CN109152817A - 具有改进的药代动力学的糖基化vwf融合蛋白 - Google Patents
具有改进的药代动力学的糖基化vwf融合蛋白 Download PDFInfo
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- Medicinal Preparation (AREA)
Abstract
本发明涉及包含主要蛋白质和一个或多个延伸肽的融合蛋白,其中主要蛋白质的氨基酸序列与哺乳动物蛋白质或其片段的氨基酸序列相同或相似,并且所述延伸肽包含O‑糖基化氨基酸簇。延伸肽与哺乳动物蛋白的非重复序列相同和/或与SEQ ID NO:1相同或相似。主要蛋白质优选地为VWF。与主要蛋白质相比,融合蛋白具有增加的半衰期,并且可以用于增加例如FVIII的结合配偶体的半衰期。本发明进一步涉及由融合蛋白,编码融合蛋白的多核苷酸以及包含该多核苷酸的载体和宿主细胞形成的复合物。
Description
技术领域
本发明涉及蛋白质的半衰期延长,特别是人凝血因子如血管性血友病因子(VWF)和因子VIII(FVIII)。
背景技术
血友病是一组损害身体控制血液凝固或凝血的能力的遗传性疾病。在其最常见的形式血友病A中,凝血因子VIII(FVIII)是缺乏的。血友病A在5,000-10,000个男性出生儿中有约1个发生。FVIII蛋白是血液凝固中具有多功能特性的必需辅助因子。FVIII的缺乏可以用血浆衍生的FVIII浓缩物或用重组产生的FVIII治疗。用FVIII浓缩物治疗可令血友病患者正常生活。
血友病A患者根据需要用FVIII治疗或作为每周施用数次的预防性治疗进行治疗。对于预防性治疗,施用15-25IU/kg体重的FVIII,每周三次,这因为对FVIII的持续需要及其在血液系统中的短的半衰期的缘故而是必要的,上述半衰期在人体中仅为约11小时(Ewenstein等,2004)。
在血液中,在正常条件下,FVIII分子总是与其辅因子血管性血友病因子(VWF)相关,其使FVIII分子稳定免于不同形式的降解。FVIII和VWF的非共价复合物具有0.2-0.3nM的高结合亲和力(Vlot等,1996)。
在历史上,血友病A已经用源自人血浆的FVIII治疗。然而,自20世纪90年代以来,市售了不同的重组产生的FVIII蛋白。然而,血浆衍生的和重组产生的FVIII蛋白都不具有最佳的药代动力学特性。与许多其他治疗性蛋白质一样,它们受到肽酶的代谢更新的影响,这显著限制了它们的体内半衰期。
如Tiede等(2015)评论,延长FVIII半衰期的尝试包括Fc融合(Eloctate、Elocta、efmoroctocogα),添加聚乙二醇(turoctocogαpegol[N8-GP]、BAY 94-9027、BAX 855)和单链构建体(CSL627)。所有这些技术改变FVIII分子并得到半衰期延长约1.5倍的FVIII。
FVIII的进一步半衰期延长限于VWF半衰期。如Yee等人所示,人VWF D`D3结构域足以稳定血浆中的FVIII。然而,D’D3-Fc融合蛋白仅能在VWF-/-小鼠中延长FVIII半衰期。在血友病A小鼠中,D’D3-Fc构建体由于蛋白质片段与内源性VWF对FVIII结合的无效竞争而不会导致FVIII半衰期延长。
WO 2014/011819A2描述了含有VWF的D’D3结构域,XTEN和IgG的Fc结构域的FVIII构建体的成功半衰期延长。由于该构建体不与内源性VWF结合,因此在VWF/FVIII-双敲除(DKO)和血友病A小鼠中均观察到相同的半衰期延长效应。然而,尽管体外功能完全,但其在体内显示出显著降低的活性。
用于增加治疗性蛋白质的半衰期的其他方法包括治疗性蛋白质与具有天然长半衰期的蛋白质如转铁蛋白和白蛋白的遗传融合,或与蛋白质结构域如绒毛膜促性腺激素(CG)的C-末端肽(CTP)的遗传融合。
CG属于糖蛋白激素家族,其包括促黄体激素(LH)、促卵泡激素(FSH)和促甲状腺激素(TSH)。这些糖激素是异二聚体并由共同的α-亚基和赋予它们不同活性的独特的β-亚基组成。人CG(hCG)的半衰期显著比其对应物LH、FSH和TSH的半衰期更长。这表明,hCG-β的O-糖基化CTP是造成这种半衰期延长的原因。CTP被描述为由序列FQSSSS*KAPPPS*LPSPS*RLPGPS*DTPILPQ组成,其具有四个O-糖基化位点(由S*表示)(Birken等,1977)。
如Strohl等(2015)所述,已经开发了治疗性蛋白质和CTP的不同融合蛋白,并且目前正在临床试验中。治疗性蛋白质包括FSHFVIIa、FIX、IFN-β和胃肠激素。
发明内容
本发明尤其基于以下发现:将O-糖基化氨基酸簇(其存在于全长人VWF中)添加到VWF片段中导致其半衰期显著增加。与不具有额外O-聚糖簇的VWF片段相比,融合蛋白的半衰期延长。
因此,根据第一方面,本发明涉及一种包含主要蛋白质和至少一个延伸肽的融合蛋白,其中主要蛋白质的氨基酸序列与哺乳动物蛋白质如VWF或其片段的氨基酸序列相同或相似,所述延伸肽包含O-糖基化氨基酸簇。
令人关注的是,被加成到VWF的片段中的包含O-糖基化氨基酸簇的延伸肽就是衍生自该蛋白质本身,即VWF。因此,申请人已经确定了延长蛋白质半衰期的一般原则。该一般原理是将蛋白质的O-糖基化氨基酸的内在簇添加到所述蛋白质或其片段中。
因此,根据第一方面的融合蛋白的优选实施例,一个或多个延伸肽的氨基酸序列与所述哺乳动物蛋白或片段的非重复氨基酸序列部分相同或相似,特别是所述主要蛋白质。
本发明人的发现的进一步结论是由SEQ ID NO:1鉴定的VWF的O-糖基化氨基酸簇可用作半衰期延伸肽。
由于半衰期延长性质不限于VWF,根据第一方面的另一优选实施例,一个或多个延伸肽与VWF的O-糖基化肽具有至少90%,优选地至少95%,更优选地至少98%,最优选地至少100%的序列同一性,特别是SEQ ID NO:1。
在第二方面中,本发明涉及一种编码根据第一方面的融合蛋白的多核苷酸。
根据第三方面,本发明涉及一种含有根据第二方面的多核苷酸的载体。
在第四方面中,本发明涉及一种含有根据第二方面的多核苷酸或根据第三方面的载体的宿主细胞,其中该宿主细胞是哺乳动物细胞。
发明人发现,不仅VWF的半衰期增加,而且其结合配偶体FVIII的半衰期也增加。因此,根据第五方面,本发明涉及根据第一方面的融合蛋白用于增加第二蛋白的半衰期的用途,其中所述融合蛋白能够与所述第二蛋白结合。
因此,在所得的融合蛋白和第二蛋白质的复合物或组合物中,第二蛋白质也具有增加的半衰期。
因此,在第六方面中,本发明涉及一种第一蛋白质和第二蛋白质的组合物,其中所述第一蛋白质是根据第一方面的融合蛋白并且能够结合所述第二蛋白质,并且所述第二蛋白质是治疗性蛋白质,其包含与第二哺乳动物蛋白质或其片段的氨基酸序列相同或相似的氨基酸序列。
并且根据第七方面,本发明涉及一种第一蛋白质和第二蛋白质的复合物,其中所述第一蛋白质是根据第一方面的融合蛋白,并且所述第二蛋白质具有与第二哺乳动物蛋白质或其片段的氨基酸序列相同或相似的氨基酸序列。
最后,在第八方面中,本发明还涉及一种药物组合物,其包含根据第一方面的融合蛋白,根据第六方面的组合物,或根据第七方面的复合物,其用于治疗或预防出血性疾病,优选地选自PUP治疗,或ITI治疗和其他相关出血性疾病治疗。
附图说明
图1显示以下的的示意图:A)VWF片段OCTA 11,和B)根据本发明的融合蛋白,其中VWF片段作为主要蛋白质:OCTA12;C)根据本发明的融合蛋白,其中VWF片段作为主要蛋白质:OCTA14;D)根据本发明的融合蛋白,其中VWF片段作为主要蛋白质:OCTA15。
图2显示静脉内施用与不同VWF蛋白或血浆衍生的全长VWF共同配制的FVIII后FVIII/VWF双敲除(DKO)小鼠血浆中的FVIII活性的时间进程。数据点和误差条表示5个值的平均值和标准偏差(SD)。由于尺寸小,有些误差条是不可辨别的。
图3显示了皮下施用与OCTA 12共同配制的100U/kg FVIII后小型猪血浆中的OCTA12抗原浓度的时间进程。
图4显示了皮下和静脉内注射100U/kg FVIII或皮下注射与VWF-蛋白质OCTA 12共同配制的100U/kg FVIII后小型猪血浆中的FVIII抗原浓度的时间进程。
具体实施方式
为了提供对说明书和权利要求,以及这些术语的指定范围的清楚和一致的理解,提供以下定义。
定义
如本文所用的“肽”可以由任何数量的任何类型的氨基酸组成,优选地天然存在的氨基酸,其优选地通过肽键连接。特别地,肽包含至少3个氨基酸,优选地至少5个、至少7个、至少9个、至少12个、或至少15个氨基酸。此外,肽的长度没有上限。然而,优选地,根据本发明的肽的长度不超过500个氨基酸,更优选地,其长度不超过300个氨基酸;甚至更优选地,其不长于250个氨基酸。
因此,术语“肽”包括“寡肽”,其通常是指长度为2至10个氨基酸的肽,和“多肽”,其通常是指长度超过10个氨基酸的肽。
如本文所用的“蛋白质”可含有一条或多条多肽链。具有一条以上多肽链的蛋白质通常被表达为来自一个基因的一条多肽链,并在翻译后切割。因此,术语“多肽”和“蛋白质”可互换使用。本文使用的多肽和蛋白质包括化学合成的蛋白质以及由基因编码的天然合成的蛋白质。多肽或蛋白质可以从天然来源如人血液获得,或者在细胞培养物中作为重组蛋白质制得。
本文所用的术语“治疗性蛋白质”涉及具有治疗作用的蛋白质或多肽,即用作活性药物成分的蛋白质。
根据本发明,术语“蛋白质前体”,“前蛋白”或“前肽”涉及无活性蛋白质(或肽),其可通过翻译后修饰,酶促切割部分氨基酸序列转化成活性形式。
两个氨基酸序列之间或两个核苷酸序列之间的相关性由参数“序列同一性”描述。出于本发明的目的,两个氨基酸序列之间的序列同一性程度使用Needleman-Wunsch算法(Needleman和Wunsch,1970,J.Mol.Biol.48:443-453)确定,如在EMBOSS程序包的Needle程序中实施(EMBOSS:The European Molecular Biology Open Software Suite,Rice等,2000,Trends Genet.16:276-277),优选版本3.0.0或更高版本。使用的任选参数是缺口开放罚分10,缺口延伸罚分0.5和EBLOSUM62(BLOSUM62的EMBOSS版本)取代矩阵。标记为“最长同一性”的Needle的输出(使用无简要选项获得)用作百分比同一性,并计算如下:
(相同残基×100)/(比对长度-比对中的缺口总数)。
出于本发明的目的,两个核苷酸序列之间的序列同一性程度使用Needleman-Wunsch算法(Needleman and Wunsch,1970,同上)确定,如在EMBOSS程序包的Needle程序中实施(EMBOSS:The European Molecular Biology Open Software Suite,Rice等,2000,同上),优选地3.0.0或更高版本。使用的任选参数是缺口开放罚分10,缺口延伸罚分0.5和EDNAFULL(NCBI NUC4.4的EMBOSS版本)取代矩阵。标记为“最长同一性”的Needle的输出(使用无简要选项获得)用作百分比同一性,并计算如下:
(相同的脱氧核糖核苷酸×100)/(比对长度-比对中的缺口总数)
本文所述的关于肽或多核苷酸的定义的术语“相似性”和“相似的”涉及氨基酸序列或核苷酸序列与参照的序列同一性的指定程度。类似的氨基酸序列包括与主题序列具有至少80%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或甚至99%同一性的氨基酸序列。通常,虽然相似的序列将在与肽或多核苷酸的功能相关的位置包括相同的残基,例如活性位点残基或糖基化的氨基酸,但是可以包括任何数量的保守氨基酸置换。类似的核苷酸序列包括与主题序列具有至少80%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或甚至99%同一性的核苷酸序列。
如本文所用,“相同的”是指与参考序列具有100%同一性的氨基酸或核苷酸序列。
术语“重组”当用于提及细胞、核酸、蛋白质或载体时,表示通过引入异源核酸或蛋白质或改变天然核酸或蛋白质而加以修饰的细胞、核酸、蛋白质或载体,或源自如此修饰的细胞的细胞。因此,例如,重组细胞表达在细胞的天然(非重组)形式内未发现的基因,或以不同水平或在自然界中发现的不同条件下表达的天然基因。
本文所用的术语“半衰期”是在达到分布的假平衡后血浆/血液浓度降低50%所需的时间(根据Toutain等,2005中的定义)。术语“半衰期”也称为“循环半衰期”、“最终半衰期”或“消除半衰期”。
如本文所用,关于细胞使用的术语“转化的”、“稳定转化的”和“转基因的”是指细胞含有整合到其基因组中或作为通过多代维持的附加体携载的非天然(例如异源)核酸序列。
如本文所用的术语“片段”是指一种多肽,其与天然或野生型蛋白质相比具有一个或多个氨基酸的氨基末端和/或羧基末端缺失,但其中剩余的氨基酸序列与从全长cDNA推导出的氨基酸序列中的相应位置相同。片段的长度通常为至少50个氨基酸。
本文所用的术语“糖基化”是指聚糖与分子的连接,例如与蛋白质的连接。糖基化可以是酶促反应。形成的连接可以通过共价键。因此,如本文所用的糖基化多肽是与一个或多个聚糖连接的多肽。短语“高度糖基化”是指在所有或几乎所有可用的糖基化位点(例如O-连接或N-连接的糖基化位点)糖基化的分子,例如酶。
如本文所用的术语“聚糖”是指多糖或寡糖,或糖蛋白或糖基化多肽的碳水化合物部分。聚糖可以是单糖残基的均聚物或杂聚物。它们可以是直链或支链分子。聚糖通常含有至少三个糖,并且可以是直链或支链的。聚糖可包括天然糖残基(例如,葡萄糖、N-乙酰葡糖胺、N-乙酰神经氨酸、N-乙酰半乳糖胺、半乳糖、甘露糖、岩藻糖、阿拉伯糖、核糖、木糖等)和/或修饰的糖(例如,2’-氟代核糖、2’-脱氧核糖、磷酸甘露糖、6’-磺基-N-乙酰葡糖胺等)。
本文所用的术语“O-聚糖”是指通常发现与哺乳动物糖蛋白的丝氨酸和苏氨酸残基共价连接的聚糖。O-聚糖可以通过O-糖苷键经N-乙酰半乳糖胺(GalNAc)部分与丝氨酸或苏氨酸的-OH进行α-连接。其他连接包括α-连接的O-岩藻糖、β-连接的O-木糖、α-连接的O-甘露糖、β-连接的O-GlcNAc(N-乙酰葡糖胺)、α-或β-连接的O-半乳糖、以及α-或β-连接的O-葡萄糖聚糖。
根据本发明,术语“O-糖基化簇”、“O-聚糖簇”和“O-糖基化氨基酸簇”可互换使用,并且涉及两种或更多种O-糖基化氨基酸。
如本文所用的术语“唾液酸化”是指已经与唾液酸或其衍生物反应的分子,特别是聚糖。
与“包括”,“含有”或“特征在于”同义的过渡术语“包含”是包含性的或开放式的,并且不排除另外的、未列举的元素或方法步骤。过渡短语“由......组成”不包括权利要求中未指定的任何元素、步骤或成分,除了通常与其相关的杂质。当短语“由......组成”出现在权利要求主体的一个条款中,而不是紧接在前序之后时,其仅限制该条款中陈述的元素;其他元素作为整体不排除在权利要求之外。过渡短语“基本上由......组成”将权利要求的范围限制于指定的材料或步骤“以及对要求保护的发明的基本和新颖特征没有实质影响的那些”。“‘基本上由权利要求组成’的A占据了以‘由......组成’格式书写的封闭式权利要求与以‘包含’格式书写的完全开放式权利要求之间的中间部分。”
在本发明的上下文中,出于实际原因,术语“糖基化蛋白质”如融合蛋白以单数形式使用。通常,在实践中,蛋白质存在于相同类型的蛋白质分子的组合物中。然而,在糖基化蛋白质的情况下,糖基化在组合物的每个分子中都是不相同的。例如,并非组合物的所有单个分子都可以被糖基化至100%。此外,可能出现与特定O-糖基化位点结合的聚糖的差异。因此,在本申请中,对“融合蛋白”的提及也涉及具有相同氨基酸序列但在O-聚糖结构中具有变化的融合蛋白分子的组合物。
本文所用的术语“结合亲和力”或“亲和力”表示两个分子之间的结合强度,特别是配体和蛋白质靶标。结合亲和力受两个分子之间的非共价分子间相互作用的影响,例如氢键、静电相互作用、疏水相互作用和范德华力。
本文所用的免疫应答涉及适应性或先天性免疫应答。先天性免疫反应是指非特异性防御机制,其在抗体在体内出现后立即或数小时内被激活。这些机制包括物理障碍,如皮肤、血液中的化学物质、以及攻击体内外来细胞的免疫系统细胞。先天性免疫应答被抗原的化学特性激活。适应性免疫应答是指抗原特异性免疫应答。为此,首先必须加工和识别抗原。一旦抗原被识别,适应性免疫系统就会产生大量专门设计用于攻击该抗原的免疫细胞。
融合蛋白
根据第一方面,本发明提供了一种融合蛋白,其包含主要蛋白质和至少一个延伸肽,其中主要蛋白质的氨基酸序列与哺乳动物蛋白质或其片段的氨基酸序列相同或相似,并且所述延伸肽包含O-糖基化氨基酸簇。
本发明人已经鉴定了导致半衰期增加的蛋白质修饰,即添加含有O-糖基化氨基酸簇的延伸肽。如实施例中所示,人VWF的O-糖基化簇1作为延伸肽与VWF片段的融合导致仅与VWF片段(OCTA 11)相比具有增加的半衰期的融合蛋白(OCTA 12)。
半衰期(t1/2)可以通过各个血浆浓度-时间曲线的对数线性部分的线性回归分析或通过非线性回归使用一相指数衰减模型来计算。用于计算的示例性软件程序是GraphPadPrism版本6.07(La Jolla,CA 92037USA)和WinNonlin,版本6.4(Pharsight Corporation,Mountain View,CA,USA)。
计算基于以下等式:
Kel=消除率常数
t1/2=消除半衰期
c=浓度
t=时间
因此,根据一个实施例,与不含延伸肽的主要蛋白质相比,融合蛋白具有增加的半衰期。
由于可以增加具有衍生自VWF的糖基化氨基酸簇的VWF片段的半衰期,因此发明人已经确定了半衰期延长的新原理。即,通过添加也存在于天然存在的蛋白质中的O-糖基化氨基酸簇增加蛋白质或蛋白质片段的半衰期。
因此,根据融合蛋白的一个实施例,一个或多个延伸肽的氨基酸序列与所述哺乳动物蛋白的一部分相同或相似。该哺乳动物蛋白质部分特别是非重复氨基酸序列。
如本文所用的非重复氨基酸序列是在根据本发明的天然存在的哺乳动物蛋白中仅在一个拷贝中发现的序列。因此,非重复氨基酸序列明确排除了蛋白质中天然存在的任何重复序列。如果序列由超过20个氨基酸,优选地超过15个氨基酸,更优选地超过10个氨基酸组成,则序列被特别认为是重复的,并且哺乳动物蛋白含有多于一个该序列。
重复序列可以衍生自所谓的可变数目的串联重复。可变数目的串联重复(VNTR)是基因组中的位置,其中短核苷酸序列被组织为“串联重复”。当重复一个或多个核苷酸的模式并且重复彼此直接相邻时,在DNA中发生“串联重复”。VNTR存在于许多染色体上,并且通常在个体之间显示出长度的变化。在串联重复位于蛋白质编码DNA序列中的情况下,这些串联重复导致氨基酸序列重复。实例是在粘蛋白家族的所有成员中发现的串联重复。粘蛋白是由动物界的大多数生物体中的上皮组织产生的高分子量、高度糖基化的蛋白质家族。根据本发明的非重复氨基酸序列明确地排除了这种氨基酸序列串联重复,特别是粘蛋白串联重复。
延伸肽不仅可以衍生自与主要蛋白质相同的哺乳动物蛋白质,更具体地可以包含也存在于主要蛋白质中的一部分。因此,根据一个实施例,一个或多个延伸肽的氨基酸序列与所述主要蛋白质的非重复氨基酸序列部分是相同或相似的。
优选地,一个或多个延伸肽不衍生自绒毛膜促性腺激素β-亚基(CG-β)。绒毛膜促性腺激素β-亚基的C-末端肽(CTP)显示出增加其他蛋白质如FSH、FVIIa和FIX的半衰期。然而,对于hCG被描述为具有另外的CTP,即多于一个CTP拷贝的情况,该蛋白质被特别排除在本发明的主题之外。因此,特别地,延伸肽与CG-β的CTP是不相同或不相似的。
根据本发明,氨基酸序列附近的两个或更多个O-糖基化氨基酸被认为是簇。因此,根据融合蛋白的一个实施例,至少一个延伸肽的O-糖基化氨基酸簇含有至少两个O-糖基化氨基酸。该簇可含有例如2、3、4、5、6、7、8、9、10、11、12、13、14或15个O-糖基化氨基酸。
根据理论,半衰期延长效应是基于O-聚糖的负电荷。因此,半衰期延长效应应随着簇中O-糖基化氨基酸的数量而增加。因此,簇优选地含有至少三个O-糖基化氨基酸。如实施例中所示,使用具有四个O-糖基化氨基酸簇的延伸肽实现显著的半衰期扩展效应。因此,根据优选的实施例,该簇含有至少四个O-糖基化氨基酸。
除了簇的O-糖基化氨基酸外,还可以存在N-糖基化氨基酸。优选地,在O-糖基化簇中没有N-糖基化氨基酸。
在存在多于一个延伸肽的情况下,延伸肽的簇可具有不同数量的O-糖基化氨基酸。例如,融合蛋白可含有一个具有两个O-糖基化氨基酸的簇和具有四个O-糖基化氨基酸的第二簇。此外,一个簇可含有三个O-糖基化位点和另外四个O-糖基化位点。
延伸肽的O-糖基化氨基酸可以是粘蛋白型O-糖基化氨基酸丝氨酸(Ser)和苏氨酸(Thr)。然而,O-糖基化酪氨酸(Tyr)、羟基赖氨酸(羟基-Lys)或羟基脯氨酸(羟基-Pro)也是本领域已知的。因此,融合蛋白中的一个或多个O-糖基化氨基酸,特别是在延伸肽中,可以选自Ser、Thr、Tyr、羟基-Lys和羟基-Pro。
导致所述片段的半衰期延长的与OCTA 12中的VWF片段融合的延伸肽含有O-糖基化苏氨酸残基和丝氨酸残基。因此,根据第一方面的一个实施例,O-糖基化氨基酸簇含有至少一个O-糖基化苏氨酸。优选地,所述簇包含苏氨酸和丝氨酸作为O-糖基化氨基酸。有趣地是,OCTA 12的延伸肽含有两个邻位O-糖基化苏氨酸残基。因此,在一个实施例中,延伸肽含有至少两个邻位O-糖基化苏氨酸残基。
如上所述,据信由O-聚糖产生的蛋白质表面的负电荷导致半衰期延长。不希望受理论束缚,据信为了表现该效应,需要两个或更多个紧邻的O-聚糖。如果O-聚糖之间的间隙太大,即在15个氨基酸中具有少于一个O-糖基化氨基酸,则该效应可能变弱或消失。因此,根据融合蛋白的一个实施例,至少一个延伸肽在15个氨基酸中含有至少一个O-糖基化氨基酸。
更优选地,至少一个延伸肽在10个氨基酸中含有至少一个O-糖基化位点。如实例中所示,测试的延伸肽含有在8个氨基酸中具有一个O-糖基化位点的簇。因此,根据优选的实施例,一个或多个簇在8个氨基酸中含有至少一个糖基化位点。
延伸肽的长度由两个不同方面限定。延伸肽必须足够长以含有促进O-糖基化氨基酸糖基化的识别位点。因此,延伸肽的长度应为至少10个氨基酸。另一方面,延伸肽越短,其越不可能干扰结构完整性或活性,从而影响主要蛋白质的治疗效果。因此,延伸肽不应超过100个氨基酸。根据一个实施例,一个或多个延伸肽的长度为15至60个氨基酸。为了使延伸肽内四个氨基酸被O-糖基化,长度优选地为22至40个氨基酸。更优选地,延伸肽的长度约为OCTA 12中延伸肽的长度,即26至36个氨基酸。根据一个实施例,一个或多个延伸肽具有约31个氨基酸的长度。
本发明人的发现并非仅导致了添加蛋白质中天然存在的O-糖基化肽的一个或多个拷贝以增加相同蛋白质或其片段的半衰期的原理的结论。除此之外,所提出的结果使人相信:VWF的特定O-糖基化肽——与CTP类似地——可以增加其他蛋白质(也就是普通蛋白质)的半衰期。
因此,根据一个实施例,一个或多个延伸肽与人VWF的O-糖基化肽具有至少90%的序列同一性。该人VWF衍生的延伸肽可以与其他哺乳动物蛋白或其片段如FVIII融合。一个或多个延伸肽与人VWF的O-糖基化肽的序列同一性优选地为至少95%。更优选地,序列同一性为至少98%。最优选地,延伸肽的序列与人VWF的O-糖基化肽相同。
人VWF的O-糖基化肽优选地包括VWF的至少部分O-糖基化簇2(SEQ ID NO:2的氨基酸1238-1268):QEPGGLVVPPTDAPVSPTTLYVEDISEPPLH(SEQ ID NO:1)或其变体。因此,根据一个实施例,延伸肽与SEQ ID NO:1具有至少90%的序列同一性。与SEQ ID NO:1的序列同一性优选地为至少95%。更优选地,延伸肽与SEQ ID NO:1的序列同一性为至少98%。最优选地,一个或多个延伸肽与SEQ ID NO:1具有100%的序列同一性。
主要蛋白质基于哺乳动物蛋白质,即含有与哺乳动物蛋白质或其片段相似或相同的氨基酸序列。哺乳动物蛋白质特别是人蛋白质。
与主要蛋白质的氨基酸序列相似或相同的哺乳动物蛋白质可以是糖基化蛋白质。根据融合蛋白的一个实施例,主要蛋白质包含哺乳动物蛋白质的糖基化部分。根据另一个实施例,主要蛋白质包含至少一个O-糖基化氨基酸簇。该O-糖基化氨基酸簇可以与延伸肽中的O-糖基化氨基酸簇相同。
主要蛋白质所基于的哺乳动物蛋白质更优选地为血液蛋白质。根据一个实施例,哺乳动物蛋白质是人血液蛋白质。
哺乳动物血液蛋白可以是血液凝固因子、转运蛋白、蛋白酶抑制剂、免疫球蛋白、细胞相关血浆蛋白、载脂蛋白、补体因子、生长因子、抗血管生成蛋白、高度糖基化蛋白、血液因子或其他血液蛋白质。
血液凝固因子,特别是人血液凝固因子,优选地选自纤维蛋白原(FI)、凝血酶原(FII)、组织因子(FIII)、FV、FVII、FVIII、FIX、FX、FXI、FXII、FXIII、VWF、以及ADAMTS13。
应理解,凝血因子FI、FII、FV、FVII、FVIII、FIX、FX、FXI、FXII和FXIII可以是非活性或活化形式。因此,在本发明的上下文中,对FI、FII、FV、FVII、FVIII、FIX、FX、FXI、FXII和FXIII的提及分别包括活化形式FIa(纤维蛋白)、FIIa(凝血酶)、Fva、FIXa、FVIIa、FVIIIa、Fxa、FXIa、FXIIa和FXIIIa,除非另有明确说明,或根据上下文在逻辑上排除活化形式。因此,例如,在这种情况下,FI、FII、FV、FIX、FVII、FVIII、FX、FXI、FXII和FXIII可以被读作FI/FIa、FII/FIIa、FV/FVa、FVII/FVIIa、FVIII/FVIIIa、FIX/FXIa、FX/FXa、FXI/FXIa、FXII/FXIIa和FXIII/FXIIIa。
转运蛋白,特别是人转运蛋白,可选自白蛋白、转铁蛋白、铜蓝蛋白、触珠蛋白、血红蛋白和血红素结合蛋白。
根据一个实施例,哺乳动物蛋白质是蛋白酶抑制剂,特别是人蛋白酶抑制剂。该蛋白酶抑制剂的实例是β-抗凝血酶、α-抗凝血酶、前潜抗凝血酶、氧化抗凝血酶、2-巨球蛋白、C1-抑制剂、组织因子途径抑制剂(TFPI)、肝素辅助因子II、蛋白C抑制剂(PAI-3)、蛋白质C、蛋白质S和蛋白质Z。
免疫球蛋白的实例例如多克隆抗体(IgG)、单克隆抗体、IgG1、IgG2、IgG3、IgG4、IgA、IgA1、IgA2、IgM、IgE、IgD和本琼氏蛋白。
细胞相关的血浆蛋白可以是例如纤连蛋白、血栓球蛋白或血小板因子4。载脂蛋白的实例是apo A-I、apo A-II和apo E。
根据本发明的补体因子是例如因子B、因子D、因子H、因子I、C3b-灭活剂、备解素、C4结合蛋白等。
生长因子的实例包括血小板衍生生长因子(PDGF)、表皮生长因子(EGF)、转化生长因子α(TGF-α)、转化生长因子β(TGF-α)、成纤维细胞生长因子(FGF)和肝细胞生长因子(HGF)。
抗血管抑制蛋白包括潜抗凝血酶、前潜抗凝血酶、氧化抗凝血酶和纤溶酶原。
高度糖基化的蛋白质的实例是α-1-酸性糖蛋白、抗胰凝乳蛋白酶、内-α-胰蛋白酶抑制剂、α-2-HS糖蛋白、C-反应蛋白。血液因子可以是例如红细胞生成素、干扰素、肿瘤因子、tPA或gCSF。
其他人血蛋白包括富含组氨酸的糖蛋白、甘露聚糖结合凝集素、C4结合蛋白、纤连蛋白、GC-球蛋白、纤溶酶原/纤溶酶、α-1微球蛋白、C-反应蛋白。
哺乳动物蛋白质特别选自人VWF、纤维蛋白原、凝血酶原、FIII、FV、FVII、FVIII、FIX、FX、FXI、FXII、FXIII、ADAMTS13、抗凝血酶、α-1抗胰蛋白酶、C1-抑制剂、抗胰凝乳蛋白酶、PAI-1、PAI-3、2-巨球蛋白、TFPI、肝素辅因子II、蛋白Z、蛋白C和蛋白S。
人体中的因子VIII由F8基因编码,F8基因在六个外显子中包含187,000个碱基对。转录的mRNA具有9,029个碱基对的长度并且被翻译成从中除去19个氨基酸的具有2,351个氨基酸的蛋白质。人体中的FVIII分子在31个氨基酸上糖基化,其中25个N-糖基化和6个O-糖基化(参见Kannicht等,2013)。
翻译后,氨基酸链在多个位置处被特异性蛋白酶切割,导致形成具有约200kDa的重链和具有约80kDa的轻链的。结构域组织通常表征为A1-A2-B-A3-C1-C2。轻链由结构域A3-C1-C2组成。重链主要由结构域A1-A2-B组成。在血浆中发现的重链具有分子量在90至200kDa范围内的不均匀组成。其原因是其糖基化的异质性,剪接变体的存在和蛋白水解产物的存在,例如B结构域耗尽的重链A1-A2。全长FVIII的氨基酸序列由UniProtKB的P00451的氨基酸20至2,351,1986年7月21日的序列版本1(在下面的UniProtKB P00451.1中)鉴定。
根据一个实施例,与主要蛋白质相似或相同的哺乳动物蛋白质是由UniProtKBP00451.1的氨基酸20至2,351鉴定的人全长FVIII。根据另一个实施例,主要蛋白质是FVIII,其中缺失至少部分B结构域。在这方面,可能缺失整个B结构域。B结构域的缺失部分任选地被接头替换。接头序列特别具有以下氨基酸序列SFSQNSRHQAYRYRRG(SEQ ID NO:12)。其中B结构域被接头替换的FVIII的实例是Simoctocogα、或的活性成分。Simoctocogα具有以下序列:
ATRRYYLGAVELSWDYMQSDLGELPVDARFPPRVPKSFPFNTSVVYKKTLFVEFTDHLFNIAKPRPPWMGLLGPTIQAEVYDTVVITLKNMASHPVSLHAVGVSYWKASEGAEYDDQTSQREKEDDKVFPGGSHTYVWQVLKENGPMASDPLCLTYSYLSHVDLVKDLNSGLIGALLVCREGSLAKEKTQTLHKFILLFAVFDEGKSWHSETKNSLMQDRDAASARAWPKMHTVNGYVNRSLPGLIGCHRKSVYWHVIGMGTTPEVHSIFLEGHTFLVRNHRQASLEISPITFLTAQTLLMDLGQFLLFCHISSHQHDGMEAYVKVDSCPEEPQLRMKNNEEAEDYDDDLTDSEMDVVRFDDDNSPSFIQIRSVAKKHPKTWVHYIAAEEEDWDYAPLVLAPDDRSYKSQYLNNGPQRIGRKYKKVRFMAYTDETFKTREAIQHESGILGPLLYGEVGDTLLIIFKNQASRPYNIYPHGITDVRPLYSRRLPKGVKHLKDFPILPGEIFKYKWTVTVEDGPTKSDPRCLTRYYSSFVNMERDLASGLIGPLLICYKESVDQRGNQIMSDKRNVILFSVFDENRSWYLTENIQRFLPNPAGVQLEDPEFQASNIMHSINGYVFDSLQLSVCLHEVAYWYILSIGAQTDFLSVFFSGYTFKHKMVYEDTLTLFPFSGETVFMSMENPGLWILGCHNSDFRNRGMTALLKVSSCDKNTGDYYEDSYEDISAYLLSKNNAIEPRSFSQNSRHQAYRYRRGEITRTTLQSDQEEIDYDDTISVEMKKEDFDIYDEDENQSPRSFQKKTRHYFIAAVERLWDYGMSSSPHVLRNRAQSGSVPQFKKVVFQEFTDGSFTQPLYRGELNEHLGLLGPYIRAEVEDNIMVTFRNQASRPYSFYSSLISYEEDQRQGAEPRKNFVKPNETKTYFWKVQHHMAPTKDEFDCKAWAYFSDVDLEKDVHSGLIGPLLVCHTNTLNPAHGRQVTVQEFALFFTIFDETKSWYFTENMERNCRAPCNIQMEDPTFKENYRFHAINGYIMDTLPGLVMAQDQRIRWYLLSMGSNENIHSIHFSGHVFTVRKKEEYKMALYNLYPGVFETVEMLPSKAGIWRVECLIGEHLHAGMSTLFLVYSNKCQTPLGMASGHIRDFQITASGQYGQWAPKLARLHYSGSINAWSTKEPFSWIKVDLLAPMIIHGIKTQGARQKFSSLYISQFIIMYSLDGKKWQTYRGNSTGTLMVFFGNVDSSGIKHNIFNPPIIARYIRLHPTHYSIRSTLRMELMGCDLNSCSMPLGMESKAISDAQITASSYFTNMFATWSPSKARLHLQGRSNAWRPQVNNPKEWLQVDFQKTMKVTGVTTQGVKSLLTSMYVKEFLISSSQDGHQWTLFFQNGKVKVFQGNQDSFTPVVNSLDPPLLTRYLRIHPQSWVHQIALRMEVLGCEAQDLY(SEQ ID NO:13)
VWF是一种存在于哺乳动物血浆中的多聚体粘附糖蛋白,其具有多种生理功能。在止血初期,VWF充当血小板表面上的特定受体与细胞外基质的组分如胶原蛋白之间的介质。此外,VWF用作促凝血因子VIII的载体和稳定蛋白。VWF在内皮细胞和巨核细胞中合成为2813个氨基酸的前体分子。
VWF的结构域组织通常表征为Til3-D3-TIL4-A1-A2-A3-D4-C1-C2-C3-CK。
前体多肽(前体Pro-VWF)由22个残基的信号肽,741个残基的前肽(结构域D1-D2)和在成熟血浆血管性血友病因子中发现的2050个残基的多肽组成(Fischer等,1994)。全长VWF由UniprotKB的条目P04275(2017年4月12日的条目版本224)鉴定。
根据本发明的人VWF具有所述UniprotKB P04275中任何序列的氨基酸序列,特别是SEQ ID NO:2(同种型1)。VWF含有两个O-糖基化氨基酸簇。在SEQ ID NO:2的氨基酸1238至1268之间发现第一O-糖基化氨基酸簇。第二簇包括SEQ ID NO:2的氨基酸1468至1487。
在分泌到血浆中时,VWF以具有不同分子大小的各种物种的形式循环。这些VWF分子由2050个氨基酸残基的成熟亚基的寡聚体和多聚体组成。VWF通常可以在血浆中被发现为大小约500至20,000kDa的多聚体(Furlan等,1996)。
根据一个实施例,主要蛋白质具有与人成熟VWF的序列相同或相似的氨基酸序列。
根据另一个实施例,主要蛋白质具有与人VWF片段的序列相似或相同的氨基酸序列。
例如,在人VWF的片段中,相对于人成熟VWF(Til3-D3-TIL4-A1-A2-A3-D4-C1-C2-C3-CK),可能缺失结构域A1、A2、A3、D4、C1、C2、C3、CK中的一个或多个。片段VWF片段可以例如具有选自Til3-D3-TIL4-A1、Til3-D3-TIL4-A1-A2、Til3-D3-TIL4-A1-A2-A3、Til3-D3-TIL4-A1-A2-A3-D4、Til3-D3-TIL4-A1-A2-A3-D4-C1、Til3-D3-TIL4-A1-A2-A3-D4-C1-C2、以及Til3-D3-TIL4-A1-A2-A3-D4-C1-C2-C3-CK的结构域组织。
在这方面,人VWF的片段尤其是以SEQ ID NO:2的氨基酸764开始的片段。SEQ IDNO:2的氨基酸764至1035包含VWF的FVIII结合结构域。
主要蛋白质可以例如含有WO 2015/185758A2中定义的VWF片段。如WO2015/185758A2中所示,与单独FVIII相比,FVIII和其中定义的VWF片段的复合物表现出与磷脂膜的结合降低,并且与FVIII和全长VWF的复合物相比,表现出与胶原III和肝素的结合降低。
优选地以SEQ ID NO:2的氨基酸764开始的VWF片段优选地以SEQ ID NO:2的1905至2153范围内的氨基酸终止。根据一个实施例,VWF片段以SEQ ID NO:2的2030至2153范围内的VWF的氨基酸终止。根据另一个实施例,VWF片段以SEQ ID NO:2的2100至2153范围内的氨基酸终止。
根据一个实施例,主要蛋白质具有与SEQ ID NO:2的氨基酸764至1268相似或相同的氨基酸序列。根据一个实施例,主要蛋白质的氨基酸序列与SEQ ID NO:2的氨基酸764至1268具有至少90%的同一性。主要蛋白质的氨基酸序列也可以与SEQ ID NO:2的氨基酸764至1268具有至少95%的同一性。此外,主要蛋白质的氨基酸序列与SEQ ID NO:2的氨基酸764至1268的同一性可以是至少98%。特别地,主要蛋白质的氨基酸序列可以与SEQ ID NO:2的氨基酸764至1268具有100%的同一性。
根据一个实施例,主要蛋白质具有与SEQ ID NO:2的氨基酸764至1905相似或相同的氨基酸序列。根据一个实施例,主要蛋白质的氨基酸序列与SEQ ID NO:2的氨基酸764至1905具有至少90%的同一性。主要蛋白质的氨基酸序列也可以与SEQ ID NO:2的氨基酸764至1905具有至少95%的同一性。此外,主要蛋白质的氨基酸序列与SEQ ID NO:2的氨基酸764至1905的同一性可以是至少98%。特别地,主要蛋白质的氨基酸序列可以与SEQ ID NO:2的氨基酸764至1905具有100%的同一性。
融合蛋白可含有任何数量的延伸肽,例如一个、两个、三个、四个、五个、六个、七个、八个、九个或十个延伸肽。与VWF片段OCTA 11相比,融合蛋白OCTA 12含有两个延伸肽拷贝并显示出半衰期的显著增加。因此,根据一个实施例,融合蛋白含有至少两个延伸肽。
目前应理解,半衰期延长效应至少部分地基于延伸肽的O-聚糖的负电荷。因此,延伸肽拷贝数量的增加导致半衰期延长效应的进一步增加。这由OCTA 14证实,OCTA 14含有四个延伸肽拷贝。因此,根据一个实施例,融合蛋白含有至少四个延伸肽。
另一方面,利用延伸肽的拷贝数量,延伸肽干扰结构完整性或活性以及因此主要蛋白质的治疗效果的机会增加。因此,根据一个实施例,延伸肽的数量低于11。
除主要蛋白质和延伸肽外,融合蛋白可包含其他肽组分。特别地,除了根据本发明的延伸肽之外,融合蛋白可以含有用于半衰期延长的其他肽,例如CTP、XTEN、转铁蛋白或其片段、白蛋白或其片段。
主要蛋白质也可能是哺乳动物蛋白质的片段,融合蛋白质含有相同哺乳动物蛋白质的另一片段。特别地,两个片段被一个或多个延伸肽分开。这种蛋白质的实例是OCTA 15,其含有VWF的氨基酸764至1268,两个具有序列SEQ ID NO:1的延伸肽和由SEQ ID NO:2的氨基酸2721至2813组成的VWF的“半胱氨酸结结构域”。
在融合蛋白中,一个或多个延伸肽可以与主要蛋白质的N-末端或C-末端连接。具体地,融合蛋白可含有一个或多个与N-末端连接的延伸肽和一个或多个与主要蛋白质的C-末端连接的延伸肽。
由于融合蛋白除主要蛋白质和一个或多个延伸肽外还可含有其他肽。因此,延伸肽可以直接或间接地与主要蛋白质连接。在这方面,“直接连接”是指主要蛋白质和延伸肽的氨基酸序列直接相邻。“间接连接”是指在主要蛋白质与延伸肽之间存在另外的肽。特别地,接头肽可位于主要蛋白质与延伸肽之间。接头可含有切割位点,使得延伸肽可从主要蛋白质切割。
