CN101379189B - 具有延长的半衰期的经修饰的凝血因子VIIa - Google Patents
具有延长的半衰期的经修饰的凝血因子VIIa Download PDFInfo
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- CN101379189B CN101379189B CN200780004623.4A CN200780004623A CN101379189B CN 101379189 B CN101379189 B CN 101379189B CN 200780004623 A CN200780004623 A CN 200780004623A CN 101379189 B CN101379189 B CN 101379189B
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- fusion polypeptide
- albumin
- polypeptide
- albumin fusion
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Abstract
本发明涉及凝血因子VII(FVII)和凝血因子VIIa(FVIIa)-白蛋白连接多肽的领域。更特别地,本发明涉及编码人凝血因子VII和凝血因子VIIa的cDNA序列以及在基因方面融合至编码人血清白蛋白的cDNA(可通过编码间插肽连接体(intervening peptidic linker)的寡核苷酸进行连接)的衍生物(此类编码的衍生物展示出提高的稳定性和延长的功能性血浆半衰期),包含此类cDNA序列的重组表达载体,用此类重组表达载体转化的宿主细胞,重组多肽和具有未修饰的野生型蛋白质的生物学活性但具有提高的稳定性和延长的保存期的衍生物,以及用于制备此类重组蛋白质和它们的衍生物的方法。本发明还包括用于人基因疗法的转移载体,其包含此类经修饰的DNA序列。
Description
发明领域
本发明涉及凝血因子VII(FVII)和凝血因子VIIa(FVIIa)-白蛋白连接多肽的领域。更特别地,本发明涉及编码人凝血因子VII和凝血因子VIIa的cDNA序列以及在基因方面融合至编码人血清白蛋白的cDNA(可通过编码间插肽连接体(intervening peptidic linker)的寡核苷酸进行连接)的衍生物(此类编码的衍生物展示出提高的稳定性和延长的功能性血浆半衰期(functional plasma half-life)),包含此类cDNA序列的重组表达载体,用此类重组表达载体转化的宿主细胞,重组多肽和具有未修饰的野生型蛋白质的生物学活性但具有提高的稳定性和延长的保存期的衍生物,以及用于制备此类重组蛋白质和它们的衍生物的方法。本发明还包括用于人基因疗法的转移载体,其包含此类经修饰的DNA序列。
发明背景
凝血因子VII和凝血因子VIIa
血友病A是遗传性出血病症(bleeding disorder)。其由血液凝血因子VIII的X染色体连锁缺乏而引起,并且几乎只影响男性,发病率为1和2个个体/10,000人。该X染色体缺陷由其本身不是血友病患者的女性携带者传递。血友病A的临床表现是增加的出血倾向。在引入使用凝血因子VIII浓缩物进行的治疗前,具有严重血友病的人的平均寿命小于20岁。来自血浆的凝血因子VIII浓缩物和后来重组形式的凝血因子VIII的使用显著改善了血友病患者的状况,大大地增加了平均寿命,使他们中的大部分可能过上或多或少正常的生活。普遍程度为血友病A的1/5的血友病B是由于无功能的或缺少的凝血因子IX造成的,并且使用来自血浆的凝血因子IX浓缩物或重组形式的凝血因子IX来进行治疗。在血友病A和血友病B中,在治疗该疾病中最严重的医学问题是针对替代凝血因子的同种抗体(alloantibody)的产生。所有血友病A患者中高达30%的形成针对凝血因子VIII的抗体。针对凝血因子IX的抗体发生的程度较小,但具有更严重的后果,因为它们对免疫耐受性诱导疗法较不敏感。
目前的凝血模型说明,凝血的生理学触发器是在表达TF的细胞表面上组织因子(TF)和凝血因子VIIa(FVIIa)之间的复合物的形成,所述表达TF的细胞通常位于脉管系统之外。这导致凝血因子IX和凝血因子X的激活,最终产生某些凝血酶。在正反馈回路中,凝血酶激活血液凝固级联系统的所谓的“内在”力量(arm)——凝血因子III和凝血因子IX,从而放大了凝血因子Xa的产生,这是产生完全的凝血酶爆发以达到完全止血所必需的。已显示,通过施用超生理浓度的凝血因子VIIa,绕开对于凝血因子VIIIa和凝血因子IXa的需求来达到止血。凝血因子VII的cDNA的克隆(US 4,784,950)使得可以开发出激活的凝血因子VII作为药物。凝血因子VIIa在1988年首次成功地进行了施用。从那时起到现在,凝血因子VIIa的适应症的数目稳定增长,显示了成为通用止血剂以终止出血的潜力(Erhardtsen,2002)。然而,凝血因子VIIa的大约2小时的短半衰期限制了其应用。
FVII是分子量为50kDa的单链糖蛋白,它作为406个氨基酸的无活性的酶原被肝细胞分泌到血流中。它包含位于该蛋白质的N-末端Gla结构域中的10个γ-羧基-谷氨酸残基(位置6、7、14、16、19、20、25、26、29和35)。Gla残基需要维生素K用于其生物合成。位于Gla结构域C-末端的是两个表皮生长因子结构域,随后为胰蛋白酶型丝氨酸蛋白酶结构域。FVII的进一步的翻译后修饰包括羟基化(Asp63)、N-型糖基化(Asn145和Asn322)以及O-型糖基化(Ser52和Ser60)。
通过在Arg152-Ile153处的单肽键的蛋白水解,FVII转化为其活性形式凝血因子VIIa,所述蛋白水解导致形成两个多肽链,N-末端的轻链(24kDa)和C-末端的重链(28kDa),它们通过一个二硫桥结合在一起。与其他维生素K依赖性凝血因子相反,对于FVII,在这些其他维生素K依赖性凝血因子的活化过程中切割掉的激活肽(activationpeptide)仍未得到描述。Arg152-Ile153切割位点和下游的一些氨基酸显示出与其他维生素K依赖性多肽的活化切割位点的同源性。
对于达到凝血因子VIIa的活性构象所必需的是活化切割后Ile153和Asp343之间盐桥的形成。凝血因子VII的活化切割在体外可以通过凝血因子Xa、凝血因子XIIa、凝血因子IXa、凝血因子VIIa、凝血因子7激活蛋白酶(FSAP)和凝血酶来实现。Mollerup等人(Biotechnol.Bioeng.(1995)48:501-505)报道,某些切割也发生在重链Arg290和/或Arg315处。
凝血因子VII在血浆中存在的浓度为500ng/ml。1%,例如5ng/ml,的凝血因子VII以凝血因子VIIa的形式存在。发现凝血因子VII的血浆半衰期为大约4小时,和凝血因子VIIa的半衰期为大约2小时。尽管FVIIa的2小时的半衰期对于激活的凝血因子(所述半衰期,对于其他激活的凝血因子,更多为分钟的级别,这是由于经丝氨酸蛋白酶抑制剂样抗凝血酶III的不可逆的抑制)来说相对较长,然而,这还是成为FVIIa的治疗用途的严重缺陷,因为它导致需要多次静脉内注射或持续输注以达到止血。这导致极高的治疗成本以及患者的不便。迄今还没有商购可得的具有提高的血浆半衰期的凝血因子VIIa的药物制剂,也未公开表明具有延长的体内半衰期的FVII/FVIIa变体的任何数据。由于凝血因子VII/VIIa具有用作通用止血剂的潜能,因此仍然存在开发具有更长的体内功能性半衰期(functional half-life)的凝血因子VIIa形式的高医学需要。
