CN110869768A - 实时制备用于质谱分析的多肽样品的系统和方法 - Google Patents
实时制备用于质谱分析的多肽样品的系统和方法 Download PDFInfo
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Abstract
提供了基本上实时地促进样品测定的性能的系统和方法。因此，与常规系统和方法相比可以快得多地进行所述测定并获得所需结果。
Description
相关申请的交叉引用
本申请要求于2017年8月1日提交的题为“用于对样品执行实时测定的系统和方法(Systems and Methods for Performing a Real-Time Assay of a Sample)”的美国临时专利申请号62/539,803的优先权，其全部公开内容通过引用并入本文。
技术领域
本披露总体上涉及测定，并且更具体地，涉及对样品执行实时测定。
序列表
本申请连同电子格式的序列表一起提交。序列表作为名为“51800_Seqlisting.txt”的文件提供，所述文件创建于2018年7月31日，大小为263,964字节。将电子格式的序列表的信息通过引用以其全文并入本文。
背景技术
测定通常用于量化分析物(如药物、生化物质、或细胞)的一个或多个属性。这种测定的一个实例是多属性方法(MAM)测定，其可以检测和量化样品的关键质量属性(CQA)，所述关键质量属性由质量目标产物概况(QTPP)鉴别(Development of a quantitative massspectrometry multi-attribute method for characterization,quality controltesting and disposition of biologics[用于生物制剂的表征、质量控制测试和处置的定量质谱多属性方法的开发].Rogers RS,Nightlinger NS,Livingston B,Campbell P,Bailey R,Balland A.MAbs.2015；7(5):881-90)。所述MAM测定是在例如大分子释放测试(LMRT)实验室中进行的手动操作过程。MAM是基于液相色谱(LC)-质谱(MS)的肽作图方法，包括三个步骤：(1)样品制备(例如多肽变性、还原、烷基化和消化)；(2)通过LC分离消化的多肽并通过MS检测；和(3)与参考标准相比，分析目标CQA的数据并检测新信号(即峰值)。
CQA是在特定值或范围值内存在的化学、物理或生物学特性。例如，对于大的多肽治疗分子，氨基酸(多肽的构建模块)的物理属性和修饰是在制造过程中、制造后、以及在药物开发过程中监测的重要CQA。与跟踪整个多肽或部分多肽的峰大小和峰形状变化的常规分析测定不同，MAM在氨基酸水平检测特定的CQA。
然而，尽管MAM是在开发、制造和储存过程中评估多肽治疗性分子CQA的重要进展(评估，例如稳定性)，但从样品制备到最终分析，分析可能需要七到十天的时间，这会增加成本并延迟开发和药物释放。例如，多肽治疗剂通常由表达靶多肽的培养细胞产生。在CQA的MAM分析等待时，这种生产系统不容易“搁置”，导致细胞产生具有不符合规格的CQA的靶多肽——浪费时间、材料和人力。此外，在药物开发过程中，例如，在优化培养条件时，会累积七到十天的延迟，这阻碍向患者提供重要的新多肽药物。因此，需要有效且更快的方法来促进使用MAM的CQA分析。
发明内容
本披露的一个方面提供了一种用于执行实时测定的方法。所述方法包括以下步骤：(a)将含有多肽的产物的样品经由第一保持盘管移动至多肽结合柱；(b)将所述样品中的所述多肽结合至所述多肽结合柱，从而将所述样品中的所述多肽与所述样品的其余部分分离；(c)将洗脱缓冲溶液经由所述第一保持盘管并通过所述多肽结合柱下游的第二保持盘管从缓冲液源移动至所述多肽结合柱，从而洗脱与所述多肽结合柱结合的多肽，并将包含所述洗脱缓冲溶液和洗脱的多肽的洗脱液/多肽混合物移动至所述第二保持盘管；(d)将所述洗脱液/多肽混合物从所述第二保持盘管移动至反应室；(e)将所述洗脱液/多肽混合物中的所述多肽在所述反应室中进行孵育，从而产生变性的多肽；(f)在(e)之后，将切割二硫键交联的还原试剂经由第一保持盘管移动至所述反应室；(g)将所述变性的多肽与所述还原试剂在所述反应室中进行孵育，从而产生变性和还原的多肽；(h)在(g)之后，将使巯基烷基化的烷基化试剂移动至所述反应室；(i)将所述变性和还原的多肽与所述烷基化试剂在所述反应室中进行孵育，从而使所述变性和还原的多肽烷基化；(j)将所述变性、还原并烷基化的多肽，所述洗脱缓冲溶液，所述还原试剂和所述烷基化试剂经由所述第一保持盘管从所述反应室移动至脱盐柱，所述脱盐柱用蛋白质水解缓冲液平衡；(k)将所述变性、还原并烷基化的多肽应用至所述脱盐柱，从而将所述变性、还原并烷基化的多肽与所述还原试剂和烷基化试剂分离，从而得到脱盐的多肽；(l)将所述脱盐的多肽移动至所述脱盐柱下游的蛋白水解酶柱；(m)在第三多肽柱中消化所述脱盐的多肽，从而产生消化的多肽；以及(n)将所述消化的多肽移动至分析装置以分析所述消化的多肽。
本披露的另一方面提供了一种用于使用封闭系统执行实时测定的方法，所述封闭系统包括多通路阀、在所述多通路阀上游的第一保持盘管、与所述多通路阀的第一通路流体地联接并位于其下游的多肽结合柱、与所述多肽结合柱流体地联接并位于其下游的第二保持盘管、与所述多通路阀的第二和第三通路流体地联接并位于其下游的反应室、与所述多通路阀的第四通路流体地联接并位于其下游的脱盐柱，以及在所述脱盐柱下游的蛋白水解酶柱。所述方法包括：(a)经由与所述封闭系统通信地联接的控制器，将含有多肽的产物的样品移动至所述第一保持盘管；(b)经由所述控制器将所述多通路阀定位在第一位置，在所述第一位置中，所述第一保持盘管经由所述多通路阀的所述第一通路连接至所述多肽结合柱，使得所述样品流动至第一柱，从而所述样品中的多肽结合至所述多肽结合柱上；(c)当所述多通路阀处于所述第一位置时，经由控制器将洗脱缓冲溶液从洗脱缓冲溶液源经由所述多肽结合柱移动至所述第二保持盘管，使得所述洗脱缓冲溶液洗脱基本上所有与所述多肽结合柱结合的多肽；(d)经由所述控制器将所述多通路阀移动至第二位置，在所述第二位置中，所述第二保持盘管经由所述多通路阀的所述第二通路连接至所述反应室；(e)当所述多通路阀处于所述第二位置时，经由所述控制器将包含所述洗脱缓冲溶液和洗脱的多肽的洗脱液/多肽混合物移动至所述反应室，从而使所述洗脱液/多肽混合物中的多肽变性；(f)经由所述控制器将多通路阀移动至第三位置，在所述第三位置中，所述第一保持盘管经由所述多通路阀的所述第三通路连接至所述反应室；(g)在(f)之后，经由所述控制器将切割二硫键交联的还原试剂移动至所述第一保持盘管，并且经由所述控制器将所述还原试剂从所述第一保持盘管经由所述多通路阀的所述第三通路移动至所述反应室，从而还原所述变性的多肽；(h)在(g)之后，经由所述控制器将使巯基烷基化的烷基化试剂移动至所述第一保持盘管，并且经由所述控制器将所述烷基化试剂从所述第一保持盘管经由所述第三通路移动至所述反应室，从而烷基化所述变性和还原的多肽；(i)经由所述控制器将所述烷基化的多肽、所述洗脱缓冲溶液、所述还原试剂和所述烷基化试剂从所述反应室经由所述第三通路移动至所述第一保持盘管；(j)经由所述控制器将所述多通路阀移动至第四位置，在所述第四位置中，所述第一保持盘管经由所述多通路阀的第四通路连接至所述脱盐柱，并且当所述多通路阀处于在所述第四位置时，将所述烷基化的多肽、所述洗脱缓冲溶液、所述还原试剂和所述烷基化试剂从所述第一保持盘管移动至所述脱盐柱，从而将所述变性、还原并烷基化的多肽应用至所述脱盐柱，由此将所述变性、还原并烷基化的多肽与所述还原试剂和烷基化试剂分离，得到脱盐的多肽；(k)经由所述控制器将所述脱盐的多肽移动至所述蛋白水解酶柱，从而消化所述脱盐的多肽；以及(l)经由所述控制器将所述消化的多肽传送至分析装置，从而分析所述消化的多肽。
本披露的另一方面提供了用于执行联机、实时测定的封闭系统。所述系统包括：第一保持盘管，所述第一保持盘管流体地布置成接收含有多肽的产物的样品；多通路阀，所述多通路阀流体地联接至所述第一保持盘管并位于其下游；多肽结合柱，所述多肽结合柱流体地联接至所述多通路阀，并布置成经由所述多通路阀的第一通路从所述第一保持盘管接收所述样品，所述多肽结合柱被配置为结合来自所述样品的所述多肽；缓冲液源，所述缓冲液源流体地联接至所述多通路阀，并被布置成向位于所述多肽结合柱下游的第二保持盘管供应洗脱缓冲溶液，使得所述洗脱缓冲溶液适于从所述多肽结合柱上洗脱基本上所有的所述多肽；反应室，所述反应室流体地联接至所述多通路阀并被布置在所述多肽结合柱下游，所述反应室适于经由所述多通路阀的第二通路从所述多肽结合柱接收混合物，所述混合物包含所述洗脱缓冲溶液和所述洗脱的多肽，其中所述混合物的多肽在所述反应室中变性，其中所述反应室被布置成经由所述多通路阀的第一保持盘管和第三通路接收切割二硫键交联的还原试剂，所述还原试剂还原所述变性的多肽，并且其中所述反应室还被布置成经由所述多通路阀的第一保持盘管和第三通路接收使巯基烷基化的烷基化试剂，其中所述烷基化试剂在所述反应室中将所述变性并还原的多肽烷基化；脱盐柱，所述脱盐柱流体地联接至所述多通路阀，并且被布置成从所述反应室接收变性、还原并烷基化的多肽，所述洗脱缓冲溶液和所述烷基化试剂，所述脱盐柱被配置为将所述变性、还原并烷基化的多肽与所述洗脱缓冲溶液、所述还原试剂和所述烷基化试剂分离；以及蛋白水解酶柱，所述蛋白水解酶柱流体地联接至第二多肽柱并被布置成在其下游以从所述脱盐柱获得所述分离的多肽，所述蛋白水解酶柱被配置为消化脱盐的多肽。
本披露的另一方面提供了用于执行实时测定的封闭系统。所述系统包括：多通路阀；第一保持盘管，所述第一保持盘管在所述多通路阀上游；多肽结合柱，所述多肽结合柱流体地联接至所述多通路阀的第一通路并在其下游；第二保持盘管，所述第二保持盘管流体地联接至所述多肽结合柱并在其下游；反应室，所述反应室流体地联接至所述多通路阀的第二和第三通路并在其下游；脱盐柱，所述脱盐柱流体地联接至所述多通路阀的第四通路并在其下游；蛋白水解酶柱，所述蛋白水解酶柱位于所述脱盐柱下游；以及控制器，所述控制器通信地联接至所述多通路阀。所述控制器包括存储器、处理器以及逻辑，所述逻辑存储在所述存储器上并且可由所述处理器执行以：(a)将含有多肽的产物的样品移动至所述第一保持盘管；(b)将所述多通路阀定位在第一位置，在所述第一位置中，所述第一保持盘管经由所述多通路阀的所述第一通路连接至所述多肽结合柱，使得所述样品流动至第一柱，从而所述样品中的多肽结合至所述多肽结合柱上；(c)当所述多通路阀处于所述第一位置时，将洗脱缓冲溶液从洗脱缓冲溶液源经由所述多肽结合柱移动至所述第二保持盘管，使得所述洗脱缓冲溶液洗脱基本上所有与所述多肽结合柱结合的所述多肽；(d)将所述多通路阀移动至第二位置，在所述第二位置中，所述第二保持盘管经由所述多通路阀的所述第二通路连接至所述反应室；(e)当所述多通路阀处于所述第二位置时，将包含所述洗脱缓冲溶液和洗脱的多肽的洗脱液/多肽混合物移动至所述反应室，从而将所述洗脱液/多肽混合物中的所述多肽变性；(f)将所述多通路阀移动至第三位置，在所述第三位置中，所述第一保持盘管经由所述多通路阀的所述第三通路连接至所述反应室；(g)在(f)之后，将切割二硫键的还原试剂移动至所述第一保持盘管，并且将所述还原试剂从所述第一保持盘管经由所述多通路阀的所述第三通路移动至所述反应室，从而还原所述变性的多肽；(h)在(g)之后，将使巯基烷基化的烷基化试剂移动至所述第一保持盘管，并且将所述烷基化试剂从所述第一保持盘管经由所述第三通路移动至所述反应室，从而烷基化所述变性并还原的多肽；(i)将所述变性、还原并烷基化的多肽，所述洗脱缓冲溶液，所述还原试剂和所述烷基化试剂从所述反应室经由所述第三通路移动至所述第一保持盘管；(j)将所述多通路阀移动至第四位置，在所述第四位置中，所述第一保持盘管经由所述多通路阀的所述第四通路连接至所述脱盐柱，并且当所述多通路阀处于所述第四位置时，将所述变性、还原并烷基化的多肽，所述洗脱缓冲溶液，所述还原试剂和所述烷基化试剂从所述第一保持盘管移动至所述脱盐柱，从而使所述变性、还原并烷基化的多肽脱盐；(k)将所述脱盐的多肽移动至所述蛋白水解酶柱，从而消化所述脱盐的多肽；以及(l)将所述消化的多肽传送至聚糖分析装置，从而分离并量化所述消化的多肽。
附图说明
图1是根据本披露的教导组装的用于执行联机、实时测定的系统的示意图。
图2是图1所示系统的控制器的示意图。
图3A和图3B是描绘在40天的生产运行期间监测图1系统的有效性的研究的结果图。
图3C是描绘8天期间图3B的结果的快照的图。
具体实施方式
本披露提供了允许实时监测和控制CQA的实时测定和方法，从而可以产生所需的最终多肽治疗产物。披露的测定和方法可以促进MAM结果的周转时间，使得结果可以在若干小时(例如，两到三小时)内获得，而不是通常的手动操作的七到十天的离线测量结果。因此，所披露的测定和方法将周转时间提高了约54倍至120倍。这样的“即时”(实时)结果可以调整生产变量，以有效地生产具有适当CQA的(联机)产物。
图1示出了根据本披露的教导组装的系统100的示意图。可以位于实验室(例如，大分子释放测试实验室)处或内的系统100是封闭系统，用于自动或基本上自动地对包含多肽的产物的样品进行测定，如下面更详细地描述。通过使用系统100使该过程自动化(或基本自动化)，可以实时(或基本实时)执行测定，从而整个过程可以小时计(例如2到3小时)地进行，并获得所需结果，这比常规上已知的手动操作的MAM分析通常需要的7到10天有显著改善。此外，利用系统100的过程的封闭性质维持无菌条件。
在该版本中，多肽可以是治疗性多肽，其在下面将进一步讨论
图1所示的系统100通常包括：多通路阀104、第一保持盘管108、第一柱112、第二保持盘管116、反应室120、第二柱124、第三柱128和控制器132。在图1所示的版本中，系统100还包括容器136、泵140、第一废物室144、第二废物室148、第三废物室152和用于分析多肽的分析装置156。然而，在其他版本中，系统100不能包括这些组件中的一个或多个。作为实例，系统100不能包括容器136和/或分析装置156。在任何情况下，通常常规的管道系统在系统100的每个组件之间延伸，以便在需要时促进系统100的组件之间的流体连通，这将在下面更详细地描述。多通路阀104通常被配置为控制系统100的各个部件之间的流体连通。在该版本中，多通路阀104是十二个卫星通路和中心共享通路阀。换句话说，多通路阀104具有中心通路160和十二个卫星通路164-175，其选择性地流体地联接至中心通路160。多通路阀104可在十二个不同的位置之间移动，所述十二个不同的位置分别将中心通路160与十二个不同的卫星通路164-175流体联接(其中一些未在图1的系统100的运行中使用)。在其他版本中，多通路阀104可以包括更多或更少的卫星通路，可以是不同类型的阀，或者可以被一个或多个不同的阀(每个具有一个或多个通路)代替。作为示例，多通路阀104可以由分别连接到控制器132并由其控制的多个单通路阀代替，其中每个单通阀有效地代替了卫星通路164-175之一。
容器136通常被配置为容纳或存储含有待测定的多肽的产物。该版本的容器136采用容纳或存储产物的生物反应器的形式。然而，在其他版本中，容器136可以替代地采取细胞培养容器的形式，例如烧瓶，平板等。容器136经由管道系统的导管180流体地联接至阀104的卫星通路164，使得当需要时，阀104可以从容器136获得容器136中包含的产物的样品。
第一保持盘管108位于阀104的上游，并通过管道系统的导管184流体地联接至阀104的中心通路160。因此，当阀104处于第一位置(在所述第一位置，中心通路160流体地联接至卫星通路164)时，第一保持盘管108被布置为经由阀104接收来自容器136的产物的样品。
第一柱112位于阀104的下游，并且通过管道系统的导管188流体地联接至阀104的卫星通路165。因此，当阀104处于第二位置(在所述第二位置，中心通路160流体地联接至卫星通路165)时，第一柱112被布置为经由阀104接收来自第一保持盘管108的样品。当第一柱112接收样品时，第一柱112被配置为在样品流过时结合来自样品的多肽。以此方式，第一柱112将样品中的多肽与样品的其余部分分开，所述其余部分可经由第二保持盘管116传送至第一废物室144。
第一柱112，在本文中也可以称为多肽结合柱，选自由以下组成的组：蛋白A柱、蛋白G柱、蛋白A/G柱、蛋白L柱、氨基酸柱、亲和素柱、链霉亲和素柱、碳水化合物结合柱、碳水化合物柱、谷胱甘肽柱、肝素柱、疏水相互作用柱、免疫亲和柱、核苷酸/辅酶柱、专门柱和固定化金属亲和色谱(IMAC)柱。例如，在多肽是1、2或4亚类的人IgG IgM、IgA或IgE(并包含人VH3家族的人Fc部分和/或Fab区)的情况下，蛋白A柱是有用的。蛋白G柱可用于纯化1-4亚类的人IgG。重组融合蛋白A/G柱也可用于纯化所有这些类型的人抗体，因为融合蛋白提供蛋白A和蛋白G结合位点。因此，蛋白A/G融合蛋白可用于纯化人IgG、IgA、IgE和IgM。此外，蛋白L柱可用于纯化人IgG、IgM、IgA、IgE和IgD，前提是靶抗体具有适当的κ(kappa)亚型轻链(即，VκI、VκIII和VκIV亚型)；蛋白L柱也可用于纯化也具有适当κ链亚型的Fab和scFv片段，因为蛋白L结合抗体的可变(V)链。
泵140位于第一保持盘管108的上游并且经由管道系统的导管192流体地联接至第一保持盘管108。该版本中的泵140采取注射泵的形式，所述注射泵流体地联接至第一缓冲液源196和第二缓冲液源200两者。在该版本中，第一缓冲液源196是洗脱缓冲液源，其可以提供洗脱缓冲溶液204，例如在蛋白A结合的抗体的情况下为酸性缓冲液；或在蛋白G结合的抗体的情况下，则为弱酸性(pH 3或更低)缓冲液；本领域技术人员能够优化和选择用于结合的抗体的至泵140(最终至第一保持盘管108)的适当洗脱缓冲液，并且第二缓冲液源200是变性缓冲液(含有变性剂，所述变性剂破坏四级、三级或二级多肽结构)源，其可以将变性试剂208提供至泵140(并且最终提供至第一保持盘管108)。在其他版本中，泵140可以是不同类型的泵和/或不同的泵140可以用于缓冲液源196、200中的每个。
在一些版本中，变性试剂可以是或包括变性去污剂或离液剂。在其中变性试剂是或包括变性去污剂的那些版本中，变性去污剂优选选自由以下组成的组：十二烷基硫酸钠(SDS)、胆酸钠、脱氧胆酸钠、甘氨胆酸钠、牛磺胆酸钠、牛磺脱氧胆酸钠、N-月桂酰肌氨酸、十二烷基硫酸锂、十六烷基三甲基溴化铵(CTAB)和三甲基(十四烷基)溴化铵(TTAB)。更优选地，变性去污剂是SDS。在变性试剂是或包括离液剂的那些版本中，离液剂优选选自由以下组成的组：尿素、正丁醇、乙醇、氯化胍、高氯酸锂、乙酸锂、氯化镁、苯酚、2-丙醇、和硫脲。可替代地或另外地，变性试剂可以是或包括加热的流体，所述加热的流体当变性试剂被传送到反应室120时具有适于在反应室120中达到(如果不维持)预定温度(例如，约22℃至约120℃)的温度。
阀212位于泵140与第一和第二缓冲液源196、200之间，以选择性地一次将泵140流体地联接至仅缓冲液源196、200之一。更特别地，阀212可在第一位置(其中泵140与第一缓冲液源196流体地联接，并且泵140与第二缓冲液源200流体隔离)和第二位置(泵140与第二缓冲液源200流体地联接，并且泵140与第一缓冲液源196流体隔离)之间移动。换句话说，取决于阀212的位置，泵140选择性地流体地联接至第一缓冲液源196或第二缓冲液源200。
如上所述，这种版本的泵140是注射泵。注射泵140通常被配置为从缓冲液源196、200之一获得缓冲液，并将该缓冲液输出到第一保持盘管108。当阀212处于第一位置时，泵140可以从第一缓冲液源196获得(例如，吸入)洗脱缓冲溶液204，并且在需要时可以输出(例如，排出)洗脱缓冲溶液204至第一保持盘管108。相反，当阀212处于第二位置时，泵140可以从第二缓冲液源200获得(例如，吸入)变性试剂208，并且在需要时可以输出(例如，排出)变性试剂208至第一保持盘管108。
第二保持盘管116位于阀104、第一保持盘管108和第一柱112的下游。第二保持盘管116经由管道系统的导管216、220选择性地流体地联接至阀104的卫星通路166。第二保持盘管116还经由导管220和导管224选择性地流体地联接至第一柱112。三通阀228被布置在导管216、220、224之间，以促进选择性联接以便产生所需流体流，如下面更详细地描述的。
因此，当泵140以上述方式输出洗脱缓冲溶液204，阀104处于第二位置(其中中心通路160流体地联接到卫星通路165)时，第二保持盘管116被布置为经由阀104并通过第一柱112从第一保持盘管108接收洗脱缓冲溶液204。随着洗脱缓冲溶液204通过第一柱112，洗脱缓冲溶液204洗脱与第一柱112结合的基本上所有的多肽。三通阀228被操作以连接导管220、224，从而将第一柱112与第二保持盘管116流体地联接，使得包括洗脱缓冲溶液204和洗脱的多肽的洗脱液/多肽混合物经由导管220、224从第一柱112流到第二保持盘管116。
反应室120位于阀104和第一柱112的下游，并通过管道系统的导管232流体地联接至阀104的卫星通路167。在该版本中，通过使用泵140将变性试剂208输出到第一保持盘管108并将多通路阀104移动至第四位置(其中中心通路160流体地偶联到阀167的卫星通路167)从而促进变性试剂208从第一保持盘管108向反应室120的移动，来使反应室120从第二缓冲液源200部分地(如果不是完全地)预填充变性试剂208(即，在系统100运行之前填充)。然而，在其他版本中，反应室120可以在系统100的运行期间(例如，在第二保持盘管116接收洗脱缓冲溶液204之后)部分地或完全地填充变性试剂208，从另一个缓冲液源和/或以其他方式部分地或完全地填充变性试剂，或者根本不填充反应室120，在这种情况下，可以通过连接到反应室120的加热元件236向反应室120施加热。
在洗脱液/多肽混合物到达第二保持盘管116之后，将洗脱液/多肽混合物移动至反应室120。在该版本中，反应室120从第二保持盘管116间接接收洗脱液/多肽混合物。更特别地，三通阀228被操作以连接导管216、224，洗脱液/多肽混合物经由导管216、224从第二保持盘管116移动至多通路阀104的卫星通路166，阀104移动至第三位置(其中中心通路160流体地联接至卫星通路166)，使混合物移动至第一保持盘管108，并且阀104移动至第四位置(其中中心通路160流体地联接至阀104的卫星通路167)，使得混合物从第一保持盘管108移动至反应室120。在其他版本中，反应室120可以直接从第二保持盘管116接收洗脱液/多肽混合物，或者可以利用一种或多种不同组件和/或以不同顺序间接地从第二保持盘管116接收混合物。
在任何情况下，一旦洗脱液/多肽混合物到达反应室120，混合物中的多肽就会在反应室120中孵育，从而使反应室120中的多肽变性。例如，当反应室120至少部分地被变性试剂填充时，混合物中的多肽将在到达反应室120并与变性试剂反应后经历变性。在一些情况下，反应室120可同时或始终被连接至反应室120(例如，紧邻、围绕反应室120)的加热元件236加热，以帮助促进变性过程。换句话说，加热元件236可以向反应室120施加热，优选地具有约22℃至约120℃的热，并且更优选地具有约40℃的热以促进变性。加热元件236可以例如采取加热块，加热线圈，感应加热器，热泵，筒式加热器，电阻丝，加热的流体或适于加热反应室120的一个或多个部分的其他元件。无论如何，通过将热从加热元件236施加到反应室120，促进变性过程。然而，在其他情况下，反应室120不能填充变性试剂，并且可以仅通过从加热元件236施加热来促进变性过程。
在混合物中的多肽变性之后，反应室120被配置为接收裂解二硫键交联的还原试剂，从而还原变性的多肽。还原试剂可以选自由以下组成的组：二硫苏糖醇(DTT)、谷胱甘肽、β-巯基乙醇(β-ME)和三(2-羧乙基)膦(TCEP)，并且通常由冷却容器240提供，所述容器可以例如采用温度为4℃的冷却器形式。在该版本中，冷却容器240位于阀104的下游并且具有第一室242，所述第一室242包含还原试剂并且经由管道系统的导管244流体地联接至阀104的卫星通路168。当阀104处于第五位置(其中中心通路160流体地联接至阀104的卫星通路168)时，第一室242将还原试剂供应至第一保持盘管108，并且然后当阀104处于(或返回)第四位置(其中中心通路160流体地联接至卫星通路167)时，还原试剂从第一保持盘管108移动至反应室120。因此，在该版本中，还原试剂经由第一保持盘管108间接地供应至反应室120。然而，在其他版本中，第一室242可以将还原试剂直接供应至反应室120(即，而无需将还原试剂移动至第一保持盘管108)。
在变性的多肽被还原之后，反应室120被配置为接收使反应室120中的巯基烷基化的烷基化剂，从而在反应室120中将变性和还原的多肽烷基化。烷基化剂优选是烷基化试剂，例如吲哚-3-乙酸(IAA)，但是也可以使用其他烷基化剂。在该版本中，冷却容器240具有第二室248，所述第二室248包含烷基化剂并且经由管道系统的导管252流体地联接至阀104的卫星通路169。当阀104处于第六位置(其中中心通路160流体地联接至阀104的卫星通路169)时，第二室248将烷基化剂供应至第一保持盘管108，并且然后当阀104处于(或返回)第四位置时，烷基化剂从第一保持盘管108移动至反应室120。因此，在该版本中，烷基化剂经由第一保持盘管108间接地供应至反应室120。然而，在其他版本中，第二室248可直接将烷基化剂供应至反应室120(即，而无需将烷基化剂移动至第一保持盘管108)和/或烷基化剂可以从不同的冷却容器(例如，与冷却容器240分开的冷却容器)供应。
在此版本中，系统100还包括第一常开阀256，所述第一常开阀256流体地联接至反应室120并位于反应室120的下游。常开阀256具有与反应室120的出口264流体地连接的入口260，与第二废物室148流体地连接的第一出口268，和流体地连接至大气的第二出口272。当系统100运行时，更特别地讲，反应室120正在接收并填充洗脱液/多肽混合物、还原试剂、烷基化剂、以及在某些情况下的变性试剂，阀256时，常开阀256通常在打开位置或第一位置运行。在该打开位置，入口260与第一出口268流体地联接，并且入口260与第二出口272流体地隔离，使得当反应室120被填充超过其固定容积时，任何过量的内容物被引导至第二废物室148。然而，当例如反应室120不再接受上述内容物并且是时候清洗反应室120时，常开阀256可从打开位置移动(例如，通过向阀256施加电流)到关闭位置或第二位置。在该关闭位置，入口260与第二出口272流体地联接，并且入口260与第一出口268流体地隔离，使得反应室120的出口264暴露于大气。反过来，空气可以流入反应室120中，从而有利于从反应室120中去除内容物。
第二柱124，在本文中也称为脱盐柱124，优选采用尺寸排阻色谱柱的形式，其位于阀104的下游并且经由管道系统的导管276流体地联接至阀104的卫星通路170。因此，第二柱124被布置成从反应室120接收变性、还原并烷基化的多肽，洗脱缓冲溶液204，烷基化剂，还原试剂和变性试剂(当使用时)。在此版本中，第二柱124间接从反应室120接收这些材料。更特别地，当阀104处于(或移动至)第四位置(其中中心通路160流体地联接至卫星通路167)时，这些材料经由阀104从反应室120移动至第一保持盘管108，并且阀104移动至第七位置(其中中心通路160流体地联接至卫星通路170)，使得材料从第一保持盘管108移动至第二柱124。在其他形式中，第二柱124可以直接从反应室120接收这些材料，或者可以利用一种或多种不同的组件和/或以不同的顺序间接地接收这些材料。
无论如何，当第二柱124接收变性、还原并烷基化的多肽，洗脱缓冲溶液204，烷基化剂，还原试剂和变性试剂(当使用时)时，第二柱124被配置为将变性、还原并烷基化的多肽与洗脱缓冲溶液204，烷基化剂，还原试剂和变性试剂(当使用时)(这些最终移动至第三废物室152)分离。因此，第二柱124在本文中可以被称为脱盐柱124。同时，第二柱124被配置为将多肽缓冲交换成所需的缓冲条件，所述条件允许第三柱128执行下述功能。
在此版本中，系统100还包括第二常开阀280，所述第二常开阀280流体地联接至第二柱124和第三柱128并且位于其之间。常开阀280具有与第二柱124的出口288流体地连接的入口284，与第三废物室152流体地连接的第一出口292，和流体地连接至第三柱128的第二出口296。当系统100在运行中时，常开阀280通常在打开位置或第一位置中运行。在该打开位置，入口284流体地联接至第一出口292，并且入口284与第二出口296流体地隔离，使得洗脱缓冲溶液204、烷基化剂、还原试剂和变性试剂被引导至第三废物室152。然而，当需要将脱盐的多肽从第二柱124移动至位于第二柱124下游的第三柱128时，常开阀280可从打开位置移动(例如，通过向阀280施加电流)到关闭位置或第二位置。在该关闭位置中，入口284流体地联接至第二出口296，并且入口284与第一出口通路292流体地隔离，使得第二柱124流体地联接至第三柱128，使得脱盐的多肽可以从第二柱124传送到第三柱128。在该版本中，第三柱128包括蛋白水解酶(例如，内肽酶，其选自由以下组成的组：胰蛋白酶、胰凝乳蛋白酶、弹性蛋白酶、嗜热菌蛋白酶、胃蛋白酶、谷氨酰内肽酶、脑啡肽酶、Lys-C蛋白酶和金黄色葡萄球菌V8蛋白酶)，使得第三柱128在本文中可以称为蛋白水解酶柱。无论如何，第三柱128消化从第二柱124获得的脱盐的多肽。
多肽在第三柱128中消化之后，可以将消化的多肽移动至分析装置156，其可以例如采用液相色谱装置、高效液相色谱装置、超高效液相色谱装置、质谱装置、聚糖分析装置，另一种分析装置或其组合的形式。在该版本中，分析装置156位于第三柱128的下游，并且经由管道系统的导管298流体地联接至第三柱128。因此，在该版本中，消化的多肽可以自动移动至分析装置156以进行分析(例如以进行定量和分离)。然而，在其他版本中，分析装置156不是系统100的一部分(例如，未流体地联接至第三柱128)，在这种情况下，消化的多肽可以以不同的方式(例如手动)移动至分析装置156。
如上所述，系统100还包括控制器132，在此版本中，控制器132通信地联接或连接至系统100的各个组件，以通过向系统100的各个组件传输信号(例如控制信号，数据)以及从系统100的各个组件接收信号(例如数据)来监测并促进或指导系统100的上述运行。控制器132可以紧邻系统100的其他组件放置(例如，在与系统100相同的环境中)，或者可以远离系统100的其他组件放置。如图所示，控制器132经由通信网络300通信地联接或连接至多通路阀104，经由通信网络328通信地联接或连接至泵140，经由通信网络332通信地联接或连接至分析装置156，经由通信网络340通信地联接或连接至加热元件236，经由通信网络344通信地联接或连接至第一常开阀256，以及经由通信网络348通信地联接或连接至第二常开阀280。在其他版本中，控制器132可以通信地联接或连接至系统100的更多或更少的组件，例如，第一保持盘管108、第一柱112、第二保持盘管116、反应室120、第二柱124、第三柱128、容器136、三通阀228和/或冷却容器240。
如本文所使用的，短语“通信地联接”和“连接”被定义为意指直接联接或连接或通过一个或多个中间组件间接联接或连接。这样的中间组件可以包括基于硬件和/或软件的组件。应当理解，网络300-348可以是无线网络、有线网络或有线和无线网络(例如，蜂窝电话网络和/或802.11x兼容网络)的组合，并且可以包括公共可访问的网络，例如因特网、专用网络或其组合。网络300-348的类型和配置取决于实现方式，并且可以使用任何类型的通信网络，所述通信网络促进现在或以后开发的控制器132与系统100的组件之间的所描述的通信。
如图2所示，控制器132包括处理器352、存储器356、通信接口360和计算逻辑364。处理器352可以是通用处理器、数字信号处理器、专用集成电路(ASIC)、现场可编程门阵列、图形处理单元、模拟电路、数字电路或任何其他已知或以后开发的处理器。处理器352根据存储器356中的指令进行操作。存储器356可以是易失性存储器或非易失性存储器。存储器356可以包括只读存储器(ROM)、随机存取存储器(RAM)、闪存、电子可擦除程序只读存储器(EEPROM)或其他类型的存储器中的一个或多个。存储器356可以包括光、磁(硬盘)或任何其他形式的数据存储装置。
提供通信接口360以经由网络300-348实现或促进控制器132与制冷系统100的组件之间的电子通信。通信接口360可以是或包括例如一个或多个通用串行总线(USB)端口、一个或多个以太网端口和/或一个或多个其他端口或接口。电子通信可以经由任何已知的通信协议发生，例如，包括USB、RS-232、RS-485、WiFi、蓝牙和/或任何其他合适的通信协议。
逻辑364通常包括体现为存储在存储器356上的计算机可读指令的一个或多个控制例程和/或一个或多个子例程。控制例程和/或子例程可以执行PID(比例-积分-微分)、模糊逻辑、非线性或任何其他合适类型的控制。处理器352通常执行逻辑364以执行与系统100的运行有关的动作。
一般而言，逻辑364在执行时使处理器352控制系统100的组件，尤其是多通路阀104，泵140，加热元件236，第一和第二常开阀256、280，和分析装置156，使得系统100以本文讨论的所需方式操作。更特别地，逻辑364在执行时可使处理器352(i)将多通路阀104移动至本文所述的任何位置或之间，从而流体地联接如上所述的系统100的各个组件，(ii)控制泵140(例如，使泵140获得并输出洗脱缓冲溶液204或变性试剂208)，(iii)控制加热元件236(当在系统100中使用时)以选择性地将热施加至反应室120(及其内容物)，(iv)控制第一常开阀256，(v)控制第二常开阀280，(vi)控制分析装置156，并执行其他所需功能。
例如，当期望对包含多肽的产物的样品进行实时测定时，逻辑364可由处理器352执行以将阀104定位在上述第一位置，通过导管180、通路164、通路160将产物的样品从容器136移动至第一保持盘管108，将阀104定位在上述第二位置，并通过导管184、通路160、164和导管188将样品从第一保持盘管108移动至并通过多肽结合柱112。反过来，样品中的基本上所有多肽都与柱112结合，使得样品中的多肽与样品的其余部分分开，所述其余部分经由导管220、224和第二保持盘管116传送第一废物室144。