主要蛋白质,一个或多个延伸肽和任选地其他肽可以通过连接基因、cDNA或编码它们的序列来产生。因此,主要蛋白质,一个或多个延伸肽和任选地其他肽通过肽键连接。根据本发明,融合蛋白的肽可以另通过其他接头如化学接头或糖苷键连接。优选地,融合蛋白的肽通过肽键连接。
根据一个实施例,延伸肽与主要蛋白质的C末端直接连接。特别地,融合蛋白含有至少两个与主要蛋白质的C末端连接的连续延伸肽。
融合蛋白可以与两个或多个亲和标签连接。亲和标签的实例是聚组氨酸、蛋白A、谷胱甘肽S转移酶、P物质、FLAG、链霉抗生物素蛋白和免疫球蛋白重链恒定区。虽然亲和标签通常形成完整构建体的氨基酸序列的一部分,但亲和标签不被认为是融合蛋白的一部分。一个或多个亲和标签优选地与融合蛋白的C-末端或N-末端连接。在融合蛋白与一个或多个亲和标签连接的情况下,融合蛋白优选地在亲和标签与蛋白质的其余部分之间含有切割位点,使亲和标签可切割,例如利用蛋白酶切割。
根据一个实施例,一个延伸肽形成融合蛋白的N-末端。如上所述,所述延伸肽的N-末端氨基酸任选地与亲和标签连接。根据一个实施例,一个延伸肽形成融合蛋白的C末端。如上所述,所述延伸肽的C-末端氨基酸任选地与亲和标签连接。
根据一个实施例,根据前述权利要求中任一项的融合蛋白,其中与主要蛋白质相比,融合蛋白包含至少4个,优选地至少8个,更优选地至少12个额外的O-聚糖。
根据一个实施例,融合蛋白包含二聚化结构域;特别地,主要蛋白质包含二聚化结构域。在VWF中,二聚体通过CK-结构域的结合而形成。因此,在主要蛋白质是VWF片段的情况下,其优选地包含CK-结构域。
根据本发明的代表性融合蛋白是OCTA 12。OCTA 12具有以下氨基酸序列(SEQ IDNO:3):
OCTA 12是SEQ ID NO:2的氨基酸764至1268的VWF片段和两个与C-末端结合的由SEQ ID NO:2的氨基酸1238至1268组成的延伸肽拷贝(粗体)的融合蛋白。
根据一个实施例,融合蛋白的氨基酸序列与SEQ ID NO:3具有至少90%的同一性。融合蛋白的氨基酸序列也可以与SEQ ID NO:3具有至少95%的同一性。此外,融合蛋白的氨基酸序列与SEQ ID NO:3的同一性可以是至少98%。特别地,融合蛋白的氨基酸序列可以与SEQ ID NO:3具有100%的同一性。
以下序列(SEQ ID NO:4)代表具有另外12个氨基酸信号肽(粗体和下划线)的OCTA12。该肽的表达提供OCTA 12的单体形式。信号肽被切除。
根据一个实施例,融合蛋白的氨基酸序列与SEQ ID NO:4具有至少90%的同一性。融合蛋白的氨基酸序列也可以与SEQ ID NO:4具有至少95%的同一性。此外,融合蛋白的氨基酸序列与SEQ ID NO:4的同一性可以是至少98%。特别地,融合蛋白的氨基酸序列可以与SEQ ID NO:4具有100%的同一性。
根据本发明的另一种代表性融合蛋白是包括具有信号肽(粗体和下划线)的OCTA12和前肽(粗体)的Pro-OCTA 12。Pro-OCTA 12由SEQ ID NO:5鉴定:
Pro-OCTA 12的表达导致二聚体的形成。肽二聚体在切割前肽后保留。
根据一个实施例,融合蛋白的氨基酸序列与SEQ ID NO:5具有至少90%的同一性。融合蛋白的氨基酸序列也可以与SEQ ID NO:5具有至少95%的同一性。此外,融合蛋白的氨基酸序列与SEQ ID NO:5的同一性可以是至少98%。特别地,融合蛋白的氨基酸序列可以与SEQ ID NO:5具有100%的同一性。
根据本发明的另一种代表性融合蛋白是OCTA 14。OCTA 14具有以下氨基酸序列:
OCTA 14是SEQ ID NO:2的氨基酸764至1268的VWF片段和四个与C-末端结合的由SEQ ID NO:2的氨基酸1238至1268组成的延伸肽拷贝(粗体)的融合蛋白。
根据一个实施例,融合蛋白的氨基酸序列与SEQ ID NO:6具有至少90%的同一性。融合蛋白的氨基酸序列也可以与SEQ ID NO:6具有至少95%的同一性。此外,融合蛋白的氨基酸序列与SEQ ID NO:6的同一性可以是至少98%。特别地,融合蛋白的氨基酸序列可以与SEQ ID NO:6具有100%的同一性。
以下序列(SEQ ID NO:7)代表具有另外的12个氨基酸信号肽(粗体和下划线)的OCTA 14。该肽的表达提供OCTA 14的单体形式。信号肽被切除。
根据一个实施例,融合蛋白的氨基酸序列与SEQ ID NO:7具有至少90%的同一性。融合蛋白的氨基酸序列也可以与SEQ ID NO:7具有至少95%的同一性。此外,融合蛋白的氨基酸序列与SEQ ID NO:7的同一性可以是至少98%。特别地,融合蛋白的氨基酸序列可以与SEQ ID NO:7具有100%的同一性。
根据本发明的另一种代表性融合蛋白是包括具有信号肽(粗体和下划线)的OCTA14和前肽(粗体)的Pro-OCTA14。Pro-OCTA 14由SEQ ID NO:8鉴定:
根据一个实施例,融合蛋白的氨基酸序列与SEQ ID NO:8具有至少90%的同一性。融合蛋白的氨基酸序列也可以与SEQ ID NO:8具有至少95%的同一性。此外,融合蛋白的氨基酸序列与SEQ ID NO:8的同一性可以是至少98%。特别地,融合蛋白的氨基酸序列可以与SEQ ID NO:8具有100%的同一性。
根据本发明的另一种代表性融合蛋白是OCTA 15。OCTA 15具有以下氨基酸序列:
OCTA 15是SEQ ID NO:2的氨基酸764至1268的VWF片段,两个与C-末端结合的由SEQ ID NO:2的氨基酸1238至1268组成的延伸肽拷贝(粗体)和由SEQ ID NO:2的氨基酸2721至2813组成的VWF的“半胱氨酸结结构域”的融合蛋白。
根据一个实施例,融合蛋白的氨基酸序列与SEQ ID NO:9具有至少90%的同一性。融合蛋白的氨基酸序列也可以与SEQ ID NO:9具有至少95%的同一性。此外,融合蛋白的氨基酸序列与SEQ ID NO:9的同一性可以是至少98%。特别地,融合蛋白的氨基酸序列可以与SEQ ID NO:9具有100%的同一性。
以下序列(SEQ ID NO:10)代表具有另外的12个氨基酸信号肽(粗体和下划线)的OCTA 15。该肽的表达提供OCTA 15的二聚体形式。信号肽被切除。
根据一个实施例,融合蛋白的氨基酸序列与SEQ ID NO:10具有至少90%的同一性。融合蛋白的氨基酸序列也可以与SEQ ID NO:10具有至少95%的同一性。此外,融合蛋白的氨基酸序列与SEQ ID NO:10的同一性可以是至少98%。特别地,融合蛋白的氨基酸序列可以与SEQ ID NO:10具有100%的同一性。
根据本发明的另一种代表性融合蛋白是包括具有信号肽(粗体和下划线)的OCTA15和前肽(粗体)的Pro-OCTA 15。该序列的表达将导致多聚体的形成。Pro-OCTA 15由SEQ ID NO:11鉴定:
根据一个实施例,融合蛋白的氨基酸序列与SEQ ID NO:11具有至少90%的同一性。融合蛋白的氨基酸序列也可以与SEQ ID NO:11具有至少95%的同一性。此外,融合蛋白的氨基酸序列与SEQ ID NO:11的同一性可以是至少98%。特别地,融合蛋白的氨基酸序列可以与SEQ ID NO:11具有100%的同一性。
根据本发明的一个实施例,融合蛋白是基于具有两个或更多个延伸肽拷贝的Simoctocogα的修饰的FVIII蛋白。
在该实施例中,主要蛋白质优选地与FVIII的重链相同或相似,特别是与UniprotKB P00451.1的氨基酸20至759相同或相似。具有与FVIII的重链,特别是UniprotKBP00451.1的氨基酸20至759相同或相似的主要蛋白质的融合蛋白,优选地另外含有与SEQID NO:12相似或相同的接头和与UniprotKB条目P0045.1的氨基酸1668至2351所鉴定的轻链相似或相同的另外的氨基酸序列。
延伸肽可以与轻链的C-末端融合。替代地,延伸肽位于重链与轻链之间。在这方面,延伸肽可以连接到接头的C-末端或N-末端。延伸肽也可以替换接头。此外,接头序列可以被一个或多个延伸肽中断。延伸肽也可能位于重链与轻链之间以及轻链的C-末端。
优选地,基于Simoctocogα的融合蛋白从N-末端到C-末端含有FVIII的重链,接头的第一部分,两个或更多个,优选地三个延伸肽(粗体),接头的第二部分(带下划线和粗体)和轻链。这种蛋白质的一个实例是由SEQ ID NO:14鉴定的蛋白质:
根据一个实施例,融合蛋白的氨基酸序列与SEQ ID NO:14具有至少90%的同一性。融合蛋白的氨基酸序列也可以与SEQ ID NO:14具有至少95%的同一性。此外,融合蛋白的氨基酸序列与SEQ ID NO:14的同一性可以是至少98%。特别地,融合蛋白的氨基酸序列可以与SEQ ID NO:14具有100%的同一性。
替代地,基于Simoctocogα的融合蛋白含有两个或更多个,优选地三个连接到Simoctocogα的C-末端的延伸肽(粗体)。这种蛋白质的实例是由SEQ ID NO:21鉴定的蛋白质。根据一个实施例,融合蛋白的氨基酸序列与SEQ ID NO:21具有至少90%的同一性。融合蛋白的氨基酸序列也可以与SEQ ID NO:21具有至少95%的同一性。此外,融合蛋白的氨基酸序列与SEQ ID NO:21的同一性可以是至少98%。特别地,融合蛋白的氨基酸序列可以与SEQ ID NO:21具有100%的同一性。
多核苷酸
根据第二方面,本发明提供了一种分离的多核苷酸,其包含编码根据本发明第一方面的融合蛋白的核酸序列。
分离的多核苷酸可以是DNA分子或RNA分子。分离的多核苷酸优选地是DNA分子,特别是cDNA分子。用于分离或克隆编码肽的多核苷酸的技术是本领域已知的,包括从基因组DNA中分离,从cDNA制备,或其组合。从这种基因组DNA克隆多核苷酸可以例如通过使用众所周知的聚合酶链反应(PCR)或表达文库的抗体筛选来进行以检测具有共有结构特征的克隆DNA片段(参见例如Innis等,1990)PCR:A Guide to Methods and Application,Academic出版社,纽约。可以使用其他核酸扩增程序,例如连接酶链反应(LCR)、连接活化转录(LAT)和基于多核苷酸的扩增(NASBA)。
特别地,分离的多核苷酸的序列可包含编码主要蛋白质的第一部分和至少第二部分序列。第一部分优选地与SEQ ID NO:15相似或相同。第一部分优选地与SEQ ID NO:15具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性程度。
所述至少第二部分优选地与SEQ ID NO:16类似或相同。所述第二部分优选地与SEQ ID NO:16具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性程度。
分离的多核苷酸可以是编码融合蛋白的DNA分子,该融合蛋白的氨基酸序列与选自由SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:14和SEQ ID NO:21组成的群组的序列相似或相同。
特别地,分离的多核苷酸可以是编码融合蛋白的DNA分子,所述融合蛋白具有与SEQ ID NO:4具有至少90%、优选地至少95%、更优选地至少98%、最优选地100%的同一性的氨基酸序列。替代地,分离的多核苷酸可以是编码融合蛋白的DNA分子,所述融合蛋白具有至少90%同一性的氨基酸序列。此外,分离的多核苷酸可以是编码融合蛋白的DNA分子,所述融合蛋白具有与SEQ ID NO:5具有至少90%、优选地至少95%、更优选地至少98%、最优选地100%的同一性的氨基酸序列。根据一个实施例,分离的多核苷酸是编码融合蛋白的DNA分子,所述融合蛋白具有与SEQ ID NO:7具有至少90%、优选地至少95%、更优选地至少98%,最优选地100%的同一性的氨基酸序列。根据一个实施例,分离的多核苷酸是编码融合蛋白的DNA分子,所述融合蛋白具有与SEQ ID NO:8具有至少90%、优选地至少95%、更优选地至少98%、最优选地100%的同一性的氨基酸序列。根据一个实施例,分离的多核苷酸是编码融合蛋白的DNA分子,所述融合蛋白具有与SEQ ID NO:10具有至少90%、优选地至少95%、更优选地至少98%、最优选地100%的同一性的氨基酸序列。根据一个实施例,分离的多核苷酸是编码融合蛋白的DNA分子,所述融合蛋白具有与SEQ ID NO:11具有至少90%、优选地至少95%、更优选地至少98%、最优选地100%的同一性的氨基酸序列。根据一个实施例,分离的多核苷酸是编码融合蛋白的DNA分子,所述融合蛋白具有与SEQ ID NO:14具有至少90%、优选地至少95%、更优选地至少98%、最优选地100%的同一性的氨基酸序列。根据一个实施例,分离的多核苷酸是编码融合蛋白的DNA分子,所述融合蛋白具有与SEQ ID NO:21具有至少90%、优选地至少95%、更优选地至少98%、最优选地100%的同一性的氨基酸序列。
分离的多核苷酸可以是具有与选自由SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20和SEQ ID NO:22组成的群组的序列相似或相同的序列的DNA分子。
根据一个实施例,分离的多核苷酸的一条链与SEQ ID NO:17具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。根据另一个实施例,分离的多核苷酸与SEQ ID NO:18具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。根据又另一个实施例,分离的多核苷酸与SEQ ID NO:19具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。根据一个实施例,分离的多核苷酸与SEQ ID NO:20具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。根据一个实施例,分离的多核苷酸与SEQ ID NO:20具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。
多核苷酸序列列表:
SEQ ID NO:15编码OCTA 11的DNA(SEQ ID NO:2的AA 1-1268)
SEQ ID NO:16编码延伸肽的DNA(SEQ ID NO:1)
SEQ ID NO:17编码Pro-OCTA 12的DNA(SEQ ID NO:5)
SEQ ID NO:18编码Pro-OCTA 14的DNA(SEQ ID NO:8)
SEQ ID NO:19编码Pro-OCTA 15的DNA(SEQ ID NO:11)
SEQ ID NO:20编码在接头区域具有三个延伸肽的Simoctocogα的DNA(SEQ ID NO14)
SEQ ID NO:22编码具有三个C-末端延伸肽的Simoctocogα的DNA序列(SEQ ID NO:21)
表达载体
在第三方面中,本发明还涉及包含根据本发明第二方面的多核苷酸的表达载体。
表达载体还优选地包含控制元件如启动子,以及转录和翻译终止信号。根据第二方面的多核苷酸和控制元件可以连接在一起以产生重组表达载体,其可以包括一个或多个限制性位点以允许在这些位点插入或取代编码多肽的多核苷酸。可以将多核苷酸插入合适的表达载体中以进行表达。在产生表达载体时,编码序列位于表达载体中,使得编码序列与恰当的控制序列可操作地连接以进行表达。
重组表达载体可以是任何载体(例如,质粒或病毒),其可以方便地进行重组DNA程序并且可以实现本发明第四方面的多核苷酸的表达。表达载体的选择通常取决于表达载体与将要导入表达载体的宿主细胞的相容性。表达载体可以是线性的或闭合环状的质粒。
表达载体优选地适于在哺乳动物细胞中表达。表达载体可以是自主复制载体,即作为染色体外实体存在的载体,其复制独立于染色体复制,例如质粒、染色体外元件、微染色体或人工染色体。对于自主复制,载体可以进一步包含复制起点,使载体能够在所讨论的宿主细胞中自主复制。复制起点可以是介导在细胞中起作用的自主复制的任何质粒复制子。术语“复制起点”或“质粒复制子”是指使质粒或载体能够在体内复制的多核苷酸。
载体优选地是当导入宿主细胞中时整合到基因组中并与其整合的染色体一起复制的载体。为了整合到宿主细胞基因组中,表达载体可以依赖于表达载体的任何其他元件以通过同源或非同源重组整合到基因组中。替代地,载体可含有用于指导通过同源重组在染色体中精确位置整合到宿主细胞基因组中的另外的多核苷酸。
本发明的载体优选地含有一个或多个(例如几个)选择性标记,其允许容易地选择转化细胞、转染细胞、转导细胞或类似细胞。选择性标记是一种基因,其产物提供杀生物剂或抗病毒性,对重金属的抗性,对营养缺陷型的原养型等。
用于连接上述元件以构建本发明的重组表达载体的程序是本领域技术人员熟知的(参见,例如,Sambrook等,1989,同上)。
根据一个实施例,根据第三方面的载体的载体骨架选自pCDNA3、pCDNA3.1、pCDNA4、pCDNA5、pCDNA6、pCEP4、pCEP-puro、pCET1019、pCMV、pEF1、pEF4、pEF5、pEF6、pExchange、pEXPR、pIRES和pSCAS。
宿主细胞
根据第四方面,本发明提供了一种宿主细胞,其包含根据本发明第三方面的表达载体。将根据第三方面的表达载体导入宿主细胞中,使得表达载体维持为染色体整合体或如前所述的自我复制的染色体外载体。术语“宿主细胞”包括由于在复制过程中发生的突变而与亲本细胞不同的亲本细胞的任何后代。宿主细胞的选择在很大程度上取决于编码多肽的基因及其来源。
根据一个实施例,融合蛋白通过在哺乳动物宿主细胞系中表达而产生。融合蛋白优选地在人宿主细胞系中产生。通常,任何人宿主细胞系都适合于融合蛋白的表达。融合蛋白的有利糖基化特别地用人肾细胞系获得。优选的人肾细胞系是HEK细胞系,特别是HEK293细胞系。
用于产生糖基化多肽的HEK细胞系的实例是HEK 293F、Flp-InTM-293(Invitrogen,R75007)、293(CRL-1573)、293EBNA、293H(ThermoScientific 11631017)、293S、293T(CRL-3216TM)、293T/17(CRL11268TM)、293T/17SF(ACS4500TM)、HEK 293 STF(CRL 3249TM)、HEK-293.2sus(CRL-1573TM)。用于产生多肽的优选细胞系是HEK 293F细胞系。
适合作为表达宿主细胞的其他细胞系包括衍生自人髓细胞白血病细胞的细胞系。宿主细胞的具体实例是K562、NM-F9、NM-D4、NM-H9D8、NM-H9D8-E6、NM H9D8-E6Q12、GT-2X、GT-5s和衍生自任何所述宿主细胞的细胞。K562是存在于美国典型培养物保藏中心(ATCCCCL-243)中的人髓细胞白血病细胞系。剩余的细胞系衍生自K562细胞,并且已经加以选择用于特定的糖基化特征。
融合蛋白的用途
如实例中所示,融合蛋白OCTA 12和OCTA 14中SEQ ID NO:1的延伸肽并非仅导致融合蛋白的半衰期增加(即与主要蛋白质、即VWF片段相比)。融合蛋白OCTA 12和OCTA 14当与FVIII(VWF的结合配偶体)一起施用于患者时也会导致FVIII的半衰期增加。
因此,根据第五方面,本发明提供了根据第一方面的融合蛋白用于增加第二蛋白的半衰期的用途,其中所述融合蛋白能够结合所述第二蛋白。
该用途还可以描述为一种用治疗性蛋白质治疗患者的方法,其中该方法包括施用治疗性蛋白质如FVIII蛋白质和根据第一方面的融合蛋白。
组合物和蛋白质复合物
因此,根据本发明的概念,即由延伸肽提供的半衰期延长不限于融合蛋白,而且另外可以延长由融合蛋白结合的第二蛋白的半衰期。
因此,根据第六方面,本发明提供一种第一蛋白质和第二蛋白质的组合物,其中所述第一蛋白质是根据第一方面的融合蛋白质并且能够结合所述第二蛋白质,并且所述第二蛋白质是治疗性蛋白质,其包含与第二哺乳动物蛋白质或其片段的氨基酸序列相同或相似的氨基酸序列。
第一蛋白质可以共价或非共价结合第二蛋白质以形成复合物。因此,本发明还涉及一种第一蛋白质和第二蛋白质的复合物,其中所述第一蛋白质是根据第一方面的融合蛋白质,并且所述第二蛋白质具有与第二哺乳动物蛋白质或其片段的氨基酸序列相同或相似的氨基酸序列。因此,复合物通过第一蛋白质与第二蛋白质的非共价结合而形成。
根据一个实施例,第一蛋白质共价结合第二蛋白质。促进第一和第二蛋白质结合的接头可选自二硫键、肽键、化学接头或糖苷键。
替代地,第一蛋白质非共价结合第二蛋白质。对于非共价结合,第一蛋白质尤其可以包含特异性结合结构域,使其能够结合所述第二蛋白质,即第二蛋白质结合结构域。取决于一个或多个延伸肽在第一蛋白质序列中的位置,可以位于第一蛋白质的不同位置。优选地,一个或多个延伸肽位于暴露于折叠状态的蛋白质的表面的位置。一个或多个延伸肽可位于相对于第二蛋白质结合位点(诸如结合结构域)的任何位置。
根据组合物的一个实施例,一个或多个延伸肽位于折叠状态的第一蛋白质的不干扰第一蛋白质与第二蛋白质结合的位置。
根据一个实施例,与所述第二蛋白质的游离形式(例如FVIII蛋白)相比,结合第一蛋白质(例如VWF片段)的第二蛋白质(例如FVIII)的半衰期增加。
优选地,与结合天然哺乳动物蛋白质(例如成熟的VWF)的所述第二蛋白质相比,结合第一蛋白质(例如OCTA 12)的第二蛋白质(例如FVIII蛋白)的半衰期增加。
更优选地,与结合不具有融合肽的主要蛋白质(例如OCTA 11)的所述第二蛋白质相比,结合第一蛋白质(例如OCTA 12)的第二蛋白质(例如FVIII蛋白)的半衰期增加。
第二哺乳动物蛋白质可以选自针对上述哺乳动物蛋白质鉴定的相同列表。然而,在组合物或复合物中,第二哺乳动物蛋白质与第一哺乳动物蛋白质不同。
根据一个实施例,第二哺乳动物蛋白质是血液蛋白质,特别是人血液蛋白质。优选地,第二哺乳动物蛋白质是凝血因子,特别是人凝血因子。
根据一个实施例,与主要蛋白质相似或相同的第二哺乳动物蛋白质是由UniProtKB P00451.1的氨基酸20至2,351鉴定的人全长FVIII。根据另一实施例,主要蛋白质是FVIII,其中缺失至少部分B结构域。在这方面,可能缺失整个B结构域。B结构域的缺失部分任选地被接头替换。接头序列特别具有以下氨基酸序列SFSQNSRHQAYRYRRG(SEQ IDNO:12)。其中B结构域被接头替换的FVIII的一个实例是Simoctocogα(SEQ ID NO:13)、或的活性成分。
根据一个实施例,FVIII蛋白是人FVIII蛋白,其在患者中具有降低的免疫应答。
FVIII蛋白的免疫应答降低优选地基于与SIGLEC SIG-5、SIG-7、SIG-8和SIG-9的结合。不希望受理论束缚,据信与抗原呈递细胞(例如树突细胞)上的SIGLECS的结合导致细胞表面上的促炎受体表达的下调和免疫抑制受体表达的上调。此外,结合导致抗炎细胞因子的产生增加,降低促炎细胞因子的产生,并因此导致T细胞增殖和抗体产生受到抑制。因此,当将糖基化多肽施用于患者时,SIGLEC SIG-5、SIG-7、SIG-8和SIG-9的结合导致免疫应答降低或免疫耐受性增加。
SIGLEC结合以及因此降低的免疫应答基于与天然存在的人FVIII的唾液酸化核心2和/或扩展核心1O-聚糖的数量相比,糖基化蛋白质中唾液酸化核心2和/或扩展核心1O-聚糖的数量或百分比增加。
因此,根据一个实施例,FVIII蛋白质表现出与天然存在的人FVIII的唾液酸化核心2和/或扩展核心1O-聚糖的数量相比,糖基化蛋白质中唾液酸化核心2和/或扩展核心1O-聚糖的数量或百分比增加。
对于第二蛋白质是FVIII蛋白质的情况,第一蛋白质的主要蛋白质优选地是包含FVIII结合结构域的VWF片段,以使其能够结合FVIII蛋白质。
根据组合物的一个实施例,第一蛋白质具有与SEQ ID NO:3具有至少95%、优选地至少98%、更优选地100%的同一性的氨基酸序列,并且第二蛋白质具有与SEQ ID NO:13具有至少95%、优选地至少98%、更优选地100%的同一性的氨基酸序列。
根据组合物的一个实施例,第一蛋白质具有与SEQ ID NO:6具有至少95%、优选地至少98%、更优选地100%的同一性的氨基酸序列,并且第二蛋白质具有与SEQ ID NO:13具有至少95%、优选地至少98%、更优选地100%的同一性的氨基酸序列。
根据组合物的一个实施例,第一蛋白质具有与SEQ ID NO:9具有至少95%、优选地至少98%、更优选地100%的同一性的氨基酸序列,并且第二蛋白质具有与SEQ ID NO:13具有至少95%、优选地至少98%、更优选地100%的同一性的氨基酸序列。
因为在患者的血液中,含有VWF片段的融合蛋白,特别是OCTA 12,与内源性VWF竞争结合FVIII蛋白,所以优选地是,该组合物包含含有VWF片段的融合蛋白,特别是OCTA 12,与FVIII蛋白相比摩尔过量。
优选地,第一蛋白质与第二蛋白质的摩尔比为0.1至250,优选地0.5至50,更优选地1至25,最优选地2至10。
为了形成稳定的非共价结合的复合物,并因此允许第二蛋白质的半衰期延长,第一蛋白质与由平衡解离常数(KD)定义的第二蛋白质的结合亲和力应低于10μM。优选地,第一蛋白质中VWF片段与FVIII蛋白质的平衡解离常数为0.05至3nM。
第一和第二蛋白质可以通过单独的重组表达,然后连接而产生。替代地,第一和第二蛋白质在相同细胞中重组表达。为此,第一和第二蛋白质可以由相同的载体编码或在两个不同的载体上编码。
实例中使用的VWF构建体(即OCTA 12、OCTA 14和OCTA 15)以其前蛋白的形式表达,导致二聚体形成或在OCTA 15的情况下导致多聚体形成。即使在切割前肽后这些二聚体仍保持完整,因此二聚体中VWF构建体的每个拷贝都可以与FVIII蛋白结合。因此,根据一个实施例,复合物含有两个拷贝的第一和第二蛋白质,其中两个拷贝的第一蛋白质形成二聚体。第一蛋白质的这个二聚体优选地是非共价结合的二聚体。
药物组合物和医疗用途
如上所述,根据第一方面的融合蛋白,根据第六方面的组合物和根据本发明的第七方面的复合物具有增加患者血液中半衰期并因此增加患者治疗效果的优点。因此,根据第一方面的融合蛋白,根据第六方面的组合物和根据第七方面的复合物可特别用作医学治疗的活性成分。优选地,它们可用于治疗或预防出血性疾病。根据第一方面的融合蛋白,根据第六方面的组合物,特别是本文所述的蛋白质复合物,可以单独施用或以药物组合物的形式施用。
因此,根据第八方面,本发明提供了一种根据第一方面的融合蛋白,根据第六方面的组合物和根据第七方面的复合物的药物组合物。
根据本发明,药物组合物可包含有效量的根据第一方面的融合蛋白,根据第六方面的组合物和根据第七方面的复合物,其配制有至少一种药学上可接受的载体。可以通过药学领域熟知的任何方法制备实施例的药物组合物并将其施用于受试者。参见,例如,Goodman&Gilman’s The Pharmacological Basis of Therapeutics,Hardman等,编著,McGraw—Hill Professional(第10版,2001);Remington:The Science and Practice ofPharmacy,Gennaro,编著,Lippincott Williams&Wilkins(第20版,2003);和Pharmaceutical Dosage Forms and Drug Delivery Systems,Ansel等(编著),Lippincott Williams&Wilkins(第7版,1999)。此外,实施例的药物组合物还可以配制成包括其他医学上有用的药物或生物制剂。药物组合物通常包含治疗有效量的融合蛋白或蛋白质复合物与药学上可接受的载体。药学上可接受的载体是本领域已知或建立的任何载体。示例性的药学上可接受的载体包括无菌无热原水和无菌无热原盐水溶液。可用于本发明实施例的其他形式的药学上可接受的载体包括粘合剂、崩解剂、表面活性剂、吸收促进剂、保湿剂、吸收剂、润滑剂、填充剂、增量剂、水分赋予剂、防腐剂、稳定剂、乳化剂、增溶剂、控制渗透压的盐、通常取决于制剂的使用形式而使用的稀释剂如缓冲剂和赋形剂。它们根据所得制剂的单位剂量任选地选择和使用。
因此,本发明的第九方面还涉及一种治疗或预防患者出血性疾病的方法,所述方法包括向所述患者施用根据第八方面的药物组合物。
如本文所用,“出血性疾病”是指损害正常止血的疾病或病症。出血性疾病可以是,例如,血友病A、血友病B、因子VIII缺乏症、因子XI缺乏症、血管性血友病、Glanzmann血小板无力症、Bernard Soulier综合征、特发性血小板减少性紫癜、脑内出血、创伤、创伤性脑损伤等。
如本文所用,“血友病”是指与没有血友病的健康个体中的血凝形成时间相比血凝形成时间增加所相关的一组出血性疾病。血友病包括血友病A,这是一种导致产生缺陷因子VIII的疾病,血友病B,这是一种导致产生缺陷因子IX的疾病和获得性血友病A,这是一种由对凝血因子(F)VIII的自身抗体引起的罕见出血性疾病。
出血性疾病优选地为血友病A或B。治疗可以是例如PUPS(先前未治疗的患者)的血友病治疗或免疫耐受诱导(ITI)治疗和/或血友病的其他相关治疗。
对于体内应用,药物组合物可以通过任何常规施用途径施用给患者,例如,口服、肠胃外或吸入。肠胃外施用包括静脉内注射、皮下注射、腹膜内注射、肌内注射、液体剂、悬浮液、乳液和滴落剂。对于肠胃外施用,药物组合物应该是注射剂,例如液体剂或悬浮液。
在其他实施例中,将药物组合物口服施用给患者。在这些实施例中,药物的一种形式包括固体制剂,例如片剂、包衣片剂、粉末剂、颗粒、胶囊和丸剂、液体制剂(诸如液体剂,例如滴眼剂、滴鼻剂)、悬浮液、乳液和糖浆,吸入剂(诸如气雾剂、雾化器和喷雾器),以及脂质体包合剂。在又一些其他实施例中,糖基化多肽、蛋白质复合物或药物组合物通过吸入施用到患者的呼吸道以靶向受试者的气管和/或肺。
根据第八方面的一个实施例,所述用途包括静脉内或非静脉内注射。非静脉内注射优选地是皮下注射。
本公开中引用的所有出版物和专利均通过引用整体并入。如果通过引用并入的材料与本说明书相矛盾或不一致,则说明书将取代任何此类材料。
实例
实例1-VWF蛋白的重组表达
以下重组VWF蛋白在具有C-末端Strep标签的HEK细胞系293F中瞬时表达,并通过StrepTactin亲和层析(IBA GmbH)纯化:
-OCTA 11
-OCTA 12
OCTA 12是根据本发明的融合蛋白。OCTA 11是比较VWF片段。VWF蛋白质在图1中示意性地描绘。前蛋白的表达导致二聚体的形成。肽二聚体在切割前肽后也保留。
基因合成和克隆
作为第一步,编码VWF蛋白的前蛋白的基因由GeneArt(Thermo FisherScientific)合成:
-Pro-OCTA 11
-Pro-OCTA 12
将编码前蛋白的基因克隆到含有Twin-Strep标签的pDSG表达载体(IBA GmbH)中。TOP10大肠杆菌(IBA GmbH)的单个培养物用载体构建体转化,并在37℃下在含氨苄青霉素的LB-琼脂平板上温育过夜后选择单个克隆。
根据制造商的推荐,使用QIAamp DNA Mini或Maxi试剂盒(Qiagen)进行质粒DNA制备。通过测序,验证了载体的完整性,特别是编码Pro-OCTA 11,Pro-OCTA 12的基因的正确取向和完整性。
蛋白质表达
对于VWF蛋白的真核表达,使用4.5mg/ml 25kDa线性聚氮丙啶,用1.5mg/l构建体转染在MEXi转染培养基(IBA GmbH)中生长的MEXi-293细胞(IBA GmbH)。在37℃,5%CO2和100-150rpm温育2-4小时后,培养物用MEXi转染-培养基1:2稀释并继续培养直至细胞存活率达到75%。
随后,通过在4℃和300×g下离心将上清液与细胞分离。为了最小化生物素在细胞培养基中的抑制作用并调节pH,将0.1体积的缓冲液(1M Tris-HCl,1.5mM NaCl,10mMEDTA,pH8.0)和0.09%(v/v)BioLock溶液(IBA GmbH)加入上清液中并在4℃下温育20分钟。
蛋白质纯化
离心后,将上清液施加在Strep-Tactin XT柱(IBA GmbH)上,用洗涤缓冲液(100mMTris-HCl,150mM NaCl,1mM EDTA,pH8.0)洗涤5次,并用洗脱缓冲液(100mM Tris-HCl,150mM NaCl,1mM EDTA,10mM脱硫生物素,pH8.0)洗脱含有结合Strep-标签的蛋白质。
实例2-全长VWF或VWF蛋白当与FVIII共同施用给FVIII/VWF双敲除(DKO)小鼠时,对FVIII半衰期的影响
2.1背景
在该实验中,测试了根据实例1产生的VWF蛋白和全长血浆衍生的VWF(pdVWF)对FVIII半衰期的影响。
已知全长VWF和FVIII是形成非共价复合物的结合配偶体。FVIII在循环中的半衰期主要由VWF的循环半衰期决定。
如在血清中内源性VWF与施用的VWF蛋白(片段)竞争FVIII结合,该竞争将影响施用的VWF蛋白对FVIII半衰期的任何影响。
因此,在本实验中,将FVIII和VWF双敲除(FVIII/VWF-DKO)的C57Bl/6小鼠用作用于评估VWF对FVIII半衰期的影响的模型生物体。
2.2实验程序
2.2.1含FVIII的产品
生产以下含FVIII的产品:
1)仅FVIII
2)FVIII和OCTA 11
3)FVIII和OCTA 12
4)FVIII和pdVWF
如实例1中所述制备VWF蛋白OCTA 11和OCTA 12。pdVWF是VWF浓缩物Wilate(Octapharma)。FVIII是B结构域缺失的人细胞系FVIII(Nuwiq,Octapharma)。Nuwiq产品包含以下缓冲组成:
含有FVIII的产物2)-4)中VWF蛋白与FVIII的摩尔比为5:1。将VWF蛋白质添加至Nuwiq产物(FVIII)中。
2.2.2 FVIII/VWF-DKO小鼠品系
使用FVIII和VWF双敲除(FVIII/VWF-DKO)的C57Bl/6小鼠。
2.2.3产品的施用
通过尾静脉输注将四种含有FVIII的产物以240IU FVIII/kg(~6IU/小鼠)的剂量施用给20只FVIII/VWF-DKO小鼠。
2.2.4采样和分析
在用含有FVIII的产品治疗后5分钟和1、4、8、12、24、36和48小时取小鼠的血样。从小鼠的眼眶后丛获得血液样品。对于每个时间点,获得每个含有FVIII的产物的5只小鼠的血液样品并单独分析。每个小鼠在5分钟时间点取样并最多在另外两个时间点取样。
使用显色测定法(CHROMOGENIX)分析每个血液样品中的FVIII活性。
2.3结果
利用血液样品中的FVIII活性值,确定每种含FVIII产品的FVIII活性的时间进程,如图2所示。
对于每个时间点和含有FVIII的产品,测量五只动物的血液样品,图2中的每个数据点代表5个值的平均值。
此外,各个时间点的FVIII活性以治疗后5分钟的FVIII活性百分比给出,其定义为每种含有FVIII的产品的100%活性。
五种产品中FVIII的半衰期使用各个血浆浓度-时间曲线的对数线性部分的线性回归分析在曲线拟合后或通过非线性回归使用一相指数衰减模型来计算。用于计算的软件程序是GraphPad Prism版本6.07(La Jolla,CA 92037USA)和WinNonlin,版本6.4(Pharsight Corporation,Mountain View,CA,USA)。
计算基于以下等式:
Kel=消除率常数
t1/2=消除半衰期
c=浓度
t=时间
结果总结在表1中。
表1.DKO小鼠中FVIII的最终半衰期
含有FVIII的产品 | t<sub>1/2</sub>[h] |
1)·仅FVIII | 0.07 |
2)FVIII和OCTA 11 | 0.45 |
3)FVIII和OCTA 12 | 1.03 |
4)FVIII和flVWF | 0.32 |
从这些数值可以明显看出,FVIII与任何VWF蛋白的共同施用导致半衰期延长。FVIII与pdVWF的共同施用导致FVIII半衰期增加为~4.6倍(0.31)。
与VWF蛋白OCTA 11共同施用的FVIII显示了0.45小时的相当的半衰期(增加为约1.4倍)。
引人注目的是,与VWF蛋白OCTA 12共同施用得到1.03小时的FVIII半衰期,这表示与flVWF相比,增加为约3.2倍。与FVIII相比,该因子为14.7倍。
该结果表明,OCTA 12中存在的额外O-聚糖重复导致对VWF片段以及继而对VWF/FVIII复合物的显著半衰期延长影响。此外,该结果表明添加内在O-聚糖簇的拷贝可以增加蛋白质的半衰期。
实例3-小型猪IV和皮下(SQ)施用后FVIII和VWF OCTA 12的药代动力学特征
3.1背景
药物的皮下递送在凝血因子领域变得越来越令人关注。然而,由于回收非常低,该途径尚不适用于FVIII的施用。由于与表皮的人体结构非常相似,因此小型猪是测试药物皮下施用的最有名的动物模型。该实验的目的是评估VWF OCTA 12和FVIII当通过皮下途径对小型猪单独施用或与5倍摩尔过量的OCTA 12施用时的半衰期。此外,将FVIII当通过常规IV途径单独施用时的半衰期与在具有或不具有VWF OCTA 12下SQ施用的FVIII进行比较。
3.2实验程序
本研究使用9只年龄为10至14个月的雌性Aachener小型猪。体重在13.7与19.5kg之间。IV注射在侧耳静脉中进行,皮下注射在腹股沟区域的皮肤下进行。剂量为100UFVIII/kg BW,每组3只动物用每种产品治疗:
-第1组:仅FVIII SQ
-第2组:含OCTA 12的FVIII SQ
-第3组:仅FVIII IV
为了每只动物获得2×200μL柠檬酸钠血浆和取样时间,在以下时间点从所有动物的颈静脉收集足够的血液:每次施用后0(给药前)、0.5、1、2、4、8、24、32、48、72、96和120小时。
将全血取样至含有柠檬酸钠(0.15M)作为抗凝血剂的管中,并立即使用IsoTherm-Rack系统(Eppendorf)冷却。在抽血30分钟内通过离心分离血浆。离心后立即将血浆样品冷冻并在≤-20℃下储存直至运输。
使用Asserachrom测定试剂盒(Diagnostica Stago)测试每个样品的FVIII抗原。使用ELISA测定法如下定量OCTA 12;将XT涂布的微孔板(IBA GmbH)用封闭缓冲液(1%BSA的PBS)在室温下封闭2小时。将血浆样品在封闭缓冲液中1:15稀释并施加在平板上。在37℃温育2小时后,用抗VWF pAb(Dako P0226)检测VWF片段。每次温育后,将平板用0.1%Tween的PBS溶液洗涤3次。
使用WinNonlin,版本6.4(Pharsight Corporation,Mountain View,CA,USA)进行分析数据的药代动力学评估。