Ballance等人(WO 01/79271)描述了许多不同的治疗性蛋白质或所述治疗性蛋白质的变体和/或片段的融合多肽,所述治疗性蛋白质或所述治疗性蛋白质的变体和/或片段,当与人血清白蛋白或所述白蛋白的变体和/或片段融合时,预计具有增加的体内功能性半衰期和延长的保存期。描述了潜在的融合伙伴的长长的列表,但对于几乎所有这些蛋白质,没有通过实验数据表明,各白蛋白融合多肽实际上保留了治疗性蛋白质融合伙伴的生物学活性和具有改善的性质。此外,根据WO 01/79271,可将来自该治疗性蛋白质列表的每个成员以许多不同的方向融合至白蛋白,例如将两个分子的治疗性蛋白质中的一个融合至白蛋白的N-末端而另一个融合至白蛋白的C-末端,或者将一个分子的治疗性蛋白质融合至白蛋白的N-末端或C-末端,或者还将每个蛋白质的多个区域融合至另一个的多个区域。在WO 01/79271中列出的许多治疗性蛋白质中,作为潜在的白蛋白融合伙伴的是凝血因子IX和FVII/FVIIa,然而对于这两种蛋白质都没有提供原理的实验证据。
Sheffield表达了凝血因子IX(由415个氨基酸组成的凝血酶原因子)-白蛋白融合多肽,并且在药物代谢动力学实验中证明,与只显示终末半衰期的适度增加(低于2倍)的白蛋白相比,兔子中凝血因子IX-白蛋白融合多肽的清除行为与凝血因子IX的清除行为更紧密地相似。(Sheffield WP等人(2004)Br.J.Haematol.126:565-573)。
考虑到Sheffield的结果和由于凝血因子IX和VII(两者都是维生素K依赖性凝血酶原因子)之间的高度同源性和它们相当的大小,本领域技术人员会认为,就体内功能性半衰期而言,凝血因子VII也将不能从与白蛋白融合中获益。
因此,作为本发明的基础的技术问题是开发功能性FVIIa-白蛋白融合蛋白,其保留生物学活性并显示出增加的体内功能性半衰期。
在该方面,凝血因子VII/VIIa多肽的生物学活性是指在自身被激活后,在组织因子存在的情况下,其激活凝血因子IX和X的能力。
体内功能性血浆半衰期是指凝血因子VII/VIIa融合多肽在注射入血浆后的生物学活性的半衰期。优选地,血浆是人血浆。
我们发现,包含融合至白蛋白或其片段或变体的至少一个凝血因子VII或凝血因子VIIa多肽或其片段或变体的白蛋白连接多肽导致形成具有在生物学上有活性的凝血因子VII/凝血因子VIIa部分的融合多肽,其中至少一个凝血因子VII或凝血因子VIIa分子位于该融合蛋白的N-末端。
因此,本发明的一个方面是具有生物学活性的融合蛋白,其中凝血因子VII/VIIa多肽融合至人血清白蛋白的N-末端。所述融合蛋白展示出至少25%,优选大于40%,更优选大于70%和最优选大于90%的野生型凝血因子VII/VIIa的摩尔比活性(molar specific activity)。
进一步令人吃惊地发现,与由Sheffield公布的凝血因子IX至人血清白蛋白的N-末端的融合相反,凝血因子VII/VIIa至人血清白蛋白的N-末端的白蛋白融合导致形成凝血因子VII/VIIa融合蛋白,其不仅保留了凝血因子VII/VIIa的生物学活性而且还展示出凝血因子VII/VIIa的体内功能性血浆半衰期的显著延长。
在白蛋白的C-末端具有所希望的FVII/FVIIa部分的白蛋白融合构建体的表达是不成功的,因为所表达的白蛋白融合蛋白不能作为完整的分子进行分泌。在转移通过细胞膜后,观察到切割成成熟的FVII/FVIIa分子(其由于受损的γ-羧化而具有减少的摩尔比活性)和具有附着至其C-末端的FVII前肽的白蛋白部分。因此,与Ballance等人的公开内容相反,发现只有将FVII/FVIIa部分融合至人血清白蛋白的N-末端才导致形成具有所希望的生物学性质(分别为FVII/FVIIa的生物学活性的保留和增加的血浆半衰期)的融合蛋白。
因此,本发明的进一步方面是其中凝血因子VII/VIIa多肽融合至白蛋白的N-末端的具有生物学活性的融合蛋白,其相比于未融合的凝血因子VII/VIIa而言展示出功能性血浆半衰期的显著延长。在优选的实施方案中,包含FVII/FVIIa多肽的本发明的FVII/FVIIa-白蛋白融合多肽与未融合的FVII/FVIIa的体内半衰期或治疗活性相比,具有延长的体内功能性半衰期或者更持久的或增加的治疗活性。
因此,本发明的一个方面是融合至白蛋白的N-末端的FVII/FVIIa,其与未融合的FVII/FVIIa相比,延长了血浆半衰期至少100%,优选大于200%,更优选大于500%,最优选大于1000%。
在本发明的进一步令人吃惊的方面,我们发现,无连接体的FVII/FVIIa-白蛋白融合多肽显示出显著减少的生物学活性,然而其中FVII/FVIIa部分通过连接体与白蛋白隔开的FVII/FVIIa白蛋白融合多肽展示出依赖于连接体长度的凝血因子VII/VIIa生物学活性增加。通过肽连接体将凝血因子VII或凝血因子VIIa肽部分偶联至白蛋白部分,从而使得该融合分子能够采取允许相比于无此类连接体序列的融合分子而言更高的摩尔比活性的构象。
因此,本发明的进一步方面是在凝血因子VII/VIIa部分和白蛋白的N-末端之间包含连接体肽的凝血因子VII/VIIa-白蛋白融合多肽,其相比于无此类连接体的凝血因子VII/VIIa融合蛋白而言具有增强的生物学凝血因子VII/VIIa活性,例如测量为摩尔比活性的活性。与相应的无此类连接体的融合蛋白相比,其中凝血因子VII/VIIa部分通过肽连接体而融合至白蛋白的N-末端的融合蛋白的摩尔比活性的增加为至少25%,优选至少50%,和最优选至少100%。这些具有连接体的凝血因子VII/VIIa-白蛋白融合多肽与野生型FVIIa相比还展示出增加的体内功能性半衰期。然而,化学连接体或连接体系统(例如但不限于抗生物素蛋白-生物素)将起着相似的功能,只要在凝血因子VII/VIIa部分和白蛋白部分之间引入相当的距离。下面,只要合适,术语“连接体肽”等应当包括这样的其他功能性连接体工具。
本发明包括连接至白蛋白的N-末端的治疗性凝血因子VII/VIIa多肽、组合物、药物组合物、制剂和试剂盒。本发明还包括所述治疗性白蛋白连接多肽在某些医学适应症中的用途。本发明还包括编码本发明的白蛋白连接多肽的核酸分子,以及包含这些核酸的载体,用这些核酸和载体转化的宿主细胞,和使用这些核酸、载体和/或宿主细胞制备本发明的白蛋白连接多肽的方法。
本发明还提供了包含连接有凝血因子VII/VIIa的白蛋白多肽和药学上可接受的载体的组合物,所述连接有凝血因子VII/VIIa的白蛋白多肽包含凝血因子VII或凝血因子VIIa肽或其片段或变体,任选地肽连接体,和白蛋白或其片段或变体。本发明的另一个目的是提供治疗具有出血病症的患者的方法。该方法包括施用有效量的所述连接有FVII/FVIIa的白蛋白多肽的步骤。
本发明的另一个目的是提供包含编码连接有凝血因子VII/VIIa的白蛋白多肽的多核苷酸序列的核酸分子以及包含此类核酸分子的载体,所述连接有凝血因子VII/VIIa的白蛋白多肽包含凝血因子VII或凝血因子VIIa肽或其片段或变体,任选地肽连接体,和白蛋白或其片段或变体。编码该融合蛋白的所述核酸序列位于编码前肽的核酸序列的3’末端,所述前肽介导凝血因子VII/VIIa融合部分的γ羧化。
本发明还提供了用于制备包含凝血因子VII或凝血因子VIIa多肽或其片段或变体、肽连接体以及白蛋白或其片段或变体的连接有凝血因子VII/VIIa的白蛋白多肽的方法,其中该方法包括:
(a)提供核酸,所述核酸包含可在哺乳动物细胞中表达的编码所述连接有凝血因子VII/VIIa的白蛋白多肽的核苷酸序列;
(b)在所述生物中表达所述核酸以形成连接有凝血因子VII/VIIa的白蛋白多肽;和
(c)纯化所述连接有凝血因子VII/VIIa的白蛋白多肽。