逻辑364可由处理器352进一步执行，以使泵140从第一缓冲液源196获得洗脱缓冲溶液204，并经由导管192将洗脱缓冲溶液204输出至第一保持盘管108。在某些情况下，可能需要将泵140从第二位置移动至第一位置(以将泵140与第一缓冲液源196流体地联接)，但是在其他情况下，泵140可能已经处于第一位置。在任何情况下，逻辑364均可由处理器352执行，以经由导管184、通路160、通路165和导管188、220和224，将洗脱缓冲溶液204从第一保持盘管108移动至并通过第一柱112并移动至第二保持盘管116。以这种方式，洗脱缓冲溶液204洗脱与第一柱112结合的基本上所有的多肽，并且包含洗脱缓冲溶液204和洗脱的多肽的洗脱液/多肽混合物从第一柱112流动至第二保持盘管116。
逻辑364可由处理器352进一步执行以将阀104移动至上述第三位置，经由导管224、导管216、通路166、通路160和导管184将洗脱液/多肽混合物从第二保持盘管116移动至第一保持盘管108，将阀104移动至上述第四位置，并经由导管184、通路160、通路167和导管232将洗脱液/多肽混合物从第一保持盘管108移动至反应室120。反过来，将洗脱液/多肽混合物中的多肽与变性试剂208和/或在加热元件236施加的热的存在下在反应室120中孵育，从而使多肽变性。
逻辑364可由处理器352进一步执行以将阀104移动至上述第五位置，经由导管244、通路168、通路160和导管184将还原试剂从冷却容器240的第一室242移动至第一保持盘管108，将阀104移动返回至第四位置，并经由导管184、通路160、通路167和导管232将还原试剂从第一保持盘管108移动至反应室120。在到达反应室120后，还原试剂裂解二硫键交联，从而这还原反应室120中的变性的多肽。
逻辑364可由处理器352进一步执行以将阀104移动至上述第六位置，经由导管252、通路169、通路160和导管184将烷基化剂从冷却容器240的第二室248移动至第一保持盘管108，将阀104移动返回至第四位置，并经由导管184、通路160、通路167和导管232将烷基化剂从第一保持盘管108移动至反应室120。在到达反应室120后，烷基化剂使反应室120中的巯基烷基化，从而这使反应室120中的变性和还原的多肽烷基化。
逻辑364可由处理器352进一步执行以将阀104移动至上述第四位置(如果尚未在所述位置)，经由导管232、通路167、通路160和导管184，将变性、还原并烷基化的多肽，洗脱缓冲溶液204，烷基化剂，还原试剂和变性试剂(当使用时)从反应室120移动至第一保持盘管108，将阀104移动至上述第七位置，并且经由导管184、通路160、通路170和导管276，将变性、还原并烷基化的多肽，洗脱缓冲溶液204，烷基化剂，还原试剂和变性试剂(当使用时)从第一保持盘管108移动至脱盐柱124。反过来，脱盐柱124将变性、还原并烷基化的多肽与洗脱缓冲溶液204，烷基化剂，还原试剂和变性试剂分离，所述洗脱缓冲溶液204，烷基化剂，还原试剂和变性试剂传送至或移动至第三废物室152。
在变性、还原并烷基化的多肽之后的某个点，将洗脱缓冲溶液204、烷基化剂、还原试剂和变性试剂(当使用时)从反应室120移动至第一保持盘管108，逻辑364可由处理器352进一步执行以将常开阀256从其打开的第一位置(其中室120的出口264流体地联接至第二废物室148，以将不能装入反应室120(由于其被填充超过其固定容积)中的内容物引导至第二废物室148)移动至其关闭的第二位置(其中出口264流体地联接至大气，使得空气可以流入反应室120中，从而有利于从反应室120中去除内容物)。常开阀256可以在反应室120被排空之后立即返回到打开的第一位置，或者可以在稍后的时间点返回到打开的第一位置。
在脱盐柱124将变性、还原并烷基化的多肽与其他材料分离之后，逻辑364可由处理器352进一步执行以将常开阀280从其打开的第一位置(其中阀280的入口流体地联接至第三废物室152)移动至其关闭的第二位置(其中阀280的入口流体地联接至蛋白水解酶柱128)。反过来，逻辑364可以由处理器352执行，以将脱盐的(或分离的)多肽从脱盐柱124移动至蛋白水解酶柱128(其消化脱盐的多肽)。
在多肽被消化之后，至少在此版本中，逻辑364可以由处理器352进一步执行，以将消化的多肽从蛋白水解酶柱128移动至分析装置156以分析多肽，并使分析装置156执行所需的分析。例如，逻辑364可以在由处理器352执行时使分析装置156分离并定量多肽。
在其他版本中，逻辑364在由处理器352执行时可以使得执行附加的、较少的和/或不同的功能。作为实例，逻辑364在由处理器352执行时可以不将消化的多肽从柱128移动至分析装置156，或者不使分析装置156执行所需的分析。此外，在其他版本中，逻辑364可以由处理器352以与本文所述不同的顺序执行。最后，应当理解，逻辑364可以由处理器352执行任意不同次数，因为系统100可以用于对多个样品(来自同一产物和/或来自不同产物)进行实时分析。
图3A-图3C示出了联机和实时MAM测定研究的结果，所述研究被设计为监测系统100在制备包含双特异性T细胞衔接
分子的产物的样品方面的有效性。特别地，所述研究在40天的生产运行中监测系统100的有效性。所述研究开始监测和收集CQA数据，例如40天生产运行的第6天，2个脱酰胺位点DS1和DS2的面积百分比，以及碎片频率FF(图3A所示)，和四个参考肽RP1、RP2、RP3和RP4的MS峰高(表示为离子计数的数量)(图3B和图3C所示)。如图3A所示，系统100在40天的生产运行的整个持续时间内能够且有效地执行本文讨论的预期功能，并且，如图3B和图3C所示，第6天到第40天之间收集的CQA数据基本一致，即，随着时间的推移产物质量没有明显变化，并且第32天后产物质量实际上提高，从而证明了系统100在自动制备样品方面的稳健性。确实，如图3C所示，在该时间段内针对RP1、RP2、RP3和RP4收集的CQA数据要好于在典型的手动MAM测定中获得的CQA数据。
治疗性多肽
蛋白质，包括与以下一种或多种结合的蛋白质，可用于所披露的装置和方法。这些包括CD蛋白，包括CD3、CD4、CD8、CD19、CD20、CD22、CD30和CD34；包括干扰受体结合的那些。HER受体家族蛋白，包括HER2、HER3、HER4和EGF受体。细胞粘附分子，例如，LFA-I、MoI、pl50、pl95、VLA-4、ICAM-I、VCAM和αv/β3整联蛋白。生长因子，例如血管内皮生长因子(“VEGF”)、生长激素、甲状腺刺激素、卵泡刺激素、黄体生成激素、生长激素释放因子、甲状旁腺激素、米勒管抑制物质(mullerian-inhibiting substance)、人类巨噬细胞炎性蛋白(MIP-I-α)、促红细胞生成素(EPO)、神经生长因子(诸如NGF-β)、血小板源性生长因子(PDGF)、成纤维细胞生长因子(包括例如aFGF和bFGF)、表皮生长因子(EGF)、转化生长因子(TGF)(其中包括TGF-α和TGF-β，包括TGF-βl、TGF-β2、TGF-β3、TGF-β4或TGF-β5)、胰岛素样生长因子-I和胰岛素样生长因子-II(IGF-I和IGF-II)、des(l-3)-IGF-I(脑IGF-I)和骨诱导因子。胰岛素和胰岛素相关蛋白，包括胰岛素、胰岛素A链、胰岛素B链、胰岛素原和类胰岛素生长因子结合蛋白。凝血蛋白和凝血相关蛋白，尤其诸如，VIII因子、组织因子、范威尔邦德(vonWillebrand)因子、蛋白C、α-1-抗胰蛋白酶、纤溶酶原激活剂(诸如尿激酶和组织纤溶酶原激活剂(“t-PA”))、邦巴辛(bombazine)、凝血酶、和血小板生成素；(vii)其他血液和血清蛋白，包括但不限于白蛋白、IgE和血型抗原。菌落刺激因子及其受体，其中包括以下：M-CSF，GM-CSF和G-CSF，及其受体，例如CSF-1受体(c-fms)。受体和受体相关蛋白，包括例如flk2/flt3受体、肥胖(OB)受体、LDL受体、生长激素受体、血小板生成素受体(“TPO-R”，“c-mpl”)、胰高血糖素受体、白介素受体、干扰素受体、T细胞受体、干细胞因子受体(例如c-Kit)和其他受体。受体配体，包括例如OX40L、OX40受体的配体。神经营养因子，包括骨源性神经营养因子(BDNF)和神经营养蛋白-3、神经营养蛋白-4、神经营养蛋白-5或神经营养蛋白-6(NT-3、NT-4、NT-5或NT-6)。松弛素A链、松弛素B链和松弛素原；干扰素和干扰素受体，包括例如干扰素-α、干扰素-β和干扰素-γ，及其受体。白介素和白介素受体，包括IL-I至IL-33和IL-I至IL-33受体，例如IL-8受体，等等。病毒抗原，包括AIDS包膜病毒抗原。脂蛋白、降钙素、胰高血糖素、心钠素、肺表面活性剂、肿瘤坏死因子-α和-β、脑啡肽酶、RANTES(受激活调节的正常T细胞表达与分泌的)、小鼠促性腺激素相关肽、DNA酶、抑制素和激活素。整联蛋白、蛋白A或D、类风湿因子、免疫毒素、骨形态发生蛋白(BMP)、超氧化物歧化酶、表面膜蛋白、衰变促进因子(DAF)、AIDS包膜、转运蛋白、归巢受体、地址素、调节蛋白、免疫粘附素、抗体。肌生长抑制素、TALL蛋白(包括TALL-I)、淀粉样蛋白(包括但不限于淀粉样β蛋白)、胸腺基质淋巴细胞生成素(“TSLP”)、RANK配体(“OPGL”)、c-kit、TNF受体(包括TNF受体1型)、TRAIL-R2、血管生成素和任何上述物质的生物活性片段或类似物或变体。
示例性的多肽和抗体包括
(阿替普酶)；阿利库单抗，
(达贝泊汀-α)，
(阿法依伯汀(Epoetin alfa)或促红细胞生成素)；
(干扰素β-Ia)；
(托西莫单抗)；
(干扰素-β)；百库珠单抗(抗PCSK9单克隆抗体，命名为L1L3，参阅US8080243)；
(阿仑单抗)；
(依伯汀δ)；
(硼替佐米)；MLN0002(抗α4β7mAb)；MLN1202(抗CCR2趋化因子受体mAb)；
(依那西普)；
(依伯汀α)；
(西妥昔单抗)；依伏库单抗；
(生长激素)；
(曲妥珠单抗)；
(注射用生长激素[rDNA来源])；
(阿达木单抗)；
(干扰素Alfacon-1)；
(奈西立肽)；
(阿那白滞素)，
(沙格司亭)；
(依帕珠单抗)；BenlystaTM(贝利木单抗)；
(替奈普酶)；
(甲氧基聚乙二醇-依伯汀β)；
(奥-吉妥珠单抗(Gemtuzumab ozogamicin))；
(依法利珠单抗)；
(赛妥珠单抗(certolizumab pegol))；SolirisTM(依库丽单抗)；培克珠单抗(抗C5补体)；MEDI-524
(兰尼单抗)；依决洛单抗
(乐地单抗(lerdelimumab))；TheraCim hR3(尼妥珠单抗)；Omnitarg(帕妥珠单抗，2C4)；
(IDM-I)；
(B43.13)；
(威司利珠单抗(visilizumab))；莫坎妥珠单抗(Cantuzumab mertansine)(huC242-DMl)；
(依伯汀β)；
(奥普瑞白介素)；
(聚乙二醇化非格司亭，聚乙二醇化G-CSF，聚乙二醇化hu-Met-G-CSF)；
(非格司亭)；Orthoclone
(莫罗单抗-CD3)，
(依伯汀α)；
(英夫利昔单抗)，
(阿昔单抗)，
(抗IL6受体mAb)，
(贝伐单抗)，HuMax-CD4(扎木单抗(zanolimumab))，
(利妥昔单抗)；
(埃罗替尼)；
(干扰素α-2a)；
(巴利昔单抗)；StelaraTM(优特克单抗)；
(罗美昔布)；
(帕利珠单抗)；146B7-CHO(抗IL15抗体，参见US7153507)，
(那他珠单抗)；
(MDX-1303，抗炭疽杆菌保护性抗原mAb)；ABthraxTM；
(帕尼单抗)；
(奥马珠单抗)，ETI211(抗MRSA mAb)，IL-I陷阱(人IgGl的Fc部分和两个IL-I受体成分(I型受体和受体辅助蛋白)的胞外结构域)，VEGF陷阱(VEGFRl的Ig结构域与IgGl Fc融合)，
(达克珠单抗)；
(达克珠单抗)，
(替坦替伊莫单抗(Ibritumomab tiuxetan)，Zetia(依泽替米贝)，阿塞西普(TACI-Ig)，抗α4β7mAb(维多珠单抗)；加利昔单抗(galiximab)(抗CD80单克隆抗体)，抗CD23 mAb(鲁昔单抗)；BR2-Fc(huBR3/huFc融合蛋白，可溶性BAFF拮抗剂)；SimponiTM(戈利木单抗)；马帕木单抗(Mapatumumab)(人抗TRAIL受体-1mAb)；奥瑞单抗(Ocrelizumab)(抗CD20人mAb)；HuMax-EGFR(扎鲁木单抗(zalutumumab))；M200(伏洛昔单抗(Volociximab)，抗α5β1整合素mAb)；MDX-010(艾匹利木单抗，抗CTLA-4mAb和VEGFR-I(IMC-18F1)；抗BR3 mAb；抗艰难梭菌毒素A和毒素B C mAb MDX-066(CDA-I)和MDX-1388)；抗CD22 dsFv-PE38缀合物(CAT-3888和CAT-8015)；抗CD25 mAb(HuMax-TAC)；抗TSLP抗体；抗TSLP受体抗体(US8101182)；指定为A5的抗TSLP抗体(US7982016)；(抗CD3 mAb(NI-0401)；阿德木单抗(Adecatumumab)(MT201，抗EpCAM-CD326 mAb)；MDX-060、SGN-30、SGN-35(抗CD30 mAb)；MDX-1333(抗IFNAR)；HuMaxCD38(抗CD38 mAb)；抗CD40L mAb；抗Cripto mAb；抗CTGF特发性肺纤维化I期纤维蛋白原(FG-3019)；抗CTLA4 mAb；抗eotaxinl mAb(CAT-213)；抗FGF8 mAb；抗神经节苷脂GD2 mAb；抗硬化蛋白抗体(参见，US8715663或US7592429)被指定为Ab-5的抗硬化蛋白抗体(US8715663或US7592429)；抗神经节苷脂GM2 mAb；抗GDF-8人mAb(MYO-029)；抗GM-CSF受体mAb(CAM-3001)；抗HepC mAb(HuMax HepC)；MEDI-545、MDX-1103(抗IFNαmAb)；抗IGFIRmAb；抗IGF-IR mAb(HuMax-Inflam)；抗IL12/IL23p40 mAb(布瑞吉努单抗)；抗IL-23p19mAb(LY2525623)；抗IL13 mAb(CAT-354)；抗IL-17mAb(AIN457)；抗IL2Ra mAb(HuMax-TAC)；抗IL5受体mAb；抗整合素受体mAb(MDX-Ol8，CNTO 95)；抗IPIO溃疡性结肠炎mAb(MDX-1100)；抗LLY抗体；BMS-66513；抗甘露糖受体/hCGβmAb(MDX-1307)；抗间皮素dsFv-PE38缀合物(CAT-5001)；抗PDlmAb(MDX-1 106(ONO-4538))；抗PDGFRα抗体(IMC-3G3)；抗TGFβmAb(GC-1008)；抗TRAIL受体-2人mAb(HGS-ETR2)；抗TWEAK mAb；抗VEGFR/Flt-1mAb；抗ZP3 mAb(HuMax-ZP3)；以及包含序列SEQ ID NO:8和SEQ ID NO:6的淀粉样蛋白β单克隆抗体(US7906625)。
适用于所述方法和药物配制品的抗体实例包括表1中所示的抗体。适合的抗体的其他实例包括英夫利昔单抗(infliximab)、贝伐单抗(bevacizumab)、西妥昔单抗(cetuximab)、兰尼单抗(ranibizumab)、帕利珠单抗(palivizumab)、阿巴伏单抗(abagovomab)、阿昔单抗(abciximab)、阿克托克单抗(actoxumab)、阿达木单抗(adalimumab)、阿非莫单抗(afelimomab)、阿托珠单抗(afutuzumab)、阿珠单抗(alacizumab)、培化阿珠单抗(alacizumab pegol)、ald518、阿仑单抗(alemtuzumab)、阿利库单抗(alirocumab)、阿妥莫单抗(altumomab)、阿麦妥昔单抗(amatuximab)、马安那莫单抗(anatumomab mafenatox)、安芦珠单抗(anrukinzumab)、阿泊珠单抗(apolizumab)、阿西莫单抗(arcitumomab)、阿塞珠单抗(aselizumab)、阿替奴单抗(altinumab)、阿替珠单抗(atlizumab)、阿托立木单抗(atorolimiumab)、托珠单抗(tocilizumab)、巴匹珠单抗(bapineuzumab)、巴利昔单抗(basiliximab)、巴维昔单抗(bavituximab)、贝妥莫单抗(bectumomab)、贝利木单抗(belimumab)、苯拉利珠单抗(benralizumab)、柏替木单抗(bertilimumab)、贝索单抗(besilesomab)、贝伐珠单抗(bevacizumab)、贝洛托单抗(bezlotoxumab)、比西单抗(biciromab)、比伐珠单抗(bivatuzumab)、莫-比伐珠单抗(bivatuzumab mertansine)、博纳吐单抗(blinatumomab)、布索珠单抗(blosozumab)、本妥昔单抗(brentuximab vedotin)、巴列津单抗(briakinumab)、布洛鲁单抗(brodalumab)、康纳单抗(canakinumab)、莫坎妥珠单抗(cantuzumab mertansine)、莫坎妥珠单抗(cantuzumab mertansine)、卡普赛珠单抗(caplacizumab)、卡罗单抗喷地肽(capromabpendetide)、卡鲁单抗(carlumab)、卡妥索单抗(catumaxomab)、cc49、西利珠单抗(cedelizumab)、赛妥珠单抗(certolizumab pegol)、西妥昔单抗(cetuximab)、泊西他珠单抗(citatuzumab bogatox)、西妥木单抗(cixutumumab)、克拉扎珠单抗(clazakizumab)、克立昔单抗(clenoliximab)、克伐珠单抗(clivatuzumab tetraxetan)、可那木单抗(conatumumab)、克雷内治单抗(crenezumab)、cr6261、达西珠单抗(dacetuzumab)、达克珠单抗(daclizumab)、达罗土珠单抗(dalotuzumab)、达雷木单抗(daratumumab)、地莫米佐单抗(demcizumab)、地诺单抗(denosumab)、地莫单抗(detumomab)、阿托度单抗(dorlimomabaritox)、德罗图单抗(drozitumab)、杜力戈图单抗(duligotumab)、杜匹鲁单抗(dupilumab)、依美昔单抗(ecromeximab)、依库丽单抗(eculizumab)、埃巴单抗(edobacomab)、依决洛单抗(edrecolomab)、依法利珠单抗(efalizumab)、依芬古单抗(efungumab)、埃罗妥珠单抗(elotuzumab)、艾西莫单抗(elsilimomab)、埃文单抗(enavatuzumab)、培化恩莫单抗(enlimomab pegol)、恩诺珠单抗(enokizumab)、依诺替库单抗(enoticumab)、埃斯托西单抗(ensituximab)、西依匹莫单抗(epitumomabcituxetan)、依帕珠单抗(epratuzumab)、厄瑞奴单抗(erenumab)、厄利珠单抗(erlizumab)、厄马索单抗(ertumaxomab)、埃达珠单抗(etaracizumab)、依卓利珠单抗(etrolizumab)、依伏库单抗(evolocumab)、艾韦单抗(exbivirumab)、法索单抗(fanolesomab)、法拉莫单抗(faralimomab)、法拉图珠单抗(farletuzumab)、法希奴单抗(fasinumab)、fbta05、非维珠单抗(felvizumab)、非扎奴单抗(fezakinumab)、费希腊妥单抗(ficlatuzumab)、芬妥木单抗(figitumumab)、弗兰托单抗(flanvotumab)、芳妥珠单抗(fontolizumab)、弗罗鲁单抗(foralumab)、福拉韦单抗(foravirumab)、夫苏木单抗(fresolimumab)、弗兰单抗(fulranumab)、弗图希单抗(futuximab)、加利昔单抗(galiximab)、盖尼柱单抗(ganitumab)、盖坦德单抗(gantenerumab)、加维莫单抗(gavilimomab)、吉妥珠单抗奥佐米星(gemtuzumab ozogamicin)、吉伏珠单抗(gevokizumab)、吉仁土昔单抗(girentuximab)、维德汀单抗(glembatumumab vedotin)、戈利木单抗(golimumab)、戈利昔单抗(gomiliximab)、gs6624、替伊立珠单抗(ibalizumab)、替伊莫单抗(ibritumomab tiuxetan)、依库单抗(icrucumab)、伊戈伏单抗(igovomab)、英西单抗(imciromab)、英戈土珠单抗(imgatuzumab)、英克拉库单抗(inclacumab)、依坦希单抗(indatuximab ravtansine)、英夫利西单抗(infliximab)、英妥木单抗(intetumumab)、伊诺莫单抗(inolimomab)、伊珠单抗奥佐米星(inotuzumab ozogamicin)、伊匹木单抗(ipilimumab)、艾雷妥木单抗(iratumumab)、依拓珠单抗(itolizumab)、希凯珠单抗(ixekizumab)、凯利昔单抗(keliximab)、拉贝珠单抗(labetuzumab)、来金珠单抗(lebrikizumab)、来马索单抗(lemalesomab)、乐地单抗(lerdelimumab)、来沙木单抗(lexatumumab)、利韦单抗(libivirumab)、利格珠单抗(ligelizumab)、林妥珠单抗(lintuzumab)、立鲁单抗(lirilumab)、莫-洛伏珠单抗(lorvotuzumab mertansine)、鲁卡木单抗(lucatumumab)、鲁昔单抗(lumiliximab)、马帕木单抗(mapatumumab)、马司莫单抗(maslimomab)、美力姆单抗(mavrilimumab)、马妥珠单抗(matuzumab)、美泊利单抗(mepolizumab)、美替木单抗(metelimumab)、米拉珠单抗(milatuzumab)、明瑞莫单抗(minretumomab)、米妥莫单抗(mitumomab)、莫格穆里单抗(mogamulizumab)、莫罗木单抗(morolimumab)、莫他珠单抗(motavizumab)、莫希土姆单抗(moxetumomab pasudotox)、莫罗单抗-cd3(muromonab-cd3)、他那可单抗(nacolomab tafenatox)、纳米鲁单抗(namilumab)、他那莫单抗(naptumomab estafenatox)、纳瑞特单抗(narnatumab)、那他珠单抗(natalizumab)、奈巴库单抗(nebacumab)、奈昔木单抗(necitumumab)、奈瑞莫单抗(nerelimomab)、耐西维单抗(nesvacumab)、尼妥珠单抗(nimotuzumab)、纳武单抗(nivolumab)、巯诺莫单抗(nofetumomab merpentan)、奥卡土珠单抗(ocaratuzumab)、奥瑞珠单抗(ocrelizumab)、奥度莫单抗(odulimomab)、奥法木单抗(ofatumumab)、奥拉图单抗(olaratumab)、奥鲁凯珠单抗(olokizumab)、奥马珠单抗(omalizumab)、欧那土珠单抗(onartuzumab)、莫奥珠单抗(oportuzumab monatox)、奥戈伏单抗(oregovomab)、奥泰单抗(orticumab)、奥昔珠单抗(otelixizumab)、欧西鲁单抗(oxelumab)、欧赞尼珠单抗(ozanezumab)、欧拉丽珠单抗(ozoralizumab)、帕吉昔单抗(pagibaximab)、帕利珠单抗(palivizumab)、帕尼单抗(panitumumab)、帕诺库单抗(panobacumab)、帕萨土珠单抗(parsatuzumab)、帕考珠单抗(pascolizumab)、帕特立珠单抗(pateclizumab)、帕图单抗(patritumab)、帕尼单抗(pemtumomab)、培拉凯珠单抗(perakizumab)、培妥珠单抗(pertuzumab)、培克珠单抗(pexelizumab)、皮地利珠单抗(pidilizumab)、平妥莫单抗(pintumomab)、普拉库鲁单抗(placulumab)、拍珠单抗(ponezumab)、普立昔单抗(priliximab)、普托木单抗(pritumumab)、PRO 140、坤立珠单抗(quilizumab)、雷库图单抗(racotumomab)、雷德图单抗(radretumab)、雷韦单抗(rafivirumab)、雷莫芦单抗(ramucirumab)、雷珠单抗(ranibizumab)、雷昔库单抗(raxibacumab)、瑞加韦单抗(regavirumab)、瑞利珠单抗(reslizumab)、利妥木单抗(rilotumumab)、利妥昔单抗(rituximab)、罗妥木单抗(robatumumab)、罗勒杜单抗(roledumab)、罗姆苏珠单抗(romosozumab)、隆他利珠单抗(rontalizumab)、罗利珠单抗(rovelizumab)、鲁利珠单抗(ruplizumab)、沙玛立珠单抗(samalizumab)、沙鲁单抗(sarilumab)、沙妥莫单抗喷地肽(satumomab pendetide)、苏金单抗(secukinumab)、司韦单抗(sevirumab)、西罗珠单抗(sibrotuzumab)、西法木单抗(sifalimumab)、司妥昔单抗(siltuximab)、西姆土珠单抗(simtuzumab)、西利珠单抗(siplizumab)、希瑞库单抗(sirukumab)、苏兰珠单抗(solanezumab)、苏力图单抗(solitomab)、松普希珠单抗(sonepcizumab)、松妥珠单抗(sontuzumab)、司他芦单抗(stamulumab)、硫索单抗(sulesomab)、索维单抗(suvizumab)、他贝鲁单抗(tabalumab)、他珠单抗(tacatuzumab tetraxetan)、他度珠单抗(tadocizumab)、他利珠单抗(talizumab)、他尼珠单抗(tanezumab)、帕他莫单抗(taplitumomab paptox)、替非珠单抗(tefibazumab)、阿替莫单抗(telimomab aritox)、替妥莫单抗(tenatumomab)、替非珠单抗(tefibazumab)、替奈昔单抗(teneliximab)、替利珠单抗(teplizumab)、替普单抗(teprotumumab)、替扎贝鲁单抗(tezepelumab)、TGN1412、曲美木单抗(tremelimumab)、替西木单抗(ticilimumab)、替拉珠单抗(tildrakizumab)、替加珠单抗(tigatuzumab)、TNX-650、托珠单抗(tocilizumab)、托利珠单抗(toralizumab)、托西莫单抗(tositumomab)、曲洛青木单抗(tralokinumab)、曲妥珠单抗(trastuzumab)、TRBS07、曲加立珠单抗(tregalizumab)、西莫白介素单抗(tucotuzumab celmoleukin)、妥韦单抗(tuvirumab)、乌波利土西单抗(ublituximab)、乌瑞鲁单抗(urelumab)、乌珠单抗(urtoxazumab)、优特克单抗(ustekinumab)、伐利昔单抗(vapaliximab)、维特立珠单抗(vatelizumab)、维多珠单抗(vedolizumab)、维妥珠单抗(veltuzumab)、维帕莫单抗(vepalimomab)、维西库单抗(vesencumab)、维西珠单抗(visilizumab)、伏洛昔单抗(volociximab)、伏妥土珠单抗(vorsetuzumab mafodotin)、伏妥莫单抗(votumumab)、扎芦木单抗(zalutumumab)、扎木单抗(zanolimumab)、扎土希单抗(zatuximab)、齐拉木单抗(ziralimumab)、阿佐莫单抗(zolimomab aritox)。
抗体还包括阿达木单抗、贝伐单抗、博纳吐单抗、西妥昔单抗、可那木单抗、地诺单抗、依库丽单抗、厄瑞奴单抗、依伏库单抗、英夫利昔单抗、那他珠单抗、帕尼单抗、利妥木单抗、利妥昔单抗、罗姆苏珠单抗、替扎贝鲁单抗、和曲妥珠单抗、和从表1选择的抗体。
表1
治疗性抗体的实例
*适用于患者施用的示例性浓度；^HC-抗体重链；LC-抗体轻链。
基于前面的描述，应当理解，本文所述的装置、系统和方法有助于基本上实时地执行样品的测定。因此，与常规方法相比可以更快地进行所述测定并获得所需结果。
还应当理解，本文所述的装置、系统和方法允许使用系统100的联机实时测定的制备过程易于监测，这又可以减轻风险并延长产物的生产运行。特别地，可以通过例如使用诸如控制器132之类的控制器和/或由系统100的操作者手动确定系统100中的条件是否最佳，即，它们是否满足预定的性能阈值来监测该过程。如图3B和图3C所示，例如可以获取四个参考肽RP1、RP2、RP3和RP4的MS峰高(以离子计数表示)，并在方法鉴定期间针对那些参考肽的历史值进行比较，以确定系统100中的条件是否是最佳的(以及它们是最佳的)，使得可以开始、继续或延长所述生产运行。然而，当确定系统100中的条件不是最佳时，可以调节至少一种细胞培养构成，直到封闭系统中的条件最佳为止。可以调整的细胞培养构成的实例包括但不限于：pH、压力、温度、培养基流量(例如，培养基流速、培养基进料速率)、培养基含量(包括氨基酸、营养物质、糖、缓冲液)、气体处理策略(氧气和二氧化碳的混合、气体速率)、搅拌(例如，搅拌速率)、添加剂(例如金属添加剂、糖添加剂)、添加剂(例如，消泡剂)进料速率和灌注速率。在一些情况下，可能只需要调整一种细胞培养构成，以使封闭系统中的条件达到最佳，而在其他情况下，可能需要调整多种细胞培养构成。可替代地，当确定条件不是最佳的时，或者即使在调整了至少一种细胞培养构成之后系统100中的条件也不是最佳的时，系统100的控制器和/或操作者可以关闭系统100。
以此方式，当条件不是最佳的或者在其他方面不希望继续系统100的运行时，本文所述的装置、系统和方法还减轻了系统100的继续运行所涉及的风险。特别地，可以通过以下来减轻风险：确定(例如，计算或获得)与系统100的当前运行有关的过程参数和产物质量数据，例如pH、温度、氧溶解、细胞生存力、细胞密度、滴度、聚集、电荷变化、糖基化等，确定所述过程参数和产物质量数据是否满足预定的风险阈值(通过控制器例如控制器132和/或对系统100的操作者输入的应答，在系统100的运行之前确定)，并且然后根据所述过程参数和产物质量数据是否满足所述预定的风险阈值来确定是否继续、停止或调整系统100的运行。预定的风险阈值可以例如通过以下来确定：(1)应用可用的过程参数数据和产物质量数据来计算与系统100或一些其他类似系统的先前运行相关的平均历史多变量(MV)数据，并且然后，(2)将计算出的平均历史MV数据建立为阈值(所述阈值可以是计算出的平均历史MV数据本身，或是基于计算出的平均历史MV数据的某些值或一组值。在一个实例中，预定的风险阈值可以表示与计算出的平均历史MV数据的可接受的偏差(例如，三个标准偏差)。可替代地或另外地，可以根据来自系统100的操作者的输入来确定预定的风险阈值。在一些情况下，当与系统100的当前运行相关的过程参数和产物质量数据不满足(例如，超过)预定的风险阈值时，系统100可以关闭。然而，在其他情况下，当与系统100的当前运行相关的过程参数和产物质量数据不满足(例如，超过)预定的风险阈值时，或者当过程参数和产物质量数据满足但接近预定的风险阈值时，可以调整系统100。
此外，申请人已经发现，本文描述的装置、系统和方法还允许使用系统100的生产运行得以延长。常规方法通常最多允许32至40天的生产运行。然而，申请人已经发现，本文所述的装置、系统和方法允许50-80(如果不是100)的群体倍增数，即，大约50-80(如果不是100)天生产运行。因此，在监测系统100的运行以确保产物满足质量目标并且减轻风险的同时，可以获得更多的产物。
本文描述了本披露的优选实施例，包括已知诸位发明人用于进行本披露的一种或多种最佳模式。尽管在此示出并描述了许多实例，但是本领域技术人员将容易理解，各个实施例的细节不必相互排斥。相反，本领域技术人员在阅读本文的教导后应该能够将一个实施例的一个或多个特征与其余实施例的一个或多个特征相组合。此外，还应当理解，所示出的实施例仅是示例性的，并且不应被视为限制本披露的范围。除非本文另外指示或另外明显地与上下文矛盾，否则本文所述的所有方法能以任何合适顺序进行。本文提供的任何和所有实例或示例性语言(诸如“例如”)的使用仅旨在更好地阐明本披露的一个或多个示例性实施例的各个方面，并且不对本披露的范围构成限制。说明书中的语言不应当被解释为指示任何未要求保护的要素为实践本披露所必需的。
序列表
<110> 安进公司
C-H·吴
<120> 进行实时样品测定的系统和方法
<130> 32263/51800
<150> 62/539,803
<151> 2017-08-01
<160> 86
<170> PatentIn 版本3.5
<210> 1
<211> 239
<212> PRT
<213> 智人
<400> 1
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Pro
1 5 10 15
Gly Ser Ser Gly Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser Pro
20 25 30
Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
35 40 45
Leu Val His Ser Asp Gly Asn Thr Tyr Leu Asn Trp Leu Gln Gln Arg
50 55 60
