2015-11-05 | 2018-04-12 | Novo Nordisk A/S | FVIII formulation |
EP3736286A1 (en) | 2019-05-09 | 2020-11-11 | Biotest AG | Single chain factor viii molecule |
CN114072420A (zh) | 2019-07-04 | 2022-02-18 | 康诺贝林伦瑙有限公司 | 用于增加凝血因子viii的体外稳定性的截短的血管性血友病因子(vwf) |
CN116322920A (zh) | 2020-11-09 | 2023-06-23 | 武田药品工业株式会社 | 使用氧化硅吸附从血浆中纯化fviii |
EP4322918A1 (en) | 2021-04-13 | 2024-02-21 | Grifols Worldwide Operations Limited | Liquid composition comprising factor viii or factor viii/von willebrand factor complex |
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GB2568624B (en) * | 2016-08-19 | 2022-05-25 | Ampsource Biopharma Shanghai Inc | Highly glycosylated human blood-clotting factor VIII fusion protein, and manufacturing method and application of same |
WO2018032637A1 (zh) * | 2016-08-19 | 2018-02-22 | 安源医药科技(上海)有限公司 | 高糖基化人凝血因子viii融合蛋白及其制备方法与用途 |
GB2568624A (en) * | 2016-08-19 | 2019-05-22 | Ampsource Biopharma Shanghai Inc | Highly glycosylated human blood-clotting factor VIII fusion protein, and manufacturing method and application of same |
US11833212B2 (en) | 2016-08-19 | 2023-12-05 | Ampsource Biopharma Shanghai Inc. | Linker peptide for constructing fusion protein |
US11472863B2 (en) | 2016-08-19 | 2022-10-18 | Ampsource Biopharma Shanghai Inc. | Human coagulation factor IX (FIX) fusion protein, preparation method therefor, and use thereof |
US11471513B2 (en) | 2016-08-19 | 2022-10-18 | Ampsource Biopharma Shanghai Inc. | Highly glycosylated human blood-clotting factor VIII fusion protein, and manufacturing method and application of same |
US11123438B2 (en) | 2016-08-19 | 2021-09-21 | Ampsource Biopharma Shanghai Inc. | Linker peptide for constructing fusion protein |
CN107561296A (zh) * | 2017-10-13 | 2018-01-09 | 山东艾科达生物科技有限公司 | 一种测定凝血酶时间(tt)的试剂盒 |
CN109929029A (zh) * | 2017-12-15 | 2019-06-25 | 广东东阳光药业有限公司 | 一种提高重组人凝血因子viii高效表达的方法 |
CN111788220A (zh) * | 2018-01-12 | 2020-10-16 | 财团法人牧岩生命科学研究所 | 体内持续释放重组凝血因子ⅷ及其制备方法 |
WO2019219049A1 (zh) * | 2018-05-18 | 2019-11-21 | 北京辅仁瑞辉生物医药研究院有限公司 | 改进的fviii融合蛋白及其应用 |
CN113301911A (zh) * | 2018-10-23 | 2021-08-24 | 费城儿童医院 | 用于调节因子viii功能的组合物和方法 |
US11981718B2 (en) | 2020-05-27 | 2024-05-14 | Ampsource Biopharma Shanghai Inc. | Dual-function protein for lipid and blood glucose regulation |
Also Published As
Publication number | Publication date |
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US20160000884A1 (en) | 2016-01-07 |
WO2014026954A1 (en) | 2014-02-20 |
JP2015527350A (ja) | 2015-09-17 |
EP2882457A1 (en) | 2015-06-17 |
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