3.3结果
图3显示了SQ施用FVIII/VWF OCTA 12混合物后小型猪血浆中VWF OCTA 12浓度的时间进程。如表2所总结,OCTA 12循环,半衰期为219.31小时。如实施例2中所述测定半衰期。
表2.小型猪中VWF OCTA 12抗原的药代动力学参数。该值代表三只动物的平均值±SD。
Cmax最高测量血浆浓度
tmax Cmax的最大时间
t1/2最终半衰期
在血管性血友病(VWD)猪中,全长重组人(rhVWF)的半衰期为约10-16小时,血浆衍生的猪VWF的半衰期为10-18小时(Nichols等)。如Yee等所示,在VWF缺陷小鼠中,仅含有FVIII结合结构域的VWF片段的半衰期短于flVWF的半衰期。因此,在猪中,OCTA 12的半衰期比rhVWF的半衰期长,为约14-22倍。
此外,还观察到对FVIII半衰期的显著延长影响。如图4所示并表3中所总结,当与OCTA 12共同施用时,FVIII具有25.3小时的半衰期,与通过相同途径(SQ)单独施用的FVIII相比,其表示半衰期增加为6.7倍,与通过常规IV途径单独施用的FVIII相比,增加为3.9倍。
表3.小型猪中FVIII抗原的药代动力学参数。该值代表三只动物的平均值±SD。
本发明所属领域的技术人员将会想到本文所阐述的本发明的许多修改和其他实施例,其具有前述说明书和相关附图中呈现的教导的益处。因此,应该理解,本发明不限于所公开的特定实施例,并且修改和其他实施例旨在包括在所附权利要求的范围内。尽管本文采用了特定术语,但它们仅在一般性和描述性意义上使用,而不用于限制的目的。
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序列表
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Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser
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Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His
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Met Ile Pro Ala Arg Phe Ala Gly Val Leu Leu Ala Leu Ala Leu Ile
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Leu Pro Gly Thr Leu Cys Ala Glu Gly Thr Arg Gly Arg Ser Ser Thr
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Ala Arg Cys Ser Leu Phe Gly Ser Asp Phe Val Asn Thr Phe Asp Gly
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Ser Met Tyr Ser Phe Ala Gly Tyr Cys Ser Tyr Leu Leu Ala Gly Gly
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Cys Gln Lys Arg Ser Phe Ser Ile Ile Gly Asp Phe Gln Asn Gly Lys
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Arg Val Ser Leu Ser Val Tyr Leu Gly Glu Phe Phe Asp Ile His Leu
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Phe Val Asn Gly Thr Val Thr Gln Gly Asp Gln Arg Val Ser Met Pro
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Tyr Ala Ser Lys Gly Leu Tyr Leu Glu Thr Glu Ala Gly Tyr Tyr Lys
115 120 125
Leu Ser Gly Glu Ala Tyr Gly Phe Val Ala Arg Ile Asp Gly Ser Gly
130 135 140
Asn Phe Gln Val Leu Leu Ser Asp Arg Tyr Phe Asn Lys Thr Cys Gly
145 150 155 160
Leu Cys Gly Asn Phe Asn Ile Phe Ala Glu Asp Asp Phe Met Thr Gln
165 170 175
Glu Gly Thr Leu Thr Ser Asp Pro Tyr Asp Phe Ala Asn Ser Trp Ala
180 185 190
Leu Ser Ser Gly Glu Gln Trp Cys Glu Arg Ala Ser Pro Pro Ser Ser
195 200 205
Ser Cys Asn Ile Ser Ser Gly Glu Met Gln Lys Gly Leu Trp Glu Gln
210 215 220
Cys Gln Leu Leu Lys Ser Thr Ser Val Phe Ala Arg Cys His Pro Leu
225 230 235 240
Val Asp Pro Glu Pro Phe Val Ala Leu Cys Glu Lys Thr Leu Cys Glu
245 250 255
Cys Ala Gly Gly Leu Glu Cys Ala Cys Pro Ala Leu Leu Glu Tyr Ala
260 265 270
Arg Thr Cys Ala Gln Glu Gly Met Val Leu Tyr Gly Trp Thr Asp His
275 280 285
Ser Ala Cys Ser Pro Val Cys Pro Ala Gly Met Glu Tyr Arg Gln Cys
290 295 300
Val Ser Pro Cys Ala Arg Thr Cys Gln Ser Leu His Ile Asn Glu Met
305 310 315 320
Cys Gln Glu Arg Cys Val Asp Gly Cys Ser Cys Pro Glu Gly Gln Leu
325 330 335
Leu Asp Glu Gly Leu Cys Val Glu Ser Thr Glu Cys Pro Cys Val His
340 345 350
Ser Gly Lys Arg Tyr Pro Pro Gly Thr Ser Leu Ser Arg Asp Cys Asn
355 360 365
Thr Cys Ile Cys Arg Asn Ser Gln Trp Ile Cys Ser Asn Glu Glu Cys
370 375 380
Pro Gly Glu Cys Leu Val Thr Gly Gln Ser His Phe Lys Ser Phe Asp
385 390 395 400
Asn Arg Tyr Phe Thr Phe Ser Gly Ile Cys Gln Tyr Leu Leu Ala Arg
405 410 415
Asp Cys Gln Asp His Ser Phe Ser Ile Val Ile Glu Thr Val Gln Cys
420 425 430
Ala Asp Asp Arg Asp Ala Val Cys Thr Arg Ser Val Thr Val Arg Leu
435 440 445
Pro Gly Leu His Asn Ser Leu Val Lys Leu Lys His Gly Ala Gly Val
450 455 460
Ala Met Asp Gly Gln Asp Val Gln Leu Pro Leu Leu Lys Gly Asp Leu
465 470 475 480
Arg Ile Gln His Thr Val Thr Ala Ser Val Arg Leu Ser Tyr Gly Glu
485 490 495
Asp Leu Gln Met Asp Trp Asp Gly Arg Gly Arg Leu Leu Val Lys Leu
500 505 510
Ser Pro Val Tyr Ala Gly Lys Thr Cys Gly Leu Cys Gly Asn Tyr Asn
515 520 525
Gly Asn Gln Gly Asp Asp Phe Leu Thr Pro Ser Gly Leu Ala Glu Pro
530 535 540
Arg Val Glu Asp Phe Gly Asn Ala Trp Lys Leu His Gly Asp Cys Gln
545 550 555 560
Asp Leu Gln Lys Gln His Ser Asp Pro Cys Ala Leu Asn Pro Arg Met
565 570 575
Thr Arg Phe Ser Glu Glu Ala Cys Ala Val Leu Thr Ser Pro Thr Phe
580 585 590
Glu Ala Cys His Arg Ala Val Ser Pro Leu Pro Tyr Leu Arg Asn Cys
595 600 605
Arg Tyr Asp Val Cys Ser Cys Ser Asp Gly Arg Glu Cys Leu Cys Gly
610 615 620
Ala Leu Ala Ser Tyr Ala Ala Ala Cys Ala Gly Arg Gly Val Arg Val
625 630 635 640
Ala Trp Arg Glu Pro Gly Arg Cys Glu Leu Asn Cys Pro Lys Gly Gln
645 650 655
Val Tyr Leu Gln Cys Gly Thr Pro Cys Asn Leu Thr Cys Arg Ser Leu
660 665 670
Ser Tyr Pro Asp Glu Glu Cys Asn Glu Ala Cys Leu Glu Gly Cys Phe
675 680 685
Cys Pro Pro Gly Leu Tyr Met Asp Glu Arg Gly Asp Cys Val Pro Lys
690 695 700
Ala Gln Cys Pro Cys Tyr Tyr Asp Gly Glu Ile Phe Gln Pro Glu Asp
705 710 715 720
Ile Phe Ser Asp His His Thr Met Cys Tyr Cys Glu Asp Gly Phe Met
725 730 735
His Cys Thr Met Ser Gly Val Pro Gly Ser Leu Leu Pro Asp Ala Val
740 745 750
Leu Ser Ser Pro Leu Ser His Arg Ser Lys Arg Ser Leu Ser Cys Arg
755 760 765
Pro Pro Met Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu
770 775 780
Gly Leu Glu Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met
785 790 795 800
Ser Met Gly Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg
805 810 815
His Glu Asn Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln
820 825 830
Gly Lys Glu Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr
835 840 845
Cys Val Cys Arg Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp
850 855 860
Ala Thr Cys Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly
865 870 875 880
Leu Lys Tyr Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp
885 890 895
Tyr Cys Gly Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys
900 905 910
Gly Cys Ser His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu
915 920 925
Val Glu Gly Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys
930 935 940
Arg Pro Met Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg
945 950 955 960
Tyr Ile Ile Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg
965 970 975
His Leu Ser Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val
980 985 990
Cys Gly Leu Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr
995 1000 1005
Ser Ser Asn Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn
1010 1015 1020
Ser Trp Lys Val Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro
1025 1030 1035
Leu Asp Ser Ser Pro Ala Thr Cys His Asn Asn Ile Met Lys Gln
1040 1045 1050
Thr Met Val Asp Ser Ser Cys Arg Ile Leu Thr Ser Asp Val Phe
1055 1060 1065
Gln Asp Cys Asn Lys Leu Val Asp Pro Glu Pro Tyr Leu Asp Val
1070 1075 1080
Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile Gly Asp Cys Ala
1085 1090 1095
Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val Cys Ala Gln
1100 1105 1110
His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys Pro Gln
1115 1120 1125
Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys Glu
1130 1135 1140
Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln
1145 1150 1155
His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys
1160 1165 1170
His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln
1175 1180 1185
Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly
1190 1195 1200
Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp
1205 1210 1215
Pro Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr
1220 1225 1230
Cys Glu Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr
1235 1240 1245
Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser
1250 1255 1260
Glu Pro Pro Leu His Asp Phe Tyr Cys Ser Arg Leu Leu Asp Leu
1265 1270 1275
Val Phe Leu Leu Asp Gly Ser Ser Arg Leu Ser Glu Ala Glu Phe
1280 1285 1290
Glu Val Leu Lys Ala Phe Val Val Asp Met Met Glu Arg Leu Arg
1295 1300 1305
Ile Ser Gln Lys Trp Val Arg Val Ala Val Val Glu Tyr His Asp
1310 1315 1320
Gly Ser His Ala Tyr Ile Gly Leu Lys Asp Arg Lys Arg Pro Ser
1325 1330 1335
Glu Leu Arg Arg Ile Ala Ser Gln Val Lys Tyr Ala Gly Ser Gln
1340 1345 1350
Val Ala Ser Thr Ser Glu Val Leu Lys Tyr Thr Leu Phe Gln Ile
1355 1360 1365
Phe Ser Lys Ile Asp Arg Pro Glu Ala Ser Arg Ile Thr Leu Leu
1370 1375 1380
Leu Met Ala Ser Gln Glu Pro Gln Arg Met Ser Arg Asn Phe Val
1385 1390 1395
Arg Tyr Val Gln Gly Leu Lys Lys Lys Lys Val Ile Val Ile Pro
1400 1405 1410
Val Gly Ile Gly Pro His Ala Asn Leu Lys Gln Ile Arg Leu Ile
1415 1420 1425
Glu Lys Gln Ala Pro Glu Asn Lys Ala Phe Val Leu Ser Ser Val
1430 1435 1440
Asp Glu Leu Glu Gln Gln Arg Asp Glu Ile Val Ser Tyr Leu Cys
1445 1450 1455
Asp Leu Ala Pro Glu Ala Pro Pro Pro Thr Leu Pro Pro Asp Met
1460 1465 1470
Ala Gln Val Thr Val Gly Pro Gly Leu Leu Gly Val Ser Thr Leu
1475 1480 1485
Gly Pro Lys Arg Asn Ser Met Val Leu Asp Val Ala Phe Val Leu
1490 1495 1500
Glu Gly Ser Asp Lys Ile Gly Glu Ala Asp Phe Asn Arg Ser Lys
1505 1510 1515
Glu Phe Met Glu Glu Val Ile Gln Arg Met Asp Val Gly Gln Asp
1520 1525 1530
Ser Ile His Val Thr Val Leu Gln Tyr Ser Tyr Met Val Thr Val
1535 1540 1545
Glu Tyr Pro Phe Ser Glu Ala Gln Ser Lys Gly Asp Ile Leu Gln
1550 1555 1560
Arg Val Arg Glu Ile Arg Tyr Gln Gly Gly Asn Arg Thr Asn Thr
1565 1570 1575
Gly Leu Ala Leu Arg Tyr Leu Ser Asp His Ser Phe Leu Val Ser
1580 1585 1590
Gln Gly Asp Arg Glu Gln Ala Pro Asn Leu Val Tyr Met Val Thr
1595 1600 1605
Gly Asn Pro Ala Ser Asp Glu Ile Lys Arg Leu Pro Gly Asp Ile
1610 1615 1620
Gln Val Val Pro Ile Gly Val Gly Pro Asn Ala Asn Val Gln Glu
1625 1630 1635
Leu Glu Arg Ile Gly Trp Pro Asn Ala Pro Ile Leu Ile Gln Asp
1640 1645 1650
Phe Glu Thr Leu Pro Arg Glu Ala Pro Asp Leu Val Leu Gln Arg
1655 1660 1665
Cys Cys Ser Gly Glu Gly Leu Gln Ile Pro Thr Leu Ser Pro Ala
1670 1675 1680
Pro Asp Cys Ser Gln Pro Leu Asp Val Ile Leu Leu Leu Asp Gly
1685 1690 1695
Ser Ser Ser Phe Pro Ala Ser Tyr Phe Asp Glu Met Lys Ser Phe
1700 1705 1710
Ala Lys Ala Phe Ile Ser Lys Ala Asn Ile Gly Pro Arg Leu Thr
1715 1720 1725
Gln Val Ser Val Leu Gln Tyr Gly Ser Ile Thr Thr Ile Asp Val
1730 1735 1740
Pro Trp Asn Val Val Pro Glu Lys Ala His Leu Leu Ser Leu Val
1745 1750 1755
Asp Val Met Gln Arg Glu Gly Gly Pro Ser Gln Ile Gly Asp Ala
1760 1765 1770
Leu Gly Phe Ala Val Arg Tyr Leu Thr Ser Glu Met His Gly Ala
1775 1780 1785
Arg Pro Gly Ala Ser Lys Ala Val Val Ile Leu Val Thr Asp Val
1790 1795 1800
Ser Val Asp Ser Val Asp Ala Ala Ala Asp Ala Ala Arg Ser Asn
1805 1810 1815
Arg Val Thr Val Phe Pro Ile Gly Ile Gly Asp Arg Tyr Asp Ala
1820 1825 1830
Ala Gln Leu Arg Ile Leu Ala Gly Pro Ala Gly Asp Ser Asn Val
1835 1840 1845
Val Lys Leu Gln Arg Ile Glu Asp Leu Pro Thr Met Val Thr Leu
1850 1855 1860
Gly Asn Ser Phe Leu His Lys Leu Cys Ser Gly Phe Val Arg Ile
1865 1870 1875
Cys Met Asp Glu Asp Gly Asn Glu Lys Arg Pro Gly Asp Val Trp
1880 1885 1890
Thr Leu Pro Asp Gln Cys His Thr Val Thr Cys Gln Pro Asp Gly
1895 1900 1905
Gln Thr Leu Leu Lys Ser His Arg Val Asn Cys Asp Arg Gly Leu
1910 1915 1920
Arg Pro Ser Cys Pro Asn Ser Gln Ser Pro Val Lys Val Glu Glu
1925 1930 1935
Thr Cys Gly Cys Arg Trp Thr Cys Pro Cys Val Cys Thr Gly Ser
1940 1945 1950
Ser Thr Arg His Ile Val Thr Phe Asp Gly Gln Asn Phe Lys Leu
1955 1960 1965
Thr Gly Ser Cys Ser Tyr Val Leu Phe Gln Asn Lys Glu Gln Asp
1970 1975 1980
Leu Glu Val Ile Leu His Asn Gly Ala Cys Ser Pro Gly Ala Arg
1985 1990 1995
Gln Gly Cys Met Lys Ser Ile Glu Val Lys His Ser Ala Leu Ser
2000 2005 2010
Val Glu Leu His Ser Asp Met Glu Val Thr Val Asn Gly Arg Leu
2015 2020 2025
Val Ser Val Pro Tyr Val Gly Gly Asn Met Glu Val Asn Val Tyr
2030 2035 2040
Gly Ala Ile Met His Glu Val Arg Phe Asn His Leu Gly His Ile
2045 2050 2055
Phe Thr Phe Thr Pro Gln Asn Asn Glu Phe Gln Leu Gln Leu Ser
2060 2065 2070
Pro Lys Thr Phe Ala Ser Lys Thr Tyr Gly Leu Cys Gly Ile Cys
2075 2080 2085
Asp Glu Asn Gly Ala Asn Asp Phe Met Leu Arg Asp Gly Thr Val
2090 2095 2100
Thr Thr Asp Trp Lys Thr Leu Val Gln Glu Trp Thr Val Gln Arg
2105 2110 2115
Pro Gly Gln Thr Cys Gln Pro Ile Leu Glu Glu Gln Cys Leu Val
2120 2125 2130
Pro Asp Ser Ser His Cys Gln Val Leu Leu Leu Pro Leu Phe Ala
2135 2140 2145
Glu Cys His Lys Val Leu Ala Pro Ala Thr Phe Tyr Ala Ile Cys
2150 2155 2160
Gln Gln Asp Ser Cys His Gln Glu Gln Val Cys Glu Val Ile Ala
2165 2170 2175
Ser Tyr Ala His Leu Cys Arg Thr Asn Gly Val Cys Val Asp Trp
2180 2185 2190
Arg Thr Pro Asp Phe Cys Ala Met Ser Cys Pro Pro Ser Leu Val
2195 2200 2205
Tyr Asn His Cys Glu His Gly Cys Pro Arg His Cys Asp Gly Asn
2210 2215 2220
Val Ser Ser Cys Gly Asp His Pro Ser Glu Gly Cys Phe Cys Pro
2225 2230 2235
Pro Asp Lys Val Met Leu Glu Gly Ser Cys Val Pro Glu Glu Ala
2240 2245 2250
Cys Thr Gln Cys Ile Gly Glu Asp Gly Val Gln His Gln Phe Leu
2255 2260 2265
Glu Ala Trp Val Pro Asp His Gln Pro Cys Gln Ile Cys Thr Cys
2270 2275 2280
Leu Ser Gly Arg Lys Val Asn Cys Thr Thr Gln Pro Cys Pro Thr
2285 2290 2295
Ala Lys Ala Pro Thr Cys Gly Leu Cys Glu Val Ala Arg Leu Arg
2300 2305 2310
Gln Asn Ala Asp Gln Cys Cys Pro Glu Tyr Glu Cys Val Cys Asp
2315 2320 2325
Pro Val Ser Cys Asp Leu Pro Pro Val Pro His Cys Glu Arg Gly
2330 2335 2340
Leu Gln Pro Thr Leu Thr Asn Pro Gly Glu Cys Arg Pro Asn Phe
2345 2350 2355
Thr Cys Ala Cys Arg Lys Glu Glu Cys Lys Arg Val Ser Pro Pro
2360 2365 2370
Ser Cys Pro Pro His Arg Leu Pro Thr Leu Arg Lys Thr Gln Cys
2375 2380 2385
Cys Asp Glu Tyr Glu Cys Ala Cys Asn Cys Val Asn Ser Thr Val
2390 2395 2400
Ser Cys Pro Leu Gly Tyr Leu Ala Ser Thr Ala Thr Asn Asp Cys
2405 2410 2415
Gly Cys Thr Thr Thr Thr Cys Leu Pro Asp Lys Val Cys Val His
2420 2425 2430
Arg Ser Thr Ile Tyr Pro Val Gly Gln Phe Trp Glu Glu Gly Cys
2435 2440 2445
Asp Val Cys Thr Cys Thr Asp Met Glu Asp Ala Val Met Gly Leu
2450 2455 2460
Arg Val Ala Gln Cys Ser Gln Lys Pro Cys Glu Asp Ser Cys Arg
2465 2470 2475
Ser Gly Phe Thr Tyr Val Leu His Glu Gly Glu Cys Cys Gly Arg
2480 2485 2490
Cys Leu Pro Ser Ala Cys Glu Val Val Thr Gly Ser Pro Arg Gly
2495 2500 2505
Asp Ser Gln Ser Ser Trp Lys Ser Val Gly Ser Gln Trp Ala Ser
2510 2515 2520
Pro Glu Asn Pro Cys Leu Ile Asn Glu Cys Val Arg Val Lys Glu
2525 2530 2535
Glu Val Phe Ile Gln Gln Arg Asn Val Ser Cys Pro Gln Leu Glu
2540 2545 2550
Val Pro Val Cys Pro Ser Gly Phe Gln Leu Ser Cys Lys Thr Ser
2555 2560 2565
Ala Cys Cys Pro Ser Cys Arg Cys Glu Arg Met Glu Ala Cys Met
2570 2575 2580
Leu Asn Gly Thr Val Ile Gly Pro Gly Lys Thr Val Met Ile Asp
2585 2590 2595
Val Cys Thr Thr Cys Arg Cys Met Val Gln Val Gly Val Ile Ser
2600 2605 2610
Gly Phe Lys Leu Glu Cys Arg Lys Thr Thr Cys Asn Pro Cys Pro
2615 2620 2625
Leu Gly Tyr Lys Glu Glu Asn Asn Thr Gly Glu Cys Cys Gly Arg
2630 2635 2640
Cys Leu Pro Thr Ala Cys Thr Ile Gln Leu Arg Gly Gly Gln Ile
2645 2650 2655
Met Thr Leu Lys Arg Asp Glu Thr Leu Gln Asp Gly Cys Asp Thr
2660 2665 2670
His Phe Cys Lys Val Asn Glu Arg Gly Glu Tyr Phe Trp Glu Lys
2675 2680 2685
Arg Val Thr Gly Cys Pro Pro Phe Asp Glu His Lys Cys Leu Ala
2690 2695 2700
Glu Gly Gly Lys Ile Met Lys Ile Pro Gly Thr Cys Cys Asp Thr
2705 2710 2715
Cys Glu Glu Pro Glu Cys Asn Asp Ile Thr Ala Arg Leu Gln Tyr
2720 2725 2730
Val Lys Val Gly Ser Cys Lys Ser Glu Val Glu Val Asp Ile His
2735 2740 2745
Tyr Cys Gln Gly Lys Cys Ala Ser Lys Ala Met Tyr Ser Ile Asp
2750 2755 2760
Ile Asn Asp Val Gln Asp Gln Cys Ser Cys Cys Ser Pro Thr Arg
2765 2770 2775
Thr Glu Pro Met Gln Val Ala Leu His Cys Thr Asn Gly Ser Val
2780 2785 2790
Val Tyr His Glu Val Leu Asn Ala Met Glu Cys Lys Cys Ser Pro
2795 2800 2805
Arg Lys Cys Ser Lys
2810
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Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu Val Cys Pro Ala Asp
1 5 10 15
Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys Thr Cys Gln Asn Tyr
20 25 30
Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser Gly Cys Leu Cys Pro
35 40 45
Pro Gly Met Val Arg His Glu Asn Arg Cys Val Ala Leu Glu Arg Cys
50 55 60
Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro Gly Glu Thr Val Lys
65 70 75 80
Ile Gly Cys Asn Thr Cys Val Cys Gln Asp Arg Lys Trp Asn Cys Thr
85 90 95
Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile Gly Met Ala His Tyr
100 105 110
Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro Gly Glu Cys Gln Tyr
115 120 125
Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro Gly Thr Phe Arg Ile
130 135 140
Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser Val Lys Cys Lys Lys
145 150 155 160
Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile Glu Leu Phe Asp Gly
165 170 175
Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu Thr His Phe Glu Val
180 185 190
Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu Gly Lys Ala Leu Ser
195 200 205
Val Val Trp Asp Arg His Leu Ser Ile Ser Val Val Leu Lys Gln Thr
210 215 220
Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn Phe Asp Gly Ile Gln
225 230 235 240
Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val Glu Glu Asp Pro Val
245 250 255
Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln Cys Ala Asp Thr Arg
260 265 270
Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys His Asn Asn Ile Met
275 280 285
Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile Leu Thr Ser Asp Val
290 295 300
Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu Pro Tyr Leu Asp Val
305 310 315 320
Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile Gly Asp Cys Ala Cys
325 330 335
Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val Cys Ala Gln His Gly
340 345 350
Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys Pro Gln Ser Cys Glu
355 360 365
Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys Glu Trp Arg Tyr Asn
370 375 380
Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln His Pro Glu Pro Leu
385 390 395 400
Ala Cys Pro Val Gln Cys Val Glu Gly Cys His Ala His Cys Pro Pro
405 410 415
Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys Val Asp Pro Glu Asp
420 425 430
Cys Pro Val Cys Val Ala Gly Arg Arg Phe Ala Ser Gly Lys Lys Val
435 440 445
Thr Leu Asn Pro Ser Asp Pro Glu His Cys Gln Ile Cys His Cys Asp
450 455 460
Val Val Asn Leu Thr Cys Glu Ala Cys Gln Glu Pro Gly Gly Leu Val
465 470 475 480
Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu
485 490 495
Asp Ile Ser Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu Val Val
500 505 510
Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp
515 520 525
Ile Ser Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu Val Val Pro
530 535 540
Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile
545 550 555 560
Ser Glu Pro Pro Leu His
565
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Met Ile Pro Ala Arg Phe Ala Gly Val Leu Leu Ala Leu Ala Leu Ile
1 5 10 15
Leu Pro Gly Thr Leu Cys Ser Leu Ser Cys Arg Pro Pro Met Val Lys
20 25 30
Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr
35 40 45
Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val
50 55 60
Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys
65 70 75 80
Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala
85 90 95
Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Gln Asp
100 105 110
Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr
115 120 125
Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe
130 135 140
Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn
145 150 155 160
Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro
165 170 175
Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu
180 185 190
Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp
195 200 205
Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu
210 215 220
Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser
225 230 235 240
Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly
245 250 255
Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln
260 265 270
Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser
275 280 285
Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr
290 295 300
Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg
305 310 315 320
Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro
325 330 335
Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser
340 345 350
Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His
355 360 365
Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu
370 375 380
Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu
385 390 395 400
Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys
405 410 415
Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys
420 425 430
His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr
435 440 445
Cys Val Asp Pro Glu Asp Cys Pro Val Cys Val Ala Gly Arg Arg Phe
450 455 460
Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys
465 470 475 480
Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln
485 490 495
Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro
500 505 510
Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Gln Glu
515 520 525
Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr
530 535 540
Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Gln Glu Pro
545 550 555 560
Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr
565 570 575
Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His
580 585
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Met Ile Pro Ala Arg Phe Ala Gly Val Leu Leu Ala Leu Ala Leu Ile
1 5 10 15
Leu Pro Gly Thr Leu Cys Ala Glu Gly Thr Arg Gly Arg Ser Ser Thr
20 25 30
Ala Arg Cys Ser Leu Phe Gly Ser Asp Phe Val Asn Thr Phe Asp Gly
35 40 45
Ser Met Tyr Ser Phe Ala Gly Tyr Cys Ser Tyr Leu Leu Ala Gly Gly
50 55 60
Cys Gln Lys Arg Ser Phe Ser Ile Ile Gly Asp Phe Gln Asn Gly Lys
65 70 75 80
Arg Val Ser Leu Ser Val Tyr Leu Gly Glu Phe Phe Asp Ile His Leu
85 90 95
Phe Val Asn Gly Thr Val Thr Gln Gly Asp Gln Arg Val Ser Met Pro
100 105 110
Tyr Ala Ser Lys Gly Leu Tyr Leu Glu Thr Glu Ala Gly Tyr Tyr Lys
115 120 125
Leu Ser Gly Glu Ala Tyr Gly Phe Val Ala Arg Ile Asp Gly Ser Gly
130 135 140
Asn Phe Gln Val Leu Leu Ser Asp Arg Tyr Phe Asn Lys Thr Cys Gly
145 150 155 160
Leu Cys Gly Asn Phe Asn Ile Phe Ala Glu Asp Asp Phe Met Thr Gln
165 170 175
Glu Gly Thr Leu Thr Ser Asp Pro Tyr Asp Phe Ala Asn Ser Trp Ala
180 185 190
Leu Ser Ser Gly Glu Gln Trp Cys Glu Arg Ala Ser Pro Pro Ser Ser
195 200 205
Ser Cys Asn Ile Ser Ser Gly Glu Met Gln Lys Gly Leu Trp Glu Gln
210 215 220
Cys Gln Leu Leu Lys Ser Thr Ser Val Phe Ala Arg Cys His Pro Leu
225 230 235 240
Val Asp Pro Glu Pro Phe Val Ala Leu Cys Glu Lys Thr Leu Cys Glu
245 250 255
Cys Ala Gly Gly Leu Glu Cys Ala Cys Pro Ala Leu Leu Glu Tyr Ala
260 265 270
Arg Thr Cys Ala Gln Glu Gly Met Val Leu Tyr Gly Trp Thr Asp His
275 280 285
Ser Ala Cys Ser Pro Val Cys Pro Ala Gly Met Glu Tyr Arg Gln Cys
290 295 300
Val Ser Pro Cys Ala Arg Thr Cys Gln Ser Leu His Ile Asn Glu Met
305 310 315 320
Cys Gln Glu Arg Cys Val Asp Gly Cys Ser Cys Pro Glu Gly Gln Leu
325 330 335
Leu Asp Glu Gly Leu Cys Val Glu Ser Thr Glu Cys Pro Cys Val His
340 345 350
Ser Gly Lys Arg Tyr Pro Pro Gly Thr Ser Leu Ser Arg Asp Cys Asn
355 360 365
Thr Cys Ile Cys Arg Asn Ser Gln Trp Ile Cys Ser Asn Glu Glu Cys
370 375 380
Pro Gly Glu Cys Leu Val Thr Gly Gln Ser His Phe Lys Ser Phe Asp
385 390 395 400
Asn Arg Tyr Phe Thr Phe Ser Gly Ile Cys Gln Tyr Leu Leu Ala Arg
405 410 415
Asp Cys Gln Asp His Ser Phe Ser Ile Val Ile Glu Thr Val Gln Cys
420 425 430
Ala Asp Asp Arg Asp Ala Val Cys Thr Arg Ser Val Thr Val Arg Leu
435 440 445
Pro Gly Leu His Asn Ser Leu Val Lys Leu Lys His Gly Ala Gly Val
450 455 460
Ala Met Asp Gly Gln Asp Val Gln Leu Pro Leu Leu Lys Gly Asp Leu
465 470 475 480
Arg Ile Gln His Thr Val Thr Ala Ser Val Arg Leu Ser Tyr Gly Glu
485 490 495
Asp Leu Gln Met Asp Trp Asp Gly Arg Gly Arg Leu Leu Val Lys Leu
500 505 510
Ser Pro Val Tyr Ala Gly Lys Thr Cys Gly Leu Cys Gly Asn Tyr Asn
515 520 525
Gly Asn Gln Gly Asp Asp Phe Leu Thr Pro Ser Gly Leu Ala Glu Pro
530 535 540
Arg Val Glu Asp Phe Gly Asn Ala Trp Lys Leu His Gly Asp Cys Gln
545 550 555 560
Asp Leu Gln Lys Gln His Ser Asp Pro Cys Ala Leu Asn Pro Arg Met
565 570 575
Thr Arg Phe Ser Glu Glu Ala Cys Ala Val Leu Thr Ser Pro Thr Phe
580 585 590
Glu Ala Cys His Arg Ala Val Ser Pro Leu Pro Tyr Leu Arg Asn Cys
595 600 605
Arg Tyr Asp Val Cys Ser Cys Ser Asp Gly Arg Glu Cys Leu Cys Gly
610 615 620
Ala Leu Ala Ser Tyr Ala Ala Ala Cys Ala Gly Arg Gly Val Arg Val
625 630 635 640
Ala Trp Arg Glu Pro Gly Arg Cys Glu Leu Asn Cys Pro Lys Gly Gln
645 650 655
Val Tyr Leu Gln Cys Gly Thr Pro Cys Asn Leu Thr Cys Arg Ser Leu
660 665 670
Ser Tyr Pro Asp Glu Glu Cys Asn Glu Ala Cys Leu Glu Gly Cys Phe
675 680 685
Cys Pro Pro Gly Leu Tyr Met Asp Glu Arg Gly Asp Cys Val Pro Lys
690 695 700
Ala Gln Cys Pro Cys Tyr Tyr Asp Gly Glu Ile Phe Gln Pro Glu Asp
705 710 715 720
Ile Phe Ser Asp His His Thr Met Cys Tyr Cys Glu Asp Gly Phe Met
725 730 735
His Cys Thr Met Ser Gly Val Pro Gly Ser Leu Leu Pro Asp Ala Val
740 745 750
Leu Ser Ser Pro Leu Ser His Arg Ser Lys Arg Ser Leu Ser Cys Arg
755 760 765
Pro Pro Met Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu
770 775 780
Gly Leu Glu Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met
785 790 795 800
Ser Met Gly Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg
805 810 815
His Glu Asn Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln
820 825 830
Gly Lys Glu Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr
835 840 845
Cys Val Cys Gln Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp
850 855 860
Ala Thr Cys Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly
865 870 875 880
Leu Lys Tyr Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp
885 890 895
Tyr Cys Gly Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys
900 905 910
Gly Cys Ser His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu
915 920 925
Val Glu Gly Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys
930 935 940
Arg Pro Met Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg
945 950 955 960
Tyr Ile Ile Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg
965 970 975
His Leu Ser Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val
980 985 990
Cys Gly Leu Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr
995 1000 1005
Ser Ser Asn Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn
1010 1015 1020
Ser Trp Lys Val Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro
1025 1030 1035
Leu Asp Ser Ser Pro Ala Thr Cys His Asn Asn Ile Met Lys Gln
1040 1045 1050
Thr Met Val Asp Ser Ser Cys Arg Ile Leu Thr Ser Asp Val Phe
1055 1060 1065
Gln Asp Cys Asn Lys Leu Val Asp Pro Glu Pro Tyr Leu Asp Val
1070 1075 1080
Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile Gly Asp Cys Ala
1085 1090 1095
Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val Cys Ala Gln
1100 1105 1110
His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys Pro Gln
1115 1120 1125
Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys Glu
1130 1135 1140
Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln
1145 1150 1155
His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys
1160 1165 1170
His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln
1175 1180 1185
Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly
1190 1195 1200
Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp
1205 1210 1215
Pro Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr
1220 1225 1230
Cys Glu Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr
1235 1240 1245
Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser
1250 1255 1260
Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu Val Val Pro Pro
1265 1270 1275
Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile
1280 1285 1290
Ser Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu Val Val Pro
1295 1300 1305
Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp
1310 1315 1320
Ile Ser Glu Pro Pro Leu His
1325 1330
<210> 6
<211> 628
<212> PRT
<213> 智人
<400> 6
Ser Leu Ser Cys Arg Pro Pro Met Val Lys Leu Val Cys Pro Ala Asp
1 5 10 15
Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr Lys Thr Cys Gln Asn Tyr
20 25 30
Asp Leu Glu Cys Met Ser Met Gly Cys Val Ser Gly Cys Leu Cys Pro
35 40 45
Pro Gly Met Val Arg His Glu Asn Arg Cys Val Ala Leu Glu Arg Cys
50 55 60
Pro Cys Phe His Gln Gly Lys Glu Tyr Ala Pro Gly Glu Thr Val Lys
65 70 75 80
Ile Gly Cys Asn Thr Cys Val Cys Gln Asp Arg Lys Trp Asn Cys Thr
85 90 95
Asp His Val Cys Asp Ala Thr Cys Ser Thr Ile Gly Met Ala His Tyr
100 105 110
Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe Pro Gly Glu Cys Gln Tyr
115 120 125
Val Leu Val Gln Asp Tyr Cys Gly Ser Asn Pro Gly Thr Phe Arg Ile
130 135 140
Leu Val Gly Asn Lys Gly Cys Ser His Pro Ser Val Lys Cys Lys Lys
145 150 155 160
Arg Val Thr Ile Leu Val Glu Gly Gly Glu Ile Glu Leu Phe Asp Gly
165 170 175
Glu Val Asn Val Lys Arg Pro Met Lys Asp Glu Thr His Phe Glu Val
180 185 190
Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu Leu Gly Lys Ala Leu Ser
195 200 205
Val Val Trp Asp Arg His Leu Ser Ile Ser Val Val Leu Lys Gln Thr
210 215 220
Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly Asn Phe Asp Gly Ile Gln
225 230 235 240
Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln Val Glu Glu Asp Pro Val
245 250 255
Asp Phe Gly Asn Ser Trp Lys Val Ser Ser Gln Cys Ala Asp Thr Arg
260 265 270
Lys Val Pro Leu Asp Ser Ser Pro Ala Thr Cys His Asn Asn Ile Met
275 280 285
Lys Gln Thr Met Val Asp Ser Ser Cys Arg Ile Leu Thr Ser Asp Val
290 295 300
Phe Gln Asp Cys Asn Lys Leu Val Asp Pro Glu Pro Tyr Leu Asp Val
305 310 315 320
Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile Gly Asp Cys Ala Cys
325 330 335
Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val Cys Ala Gln His Gly
340 345 350
Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys Pro Gln Ser Cys Glu
355 360 365
Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys Glu Trp Arg Tyr Asn
370 375 380
Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln His Pro Glu Pro Leu
385 390 395 400
Ala Cys Pro Val Gln Cys Val Glu Gly Cys His Ala His Cys Pro Pro
405 410 415
Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr Cys Val Asp Pro Glu Asp
420 425 430
Cys Pro Val Cys Val Ala Gly Arg Arg Phe Ala Ser Gly Lys Lys Val
435 440 445
Thr Leu Asn Pro Ser Asp Pro Glu His Cys Gln Ile Cys His Cys Asp
450 455 460
Val Val Asn Leu Thr Cys Glu Ala Cys Gln Glu Pro Gly Gly Leu Val
465 470 475 480
Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu
485 490 495
Asp Ile Ser Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu Val Val
500 505 510
Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp
515 520 525
Ile Ser Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu Val Val Pro
530 535 540
Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile
545 550 555 560
Ser Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu Val Val Pro Pro
565 570 575
Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser
580 585 590
Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr
595 600 605
Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu
610 615 620
Pro Pro Leu His
625
<210> 7
<211> 650
<212> PRT
<213> 智人
<400> 7
Met Ile Pro Ala Arg Phe Ala Gly Val Leu Leu Ala Leu Ala Leu Ile
1 5 10 15
Leu Pro Gly Thr Leu Cys Ser Leu Ser Cys Arg Pro Pro Met Val Lys
20 25 30
Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr
35 40 45
Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val
50 55 60
Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys
65 70 75 80
Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala
85 90 95
Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Gln Asp
100 105 110
Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr
115 120 125
Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe
130 135 140
Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn
145 150 155 160
Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro
165 170 175
Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu
180 185 190
Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp
195 200 205
Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu
210 215 220
Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser
225 230 235 240
Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly
245 250 255
Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln
260 265 270
Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser
275 280 285
Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr
290 295 300
Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg
305 310 315 320
Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro
325 330 335
Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser
340 345 350
Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His
355 360 365
Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu
370 375 380
Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu
385 390 395 400
Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys
405 410 415
Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys
420 425 430
His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr
435 440 445
Cys Val Asp Pro Glu Asp Cys Pro Val Cys Val Ala Gly Arg Arg Phe
450 455 460
Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His Cys
465 470 475 480
Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys Gln
485 490 495
Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro
500 505 510
Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Gln Glu
515 520 525
Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr
530 535 540
Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Gln Glu Pro
545 550 555 560
Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr
565 570 575
Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Gln Glu Pro Gly
580 585 590
Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu
595 600 605
Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Gln Glu Pro Gly Gly