Pro Gly Gln Pro Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe
65 70 75 80
Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ala Gly Thr Asp Phe
85 90 95
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Thr
100 105 110
Cys Met Gln Val Thr Gln Phe Pro Leu Thr Phe Gly Gln Gly Thr Arg
115 120 125
Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
130 135 140
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
145 150 155 160
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
165 170 175
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
180 185 190
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
195 200 205
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
210 215 220
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 2
<211> 470
<212> PRT
<213> 智人
<400> 2
Met Asp Thr Leu Cys Tyr Thr Leu Leu Leu Leu Thr Thr Pro Ser Trp
1 5 10 15
Val Leu Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Leu Lys
20 25 30
Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu
35 40 45
Ser Asn Ala Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys
50 55 60
Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr
65 70 75 80
Ile Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys
85 90 95
Ser Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala
100 105 110
Thr Tyr Tyr Cys Ala Arg Ile Pro Leu Arg Ser Pro Gly Ala Phe Asp
115 120 125
Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
145 150 155 160
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
210 215 220
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro
225 230 235 240
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys
465 470
<210> 3
<211> 235
<212> PRT
<213> 智人
<400> 3
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Ser Tyr Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr
100 105 110
Asp Arg Ser Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 4
<211> 463
<212> PRT
<213> 智人
<400> 4
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ser Ser Gly Tyr Thr Phe
35 40 45
Thr Gly Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala
65 70 75 80
Gln Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Asp Lys Trp Leu Asp Gly Phe Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
225 230 235 240
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
340 345 350
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 5
<211> 235
<212> PRT
<213> 智人
<400> 5
Met Ala Trp Ala Leu Leu Leu Leu Thr Leu Leu Thr Gln Asp Thr Gly
1 5 10 15
Ser Trp Ala Gln Ser Val Leu Thr Gln Ser Pro Ser Ala Ser Gly Thr
20 25 30
Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile
35 40 45
Gly Ser Asn Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro
50 55 60
Lys Leu Leu Ile Leu Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Thr Ile Ser
85 90 95
Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp
100 105 110
Asp Ser Leu Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
115 120 125
Leu Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser
130 135 140
Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser
145 150 155 160
Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser
165 170 175
Pro Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn
180 185 190
Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp
195 200 205
Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr
210 215 220
Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230 235
<210> 6
<211> 479
<212> PRT
<213> 智人
<400> 6
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Asn Ala Trp Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly
65 70 75 80
Thr Thr Asp Tyr Thr Ala Pro Val Lys Gly Arg Phe Thr Ile Ser Arg
85 90 95
Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Ala
100 105 110
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Thr Asp Arg Thr Gly Tyr Ser
115 120 125
Ile Ser Trp Ser Ser Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly
130 135 140
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
145 150 155 160
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
165 170 175
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
180 185 190
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
195 200 205
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
210 215 220
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
225 230 235 240
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
245 250 255
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
260 265 270
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
275 280 285
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
290 295 300
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
305 310 315 320
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
325 330 335
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
340 345 350
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
355 360 365
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
370 375 380
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
385 390 395 400
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
405 410 415
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
420 425 430
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
435 440 445
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
450 455 460
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 7
<211> 235
<212> PRT
<213> 智人
<400> 7
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Arg Gly Arg Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Phe Tyr Cys Gln Gln Tyr
100 105 110
Gly Ser Ser Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 8
<211> 467
<212> PRT
<213> 智人
<400> 8
Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ser Gly Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Lys Asp Pro Gly Thr Thr Val Ile Met Ser Trp Phe
115 120 125
Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
145 150 155 160
Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys
210 215 220
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu
225 230 235 240
Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 9
<211> 242
<212> PRT
<213> 智人
<400> 9
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Val Met Thr Gln Thr Pro Leu Ser
20 25 30
Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Leu Leu Asn Ser Val Asp Gly Ser Thr Asn Leu Asp Trp Tyr
50 55 60
Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Thr Leu Ser
65 70 75 80
Tyr Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
85 90 95
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
100 105 110
Val Tyr Tyr Cys Met Gln Arg Ile Glu Phe Pro Leu Thr Phe Gly Gly
115 120 125
Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe
130 135 140
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val
145 150 155 160
Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp
165 170 175
Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
180 185 190
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
195 200 205
Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val
210 215 220
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
225 230 235 240
Glu Cys
<210> 10
<211> 465
<212> PRT
<213> 智人
<400> 10
Met Glu Leu Gly Leu Cys Trp Val Phe Leu Val Ala Ile Leu Glu Gly
1 5 10 15
Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Ser Ile Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Arg Tyr Tyr Gly Asp Thr Pro Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
210 215 220
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
225 230 235 240
Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
275 280 285
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
450 455 460
Lys
465
<210> 11
<211> 233
<212> PRT
<213> 智人
<400> 11
Met Ser Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Ala
1 5 10 15
Ser Arg Gly Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val
20 25 30
Thr Pro Lys Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile
35 40 45
Gly Ser Ser Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys
50 55 60
Leu Leu Ile Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser
85 90 95
Leu Glu Ala Glu Asp Ala Ala Ala Tyr Tyr Cys His Gln Ser Ser Ser
100 105 110
Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr
115 120 125
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
130 135 140
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
145 150 155 160
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
165 170 175
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
180 185 190
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
195 200 205
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
210 215 220
Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 12
<211> 463
<212> PRT
<213> 智人
<400> 12
Met Gly Ser Thr Ala Ile Leu Ala Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Val Cys Ala Glu Val Gln Leu Met Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe
35 40 45
Ser Phe His Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu
50 55 60
Glu Trp Met Gly Ile Ile His Pro Gly Ala Ser Asp Thr Arg Tyr Ser
65 70 75 80
Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Asn Ser Asn Ser
85 90 95
Ala Thr Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met
100 105 110
Tyr Phe Cys Ala Arg Gln Arg Glu Leu Asp Tyr Phe Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
225 230 235 240
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
340 345 350
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 13
<211> 236
<212> PRT
<213> 智人
<400> 13
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser
35 40 45
Gln Asp Ile Asn Lys Tyr Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Trp Leu Gln Pro Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln
100 105 110
Tyr Asp Asn Leu Leu Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 14
<211> 467
<212> PRT
<213> 智人
<400> 14
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Arg Tyr Trp Met Asn Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr
65 70 75 80
Ala Thr His Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
85 90 95
Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
100 105 110
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Glu Gly Leu Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 15
<211> 236
<212> PRT
<213> 智人
<400> 15
Met Asp Met Arg Val Leu Ala Gln Leu Leu Gly Leu Leu Leu Leu Cys
1 5 10 15
Phe Pro Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Ser Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys
50 55 60
Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Tyr Asp Ser Tyr Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 16
<211> 466
<212> PRT
<213> 智人
<400> 16
Met Glu Leu Gly Leu Asn Trp Val Phe Leu Val Ala Ile Leu Glu Gly
1 5 10 15
Val His Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Tyr Ile Lys Gln Asp Gly Asn Glu Lys Tyr Tyr Val
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Gly Ile Leu Trp Phe Gly Asp Leu Pro Thr
115 120 125
Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu
145 150 155 160
Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn
210 215 220
Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg
225 230 235 240
Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Lys
465
<210> 17
<211> 241
<212> PRT
<213> 智人
<400> 17
Met Asp Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp
1 5 10 15
Val Pro Gly Ser Ser Gly Asp Val Leu Met Thr Gln Ser Pro Leu Ser
20 25 30
Leu Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu
50 55 60
Gln Arg Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn
65 70 75 80
Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Leu Thr Phe Gly Ala Gly
115 120 125
Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
130 135 140
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
165 170 175
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
180 185 190
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
210 215 220
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
225 230 235 240
Cys
<210> 18
<211> 470
<212> PRT
<213> 智人
<400> 18
Met Asp Thr Leu Cys Ser Thr Leu Leu Leu Leu Thr Ile Pro Ser Trp
1 5 10 15
Val Leu Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys
20 25 30
Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu
35 40 45
Arg Thr Ser Gly Met Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys
50 55 60
Ala Leu Glu Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Ser Tyr
65 70 75 80
Asn Pro Ser Leu Lys Ser Gln Leu Thr Ile Ser Lys Asp Thr Ser Lys
85 90 95
Asn Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala
100 105 110
Thr Tyr Tyr Cys Ala Arg Arg Asn Tyr Tyr Tyr Asp Asp Tyr Phe Ala
115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
145 150 155 160
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
210 215 220
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
225 230 235 240
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys
465 470
<210> 19
<211> 235
<212> PRT
<213> 智人
<400> 19
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Ser Tyr Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Thr Ser Ser Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Val
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr
100 105 110
Asp Arg Ser Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 20
<211> 463
<212> PRT
<213> 智人
<400> 20
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Ala Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Gly Tyr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala
65 70 75 80
Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
85 90 95
Thr Ala Ser Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Phe Cys Ala Arg Asp Arg Trp Leu Asp Ala Phe Asp Ile Trp Gly
115 120 125
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
225 230 235 240
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
340 345 350
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 21
<211> 235
<212> PRT
<213> 智人
<400> 21
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Gly Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr
100 105 110
Gly Asn Ser Leu Ser Arg Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 22
<211> 474
<212> PRT
<213> 智人
<400> 22
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys
65 70 75 80
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Lys
85 90 95
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Ala Gly Gly Ile Ala Ala Ala Gly
115 120 125
Leu Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val
130 135 140
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
145 150 155 160
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
165 170 175
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
180 185 190
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
195 200 205
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe
210 215 220
Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
225 230 235 240
Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro
245 250 255
Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro
260 265 270