在一个方面,本发明涉及用于治疗、预防或改善疾病或病症的白蛋白融合多肽和方法。如此处所使用的,“凝血因子VII/VIIa-白蛋白融合多肽”是指通过将凝血因子VII/VIIa(或其片段或变体)的至少一个分子融合至白蛋白(或其片段或变体)的至少一个分子的N-末端而形成的多肽,所述两个部分任选地通过肽连接体隔开。
本发明的凝血因子VII/VIIa-白蛋白融合多肽包含至少凝血因子VII/VIIa的片段或变体和至少人血清白蛋白的片段或变体,所述片段或变体例如通过基因融合而相互联合(即通过核酸的翻译产生白蛋白融合多肽,在所述核酸中将编码凝血因子VII/VIIa的全部或一部分的多核苷酸按读框连接至编码白蛋白的全部或一部分的多核苷酸的5’末端,任选地通过编码连接体序列的多核苷酸进行连接,从而在凝血因子VII/VIIa部分和白蛋白部分之间引入连接体肽)。
在一个实施方案中,本发明提供了凝血因子VII/VIIa-白蛋白融合多肽,其包含或备选地由融合至血清白蛋白多肽的N-末端的具有生物学活性和/或治疗活性的凝血因子VII/VIIa组成。
在其他实施方案中,本发明提供了白蛋白融合多肽,其包含或备选地由融合至血清白蛋白蛋白质的N-末端的具有生物学活性和/或治疗活性的凝血因子VII/VIIa片段以及肽连接体组成。
在其他实施方案中,本发明提供了凝血因子VII/VIIa-白蛋白融合多肽,其包含或备选地由融合至血清白蛋白多肽的N-末端的具有生物学活性和/或治疗活性的凝血因子VII/VIIa变体以及任选地肽连接体组成。
在进一步的实施方案中,本发明提供了凝血因子VII/VIIa-白蛋白融合多肽,其包含或备选地由融合至血清白蛋白片段或变体的N-末端的具有生物学活性和/或治疗活性的FVII/FVIIa片段或变体以及任选地肽连接体组成。
在一些实施方案中,本发明提供了白蛋白融合多肽,其包含或备选地由融合至血清白蛋白的成熟部分的N-末端的FVII/FVIIa的成熟部分以及任选地肽连接体组成。
根据WO 01/79271,包含FVII/FVIIa的白蛋白融合多肽可在“出血病症”、“血友病A和B”、“肝病症”和“手术相关的出血事件”这些适应症中用作治疗剂。
本发明的另一个方面是,包含FVII/FVIIa的白蛋白融合多肽还可在治疗上用于其他适应症。最优选的适应症是“在具有带有凝血因子(FVIII或FIX)抑制剂的遗传性或获得性血友病的患者中的出血事件和手术”、“由于药物治疗例如抗血小板药或抗凝血药而形成的止血缺陷的逆转”、“次级止血(secondary hemostasis)的改善”、“在感染期间或者在疾病例如维生素K缺乏或严重肝病期间形成的止血缺陷”、“肝切除”、“由于蛇咬伤而形成的止血缺陷”、“胃肠出血”、“创伤”、“大量输液的结果(稀释性凝血病(dilutionalcoagulopathy))”、“除了FVIII和FIX外的凝血因子缺乏”、“VWD”、“FI缺乏”、“FV缺乏”、“FVII缺乏”、“FX缺乏”、“FXIII缺乏”、“HUS”、“遗传性或获得性血小板疾病和病症例如血小板减少症、ITP、TTP、HELLP综合征、贝-苏综合征、格兰茨曼血小板无力症、HIT”、“谢-希综合征”、“赫-普综合征”、“朗-奥综合征”、“过敏性紫癜”和“创伤愈合”。
发明详述
本发明的目标是提供融合至人白蛋白或其片段或变体的N-末端的人凝血因子VII和人凝血因子VIIa或其片段或变体,其与人凝血因子VII和人凝血因子VIIa或其片段或变体相比具有更长的体内功能性半衰期。本发明的另一个目标是提供融合至人白蛋白或片段或变体的N-末端的人凝血因子VII和人凝血因子VIIa或其片段或变体,其具有增加的摩尔比活性。为了实现该目标,提供凝血因子VII或凝血因子VIIa至血清白蛋白的N-末端的融合物,其任选地在FVII/FVIIa和白蛋白之间具有间插肽连接体。
术语“人血清白蛋白(HSA)”和“人白蛋白(HA)”此处可互换使用。术语“白蛋白”和“血清白蛋白”意义更广,包括人血清白蛋白(及其片段和变体)以及来自其他物种的白蛋白(及其片段和变体)。不使用白蛋白,还可使用其他白蛋白样蛋白(例如但不限于人甲胎蛋白(如WO 2005/024044中所描述的))以及它们的功能性片段或变体。
如此处所使用的,“白蛋白”统指白蛋白多肽或氨基酸序列,或者具有白蛋白的一种或多种功能活性(例如生物学活性)的白蛋白片段或变体。特别地,“白蛋白”是指人白蛋白或其片段(尤其是此处SEQ ID No:22中所示的人白蛋白的成熟形式)或来自其他脊椎动物的白蛋白或其片段,或者这些分子或其片段的类似物或变体。
所述白蛋白连接多肽的白蛋白部分可包含上述HA序列的全长,或者可以包括一个或多个能够稳定或延长治疗活性的其片段。此类片段的长度可以是10个或更多个氨基酸,或者可以包含来自HA序列的大约15、20、25、30、50或更多个连续氨基酸,或者可以包含HA的一部分或所有结构域。
本发明的白蛋白连接多肽的白蛋白部分可以是正常HA的变体。本发明的白蛋白连接多肽的凝血因子VII蛋白部分也可以是此处描述的凝血因子VII多肽的变体。术语“变体”包括插入、缺失和置换(保守的或非保守的),其中此类变化基本上不改变活性位点或活性结构域,所述活性位点或活性结构域赋予了凝血因子VII多肽的治疗活性。
特别地,本发明的白蛋白连接多肽可包含人白蛋白的天然发生的多态性变体和人白蛋白的片段。白蛋白可来源于任何脊椎动物,特别是任何哺乳动物,例如人、牛、绵羊或猪。非哺乳动物白蛋白包括但不限于鸡和鲑鱼。白蛋白连接多肽的白蛋白部分相对于FVII/FVIIa部分而言可来自不同的动物。
一般说来,白蛋白片段或变体的长度可以为至少20个,优选至少40个,最优选多于70个氨基酸。白蛋白变体可以优选地由白蛋白的至少一个完整结构域或所述结构域的片段组成或者包含白蛋白的至少一个完整结构域或所述结构域的片段,所述结构域例如为结构域1(SEQ ID NO:22的氨基酸1-194)、2(SEQ ID NO:22的氨基酸195-387)、3(SEQ ID NO:22的氨基酸388-585)、1+2(SEQ ID NO:22的1-387)、2+3(SEQ ID NO:22的195-585)或1+3(SEQ ID NO:22的氨基酸1-194+SEQ ID NO:22的氨基酸388-585)。各结构域本身由两个同源的亚结构域即1-105、120-194、195-291、316-387、388-491和512-585组成,其中具有包含残基Lys106至Glu119、Glu292至Val315和Glu492至Ala511的柔韧的亚结构域间连接体区域。
本发明的白蛋白融合多肽的白蛋白部分可包含HA的至少一个亚结构域或结构域或者其保守修饰。
本发明涉及经修饰的凝血因子VII或凝血因子VIIa多肽,其包括将凝血因子VII或凝血因子VIIa多肽或其片段或变体连接至白蛋白多肽或其片段或变体的N-末端,任选地这样进行连接,即在经修饰的凝血因子VII或凝血因子VIIa与白蛋白之间引入间插肽连接体,从而使得经修饰的凝血因子VII或凝血因子VIIa多肽与未连接至白蛋白的凝血因子VII或凝血因子VIIa多肽相比具有增加的体内功能性半衰期,或者使得使用间插肽连接体融合至白蛋白的FVII/FVIIa的摩尔比活性比不使用间插肽连接体融合至白蛋白的FVII/FVIIa的摩尔比活性更高。