610 615 620
Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr
625 630 635 640
Val Glu Asp Ile Ser Glu Pro Pro Leu His
645 650
<210> 8
<211> 1392
<212> PRT
<213> 智人
<400> 8
Met Ile Pro Ala Arg Phe Ala Gly Val Leu Leu Ala Leu Ala Leu Ile
1 5 10 15
Leu Pro Gly Thr Leu Cys Ala Glu Gly Thr Arg Gly Arg Ser Ser Thr
20 25 30
Ala Arg Cys Ser Leu Phe Gly Ser Asp Phe Val Asn Thr Phe Asp Gly
35 40 45
Ser Met Tyr Ser Phe Ala Gly Tyr Cys Ser Tyr Leu Leu Ala Gly Gly
50 55 60
Cys Gln Lys Arg Ser Phe Ser Ile Ile Gly Asp Phe Gln Asn Gly Lys
65 70 75 80
Arg Val Ser Leu Ser Val Tyr Leu Gly Glu Phe Phe Asp Ile His Leu
85 90 95
Phe Val Asn Gly Thr Val Thr Gln Gly Asp Gln Arg Val Ser Met Pro
100 105 110
Tyr Ala Ser Lys Gly Leu Tyr Leu Glu Thr Glu Ala Gly Tyr Tyr Lys
115 120 125
Leu Ser Gly Glu Ala Tyr Gly Phe Val Ala Arg Ile Asp Gly Ser Gly
130 135 140
Asn Phe Gln Val Leu Leu Ser Asp Arg Tyr Phe Asn Lys Thr Cys Gly
145 150 155 160
Leu Cys Gly Asn Phe Asn Ile Phe Ala Glu Asp Asp Phe Met Thr Gln
165 170 175
Glu Gly Thr Leu Thr Ser Asp Pro Tyr Asp Phe Ala Asn Ser Trp Ala
180 185 190
Leu Ser Ser Gly Glu Gln Trp Cys Glu Arg Ala Ser Pro Pro Ser Ser
195 200 205
Ser Cys Asn Ile Ser Ser Gly Glu Met Gln Lys Gly Leu Trp Glu Gln
210 215 220
Cys Gln Leu Leu Lys Ser Thr Ser Val Phe Ala Arg Cys His Pro Leu
225 230 235 240
Val Asp Pro Glu Pro Phe Val Ala Leu Cys Glu Lys Thr Leu Cys Glu
245 250 255
Cys Ala Gly Gly Leu Glu Cys Ala Cys Pro Ala Leu Leu Glu Tyr Ala
260 265 270
Arg Thr Cys Ala Gln Glu Gly Met Val Leu Tyr Gly Trp Thr Asp His
275 280 285
Ser Ala Cys Ser Pro Val Cys Pro Ala Gly Met Glu Tyr Arg Gln Cys
290 295 300
Val Ser Pro Cys Ala Arg Thr Cys Gln Ser Leu His Ile Asn Glu Met
305 310 315 320
Cys Gln Glu Arg Cys Val Asp Gly Cys Ser Cys Pro Glu Gly Gln Leu
325 330 335
Leu Asp Glu Gly Leu Cys Val Glu Ser Thr Glu Cys Pro Cys Val His
340 345 350
Ser Gly Lys Arg Tyr Pro Pro Gly Thr Ser Leu Ser Arg Asp Cys Asn
355 360 365
Thr Cys Ile Cys Arg Asn Ser Gln Trp Ile Cys Ser Asn Glu Glu Cys
370 375 380
Pro Gly Glu Cys Leu Val Thr Gly Gln Ser His Phe Lys Ser Phe Asp
385 390 395 400
Asn Arg Tyr Phe Thr Phe Ser Gly Ile Cys Gln Tyr Leu Leu Ala Arg
405 410 415
Asp Cys Gln Asp His Ser Phe Ser Ile Val Ile Glu Thr Val Gln Cys
420 425 430
Ala Asp Asp Arg Asp Ala Val Cys Thr Arg Ser Val Thr Val Arg Leu
435 440 445
Pro Gly Leu His Asn Ser Leu Val Lys Leu Lys His Gly Ala Gly Val
450 455 460
Ala Met Asp Gly Gln Asp Val Gln Leu Pro Leu Leu Lys Gly Asp Leu
465 470 475 480
Arg Ile Gln His Thr Val Thr Ala Ser Val Arg Leu Ser Tyr Gly Glu
485 490 495
Asp Leu Gln Met Asp Trp Asp Gly Arg Gly Arg Leu Leu Val Lys Leu
500 505 510
Ser Pro Val Tyr Ala Gly Lys Thr Cys Gly Leu Cys Gly Asn Tyr Asn
515 520 525
Gly Asn Gln Gly Asp Asp Phe Leu Thr Pro Ser Gly Leu Ala Glu Pro
530 535 540
Arg Val Glu Asp Phe Gly Asn Ala Trp Lys Leu His Gly Asp Cys Gln
545 550 555 560
Asp Leu Gln Lys Gln His Ser Asp Pro Cys Ala Leu Asn Pro Arg Met
565 570 575
Thr Arg Phe Ser Glu Glu Ala Cys Ala Val Leu Thr Ser Pro Thr Phe
580 585 590
Glu Ala Cys His Arg Ala Val Ser Pro Leu Pro Tyr Leu Arg Asn Cys
595 600 605
Arg Tyr Asp Val Cys Ser Cys Ser Asp Gly Arg Glu Cys Leu Cys Gly
610 615 620
Ala Leu Ala Ser Tyr Ala Ala Ala Cys Ala Gly Arg Gly Val Arg Val
625 630 635 640
Ala Trp Arg Glu Pro Gly Arg Cys Glu Leu Asn Cys Pro Lys Gly Gln
645 650 655
Val Tyr Leu Gln Cys Gly Thr Pro Cys Asn Leu Thr Cys Arg Ser Leu
660 665 670
Ser Tyr Pro Asp Glu Glu Cys Asn Glu Ala Cys Leu Glu Gly Cys Phe
675 680 685
Cys Pro Pro Gly Leu Tyr Met Asp Glu Arg Gly Asp Cys Val Pro Lys
690 695 700
Ala Gln Cys Pro Cys Tyr Tyr Asp Gly Glu Ile Phe Gln Pro Glu Asp
705 710 715 720
Ile Phe Ser Asp His His Thr Met Cys Tyr Cys Glu Asp Gly Phe Met
725 730 735
His Cys Thr Met Ser Gly Val Pro Gly Ser Leu Leu Pro Asp Ala Val
740 745 750
Leu Ser Ser Pro Leu Ser His Arg Ser Lys Arg Ser Leu Ser Cys Arg
755 760 765
Pro Pro Met Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu
770 775 780
Gly Leu Glu Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met
785 790 795 800
Ser Met Gly Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg
805 810 815
His Glu Asn Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln
820 825 830
Gly Lys Glu Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr
835 840 845
Cys Val Cys Gln Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp
850 855 860
Ala Thr Cys Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly
865 870 875 880
Leu Lys Tyr Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp
885 890 895
Tyr Cys Gly Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys
900 905 910
Gly Cys Ser His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu
915 920 925
Val Glu Gly Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys
930 935 940
Arg Pro Met Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg
945 950 955 960
Tyr Ile Ile Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg
965 970 975
His Leu Ser Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val
980 985 990
Cys Gly Leu Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr
995 1000 1005
Ser Ser Asn Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn
1010 1015 1020
Ser Trp Lys Val Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro
1025 1030 1035
Leu Asp Ser Ser Pro Ala Thr Cys His Asn Asn Ile Met Lys Gln
1040 1045 1050
Thr Met Val Asp Ser Ser Cys Arg Ile Leu Thr Ser Asp Val Phe
1055 1060 1065
Gln Asp Cys Asn Lys Leu Val Asp Pro Glu Pro Tyr Leu Asp Val
1070 1075 1080
Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile Gly Asp Cys Ala
1085 1090 1095
Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val Cys Ala Gln
1100 1105 1110
His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys Pro Gln
1115 1120 1125
Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys Glu
1130 1135 1140
Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln
1145 1150 1155
His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys
1160 1165 1170
His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln
1175 1180 1185
Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly
1190 1195 1200
Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp
1205 1210 1215
Pro Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr
1220 1225 1230
Cys Glu Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr
1235 1240 1245
Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser
1250 1255 1260
Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu Val Val Pro Pro
1265 1270 1275
Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile
1280 1285 1290
Ser Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu Val Val Pro
1295 1300 1305
Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp
1310 1315 1320
Ile Ser Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu Val Val
1325 1330 1335
Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu
1340 1345 1350
Asp Ile Ser Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu Val
1355 1360 1365
Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val
1370 1375 1380
Glu Asp Ile Ser Glu Pro Pro Leu His
1385 1390
<210> 9
<211> 682
<212> PRT
<213> 智人
<400> 9
Met Ile Pro Ala Arg Phe Ala Gly Val Leu Leu Ala Leu Ala Leu Ile
1 5 10 15
Leu Pro Gly Thr Leu Cys Ser Leu Ser Cys Arg Pro Pro Met Val Lys
20 25 30
Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr
35 40 45
Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val
50 55 60
Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys
65 70 75 80
Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala
85 90 95
Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Gln Asp
100 105 110
Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr
115 120 125
Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe
130 135 140
Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn
145 150 155 160
Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro
165 170 175
Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu
180 185 190
Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp
195 200 205
Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu
210 215 220
Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser
225 230 235 240
Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly
245 250 255
Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln
260 265 270
Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser
275 280 285
Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr
290 295 300
Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg
305 310 315 320
Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro
325 330 335
Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser
340 345 350
Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His
355 360 365
Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu
370 375 380
Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu
385 390 395 400
Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys
405 410 415
Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys
420 425 430
His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr
435 440 445
Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg
450 455 460
Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His
465 470 475 480
Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys
485 490 495
Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser
500 505 510
Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Gln
515 520 525
Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro
530 535 540
Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Gln Glu
545 550 555 560
Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Pro Thr Thr
565 570 575
Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Glu Glu Pro Glu
580 585 590
Cys Asn Asp Ile Thr Ala Arg Leu Gln Tyr Val Lys Val Gly Ser Cys
595 600 605
Lys Ser Glu Val Glu Val Asp Ile His Tyr Cys Gln Gly Lys Cys Ala
610 615 620
Ser Lys Ala Met Tyr Ser Ile Asp Ile Asn Asp Val Gln Asp Gln Cys
625 630 635 640
Ser Cys Cys Ser Pro Thr Arg Thr Glu Pro Met Gln Val Ala Leu His
645 650 655
Cys Thr Asn Gly Ser Val Val Tyr His Glu Val Leu Asn Ala Met Glu
660 665 670
Cys Lys Cys Ser Pro Arg Lys Cys Ser Lys
675 680
<210> 10
<211> 682
<212> PRT
<213> 智人
<400> 10
Met Ile Pro Ala Arg Phe Ala Gly Val Leu Leu Ala Leu Ala Leu Ile
1 5 10 15
Leu Pro Gly Thr Leu Cys Ser Leu Ser Cys Arg Pro Pro Met Val Lys
20 25 30
Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu Gly Leu Glu Cys Thr
35 40 45
Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met Ser Met Gly Cys Val
50 55 60
Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg His Glu Asn Arg Cys
65 70 75 80
Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln Gly Lys Glu Tyr Ala
85 90 95
Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr Cys Val Cys Gln Asp
100 105 110
Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp Ala Thr Cys Ser Thr
115 120 125
Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly Leu Lys Tyr Leu Phe
130 135 140
Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp Tyr Cys Gly Ser Asn
145 150 155 160
Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys Gly Cys Ser His Pro
165 170 175
Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu Val Glu Gly Gly Glu
180 185 190
Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys Arg Pro Met Lys Asp
195 200 205
Glu Thr His Phe Glu Val Val Glu Ser Gly Arg Tyr Ile Ile Leu Leu
210 215 220
Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg His Leu Ser Ile Ser
225 230 235 240
Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val Cys Gly Leu Cys Gly
245 250 255
Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr Ser Ser Asn Leu Gln
260 265 270
Val Glu Glu Asp Pro Val Asp Phe Gly Asn Ser Trp Lys Val Ser Ser
275 280 285
Gln Cys Ala Asp Thr Arg Lys Val Pro Leu Asp Ser Ser Pro Ala Thr
290 295 300
Cys His Asn Asn Ile Met Lys Gln Thr Met Val Asp Ser Ser Cys Arg
305 310 315 320
Ile Leu Thr Ser Asp Val Phe Gln Asp Cys Asn Lys Leu Val Asp Pro
325 330 335
Glu Pro Tyr Leu Asp Val Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser
340 345 350
Ile Gly Asp Cys Ala Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His
355 360 365
Val Cys Ala Gln His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu
370 375 380
Cys Pro Gln Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu
385 390 395 400
Cys Glu Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys
405 410 415
Gln His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys
420 425 430
His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln Thr
435 440 445
Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly Arg Arg
450 455 460
Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp Pro Glu His
465 470 475 480
Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr Cys Glu Ala Cys
485 490 495
Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser
500 505 510
Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Gln
515 520 525
Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro
530 535 540
Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Gln Glu
545 550 555 560
Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Pro Thr Thr
565 570 575
Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Glu Glu Pro Glu
580 585 590
Cys Asn Asp Ile Thr Ala Arg Leu Gln Tyr Val Lys Val Gly Ser Cys
595 600 605
Lys Ser Glu Val Glu Val Asp Ile His Tyr Cys Gln Gly Lys Cys Ala
610 615 620
Ser Lys Ala Met Tyr Ser Ile Asp Ile Asn Asp Val Gln Asp Gln Cys
625 630 635 640
Ser Cys Cys Ser Pro Thr Arg Thr Glu Pro Met Gln Val Ala Leu His
645 650 655
Cys Thr Asn Gly Ser Val Val Tyr His Glu Val Leu Asn Ala Met Glu
660 665 670
Cys Lys Cys Ser Pro Arg Lys Cys Ser Lys
675 680
<210> 11
<211> 1423
<212> PRT
<213> 智人
<400> 11
Met Ile Pro Ala Arg Phe Ala Gly Val Leu Leu Ala Leu Ala Leu Ile
1 5 10 15
Leu Pro Gly Thr Leu Cys Ala Glu Gly Thr Arg Gly Arg Ser Ser Thr
20 25 30
Ala Arg Cys Ser Leu Phe Gly Ser Asp Phe Val Asn Thr Phe Asp Gly
35 40 45
Ser Met Tyr Ser Phe Ala Gly Tyr Cys Ser Tyr Leu Leu Ala Gly Gly
50 55 60
Cys Gln Lys Arg Ser Phe Ser Ile Ile Gly Asp Phe Gln Asn Gly Lys
65 70 75 80
Arg Val Ser Leu Ser Val Tyr Leu Gly Glu Phe Phe Asp Ile His Leu
85 90 95
Phe Val Asn Gly Thr Val Thr Gln Gly Asp Gln Arg Val Ser Met Pro
100 105 110
Tyr Ala Ser Lys Gly Leu Tyr Leu Glu Thr Glu Ala Gly Tyr Tyr Lys
115 120 125
Leu Ser Gly Glu Ala Tyr Gly Phe Val Ala Arg Ile Asp Gly Ser Gly
130 135 140
Asn Phe Gln Val Leu Leu Ser Asp Arg Tyr Phe Asn Lys Thr Cys Gly
145 150 155 160
Leu Cys Gly Asn Phe Asn Ile Phe Ala Glu Asp Asp Phe Met Thr Gln
165 170 175
Glu Gly Thr Leu Thr Ser Asp Pro Tyr Asp Phe Ala Asn Ser Trp Ala
180 185 190
Leu Ser Ser Gly Glu Gln Trp Cys Glu Arg Ala Ser Pro Pro Ser Ser
195 200 205
Ser Cys Asn Ile Ser Ser Gly Glu Met Gln Lys Gly Leu Trp Glu Gln
210 215 220
Cys Gln Leu Leu Lys Ser Thr Ser Val Phe Ala Arg Cys His Pro Leu
225 230 235 240
Val Asp Pro Glu Pro Phe Val Ala Leu Cys Glu Lys Thr Leu Cys Glu
245 250 255
Cys Ala Gly Gly Leu Glu Cys Ala Cys Pro Ala Leu Leu Glu Tyr Ala
260 265 270
Arg Thr Cys Ala Gln Glu Gly Met Val Leu Tyr Gly Trp Thr Asp His
275 280 285
Ser Ala Cys Ser Pro Val Cys Pro Ala Gly Met Glu Tyr Arg Gln Cys
290 295 300
Val Ser Pro Cys Ala Arg Thr Cys Gln Ser Leu His Ile Asn Glu Met
305 310 315 320
Cys Gln Glu Arg Cys Val Asp Gly Cys Ser Cys Pro Glu Gly Gln Leu
325 330 335
Leu Asp Glu Gly Leu Cys Val Glu Ser Thr Glu Cys Pro Cys Val His
340 345 350
Ser Gly Lys Arg Tyr Pro Pro Gly Thr Ser Leu Ser Arg Asp Cys Asn
355 360 365
Thr Cys Ile Cys Arg Asn Ser Gln Trp Ile Cys Ser Asn Glu Glu Cys
370 375 380
Pro Gly Glu Cys Leu Val Thr Gly Gln Ser His Phe Lys Ser Phe Asp
385 390 395 400
Asn Arg Tyr Phe Thr Phe Ser Gly Ile Cys Gln Tyr Leu Leu Ala Arg
405 410 415
Asp Cys Gln Asp His Ser Phe Ser Ile Val Ile Glu Thr Val Gln Cys
420 425 430
Ala Asp Asp Arg Asp Ala Val Cys Thr Arg Ser Val Thr Val Arg Leu
435 440 445
Pro Gly Leu His Asn Ser Leu Val Lys Leu Lys His Gly Ala Gly Val
450 455 460
Ala Met Asp Gly Gln Asp Val Gln Leu Pro Leu Leu Lys Gly Asp Leu
465 470 475 480
Arg Ile Gln His Thr Val Thr Ala Ser Val Arg Leu Ser Tyr Gly Glu
485 490 495
Asp Leu Gln Met Asp Trp Asp Gly Arg Gly Arg Leu Leu Val Lys Leu
500 505 510
Ser Pro Val Tyr Ala Gly Lys Thr Cys Gly Leu Cys Gly Asn Tyr Asn
515 520 525
Gly Asn Gln Gly Asp Asp Phe Leu Thr Pro Ser Gly Leu Ala Glu Pro
530 535 540
Arg Val Glu Asp Phe Gly Asn Ala Trp Lys Leu His Gly Asp Cys Gln
545 550 555 560
Asp Leu Gln Lys Gln His Ser Asp Pro Cys Ala Leu Asn Pro Arg Met
565 570 575
Thr Arg Phe Ser Glu Glu Ala Cys Ala Val Leu Thr Ser Pro Thr Phe
580 585 590
Glu Ala Cys His Arg Ala Val Ser Pro Leu Pro Tyr Leu Arg Asn Cys
595 600 605
Arg Tyr Asp Val Cys Ser Cys Ser Asp Gly Arg Glu Cys Leu Cys Gly
610 615 620
Ala Leu Ala Ser Tyr Ala Ala Ala Cys Ala Gly Arg Gly Val Arg Val
625 630 635 640
Ala Trp Arg Glu Pro Gly Arg Cys Glu Leu Asn Cys Pro Lys Gly Gln