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
275 280 285
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp
290 295 300
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
305 310 315 320
Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val
325 330 335
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
340 345 350
Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly
355 360 365
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
370 375 380
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
385 390 395 400
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
405 410 415
Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe
420 425 430
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
435 440 445
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
450 455 460
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 23
<211> 236
<212> PRT
<213> 智人
<400> 23
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ser Ser Glu Leu Thr Gln Asp Pro Thr Val
20 25 30
Ser Val Ala Leu Gly Gln Thr Val Lys Ile Thr Cys Gln Gly Asp Ser
35 40 45
Leu Arg Ser Phe Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Val Leu Val Phe Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile
85 90 95
Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg
100 105 110
Asp Ser Ser Val Tyr His Leu Val Leu Gly Gly Gly Thr Lys Leu Thr
115 120 125
Val Leu Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro
130 135 140
Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile
145 150 155 160
Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly
165 170 175
Ser Pro Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser
180 185 190
Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln
195 200 205
Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser
210 215 220
Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230 235
<210> 24
<211> 478
<212> PRT
<213> 智人
<400> 24
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Gln Ser Gly Ala Glu
20 25 30
Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly
35 40 45
Tyr Thr Phe Thr Gly Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Gln Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr
65 70 75 80
Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr
85 90 95
Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp
100 105 110
Thr Ala Val Tyr Phe Cys Ala Arg Asp Gln Met Ser Ile Ile Met Leu
115 120 125
Arg Gly Val Phe Pro Pro Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln
130 135 140
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
145 150 155 160
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
165 170 175
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
180 185 190
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
195 200 205
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
210 215 220
Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys
225 230 235 240
Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val
245 250 255
Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val
325 330 335
Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
355 360 365
Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
370 375 380
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp
420 425 430
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 25
<211> 241
<212> PRT
<213> 智人
<400> 25
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Val Met Thr Gln Ser Pro Leu Ser
20 25 30
Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu
50 55 60
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn
65 70 75 80
Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
Tyr Tyr Cys Met Gln Ala Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly
115 120 125
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
130 135 140
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
165 170 175
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
180 185 190
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
210 215 220
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
225 230 235 240
Cys
<210> 26
<211> 475
<212> PRT
<213> 智人
<400> 26
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Ser Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ala Ser Ile Lys Gln Asp Gly Ser Glu Lys
65 70 75 80
Tyr Tyr Val Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Arg Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Leu Val Leu Met Val Tyr Asp
115 120 125
Ile Asp Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
130 135 140
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
145 150 155 160
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
165 170 175
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
180 185 190
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
195 200 205
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
210 215 220
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
225 230 235 240
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
245 250 255
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
325 330 335
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
340 345 350
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
370 375 380
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 27
<211> 241
<212> PRT
<213> 智人
<400> 27
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Val Met Thr Gln Ser Pro Leu Ser
20 25 30
Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu
50 55 60
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn
65 70 75 80
Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
His Leu Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
Tyr Tyr Cys Met Gln Thr Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly
115 120 125
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
130 135 140
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
165 170 175
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
180 185 190
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
210 215 220
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
225 230 235 240
Cys
<210> 28
<211> 475
<212> PRT
<213> 智人
<400> 28
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Asn Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ala Ser Ile Lys Gln Asp Gly Ser Glu Lys
65 70 75 80
Tyr Tyr Val Asp Ser Val Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn
85 90 95
Ala Lys Asn Ser Leu Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Leu Val Leu Met Val Tyr Asp
115 120 125
Ile Asp Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
130 135 140
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
145 150 155 160
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
165 170 175
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
180 185 190
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
195 200 205
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
210 215 220
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
225 230 235 240
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
245 250 255
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
325 330 335
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
340 345 350
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
370 375 380
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 29
<211> 235
<212> PRT
<213> 智人
<400> 29
Met Thr Cys Ser Pro Leu Leu Leu Thr Leu Leu Ile His Cys Thr Gly
1 5 10 15
Ser Trp Ala Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala
20 25 30
Pro Gly Gln Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile
35 40 45
Gly Asn Asn Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro
50 55 60
Lys Leu Leu Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Thr Thr Leu Gly Ile Thr
85 90 95
Gly Leu Gln Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp
100 105 110
Ser Arg Leu Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val
115 120 125
Leu Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser
130 135 140
Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser
145 150 155 160
Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser
165 170 175
Pro Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn
180 185 190
Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp
195 200 205
Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr
210 215 220
Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230 235
<210> 30
<211> 475
<212> PRT
<213> 智人
<400> 30
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Phe Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Ile Ser Phe Asp Gly Ser Ile Lys Tyr Ser Val
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Asp Arg Leu Asn Tyr Tyr Asp Ser Ser Gly Tyr
115 120 125
Tyr His Tyr Lys Tyr Tyr Gly Met Ala Val Trp Gly Gln Gly Thr Thr
130 135 140
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
145 150 155 160
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
165 170 175
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
180 185 190
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
195 200 205
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
210 215 220
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
225 230 235 240
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
245 250 255
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
325 330 335
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
340 345 350
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
370 375 380
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 31
<211> 234
<212> PRT
<213> 智人
<400> 31
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser
20 25 30
Val Ser Pro Gly Gln Thr Ala Thr Ile Thr Cys Ser Gly Asp Lys Leu
35 40 45
Gly Glu Arg Tyr Ala Ser Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro
50 55 60
Val Leu Val Ile Tyr Gln Asp Ile Lys Arg Pro Ser Gly Ile Pro Glu
65 70 75 80
Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser
85 90 95
Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Phe Cys Gln Ala Trp Tyr
100 105 110
Ser Ser Thr Asn Val Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
115 120 125
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
130 135 140
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
145 150 155 160
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
165 170 175
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
180 185 190
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
195 200 205
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
210 215 220
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230
<210> 32
<211> 466
<212> PRT
<213> 智人
<400> 32
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Ile Trp Tyr Ala Glu Ser Asn Lys Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ala Gln Glu Gly Ile Ala Pro Asp Ala Phe Asp
115 120 125
Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu
145 150 155 160
Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn
210 215 220
Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg
225 230 235 240
Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Lys
465
<210> 33
<211> 234
<212> PRT
<213> 智人
<400> 33
Met Gly Ser Thr Ala Ile Leu Gly Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Gly Arg Ala Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
20 25 30
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val
35 40 45
Ser Ser Ser Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Gln Ala Pro
50 55 60
Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly
100 105 110
Ser Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 34
<211> 463
<212> PRT
<213> 智人
<400> 34
Met Gly Ser Thr Ala Ile Leu Gly Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Gly Arg Ala Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Thr Tyr Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Leu Gly Ser Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Lys Glu Ala His Arg Gly Pro Phe Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
225 230 235 240
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
340 345 350
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 35
<211> 239
<212> PRT
<213> 智人
<400> 35
Met Arg Leu Leu Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Pro
1 5 10 15
Gly Ser Ser Gly Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser Pro
20 25 30
Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
35 40 45
Leu Val His Ser Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg
50 55 60
Pro Gly Gln Pro Pro Arg Leu Leu Ile Tyr Lys Lys Phe Asn Arg Phe
65 70 75 80
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe
85 90 95
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
100 105 110
Cys Met Gln Ala Thr Gln Ile Pro Leu Thr Phe Gly Pro Gly Thr Lys
115 120 125
Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
130 135 140
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
145 150 155 160
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
165 170 175
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
180 185 190
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
195 200 205
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
210 215 220
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 36
<211> 472
<212> PRT
<213> 智人
<400> 36
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Phe Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gly Gly Tyr Asp Tyr Val Trp Gly Ser Tyr Arg
115 120 125
Arg Asn Ser Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
130 135 140
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys
145 150 155 160
Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys
165 170 175
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
180 185 190
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
195 200 205
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr
210 215 220
Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val
225 230 235 240
Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro
245 250 255
Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
260 265 270
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
275 280 285
Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
290 295 300
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
305 310 315 320
Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln
325 330 335
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
340 345 350
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro
355 360 365
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
370 375 380
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
385 390 395 400
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
405 410 415
Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
420 425 430
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
435 440 445
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
450 455 460
Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 37
<211> 235
<212> PRT
<213> 智人
<400> 37
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Asp Ser Asn Leu Ala Trp Tyr Arg Gln Lys Pro Gly Gln Ala Pro