本申请中所使用的“凝血因子VII/VIIa”是指由非活化形式(凝血因子VII)或活化形式(凝血因子VIIa)或其混合物组成的治疗性多肽。在上述定义内的“凝血因子VII/VIIa”包括具有天然人凝血因子VII/VIIa的氨基酸序列的多肽。其还包括具有经少许修饰的氨基酸序列(例如包含末端氨基酸缺失或添加的经修饰的N-末端或C-末端)的多肽,只要这些多肽基本上保留凝血因子VIIa的生物学活性。在上述定义内的“凝血因子VII”还包括可在不同个体之间存在和发生的天然等位基因变体。在上述定义内的“凝血因子VII”进一步包括FVII/FVIIa的变体。此类变体与野生型序列相差一个或多个氨基酸残基。此类差异的实例可包括将N-和/或C-末端截断一个或多个氨基酸残基(例如1至10个氨基酸残基),或者在N-和/或C-末端添加一个或多个额外的残基,以及保守氨基酸置换,即在具有相似特征的氨基酸组内进行的置换,例如(1)小氨基酸,(2)酸性氨基酸,(3)极性氨基酸,(4)碱性氨基酸,(5)疏水氨基酸和(6)芳香族氨基酸。此类保守置换的实例显示于下表中。
表1
所述融合蛋白展示出至少25%,优选大于40%,更优选大于70%和最优选大于90%的未融合的野生型凝血因子VII/VIIa或其各自的FVII/FVIIa片段或变体的摩尔比活性。
通过间插肽连接体连接至白蛋白的N-末端的本发明的FVII/FVIIa多肽具有相比于无间插肽连接体的同源凝血因子VII/VIIa-白蛋白融合物的摩尔比活性而言增加的摩尔比活性。与无间插肽连接体的凝血因子VII/VIIa-白蛋白融合物的摩尔比活性相比,本发明的连接有白蛋白的凝血因子VII/VIIa多肽的摩尔比活性的增加是至少25%,优选至少50%,更优选至少100%和最优选至少200%。凝血因子VII/VIIa的活性是将底物凝血因子X转化成具有活性的凝血因子Xa的能力。可以优选地使用来测量连接有凝血因子VII/VIIa的白蛋白多肽的FVIIa活性。本发明中所使用的摩尔比活性是指:在激活连接有FVII的白蛋白融合蛋白后,在测定法中测量的活性,其表示为国际单位(IU)/100IU的凝血因子VII/VIIa抗原(通过ELISA测量的)。
本发明的FVII/FVIIa-白蛋白连接多肽与无间插肽连接体的凝血因子VII/VIIa-白蛋白融合物相比具有高至少25%的摩尔比活性,并且与未连接形式的凝血因子VII或凝血因子VIIa多肽相比展示出增加的体内功能性半衰期。可以如Lindley等人(Pharmacokinetics andpharmacodynamics of recombinant Factor VIIa,Clin.PharmacolTher.(1994)55:638-648)中所述的来测定体内功能性半衰期。
本发明的FVII/FVIIa-白蛋白连接多肽与无间插肽连接体的凝血因子VII/VIIa-白蛋白融合蛋白相比具有高至少25%的摩尔比活性,并且它们的体内功能性半衰期与未连接形式的凝血因子VII或凝血因子VIIa多肽相比,通常增加至少100%,优选至少200%,更优选至少500%。
因此,本发明的一个实施方案是具有由至少1个氨基酸,优选至少3个氨基酸,更优选至少7个氨基酸和最优选至少25个氨基酸组成的肽连接体的FVII/FVIIa-白蛋白连接多肽。
野生型形式的人凝血因子VII的体内功能性半衰期在人中为大约4小时。本发明的凝血因子VII-白蛋白连接多肽的功能性半衰期通常为至少大约8小时,优选至少大约12小时,更优选至少大约24小时。
野生型形式的人凝血因子VIIa的体内功能性半衰期在人中为大约2小时。本发明的连接有凝血因子VIIa的白蛋白多肽的功能性半衰期通常为至少大约4小时,优选至少大约6小时,更优选至少大约12小时。
根据本发明,通过肽连接体将凝血因子VII/VIIa部分偶联至白蛋白部分。连接体优选是柔韧的和非免疫原性的,并且在人白蛋白和FVII/FVIIa之间产生距离,所述距离使这两个融合伙伴的潜在干扰减小至最低限度,从而导致该融合蛋白的FVII/FVIIa活性增加。示例性的连接体包括(GGGGS)N或(GGGS)N或(GGS)N,其中N是大于或等于1的整数,并且其中G代表甘氨酸和S代表丝氨酸。这些氨基酸属于天然氨基酸组并且被选择作为所有可能的天然氨基酸的实例。
在本发明的另一个实施方案中,凝血因子VII/VIIa部分和白蛋白部分之间的肽连接体包含用于添加翻译后修饰的共有位点。优选地,此类修饰由糖基化位点组成。更优选地,此类修饰由结构Asn-X-Ser/Thr的至少一个N-糖基化位点组成,其中X表示除了脯氨酸外的任何氨基酸。更加优选地,在靠近肽连接体的氨基和/或羧基末端处插入此类N-糖基化位点,以使它们能够遮蔽潜在的新表位,所述新表位可能分别在其中凝血因子VII/VIIa部分过渡入肽连接体的序列处和在其中肽连接体过渡入白蛋白部分序列的序列处形成。
在本发明的另一个实施方案中,凝血因子VII/VIIa部分和白蛋白部分之间的肽连接体由在人蛋白质中用作天然的结构域间连接体的肽序列组成。优选地,此类肽序列在它们的天然环境中位于靠近蛋白质表面处并且对于免疫系统是易接近的,从而人们可采用针对该序列的天然耐受力。表2中提供了实例。
表2
序列 | 蛋白质 | 登录号 | 连接体的位置 |
EPQ GGGGSGGGGSG E | 原钙粘着蛋白-10 | Q9P2E7 | 靠近膜,细胞外 |
GGVGGGGGGAGI | ANP受体 | P17342 | N-末端,细胞外 |
PAR GGGGGG KAR | Frizzled-8 | Q9H461 | 结构域之间,分泌的 |
GGPGGGGGGGPGG | Frizzled-8 | Q9H461 | C-末端,分泌的 |
TSR GGGGSGGG EPP | LRRFN2 | Q9ULH4 | 结构域之间,细胞外 |
在本发明的另一个实施方案中,凝血因子VII/VIIa部分和白蛋白部分之间的肽连接体由这样的肽序列组成,所述肽序列是已知的血浆蛋白质的结构域间连接体。表3中提供了实例。
表3
序列 | 蛋白质 | 登录号 | 连接体的位置 |
MYGAKKPLNTEGVMKSRS | FXIIIa | P00488 | 催化和Ig样结构域之间 |
RGEVKYPLCTRKESK | FXIIIb | P05160 | 两个Sushi结构域之间 |
ESGGPLSLS | FVIII | P00451 | B结构域内 |
APEAPPPTLPP | vWF | P04275 | 两个vWAs之间 |
在本发明的另一个实施方案中,通过肽连接体将凝血因子VII/VIIa部分偶联至白蛋白部分,所述肽连接体在凝血位置处释放凝血因子VII/VIIa多肽,其中所述连接体包含血浆蛋白酶切割位点。优选地,此类血浆蛋白酶切割位点是丝氨酸蛋白酶的切割位点。更优选地,所述切割位点来自凝血蛋白酶(coagulation protease)切割位点。最优选地,所述凝血蛋白酶选自凝血因子IIa、凝血因子IXa、凝血因子Xa、凝血因子XIa、凝血因子XIIa、激活的C蛋白、弹性蛋白酶或激肽释放酶。由这些丝氨酸蛋白酶所识别和切割的氨基酸序列对于本领域技术人员来说是已知的,例如如“Hemostasis and Thrombosis,Basic Principles and Clinical Practice”(第4版,Colman等人,2001)中所描述的。凝血因子IIa:p34-35,p176;凝血因子IXa:p40-41;凝血因子Xa:p34-35;凝血因子XIa:p128-129;凝血因子XIIa:p194;aPC:p34-35,p159;激肽释放酶:p103-104或弹性蛋白酶(O′Reilly等人,1999;Antiangiogenic activity of the cleaved conformationof the serpin antithrombin:Science 285:1926-1928)。
本发明进一步涉及本发明的经修饰的凝血因子VII/VIIa-白蛋白融合多肽,其在凝血因子VII/VIIa部分中包含额外的修饰。