645 650 655
Val Tyr Leu Gln Cys Gly Thr Pro Cys Asn Leu Thr Cys Arg Ser Leu
660 665 670
Ser Tyr Pro Asp Glu Glu Cys Asn Glu Ala Cys Leu Glu Gly Cys Phe
675 680 685
Cys Pro Pro Gly Leu Tyr Met Asp Glu Arg Gly Asp Cys Val Pro Lys
690 695 700
Ala Gln Cys Pro Cys Tyr Tyr Asp Gly Glu Ile Phe Gln Pro Glu Asp
705 710 715 720
Ile Phe Ser Asp His His Thr Met Cys Tyr Cys Glu Asp Gly Phe Met
725 730 735
His Cys Thr Met Ser Gly Val Pro Gly Ser Leu Leu Pro Asp Ala Val
740 745 750
Leu Ser Ser Pro Leu Ser His Arg Ser Lys Arg Ser Leu Ser Cys Arg
755 760 765
Pro Pro Met Val Lys Leu Val Cys Pro Ala Asp Asn Leu Arg Ala Glu
770 775 780
Gly Leu Glu Cys Thr Lys Thr Cys Gln Asn Tyr Asp Leu Glu Cys Met
785 790 795 800
Ser Met Gly Cys Val Ser Gly Cys Leu Cys Pro Pro Gly Met Val Arg
805 810 815
His Glu Asn Arg Cys Val Ala Leu Glu Arg Cys Pro Cys Phe His Gln
820 825 830
Gly Lys Glu Tyr Ala Pro Gly Glu Thr Val Lys Ile Gly Cys Asn Thr
835 840 845
Cys Val Cys Gln Asp Arg Lys Trp Asn Cys Thr Asp His Val Cys Asp
850 855 860
Ala Thr Cys Ser Thr Ile Gly Met Ala His Tyr Leu Thr Phe Asp Gly
865 870 875 880
Leu Lys Tyr Leu Phe Pro Gly Glu Cys Gln Tyr Val Leu Val Gln Asp
885 890 895
Tyr Cys Gly Ser Asn Pro Gly Thr Phe Arg Ile Leu Val Gly Asn Lys
900 905 910
Gly Cys Ser His Pro Ser Val Lys Cys Lys Lys Arg Val Thr Ile Leu
915 920 925
Val Glu Gly Gly Glu Ile Glu Leu Phe Asp Gly Glu Val Asn Val Lys
930 935 940
Arg Pro Met Lys Asp Glu Thr His Phe Glu Val Val Glu Ser Gly Arg
945 950 955 960
Tyr Ile Ile Leu Leu Leu Gly Lys Ala Leu Ser Val Val Trp Asp Arg
965 970 975
His Leu Ser Ile Ser Val Val Leu Lys Gln Thr Tyr Gln Glu Lys Val
980 985 990
Cys Gly Leu Cys Gly Asn Phe Asp Gly Ile Gln Asn Asn Asp Leu Thr
995 1000 1005
Ser Ser Asn Leu Gln Val Glu Glu Asp Pro Val Asp Phe Gly Asn
1010 1015 1020
Ser Trp Lys Val Ser Ser Gln Cys Ala Asp Thr Arg Lys Val Pro
1025 1030 1035
Leu Asp Ser Ser Pro Ala Thr Cys His Asn Asn Ile Met Lys Gln
1040 1045 1050
Thr Met Val Asp Ser Ser Cys Arg Ile Leu Thr Ser Asp Val Phe
1055 1060 1065
Gln Asp Cys Asn Lys Leu Val Asp Pro Glu Pro Tyr Leu Asp Val
1070 1075 1080
Cys Ile Tyr Asp Thr Cys Ser Cys Glu Ser Ile Gly Asp Cys Ala
1085 1090 1095
Cys Phe Cys Asp Thr Ile Ala Ala Tyr Ala His Val Cys Ala Gln
1100 1105 1110
His Gly Lys Val Val Thr Trp Arg Thr Ala Thr Leu Cys Pro Gln
1115 1120 1125
Ser Cys Glu Glu Arg Asn Leu Arg Glu Asn Gly Tyr Glu Cys Glu
1130 1135 1140
Trp Arg Tyr Asn Ser Cys Ala Pro Ala Cys Gln Val Thr Cys Gln
1145 1150 1155
His Pro Glu Pro Leu Ala Cys Pro Val Gln Cys Val Glu Gly Cys
1160 1165 1170
His Ala His Cys Pro Pro Gly Lys Ile Leu Asp Glu Leu Leu Gln
1175 1180 1185
Thr Cys Val Asp Pro Glu Asp Cys Pro Val Cys Glu Val Ala Gly
1190 1195 1200
Arg Arg Phe Ala Ser Gly Lys Lys Val Thr Leu Asn Pro Ser Asp
1205 1210 1215
Pro Glu His Cys Gln Ile Cys His Cys Asp Val Val Asn Leu Thr
1220 1225 1230
Cys Glu Ala Cys Gln Glu Pro Gly Gly Leu Val Val Pro Pro Thr
1235 1240 1245
Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser
1250 1255 1260
Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu Val Val Pro Pro
1265 1270 1275
Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val Glu Asp Ile
1280 1285 1290
Ser Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu Val Val Pro
1295 1300 1305
Pro Thr Asp Ala Pro Val Pro Thr Thr Leu Tyr Val Glu Asp Ile
1310 1315 1320
Ser Glu Pro Pro Leu His Glu Glu Pro Glu Cys Asn Asp Ile Thr
1325 1330 1335
Ala Arg Leu Gln Tyr Val Lys Val Gly Ser Cys Lys Ser Glu Val
1340 1345 1350
Glu Val Asp Ile His Tyr Cys Gln Gly Lys Cys Ala Ser Lys Ala
1355 1360 1365
Met Tyr Ser Ile Asp Ile Asn Asp Val Gln Asp Gln Cys Ser Cys
1370 1375 1380
Cys Ser Pro Thr Arg Thr Glu Pro Met Gln Val Ala Leu His Cys
1385 1390 1395
Thr Asn Gly Ser Val Val Tyr His Glu Val Leu Asn Ala Met Glu
1400 1405 1410
Cys Lys Cys Ser Pro Arg Lys Cys Ser Lys
1415 1420
<210> 12
<211> 16
<212> PRT
<213> 智人
<400> 12
Ser Phe Ser Gln Asn Ser Arg His Gln Ala Tyr Arg Tyr Arg Arg Gly
1 5 10 15
<210> 13
<211> 1440
<212> PRT
<213> 智人
<400> 13
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 Gln Ala Tyr Arg
740 745 750
Tyr Arg Arg Gly Glu Ile Thr Arg Thr Thr Leu Gln Ser Asp Gln Glu
755 760 765
Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp
770 775 780
Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln
785 790 795 800
Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp
805 810 815
Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser
820 825 830
Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp
835 840 845
Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu
850 855 860
Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met
865 870 875 880
Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser
885 890 895
Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys
900 905 910
Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln
915 920 925
His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala
930 935 940
Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile
945 950 955 960
Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly
965 970 975
Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp
980 985 990
Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg
995 1000 1005
Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn
1010 1015 1020
Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro
1025 1030 1035
Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu
1040 1045 1050
Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly
1055 1060 1065
His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu
1070 1075 1080
Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro
1085 1090 1095
Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His
1100 1105 1110
Leu His Ala Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys
1115 1120 1125
Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe
1130 1135 1140
Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu
1145 1150 1155
Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys
1160 1165 1170
Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile
1175 1180 1185
Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser
1190 1195 1200
Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys
1205 1210 1215
Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val
1220 1225 1230
Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe
1235 1240 1245
Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His
1250 1255 1260
Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp
1265 1270 1275
Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala Ile
1280 1285 1290
Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe
1295 1300 1305
Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg
1310 1315 1320
Ser Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu
1325 1330 1335
Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr
1340 1345 1350
Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe
1355 1360 1365
Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe
1370 1375 1380
Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp Ser Phe
1385 1390 1395
Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr
1400 1405 1410
Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg
1415 1420 1425
Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr
1430 1435 1440
<210> 14
<211> 1530
<212> PRT
<213> 智人
<400> 14
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 Gln Glu Pro Gly
740 745 750
Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu
755 760 765
Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Gln Glu Pro Gly Gly
770 775 780
Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr
785 790 795 800
Val Glu Asp Ile Ser Glu Pro Pro Leu His Gln Glu Pro Gly Gly Leu
805 810 815
Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr Thr Leu Tyr Val
820 825 830
Glu Asp Ile Ser Glu Pro Pro Leu His Arg Tyr Arg Arg Gly Glu Ile
835 840 845
Thr Arg Thr Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp
850 855 860
Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu
865 870 875 880
Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr Arg His Tyr
885 890 895
Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser
900 905 910
Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro Gln Phe
915 920 925
Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro
930 935 940
Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly Pro Tyr
945 950 955 960
Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Arg Asn Gln
965 970 975
Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu
980 985 990
Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val Lys Pro Asn
995 1000 1005
Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met Ala Pro
1010 1015 1020
Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp
1025 1030 1035
Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu
1040 1045 1050
Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln
1055 1060 1065
Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu
1070 1075 1080
Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg
1085 1090 1095
Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn
1100 1105 1110
Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro
1115 1120 1125
Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu
1130 1135 1140
Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly
1145 1150 1155
His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu
1160 1165 1170
Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro
1175 1180 1185
Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His
1190 1195 1200
Leu His Ala Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys
1205 1210 1215
Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe
1220 1225 1230
Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu
1235 1240 1245
Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys
1250 1255 1260
Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile
1265 1270 1275
Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser
1280 1285 1290
Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys
1295 1300 1305
Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val
1310 1315 1320
Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe
1325 1330 1335
Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His
1340 1345 1350
Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp
1355 1360 1365
Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala Ile
1370 1375 1380
Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe
1385 1390 1395
Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg
1400 1405 1410
Ser Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu
1415 1420 1425
Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr
1430 1435 1440
Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe
1445 1450 1455
Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe
1460 1465 1470
Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp Ser Phe
1475 1480 1485
Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr
1490 1495 1500
Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg
1505 1510 1515
Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr
1520 1525 1530
<210> 15
<211> 3807
<212> DNA
<213> 智人
<400> 15
atgatccccg ccagatttgc cggcgtgctg ctggccctgg ctctgatcct gcctggaaca 60
ctgtgtgccg agggcaccag aggcagatcc agcaccgcca gatgcagcct gttcggcagc 120
gacttcgtga acaccttcga cggcagcatg tacagcttcg ccggctactg ctcctacctg 180
ctggctggcg gctgccagaa gcggagcttt agcatcatcg gcgacttcca gaacggcaag 240
cgggtgtccc tgagcgtgta cctgggcgag ttcttcgaca tccacctgtt cgtgaacggc 300
accgtgaccc agggcgatca gagggtgtcc atgccctacg ccagcaaggg cctgtacctg 360
gaaacagagg ccggctatta caagctgagc ggcgaggcct acggcttcgt ggccagaatc 420
gatggcagcg gcaacttcca ggtgctgctg agcgaccggt acttcaacaa gacctgcggc 480
ctgtgcggca atttcaacat cttcgccgag gacgacttca tgacccagga aggcaccctg 540
accagcgacc cctacgactt cgccaatagc tgggccctgt ctagcggcga gcagtggtgc 600
gaaagagcca gccctcctag cagcagctgc aacatcagca gcggcgagat gcagaaaggc 660
ctgtgggagc agtgccagct gctgaagtcc accagcgtgt tcgccaggtg ccaccctctg 720
gtggaccctg agccttttgt ggccctgtgc gagaaaacac tgtgcgagtg tgccggcgga 780
ctggaatgtg cctgtcctgc cctgctggaa tacgccagaa cctgcgctca ggaagggatg 840
gtgctgtacg gctggaccga ccactctgcc tgtagccctg tgtgtcctgc cggcatggaa 900
tatcggcagt gcgtgtcccc ctgcgccagg acctgtcaga gcctgcacat caacgagatg 960
tgccaggaac gctgcgtgga cggctgtagc tgtcctgagg gacagctgct ggatgagggc 1020
ctgtgtgtgg aaagcaccga gtgcccttgt gtgcacagcg gcaagagata cccccctggc 1080
accagcctga gccgggactg caatacctgc atctgccgga acagccagtg gatctgctcc 1140
aacgaggaat gccctggcga gtgcctcgtg acaggccaga gccacttcaa gagcttcgac 1200
aacagatact tcaccttcag cggcatctgc cagtatctgc tggccagaga ctgccaggac 1260
cacagcttca gcatcgtgat cgagacagtg cagtgcgccg acgacagaga tgccgtgtgc 1320
accagatccg tgaccgtgcg gctgcctggc ctgcacaaca gcctcgtgaa gctgaaacac 1380
ggcgctgggg tggccatgga cggacaggac gtgcagctgc ctctgctgaa gggcgacctg 1440
agaatccagc acaccgtgac agcctctgtg cggctgagct acggcgagga cctccagatg 1500
gactgggatg gcaggggcag actgctcgtg aaactgagcc cagtgtatgc cggcaagact 1560
tgtggactgt gtggcaacta caacggcaac cagggcgacg atttcctgac cccttctggc 1620
ctggccgagc cccgggtgga agattttggc aacgcctgga agctgcacgg cgactgtcag 1680
gatctccaga agcagcacag cgacccttgc gccctgaacc cccggatgac cagattcagc 1740
gaagaggcct gtgccgtgct gaccagccct acctttgagg cctgccacag agccgtgtct 1800
ccactgcctt acctgcggaa ttgcagatac gacgtgtgct cctgctccga cggccgcgaa 1860
tgtctgtgtg gcgccctggc ctcttatgcc gccgcttgtg ctggaagagg cgtgcgggtg 1920
gcatggcggg aaccaggcag atgcgagctg aactgcccta agggccaggt gtacctccag 1980
tgcggcaccc cctgcaacct gacctgtaga agcctgagct accccgacga agagtgcaac 2040
gaggcctgtc tggaaggctg cttttgccct cccggcctgt atatggacga gcggggcgat 2100
tgtgtgccca aggcccagtg cccctgctac tacgacggcg agattttcca gcccgaggac 2160
atcttcagcg accaccacac catgtgctac tgcgaggatg gcttcatgca ctgcaccatg 2220
agcggcgtgc caggctccct gctgcctgat gctgtgctgt ctagccccct gagccacaga 2280
agcaagagaa gcctgtcttg cagacccccc atggtcaagc tcgtgtgccc tgccgacaac 2340
ctgagagccg agggcctgga atgcaccaag acatgccaga actacgacct ggaatgcatg 2400
agcatgggct gcgtgtccgg ctgtctgtgc cctcctggca tggtgcgcca cgagaataga 2460
tgcgtggccc tggaacggtg cccgtgcttt catcagggca aagagtacgc cccaggcgaa 2520
accgtgaaga tcggctgcaa cacatgcgtg tgtcaggacc ggaagtggaa ctgcaccgac 2580
cacgtgtgcg acgccacctg tagcacaatc ggcatggccc actacctgac cttcgatggc 2640
ctgaagtacc tgttccccgg cgagtgtcag tacgtgctgg tgcaggatta ctgcggcagc 2700
aaccccggca ccttcagaat cctcgtgggc aacaagggct gtagccaccc ctccgtgaag 2760
tgcaagaaac gcgtgaccat cctggtggaa ggcggagaga tcgagctgtt cgacggcgaa 2820
gtgaacgtga agcggcccat gaaggacgag acacacttcg aggtggtgga aagcggccgg 2880
tacatcatcc tgctgctggg caaagccctg tccgtcgtgt gggacagaca cctgagcatc 2940
agcgtggtgc tgaagcagac ctaccaggaa aaagtgtgcg ggctgtgtgg gaactttgac 3000
ggcatccaga acaacgatct gaccagcagc aatctccagg tggaagagga ccccgtggac 3060
ttcggcaatt cctggaaggt gtccagccag tgtgccgaca ccagaaaggt gcccctggat 3120
agcagccccg ccacatgcca caacaacatc atgaagcaga caatggtgga cagcagctgc 3180
cgcatcctga cctccgatgt gtttcaggac tgcaacaaac tggtggaccc cgaaccctac 3240
ctggacgtgt gcatctacga cacatgcagc tgcgagagca tcggcgattg cgcctgcttc 3300
tgcgacacca ttgccgccta cgcccatgtg tgcgcccagc acggaaaggt cgtgacttgg 3360
agaaccgcca ccctgtgccc acagagctgc gaggaacgga acctgcggga aaacggctac 3420
gagtgcgagt ggcggtacaa cagctgtgcc ccagcctgcc aagtgacctg ccagcaccct 3480
gaacctctgg cttgccccgt gcagtgcgtg gaaggatgtc acgcccattg cccacccggc 3540
aagatcctgg atgagctgct ccagacctgt gtggacccag aggactgccc agtgtgcgaa 3600
gtggccggaa gaagattcgc ctccggcaag aaagtgaccc tgaatccctc cgaccccgag 3660
cactgtcaga tttgtcactg cgacgtcgtg aatctgacat gcgaagcctg ccaggaacct 3720
ggcggactgg tggtgcctcc tacagatgcc cctgtgtccc ccaccaccct gtacgtggaa 3780
gatatcagcg agccccccct gcactaa 3807
<210> 16
<211> 93
<212> DNA
<213> 智人
<400> 16
caggaacctg gcggactggt ggtgcctcct acagatgccc ctgtgtcccc caccaccctg 60
tacgtggaag atatcagcga gccccccctg cac 93
<210> 17
<211> 3993
<212> DNA
<213> 智人
<400> 17
atgatccccg ccagatttgc cggcgtgctg ctggccctgg ctctgatcct gcctggaaca 60
ctgtgtgccg agggcaccag aggcagatcc agcaccgcca gatgcagcct gttcggcagc 120
gacttcgtga acaccttcga cggcagcatg tacagcttcg ccggctactg ctcctacctg 180
ctggctggcg gctgccagaa gcggagcttt agcatcatcg gcgacttcca gaacggcaag 240
cgggtgtccc tgagcgtgta cctgggcgag ttcttcgaca tccacctgtt cgtgaacggc 300
accgtgaccc agggcgatca gagggtgtcc atgccctacg ccagcaaggg cctgtacctg 360
gaaacagagg ccggctatta caagctgagc ggcgaggcct acggcttcgt ggccagaatc 420
gatggcagcg gcaacttcca ggtgctgctg agcgaccggt acttcaacaa gacctgcggc 480
ctgtgcggca atttcaacat cttcgccgag gacgacttca tgacccagga aggcaccctg 540
accagcgacc cctacgactt cgccaatagc tgggccctgt ctagcggcga gcagtggtgc 600
gaaagagcca gccctcctag cagcagctgc aacatcagca gcggcgagat gcagaaaggc 660
ctgtgggagc agtgccagct gctgaagtcc accagcgtgt tcgccaggtg ccaccctctg 720
gtggaccctg agccttttgt ggccctgtgc gagaaaacac tgtgcgagtg tgccggcgga 780