50 55 60
Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ile
100 105 110
Asn Trp Pro Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 38
<211> 465
<212> PRT
<213> 智人
<400> 38
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys
20 25 30
Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile
35 40 45
Ser Ile Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Val Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro
65 70 75 80
Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln
85 90 95
Phe Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
100 105 110
Tyr Cys Ala Arg Gly Gly Tyr Asp Phe Trp Ser Gly Tyr Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
210 215 220
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
225 230 235 240
Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
275 280 285
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
450 455 460
Lys
465
<210> 39
<211> 240
<212> PRT
<213> 智人
<400> 39
Met Val Leu Gln Thr Gln Val Phe Ile Ser Leu Leu Leu Trp Ile Ser
1 5 10 15
Gly Ala Tyr Gly Asp Ile Val Leu Thr Gln Ser Pro Asp Ser Leu Ala
20 25 30
Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser
35 40 45
Ile Leu Tyr Ser Ser Ser Asn Glu Asn Phe Leu Thr Trp Tyr Gln Gln
50 55 60
Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
65 70 75 80
Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Val Tyr
100 105 110
Tyr Cys Gln Gln Tyr Phe Ser Val Phe Arg Thr Phe Gly Gln Gly Thr
115 120 125
Arg Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
130 135 140
Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys
145 150 155 160
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
165 170 175
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
180 185 190
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
195 200 205
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
210 215 220
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235 240
<210> 40
<211> 465
<212> PRT
<213> 智人
<400> 40
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Gly Tyr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Ser Ala
65 70 75 80
Gln Lys Phe Arg Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Gly Gly Tyr Ser Tyr Gly Tyr Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
210 215 220
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
225 230 235 240
Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
275 280 285
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
450 455 460
Lys
465
<210> 41
<211> 236
<212> PRT
<213> 智人
<400> 41
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
85 90 95
Ile Ser Ser Val Gln Pro Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln
100 105 110
His Asn Ser Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 42
<211> 473
<212> PRT
<213> 智人
<400> 42
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Met Trp Tyr Asp Gly Ser Asn Lys Asp Tyr Val
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Arg Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Lys Asp His Tyr Asp Ile Leu Thr Gly Tyr
115 120 125
Asn Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr
130 135 140
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
145 150 155 160
Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val
165 170 175
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
180 185 190
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
195 200 205
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly
210 215 220
Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys
225 230 235 240
Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys
245 250 255
Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
260 265 270
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
275 280 285
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
290 295 300
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
305 310 315 320
Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His
325 330 335
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
340 345 350
Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
355 360 365
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
370 375 380
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
385 390 395 400
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
405 410 415
Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
420 425 430
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
435 440 445
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
450 455 460
Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 43
<211> 235
<212> PRT
<213> 智人
<400> 43
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Tyr
35 40 45
Ile Ser Asn Thr Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ala Thr Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr
100 105 110
Gly Ser Ser Pro Trp Thr Phe Gly Gln Gly Thr Thr Val Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 44
<211> 463
<212> PRT
<213> 智人
<400> 44
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Gly Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala
65 70 75 80
Gln Arg Phe Arg Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ala Pro Tyr Asp Trp Thr Phe Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
225 230 235 240
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
340 345 350
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 45
<211> 236
<212> PRT
<213> 智人
<400> 45
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Ser Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Thr
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Ala Asn Ser Phe Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 46
<211> 469
<212> PRT
<213> 智人
<400> 46
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Gln Ser Gly Thr Glu
20 25 30
Val Lys Lys Pro Gly Ala Ser Met Lys Val Ser Cys Lys Ala Ser Gly
35 40 45
Tyr Thr Phe Thr Ser Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Gln Gly Leu Glu Trp Met Gly Ile Ile Asn Pro Ser Gly Asp Ser Thr
65 70 75 80
Ser Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr
85 90 95
Ser Thr Asn Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp
100 105 110
Thr Ala Met Tyr Tyr Cys Ala Arg Asp Val Glu Val Arg Gly Ile Ser
115 120 125
His Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
130 135 140
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser
145 150 155 160
Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
165 170 175
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
180 185 190
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
195 200 205
Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr
210 215 220
Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr
225 230 235 240
Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro
245 250 255
Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
260 265 270
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
275 280 285
Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
290 295 300
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
305 310 315 320
Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu
325 330 335
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala
340 345 350
Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro
355 360 365
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
370 375 380
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
405 410 415
Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
420 425 430
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly Lys
465
<210> 47
<211> 238
<212> PRT
<213> 智人
<400> 47
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val
35 40 45
Leu Tyr Ser Ala Asn His Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys
50 55 60
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu
65 70 75 80
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
85 90 95
Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr
100 105 110
Cys His Gln Tyr Leu Ser Ser Trp Thr Phe Gly Gly Gly Thr Lys Val
115 120 125
Gln Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
130 135 140
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
165 170 175
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
195 200 205
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
210 215 220
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 48
<211> 465
<212> PRT
<213> 智人
<400> 48
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Trp Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Ile Asn Pro Arg Asn Asp Tyr Thr Glu Tyr Asn
65 70 75 80
Gln Asn Phe Lys Asp Lys Ala Thr Ile Thr Ala Asp Glu Ser Thr Asn
85 90 95
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe
100 105 110
Tyr Phe Cys Ala Arg Arg Asp Ile Thr Thr Phe Tyr Trp Gly Gln Gly
115 120 125
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
130 135 140
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
145 150 155 160
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
165 170 175
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
180 185 190
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
195 200 205
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
210 215 220
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
225 230 235 240
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
275 280 285
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
450 455 460
Lys
465
<210> 49
<211> 235
<212> PRT
<213> 智人
<400> 49
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Ser
100 105 110
Gly Gly Ser Ser Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 50
<211> 466
<212> PRT
<213> 智人
<400> 50
Met Gly Ser Thr Ala Ile Leu Ala Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Val Cys Ala Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe
35 40 45
Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu
50 55 60
Glu Leu Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser
65 70 75 80
Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser
85 90 95
Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met
100 105 110
Tyr Tyr Cys Gly Ser Gly Ser Tyr Phe Tyr Phe Asp Leu Trp Gly Arg
115 120 125
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
130 135 140
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
145 150 155 160
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
165 170 175
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
180 185 190
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
195 200 205
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
210 215 220
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
225 230 235 240
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Lys
465
<210> 51
<211> 241
<212> PRT
<213> 智人
<400> 51
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Val Met Thr Gln Ser Pro Leu Ser
20 25 30
Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Leu Leu His Ser His Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu
50 55 60
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn
65 70 75 80
Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
Tyr Tyr Cys Met Gln Gly Thr His Trp Pro Pro Thr Phe Gly Gln Gly
115 120 125
Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
130 135 140
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
165 170 175
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
180 185 190
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
210 215 220
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
225 230 235 240
Cys
<210> 52
<211> 470
<212> PRT
<213> 智人
<400> 52
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Gln Ser Gly Gly Gly
20 25 30
Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile
65 70 75 80
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Leu Leu Asp Tyr Asp Leu Leu
115 120 125
Thr Gly Tyr Gly Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
130 135 140
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
145 150 155 160
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
165 170 175
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
180 185 190
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
195 200 205
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
210 215 220
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
225 230 235 240
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
245 250 255
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
305 310 315 320
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys
465 470
<210> 53
<211> 235
<212> PRT
<213> 智人
<400> 53
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Gly
35 40 45
Ile Ser Arg Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Ser Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe
100 105 110
Gly Ser Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 54
<211> 471
<212> PRT
<213> 智人
<400> 54
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys
20 25 30
Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile
35 40 45
Ser Ser Gly Asp Tyr Phe Trp Ser Trp Ile Arg Gln Leu Pro Gly Lys
50 55 60
Gly Leu Glu Trp Ile Gly His Ile His Asn Ser Gly Thr Thr Tyr Tyr
65 70 75 80
Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys
85 90 95
Lys Gln Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Arg Asp Arg Gly Gly Asp Tyr Tyr Tyr Gly Met
115 120 125
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
145 150 155 160
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
210 215 220
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
225 230 235 240
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
245 250 255
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
260 265 270
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
275 280 285
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
290 295 300
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
305 310 315 320
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
325 330 335
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
340 345 350
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
355 360 365
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
370 375 380
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
385 390 395 400
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
405 410 415
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
420 425 430
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
435 440 445
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
450 455 460
Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 55
<211> 236
<212> PRT
<213> 智人
<400> 55
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Ser Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser
35 40 45
Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe Cys Gln His
100 105 110
Phe Asp His Leu Pro Leu Ala Phe Gly Gly Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 56
<211> 464
<212> PRT
<213> 智人
<400> 56
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys
20 25 30
Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val
35 40 45
Ser Ser Gly Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys
50 55 60
Gly Leu Glu Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr
65 70 75 80
Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys
85 90 95
Thr Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala
100 105 110
Ile Tyr Tyr Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp
115 120 125
Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
130 135 140
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
145 150 155 160
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
165 170 175
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
180 185 190
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
195 200 205
Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp
210 215 220
His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys
225 230 235 240
Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser
245 250 255
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
260 265 270
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
275 280 285
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
290 295 300
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val
305 310 315 320
Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
325 330 335
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr
340 345 350
Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
355 360 365
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
370 375 380
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
385 390 395 400
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp
405 410 415
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
420 425 430
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
435 440 445
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 57
<211> 236
<212> PRT
<213> 智人
<400> 57
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Ala Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Asn Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Pro Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr
100 105 110
Asp His Ser Ala Gly Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 58
<211> 460
<212> PRT
<213> 智人
<400> 58
Met Gly Ser Thr Ala Ile Leu Gly Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Val Ala Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Arg Asn Ala Met Phe Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ser Gly Ile Gly Thr Gly Gly Ala Thr Ser Tyr Ala Asp
65 70 75 80
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser
85 90 95
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
100 105 110
Tyr Cys Ala Arg Gly Arg Tyr Tyr Phe Pro Trp Trp Gly Gln Gly Thr
115 120 125
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
130 135 140
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly
145 150 155 160
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
165 170 175
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
180 185 190
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
195 200 205
Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser
210 215 220
Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys
225 230 235 240
Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe
245 250 255
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
260 265 270
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe
275 280 285
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
290 295 300
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr
305 310 315 320
Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
325 330 335
Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
340 345 350
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
355 360 365
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
370 375 380
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
385 390 395 400
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser
405 410 415
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
420 425 430
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
435 440 445
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 59
<211> 234
<212> PRT
<213> 智人
<400> 59
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr
100 105 110
Gly Ser Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 60
<211> 467
<212> PRT
<213> 智人
<400> 60
Met Gly Ser Thr Ala Ile Leu Ala Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Val Cys Ala Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe
35 40 45
Thr Thr Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu
50 55 60
Glu Tyr Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser
65 70 75 80
Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser
85 90 95
Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met
100 105 110
Tyr Tyr Cys Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 61
<211> 241
<212> PRT
<213> 智人
<400> 61
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Val Val Met Thr Gln Ser Pro Leu Ser
20 25 30
Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu
50 55 60
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn
65 70 75 80
Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
Tyr Tyr Cys Met Gln Gly Thr His Trp Pro Leu Thr Phe Gly Gln Gly
115 120 125
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
130 135 140
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
165 170 175
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
180 185 190
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
210 215 220
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
225 230 235 240
Cys
<210> 62
<211> 471
<212> PRT
<213> 智人
<400> 62
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Pro Gly
20 25 30
Leu Val Lys Pro Ser Gly Thr Leu Ser Leu Thr Cys Ala Val Ser Gly
35 40 45
Gly Ser Ile Ser Ser Ser Asn Trp Trp Ser Trp Val Arg Gln Pro Pro
50 55 60
Gly Lys Gly Leu Glu Trp Ile Gly Glu Ile Tyr His Ser Gly Ser Thr
65 70 75 80
Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Lys
85 90 95
Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Trp Thr Gly Arg Thr Asp Ala Phe
115 120 125
Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
145 150 155 160
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
210 215 220
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu
225 230 235 240
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
245 250 255
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
260 265 270
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
275 280 285
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
290 295 300
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
305 310 315 320
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
325 330 335
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
340 345 350
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
355 360 365
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
370 375 380
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
385 390 395 400
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
405 410 415
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
420 425 430
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
435 440 445
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
450 455 460
Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 63
<211> 234
<212> PRT
<213> 智人
<400> 63
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Asn Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro
50 55 60
Arg Pro Leu Ile Tyr Asp Ala Ser Thr Arg Ala Thr Gly Val Pro Ala
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp
100 105 110
Asn Trp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 64
<211> 461
<212> PRT
<213> 智人
<400> 64
Met Glu Trp Thr Trp Arg Val Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Arg Tyr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Ser Thr Tyr Ser Gly Asn Thr Asn Tyr Ala
65 70 75 80
Gln Lys Leu Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Arg Gln Leu Tyr Phe Asp Tyr Trp Gly Gln Gly
115 120 125
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
130 135 140
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
145 150 155 160
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
165 170 175
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
180 185 190
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
195 200 205
Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
210 215 220
Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu
225 230 235 240
Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu
245 250 255
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
260 265 270
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln
275 280 285
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
290 295 300
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu
305 310 315 320
Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
325 330 335
Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
340 345 350
Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
355 360 365
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
370 375 380
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
385 390 395 400
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly
405 410 415
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
420 425 430
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
435 440 445
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 65
<211> 239
<212> PRT
<213> 智人
<400> 65
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Ile Pro
1 5 10 15
Gly Ser Ser Ala Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser
20 25 30
Val Thr Pro Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Gly Gln Ser
35 40 45
Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys
50 55 60
Pro Gly Gln Pro Pro Gln Phe Leu Ile Tyr Glu Val Ser Asn Arg Phe
65 70 75 80
Ser Arg Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
85 90 95
Thr Leu Arg Ile Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr
100 105 110
Cys Met Gln Ser Ile Gln Leu Pro Trp Thr Phe Gly Gln Gly Thr Gln
115 120 125
Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
130 135 140
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
145 150 155 160
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
165 170 175
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
180 185 190
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
195 200 205
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
210 215 220
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 66
<211> 459
<212> PRT
<213> 智人
<400> 66
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Gly Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Asn Asp Lys Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Leu Arg Val Leu Trp Gly Gln Gly Thr Leu
115 120 125
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
130 135 140
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
145 150 155 160
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
165 170 175
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
180 185 190
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
195 200 205
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
210 215 220
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
225 230 235 240
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
245 250 255
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
260 265 270
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
275 280 285
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
290 295 300
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
305 310 315 320
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
325 330 335
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
340 345 350
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
355 360 365
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
370 375 380
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
385 390 395 400
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
405 410 415
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
420 425 430
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
435 440 445
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 67
<211> 235
<212> PRT
<213> 智人
<400> 67
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Ser Thr Ser Arg Leu Asn Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Asp Ile Lys His Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 68
<211> 465
<212> PRT
<213> 智人
<400> 68
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe
35 40 45
Thr Asp Tyr Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
210 215 220
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
225 230 235 240
Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
275 280 285
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
450 455 460
Lys
465
<210> 69
<211> 233
<212> PRT
<213> 智人
<400> 69
Met Gly Ser Thr Ala Ile Leu Gly Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Gly Arg Ala Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala
20 25 30
Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Leu Gly Ser
35 40 45
Lys Ser Val His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu
50 55 60
Val Val Tyr Asp Asp Ser Asp Arg Pro Ser Trp Ile Pro Glu Arg Phe
65 70 75 80
Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Gly
85 90 95
Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser
100 105 110
Ser Asp His Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
115 120 125
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
130 135 140
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
145 150 155 160
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
165 170 175
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
180 185 190
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
195 200 205
His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
210 215 220
Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230
<210> 70
<211> 467
<212> PRT
<213> 智人
<400> 70
Met Gly Ser Thr Ala Ile Leu Gly Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Gly Arg Ala Gln Met Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Arg Thr Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys His Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Thr Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Asn Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ala Pro Gln Trp Glu Leu Val His Glu Ala Phe
115 120 125
Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
145 150 155 160
Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys
210 215 220
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu
225 230 235 240
Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 71
<211> 234
<212> PRT
<213> 智人
<400> 71
Met Gly Val Pro Thr His Leu Leu Gly Leu Leu Leu Leu Trp Ile Thr
1 5 10 15
His Ala Ile Cys Asp Ile Arg Met Thr Gln Ser Pro Ala Ser Leu Ser
20 25 30
Ala Ser Leu Gly Glu Thr Val Asn Ile Glu Cys Leu Ala Ser Glu Asp
35 40 45
Ile Tyr Ser Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro
50 55 60