特别地,本发明包括凝血因子VII/VIIa的修饰,其中通过加入不同的维生素K依赖性多肽的激活肽的至少部分或通过用不同的维生素K依赖性多肽的激活肽的至少部分置换凝血因子VII/VIIa多肽的推定的激活肽的至少部分,来在多肽的Arg144和Arg152之间修饰凝血因子VII/VIIa,如欧洲专利申请04019485.4(其通过提及而整合入本申请中)中所描述的和在下面的段落中所描述的。
FVII特别地与其他Gla结构域蛋白质例如FIX、FX和C蛋白(在这些蛋白中,N-末端Gla结构域之后接着两个表皮生长因子(EGF)结构域,随后是胰蛋白酶型丝氨酸蛋白酶结构域)紧密相关。
令人吃惊的是这些紧密相关的血浆蛋白质的血浆半衰期的巨大差异:
FVII: 2-4小时
C蛋白: 6-8小时
FIX: 18-30小时
FX: 20-42小时。
这些分子是高度保守的,最显著的差异在激活结构域内。对于FVII,未曾描述过激活肽。然而,在激活过程中,除了在Arg152处进行切割外,FVII还可能在Arg144被切割,从而导致包含保守的N-糖基化位点的、具有8个氨基酸的推定的激活肽的释放。Arg144和Arg152之间的序列在欧洲专利申请04019485.4中被称为“推定的激活肽”。
令人吃惊地,激活肽的长度和所述激活肽的翻译后修饰与增加的半衰期相关:
表4
血浆半衰期 | 在各自人蛋白质内的激活肽的长度 | 在各自激活肽内的N-糖基化位点 | |
FVII | 2-4小时 | 无激活肽(或推定的具有8个氨基酸的激活肽) | 1,在推定的具有8个氨基酸的激活肽中 |
C蛋白 | 6-8小时 | 16个氨基酸 | 0 |
FIX | 18-30小时 | 34个氨基酸 | 2 |
FX | 20-42小时 | 51个氨基酸 | 2 |
因此,本发明涉及用于制备连接至白蛋白的经修饰的凝血因子VII/VIIa多肽的方法,该方法包括在Arg144和Arg152之间的区域内修饰凝血因子VII/VIIa多肽,从而使得经修饰的凝血因子VII/VIIa多肽与其中该区域未被修饰的凝血因子VII/VIIa多肽相比具有增加的半衰期。
本发明还涉及用于制备这样的连接至白蛋白多肽的经修饰的凝血因子VII/VIIa的方法,该方法包括通过加入第二维生素K依赖性多肽的激活肽的至少部分或通过用不同的维生素K依赖性多肽的激活肽的至少部分置换凝血因子VII/VIIa多肽的推定的激活肽的至少部分,来在所述连接有凝血因子VII/VIIa的白蛋白多肽的Arg144和Arg152之间的区域中修饰凝血因子VII/VIIa多肽。
本发明进一步包括在凝血因子VII/VIIa多肽序列内的额外的突变,所述突变增强了催化活性、延长了血浆半衰期或改变了组织因子相互作用。特别有用的凝血因子VII突变描述于Shah等人(1998)Proc.Natl.Acad.Sci.USA 95:4229-4234中,其中报导了蛋白质功能的增强。在欧洲专利申请04019485.4的现有技术的描述中描述了其他有用的凝血因子VII/VIIa突变。
本发明还涉及编码本申请中描述的凝血因子VII/VIIa-白蛋白融合多肽的多核苷酸。术语“多核苷酸”通常是指可以是未修饰的RNA或DNA或者经修饰的RNA或DNA的任何多核糖核苷酸或多脱氧核糖核苷酸。多核苷酸可以是单链或双链DNA、单链或双链RNA。如此处所使用的,术语“多核苷酸”还包括包含一个或多个经修饰的碱基和/或稀有碱基例如肌苷的DNA或RNA。要认识到,可对用于本领域技术人员已知的许多有用目的的DNA和RNA进行多种修饰。如此处所使用的,术语“多核苷酸”包括多核苷酸的此类经化学地、酶促地或代谢地修饰的形式,以及病毒和细胞(包括例如简单和复杂的细胞)所特有的DNA和RNA的化学形式。
本领域技术人员将理解,由于遗传密码的简并性,给定的多肽可以由不同的多核苷酸编码。本发明包括这些“变体”。
优选地,本发明的多核苷酸是分离的多核苷酸。术语“分离的”多核苷酸是指基本上不含其他核酸序列(例如但不限于其他染色体和染色体外DNA和RNA)的多核苷酸。可从宿主细胞中纯化出分离的多核苷酸。本领域技术人员已知的常规的核酸纯化方法可用于获得分离的多核苷酸。该术语还包括重组多核苷酸和化学合成的多核苷酸。
本发明的另一个方面是包含本发明的多核苷酸的质粒或载体。优选地,所述质粒或载体是表达载体。在一个具体的实施方案中,所述载体是用于人基因疗法的转移载体。
本发明的另一个方面是包含本发明的多核苷酸或本发明的质粒或载体的宿主细胞。
本发明的宿主细胞可在产生FVII/VIIa-白蛋白融合多肽的方法中使用,所述方法是本发明的一部分。所述方法包括:
-在使FVII/VIIa-白蛋白融合多肽表达的条件下培养本发明的宿主细胞;和
-任选地,从培养基中回收FVII/VIIa-白蛋白融合多肽。所提及的变体的表达:
重组蛋白以高水平在合适的宿主细胞中的产生需要在重组表达载体中将上述经修饰的cDNA与合适的调控元件一起装配成有效的转录单元,所述重组表达载体可按照本领域技术人员已知的方法在各种表达系统中进行扩增。有效的转录调控元件可来源于将动物细胞作为它们的天然宿主的病毒或者来源于动物细胞的染色体DNA。优选地,可使用来源于猿猴病毒40、腺病毒、BK多瘤病毒、人巨细胞病毒或劳斯肉瘤病毒的长末端重复序列的启动子-增强子组合,或者包括在动物细胞中强组成性地转录的基因例如β-肌动蛋白或GRP78的启动子-增强子组合。为了获得稳定的高水平的从cDNA转录的mRNA,转录单元应当在其3′-近端部分中包含编码转录终止-多腺苷化序列的DNA区域。优选地,该序列来源于猿猴病毒40早期转录区、兔β-珠蛋白基因或人组织纤溶酶原激活物基因。
然后将cDNA整合入用于表达凝血因子VII/VIIa-白蛋白融合多肽的合适的宿主细胞系的基因组中。优选地,该细胞系应当是脊椎动物来源的动物细胞系,以确保正确的折叠、Gla结构域内的谷氨酸残基的γ羧化、二硫键的形成、天冬酰胺-联糖基化、O-联糖基化和其他翻译后修饰以及分泌入培养基中。其他翻译后修饰的实例是酪氨酸O-硫酸化、羟基化、新生多肽链的蛋白酶解加工和前肽区域的切割。可使用的细胞的实例是猴COS细胞、小鼠L细胞、小鼠C127细胞、仓鼠BHK-21细胞、人胚肾293细胞和优选地仓鼠CHO细胞。
可以以几种不同的方式将编码相应的cDNA的重组表达载体导入动物细胞系中。例如,可从基于不同动物病毒的载体产生重组表达载体。这些载体的实例是基于杆状病毒、痘苗病毒、腺病毒和优选地牛乳头状瘤病毒的载体。
还可将编码相应的DNA的转录单元与另一个重组基因一起导入动物细胞中,所述另一个重组基因可在这些细胞中用作显性选择标记以有助于分离已将该重组DNA整合入它们的基因组中的特定细胞克隆。这种类型的显性选择标记基因的实例是Tn5氨基糖苷磷酸转移酶(其赋予对遗传霉素(G418)的抗性)、潮霉素磷酸转移酶(其赋予对潮霉素的抗性)和嘌呤霉素乙酰基转移酶(其赋予对嘌呤霉素的抗性)。编码这样的选择标记的重组表达载体可存在于与编码所述蛋白质的cDNA的载体相同的载体上,或者可以在分开的载体上编码其,所述分开的载体被同时导入和整合入宿主细胞的基因组中,从而常常导致不同转录单元之间的紧密物理连锁。
可以与所需蛋白质的cDNA一起使用的其他类型的选择标记基因基于编码二氢叶酸还原酶(dhfr)的各种转录单元。在将该类型的基因导入缺乏内源性的dhfr活性的细胞优选CHO细胞(DUKX-B11、DG-44)中之后,其将使这些细胞能够在缺乏核苷的培养基中生长。这样的培养基的实例是没有次黄嘌呤、胸苷和甘氨酸的Ham′s F12。可将这些dhfr基因与凝血因子cDNA转录单元一起(连接在相同的载体上或在不同的载体上)导入上述类型的CHO细胞中,从而建立产生重组蛋白质的dhfr阳性细胞系。
如果上述细胞系在细胞毒性dhfr抑制剂氨甲蝶呤存在的情况下生长,则将产生对氨甲蝶呤具有抗性的新细胞系。由于经扩增的数目的连锁的dhfr和所需蛋白质的转录单元,这些细胞系可以以增加的比率产生重组蛋白。当在浓度不断增加的氨甲蝶呤(1-10000nM)中繁殖这些细胞系时,可获得以非常高的比率产生所需蛋白质的新细胞系。