ctggaatgtg cctgtcctgc cctgctggaa tacgccagaa cctgcgctca ggaagggatg 840
gtgctgtacg gctggaccga ccactctgcc tgtagccctg tgtgtcctgc cggcatggaa 900
tatcggcagt gcgtgtcccc ctgcgccagg acctgtcaga gcctgcacat caacgagatg 960
tgccaggaac gctgcgtgga cggctgtagc tgtcctgagg gacagctgct ggatgagggc 1020
ctgtgtgtgg aaagcaccga gtgcccttgt gtgcacagcg gcaagagata cccccctggc 1080
accagcctga gccgggactg caatacctgc atctgccgga acagccagtg gatctgctcc 1140
aacgaggaat gccctggcga gtgcctcgtg acaggccaga gccacttcaa gagcttcgac 1200
aacagatact tcaccttcag cggcatctgc cagtatctgc tggccagaga ctgccaggac 1260
cacagcttca gcatcgtgat cgagacagtg cagtgcgccg acgacagaga tgccgtgtgc 1320
accagatccg tgaccgtgcg gctgcctggc ctgcacaaca gcctcgtgaa gctgaaacac 1380
ggcgctgggg tggccatgga cggacaggac gtgcagctgc ctctgctgaa gggcgacctg 1440
agaatccagc acaccgtgac agcctctgtg cggctgagct acggcgagga cctccagatg 1500
gactgggatg gcaggggcag actgctcgtg aaactgagcc cagtgtatgc cggcaagact 1560
tgtggactgt gtggcaacta caacggcaac cagggcgacg atttcctgac cccttctggc 1620
ctggccgagc cccgggtgga agattttggc aacgcctgga agctgcacgg cgactgtcag 1680
gatctccaga agcagcacag cgacccttgc gccctgaacc cccggatgac cagattcagc 1740
gaagaggcct gtgccgtgct gaccagccct acctttgagg cctgccacag agccgtgtct 1800
ccactgcctt acctgcggaa ttgcagatac gacgtgtgct cctgctccga cggccgcgaa 1860
tgtctgtgtg gcgccctggc ctcttatgcc gccgcttgtg ctggaagagg cgtgcgggtg 1920
gcatggcggg aaccaggcag atgcgagctg aactgcccta agggccaggt gtacctccag 1980
tgcggcaccc cctgcaacct gacctgtaga agcctgagct accccgacga agagtgcaac 2040
gaggcctgtc tggaaggctg cttttgccct cccggcctgt atatggacga gcggggcgat 2100
tgtgtgccca aggcccagtg cccctgctac tacgacggcg agattttcca gcccgaggac 2160
atcttcagcg accaccacac catgtgctac tgcgaggatg gcttcatgca ctgcaccatg 2220
agcggcgtgc caggctccct gctgcctgat gctgtgctgt ctagccccct gagccacaga 2280
agcaagagaa gcctgtcttg cagacccccc atggtcaagc tcgtgtgccc tgccgacaac 2340
ctgagagccg agggcctgga atgcaccaag acatgccaga actacgacct ggaatgcatg 2400
agcatgggct gcgtgtccgg ctgtctgtgc cctcctggca tggtgcgcca cgagaataga 2460
tgcgtggccc tggaacggtg cccgtgcttt catcagggca aagagtacgc cccaggcgaa 2520
accgtgaaga tcggctgcaa cacatgcgtg tgtcaggacc ggaagtggaa ctgcaccgac 2580
cacgtgtgcg acgccacctg tagcacaatc ggcatggccc actacctgac cttcgatggc 2640
ctgaagtacc tgttccccgg cgagtgtcag tacgtgctgg tgcaggatta ctgcggcagc 2700
aaccccggca ccttcagaat cctcgtgggc aacaagggct gtagccaccc ctccgtgaag 2760
tgcaagaaac gcgtgaccat cctggtggaa ggcggagaga tcgagctgtt cgacggcgaa 2820
gtgaacgtga agcggcccat gaaggacgag acacacttcg aggtggtgga aagcggccgg 2880
tacatcatcc tgctgctggg caaagccctg tccgtcgtgt gggacagaca cctgagcatc 2940
agcgtggtgc tgaagcagac ctaccaggaa aaagtgtgcg ggctgtgtgg gaactttgac 3000
ggcatccaga acaacgatct gaccagcagc aatctccagg tggaagagga ccccgtggac 3060
ttcggcaatt cctggaaggt gtccagccag tgtgccgaca ccagaaaggt gcccctggat 3120
agcagccccg ccacatgcca caacaacatc atgaagcaga caatggtgga cagcagctgc 3180
cgcatcctga cctccgatgt gtttcaggac tgcaacaaac tggtggaccc cgaaccctac 3240
ctggacgtgt gcatctacga cacatgcagc tgcgagagca tcggcgattg cgcctgcttc 3300
tgcgacacca ttgccgccta cgcccatgtg tgcgcccagc acggaaaggt cgtgacttgg 3360
agaaccgcca ccctgtgccc acagagctgc gaggaacgga acctgcggga aaacggctac 3420
gagtgcgagt ggcggtacaa cagctgtgcc ccagcctgcc aagtgacctg ccagcaccct 3480
gaacctctgg cttgccccgt gcagtgcgtg gaaggatgtc acgcccattg cccacccggc 3540
aagatcctgg atgagctgct ccagacctgt gtggacccag aggactgccc agtgtgcgaa 3600
gtggccggaa gaagattcgc ctccggcaag aaagtgaccc tgaatccctc cgaccccgag 3660
cactgtcaga tttgtcactg cgacgtcgtg aatctgacat gcgaagcctg ccaggaacct 3720
ggcggactgg tggtgcctcc tacagatgcc cctgtgtccc ccaccaccct gtacgtggaa 3780
gatatcagcg agccccccct gcaccaggaa cctggcggac tggtggtgcc tcctacagac 3840
gctcctgtgt ctcctacaac actgtatgtg gaagatattt ccgagcctcc tctgcatcag 3900
gaaccagggg gcctggtggt gccaccaact gatgcaccag tgtctccaac tactctgtac 3960
gtggaagata tttctgaacc ccccctgcat taa 3993
<210> 18
<211> 4179
<212> DNA
<213> 智人
<400> 18
atgatccccg ccagatttgc cggcgtgctg ctggccctgg ctctgatcct gcctggaaca 60
ctgtgtgccg agggcaccag aggcagatcc agcaccgcca gatgcagcct gttcggcagc 120
gacttcgtga acaccttcga cggcagcatg tacagcttcg ccggctactg ctcctacctg 180
ctggctggcg gctgccagaa gcggagcttt agcatcatcg gcgacttcca gaacggcaag 240
cgggtgtccc tgagcgtgta cctgggcgag ttcttcgaca tccacctgtt cgtgaacggc 300
accgtgaccc agggcgatca gagggtgtcc atgccctacg ccagcaaggg cctgtacctg 360
gaaacagagg ccggctatta caagctgagc ggcgaggcct acggcttcgt ggccagaatc 420
gatggcagcg gcaacttcca ggtgctgctg agcgaccggt acttcaacaa gacctgcggc 480
ctgtgcggca atttcaacat cttcgccgag gacgacttca tgacccagga aggcaccctg 540
accagcgacc cctacgactt cgccaatagc tgggccctgt ctagcggcga gcagtggtgc 600
gaaagagcca gccctcctag cagcagctgc aacatcagca gcggcgagat gcagaaaggc 660
ctgtgggagc agtgccagct gctgaagtcc accagcgtgt tcgccaggtg ccaccctctg 720
gtggaccctg agccttttgt ggccctgtgc gagaaaacac tgtgcgagtg tgccggcgga 780
ctggaatgtg cctgtcctgc cctgctggaa tacgccagaa cctgcgctca ggaagggatg 840
gtgctgtacg gctggaccga ccactctgcc tgtagccctg tgtgtcctgc cggcatggaa 900
tatcggcagt gcgtgtcccc ctgcgccagg acctgtcaga gcctgcacat caacgagatg 960
tgccaggaac gctgcgtgga cggctgtagc tgtcctgagg gacagctgct ggatgagggc 1020
ctgtgtgtgg aaagcaccga gtgcccttgt gtgcacagcg gcaagagata cccccctggc 1080
accagcctga gccgggactg caatacctgc atctgccgga acagccagtg gatctgctcc 1140
aacgaggaat gccctggcga gtgcctcgtg acaggccaga gccacttcaa gagcttcgac 1200
aacagatact tcaccttcag cggcatctgc cagtatctgc tggccagaga ctgccaggac 1260
cacagcttca gcatcgtgat cgagacagtg cagtgcgccg acgacagaga tgccgtgtgc 1320
accagatccg tgaccgtgcg gctgcctggc ctgcacaaca gcctcgtgaa gctgaaacac 1380
ggcgctgggg tggccatgga cggacaggac gtgcagctgc ctctgctgaa gggcgacctg 1440
agaatccagc acaccgtgac agcctctgtg cggctgagct acggcgagga cctccagatg 1500
gactgggatg gcaggggcag actgctcgtg aaactgagcc cagtgtatgc cggcaagact 1560
tgtggactgt gtggcaacta caacggcaac cagggcgacg atttcctgac cccttctggc 1620
ctggccgagc cccgggtgga agattttggc aacgcctgga agctgcacgg cgactgtcag 1680
gatctccaga agcagcacag cgacccttgc gccctgaacc cccggatgac cagattcagc 1740
gaagaggcct gtgccgtgct gaccagccct acctttgagg cctgccacag agccgtgtct 1800
ccactgcctt acctgcggaa ttgcagatac gacgtgtgct cctgctccga cggccgcgaa 1860
tgtctgtgtg gcgccctggc ctcttatgcc gccgcttgtg ctggaagagg cgtgcgggtg 1920
gcatggcggg aaccaggcag atgcgagctg aactgcccta agggccaggt gtacctccag 1980
tgcggcaccc cctgcaacct gacctgtaga agcctgagct accccgacga agagtgcaac 2040
gaggcctgtc tggaaggctg cttttgccct cccggcctgt atatggacga gcggggcgat 2100
tgtgtgccca aggcccagtg cccctgctac tacgacggcg agattttcca gcccgaggac 2160
atcttcagcg accaccacac catgtgctac tgcgaggatg gcttcatgca ctgcaccatg 2220
agcggcgtgc caggctccct gctgcctgat gctgtgctgt ctagccccct gagccacaga 2280
agcaagagaa gcctgtcttg cagacccccc atggtcaagc tcgtgtgccc tgccgacaac 2340
ctgagagccg agggcctgga atgcaccaag acatgccaga actacgacct ggaatgcatg 2400
agcatgggct gcgtgtccgg ctgtctgtgc cctcctggca tggtgcgcca cgagaataga 2460
tgcgtggccc tggaacggtg cccgtgcttt catcagggca aagagtacgc cccaggcgaa 2520
accgtgaaga tcggctgcaa cacatgcgtg tgtcaggacc ggaagtggaa ctgcaccgac 2580
cacgtgtgcg acgccacctg tagcacaatc ggcatggccc actacctgac cttcgatggc 2640
ctgaagtacc tgttccccgg cgagtgtcag tacgtgctgg tgcaggatta ctgcggcagc 2700
aaccccggca ccttcagaat cctcgtgggc aacaagggct gtagccaccc ctccgtgaag 2760
tgcaagaaac gcgtgaccat cctggtggaa ggcggagaga tcgagctgtt cgacggcgaa 2820
gtgaacgtga agcggcccat gaaggacgag acacacttcg aggtggtgga aagcggccgg 2880
tacatcatcc tgctgctggg caaagccctg tccgtcgtgt gggacagaca cctgagcatc 2940
agcgtggtgc tgaagcagac ctaccaggaa aaagtgtgcg ggctgtgtgg gaactttgac 3000
ggcatccaga acaacgatct gaccagcagc aatctccagg tggaagagga ccccgtggac 3060
ttcggcaatt cctggaaggt gtccagccag tgtgccgaca ccagaaaggt gcccctggat 3120
agcagccccg ccacatgcca caacaacatc atgaagcaga caatggtgga cagcagctgc 3180
cgcatcctga cctccgatgt gtttcaggac tgcaacaaac tggtggaccc cgaaccctac 3240
ctggacgtgt gcatctacga cacatgcagc tgcgagagca tcggcgattg cgcctgcttc 3300
tgcgacacca ttgccgccta cgcccatgtg tgcgcccagc acggaaaggt cgtgacttgg 3360
agaaccgcca ccctgtgccc acagagctgc gaggaacgga acctgcggga aaacggctac 3420
gagtgcgagt ggcggtacaa cagctgtgcc ccagcctgcc aagtgacctg ccagcaccct 3480
gaacctctgg cttgccccgt gcagtgcgtg gaaggatgtc acgcccattg cccacccggc 3540
aagatcctgg atgagctgct ccagacctgt gtggacccag aggactgccc agtgtgcgaa 3600
gtggccggaa gaagattcgc ctccggcaag aaagtgaccc tgaatccctc cgaccccgag 3660
cactgtcaga tttgtcactg cgacgtcgtg aatctgacat gcgaagcctg ccaggaacct 3720
ggcggactgg tggtgcctcc tacagatgcc cctgtgtccc ccaccaccct gtacgtggaa 3780
gatatcagcg agccccccct gcaccaagaa cctggtggac tggtggtgcc tcctacagat 3840
gctcctgtgt ctcccaccac actgtacgtg gaagatatca gcgagcctcc tctgcaccaa 3900
gagccaggcg gacttgtggt cccaccaact gatgcccctg tcagccctac aactctgtac 3960
gtcgaggaca tctccgagcc accactgcat caagaacctg gcggccttgt cgttcctcca 4020
acagacgcac ctgttagccc aactacactg tatgttgagg acataagcga accgcctctc 4080
catcaagaac ccggtggtct tgttgtccca cctacagacg ccccagtctc tcctaccact 4140
ctctatgtcg aagatatttc cgaacctcca ctgcactaa 4179
<210> 19
<211> 4275
<212> DNA
<213> 智人
<400> 19
atgatccccg ccagatttgc cggcgtgctg ctggccctgg ctctgatcct gcctggaaca 60
ctgtgtgccg agggcaccag aggcagatcc agcaccgcca gatgcagcct gttcggcagc 120
gacttcgtga acaccttcga cggcagcatg tacagcttcg ccggctactg ctcctacctg 180
ctggctggcg gctgccagaa gcggagcttt agcatcatcg gcgacttcca gaacggcaag 240
cgggtgtccc tgagcgtgta cctgggcgag ttcttcgaca tccacctgtt cgtgaacggc 300
accgtgaccc agggcgatca gagggtgtcc atgccctacg ccagcaaggg cctgtacctg 360
gaaacagagg ccggctatta caagctgagc ggcgaggcct acggcttcgt ggccagaatc 420
gatggcagcg gcaacttcca ggtgctgctg agcgaccggt acttcaacaa gacctgcggc 480
ctgtgcggca atttcaacat cttcgccgag gacgacttca tgacccagga aggcaccctg 540
accagcgacc cctacgactt cgccaatagc tgggccctgt ctagcggcga gcagtggtgc 600
gaaagagcca gccctcctag cagcagctgc aacatcagca gcggcgagat gcagaaaggc 660
ctgtgggagc agtgccagct gctgaagtcc accagcgtgt tcgccaggtg ccaccctctg 720
gtggaccctg agccttttgt ggccctgtgc gagaaaacac tgtgcgagtg tgccggcgga 780
ctggaatgtg cctgtcctgc cctgctggaa tacgccagaa cctgcgctca ggaagggatg 840
gtgctgtacg gctggaccga ccactctgcc tgtagccctg tgtgtcctgc cggcatggaa 900
tatcggcagt gcgtgtcccc ctgcgccagg acctgtcaga gcctgcacat caacgagatg 960
tgccaggaac gctgcgtgga cggctgtagc tgtcctgagg gacagctgct ggatgagggc 1020
ctgtgtgtgg aaagcaccga gtgcccttgt gtgcacagcg gcaagagata cccccctggc 1080
accagcctga gccgggactg caatacctgc atctgccgga acagccagtg gatctgctcc 1140
aacgaggaat gccctggcga gtgcctcgtg acaggccaga gccacttcaa gagcttcgac 1200
aacagatact tcaccttcag cggcatctgc cagtatctgc tggccagaga ctgccaggac 1260
cacagcttca gcatcgtgat cgagacagtg cagtgcgccg acgacagaga tgccgtgtgc 1320
accagatccg tgaccgtgcg gctgcctggc ctgcacaaca gcctcgtgaa gctgaaacac 1380
ggcgctgggg tggccatgga cggacaggac gtgcagctgc ctctgctgaa gggcgacctg 1440
agaatccagc acaccgtgac agcctctgtg cggctgagct acggcgagga cctccagatg 1500
gactgggatg gcaggggcag actgctcgtg aaactgagcc cagtgtatgc cggcaagact 1560
tgtggactgt gtggcaacta caacggcaac cagggcgacg atttcctgac cccttctggc 1620
ctggccgagc cccgggtgga agattttggc aacgcctgga agctgcacgg cgactgtcag 1680
gatctccaga agcagcacag cgacccttgc gccctgaacc cccggatgac cagattcagc 1740
gaagaggcct gtgccgtgct gaccagccct acctttgagg cctgccacag agccgtgtct 1800
ccactgcctt acctgcggaa ttgcagatac gacgtgtgct cctgctccga cggccgcgaa 1860
tgtctgtgtg gcgccctggc ctcttatgcc gccgcttgtg ctggaagagg cgtgcgggtg 1920
gcatggcggg aaccaggcag atgcgagctg aactgcccta agggccaggt gtacctccag 1980
tgcggcaccc cctgcaacct gacctgtaga agcctgagct accccgacga agagtgcaac 2040
gaggcctgtc tggaaggctg cttttgccct cccggcctgt atatggacga gcggggcgat 2100
tgtgtgccca aggcccagtg cccctgctac tacgacggcg agattttcca gcccgaggac 2160
atcttcagcg accaccacac catgtgctac tgcgaggatg gcttcatgca ctgcaccatg 2220
agcggcgtgc caggctccct gctgcctgat gctgtgctgt ctagccccct gagccacaga 2280
agcaagagaa gcctgtcttg cagacccccc atggtcaagc tcgtgtgccc tgccgacaac 2340
ctgagagccg agggcctgga atgcaccaag acatgccaga actacgacct ggaatgcatg 2400
agcatgggct gcgtgtccgg ctgtctgtgc cctcctggca tggtgcgcca cgagaataga 2460
tgcgtggccc tggaacggtg cccgtgcttt catcagggca aagagtacgc cccaggcgaa 2520
accgtgaaga tcggctgcaa cacatgcgtg tgtcaggacc ggaagtggaa ctgcaccgac 2580
cacgtgtgcg acgccacctg tagcacaatc ggcatggccc actacctgac cttcgatggc 2640
ctgaagtacc tgttccccgg cgagtgtcag tacgtgctgg tgcaggatta ctgcggcagc 2700
aaccccggca ccttcagaat cctcgtgggc aacaagggct gtagccaccc ctccgtgaag 2760
tgcaagaaac gcgtgaccat cctggtggaa ggcggagaga tcgagctgtt cgacggcgaa 2820
gtgaacgtga agcggcccat gaaggacgag acacacttcg aggtggtgga aagcggccgg 2880
tacatcatcc tgctgctggg caaagccctg tccgtcgtgt gggacagaca cctgagcatc 2940
agcgtggtgc tgaagcagac ctaccaggaa aaagtgtgcg ggctgtgtgg gaactttgac 3000
ggcatccaga acaacgatct gaccagcagc aatctccagg tggaagagga ccccgtggac 3060
ttcggcaatt cctggaaggt gtccagccag tgtgccgaca ccagaaaggt gcccctggat 3120
agcagccccg ccacatgcca caacaacatc atgaagcaga caatggtgga cagcagctgc 3180
cgcatcctga cctccgatgt gtttcaggac tgcaacaaac tggtggaccc cgaaccctac 3240
ctggacgtgt gcatctacga cacatgcagc tgcgagagca tcggcgattg cgcctgcttc 3300
tgcgacacca ttgccgccta cgcccatgtg tgcgcccagc acggaaaggt cgtgacttgg 3360
agaaccgcca ccctgtgccc acagagctgc gaggaacgga acctgcggga aaacggctac 3420
gagtgcgagt ggcggtacaa cagctgtgcc ccagcctgcc aagtgacctg ccagcaccct 3480
gaacctctgg cttgccccgt gcagtgcgtg gaaggatgtc acgcccattg cccacccggc 3540
aagatcctgg atgagctgct ccagacctgt gtggacccag aggactgccc agtgtgcgaa 3600
gtggccggaa gaagattcgc ctccggcaag aaagtgaccc tgaatccctc cgaccccgag 3660
cactgtcaga tttgtcactg cgacgtcgtg aatctgacat gcgaagcctg ccaggaacct 3720
ggcggactgg tggtgcctcc tacagatgcc cctgtgtccc ccaccaccct gtacgtggaa 3780
gatatcagcg agccccccct gcaccaagaa cctggtggac tggtggtgcc tcctacagat 3840
gctcctgtgt ctcccaccac actgtacgtg gaagatatca gcgagcctcc tctgcaccaa 3900
gagccaggcg gacttgtggt cccaccaact gatgcccctg tcagccctac aactctgtac 3960
gtcgaggaca tctccgagcc accactgcac gaggaacccg agtgcaacga tatcaccgcc 4020
agactgcagt acgtgaaagt gggcagctgc aagagcgagg tggaagtgga catccactac 4080
tgccagggca agtgtgccag caaggccatg tacagcatcg acatcaacga cgtgcaggac 4140
cagtgcagct gctgcagccc aacaagaacc gagcctatgc aggtcgccct gcactgtaca 4200
aatggcagcg tggtgtacca cgaggtgctg aacgccatgg aatgcaagtg cagccccaga 4260
aagtgcagca agtaa 4275
<210> 20
<211> 4659
<212> DNA
<213> 智人
<400> 20
atgcaaatag agctctccac ctgcttcttt ctgtgccttt tgcgattctg ctttagtgcc 60
accagaagat actacctggg tgcagtggaa ctgtcatggg actatatgca aagtgatctc 120
ggtgagctgc ctgtggacgc aagatttcct cctagagtgc caaaatcttt tccattcaac 180
acctcagtcg tgtacaaaaa gactctgttt gtagaattca cggatcacct tttcaacatc 240
gctaagccaa ggccaccctg gatgggtctg ctaggtccta ccatccaggc tgaggtttat 300
gatacagtgg tcattacact taagaacatg gcttcccatc ctgtcagtct tcatgctgtt 360
ggtgtatcct actggaaagc ttctgaggga gctgaatatg atgatcagac cagtcaaagg 420
gagaaagaag atgataaagt cttccctggt ggaagccata catatgtctg gcaggtcctg 480
aaagagaatg gtccaatggc ctctgaccca ctgtgcctta cctactcata tctttctcat 540
gtggacctgg taaaagactt gaattcaggc ctcattggag ccctactagt atgtagagaa 600
gggagtctgg ccaaggaaaa gacacagacc ttgcacaaat ttatactact ttttgctgta 660
tttgatgaag ggaaaagttg gcactcagaa acaaagaact ccttgatgca ggatagggat 720
gctgcatctg ctcgggcctg gcctaaaatg cacacagtca atggttatgt aaacaggtct 780
ctgccaggtc tgattggatg ccacaggaaa tcagtctatt ggcatgtgat tggaatgggc 840
accactcctg aagtgcactc aatattcctc gaaggtcaca catttcttgt gaggaaccat 900
cgccaggcgt ccttggaaat ctcgccaata actttcctta ctgctcaaac actcttgatg 960
gaccttggac agtttctact gttttgtcat atctcttccc accaacatga tggcatggaa 1020
gcttatgtca aagtagacag ctgtccagag gaaccccaac tacgaatgaa aaataatgaa 1080
gaagcggaag actatgatga tgatcttact gattctgaaa tggatgtggt caggtttgat 1140
gatgacaact ctccttcctt tatccaaatt cgctcagttg ccaagaagca tcctaaaact 1200
tgggtacatt acattgctgc tgaagaggag gactgggact atgctccctt agtcctcgcc 1260
cccgatgaca gaagttataa aagtcaatat ttgaacaatg gccctcagcg gattggtagg 1320
aagtacaaaa aagtccgatt tatggcatac acagatgaaa cctttaagac tcgtgaagct 1380
attcagcatg aatcaggaat cttgggacct ttactttatg gggaagttgg agacacactg 1440
ttgattatat ttaagaatca agcaagcaga ccatataaca tctaccctca cggaatcact 1500
gatgtccgtc ctttgtattc aaggagatta ccaaaaggtg taaaacattt gaaggatttt 1560
ccaattctgc caggagaaat attcaaatat aaatggacag tgactgtaga agatgggcca 1620
actaaatcag atcctcggtg cctgacccgc tattactcta gtttcgttaa tatggagaga 1680
gatctagctt caggactcat tggccctctc ctcatctgct acaaagaatc tgtagatcaa 1740
agaggaaacc agataatgtc agacaagagg aatgtcatcc tgttttctgt atttgatgag 1800
aaccgaagct ggtacctcac agagaatata caacgctttc tccccaatcc agctggagtg 1860
cagcttgagg atccagagtt ccaagcctcc aacatcatgc acagcatcaa tggctatgtt 1920
tttgatagtt tgcagttgtc agtttgtttg catgaggtgg catactggta cattctaagc 1980
attggagcac agactgactt cctttctgtc ttcttctctg gatatacctt caaacacaaa 2040
atggtctatg aagacacact caccctattc ccattctcag gagaaactgt cttcatgtcg 2100
atggaaaacc caggtctatg gattctgggg tgccacaact cagactttcg gaacagaggc 2160
atgaccgcct tactgaaggt ttctagttgt gacaagaaca ctggtgatta ttacgaggac 2220
agttatgaag atatttcagc atacttgctg agtaaaaaca atgccattga accaagaagc 2280
ttctcccaga attcaagaca tcaggaacct ggcggactgg tggtgcctcc tacagatgcc 2340