Gln Leu Leu Ile Tyr Asn Ala Asn Ser Leu Gln Asn Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn
85 90 95
Ser Leu Gln Ser Glu Asp Val Ala Thr Tyr Phe Cys Gln Gln Tyr Asn
100 105 110
Asn Tyr Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Thr Glu Gln
130 135 140
Leu Ala Thr Gly Gly Ala Ser Val Val Cys Leu Met Asn Asn Phe Tyr
145 150 155 160
Pro Arg Asp Ile Ser Val Lys Trp Lys Ile Asp Gly Thr Glu Arg Arg
165 170 175
Asp Gly Val Leu Asp Ser Val Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Ser Leu Thr Lys Ala Asp Tyr Glu Ser
195 200 205
His Asn Leu Tyr Thr Cys Glu Val Val His Lys Thr Ser Ser Ser Pro
210 215 220
Val Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 72
<211> 465
<212> PRT
<213> 智人
<400> 72
Met Asp Ile Arg Leu Ser Leu Ala Phe Leu Val Leu Phe Ile Lys Gly
1 5 10 15
Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Ala Asn Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Asp Tyr Ala Met Ala Trp Val Arg Gln Ser Pro Lys Lys Gly Leu
50 55 60
Glu Trp Val Ala Thr Ile Ile Tyr Asp Gly Ser Ser Thr Tyr Tyr Arg
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser
85 90 95
Thr Leu Tyr Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr
100 105 110
Tyr Tyr Cys Ala Thr Gly Leu Gly Ile Ala Thr Asp Tyr Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Val Leu Val Thr Val Ser Ser Ala Glu Thr Thr Ala
130 135 140
Pro Ser Val Tyr Pro Leu Ala Pro Gly Thr Ala Leu Lys Ser Asn Ser
145 150 155 160
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Thr Trp Asn Ser Gly Ala Leu Ser Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Gly Leu Tyr Thr Leu Thr Ser Ser Val Thr
195 200 205
Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala
210 215 220
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asn
225 230 235 240
Cys Gly Gly Asp Cys Lys Pro Cys Ile Cys Thr Gly Ser Glu Val Ser
245 250 255
Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr
260 265 270
Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Gln Asp Asp
275 280 285
Pro Glu Val His Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr
290 295 300
Ala Gln Thr Arg Pro Pro Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser
305 310 315 320
Val Ser Glu Leu Pro Ile Leu His Gln Asp Trp Leu Asn Gly Arg Thr
325 330 335
Phe Arg Cys Lys Val Thr Ser Ala Ala Phe Pro Ser Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Pro Glu Gly Arg Thr Gln Val Pro His Val Tyr Thr
355 360 365
Met Ser Pro Thr Lys Glu Glu Met Thr Gln Asn Glu Val Ser Ile Thr
370 375 380
Cys Met Val Lys Gly Phe Tyr Pro Pro Asp Ile Tyr Val Glu Trp Gln
385 390 395 400
Met Asn Gly Gln Pro Gln Glu Asn Tyr Lys Asn Thr Pro Pro Thr Met
405 410 415
Asp Thr Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Asn Val Lys Lys
420 425 430
Glu Lys Trp Gln Gln Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu
435 440 445
Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly
450 455 460
Lys
465
<210> 73
<211> 237
<212> PRT
<213> 智人
<400> 73
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Ser Ala Leu Thr Gln Pro Ala Ser Val
20 25 30
Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser
35 40 45
Ser Asp Val Gly Gly Tyr Asn Ser Val Ser Trp Tyr Gln Gln His Pro
50 55 60
Gly Lys Ala Pro Lys Leu Met Ile Tyr Glu Val Ser Asn Arg Pro Ser
65 70 75 80
Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser
85 90 95
Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
100 105 110
Asn Ser Tyr Thr Ser Thr Ser Met Val Phe Gly Gly Gly Thr Lys Leu
115 120 125
Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro
130 135 140
Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu
145 150 155 160
Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp
165 170 175
Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln
180 185 190
Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu
195 200 205
Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly
210 215 220
Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230 235
<210> 74
<211> 460
<212> PRT
<213> 智人
<400> 74
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Leu
35 40 45
Thr Ser Tyr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Val Ser Phe Tyr Asn Gly Asn Thr Asn Tyr Ala
65 70 75 80
Gln Lys Leu Gln Gly Arg Gly Thr Met Thr Thr Asp Pro Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gly Tyr Gly Met Asp Val Trp Gly Gln Gly Thr
115 120 125
Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
130 135 140
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly
145 150 155 160
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
165 170 175
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
180 185 190
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
195 200 205
Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser
210 215 220
Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys
225 230 235 240
Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe
245 250 255
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
260 265 270
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe
275 280 285
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
290 295 300
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr
305 310 315 320
Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
325 330 335
Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
340 345 350
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
355 360 365
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
370 375 380
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
385 390 395 400
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser
405 410 415
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
420 425 430
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
435 440 445
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 75
<211> 234
<212> PRT
<213> 智人
<400> 75
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
50 55 60
Arg Leu Leu Ile Tyr Gly Ala Ala Thr Arg Ala Thr Gly Ile Pro Ala
65 70 75 80
Arg Val Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn
100 105 110
Asn Trp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 76
<211> 472
<212> PRT
<213> 智人
<400> 76
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Asn Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Glu Gly Leu Glu Trp Val Ala Ala Ile Trp Phe Asp Ala Ser Asp Lys
65 70 75 80
Tyr Tyr Ala Asp Ala Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Gln Ala Ile Phe Gly Val Val
115 120 125
Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser
130 135 140
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
145 150 155 160
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
165 170 175
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
195 200 205
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
210 215 220
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
225 230 235 240
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
245 250 255
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
260 265 270
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
275 280 285
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
290 295 300
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
305 310 315 320
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
325 330 335
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
340 345 350
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
355 360 365
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
370 375 380
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
385 390 395 400
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
405 410 415
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
420 425 430
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
435 440 445
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
450 455 460
Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 77
<211> 231
<212> PRT
<213> 智人
<400> 77
Met Ala Trp Ile Pro Leu Phe Leu Gly Val Leu Ala Tyr Cys Thr Gly
1 5 10 15
Ser Val Ala Ser Tyr Glu Val Thr Gln Ala Pro Ser Val Ser Val Ser
20 25 30
Pro Gly Gln Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp
35 40 45
Lys Tyr Ala Cys Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu
50 55 60
Val Ile Tyr Gln Asp Ser Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe
65 70 75 80
Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr
85 90 95
Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Ser Ser
100 105 110
Thr Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro
115 120 125
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu
130 135 140
Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro
145 150 155 160
Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala
165 170 175
Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala
180 185 190
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg
195 200 205
Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr
210 215 220
Val Ala Pro Thr Glu Cys Ser
225 230
<210> 78
<211> 467
<212> PRT
<213> 智人
<400> 78
Met Asp Trp Thr Trp Ser Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Ile Pro Tyr Asn Gly Asn Thr Asn Ser Ala
65 70 75 80
Gln Lys Leu Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Phe Cys Ala Arg Asp Arg Asp Tyr Gly Val Asn Tyr Asp Ala Phe
115 120 125
Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
145 150 155 160
Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys
210 215 220
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu
225 230 235 240
Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 79
<211> 235
<212> PRT
<213> 智人
<400> 79
Met Ala Trp Ala Pro Leu Leu Leu Thr Leu Leu Ala His Cys Thr Gly
1 5 10 15
Ser Trp Ala Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser
20 25 30
Pro Gly Lys Thr Val Ala Ile Ser Cys Thr Arg Asn Ser Gly Ser Ile
35 40 45
Ala Ser Asn Ser Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ser Pro
50 55 60
Thr Thr Val Ile Phe Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr
85 90 95
Ile Ser Gly Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser
100 105 110
Tyr Asp Ser Asn Asn Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
115 120 125
Leu Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser
130 135 140
Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser
145 150 155 160
Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser
165 170 175
Pro Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn
180 185 190
Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp
195 200 205
Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr
210 215 220
Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230 235
<210> 80
<211> 470
<212> PRT
<213> 智人
<400> 80
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Gly Tyr Asp Tyr Gly Glu Asp Tyr Tyr Tyr
115 120 125
Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
130 135 140
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
145 150 155 160
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
165 170 175
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
180 185 190
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
195 200 205
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
210 215 220
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
225 230 235 240
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
245 250 255
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
305 310 315 320
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys
465 470
<210> 81
<211> 236
<212> PRT
<213> 智人
<400> 81
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Leu Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Gly Asp Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 82
<211> 468
<212> PRT
<213> 智人
<400> 82
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr
115 120 125
Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser
130 135 140
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr
145 150 155 160
Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
165 170 175
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
195 200 205
Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr
210 215 220
Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val
225 230 235 240
Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val
245 250 255
Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
260 265 270
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
275 280 285
His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
290 295 300
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
305 310 315 320
Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn
325 330 335
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro
340 345 350
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln
355 360 365
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
370 375 380
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
385 390 395 400
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
405 410 415
Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
420 425 430
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
435 440 445
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
450 455 460
Ser Pro Gly Lys
465
<210> 83
<211> 240
<212> PRT
<213> 智人
<400> 83
Met Val Leu Gln Thr Gln Val Phe Ile Ser Leu Leu Leu Trp Ile Ser
1 5 10 15
Gly Ala Tyr Gly Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala
20 25 30
Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser
35 40 45
Val Leu Asp Ser Ser Asp Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln
50 55 60
Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Asn Arg
65 70 75 80
Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr
100 105 110
Tyr Cys Gln Gln Tyr Tyr Ser Asp Pro Phe Thr Phe Gly Pro Gly Thr
115 120 125
Lys Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
130 135 140
Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys
145 150 155 160
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
165 170 175
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
180 185 190
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
195 200 205
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
210 215 220
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235 240
<210> 84
<211> 465
<212> PRT
<213> 智人
<400> 84
Met Asp Trp Thr Trp Ser Ile Leu Phe Leu Val Ala Ala Pro Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala
65 70 75 80
Gln Lys Leu Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Ser Trp Phe Gly Glu Val Phe Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
210 215 220
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
225 230 235 240
Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
275 280 285
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
450 455 460
Lys
465
<210> 85
<211> 236
<212> PRT
<213> 智人
<400> 85
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Gly Ala Ser Asn Leu Glu Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Asn Tyr Tyr Cys Gln Gln
100 105 110
Ala Asn Ser Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 86
<211> 466
<212> PRT