可在悬浮培养中或在各种不同的固体支持物上大规模生长产生所需蛋白质的上述细胞系。这些支持物的实例是基于葡聚糖或胶原基质的微载体,或者以中空纤维或各种陶瓷材料形式存在的固体支持物。当在细胞悬浮培养中或在微载体上培养时,可以以分批培养的方式或者以灌注培养的方式(在延长的时间内连续产生条件培养基)进行上述细胞系的培养。因此,根据本发明,上述细胞系非常适合于开发用于所需重组蛋白的生产的工业方法。
可通过各种生物化学和层析方法(包括利用所需蛋白质与细胞培养基中的其他物质之间的大小、电荷、疏水性、溶解度、特异的亲和力(specific affinity)等的差异的方法)来浓缩和纯化在上述类型的分泌性细胞的培养基中积累的重组蛋白。
这种纯化的实例是将重组蛋白吸附至固定在固体支持物上的单克隆抗体。在解吸后,可通过各种基于上述性质的层析技术来进一步纯化该蛋白质。
优选地,将本发明的连接有凝血因子VII/VIIa的白蛋白多肽纯化至≥80%的纯度,更优选≥95%的纯度,和特别优选的是具有大于99.9%的纯度(相对于污染性大分子,特别是其他蛋白质和核酸)且不含感染性和热原性因子的药学上纯的状态。优选地,本发明的分离的或纯化的连接有FVII/VIIa的白蛋白多肽基本上不含其他多肽。
本发明中描述的连接有凝血因子VII/VIIa的白蛋白多肽可以配制成用于治疗用途的药物制剂。可将纯化的蛋白质溶解在常规的生理学上相容的缓冲水溶液中,可任选地向该缓冲水溶液中加入药物学赋形剂以提供药物制剂。
此类药物学载体和赋形剂以及合适的药物制剂在本领域内是熟知的(参见例如“Pharmaceutical Formulation Development ofPeptides and Proteins”,Frokjaer等人,Taylor & Francis(2000),或“Handbook of Pharmaceutical Excipients”,第3版,Kibbe等人,Pharmaceutical Press(2000))。特别地,可以将包含本发明的多肽变体的药物组合物配制成冻干的或稳定的可溶的形式。可通过本领域内已知的各种方法来冻干多肽变体。在使用前通过加入一种或多种药学上可接受的稀释剂例如用于注射的无菌水或无菌生理盐水溶液来重构冻干的制剂。
可通过任何药学上合适的施用方式将该组合物的制剂递送至个体。已知各种不同的递送系统,并且可用于通过任何方便的途径来施用该组合物。优选地,全身性地施用本发明的组合物。为了进行全身使用,将本发明的连接有白蛋白的凝血因子VII/VIIa变体配制成用于按照常规方法进行的肠胃外(例如静脉内、皮下、肌内、腹膜内、大脑内、肺内、鼻内或经皮)或肠(例如,口服、阴道或直肠)递送。最优选的施用途径是静脉内施用。可连续地通过输注或通过快速浓注来施用制剂。一些制剂包含缓释系统。
可以以治疗有效剂量给患者施用本发明的经修饰的具有生物学活性的连接有白蛋白的凝血因子VII/VIIa多肽,所述治疗有效剂量表示足以产生所希望的效果的剂量,其预防或减轻被治疗的病状或适应症的严重度或传播而未达到产生不能耐受的不利副作用的剂量。确切的剂量取决于许多因素例如适应症、制剂和施用方式,并且对于每一种各自的适应症必须在临床前和临床试验中确定确切的剂量。
本发明的药物组合物可单独地或与其他治疗剂一起施用。可以作为相同药物的一部分来整合入这些试剂。
本发明的各种不同产品可用作药物。因此,本发明涉及包含此处描述的连接有FVII/VIIa的白蛋白多肽、本发明的多核苷酸或者本发明的质粒或载体的药物组合物。
还可将本发明的经修饰的DNA整合入用于人基因疗法的转移载体中。
本发明的另一个方面是此处描述的连接有FVII/VIIa的白蛋白多肽、本发明的多核苷酸、本发明的质粒或载体、或者本发明的宿主细胞在制备用于治疗或预防出血病症的药物中的用途。出血病症包括但不限于血友病A。在本发明的另一个实施方案中,治疗包括人基因疗法。
本发明还涉及治疗具有一个或多个下列适应症的个体的方法:“在具有带有凝血因子(FVIII或FIX)抑制剂的遗传性或获得性血友病的患者中的出血事件和手术”、“由于药物治疗例如抗血小板药或抗凝血药而形成的止血缺陷的逆转”、“次级止血的改善”、“在感染期间或者在疾病例如维生素K缺乏或严重肝病期间形成的止血缺陷”、“肝切除”、“由于蛇咬伤而形成的止血缺陷”、“胃肠出血”。也优选的适应症是“创伤”、“大量输液的结果(稀释性凝血病)”、“除了FVIII和FIX外的凝血因子缺乏”、“VWD”、“FI缺乏”、“FV缺乏”、“FVII缺乏”、“FX缺乏”、“FXIII缺乏”、“HUS”、“遗传性或获得性血小板疾病和病症例如血小板减少症、ITP、TTP、HELLP综合征、贝-苏综合征、格兰茨曼血小板无力症、HIT”、“谢-希综合征”、“赫-普综合征”、“朗-奥综合征”、“过敏性紫癜”和“创伤愈合”。该方法包括给所述个体施用有效量的此处描述的连接有FVII/VIIa的白蛋白多肽。在另一个实施方案中,该方法包括给个体施用有效量的本发明的多核苷酸或者本发明的质粒或载体。备选地,该方法可包括给个体施用有效量的此处描述的本发明的宿主细胞。
表和附图的描述
图1:
通过用TCG替代TAG而在天然FVII终止密码子位点处引入的XhoI限制位点以下划线标示。用于进一步构建的NotI位点以双下划线标示。以三字母密码给出凝血因子VIIC-末端的氨基酸序列(以加框标示)。
图2:
在各种pFVII构建体中在凝血因子VII的C-末端和白蛋白的N-末端之间插入的连接体序列的概述。pFVII-834中的凝血酶切割位点以下划线标示。N-糖基化位点的天冬酰胺以双下划线标示。
图3:
通过FXa激活FVII-白蛋白融合蛋白,和在测定法中测量FVIIa活性。该图显示了与无连接体的蛋白质(来源于质粒pFVII-974)相比,具有不断增加的连接体长度的蛋白质的活性。
图4:
使用野生型凝血因子VII(pFVII-659)、FVII-白蛋白融合蛋白、血浆来源的FVII(pdFVII)和rFVIIa()的PK实验的结果,其通过ELISA进行测量。
实施例
实施例1:编码FVII-白蛋白融合多肽的cDNA的产生
使用引物We1303和We1304(SEQ ID NO 1和2)通过PCR从人肝cDNA文库(ProQuest,Invitrogen)中扩增出凝血因子VII编码序列。在使用引物We1286和We1287(SEQ ID NO 3和4)进行第二轮PCR后,将所得的片段克隆入pCR4TOPO(Invitrogen)中。由此,以EcoRI片段的形式将FVII cDNA转移入pIRESpuro3(BD Biosciences)的EcoRI位点中,其中事先已将内部XhoI位点删除。所得的质粒称为pFVII-659。
然后,按照标准方案(QuickChange XL Site DirectedMutagenesis Kit,Stratagene),使用寡核苷酸We1643和We1644(SEQ ID NO 5和6)通过定向诱变在天然FVII终止密码子的位点处将XhoI限制性位点引入pFVII-659中(图1)。所得的质粒称为pFVII-700。
将寡核苷酸We1731和We1732(SEQ ID NO 7和8)在标准PCR条件下以等摩尔浓度(10pmol)进行退火,填补和使用PCR方案进行扩增,所述PCR方案是:在94℃下进行2分钟的初始变性,然后进行7个循环(在94℃下进行15秒的变性、在55℃下进行15秒的退火和在72℃下进行15秒的延长),最后在72℃下进行5分钟的延伸步骤。用限制性核酸内切酶XhoI和NotI消化所得的片段,并连接入使用相同的酶消化的pFVII-700中。所得的质粒称为pFVII-733,其包含FVII以及凝血酶可切割的甘氨酸/丝氨酸连接体的C-末端延伸的编码序列。