cctgtgtccc ccaccaccct gtacgtggaa gatatcagcg agccccccct gcaccaggaa 2400
cctggcggac tggtggtgcc tcctacagac gctcctgtgt ctcctacaac actgtatgtg 2460
gaagatattt ccgagcctcc tctgcatcag gaaccagggg gcctggtggt gccaccaact 2520
gatgcaccag tgtctccaac tactctgtac gtggaagata tttctgaacc ccccctgcat 2580
caagcttatc gataccgtcg aggggaaata actcgtacta ctcttcagtc agatcaagag 2640
gaaattgact atgatgatac catatcagtt gaaatgaaga aggaagattt tgacatttat 2700
gatgaggatg aaaatcagag cccccgcagc tttcaaaaga aaacacgaca ctattttatt 2760
gctgcagtgg agaggctctg ggattatggg atgagtagct ccccacatgt tctaagaaac 2820
agggctcaga gtggcagtgt ccctcagttc aagaaagttg ttttccagga atttactgat 2880
ggctccttta ctcagccctt ataccgtgga gaactaaatg aacatttggg actcctgggg 2940
ccatatataa gagcagaagt tgaagataat atcatggtaa ctttcagaaa tcaggcctct 3000
cgtccctatt ccttctattc tagccttatt tcttatgagg aagatcagag gcaaggagca 3060
gaacctagaa aaaactttgt caagcctaat gaaaccaaaa cttacttttg gaaagtgcaa 3120
catcatatgg cacccactaa agatgagttt gactgcaaag cctgggctta tttctctgat 3180
gttgacctgg aaaaagatgt gcactcaggc ctgattggac cccttctggt ctgccacact 3240
aacacactga accctgctca tgggagacaa gtgacagtac aggaatttgc tctgtttttc 3300
accatctttg atgagaccaa aagctggtac ttcactgaaa atatggaaag aaactgcagg 3360
gctccctgca atatccagat ggaagatccc acttttaaag agaattatcg cttccatgca 3420
atcaatggct acataatgga tacactacct ggcttagtaa tggctcagga tcaaaggatt 3480
cgatggtatc tgctcagcat gggcagcaat gaaaacatcc attctattca tttcagtgga 3540
catgtgttca ctgtacgaaa aaaagaggag tataaaatgg cactgtacaa tctctatcca 3600
ggtgtttttg agacagtgga aatgttacca tccaaagctg gaatttggcg ggtggaatgc 3660
cttattggcg agcatctaca tgctgggatg agcacacttt ttctggtgta cagcaataag 3720
tgtcagactc ccctgggaat ggcttctgga cacattagag attttcagat tacagcttca 3780
ggacaatatg gacagtgggc cccaaagctg gccagacttc attattccgg atcaatcaat 3840
gcctggagca ccaaggagcc cttttcttgg atcaaggtgg atctgttggc accaatgatt 3900
attcacggca tcaagaccca gggtgcccgt cagaagttct ccagcctcta catctctcag 3960
tttatcatca tgtatagtct tgatgggaag aagtggcaga cttatcgagg aaattccact 4020
ggaaccttaa tggtcttctt tggcaatgtg gattcatctg ggataaaaca caatattttt 4080
aaccctccaa ttattgctcg atacatccgt ttgcacccaa ctcattatag cattcgcagc 4140
actcttcgca tggagttgat gggctgtgat ttaaatagtt gcagcatgcc attgggaatg 4200
gagagtaaag caatatcaga tgcacagatt actgcttcat cctactttac caatatgttt 4260
gccacctggt ctccttcaaa agctcgactt cacctccaag ggaggagtaa tgcctggaga 4320
cctcaggtga ataatccaaa agagtggctg caagtggact tccagaagac aatgaaagtc 4380
acaggagtaa ctactcaggg agtaaaatct ctgcttacca gcatgtatgt gaaggagttc 4440
ctcatctcca gcagtcaaga tggccatcag tggaccctct tttttcagaa tggcaaagta 4500
aaggtttttc agggaaatca agactccttc acacctgtgg tgaactctct agacccaccg 4560
ttactgactc gctaccttcg aattcacccc cagagttggg tgcaccagat tgccctgagg 4620
atggaggttc tgggctgcga ggcacaggac ctctactga 4659
<210> 21
<211> 1533
<212> PRT
<213> 智人
<400> 21
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 Gln Ala Tyr Arg
740 745 750
Tyr Arg Arg Gly Glu Ile Thr Arg Thr Thr Leu Gln Ser Asp Gln Glu
755 760 765
Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp
770 775 780
Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln
785 790 795 800
Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp
805 810 815
Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser
820 825 830
Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp
835 840 845
Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu
850 855 860
Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met
865 870 875 880
Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser
885 890 895
Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys
900 905 910
Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln
915 920 925
His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala
930 935 940
Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile
945 950 955 960
Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly
965 970 975
Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp
980 985 990
Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg
995 1000 1005
Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn
1010 1015 1020
Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro
1025 1030 1035
Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu
1040 1045 1050
Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly
1055 1060 1065
His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu
1070 1075 1080
Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro
1085 1090 1095
Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His
1100 1105 1110
Leu His Ala Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys
1115 1120 1125
Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe
1130 1135 1140
Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu
1145 1150 1155
Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys
1160 1165 1170
Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile
1175 1180 1185
Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser
1190 1195 1200
Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys
1205 1210 1215
Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val
1220 1225 1230
Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe
1235 1240 1245
Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His
1250 1255 1260
Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp
1265 1270 1275
Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala Ile
1280 1285 1290
Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe
1295 1300 1305
Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg
1310 1315 1320
Ser Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu
1325 1330 1335
Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr
1340 1345 1350
Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe
1355 1360 1365
Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe
1370 1375 1380
Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp Ser Phe
1385 1390 1395
Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr
1400 1405 1410
Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg
1415 1420 1425
Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr Gln Glu Pro
1430 1435 1440
Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro Thr
1445 1450 1455
Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Gln Glu
1460 1465 1470
Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser Pro
1475 1480 1485
Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His Gln
1490 1495 1500
Glu Pro Gly Gly Leu Val Val Pro Pro Thr Asp Ala Pro Val Ser
1505 1510 1515
Pro Thr Thr Leu Tyr Val Glu Asp Ile Ser Glu Pro Pro Leu His
1520 1525 1530
<210> 22
<211> 4659
<212> DNA
<213> 智人
<400> 22
atgcaaatag agctctccac ctgcttcttt ctgtgccttt tgcgattctg ctttagtgcc 60
accagaagat actacctggg tgcagtggaa ctgtcatggg actatatgca aagtgatctc 120
ggtgagctgc ctgtggacgc aagatttcct cctagagtgc caaaatcttt tccattcaac 180
acctcagtcg tgtacaaaaa gactctgttt gtagaattca cggatcacct tttcaacatc 240
gctaagccaa ggccaccctg gatgggtctg ctaggtccta ccatccaggc tgaggtttat 300
gatacagtgg tcattacact taagaacatg gcttcccatc ctgtcagtct tcatgctgtt 360
ggtgtatcct actggaaagc ttctgaggga gctgaatatg atgatcagac cagtcaaagg 420
gagaaagaag atgataaagt cttccctggt ggaagccata catatgtctg gcaggtcctg 480
aaagagaatg gtccaatggc ctctgaccca ctgtgcctta cctactcata tctttctcat 540
gtggacctgg taaaagactt gaattcaggc ctcattggag ccctactagt atgtagagaa 600
gggagtctgg ccaaggaaaa gacacagacc ttgcacaaat ttatactact ttttgctgta 660
tttgatgaag ggaaaagttg gcactcagaa acaaagaact ccttgatgca ggatagggat 720
gctgcatctg ctcgggcctg gcctaaaatg cacacagtca atggttatgt aaacaggtct 780
ctgccaggtc tgattggatg ccacaggaaa tcagtctatt ggcatgtgat tggaatgggc 840
accactcctg aagtgcactc aatattcctc gaaggtcaca catttcttgt gaggaaccat 900
cgccaggcgt ccttggaaat ctcgccaata actttcctta ctgctcaaac actcttgatg 960
gaccttggac agtttctact gttttgtcat atctcttccc accaacatga tggcatggaa 1020
gcttatgtca aagtagacag ctgtccagag gaaccccaac tacgaatgaa aaataatgaa 1080
gaagcggaag actatgatga tgatcttact gattctgaaa tggatgtggt caggtttgat 1140
gatgacaact ctccttcctt tatccaaatt cgctcagttg ccaagaagca tcctaaaact 1200
tgggtacatt acattgctgc tgaagaggag gactgggact atgctccctt agtcctcgcc 1260
cccgatgaca gaagttataa aagtcaatat ttgaacaatg gccctcagcg gattggtagg 1320
aagtacaaaa aagtccgatt tatggcatac acagatgaaa cctttaagac tcgtgaagct 1380
attcagcatg aatcaggaat cttgggacct ttactttatg gggaagttgg agacacactg 1440
ttgattatat ttaagaatca agcaagcaga ccatataaca tctaccctca cggaatcact 1500
gatgtccgtc ctttgtattc aaggagatta ccaaaaggtg taaaacattt gaaggatttt 1560
ccaattctgc caggagaaat attcaaatat aaatggacag tgactgtaga agatgggcca 1620
actaaatcag atcctcggtg cctgacccgc tattactcta gtttcgttaa tatggagaga 1680
gatctagctt caggactcat tggccctctc ctcatctgct acaaagaatc tgtagatcaa 1740
agaggaaacc agataatgtc agacaagagg aatgtcatcc tgttttctgt atttgatgag 1800
aaccgaagct ggtacctcac agagaatata caacgctttc tccccaatcc agctggagtg 1860
cagcttgagg atccagagtt ccaagcctcc aacatcatgc acagcatcaa tggctatgtt 1920
tttgatagtt tgcagttgtc agtttgtttg catgaggtgg catactggta cattctaagc 1980
attggagcac agactgactt cctttctgtc ttcttctctg gatatacctt caaacacaaa 2040
atggtctatg aagacacact caccctattc ccattctcag gagaaactgt cttcatgtcg 2100
atggaaaacc caggtctatg gattctgggg tgccacaact cagactttcg gaacagaggc 2160
atgaccgcct tactgaaggt ttctagttgt gacaagaaca ctggtgatta ttacgaggac 2220
agttatgaag atatttcagc atacttgctg agtaaaaaca atgccattga accaagaagc 2280
ttctcccaga attcaagaca tcaagcttat cgataccgtc gaggggaaat aactcgtact 2340
actcttcagt cagatcaaga ggaaattgac tatgatgata ccatatcagt tgaaatgaag 2400
aaggaagatt ttgacattta tgatgaggat gaaaatcaga gcccccgcag ctttcaaaag 2460
aaaacacgac actattttat tgctgcagtg gagaggctct gggattatgg gatgagtagc 2520
tccccacatg ttctaagaaa cagggctcag agtggcagtg tccctcagtt caagaaagtt 2580
gttttccagg aatttactga tggctccttt actcagccct tataccgtgg agaactaaat 2640
gaacatttgg gactcctggg gccatatata agagcagaag ttgaagataa tatcatggta 2700
actttcagaa atcaggcctc tcgtccctat tccttctatt ctagccttat ttcttatgag 2760
gaagatcaga ggcaaggagc agaacctaga aaaaactttg tcaagcctaa tgaaaccaaa 2820
acttactttt ggaaagtgca acatcatatg gcacccacta aagatgagtt tgactgcaaa 2880
gcctgggctt atttctctga tgttgacctg gaaaaagatg tgcactcagg cctgattgga 2940
ccccttctgg tctgccacac taacacactg aaccctgctc atgggagaca agtgacagta 3000
caggaatttg ctctgttttt caccatcttt gatgagacca aaagctggta cttcactgaa 3060
aatatggaaa gaaactgcag ggctccctgc aatatccaga tggaagatcc cacttttaaa 3120
gagaattatc gcttccatgc aatcaatggc tacataatgg atacactacc tggcttagta 3180
atggctcagg atcaaaggat tcgatggtat ctgctcagca tgggcagcaa tgaaaacatc 3240
cattctattc atttcagtgg acatgtgttc actgtacgaa aaaaagagga gtataaaatg 3300
gcactgtaca atctctatcc aggtgttttt gagacagtgg aaatgttacc atccaaagct 3360
ggaatttggc gggtggaatg ccttattggc gagcatctac atgctgggat gagcacactt 3420
tttctggtgt acagcaataa gtgtcagact cccctgggaa tggcttctgg acacattaga 3480
gattttcaga ttacagcttc aggacaatat ggacagtggg ccccaaagct ggccagactt 3540
cattattccg gatcaatcaa tgcctggagc accaaggagc ccttttcttg gatcaaggtg 3600
gatctgttgg caccaatgat tattcacggc atcaagaccc agggtgcccg tcagaagttc 3660
tccagcctct acatctctca gtttatcatc atgtatagtc ttgatgggaa gaagtggcag 3720
acttatcgag gaaattccac tggaacctta atggtcttct ttggcaatgt ggattcatct 3780
gggataaaac acaatatttt taaccctcca attattgctc gatacatccg tttgcaccca 3840
actcattata gcattcgcag cactcttcgc atggagttga tgggctgtga tttaaatagt 3900
tgcagcatgc cattgggaat ggagagtaaa gcaatatcag atgcacagat tactgcttca 3960
tcctacttta ccaatatgtt tgccacctgg tctccttcaa aagctcgact tcacctccaa 4020
gggaggagta atgcctggag acctcaggtg aataatccaa aagagtggct gcaagtggac 4080
ttccagaaga caatgaaagt cacaggagta actactcagg gagtaaaatc tctgcttacc 4140
agcatgtatg tgaaggagtt cctcatctcc agcagtcaag atggccatca gtggaccctc 4200
ttttttcaga atggcaaagt aaaggttttt cagggaaatc aagactcctt cacacctgtg 4260
gtgaactctc tagacccacc gttactgact cgctaccttc gaattcaccc ccagagttgg 4320
gtgcaccaga ttgccctgag gatggaggtt ctgggctgcg aggcacagga cctctaccag 4380
gaacctggcg gactggtggt gcctcctaca gatgcccctg tgtcccccac caccctgtac 4440
gtggaagata tcagcgagcc ccccctgcac caggaacctg gcggactggt ggtgcctcct 4500
acagacgctc ctgtgtctcc tacaacactg tatgtggaag atatttccga gcctcctctg 4560
catcaggaac cagggggcct ggtggtgcca ccaactgatg caccagtgtc tccaactact 4620
ctgtacgtgg aagatatttc tgaacccccc ctgcattga 4659
Claims (39)
1.一种融合蛋白,其包含主要蛋白质和一个或多个延伸肽,其中所述主要蛋白质的氨基酸序列与哺乳动物蛋白质或其片段的氨基酸序列相同或相似,并且所述延伸肽包含O-糖基化氨基酸簇。
2.根据权利要求1所述的融合蛋白,其中所述融合蛋白与不含延伸肽的主要蛋白质相比具有增加的半衰期。
3.根据权利要求1或2所述的融合蛋白,其中所述一个或多个延伸肽的所述氨基酸序列与所述主要蛋白质或片段的非重复氨基酸序列部分相同或相似。
4.根据前述权利要求中任一项所述的融合蛋白,条件是所述一个或多个延伸肽不衍生自绒毛膜促性腺激素β-亚基(CG-β),特别是与CG-β的C-末端肽(CTP)并不相同或相似。
5.根据前述权利要求中任一项所述的融合蛋白,其中所述延伸肽的O-糖基化氨基酸簇含有至少两个、优选为至少三个、更优选为至少四个O-糖基化氨基酸。
6.根据前述权利要求中任一项所述的融合蛋白,其中所述O-糖基化位点簇含有至少一个苏氨酸作为O-糖基化氨基酸,优选地所述簇含有苏氨酸和丝氨酸作为O-糖基化氨基酸。
7.根据前述权利要求中任一项所述的融合蛋白,其中所述一个或多个延伸肽在10个氨基酸中含有至少一个O-糖基化位点,优选地在8个氨基酸中含有至少一个O-糖基化位点。
8.根据前述权利要求中任一项所述的融合蛋白,其中所述一个或多个延伸肽的长度为20至60个氨基酸,优选为22至40个氨基酸,更优选为26至36个氨基酸。
9.根据前述权利要求中任一项所述的融合蛋白,其中所述一个或多个延伸肽与血管性血友病因子(VWF)的O-糖基化肽具有至少90%的序列同一性。
10.根据权利要求9所述的融合蛋白,其中所述一个或多个延伸肽与特别是SEQ ID NO:1的VWF的O-糖基化肽具有至少90%、优选为至少95%、更优选为至少98%、最优选为至少100%的序列同一性。
11.根据前述权利要求中任一项所述的融合蛋白,其包含延伸肽的至少两个拷贝、优选地至少四个拷贝。
12.根据前述权利要求中任一项所述的融合蛋白,其中延伸肽直接或间接与所述主要蛋白质的C-末端融合。
13.根据前述权利要求中任一项所述的融合蛋白,其中延伸肽形成所述融合蛋白的C-末端,其中所述延伸肽的所述C-末端氨基酸任选地与亲和标签融合肽连接。
14.根据权利要求9至13中任一项所述的融合蛋白,其中所述主要蛋白质包含至少一个O-糖基化氨基酸簇。
15.根据前述权利要求中任一项所述的融合蛋白,其中所述融合蛋白包含二聚化结构域,特别是所述主要蛋白质包含二聚化结构域。
16.根据前述权利要求中任一项所述的融合蛋白,其中所述哺乳动物蛋白是人血蛋白,优选地凝血因子或蛋白酶抑制剂,更优选地选自VWF、凝血酶原、纤维蛋白原、FIII、FV、FVII、FVIII、FIX、FX、FXI、FXII、FXIII、ADAMTS13、抗凝血酶、α-1抗胰蛋白酶、C1-抑制剂、抗胰凝乳蛋白酶、PAI-1、PAI-3、2-巨球蛋白、TFPI、肝素辅因子II蛋白Z、蛋白C、以及蛋白S。
17.根据前述权利要求中任一项所述的融合蛋白,其中所述主要蛋白质与SEQ ID NO:2的氨基酸764至1268具有至少90%、优选为至少95%、更优选为至少98%、最优选为100%的序列同一性。
18.根据前述权利要求中任一项所述的融合蛋白,其中与所述主要蛋白质相比,所述融合蛋白包含至少4个、优选为至少8个、更优选为至少12个额外的O-聚糖。
19.根据前述权利要求中任一项所述的融合蛋白,其中所述融合蛋白的氨基酸序列与选自SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10或SEQ ID NO:11的序列具有至少90%、优选为至少95%、更优选为至少98%、最优选为100%的同一性。
20.根据前述权利要求中任一项所述的融合蛋白,其中所述融合蛋白通过在哺乳动物细胞系中表达而产生,优选为人细胞系,更优选为人肾细胞系,最优选为人胚肾细胞系,特别是HEK293细胞系,例如HEK293F。
21.一种第一蛋白质和第二蛋白质的组合物,其中所述第一蛋白质是根据权利要求1至20中任一项所述的融合蛋白并且能够结合所述第二蛋白质,并且所述第二蛋白质是包含与第二哺乳动物蛋白质或其片段的氨基酸序列相同或相似的氨基酸序列的治疗性蛋白质。
22.根据权利要求21所述的组合物,其中与所述第二蛋白质的游离形式相比,与所述第一蛋白质结合的所述第二蛋白质的半衰期增加,优选地,其中与结合天然哺乳动物蛋白或没有融合肽的主要蛋白质的所述第二蛋白质相比,与所述第一蛋白质结合的所述第二蛋白质的半衰期增加。
23.根据权利要求21或22所述的组合物,其中所述第一蛋白质与所述第二蛋白质的摩尔比为0.1至250,优选为0.5至50,更优选为1至25,最优选为2至10。
24.根据权利要求21至23中任一项所述的组合物,其中所述第一蛋白质与所述第二蛋白质的结合亲和力为0.05至3nM。
25.根据权利要求21至24中任一项所述的组合物,其中所述第二哺乳动物蛋白质是血液蛋白质,更优选地,所述第二哺乳动物蛋白质是血浆蛋白质,最优选地,所述第二种蛋白质是凝血因子。
26.根据权利要求25所述的组合物,其中所述第二哺乳动物蛋白质是人蛋白质。
27.根据权利要求21至25中任一项所述的组合物,其中所述第二蛋白质是FVIII蛋白质,选自全长FVIII、其中至少部分B结构域缺失的FVIII蛋白质、以及其中B-结构域的至少一部分被延伸肽替换的FVIII蛋白质,其中所述延伸肽根据权利要求5至10中任一项所定义。
28.根据权利要求21至27中任一项所述的组合物,其中所述一个或多个延伸肽位于折叠状态的所述第一蛋白质的不干扰所述第一蛋白质与所述第二蛋白质结合的位置。
29.一种第一蛋白质和第二蛋白质的复合物,其中所述第一蛋白质是根据权利要求1至20中任一项所述的融合蛋白,并且所述第二蛋白质具有与第二哺乳动物蛋白质或其片段的氨基酸序列相同或相似的氨基酸序列。
30.根据权利要求29所述的复合物,其中所述第一蛋白质与所述第二蛋白质非共价结合。
31.根据权利要求29或30所述的复合物,其含有所述第一和所述第二蛋白质的两个拷贝,其中所述第一蛋白质的两个拷贝形成二聚体,优选为非共价结合的二聚体。
32.根据权利要求29所述的复合物,其中所述第一蛋白质与所述第二蛋白质共价结合,其中所述接头选自肽键、化学接头或糖苷键。
33.一种编码根据权利要求1至20中任一项所述的融合蛋白的多核苷酸。
34.编码融合蛋白的多核苷酸,所述融合蛋白具有与选自SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:11、以及SEQ ID NO:14的序列具有至少90%、优选为至少95%、更优选为至少98%、最优选为100%的同一性的氨基酸序列。
35.一种含有根据权利要求33或34所述的多核苷酸的载体,其中所述载体骨架优选地选自pCDNA3、pCDNA3.1、pCDNA4、pCDNA5、pCDNA6、pCEP4、pCEP-puro、pCET1019、pCMV、pEF1、pEF4、pEF5、pEF6、pExchange、pEXPR、pIRES、以及pSCAS。
36.一种含有根据权利要求33或34所述的多核苷酸或根据权利要求35所述的载体的宿主细胞,其中所述宿主细胞优选地是哺乳动物细胞,优选为人细胞,更优选为人肾细胞,最优选为人胚肾细胞系,特别是HEK293细胞系,例如HEK293F。
37.一种根据权利要求1至20中任一项所述的融合蛋白用于增加第二蛋白质的半衰期的用途,其中所述融合蛋白能够结合所述第二蛋白质。
38.一种药物组合物,其包含根据权利要求1至20中任一项所述的融合蛋白,根据权利要求21至28中任一项所述的组合物,或根据权利要求29至32中任一项所述的复合物,其用于治疗或预防出血性疾病,优选地选自PUP和ITI治疗和/或相关出血性疾病的治疗。
39.根据权利要求35使用的药物组合物,其中所述用途包括静脉内或非静脉内注射,优选为皮下注射。
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EP16170690 | 2016-05-20 | ||
EP16170690.8 | 2016-05-20 | ||
PCT/EP2017/059976 WO2017198435A1 (en) | 2016-05-20 | 2017-04-26 | Glycosylated vwf fusion proteins with improved pharmacokinetics |
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CN201780031097.4A Pending CN109152809A (zh) | 2016-05-20 | 2017-05-22 | 调节siglec依赖性免疫反应的多肽 |
CN202211456492.6A Pending CN115960208A (zh) | 2016-05-20 | 2017-05-22 | 调节siglec依赖性免疫反应的多肽 |
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CN114867739A (zh) * | 2019-12-11 | 2022-08-05 | 株式会社Lg化学 | 包含gdf15和能够进行o-糖基化的多肽区的融合多肽 |
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US20210340281A1 (en) * | 2018-09-05 | 2021-11-04 | Lg Chem, Ltd. | Fusion polypeptide comprising polypeptide region that can be o-glycosylated |
EP4013389A1 (en) | 2019-08-16 | 2022-06-22 | Octapharma AG | Stabilizing buffer for factor viii and vwf |
CN113899902A (zh) * | 2020-06-22 | 2022-01-07 | 上海科技大学 | 一种酪氨酸磷酸酶底物鉴定方法 |
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PL2814502T3 (pl) * | 2012-02-15 | 2018-02-28 | Csl Behring Gmbh | Warianty czynnika von Willebranda mające ulepszone powinowactwo do wiązania czynnika VIII |
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