<213> 智人
<400> 86
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Gln Ser Gly Ala Glu
20 25 30
Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly
35 40 45
Tyr Thr Leu Ser Asp Leu Ser Ile His Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Met Gly Gly Phe Asp Pro Gln Asp Gly Glu Thr
65 70 75 80
Ile Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Glu Asp Thr
85 90 95
Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu Lys Ser Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Thr Gly Ser Ser Ser Ser Trp Phe Asp
115 120 125
Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu
145 150 155 160
Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn
210 215 220
Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg
225 230 235 240
Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Lys
465
Claims (77)
1.一种进行实时测定的方法，所述方法包括以下步骤：
(a)将含有多肽的产物的样品经由第一保持盘管移动至多肽结合柱；
(b)将所述样品中的所述多肽结合至所述多肽结合柱，从而将所述样品中的所述多肽与所述样品的其余部分分离；
(c)将洗脱缓冲溶液经由所述第一保持盘管并通过所述多肽结合柱下游的第二保持盘管从缓冲液源移动至所述多肽结合柱，从而洗脱与所述多肽结合柱结合的多肽，并将包含所述洗脱缓冲溶液和洗脱的多肽的洗脱液/多肽混合物移动至所述第二保持盘管；
(d)将所述洗脱液/多肽混合物从所述第二保持盘管移动至反应室；
(e)将所述洗脱液/多肽混合物中的所述多肽在所述反应室中进行孵育，从而产生变性的多肽；
(f)在(e)之后，将切割二硫键交联的还原试剂经由第一保持盘管移动至所述反应室；
(g)将所述变性的多肽与所述还原试剂在所述反应室中进行孵育，从而产生变性和还原的多肽；
(h)在(g)之后，将使巯基烷基化的烷基化试剂移动至所述反应室；
(i)将所述变性和还原的多肽与所述烷基化试剂在所述反应室中进行孵育，从而使所述变性和还原的多肽烷基化；
(j)将所述变性、还原并烷基化的多肽，所述洗脱缓冲溶液，所述还原试剂和所述烷基化试剂经由所述第一保持盘管从所述反应室移动至脱盐柱，所述脱盐柱用蛋白质水解缓冲液平衡；
(k)将所述变性、还原并烷基化的多肽应用至所述脱盐柱，从而将所述变性、还原并烷基化的多肽与所述还原试剂和烷基化试剂分离，从而得到脱盐的多肽；
(l)将所述脱盐的多肽移动至所述脱盐柱下游的蛋白水解酶柱；
(m)在第三多肽柱中消化所述脱盐的多肽，从而产生消化的多肽；以及
(n)将所述消化的多肽移动至分析装置以分析所述消化的多肽。
2.如权利要求1所述的方法，其中自动执行(a)、(c)、(d)、(f)、(h)、(i)、(l)和(n)中的一个或多个。
3.如权利要求1或2所述的方法，其中(a)至(n)在封闭系统中执行。
4.如权利要求1至3中任一项所述的方法，其中(a)包括将多通路阀定位在第一位置，在所述第一位置中，所述第一保持盘管和所述多肽结合柱经由所述多通路阀的第一通路流体地联接。
5.如权利要求4所述的方法，其中(d)包括将所述多通路阀定位在第二位置，在所述第二位置中，所述第二保持盘管和所述反应室经由所述多通路阀的第二通路流体地联接。
6.如权利要求5所述的方法，其中(f)和(h)各自包括将所述多通路阀定位在第三位置，在所述第三位置中，所述第一保持盘管和所述反应室经由所述多通路阀的第三通路流体地联接。
7.如权利要求6所述的方法，其中(j)包括：
将所述变性、还原并烷基化的多肽，所述洗脱缓冲溶液，所述还原试剂和所述烷基化试剂经由所述多通路阀的所述第三通路从所述反应室移动至所述脱盐柱；并且
将所述多通路阀定位在第四位置，在所述第四位置中，所述第一保持盘管和所述脱盐柱经由所述多通路阀的第四通路流体地联接。
8.如权利要求1至7中任一项所述的方法，所述方法进一步包括在(d)之前或期间，将与所述反应室流体地联接并位于其下游的第一阀移动至第一位置，在所述第一位置中，所述第一阀将从所述第一保持盘管接收的超过所述反应室容积的内容物引导至废物室。
9.如权利要求8所述的方法，所述方法进一步包括在(i)之后，将所述第一阀从所述第一位置移动至第二位置，在所述第二位置中，所述第一阀将空气引导至所述反应室中。
10.如权利要求1至9中任一项所述的方法，所述方法进一步包括在(k)之后并且在(l)之前，(o)将与所述脱盐柱和所述蛋白水解酶柱流体地联接并位于其之间的第二阀从第一位置移动至第二位置，在所述第一位置中所述第二阀将从所述脱盐柱接收的内容物引导至废物室，在所述第二位置中所述第二阀将从所述脱盐柱接收的内容物引导至所述蛋白水解酶柱。
11.如权利要求1至10中任一项所述的方法，其中(a)包括将所述产物的所述样品经由所述第一保持盘管从含有所述多肽的容器移动至所述多肽结合柱。
12.如权利要求1至11中任一项所述的方法，所述方法进一步包括在(d)之前，用变性试剂至少部分地填充所述反应室，并且其中(e)包括将所述洗脱液/多肽混合物中的多肽与所述变性试剂在所述反应室中进行孵育。
13.如权利要求12所述的方法，其中用所述变性试剂至少部分地填充所述反应室包括将所述变性试剂经由所述第一保持盘管从变性缓冲液源移动至所述反应室。
14.如权利要求1至13中任一项所述的方法，所述方法进一步包括向所述反应室施加热。
15.如权利要求12所述的方法，其中(j)进一步包括将所述变性试剂经由所述第一保持盘管从所述反应室移动至所述脱盐柱，并且其中(k)进一步将所述变性、还原并烷基化的多肽与所述变性试剂分离。
16.一种用于使用封闭系统执行实时测定的方法，所述封闭系统包括多通路阀、在所述多通路阀上游的第一保持盘管、与所述多通路阀的第一通路流体地联接并位于其下游的多肽结合柱、与所述多肽结合柱流体地联接并位于其下游的第二保持盘管、与所述多通路阀的第二和第三通路流体地联接并位于其下游的反应室、与所述多通路阀的第四通路流体地联接并位于其下游的脱盐柱，以及在所述脱盐柱下游的蛋白水解酶柱，所述方法包括：
(a)经由与所述封闭系统通信地联接的控制器，将含有多肽的产物的样品移动至所述第一保持盘管；
(b)经由所述控制器将所述多通路阀定位在第一位置，在所述第一位置中，所述第一保持盘管经由所述多通路阀的所述第一通路连接至所述多肽结合柱，使得所述样品流动至第一柱，从而所述样品中的多肽结合至所述多肽结合柱上；
(c)当所述多通路阀处于所述第一位置时，经由控制器将洗脱缓冲溶液从洗脱缓冲溶液源经由所述多肽结合柱移动至所述第二保持盘管，使得所述洗脱缓冲溶液洗脱基本上所有与所述多肽结合柱结合的多肽；
(d)经由所述控制器将所述多通路阀移动至第二位置，在所述第二位置中，所述第二保持盘管经由所述多通路阀的所述第二通路连接至所述反应室；
(e)当所述多通路阀处于所述第二位置时，经由所述控制器将包含所述洗脱缓冲溶液和洗脱的多肽的洗脱液/多肽混合物移动至所述反应室，从而使所述洗脱液/多肽混合物中的多肽变性；
(f)经由所述控制器将多通路阀移动至第三位置，在所述第三位置中，所述第一保持盘管经由所述多通路阀的所述第三通路连接至所述反应室；
(g)在(f)之后，经由所述控制器将切割二硫键交联的还原试剂移动至所述第一保持盘管，并且经由所述控制器将所述还原试剂从所述第一保持盘管经由所述多通路阀的所述第三通路移动至所述反应室，从而还原所述变性的多肽；
(h)在(g)之后，经由所述控制器将使巯基烷基化的烷基化试剂移动至所述第一保持盘管，并且经由所述控制器将所述烷基化试剂从所述第一保持盘管经由所述第三通路移动至所述反应室，从而烷基化所述变性和还原的多肽；
(i)经由所述控制器将所述烷基化的多肽、所述洗脱缓冲溶液、所述还原试剂和所述烷基化试剂从所述反应室经由所述第三通路移动至所述第一保持盘管；
(j)经由所述控制器将所述多通路阀移动至第四位置，在所述第四位置中，所述第一保持盘管经由所述多通路阀的第四通路连接至所述脱盐柱，并且当所述多通路阀处于在所述第四位置时，将所述烷基化的多肽、所述洗脱缓冲溶液、所述还原试剂和所述烷基化试剂从所述第一保持盘管移动至所述脱盐柱，从而将所述变性、还原并烷基化的多肽应用至所述脱盐柱，由此将所述变性、还原并烷基化的多肽与所述还原试剂和烷基化试剂分离，得到脱盐的多肽；
(k)经由所述控制器将所述脱盐的多肽移动至所述蛋白水解酶柱，从而消化所述脱盐的多肽；以及
(l)经由所述控制器将所述消化的多肽传送至分析装置，从而分析所述消化的多肽。
17.如权利要求16所述的方法，其中(a)包括经由所述控制器将所述样品从含有所述多肽的容器移动至所述第一保持盘管。
18.如权利要求16或17所述的方法，其中(k)包括将所述消化的多肽传送至选自由以下组成的组的分析装置：液相色谱装置、高效液相色谱装置、超高效液相色谱装置、质谱装置和聚糖分析装置，或其组合。
19.如权利要求16至18中任一项所述的方法，所述方法进一步包括在(e)之前，经由所述控制器将所述多通路阀移动至所述第三位置，并经由所述控制器将变性试剂移动至所述反应室。
20.如权利要求19所述的方法，其中将所述变性试剂移动至所述反应室包括：经由所述控制器将所述变性试剂从变性缓冲液源经由泵移动至所述第一保持盘管，并经由所述控制器将所述变性试剂从所述第一保持盘管经由所述多通路阀的第三通路移动至所述反应室。
21.如权利要求19或20所述的方法，其中(i)进一步包括将所述变性试剂从所述反应室经由所述第三通路移动至所述第一保持盘管，并且其中(j)进一步包括将所述变性试剂从所述第一保持盘管移动至所述脱盐柱，并且当所述变性、还原并烷基化的多肽应用于所述脱盐柱时，所述变性、还原并烷基化的多肽与所述变性试剂借此进一步分离。
22.一种用于执行联机实时测定的封闭系统，所述系统包括：
第一保持盘管，所述第一保持盘管流体地布置成接收含有多肽的产物的样品；
多通路阀，所述多通路阀流体地联接至所述第一保持盘管并位于其下游；
多肽结合柱，所述多肽结合柱流体地联接至所述多通路阀，并布置成经由所述多通路阀的第一通路从所述第一保持盘管接收所述样品，所述多肽结合柱被配置为结合来自所述样品的所述多肽，
缓冲液源，所述缓冲液源流体地联接至所述多通路阀，并被布置成向位于所述多肽结合柱下游的第二保持盘管供应洗脱缓冲溶液，使得所述洗脱缓冲溶液适于从所述多肽结合柱上洗脱基本上所有的所述多肽；
反应室，所述反应室流体地联接至所述多通路阀并被布置在所述多肽结合柱下游，所述反应室适于经由所述多通路阀的第二通路从所述多肽结合柱接收混合物，所述混合物包含所述洗脱缓冲溶液和所述洗脱的多肽，其中所述混合物的多肽在所述反应室中变性，其中所述反应室被布置成经由所述多通路阀的第一保持盘管和第三通路接收切割二硫键交联的还原试剂，所述还原试剂还原所述变性的多肽，并且其中所述反应室还被布置成经由所述多通路阀的第一保持盘管和第三通路接收使巯基烷基化的烷基化试剂，其中所述烷基化试剂在所述反应室中将所述变性并还原的多肽烷基化；
脱盐柱，所述脱盐柱流体地联接至所述多通路阀，并且被布置成从所述反应室接收变性、还原并烷基化的多肽，所述洗脱缓冲溶液和所述烷基化试剂，所述脱盐柱被配置为将所述变性、还原并烷基化的多肽与所述洗脱缓冲溶液、所述还原试剂和所述烷基化试剂分离；以及
蛋白水解酶柱，所述蛋白水解酶柱流体地联接至第二多肽柱并被布置成在其下游以从所述脱盐柱获得所述分离的多肽，所述蛋白水解酶柱被配置为消化脱盐的多肽。
23.如权利要求22所述的系统，所述系统进一步包括生物反应器，所述生物反应器被配置为产生含有多肽的产物，其中所述第一保持盘管流体地联接至所述生物反应器。
24.如权利要求22或23所述的系统，其中所述多通路阀包含12个卫星通路和中心共享通路阀。
25.如权利要求22至24中任一项所述的系统，其中所述多肽结合柱选自由以下组成的组：蛋白A柱、蛋白G柱、蛋白A/G柱、蛋白L柱、氨基酸柱、亲和素柱、链霉亲和素柱、碳水化合物结合柱、碳水化合物柱、谷胱甘肽柱、肝素柱、疏水相互作用柱、免疫亲和柱、核苷酸/辅酶柱、专门柱和固定化金属亲和色谱(IMAC)柱。
26.如权利要求22至25中任一项所述的系统，所述系统进一步包括泵，所述其被配置为将所述产物的样品从所述生物反应器泵送至所述第一保持盘管。
27.如权利要求22至26中任一项所述的系统，其中所述还原试剂选自由以下组成的组：二硫苏糖醇(DTT)、谷胱甘肽、β-巯基乙醇(β-ME)和三(2-羧乙基)膦(TCEP)。
28.如权利要求22至27中任一项所述的系统，其中所述烷基化试剂是吲哚-3-乙酸(IAA)。
29.如权利要求22至28中任一项所述的系统，其中所述脱盐柱是尺寸排阻色谱柱。
30.如权利要求22至29中任一项所述的系统，其中所述蛋白水解酶柱包含蛋白水解酶，并且其中所述蛋白水解酶是内肽酶。
31.如权利要求30所述的系统，其中所述内肽酶选自由以下组成的组：胰蛋白酶、胰凝乳蛋白酶、弹性蛋白酶、嗜热菌蛋白酶、胃蛋白酶、谷氨酰内肽酶、脑啡肽酶、Lys-C蛋白酶和金黄色葡萄球菌V8蛋白酶。
32.如权利要求22至31中任一项所述的系统，其中所述反应室至少部分地预填充有变性试剂。
33.如权利要求32所述的系统，所述系统进一步包括泵，所述泵被配置为将所述变性试剂从变性缓冲液源经由所述第一保持盘管泵送至所述反应室。
34.如权利要求32或33所述的系统，其中所述变性试剂包括变性去污剂或离液剂。
35.如权利要求34所述的系统，其中所述离液剂选自由以下组成的组：尿素、正丁醇、乙醇、氯化胍、高氯酸锂、乙酸锂、氯化镁、苯酚、2-丙醇、和硫脲。
36.如权利要求34所述的系统，其中所述变性去污剂选自由以下组成的组：十二烷基硫酸钠(SDS)、胆酸钠、脱氧胆酸钠、甘氨胆酸钠、牛磺胆酸钠、牛磺脱氧胆酸钠、N-月桂酰肌氨酸、十二烷基硫酸锂、十六烷基三甲基溴化铵(CTAB)和三甲基(十四烷基)溴化铵(TTAB)。
37.如权利要求36所述的系统，其中所述变性去污剂是SDS。
38.如权利要求32所述的系统，其中所述变性试剂包括加热的流体。
39.如权利要求22至38中任一项所述的系统，所述系统进一步包括加热元件，所述加热元件紧邻所述反应室定位，所述加热元件被配置为向所述反应室施加热。
40.如权利要求39所述的系统，其中所述热具有在约22℃至约120℃之间的温度。
41.如权利要求40所述的系统，其中所述热具有约40℃的温度。
42.如权利要求22至41中任一项所述的系统，所述系统进一步包括第一阀，所述第一阀流体地联接至所述反应室并位于其下游，其中所述第一阀在第一位置和第二位置中可操作，在所述第一位置中所述第一阀将从所述第一保持盘管接收的超过所述反应室容积的内容物引导至废物，在所述第二位置中所述第一阀将空气引导至所述反应室中。
43.如权利要求42所述的系统，所述系统进一步包括控制器，所述控制器通信地联接至所述第一阀以控制所述第一阀的位置，其中在将所述变性、还原并烷基化的多肽，所述洗脱缓冲溶液，所述变性试剂，所述还原试剂和所述烷基化试剂从所述反应室移动至所述脱盐柱之前，所述控制器将所述第一阀从所述第一位置移动至所述第二位置。
44.如权利要求22至43中任一项所述的系统，所述系统进一步包括第二阀，所述第二阀流体地联接至所述脱盐柱和所述蛋白水解酶柱并位于其之间，其中所述第二阀在第一位置和第二位置中可操作，在所述第一位置中所述第二阀将从所述脱盐柱接收的内容物引导至废物，在所述第二位置中所述第二阀将从所述脱盐柱接收的内容物引导至所述蛋白水解酶柱。
45.如权利要求44所述的系统，所述系统进一步包括控制器，所述控制器通信地联接至所述第二阀以控制所述第二阀的位置，其中在所述脱盐柱将所述变性、还原并烷基化的多肽与所述洗脱缓冲溶液、所述变性试剂、所述还原试剂和所述烷基化试剂分离之后，所述控制器将所述第二阀从所述第一位置移动至所述第二位置。
46.如权利要求22至41中任一项所述的系统，所述系统进一步包括控制器，所述控制器通信地联接至所述反应室，所述控制器被配置为将所述反应室保持在大约40摄氏度的温度。
47.如权利要求22至41中任一项所述的系统，所述系统进一步包括控制器，所述控制器通信地联接至所述多通路阀，所述控制器被配置为选择性地打开和关闭所述多通路阀的第一、第二、第三和第四通路。
48.一种用于执行实时测定的封闭系统，所述系统包括：
多通路阀；
第一保持盘管，所述第一保持盘管在所述多通路阀上游；
多肽结合柱，所述多肽结合柱流体地联接至所述多通路阀的第一通路并在其下游；
第二保持盘管，所述第二保持盘管流体地联接至所述多肽结合柱并在其下游；
反应室，所述反应室流体地联接至所述多通路阀的第二和第三通路并在其下游；
脱盐柱，所述脱盐柱流体地联接至所述多通路阀的第四通路并在其下游；
蛋白水解酶柱，所述蛋白水解酶柱位于所述脱盐柱下游；以及
控制器，所述控制器通信地联接至所述多通路阀并且包括存储器、处理器以及逻辑，所述逻辑存储在所述存储器上并且可由所述处理器执行以：
(a)将含有多肽的产物的样品移动至所述第一保持盘管；
(b)将所述多通路阀定位在第一位置，在所述第一位置中，所述第一保持盘管经由所述多通路阀的所述第一通路连接至所述多肽结合柱，使得所述样品流动至第一柱，从而所述样品中的多肽结合至所述多肽结合柱上；
(c)当所述多通路阀处于所述第一位置时，将洗脱缓冲溶液从洗脱缓冲溶液源经由所述多肽结合柱移动至所述第二保持盘管，使得所述洗脱缓冲溶液洗脱基本上所有与所述多肽结合柱结合的所述多肽；
(d)将所述多通路阀移动至第二位置，在所述第二位置中，所述第二保持盘管经由所述多通路阀的所述第二通路连接至所述反应室；
(e)当所述多通路阀处于所述第二位置时，将包含所述洗脱缓冲溶液和洗脱的多肽的洗脱液/多肽混合物移动至所述反应室，从而将所述洗脱液/多肽混合物中的所述多肽变性；
(f)将所述多通路阀移动至第三位置，在所述第三位置中，所述第一保持盘管经由所述多通路阀的所述第三通路连接至所述反应室；
(g)在(f)之后，将切割二硫键的还原试剂移动至所述第一保持盘管，并且将所述还原试剂从所述第一保持盘管经由所述多通路阀的所述第三通路移动至所述反应室，从而还原所述变性的多肽；
(h)在(g)之后，将使巯基烷基化的烷基化试剂移动至所述第一保持盘管，并且将所述烷基化试剂从所述第一保持盘管经由所述第三通路移动至所述反应室，从而烷基化所述变性并还原的多肽；
(i)将所述变性、还原并烷基化的多肽，所述洗脱缓冲溶液，所述还原试剂和所述烷基化试剂从所述反应室经由所述第三通路移动至所述第一保持盘管；
(j)将所述多通路阀移动至第四位置，在所述第四位置中，所述第一保持盘管经由所述多通路阀的所述第四通路连接至所述脱盐柱，并且当所述多通路阀处于所述第四位置时，将所述变性、还原并烷基化的多肽，所述洗脱缓冲溶液，所述还原试剂和所述烷基化试剂从所述第一保持盘管移动至所述脱盐柱，从而使所述变性、还原并烷基化的多肽脱盐；
(k)将所述脱盐的多肽移动至所述蛋白水解酶柱，从而消化所述脱盐的多肽；以及
(l)将所述消化的多肽传送至聚糖分析装置，从而分离并量化所述消化的多肽。
49.如权利要求48所述的系统，其中所述多肽结合柱选自由以下组成的组：蛋白A柱、蛋白G柱、蛋白A/G柱、蛋白L柱、氨基酸柱、亲和素柱、链霉亲和素柱、碳水化合物结合柱、碳水化合物柱、谷胱甘肽柱、肝素柱、疏水相互作用柱、免疫亲和柱、核苷酸/辅酶柱、专门柱和固定化金属亲和色谱(IMAC)柱。
50.如权利要求48或49所述的系统，所述系统进一步包括泵，所述泵被配置为将所述产物的所述样品从包含所述产物的生物反应器泵送至所述第一保持盘管。
51.如权利要求48至50中任一项所述的系统，其中所述还原试剂选自由以下组成的组：二硫苏糖醇(DTT)、谷胱甘肽、β-巯基乙醇(β-ME)和三(2-羧乙基)膦(TCEP)。
52.如权利要求48所述的系统，其中所述烷基化试剂是吲哚-3-乙酸(IAA)。
53.如权利要求48所述的系统，其中所述脱盐柱是尺寸排阻色谱柱。
54.如权利要求48所述的系统，其中所述蛋白水解酶柱包含蛋白水解酶，并且其中所述蛋白水解酶是内切蛋白酶。
55.如权利要求54所述的系统，其中所述内切蛋白酶选自由以下组成的组：胰蛋白酶、胰凝乳蛋白酶、弹性蛋白酶、嗜热菌蛋白酶、胃蛋白酶、谷氨酰内肽酶、脑啡肽酶、Lys-C蛋白酶和金黄色葡萄球菌V8蛋白酶。
56.如权利要求48所述的系统，其中在(e)之前，所述逻辑可由所述处理器执行以将所述多通路阀移动至所述第三位置并且将变性试剂移动至所述反应室。
57.如权利要求56所述的系统，其中所述逻辑可由所述处理器执行，以将所述变性试剂从变性缓冲液源经由布置在所述第一保持盘管上游的泵移动至所述第一保持盘管，并且将所述变性试剂从所述第一保持盘管经由所述多通路阀的所述第三通路移动至所述反应室。
58.如权利要求56或57所述的系统，其中所述变性试剂包括变性去污剂或离液剂。
59.如权利要求58所述的系统，其中所述离液剂选自由以下组成的组：尿素、正丁醇、乙醇、氯化胍、高氯酸锂、乙酸锂、氯化镁、苯酚、2-丙醇、和硫脲。
60.如权利要求58所述的系统，其中所述变性去污剂选自由以下组成的组：十二烷基硫酸钠(SDS)、胆酸钠、脱氧胆酸钠、甘氨胆酸钠、牛磺胆酸钠、牛磺脱氧胆酸钠、N-月桂酰肌氨酸、十二烷基硫酸锂、十六烷基三甲基溴化铵(CTAB)和三甲基(十四烷基)溴化铵(TTAB)。
61.如权利要求60所述的系统，其中所述变性去污剂是SDS。
62.如权利要求57或58所述的系统，其中所述变性试剂包括热。
63.如权利要求56至62中任一项所述的系统，其中在(e)之前或期间，所述逻辑可由所述处理器执行以将热施加至所述反应室。
64.如权利要求62或63所述的系统，其中所述热具有从约22℃至约120℃的温度。
65.如权利要求64所述的系统，其中所述热具有约40℃的温度。
66.如权利要求48所述的系统，所述系统进一步包括第一阀，所述第一阀流体地联接至所述反应室并位于其下游，其中所述第一阀在第一位置和第二位置中可操作，在所述第一位置中所述第一阀将从所述第一保持盘管接收的超过所述反应室容积的内容物引导至废物室，在所述第二位置中所述第一阀将空气引导至所述反应室中，其中所述控制器通信地联接至所述第一阀以控制所述第一阀的位置，其中在(h)之后，所述控制器将所述第一阀从所述第一位置移动至所述第二位置。
67.如权利要求48所述的系统，所述系统进一步包括第二阀，所述第二阀流体地联接至所述脱盐柱和所述蛋白水解酶柱并位于其之间，其中所述第二阀在第一位置和第二位置中可操作，在所述第一位置中所述第二阀将从所述脱盐柱接收的内容物引导至废物室，在所述第二位置中所述第二阀将从所述脱盐柱接收的内容物引导至所述蛋白水解酶柱，其中所述控制器通信地联接至所述第二阀以控制所述第二阀的位置，其中在(j)之后，所述控制器将所述第二阀从所述第一位置移动至所述第二位置。
68.如权利要求48所述的系统，其中所述控制器通信地联接至所述反应室，所述控制器被配置为将所述反应室保持在大约40℃的温度。
69.如权利要求1-21所述的方法或如权利要求22-68所述的系统，其中所述产物的所述多肽是治疗性多肽。
70.如权利要求69所述的方法或系统，其中所述治疗性多肽选自由以下组成的组：抗体或其抗原结合片段、抗体或抗体片段的衍生物、和融合多肽。
71.如权利要求70所述的方法或系统，其中所述抗体选自由以下组成的组：英夫利昔单抗、贝伐单抗、兰尼单抗、西妥昔单抗、兰尼单抗、帕利珠单抗、阿巴伏单抗、阿昔单抗、阿克托克单抗、阿达木单抗、阿非莫单抗、阿托珠单抗、阿珠单抗、培化阿珠单抗、ald518、阿仑单抗、阿利库单抗、阿仑单抗、阿妥莫单抗、阿麦妥昔单抗、马安那莫单抗、安芦珠单抗、阿泊珠单抗、阿西莫单抗、阿塞珠单抗、阿替奴单抗、阿替珠单抗、阿托立木单抗、托珠单抗、巴匹珠单抗、巴利昔单抗、巴维昔单抗、贝妥莫单抗、贝利木单抗、苯拉利珠单抗、柏替木单抗、贝索单抗、贝伐珠单抗、贝洛托单抗、比西单抗、比伐珠单抗、莫-比伐珠单抗、博纳吐单抗、布索珠单抗、本妥昔单抗、巴列津单抗、布洛鲁单抗、康纳单抗、莫坎妥珠单抗、莫坎妥珠单抗、卡普赛珠单抗、卡罗单抗喷地肽、卡鲁单抗、卡妥索单抗、cc49、西利珠单抗、赛妥珠单抗、西妥昔单抗、泊西他珠单抗、西妥木单抗、克拉扎珠单抗、克立昔单抗、克伐珠单抗、可那木单抗、克雷内治单抗、cr6261、达西珠单抗、达克珠单抗、达罗土珠单抗、达雷木单抗、地莫米佐单抗、地诺单抗、地莫单抗、阿托度单抗、德罗图单抗、杜力戈图单抗、杜匹鲁单抗、依美昔单抗、依库丽单抗、埃巴单抗、依决洛单抗、依法利珠单抗、依芬古单抗、埃罗妥珠单抗、艾西莫单抗、埃文单抗、培化恩莫单抗、恩诺珠单抗、恩诺珠单抗、依诺替库单抗、依诺替库单抗、埃斯托西单抗、西依匹莫单抗、依帕珠单抗、厄利珠单抗、厄马索单抗、埃达珠单抗、依卓利珠单抗、艾韦单抗、艾韦单抗、法索单抗、法拉莫单抗、法拉图珠单抗、法希奴单抗、fbta05、非维珠单抗、非扎奴单抗、费希腊妥单抗、芬妥木单抗、弗兰托单抗、芳妥珠单抗、弗罗鲁单抗、福拉韦单抗、夫苏木单抗、弗兰单抗、弗图希单抗、加利昔单抗、盖尼柱单抗、盖坦德单抗、加维莫单抗、吉妥珠单抗奥佐米星、吉伏珠单抗、吉仁土昔单抗、维德汀单抗、戈利木单抗、戈利昔单抗、gs6624、替伊立珠单抗、替伊莫单抗、依库单抗、伊戈伏单抗、英西单抗、英戈土珠单抗、英克拉库单抗、依坦希单抗、英夫利西单抗、英妥木单抗、伊诺莫单抗、伊珠单抗奥佐米星、伊匹木单抗、艾雷妥木单抗、依拓珠单抗、希凯珠单抗、凯利昔单抗、拉贝珠单抗、来金珠单抗、来马索单抗、乐地单抗、来沙木单抗、利韦单抗、利格珠单抗、林妥珠单抗、立鲁单抗、莫-洛伏珠单抗、鲁卡木单抗、鲁昔单抗、马帕木单抗、马司莫单抗、美力姆单抗、马妥珠单抗、美泊利单抗、美替木单抗、米拉珠单抗、明瑞莫单抗、米妥莫单抗、莫格穆里单抗、莫罗木单抗、莫他珠单抗、莫希土姆单抗、莫罗单抗-cd3、他那可单抗、纳米鲁单抗、他那莫单抗、纳瑞特单抗、那他珠单抗、奈巴库单抗、奈昔木单抗、奈瑞莫单抗、耐西维单抗、尼妥珠单抗、纳武单抗、巯诺莫单抗、奥卡土珠单抗、奥瑞珠单抗、奥度莫单抗、奥法木单抗、奥拉图单抗、奥鲁凯珠单抗、奥马珠单抗、欧那土珠单抗、莫奥珠单抗、奥戈伏单抗、奥泰单抗、奥昔珠单抗、欧西鲁单抗、欧赞尼珠单抗、欧拉丽珠单抗、帕吉昔单抗、帕利珠单抗、帕尼单抗、帕诺库单抗、帕萨土珠单抗、帕考珠单抗、帕特立珠单抗、帕图单抗、帕尼单抗、培拉凯珠单抗、培妥珠单抗、培克珠单抗、皮地利珠单抗、平妥莫单抗、普拉库鲁单抗、拍珠单抗、普立昔单抗、普托木单抗、PRO140、坤立珠单抗、雷库图单抗、雷德图单抗、雷韦单抗、雷莫芦单抗、雷珠单抗、雷昔库单抗、瑞加韦单抗、瑞利珠单抗、利妥木单抗、利妥昔单抗、罗妥木单抗、罗勒杜单抗、罗姆苏珠单抗、隆他利珠单抗、罗利珠单抗、鲁利珠单抗、沙玛立珠单抗、沙鲁单抗、沙妥莫单抗喷地肽、苏金单抗、司韦单抗、西罗珠单抗、西法木单抗、司妥昔单抗、西姆土珠单抗、西利珠单抗、希瑞库单抗、苏兰珠单抗、苏力图单抗、松普希珠单抗、松妥珠单抗、司他芦单抗、硫索单抗、索维单抗、他贝鲁单抗、他珠单抗、他度珠单抗、他利珠单抗、他尼珠单抗、帕他莫单抗、替非珠单抗、阿替莫单抗、替妥莫单抗、替非珠单抗、阿替莫单抗、替妥莫单抗、替奈昔单抗、替利珠单抗、替普单抗、替扎贝鲁单抗、TGN1412、曲美木单抗、替西木单抗、替拉珠单抗、替加珠单抗、TNX-650、托珠单抗、托利珠单抗、托西莫单抗、曲洛青木单抗、曲妥珠单抗、TRBS07、曲加立珠单抗、曲美木单抗、西莫白介素单抗、妥韦单抗、乌波利土西单抗、乌瑞鲁单抗、乌珠单抗、优特克单抗、伐利昔单抗、维特立珠单抗、维多珠单抗、维妥珠单抗、维帕莫单抗、维西库单抗、维西珠单抗、伏洛昔单抗、伏妥土珠单抗、伏妥莫单抗、扎芦木单抗、扎木单抗、扎土希单抗、齐拉木单抗、阿佐莫单抗，以及表1中显示的那些抗体。
72.如权利要求70所述的方法或系统，其中所述治疗性多肽是选自由以下组成的组的多肽：糖蛋白、CD多肽、HER受体多肽、细胞粘附多肽、生长因子多肽、胰岛素多肽、胰岛素相关多肽、凝血多肽、凝血相关多肽、白蛋白、IgE、血型抗原、集落刺激因子、受体、神经营养因子、干扰素、白介素、病毒抗原、脂蛋白、降钙素、胰高血糖素、心钠素、肺表面活性剂、肿瘤坏死因子-α和-β、脑啡肽酶、小鼠促性腺激素相关肽、DNA酶、抑制素、激活素、整联蛋白、蛋白A、蛋白D、类风湿因子、免疫毒素、骨形态发生蛋白、超氧化物歧化酶、表面膜多肽、衰变促进因子、AIDS包膜、转运多肽、归巢受体、地址素、调节多肽、免疫粘附素、肌生长抑制素、TALL多肽、淀粉样多肽、胸腺基质淋巴细胞生成素、RANK配体、c-kit多肽、TNF受体和血管生成素、及其生物活性片段、类似物或变体。
73.一种监测由权利要求22或48所述的封闭系统执行的联机实时测定的方法，所述方法包括：
确定所述封闭系统中的条件是否满足预定的性能阈值；并且
当确定所述封闭系统中的条件不满足所述预定的性能阈值时，调整至少一种细胞培养构成，直到所述封闭系统中的条件满足所述预定的性能阈值。
74.如权利要求73所述的方法，其中调节至少一种细胞培养构成包括调节以下中的一种或多种：pH、压力、温度、培养基流量、培养基含量、气体处理策略、搅拌、添加剂含量、添加剂进料速率或灌注速率。
75.一种使用如权利要求22或48所述的封闭系统来延长生产运行的方法，所述方法包括：
确定所述封闭系统中的条件是否满足预定的性能阈值；并且
当确定所述封闭系统中的条件不满足所述预定的性能阈值时，调整至少一种细胞培养构成，直到所述封闭系统中的条件满足所述预定的性能阈值。
76.如权利要求75所述的方法，其中调节至少一种细胞培养构成包括调节以下中的一种或多种：pH、压力、温度、培养基流量、培养基含量、气体处理策略、搅拌、添加剂含量、添加剂进料速率或灌注速率。
77.一种减轻风险的方法，所述方法包括：
确定与如权利要求22或48所述的封闭系统的运行相关的过程和产物质量数据；
确定所述过程和产物质量数据是否满足预定的风险阈值；并且
根据所述过程和产物质量数据是否满足所述预定的风险阈值来确定是否继续、调整或停止所述封闭系统的运行。
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| PCT/US2018/044887 WO2019028187A1 (en) | 2017-08-01 | 2018-08-01 | SYSTEMS AND METHODS FOR REAL-TIME PREPARATION OF A POLYPEPTIDE SAMPLE FOR MASS SPECTROMETRY ANALYSIS |
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| EP3924083B1 (en) * | 2019-02-14 | 2024-05-15 | Amgen Inc. | Systems and methods for preparing a sample and performing a real-time assay of the sample |
| FR3096459B1 (fr) * | 2019-05-20 | 2024-03-08 | Ct Hospitalier Universitaire Montpellier | Procédé de préparation d’un échantillon peptidique |
| BR112023022041A2 (pt) * | 2021-04-23 | 2023-12-26 | Amgen Inc | Anticorpos anti-tslp modificados |
| WO2022226339A1 (en) * | 2021-04-23 | 2022-10-27 | Amgen Inc. | Anti-tslp antibody compositions and uses thereof |
| WO2023164672A2 (en) * | 2022-02-24 | 2023-08-31 | Venn Biosciences Corporation | Sample preparation for glycoproteomic analysis that includes diagnosis of disease |
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| Publication number | Publication date |
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| JP7237022B2 (ja) | 2023-03-10 |
| US20200355582A1 (en) | 2020-11-12 |
| EA202090399A1 (ru) | 2020-05-20 |
| CA3071676A1 (en) | 2019-02-07 |
| WO2019028187A1 (en) | 2019-02-07 |
| MA49757A (fr) | 2020-06-10 |
| KR102560646B1 (ko) | 2023-07-27 |
| CL2020000248A1 (es) | 2020-08-14 |
| KR20200035093A (ko) | 2020-04-01 |
| BR112020001885A2 (pt) | 2020-08-04 |
| CN110869768B (zh) | 2023-11-21 |
| JP2020530103A (ja) | 2020-10-15 |
| IL271499A (en) | 2020-02-27 |
| SG11202000727SA (en) | 2020-02-27 |
| EP3662287B1 (en) | 2024-02-28 |
| AU2018309027A1 (en) | 2020-01-16 |
| EP3662287A1 (en) | 2020-06-10 |
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