基于pFVII-733,插入无凝血酶切割位点和额外的N-糖基化位点的其他连接体。为此,如上所述,分别使引物对We2148和We2149(SEQID NO 9和10)、We2148和We2150(SEQ ID NO 9和11)、We2148和We2151(SEQ ID NO 9和12)、We2152和We2153(SEQ ID NO 13和14)、We2152和We2154(SEQ ID NO 13和15)、We2152和2155(SEQ ID NO 13和16)以及We2156和We2157(SEQ ID NO 17和18)进行退火并扩增。用限制性核酸内切酶XhoI和BamH1消化各PCR片段,并插入用相同的酶消化的pFVII-733中。将包含成熟人白蛋白的cDNA的BamH1片段插入所得的质粒的BamH1位点中以及插入pFVII-733的BamH1位点中。通过在标准条件下使用引物We1862和We1902(SEQ IDNO 19和20)对白蛋白cDNA序列进行PCR来产生该片段。最终的质粒分别称为pFVII-935、pFVII-936、pFVII-937、pFVII-938、pFVII-939、pFVII-940、pFVII-941和pFVII-834。它们的连接体序列以及C-末端FVII和N-末端白蛋白序列概述于图2中。
基于pFVII-938,通过缺失诱变来产生更短的连接体序列。为此,在标准的诱变方案(QuickChange XL Site Directed Mutagenesis Kit,Stratagene)中使用诱变引物We2247和We2248(SEQ ID No 23和24)、We2249和We2250(SEQ ID No 25和26)、We2251和We2252(SEQ IDNo 27和28)以及We2253和We2254(SEQ ID No 29和30),从而分别产生质粒pFVII-1014、pFVII-1015、pFVII-1016和pFVII-1370。
为了产生无连接体的FVII-白蛋白融合蛋白,如上所述,使用引物We2181和We2182(SEQ ID NO 31和32)对质粒pFVII-935进行缺失诱变。所得的质粒称为pFVII-974。
基于质粒pFVII-974,应用插入诱变以产生具有1至3个氨基酸的连接体。为此,在标准诱变方案(QuickChange XL Site DirectedMutagenesis Kit,Stratagene)中使用诱变引物We2432和We2433(SEQ ID No 33和34)、We2434和We2435(SEQ ID No 35和36)以及We2436和We2437(SEQ ID No 37和38),从而分别产生质粒pFVII-1158、pFVII-1159和pFVII-1160。
以类似的程序产生其他构建体,其中在标准诱变方案中对质粒pFVII-1370应用诱变引物We2713和We2714(SEQ ID No 39和40),对质粒pFVII-1370应用We2715和We2716(SEQ ID No 41和42)、对质粒pFVII-1016应用We2717和We2718(SEQ ID No 43和44),以及对质粒pFVII-935应用We2756和We2757(SEQ ID No 45和46),从而分别产生质粒pFVII-1361、pFVII-1362、pFVII-1363和pFVII-1382。
在图2中概述了上述质粒的连接体序列以及C-末端FVII和N-末端白蛋白序列。
实施例2:凝血因子VII-白蛋白融合多肽的转染和表达
质粒在大肠杆菌(E.coli)TOP10(Invitrogen)中进行增长,并使用标准方案(Qiagen)对其进行纯化。使用Lipofectamine 2000试剂(Invitrogen)转染HEK-293细胞,并且使所述细胞在50ng/ml维生素K和4μg/ml嘌呤霉素存在的情况下在无血清培养基(Invitrogen 293 Express)中进行生长。经转染的细胞群体通过T型烧瓶扩散入滚瓶中,从所述滚瓶中收获上清液以用于纯化。
实施例3:FVII和FVII-白蛋白融合多肽的纯化
将包含FVII或FVII-白蛋白融合蛋白的细胞培养收获物施加于事先用20mM HEPES缓冲液(pH 7.4)平衡的2.06mL Q-Sepharose FF柱上。然而,用10倍体积的所述HEPES缓冲液洗涤柱子。通过在20倍柱体积内流过在20mM HEPES缓冲液中的0-1.0M NaCl线性梯度来洗脱结合的FVII分子。洗出液以0.5至1g/L的蛋白质浓度包含大约85-90%的所施加的FVII抗原。
备选地,使用固定的组织因子通过层析法来纯化FVII,如EP0770625B1中所描述的。
如实施例4中所述的,测定FVII抗原和活性。
实施例4:FVII活性和抗原的测定
基于由Seligsohn等人,Blood(1978)52:978-988描述的方法,使用商购可得的显色测试试剂盒(Chromogenix Coaset FVII,使用标准人血浆[Dade Behring]作为标准)来测定FVII的活性。
基于由Morissey等人,(1993)Blood 81:734-744描述的方法,使用商购可得的测试试剂盒()VIIa-rTF,Diagnostica Stago)来测定FVIIa的活性。
通过ELISA来测定FVII抗原,所述ELISA的施行对于本领域人员来说是已知的。简而言之,用120μL/孔的捕获抗体(绵羊抗人FVIIIgG,Cedarlane CL20030AP,以1∶1000在缓冲液A[Sigma C3041]中稀释的)在环境温度下温育微量培养板过夜。在用缓冲液B(SigmaP3563)洗涤板三次后,用200μL缓冲液C(Sigma P3688)在环境温度下温育各孔1小时。在另外三次使用缓冲液B的洗涤步骤后,将受试样品在缓冲液B中的系列稀释物以及标准人血浆(Dade Behring;50-0.5mU/mL[1mU等于0.5ng])在缓冲液B中的系列稀释物(每孔体积:100μL)在环境温度下温育2小时。在三次使用缓冲液B的洗涤步骤后,向每个孔中加入100μL的在缓冲液B中的检测抗体(绵羊抗人FVII IgG,Cedarlane CL20030K,经过氧化物酶标记的)1∶5000稀释物,在环境温度下温育2小时。在三次使用缓冲液B的洗涤步骤后,每孔中加入100μL底物溶液(TMB,Dade Behring,OUVF),并在黑暗处在环境温度下温育30分钟。加入100μL未稀释的终止溶液(Dade Behring,OSFA),从而制得用于在合适的微量培养板阅读器中于450nm波长处进行读数的样品。然后,使用标准曲线(该曲线使用标准人血浆作为参照)来计算受试样品的浓度。
实施例5:通过凝血因子Xa来激活FVII和FVII-白蛋白融合多肽
将如实施例3中所述进行纯化的FVII多肽对由20mM HEPES、150mM NaCl、1mM柠檬酸钠、1g/L辛酸钠组成的缓冲液(pH 8.5)进行透析。在该缓冲液环境内,通过在37℃下与FXa(商购可得的制剂,100IU/mL,ERL)、磷脂(Phospholipon 25P,1g/L,RhonePoulenc-Nattermann,)和Ca++(Aqua dest中的CaCl2溶液,1M)一起温育各种不同的时间间隔来将FVII激活成FVIIa。终浓度为~30至65IU/mL FVII(通过显色测定法测量的);相对于FVII的0.5%FXa,即1IU FXa和200IU FVII,0.02g/L磷脂,和5mM CaCl2。
通过加入由20mM HEPES、150mM NaCl、200mM柠檬酸钠、1g/L辛酸钠组成的10%(v/v)的缓冲液(pH 5.0)来终止激活。
为了平行地监控分子的切割,将激活混合物的样品和相应的未激活的样品施加至SDS-PAGE,用考马斯蓝进行染色,并就条带密度进行扫描。
简而言之,还原样品,将其施加至SDS-PAGE(梯度8-16%聚丙烯酰胺,Tris-Glycin Gels,Invitrogen;按照厂商说明书),并用考马斯蓝G-250进行染色。扫描所得的条带(VersaBio-Rad),并使用软件Image Quant(V 4.20,Amersham)计算相对蛋白质浓度。
实施例6:FVII白蛋白融合蛋白的活性取决于连接体的长度
如上所述激活具有0至31个氨基酸的连接体长度的FVII-白蛋白融合蛋白,并在测定法中测定FVIIa的活性。尽管所述融合多肽(无论连接体的长度如何)显示出相当的FXa切割的程度,但通过该活性测定法测量的所述白蛋白融合蛋白的FVIIa活性显示出令人吃惊的结果:FVII和白蛋白部分之间的连接体变得越长,所测得的摩尔比FVIIa活性就越高(图3和表5),并且无连接体的构建体(974)与具有长度为19或更多个氨基酸的连接体肽的构建体相比展示出低于一半的FVIIa活性。甚至作为连接体的一个氨基酸(pFVII-1158)也使融合蛋白的摩尔比活性相比于无连接体的融合蛋白(pFVII-974)而言增加了31%。这强有力地表明,FVII与白蛋白序列的直接融合可能导致这样的构象情形,即其中白蛋白部分干扰其FVIIa部分的构象或者FVIIa部分与其底物的相互作用。这种干扰似乎于在凝血因子VII/VIIa与白蛋白之间具有间插肽连接体的构建体中显著减少。
当与相比时,无连接体的白蛋白融合蛋白(974)展示出大约25%的摩尔比活性(表6)。
表5
源自下列pFVII-编号的白蛋白融合蛋白 | 连接体长度[氨基酸] | 连接体内N-糖基化位点的数目 | %与无连接体的融合蛋白相比,Staclot活性的增加 |
974 | 0 | 0 | 0 |
1158 | 1 | 0 | 31.3 |
1159 | 2 | 0 | 75.6 |
1160 | 3 | 0 | 104.0 |
1370 | 4 | 0 | 81.6 |
1361 | 5 | 0 | 107.0 |
1362 | 6 | 0 | 98.5 |
1363 | 7 | 0 | 178.1 |
1015 | 10 | 1 | 155.7 |
1014 | 13 | 2 | 201.5 |
1382 | 16 | 0 | 149.8 |
935 | 19 | 0 | 194.5 |
936 | 25 | 0 | 255.7 |
937 | 31 | 0 | 249.8 |
表6
无连接体的FVII-白蛋白融合蛋白(974)和之间的摩尔比活性(表示为通过Staclot测定法测量的FVIIa单位/100个单位的通过ELISA测定的FVII抗原)的比较
序列表
<110>CSL Behring GmbH
CSL Behring GmbH
<120>具有延长的半衰期的经修饰的凝血因子VIIa
<130>2006/M001-A107
<150>EP 06002359.5
<151>2006-02-06
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Thr Ser Arg Gly Gly Gly Gly Ser Gly Gly Gly Glu Pro Pro
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Met Tyr Gly Ala Lys Lys Pro Leu Asn Thr Glu Gly Val Met Lys Ser
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Arg Ser
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Arg Gly Glu Val Lys Tyr Pro Leu Cys Thr Arg Lys Glu Ser Lys
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Glu Ser Gly Gly Pro Leu Ser Leu Ser
1 5
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Ala Pro Glu Ala Pro Pro Pro Thr Leu Pro Pro
1 5 10
Claims (18)
1.白蛋白融合多肽,其由融合至白蛋白的凝血因子VII或凝血因子VIIa多肽组成,其中所述凝血因子VII或凝血因子VIIa多肽位于所述融合多肽的N-末端,并且其中所述融合多肽具有凝血因子VII/VIIa的生物学活性;并且其中肽连接体将位于所述融合多肽的N-末端的凝血因子VII或凝血因子VIIa部分与白蛋白部分隔开,所述肽连接体由至少3个且至多31个氨基酸组成。
2.权利要求1的白蛋白融合多肽,其中所述肽连接体由SEQ IDNo.47至55中任一个组成。
3.权利要求1的白蛋白融合多肽,其中所述肽连接体由31个氨基酸组成。
4.权利要求3的白蛋白融合多肽,其中所述肽连接体为SS(GGS)9GS。
5.权利要求1的白蛋白融合多肽,其中所述融合多肽相比于各自未融合的野生型凝血因子VII或凝血因子VIIa而言具有至少25%的摩尔比凝血因子VII/VIIa生物学活性。
6.权利要求1的白蛋白融合多肽,其中所述融合多肽相比于非融合的凝血因子VII或凝血因子VIIa而言具有增加的体内功能性血浆半衰期。
7.权利要求6的白蛋白融合多肽,其中所述融合多肽所具有的体内功能性血浆半衰期相比于未融合的凝血因子VII或凝血因子VIIa而言增加至少100%。
8.权利要求1的白蛋白融合多肽,其中所述肽连接体包含蛋白酶切割位点。
9.权利要求8的白蛋白融合多肽,其中所述切割位点可被凝血蛋白酶切割,所述凝血蛋白酶选自凝血因子IIa、凝血因子IXa、凝血因子Xa、凝血因子XIa、凝血因子XIIa、激活的C蛋白、弹性蛋白酶或激肽释放酶。
10.权利要求1的白蛋白融合多肽,其中通过插入用于翻译后修饰的位点来修饰所述肽连接体。
11.权利要求10的白蛋白融合多肽,其中所述翻译后修饰包括结构Asn-X-Ser/Thr的一个或多个N-糖基化位点,其中X表示除了脯氨酸外的任何氨基酸。
12.权利要求1至11中任一项的白蛋白融合多肽,其中所述凝血因子VII或凝血因子VIIa多肽部分具有促凝血活性。
13.核酸分子,其中所述核酸分子由编码权利要求1至12中任一项的白蛋白融合多肽的多核苷酸序列和编码前肽的核苷酸序列组成,其中所述多核苷酸序列位于所述编码前肽的核苷酸序列的3’末端,所述前肽介导凝血因子VII/VIIa融合部分的Y羧化。
14.质粒或载体,其中所述质粒或载体包含权利要求13的核酸分子。
15.权利要求14的质粒或载体,其中所述质粒或载体是表达载体。
16.权利要求14的载体,其中所述载体是用于人基因疗法的转移载体。
17.宿主细胞,其中所述宿主细胞包含权利要求13的核酸分子或者权利要求14至16中任一项的质粒或载体。
18.用于制备权利要求1至12中任一项的白蛋白融合多肽的方法,其中所述方法包括:
a.提供核酸,所述核酸包含可在生物中表达的编码所述白蛋白融合多肽的核苷酸序列;
b.在所述生物中表达所述核酸以形成白蛋白融合多肽;和
c.纯化所述白蛋白融合多肽。
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